Trial Outcomes & Findings for A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF (NCT NCT01787552)

NCT ID: NCT01787552

Last Updated: 2020-04-15

Results Overview

A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 50 participants
• Primary outcome timeframe: 6 weeks (42 days)
• Results posted on: 2020-04-15

Participant Flow

A total of 50 subjects were enrolled in the study, of which 23 subjects were enrolled in Phase Ib part of dose-escalation phase and 27 subjects were enrolled in Phase Ib dose-expansion phase and Phase II Stage 1.

A total of 50 subjects were enrolled in the study, of which 23 subjects were enrolled in Phase Ib part of dose-escalation phase and 27 subjects were enrolled in Phase Ib dose-expansion phase and Phase II Stage 1.

Participant milestones

Measure	LDE225 400mg + INC424 10 mg (Dose Escalation Phase) Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15 mg (Dose Escalation Phase) Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) Participants who took a combination of LDE225 400mg and INC424 20mg in the dose escalation phase.	LDED225 400mg + INC424 20mg (Dose Expansion Phase) Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Overall Study STARTED	8	10	5	27
Overall Study COMPLETED	0	1	0	0
Overall Study NOT COMPLETED	8	9	5	27

Reasons for withdrawal

Measure	LDE225 400mg + INC424 10 mg (Dose Escalation Phase) Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15 mg (Dose Escalation Phase) Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) Participants who took a combination of LDE225 400mg and INC424 20mg in the dose escalation phase.	LDED225 400mg + INC424 20mg (Dose Expansion Phase) Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Overall Study Withdrawal by Subject	2	0	0	4
Overall Study Physician Decision	2	2	1	2
Overall Study Death	0	0	0	1
Overall Study Adverse Event	2	5	2	16
Overall Study Study terminated by Sponsor	0	0	1	3
Overall Study Progressive Disease	2	2	1	1

Baseline Characteristics

A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF

Baseline characteristics by cohort

Measure	LDE225 400mg + INC424 10 mg (Dose Escalation Phase) n=8 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15 mg (Dose Escalation Phase) n=10 Participants Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) n=5 Participants Participants who took a combination of LDE225 400mg and INC424 20mg in the dose escalation phase.	LDED225 400mg + INC424 20mg (Dose Expansion Phase) n=27 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase	Total n=50 Participants Total of all reporting groups
Age, Continuous	70.9 Years STANDARD_DEVIATION 5.19 • n=5 Participants	59.9 Years STANDARD_DEVIATION 11.59 • n=7 Participants	64.6 Years STANDARD_DEVIATION 13.18 • n=5 Participants	67.4 Years STANDARD_DEVIATION 10.02 • n=4 Participants	66.2 Years STANDARD_DEVIATION 10.42 • n=21 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	5 Participants n=7 Participants	1 Participants n=5 Participants	8 Participants n=4 Participants	15 Participants n=21 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	5 Participants n=7 Participants	4 Participants n=5 Participants	19 Participants n=4 Participants	35 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	3 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	10 Participants n=7 Participants	5 Participants n=5 Participants	26 Participants n=4 Participants	47 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants

PRIMARY outcome

Timeframe: 6 weeks (42 days)

Population: Safety Analysis Set (SAS) included all participants in Phase Ib \& Phase II who received at least 1 dose of LDE225 and/or INC424 \& had at least 1 valid post-baseline safety assessment. DLT was measured in the Phase Ib dose escalation \& expansion phase, as part of the primary outcome. All participants in the safety set were considered for toxicities.

A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.

Outcome measures

Measure	LDE225 400mg + INC424 10mg (Dose Escalation Phase) n=8 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15mg (Dose Escalation Phase) n=10 Participants Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) n=5 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDED225 400mg + INC424 20mg (Dose Expansion Phase) n=27 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b) Blood creatine phosphokinase increased	0 Participants	2 Participants	0 Participants	1 Participants

PRIMARY outcome

Timeframe: Week 24 and Week 48

Population: The Full Analysis Set (FAS) comprised all subjects in Phase Ib and Phase II who received at least one dose of LDE225 and/or INC424. The data disclosed includes only participants from Phase Ib dose expansion phase and Ph II Stage 1. This data does not include dose escalation Phase Ib participants.

Reduction in spleen volume as measured by magnetic resonance imaging/Cat Scan (MRI/CT) in Phase Ib expansion and Phase II Stage 1 patients

Outcome measures

Measure	LDE225 400mg + INC424 10mg (Dose Escalation Phase) n=27 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15mg (Dose Escalation Phase) Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDED225 400mg + INC424 20mg (Dose Expansion Phase) Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Percentage of Patients Achieving >= 35% Reduction in Spleen Volume in Phase Ib Expansion and Phase II Stage 1 Week 24	44.4 Percentage of Participants	—	—	—
Percentage of Patients Achieving >= 35% Reduction in Spleen Volume in Phase Ib Expansion and Phase II Stage 1 Week 48	29.6 Percentage of Participants	—	—	—

SECONDARY outcome

Timeframe: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1

Population: The Pharmacokinetic Analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.

Plasma Concentration Time Curve: AUC0-24h: Area under the concentration-time curve from time zero to 24 hours extrapolate from AUClast[mass x time x volume-1]

Outcome measures

Measure	LDE225 400mg + INC424 10mg (Dose Escalation Phase) n=8 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15mg (Dose Escalation Phase) n=10 Participants Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) n=5 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDED225 400mg + INC424 20mg (Dose Expansion Phase) n=27 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Phase Ib and Phase II: LDE225: Plasma Pharmacokinetics (PK) Parameter: Area Under the Curve(AUC0-24h) LDE225 (Week 9, Day 1) (n=6,6,4,14)	15500 ng*hr/mL Geometric Coefficient of Variation 31.8	13000 ng*hr/mL Geometric Coefficient of Variation 66.8	17100 ng*hr/mL Geometric Coefficient of Variation 30.8	14500 ng*hr/mL Geometric Coefficient of Variation 45.4
Phase Ib and Phase II: LDE225: Plasma Pharmacokinetics (PK) Parameter: Area Under the Curve(AUC0-24h) LDE225 (Week 1, Day 1) (n=6,10,4,24)	2680 ng*hr/mL Geometric Coefficient of Variation 33.1	1900 ng*hr/mL Geometric Coefficient of Variation 100.4	1090 ng*hr/mL Geometric Coefficient of Variation 84.0	2060 ng*hr/mL Geometric Coefficient of Variation 78.7

SECONDARY outcome

Timeframe: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1

Population: The Pharmacokinetic Analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.

AUC0-12h: Area under the concentration-time curve from time zero to 12 hours extrapolate from AUClast[mass x time x volume-1]. AUCinf: Area under the concentration-time curve from time zero to infinity with extrapolation of the terminal phase [mass x time x volume-1]. AUClast: Area under the concentration-time curve from time zero to the time of last measurable concentration [mass x time x volume-1].

Outcome measures

Measure	LDE225 400mg + INC424 10mg (Dose Escalation Phase) n=8 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15mg (Dose Escalation Phase) n=10 Participants Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) n=5 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDED225 400mg + INC424 20mg (Dose Expansion Phase) n=27 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast AUCinf: Wk1 Day 1 (n=7,9,4,16)	466 ng*hr/mL Geometric Coefficient of Variation 30.9	789 ng*hr/mL Geometric Coefficient of Variation 46.1	1140 ng*hr/mL Geometric Coefficient of Variation 28.0	1130 ng*hr/mL Geometric Coefficient of Variation 47.7
Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast AUClast: Wk1 Day 1 (n=8,10,5,26)	443 ng*hr/mL Geometric Coefficient of Variation 26.2	730 ng*hr/mL Geometric Coefficient of Variation 39.7	1030 ng*hr/mL Geometric Coefficient of Variation 20.8	1070 ng*hr/mL Geometric Coefficient of Variation 38.6
Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast AUC0-12h: Wk1 Day 1 (n=8,10,5,25)	473 ng*hr/mL Geometric Coefficient of Variation 29.5	805 ng*hr/mL Geometric Coefficient of Variation 45.6	1130 ng*hr/mL Geometric Coefficient of Variation 23.0	1190 ng*hr/mL Geometric Coefficient of Variation 41.0
Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast AUC0-12h: Wk 9 Day 1 (n=8,9,4,20)	489 ng*hr/mL Geometric Coefficient of Variation 42.5	835 ng*hr/mL Geometric Coefficient of Variation 46.6	962 ng*hr/mL Geometric Coefficient of Variation 23.7	1230 ng*hr/mL Geometric Coefficient of Variation 42.4
Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast AUCinf: Wk 9 Day 1 (n=8,9,3,15)	498 ng*hr/mL Geometric Coefficient of Variation 43.1	867 ng*hr/mL Geometric Coefficient of Variation 48.7	978 ng*hr/mL Geometric Coefficient of Variation 29.5	1140 ng*hr/mL Geometric Coefficient of Variation 43.0
Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast AUClast: Wk 9 Day 1 (n=8,9,4,20)	460 ng*hr/mL Geometric Coefficient of Variation 44.3	776 ng*hr/mL Geometric Coefficient of Variation 43.9	891 ng*hr/mL Geometric Coefficient of Variation 24.3	1130 ng*hr/mL Geometric Coefficient of Variation 38.6

SECONDARY outcome

Timeframe: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1

Population: The pharmacokinetic analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.

