Trial Outcomes & Findings for Study of Pharmacodynamics, Pharmacokinetics, Safety and Tolerability of VAY736 in Patients With Idiopathic Pulmonary Fibrosis (NCT NCT03287414)

NCT ID: NCT03287414

Last Updated: 2024-06-18

Results Overview

FVC was defined as the maximum amount of air that an individual was able to forcibly exhale from his / her lungs after taking the deepest breath they could. Change from baseline to end of treatment epoch (48 weeks of treatment) in Forced Vital Capacity (FVC) was analyzed using a Mixed Effects Model for Repeated Measures (MMRM) and considering all assessments collected during the treatment epoch. The model included treatment and visit as fixed effects, standard of care treatment (Nintedanib, Pirfenidone, or no treatment) as factor and baseline value as a covariate, treatment-by-visit and baseline-by-visit as interaction terms. A positive change from baseline indicates improvement. Baseline was defined as the last available assessment pre-dose before or on randomization date.

• Recruitment status: TERMINATED
• Study phase: PHASE2
• Target enrollment: 30 participants
• Primary outcome timeframe: From baseline up to 48 weeks post first dose of study treatment
• Results posted on: 2024-06-18

Participant Flow

The study was conducted across 16 centers in 6 countries.

A total of 142 participants were screened of which 30 participants were randomized. 1 participant in the VAY736 arm did not receive treatment as the patient withdrew consent before first dosing. Treatment epoch (duration of up to 48 weeks) was followed by: i) PK/safety follow-up epoch with duration of 20 weeks, and ii) PD/safety follow-up (only for participants who had received VAY736) until participants met pre-specified criteria for B-Cell recover or up to 2 years from the last dose of VAY736.

Participant milestones

Measure	VAY736 Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Treatment Epoch STARTED	14	16
Treatment Epoch Treated	13	16
Treatment Epoch COMPLETED	6	12
Treatment Epoch NOT COMPLETED	8	4
PK/Safety Follow-up Epoch STARTED	7	13
PK/Safety Follow-up Epoch COMPLETED	7	13
PK/Safety Follow-up Epoch NOT COMPLETED	0	0
PD/Safety Follow-up Epoch STARTED	7	0
PD/Safety Follow-up Epoch COMPLETED	5	0
PD/Safety Follow-up Epoch NOT COMPLETED	2	0

Reasons for withdrawal

Measure	VAY736 Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Treatment Epoch Adverse Event	0	1
Treatment Epoch Study terminated by sponsor	2	2
Treatment Epoch Subject/Guardian decision	4	0
Treatment Epoch Discontinued early with reason "other" selected	1	1
Treatment Epoch Withdrawal by Subject	1	0
PD/Safety Follow-up Epoch Lost to Follow-up	1	0
PD/Safety Follow-up Epoch Subject/Guardian decision	1	0

Baseline Characteristics

Study of Pharmacodynamics, Pharmacokinetics, Safety and Tolerability of VAY736 in Patients With Idiopathic Pulmonary Fibrosis

Baseline characteristics by cohort

Measure	VAY736 n=13 Participants Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo n=16 Participants Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Total n=29 Participants Total of all reporting groups
Age, Continuous	69.7 Years STANDARD_DEVIATION 9.30 • n=5 Participants	68.3 Years STANDARD_DEVIATION 8.15 • n=7 Participants	68.9 Years STANDARD_DEVIATION 8.55 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants	15 Participants n=7 Participants	27 Participants n=5 Participants
Race/Ethnicity, Customized White	13 Participants n=5 Participants	16 Participants n=7 Participants	29 Participants n=5 Participants

PRIMARY outcome

Timeframe: From baseline up to 48 weeks post first dose of study treatment

Population: Pharmacodynamic (PD) analysis set including participants with available PD data and no protocol deviations with relevant impact on PD data. Only participants with a value at both Baseline and end of treatment (48 weeks post-first dose of treatment) were included in the analysis.

FVC was defined as the maximum amount of air that an individual was able to forcibly exhale from his / her lungs after taking the deepest breath they could. Change from baseline to end of treatment epoch (48 weeks of treatment) in Forced Vital Capacity (FVC) was analyzed using a Mixed Effects Model for Repeated Measures (MMRM) and considering all assessments collected during the treatment epoch. The model included treatment and visit as fixed effects, standard of care treatment (Nintedanib, Pirfenidone, or no treatment) as factor and baseline value as a covariate, treatment-by-visit and baseline-by-visit as interaction terms. A positive change from baseline indicates improvement. Baseline was defined as the last available assessment pre-dose before or on randomization date.

Outcome measures

Measure	VAY736 n=3 Participants Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo n=7 Participants Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Change From Baseline to End of Treatment Epoch (48 Weeks of Treatment) in Forced Vital Capacity (FVC).	0.039 Liter (L) Standard Error 0.1116	-0.023 Liter (L) Standard Error 0.0773

SECONDARY outcome

Timeframe: Up to 48 weeks post first dose of study treatment

Population: PD analysis set including participants with available PD data and no protocol deviations with relevant impact on PD data.

All-cause mortality events were defined as deaths due to any cause. Kaplan-Meier estimates of the percentage of participants with the event of interest along with 80% two-sided confidence intervals using Greenwood's formula are provided.

Outcome measures

Measure	VAY736 n=12 Participants Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo n=16 Participants Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Percentage of Participants With All-cause Mortality Events	8.3 Percentage of participants Interval 2.39 to 26.92	0 Percentage of participants NA: Not estimable because no events occurred within this group

SECONDARY outcome

Timeframe: Up to 48 weeks post first dose of study treatment

Population: PD analysis set including participants with available PD data and no protocol deviations with relevant impact on PD data.

IPF-related mortality events were defined as deaths due to IPF related cause. Kaplan-Meier estimates of the percentage of participants with the event of interest along with 80% two-sided confidence intervals using Greenwood's formula are provided.

Outcome measures

Measure	VAY736 n=12 Participants Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo n=16 Participants Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Percentage of Participants With Survival Idiopathic Pulmonary Fibrosis (IPF) -Related Mortality Events	0 Percentage of participants NA: Not estimable because no events occurred within this group	0 Percentage of participants NA: Not estimable because no events occurred within this group

SECONDARY outcome

Timeframe: Up to 48 weeks post first dose of study treatment

Population: PD analysis set including participants with available PD data and no protocol deviations with relevant impact on PD data.

PFS events were divided into: 1) PFS1 events including progression (relative reduction in FVC ≥ 10%) or death due to all causes, and 2) PFS2 events including progression (relative reduction in FVC ≥ 10%) or death due to IPF-related causes. Kaplan-Meier estimates of the percentage of participants with the event of interest (PFS1 events or PFS2 events) along with 80% two-sided confidence intervals using Greenwood's formula are provided.

Outcome measures

Measure	VAY736 n=12 Participants Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo n=16 Participants Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Percentage of Participants With Progression-free Survival (PFS) Events PFS1	61.0 Percentage of participants Interval 38.22 to 84.2	31.9 Percentage of participants Interval 18.04 to 52.