Cmax: Maximum observed plasma concentration after drug administration [mass x volume-

1].

Outcome measures

Measure	LDE225 400mg + INC424 10mg (Dose Escalation Phase) n=8 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15mg (Dose Escalation Phase) n=10 Participants Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) n=5 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDED225 400mg + INC424 20mg (Dose Expansion Phase) n=27 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax) INC424 (Week 9, Day 1) (n=8,9,4,20)	168 ng/mL Geometric Coefficient of Variation 38.8	269 ng/mL Geometric Coefficient of Variation 33.2	281 ng/mL Geometric Coefficient of Variation 36.5	350 ng/mL Geometric Coefficient of Variation 36.0
Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax) LDE225 (Week 1, Day 1) (n=6,10,5,26)	311 ng/mL Geometric Coefficient of Variation 35.1	221 ng/mL Geometric Coefficient of Variation 103.4	161 ng/mL Geometric Coefficient of Variation 94.9	251 ng/mL Geometric Coefficient of Variation 83.4
Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax) LDE225 (Week 9, Day 1) (n=8,8,5,20)	879 ng/mL Geometric Coefficient of Variation 38.0	720 ng/mL Geometric Coefficient of Variation 57.5	959 ng/mL Geometric Coefficient of Variation 39.4	951 ng/mL Geometric Coefficient of Variation 51.1
Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax) INC424 (Week 1, Day 1) (n=8,10,5,27)	154 ng/mL Geometric Coefficient of Variation 29.0	244 ng/mL Geometric Coefficient of Variation 40.4	351 ng/mL Geometric Coefficient of Variation 27.7	338 ng/mL Geometric Coefficient of Variation 40.1

SECONDARY outcome

Timeframe: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1

Population: The Pharmacokinetic Analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.

Tmax: Time to reach Cmax [time]

Outcome measures

Measure	LDE225 400mg + INC424 10mg (Dose Escalation Phase) n=8 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15mg (Dose Escalation Phase) n=10 Participants Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) n=5 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDED225 400mg + INC424 20mg (Dose Expansion Phase) n=27 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax) LDE225 (Week 1, Day 1) (n=6,10,5,26)	3.01 hour (hr) Interval 2.0 to 4.0	2.08 hour (hr) Interval 1.5 to 4.22	2.00 hour (hr) Interval 1.5 to 8.0	2.00 hour (hr) Interval 1.0 to 6.0
Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax) LDE225 (Week 9, Day 1) (n=8,8,5,20)	1.79 hour (hr) Interval 0.17 to 4.0	2.00 hour (hr) Interval 1.5 to 4.0	2.00 hour (hr) Interval 1.5 to 6.0	3.21 hour (hr) Interval 1.5 to 23.9
Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax) INC424 (Week 1, Day 1) (n=8,10,5,27)	0.500 hour (hr) Interval 0.5 to 2.0	0.575 hour (hr) Interval 0.33 to 2.03	0.500 hour (hr) Interval 0.5 to 0.97	0.580 hour (hr) Interval 0.42 to 4.0
Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax) INC424 (Week 9, Day 1) (n=8,9,4,20)	0.875 hour (hr) Interval 0.17 to 1.5	0.500 hour (hr) Interval 0.5 to 1.52	1.00 hour (hr) Interval 0.5 to 1.0	1.00 hour (hr) Interval 0.33 to 2.0

SECONDARY outcome

Timeframe: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1

Population: The Pharmacokinetic Analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.

CL/F: Apparent total plasma clearance of drug after oral administration [volume x time-1]

Outcome measures

Measure	LDE225 400mg + INC424 10mg (Dose Escalation Phase) n=8 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15mg (Dose Escalation Phase) n=10 Participants Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) n=5 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDED225 400mg + INC424 20mg (Dose Expansion Phase) n=27 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Phase Ib and Phase II: LDE225 & INC424:: Plasma Pharmacokinetics (PK) Parameters: Area Under the Curve(CL/F) INC424 (Week 1, Day 1) (n=7,9,4,16)	23.8 L/hr Interval 12.2 to 26.9	18.7 L/hr Interval 9.04 to 39.0	16.5 L/hr Interval 13.3 to 25.6	16.9 L/hr Interval 7.54 to 35.0
Phase Ib and Phase II: LDE225 & INC424:: Plasma Pharmacokinetics (PK) Parameters: Area Under the Curve(CL/F) LDE225 (Week 1, Day 1) (n=5,5,1,12)	145 L/hr Interval 120.0 to 166.0	238 L/hr Interval 53.7 to 508.0	727 L/hr Interval 727.0 to 727.0	122 L/hr Interval 46.2 to 525.0
Phase Ib and Phase II: LDE225 & INC424:: Plasma Pharmacokinetics (PK) Parameters: Area Under the Curve(CL/F) LDE225 (Week 9, Day 1) (n=6,6,4,14)	27.8 L/hr Interval 14.9 to 35.7	34.5 L/hr Interval 12.9 to 62.3	25.1 L/hr Interval 15.4 to 30.9	27.0 L/hr Interval 12.6 to 56.9

SECONDARY outcome

Timeframe: Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)

Population: The Full Analysis Set (FAS) comprised all subjects in Phase Ib and Phase II who received at least one dose of LDE225 and/or INC424.

The number of patients experiencing improvement in their bone marrow fibrosis by at least one grade and assessment of cellularity.

Outcome measures

Measure	LDE225 400mg + INC424 10mg (Dose Escalation Phase) n=8 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15mg (Dose Escalation Phase) n=10 Participants Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) n=5 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDED225 400mg + INC424 20mg (Dose Expansion Phase) n=27 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1 Baseline, grade 0 (n=0,0,0,1)	—	—	—	3.7 Percentage of Participants
Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1 Baseline, grade 1 (n=0,1,0,4)	—	10.0 Percentage of Participants	—	14.8 Percentage of Participants
Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1 Baseline, grade 2 (n=4,6,3,8)	50.0 Percentage of Participants	50.0 Percentage of Participants	60.0 Percentage of Participants	29.6 Percentage of Participants
Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1 Baseline, grade 3 (n=3,3,0,8)	37.5 Percentage of Participants	30.0 Percentage of Participants	—	29.6 Percentage of Participants
Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1 Week 25 Day 1, grade 2 (n=0,3,2,7)	—	30.0 Percentage of Participants	40.0 Percentage of Participants	25.9 Percentage of Participants
Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1 Week 25 Day 1, grade 3 (n=5,4,1,5)	62.5 Percentage of Participants	40.0 Percentage of Participants	20.0 Percentage of Participants	18.5 Percentage of Participants
Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1 Week 49 Day 1, grade 3 (n=2,2,2,3)	25.0 Percentage of Participants	20.0 Percentage of Participants	40.0 Percentage of Participants	11.1 Percentage of Participants
Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1 Week 49 Day 1, missing grade (n=6,7,2,20)	75.0 Percentage of Participants	70.0 Percentage of Participants	40.0 Percentage of Participants	74.1 Percentage of Participants
Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1 Baseline, missing grade (n=1,0,2,6)	12.5 Percentage of Participants	—	40.0 Percentage of Participants	22.2 Percentage of Participants
Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1 Week 25 Day 1, grade 1 (n=1,1,0,1)	12.5 Percentage of Participants	10.0 Percentage of Participants	—	3.7 Percentage of Participants
Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1 Week 25 Day 1, missing grade (n=2,2,2,14)	25.0 Percentage of Participants	20.0 Percentage of Participants	40.0 Percentage of Participants	51.9 Percentage of Participants
Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1 Week 49 Day 1, grade 0 (n=0,0,0,1)	—	—	—	3.7 Percentage of Participants
Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1 Week 49, Day 1 grade 1 (n=0,0,0,1)	—	—	—	3.7 Percentage of Participants
Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1 Week 49 Day 1, grade 2 (n=0,1,1,2)	—	10.0 Percentage of Participants	20.0 Percentage of Participants	7.4 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)

Population: The Biomarker Analysis Set (BAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable biomarker sample.

Phase Ib and Phase ll: Change in Pharmacodynamic Biomarkers: JAK2V617F allele burden

Outcome measures

Measure	LDE225 400mg + INC424 10mg (Dose Escalation Phase) n=8 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15mg (Dose Escalation Phase) n=10 Participants Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) n=5 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDED225 400mg + INC424 20mg (Dose Expansion Phase) n=27 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Phase Ib and Phase ll: Summary of JAK2V617F Allele Burden by Visit and Treatment in Phase Ib and Phase II Stage 1 Baseline	84.7 Percentage of JAK allele burden mutation Interval 48.4 to 95.1	61.7 Percentage of JAK allele burden mutation Interval 2.5 to 92.1	88.3 Percentage of JAK allele burden mutation Interval 52.7 to 94.4	55.4 Percentage of JAK allele burden mutation Interval 2.5 to 93.5
Phase Ib and Phase ll: Summary of JAK2V617F Allele Burden by Visit and Treatment in Phase Ib and Phase II Stage 1 Week 49 Day 1 (n=4,3,4,13)	86.0 Percentage of JAK allele burden mutation Interval 20.1 to 94.1	54.3 Percentage of JAK allele burden mutation Interval 2.5 to 80.0	75.7 Percentage of JAK allele burden mutation Interval 56.9 to 90.0	46.1 Percentage of JAK allele burden mutation Interval 2.5 to 85.6
Phase Ib and Phase ll: Summary of JAK2V617F Allele Burden by Visit and Treatment in Phase Ib and Phase II Stage 1 Week 25 Day 1 (n=7,6,5,21)	88.6 Percentage of JAK allele burden mutation Interval 49.8 to 94.1	48.0 Percentage of JAK allele burden mutation Interval 2.5 to 78.4	74.9 Percentage of JAK allele burden mutation Interval 52.1 to 89.6	43.8 Percentage of JAK allele burden mutation Interval 2.5 to 93.9

SECONDARY outcome

Timeframe: Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)

Population: The Biomarker Analysis Set (BAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable biomarker sample.

Summary of cytokine levels in Pharmacodynamic Biomarkers for all 26 collected at Week 25 Day 1 and Week 49 Day 1

Outcome measures

Measure	LDE225 400mg + INC424 10mg (Dose Escalation Phase) n=8 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15mg (Dose Escalation Phase) n=10 Participants Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) n=5 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDED225 400mg + INC424 20mg (Dose Expansion Phase) n=27 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers AFP: Week 25 Day 1 (Wk 25 D1) (n=7,8,5,22)	0.75 ng/mL Interval 0.3 to 2.5	0.79 ng/mL Interval 0.3 to 1.4	1.10 ng/mL Interval 0.3 to 2.2	0.49 ng/mL Interval 0.49 to 2.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers AFP: Week 49 Day 1 (WK25 D1) (n=4,3,4,14)	0.68 ng/mL Interval 0.3 to 1.6	0.60 ng/mL Interval 0.5 to 0.9	0.49 ng/mL Interval 0.49 to 1.1	0.49 ng/mL Interval 0.49 to 2.6
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers B2M: Week 25 Day 1 (n=7,8,5,22)	5.00 ng/mL Interval 2.8 to 7.4	3.15 ng/mL Interval 2.1 to 5.9	3.70 ng/mL Interval 2.4 to 5.2	3.15 ng/mL Interval 1.8 to 7.2
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers B2M: Week 49 Day 1 (n=4,3,4,14)	5.75 ng/mL Interval 4.5 to 11.0	4.60 ng/mL Interval 1.9 to 6.1	3.25 ng/mL Interval 2.4 to 4.4	3.00 ng/mL Interval 1.0 to 6.3
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Eotaxin1: Wk 49 D1 (n=4,3,4,14)	136.00 ng/mL Interval 42.5 to 290.0	145.00 ng/mL Interval 58.5 to 622.0	157.00 ng/mL Interval 58.5 to 380.0	175.00 ng/mL Interval 58.5 to 360.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers ICAM1: Wk 25 D1 (n=7,8,5,22)	266.00 ng/mL Interval 139.0 to 451.0	203.00 ng/mL Interval 137.0 to 339.0	168.00 ng/mL Interval 82.0 to 316.0	185.50 ng/mL Interval 93.0 to 324.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers VEGF: Wks. 49 D1 (n=4,3,4,14)	227.00 ng/mL Interval 56.0 to 286.0	106.00 ng/mL Interval 83.0 to 223.0	163.00 ng/mL Interval 87.0 to 406.0	217.00 ng/mL Interval 87.0 to 543.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers VWF: Wk. 49 D1 (n=4,3,4,14)	140.50 ng/mL Interval 26.0 to 385.0	67.00 ng/mL Interval 37.0 to 110.0	716.00 ng/mL Interval 25.0 to 2200.0	154.50 ng/mL Interval 28.0 to 2290.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers VWF: Wk. 25 D1 (n=7,8,5,22)	135.00 ng/mL Interval 78.0 to 726.0	65.50 ng/mL Interval 34.0 to 140.0	398.00 ng/mL Interval 81.0 to 1540.0	156.50 ng/mL Interval 26.0 to 1230.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers VEGF: Wk. 25 D1 (n=7,8,5,22)	145.00 ng/mL Interval 132.0 to 429.0	202.50 ng/mL Interval 133.0 to 301.0	108.00 ng/mL Interval 64.0 to 113.0	168.00 ng/mL Interval 86.0 to 469.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers VCAM1: Wk 49 D1 (n=4,3,4,14)	2425.00 ng/mL Interval 1200.0 to 3220.0	1210.00 ng/mL Interval 1160.0 to 2230.0	2225.00 ng/mL Interval 1410.0 to 3050.0	1715.00 ng/mL Interval 1030.0 to 3260.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers APOA-1: Week 25 Day 1 (n=7,8,5,22)	1.10 ng/mL Interval 0.7 to 1.7	1.65 ng/mL Interval 1.0 to 2.2	1.60 ng/mL Interval 1.2 to 1.6	2.10 ng/mL Interval 1.5 to 3.8
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers APOA-1: Week 49 Day 1 (n=4,3,4,14)	1.30 ng/mL Interval 0.9 to 1.5	1.50 ng/mL Interval 1.0 to 2.9	1.80 ng/mL Interval 1.6 to 2.6	2.05 ng/mL Interval 1.4 to 3.1
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers BDNF: Week 25 Day 1 (n=7,8,5,22)	0.46 ng/mL Interval 0.0 to 2.0	0.85 ng/mL Interval 0.2 to 2.5	0.15 ng/mL Interval 0.1 to 0.4	0.55 ng/mL Interval 0.0 to 2.7
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers BDNF: Week 49 Day 1 (n=4,3,4,14)	1.16 ng/mL Interval 0.3 to 2.4	0.19 ng/mL Interval 0.0 to 3.8	0.41 ng/mL Interval 0.0 to 5.6	0.52 ng/mL Interval 0.0 to 12.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers C Reactive Protein: Week 25 Day 1 (n=7,8,5,22)	2.60 ng/mL Interval 1.0 to 16.0	2.70 ng/mL Interval 0.3 to 51.0	1.30 ng/mL Interval 0.1 to 4.1	4.50 ng/mL Interval 0.1 to 182.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers C Reactive Protein: Week 49 Day 1 (n=4,3,4,14)	4.65 ng/mL Interval 0.4 to 9.0	2.40 ng/mL Interval 0.0 to 6.3	1.30 ng/mL Interval 0.7 to 2.5	0.79 ng/mL Interval 0.1 to 30.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Carcinoembryyonic Antigen: Wk 25 D1 (n=7,8,5,22)	1.40 ng/mL Interval 0.3 to 58.0	1.20 ng/mL Interval 0.8 to 5.6	1.20 ng/mL Interval 0.3 to 3.4	1.80 ng/mL Interval 0.2 to 12.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Carcinoembryyonic Antigen: Wk 49 D1 (n=4,3,4,14)	1.72 ng/mL Interval 0.8 to 3.7	1.20 ng/mL Interval 1.1 to 1.3	1.45 ng/mL Interval 0.5 to 2.6	1.80 ng/mL Interval 0.5 to 12.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Cluster of. Diff 40: Wk 25 D1 (n=7,7,5,0)	1.90 ng/mL Interval 0.8 to 3.4	1.10 ng/mL Interval 0.6 to 1.6	0.91 ng/mL Interval 0.6 to 1.4	—
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Cluster of. Diff 40: Wk 49 D1 (n=4,2,0,0)	1.65 ng/mL Interval 0.9 to 2.4	1.3 ng/mL Interval 1.2 to 1.4	—	—
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Eotaxin1: Wk 25 D1 (n=7,8,5,22)	155.00 ng/mL Interval 42.5 to 214.0	119.00 ng/mL Interval 42.5 to 429.0	101.00 ng/mL Interval 42.5 to 152.0	118.00 ng/mL Interval 58.5 to 294.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers ICAM1: Wk 49 D1 (n=4,3,4,14)	321.00 ng/mL Interval 95.0 to 470.0	173.00 ng/mL Interval 94.0 to 193.0	152.50 ng/mL Interval 91.0 to 553.0	163.00 ng/mL Interval 92.0 to 310.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers IL10: Wk 25 D1 (n=7,8,5,22)	9.30 ng/mL Interval 6.9 to 21.0	7.50 ng/mL Interval 3.4 to 11.0	3.40 ng/mL Interval 3.4 to 12.0	6.23 ng/mL Interval 4.1 to 29.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers IL10: Wk 49 D1 (n=4,3,4,14)	8.10 ng/mL Interval 3.4 to 12.0	4.05 ng/mL Interval 3.4 to 18.0	11.00 ng/mL Interval 8.4 to 24.0	8.40 ng/mL Interval 4.1 to 28.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers IL18: Wk 25 D1 (n=7,8,5,22)	292.00 ng/mL Interval 132.0 to 520.0	220.50 ng/mL Interval 108.0 to 907.0	445.00 ng/mL Interval 161.0 to 687.0	415.50 ng/mL Interval 127.0 to 1160.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers IL18: Wk 49 D1 (n=4,3,4,14)	278.00 ng/mL Interval 146.0 to 606.0	199.00 ng/mL Interval 168.0 to 575.0	550.50 ng/mL Interval 313.0 to 1260.0	318.50 ng/mL Interval 134.0 to 886.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers IL1B: Wk 25 D1 (n=7,8,5,22)	3.30 ng/mL Interval 3.3 to 3.3	3.30 ng/mL Interval 3.3 to 4.3	3.30 ng/mL Interval 3.3 to 6.9	4.3 ng/mL Interval 4.3 to 16.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers IL1B: Wk 49 D1 (n=4,3,4,14)	3.30 ng/mL Interval 3.3 to 3.3	3.30 ng/mL Interval 3.3 to 4.3	4.3 ng/mL Interval 4.3 to 8.9	4.3 ng/mL Interval 4.3 to 10.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers IL1RN: Wk 25 D1 (n=7,8,5,22)	130.00 ng/mL Interval 92.0 to 218.0	147.00 ng/mL Interval 85.0 to 496.0	114.00 ng/mL Interval 89.0 to 183.0	88.00 ng/mL Interval 63.0 to 328.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers IL1RN: Wk 49 D1 (n=4,3,4,14)	98.00 ng/mL Interval 71.0 to 124.0	281.00 ng/mL Interval 29.5 to 782.0	88.00 ng/mL Interval 73.0 to 214.0	85.50 ng/mL Interval 29.5 to 162.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers IL6: Wk 25 D1 (n=7,8,5,22)	4.70 ng/mL Interval 2.3 to 6.8	2.3 ng/mL Interval 2.3 to 6.3	2.3 ng/mL Interval 2.3 to 6.0	3.40 ng/mL Interval 3.4 to 11.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers IL6: Wk 49 D1 (n=4,3,4,14)	3.48 ng/mL Interval 2.3 to 6.8	3.40 ng/mL Interval 2.3 to 4.7	3.40 ng/mL Interval 3.4 to 11.0	3.40 ng/mL Interval 3.4 to 7.3
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers IL8: Wk 25 D1 (n=7,8,5,22)	28.00 ng/mL Interval 15.0 to 84.0	9.50 ng/mL Interval 7.2 to 74.0	15.00 ng/mL Interval 10.0 to 34.0	29.50 ng/mL Interval 6.9 to 280.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers IL8: Wk 49 D1 (n=4,3,4,14)	18.50 ng/mL Interval 9.6 to 161.0	11.00 ng/mL Interval 8.4 to 19.0	58.50 ng/mL Interval 19.0 to 166.0	32.00 ng/mL Interval 3.1 to 261.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Insulin: Wk 25 D1 (n=7,8,5,22)	2.70 ng/mL Interval 0.8 to 5.4	1.35 ng/mL Interval 0.6 to 3.3	2.30 ng/mL Interval 1.8 to 3.8	0.6 ng/mL Interval 0.6 to 8.9
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Insulin: Wk 49 D1 (n=4,3,4,14)	2.90 ng/mL Interval 1.4 to 3.1	2.90 ng/mL Interval 0.6 to 4.9	1.65 ng/mL Interval 0.6 to 3.0	1.60 ng/mL Interval 0.6 to 14.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers LEP: Wk 25 D1 (n=7,8,5,22)	1.50 ng/mL Interval 0.7 to 34.0	4.75 ng/mL Interval 1.2 to 30.0	6.00 ng/mL Interval 3.4 to 6.1	6.40 ng/mL Interval 1.2 to 49.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers LEP: Wk 49 D1 (n=4,3,4,14)	3.45 ng/mL Interval 0.7 to 16.0	17.00 ng/mL Interval 2.7 to 29.0	5.95 ng/mL Interval 1.0 to 10.0	5.60 ng/mL Interval 3.3 to 28.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Macro. Inflam. Prot-1 Beta: Wk 25 D1 (n=7,8,5,22)	491.00 ng/mL Interval 269.0 to 1160.0	375.50 ng/mL Interval 203.0 to 1260.0	410.00 ng/mL Interval 330.0 to 873.0	513.00 ng/mL Interval 190.0 to 1010.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Macro. Inflam. Prot-1 Beta: Wk 49 D1 (n=4,3,4,14)	406.50 ng/mL Interval 242.0 to 758.0	487.00 ng/mL Interval 357.0 to 594.0	970.50 ng/mL Interval 489.0 to 1850.0	521.00 ng/mL Interval 159.0 to 1100.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Macro.-derived Chemokine: Wk 25 D1 (n=7,8,5,22)	253.00 ng/mL Interval 43.0 to 599.0	274.00 ng/mL Interval 93.0 to 1040.0	516.00 ng/mL Interval 193.0 to 1100.0	254.00 ng/mL Interval 55.0 to 760.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Macro.-derived Chemokine: Wk 49 D1 (n=4,3,4,14)	190.50 ng/mL Interval 9.5 to 852.0	327.00 ng/mL Interval 218.0 to 963.0	430.50 ng/mL Interval 132.0 to 801.0	212.00 ng/mL Interval 97.0 to 696.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers MPO: Wk 25 D1 (n=7,8,5,22)	327.00 ng/mL Interval 127.0 to 1600.0	323.00 ng/mL Interval 134.0 to 3120.0	335.00 ng/mL Interval 134.0 to 3350.0	164.50 ng/mL Interval 63.0 to 1310.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers MPO: Wk 49 D1 (n=4,3,4,14)	175.00 ng/mL Interval 87.0 to 377.0	180.00 ng/mL Interval 122.0 to 1340.0	237.00 ng/mL Interval 147.0 to 794.0	116.50 ng/mL Interval 43.0 to 1760.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Myoglobin: Wk 25 D1 (n=7,8,5,22)	31.00 ng/mL Interval 19.0 to 51.0	31.50 ng/mL Interval 16.0 to 47.0	54.00 ng/mL Interval 28.0 to 112.0	39.50 ng/mL Interval 16.0 to 140.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Myoglobin: Wk 49 D1 (n=4,3,4,14)	35.00 ng/mL Interval 13.0 to 47.0	18.00 ng/mL Interval 14.0 to 49.0	45.50 ng/mL Interval 31.0 to 55.0	45.00 ng/mL Interval 14.0 to 76.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Plasmin. Activ. Inhibitor 1: Wk 25 D1 (n=7,8,5,22)	34.00 ng/mL Interval 13.0 to 52.0	45.50 ng/mL Interval 9.2 to 73.0	17.00 ng/mL Interval 12.0 to 41.0	51.50 ng/mL Interval 5.5 to 240.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Plasmin. Activ. Inhibitor 1: Wk 49 D1 (n=4,3,4,14)	31.50 ng/mL Interval 12.0 to 42.0	25.00 ng/mL Interval 13.0 to 80.0	49.00 ng/mL Interval 14.0 to 117.0	52.50 ng/mL Interval 21.0 to 226.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers RANTES: Wk 25 D1 (n=7,8,5,22)	4.80 ng/mL Interval 1.6 to 15.0	5.85 ng/mL Interval 1.6 to 18.0	4.20 ng/mL Interval 1.8 to 13.0	8.80 ng/mL Interval 0.3 to 37.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers RANTES: Wk 49 D1 (n=4,3,4,14)	8.25 ng/mL Interval 3.4 to 14.0	3.20 ng/mL Interval 0.7 to 14.0	10.55 ng/mL Interval 0.9 to 35.0	6.50 ng/mL Interval 0.8 to 73.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Thyroxine binding globulin Wk 25 D1 (n=7,8,5,22)	38.00 ng/mL Interval 31.0 to 47.0	41.50 ng/mL Interval 30.0 to 75.0	45.00 ng/mL Interval 40.0 to 67.0	54.50 ng/mL Interval 33.0 to 82.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers Thyroxine binding globulin: Wk 49 D1 (n=4,3,4,14)	42.00 ng/mL Interval 29.0 to 58.0	45.00 ng/mL Interval 38.0 to 51.0	72.50 ng/mL Interval 71.0 to 76.0	54.00 ng/mL Interval 37.0 to 76.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers TNFA: Wk 25 D1 (n=7,8,5,22)	27.00 ng/mL Interval 7.0 to 77.0	18.50 ng/mL Interval 7.0 to 79.0	25.00 ng/mL Interval 16.0 to 38.0	12.00 ng/mL Interval 12.0 to 319.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers TNFA: Wk 49 D1 (n=4,3,4,14)	32.50 ng/mL Interval 7.0 to 57.0	32.00 ng/mL Interval 12.0 to 51.0	26.50 ng/mL Interval 12.0 to 112.0	12.00 ng/mL Interval 12.0 to 79.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers TNFRT 2: Wk 25 D1 (n=7,8,5,22)	33.00 ng/mL Interval 16.0 to 36.0	12.00 ng/mL Interval 6.2 to 53.0	15.00 ng/mL Interval 7.8 to 30.0	17.50 ng/mL Interval 5.9 to 40.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers TNFRT 2: Wk 49 D1 (n=4,3,4,14)	28.00 ng/mL Interval 21.0 to 38.0	21.00 ng/mL Interval 5.5 to 29.0	16.00 ng/mL Interval 12.0 to 27.0	12.50 ng/mL Interval 3.8 to 33.0
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers VCAM1: Wk 25 D1 (n=7,8,5,22)	2040.00 ng/mL Interval 1200.0 to 3420.0	1130.00 ng/mL Interval 809.0 to 2830.0	1690.00 ng/mL Interval 986.0 to 2770.0	1930.00 ng/mL Interval 984.0 to 3760.0

SECONDARY outcome

Timeframe: Week 24, Week 48

Population: The Full Analysis Set (FAS) comprised all subjects in Phase Ib and Phase II who received at least one dose of LDE225 and/or INC424.

The 7-day modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 is a 7-item PRO instrument based on the modified MFSAF v2.0 diary administered at specified visits. The first 6 items assess MF symptom severity at its worst as recalled in the 7 days prior to the clinic visit assessment. The symptoms measured include night sweats, itching, abdominal discomfort, pain under the ribs (left side), early satiety, & bone/muscle pain. The 7th item captures MF-related inactivity in the past 7 days prior to the clinic visit assessment. All 7 items ask subjects to record their answers on an 11-point numeric rating scale (NRS), (0 = Absent, 10 = Worst Imaginable). The first 6 items of the instrument focus on MF symptoms & are summed to create a Total Symptom score.

Outcome measures

Measure	LDE225 400mg + INC424 10mg (Dose Escalation Phase) n=8 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15mg (Dose Escalation Phase) n=10 Participants Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) n=5 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDED225 400mg + INC424 20mg (Dose Expansion Phase) n=27 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Phase Ib and Phase II: Percentage of Participants With >= 50% Reduction From Baseline in MFSAF Total Symptom Scores Week 24	50.00 Percentage of participants Interval 15.7 to 84.3	40.0 Percentage of participants Interval 12.16 to 73.76	80.0 Percentage of participants Interval 28.36 to 99.49	33.3 Percentage of participants Interval 16.52 to 53.96
Phase Ib and Phase II: Percentage of Participants With >= 50% Reduction From Baseline in MFSAF Total Symptom Scores Week 48	25.00 Percentage of participants Interval 3.19 to 65.09	20.0 Percentage of participants Interval 2.52 to 55.61	80.0 Percentage of participants Interval 28.36 to 99.49	18.5 Percentage of participants Interval 6.3 to 38.08

SECONDARY outcome

Timeframe: Baseline, Week 25, Week 49

Population: The Full Analysis Set (FAS) comprised all subjects in Phase Ib and Phase II who received at least one dose of LDE225 and/or INC424.

The 7-day modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 is a 7-item PRO instrument based on the modified MFSAF v2.0 diary administered at specified visits. The first 6 items assess MF symptom severity at its worst as recalled in the 7 days prior to the clinic visit assessment. The symptoms measured include night sweats, itching, abdominal discomfort, pain under the ribs (left side), early satiety, & bone/muscle pain. The 7th item captures MF-related inactivity in the past 7 days prior to the clinic visit assessment. All 7 items ask subjects to record their answers on an 11-point numeric rating scale (NRS), (0 = Absent, 10 = Worst Imaginable). The first 6 items of the instrument focus on MF symptoms & are summed to create a Total Symptom score.

Outcome measures

Measure	LDE225 400mg + INC424 10mg (Dose Escalation Phase) n=8 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15mg (Dose Escalation Phase) n=10 Participants Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) n=5 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDED225 400mg + INC424 20mg (Dose Expansion Phase) n=27 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Phase Ib and Phase II: Change in Total Symptom Score (TSS) From Baseline to Week 25 & Week 49 Using the MFSAF Total Symptom Scores Week 25 (n = 6, 7, 5, 19)	-18.8 scores on a scale Standard Deviation 15.20	-14.0 scores on a scale Standard Deviation 8.58	-19.4 scores on a scale Standard Deviation 6.43	-6.5 scores on a scale Standard Deviation 9.26
Phase Ib and Phase II: Change in Total Symptom Score (TSS) From Baseline to Week 25 & Week 49 Using the MFSAF Total Symptom Scores Week 49 (n = 4, 5, 4, 10)	-18.5 scores on a scale Standard Deviation 12.07	-13.6 scores on a scale Standard Deviation 10.43	-21.0 scores on a scale Standard Deviation 5.66	-8.0 scores on a scale Standard Deviation 14.61

SECONDARY outcome

Timeframe: Week 24, Week 48

Population: The Full Analysis Set (FAS) comprised all subjects in Phase Ib and Phase II who received at least one dose of LDE225 and/or INC424.

EORTC QLQ-C30 is the European Organization for Research & Treatment of Cancer, Quality of Life (QoL) Questionnaire & is one of the most widely used & validated instruments to measure health-related QoL in subjects with cancer. The scale includes 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning & social functioning), global health status/QoL & 9 symptom scale/items (fatigue, nausea & vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, & financial difficulties). This instrument asks the subject to respond according to the past week, with the exception of the first 5 questions that represent physical functioning & capture the subject's current status. The range of scores for all of the scales is from 0 to 100. For functional & global health status/QoL scales, higher scores indicate better QoL & level of functioning; for symptom scales, higher scores indicate greater level of symptoms or difficulties.

Outcome measures

Measure	LDE225 400mg + INC424 10mg (Dose Escalation Phase) n=8 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15mg (Dose Escalation Phase) n=10 Participants Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) n=5 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDED225 400mg + INC424 20mg (Dose Expansion Phase) n=27 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Glob. Health Status/Qol: Wk 25 (n=6,7,5,19)	-2.8 scores on a scale Standard Deviation 21.52	-2.4 scores on a scale Standard Deviation 21.90	16.7 scores on a scale Standard Deviation 27.64	2.6 scores on a scale Standard Deviation 22.75
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Glob. Health Status/Qol: Wk 49(n=4,4,4,10)	-2.1 scores on a scale Standard Deviation 23.94	14.6 scores on a scale Standard Deviation 45.33	-0.0 scores on a scale Standard Deviation 20.41	-3.3 scores on a scale Standard Deviation 24.91
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Phys. Func: Wk 25 (n=6,7,5,19)	15.6 scores on a scale Standard Deviation 25.88	-1.0 scores on a scale Standard Deviation 14.10	17.3 scores on a scale Standard Deviation 16.73	1.0 scores on a scale Standard Deviation 23.74
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Phys. Func: Wk 49 (n=4,4,4,10)	25.0 scores on a scale Standard Deviation 16.67	-10.0 scores on a scale Standard Deviation 25.82	15.0 scores on a scale Standard Deviation 22.03	6.0 scores on a scale Standard Deviation 15.85
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Role Func: Wk 25 (n=6,7,5,19)	33.3 scores on a scale Standard Deviation 39.44	-7.1 scores on a scale Standard Deviation 18.90	16.7 scores on a scale Standard Deviation 20.41	7.9 scores on a scale Standard Deviation 32.09
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Role Func: Wk 49 (n=4,4,4,10)	41.7 scores on a scale Standard Deviation 21.52	-33.3 scores on a scale Standard Deviation 27.22	12.5 scores on a scale Standard Deviation 25.00	10.2 scores on a scale Standard Deviation 22.50
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Emo. Func: Wk 25 (n=6,7,5,19)	25.0 scores on a scale Standard Deviation 16.67	-8.3 scores on a scale Standard Deviation 31.18	5.6 scores on a scale Standard Deviation 12.42	2.5 scores on a scale Standard Deviation 18.61
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Emo. Func: Wk 49 (n=4,4,4,10)	33.3 scores on a scale Standard Deviation 11.79	-12.5 scores on a scale Standard Deviation 41.67	0.0 scores on a scale Standard Deviation 15.21	-2.5 scores on a scale Standard Deviation 10.43
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Cog. Func: Wk 25 (n=6,7,5,19	14.6 scores on a scale Standard Deviation 18.77	-6.3 scores on a scale Standard Deviation 19.80	-3.3 scores on a scale Standard Deviation 13.94	2.6 scores on a scale Standard Deviation 18.64
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Cog. Func: Wk 49 (n=4,4,4,10)	20.8 scores on a scale Standard Deviation 15.96	-8.3 scores on a scale Standard Deviation 28.87	4.2 scores on a scale Standard Deviation 8.33	-5.0 scores on a scale Standard Deviation 22.29
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Soc. Func: Wk 25 (n=6,7,4,19)	8.3 scores on a scale Standard Deviation 39.09	-7.1 scores on a scale Standard Deviation 18.90	12.5 scores on a scale Standard Deviation 15.96	-2.6 scores on a scale Standard Deviation 24.38
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Soc. Func: Wk 49 (n=3,4,4,10)	16.7 scores on a scale Standard Deviation 16.67	-4.2 scores on a scale Standard Deviation 8.33	12.5 scores on a scale Standard Deviation 25.00	-3.3 scores on a scale Standard Deviation 18.92
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Fatigue: Wk 25 (n=6,7,5,19)	-20.4 scores on a scale Standard Deviation 25.74	-1.6 scores on a scale Standard Deviation 26.78	-28.9 scores on a scale Standard Deviation 16.85	-8.8 scores on a scale Standard Deviation 26.86
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Fatigue: Wk 49 (n=4,4,4,10)	-27.8 scores on a scale Standard Deviation 6.42	0. scores on a scale Standard Deviation 15.71	-33.3 scores on a scale Standard Deviation 18.14	4.4 scores on a scale Standard Deviation 36.74
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Naus & Vom: Wk 25 (n=6,7,5,19)	-5.6 scores on a scale Standard Deviation 13.61	-4.8 scores on a scale Standard Deviation 18.54	-3.3 scores on a scale Standard Deviation 7.45	-3.5 scores on a scale Standard Deviation 11.89
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Naus & Vom: Wk 49 (n=4,4,4,10)	-4.2 scores on a scale Standard Deviation 15.96	4.2 scores on a scale Standard Deviation 28.46	0.0 scores on a scale Standard Deviation 13.61	-10.0 scores on a scale Standard Deviation 11.65
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Pain: Wk 25 (n=6,7,5,18)	-11.1 scores on a scale Standard Deviation 40.37	-4.8 scores on a scale Standard Deviation 38.14	-26.7 scores on a scale Standard Deviation 25.28	-8.3 scores on a scale Standard Deviation 21.58
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Pain: Wk 49 (n=4,4,4,10)	25.0 scores on a scale Standard Deviation 21.52	-8.3 scores on a scale Standard Deviation 56.93	-20.8 scores on a scale Standard Deviation 25.00	3.3 scores on a scale Standard Deviation 10.54
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Dyspnoea: Wk 25 (n=6,7,5,19)	-33.3 scores on a scale Standard Deviation 29.81	-4.8 scores on a scale Standard Deviation 29.99	-6.7 scores on a scale Standard Deviation 14.91	-1.8 scores on a scale Standard Deviation 26.00
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Dyspnoea: Wk 49 (n=4,4,4,10)	-33.3 scores on a scale Standard Deviation 27.22	-16.7 scores on a scale Standard Deviation 43.03	0.0 scores on a scale Standard Deviation 0.00	6.7 scores on a scale Standard Deviation 26.29
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Insomnia: Wk 25 (n=6,7,5,19)	-22.2 scores on a scale Standard Deviation 27.22	0.0 scores on a scale Standard Deviation 38.49	-33.3 scores on a scale Standard Deviation 23.57	-17.5 scores on a scale Standard Deviation 34.01
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Insomnia: Wk 49 (n=4,4,4,10)	-25.0 scores on a scale Standard Deviation 31.91	8.3 scores on a scale Standard Deviation 16.67	-33.3 scores on a scale Standard Deviation 27.22	-33.3 scores on a scale Standard Deviation 41.57
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Appetite loss: Wk 25 (n=6,7,5,19)	-27.8 scores on a scale Standard Deviation 25.09	4.8 scores on a scale Standard Deviation 12.60	-13.3 scores on a scale Standard Deviation 18.26	-12.3 scores on a scale Standard Deviation 29.84
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Appetite loss: Wk 49 (n=4,4,4,10)	-25.0 scores on a scale Standard Deviation 41.94	8.3 scores on a scale Standard Deviation 16.67	-16.7 scores on a scale Standard Deviation 19.25	0.0 scores on a scale Standard Deviation 44.44
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Constipation: Wk 25 (n=6,7,5,19)	-11.1 scores on a scale Standard Deviation 17.21	0.0 scores on a scale Standard Deviation 0.00	13.3 scores on a scale Standard Deviation 29.81	7.0 scores on a scale Standard Deviation 30.59
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Constipation: Wk 49 (n=4,4,4,10)	-33.3 scores on a scale Standard Deviation 47.14	0.0 scores on a scale Standard Deviation 27.22	8.3 scores on a scale Standard Deviation 16.67	3.3 scores on a scale Standard Deviation 36.68
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Diarrhoea: Wk 25 (n=6,7,5,19)	5.6 scores on a scale Standard Deviation 64.69	-9.5 scores on a scale Standard Deviation 16.27	-13.3 scores on a scale Standard Deviation 18.26	-1.8 scores on a scale Standard Deviation 20.71
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Diarrhoea: Wk 49 (n=4,4,4,10)	-8.3 scores on a scale Standard Deviation 16.67	-0.0 scores on a scale Standard Deviation 27.22	16.7 scores on a scale Standard Deviation 57.74	-3.3 scores on a scale Standard Deviation 18.92
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Fin. diff: Wk 25 (n=6,7,5,19)	16.7 scores on a scale Standard Deviation 49.95	19.0 scores on a scale Standard Deviation 32.53	20.0 scores on a scale Standard Deviation 50.55	8.8 scores on a scale Standard Deviation 24.45
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 Fin. diff: Wk 49 (n=4,4,4,10)	8.3 scores on a scale Standard Deviation 63.10	25.0 scores on a scale Standard Deviation 31.91	0.0 scores on a scale Standard Deviation 27.22	3.3 scores on a scale Standard Deviation 18.92

SECONDARY outcome

Timeframe: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 9 Day 1

Population: The Pharmacokinetic Analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.

Racc: Accumulation ratio calculated as AUC0-12h on Week 9 Day 1 divided by AUC0-12h on Week 1 Day 1 [fold]

Outcome measures

Measure	LDE225 400mg + INC424 10mg (Dose Escalation Phase) n=8 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15mg (Dose Escalation Phase) n=10 Participants Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) n=5 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDED225 400mg + INC424 20mg (Dose Expansion Phase) n=27 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Phase Ib and Phase II: LDE225: PK Parameter: Racc LDE225 (Week 9, Day 1) (n=4,6,3,13)	4.60 ratio Interval 2.61 to 7.03	7.40 ratio Interval 4.38 to 19.6	10.9 ratio Interval 6.41 to 17.0	4.75 ratio Interval 1.84 to 20.0

SECONDARY outcome

Timeframe: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1

Population: The Pharmacokinetic Analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.

T1/2: Elimination half-life associated with the terminal slope (lambda_z) of a semi logarithmic concentration-time curve [time]

Outcome measures

Measure	LDE225 400mg + INC424 10mg (Dose Escalation Phase) n=8 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15mg (Dose Escalation Phase) n=10 Participants Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) n=5 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDED225 400mg + INC424 20mg (Dose Expansion Phase) n=27 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Phase Ib and Phase II: INC424: PK Parameter: T1/2	1.81 hour (h) Interval 1.66 to 3.65	2.42 hour (h) Interval 1.28 to 3.14	2.20 hour (h) Interval 1.96 to 2.84	1.99 hour (h) Interval 1.34 to 3.1

SECONDARY outcome

Timeframe: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1

Population: The Pharmacokinetic Analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.

Vss/F: Apparent volume of distribution at steady state after oral administration [volume]

Outcome measures

Measure	LDE225 400mg + INC424 10mg (Dose Escalation Phase) n=8 Participants Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.	LDE225 400mg + INC424 15mg (Dose Escalation Phase) n=10 Participants Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400mg + INC424 20mg (Dose Escalation Phase) n=5 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDED225 400mg + INC424 20mg (Dose Expansion Phase) n=27 Participants Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Phase Ib and Phase II: INC424: PK Parameter: Vss/F	63.7 Litre (L) Interval 44.5 to 86.5	67.1 Litre (L) Interval 41.0 to 75.7	53.1 Litre (L) Interval 47.7 to 80.5	54.5 Litre (L) Interval 22.9 to 102.0

Adverse Events

LDE225 400 mg + INC424 10 mg

Serious events: 5 serious events

Other events: 8 other events

Deaths: 1 deaths

LDE225 400 mg + INC424 15 mg

Serious events: 6 serious events

Other events: 10 other events

Deaths: 1 deaths

LDE225 400 mg + INC424 20 mg

Serious events: 2 serious events

Other events: 5 other events

Deaths: 1 deaths

LDE225 400 mg + INC424 20 mg (Dose Expansion)

Serious events: 13 serious events

Other events: 27 other events

Deaths: 1 deaths

All Patients

Serious events: 26 serious events

Other events: 50 other events

Deaths: 4 deaths

Serious adverse events

Measure	LDE225 400 mg + INC424 10 mg n=8 participants at risk Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase	LDE225 400 mg + INC424 15 mg n=10 participants at risk Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400 mg + INC424 20 mg n=5 participants at risk Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDE225 400 mg + INC424 20 mg (Dose Expansion) n=27 participants at risk Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase	All Patients n=50 participants at risk All Patients
Investigations Blood creatine phosphokinase increased	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 2/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	11.1% 3/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 5/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Blood and lymphatic system disorders Anaemia	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Blood and lymphatic system disorders Extramedullary haemopoiesis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Cardiac disorders Atrial fibrillation	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Cardiac disorders Right ventricular failure	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Constipation	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Diarrhoea	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Duodenal ulcer haemorrhage	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Gastric ulcer	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Gastric ulcer haemorrhage	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 2/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Melaena	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Vomiting	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
General disorders Face oedema	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
General disorders Multiple organ dysfunction syndrome	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
General disorders Pyrexia	25.0% 2/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	11.1% 3/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 5/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Diverticulitis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Erysipelas	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Gastroenteritis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Infection	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Injury, poisoning and procedural complications Fall	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Injury, poisoning and procedural complications Meniscus injury	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Injury, poisoning and procedural complications Post procedural haemorrhage	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Aspartate aminotransferase increased	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Myoglobin blood increased	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Metabolism and nutrition disorders Hyperkalaemia	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Metabolism and nutrition disorders Hyponatraemia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Musculoskeletal and connective tissue disorders Myositis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Acute myeloid leukaemia	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) B-cell lymphoma	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cholangiocarcinoma	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Chronic myeloid leukaemia	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Cerebrovascular accident	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Presyncope	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.

Other adverse events

Measure	LDE225 400 mg + INC424 10 mg n=8 participants at risk Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase	LDE225 400 mg + INC424 15 mg n=10 participants at risk Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase	LDE225 400 mg + INC424 20 mg n=5 participants at risk Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase	LDE225 400 mg + INC424 20 mg (Dose Expansion) n=27 participants at risk Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase	All Patients n=50 participants at risk All Patients
Eye disorders Retinal detachment	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Eye disorders Vision blurred	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Musculoskeletal and connective tissue disorders Muscle fatigue	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Musculoskeletal and connective tissue disorders Muscle spasms	37.5% 3/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	60.0% 6/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	80.0% 4/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	66.7% 18/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	62.0% 31/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Blood and lymphatic system disorders Anaemia	62.5% 5/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	40.0% 4/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	80.0% 4/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	59.3% 16/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	58.0% 29/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Blood and lymphatic system disorders Extramedullary haemopoiesis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Blood and lymphatic system disorders Leukocytosis	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Blood and lymphatic system disorders Neutropenia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Blood and lymphatic system disorders Thrombocytopenia	37.5% 3/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 2/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	60.0% 3/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	25.9% 7/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	30.0% 15/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Cardiac disorders Supraventricular extrasystoles	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Abdominal discomfort	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	6.0% 3/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Abdominal distension	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Abdominal pain	25.0% 2/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	30.0% 3/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	14.8% 4/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	18.0% 9/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Bile acid malabsorption	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Constipation	25.0% 2/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	25.9% 7/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	22.0% 11/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Diarrhoea	37.5% 3/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	30.0% 3/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	80.0% 4/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	40.7% 11/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	42.0% 21/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Diverticulum	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Diverticulum intestinal	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Dry mouth	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	11.1% 3/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	6.0% 3/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Duodenal ulcer	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Dyspepsia	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Flatulence	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Functional gastrointestinal disorder	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Gastric ulcer	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Gastric varices	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Gastritis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Haematochezia	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Melaena	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Nausea	37.5% 3/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	29.6% 8/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	24.0% 12/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Stomatitis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Toothache	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Gastrointestinal disorders Vomiting	37.5% 3/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 2/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	18.5% 5/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	22.0% 11/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
General disorders Asthenia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 2/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	11.1% 3/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	14.0% 7/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
General disorders Catheter site bruise	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
General disorders Early satiety	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
General disorders Fatigue	75.0% 6/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	30.0% 3/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	29.6% 8/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	34.0% 17/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
General disorders Gait disturbance	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
General disorders General physical health deterioration	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
General disorders Influenza like illness	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	6.0% 3/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
General disorders Malaise	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	11.1% 3/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	6.0% 3/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
General disorders Oedema peripheral	25.0% 2/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 2/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 5/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
General disorders Pyrexia	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 2/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	40.0% 2/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	25.9% 7/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	22.0% 11/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
General disorders Thirst	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Hepatobiliary disorders Cholelithiasis	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Hepatobiliary disorders Hyperbilirubinaemia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Bronchitis	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	6.0% 3/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Cystitis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Ear infection	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Escherichia infection	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Folliculitis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	11.1% 3/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	6.0% 3/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Fungal skin infection	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Gastroenteritis viral	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Herpes zoster	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	6.0% 3/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Influenza	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Nasopharyngitis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 2/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	40.0% 2/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	12.0% 6/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Oesophageal candidiasis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Oral herpes	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Pharyngitis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Pneumonia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	8.0% 4/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Tooth infection	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Upper respiratory tract infection	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	30.0% 3/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	14.0% 7/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Urinary tract infection	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	8.0% 4/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Urinary tract infection bacterial	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Infections and infestations Wound infection	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Injury, poisoning and procedural complications Animal bite	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Injury, poisoning and procedural complications Contusion	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	40.0% 2/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	11.1% 3/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	12.0% 6/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Injury, poisoning and procedural complications Fall	25.0% 2/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	8.0% 4/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Injury, poisoning and procedural complications Hyphaema	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Injury, poisoning and procedural complications Laceration	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Injury, poisoning and procedural complications Meniscus injury	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Injury, poisoning and procedural complications Procedural hypotension	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Injury, poisoning and procedural complications Scratch	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Injury, poisoning and procedural complications Spinal compression fracture	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Injury, poisoning and procedural complications Tooth fracture	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Alanine aminotransferase increased	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 2/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	12.0% 6/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Amylase increased	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Aspartate aminotransferase increased	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	30.0% 3/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	14.0% 7/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Blood alkaline phosphatase increased	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Blood bilirubin increased	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	8.0% 4/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Blood creatine phosphokinase increased	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 2/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	60.0% 3/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	44.4% 12/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	36.0% 18/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Blood creatinine increased	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	11.1% 3/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	6.0% 3/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Blood prolactin increased	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Blood uric acid increased	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Cytomegalovirus test	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Electrocardiogram QT prolonged	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Gamma-glutamyltransferase increased	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations International normalised ratio increased	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Lipase increased	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Low density lipoprotein increased	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	40.0% 2/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	6.0% 3/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Platelet count decreased	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	14.8% 4/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	8.0% 4/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Prothrombin level increased	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Prothrombin time prolonged	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Weight decreased	25.0% 2/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	8.0% 4/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Investigations Weight increased	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	6.0% 3/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Metabolism and nutrition disorders Decreased appetite	37.5% 3/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	14.8% 4/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	14.0% 7/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Metabolism and nutrition disorders Hyperkalaemia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Metabolism and nutrition disorders Hypertriglyceridaemia	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Metabolism and nutrition disorders Hyperuricaemia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	30.0% 3/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	12.0% 6/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Metabolism and nutrition disorders Hypocalcaemia	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Metabolism and nutrition disorders Hypokalaemia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Metabolism and nutrition disorders Hypomagnesaemia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Metabolism and nutrition disorders Hyponatraemia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Metabolism and nutrition disorders Increased appetite	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Metabolism and nutrition disorders Iron deficiency	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Musculoskeletal and connective tissue disorders Arthralgia	25.0% 2/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 2/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 5/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 2/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Musculoskeletal and connective tissue disorders Joint lock	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Musculoskeletal and connective tissue disorders Muscle twitching	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Musculoskeletal and connective tissue disorders Muscular weakness	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	40.0% 4/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	16.0% 8/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	11.1% 3/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	8.0% 4/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	25.0% 2/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Musculoskeletal and connective tissue disorders Myalgia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	30.0% 3/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	33.3% 9/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	26.0% 13/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Musculoskeletal and connective tissue disorders Pain in extremity	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	11.1% 3/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 5/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Musculoskeletal and connective tissue disorders Polyarthritis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Acute myeloid leukaemia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Atypical fibroxanthoma	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Amnesia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Carpal tunnel syndrome	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Cerebral ischaemia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Dizziness	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	14.8% 4/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 5/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Dysaesthesia	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Dysgeusia	37.5% 3/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	40.0% 4/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	60.0% 3/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	33.3% 9/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	38.0% 19/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Head discomfort	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Headache	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 2/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	18.5% 5/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	16.0% 8/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Hypoaesthesia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Memory impairment	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	6.0% 3/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Muscle contractions involuntary	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Paraesthesia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Peripheral sensory neuropathy	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Post herpetic neuralgia	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Restless legs syndrome	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Syncope	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Transient ischaemic attack	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Nervous system disorders Tremor	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Psychiatric disorders Depression	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 2/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	6.0% 3/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Psychiatric disorders Insomnia	25.0% 2/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	8.0% 4/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Renal and urinary disorders Dysuria	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Renal and urinary disorders Haematuria	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Renal and urinary disorders Urinary retention	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Reproductive system and breast disorders Erectile dysfunction	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Respiratory, thoracic and mediastinal disorders Cough	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	30.0% 3/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	40.0% 2/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	18.5% 5/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	22.0% 11/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Respiratory, thoracic and mediastinal disorders Dry throat	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Respiratory, thoracic and mediastinal disorders Dysphonia	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	6.0% 3/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 2/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	11.1% 3/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 5/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	40.0% 2/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	11.1% 3/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 5/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Skin and subcutaneous tissue disorders Acne	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Skin and subcutaneous tissue disorders Alopecia	37.5% 3/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	70.0% 7/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	60.0% 3/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	44.4% 12/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	50.0% 25/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Skin and subcutaneous tissue disorders Erythema	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Skin and subcutaneous tissue disorders Hair growth abnormal	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Skin and subcutaneous tissue disorders Hyperkeratosis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Skin and subcutaneous tissue disorders Madarosis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Skin and subcutaneous tissue disorders Night sweats	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	11.1% 3/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 5/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Skin and subcutaneous tissue disorders Onychoclasis	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 2/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	40.0% 2/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	8.0% 4/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Skin and subcutaneous tissue disorders Pruritus generalised	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	40.0% 2/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	4.0% 2/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Skin and subcutaneous tissue disorders Rash	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	7.4% 2/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	8.0% 4/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Skin and subcutaneous tissue disorders Skin discolouration	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Skin and subcutaneous tissue disorders Swelling face	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Vascular disorders Aortic stenosis	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Vascular disorders Haematoma	12.5% 1/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	3.7% 1/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	6.0% 3/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Vascular disorders Hypertension	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	18.5% 5/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	14.0% 7/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Vascular disorders Intermittent claudication	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	20.0% 1/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Vascular disorders Peripheral venous disease	0.00% 0/8 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	10.0% 1/10 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/5 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	0.00% 0/27 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.	2.0% 1/50 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: Novartis.email@novartis.com

Results disclosure agreements

• Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie. data from all sites) in the clinical trial.
• Publication restrictions are in place

Restriction type: OTHER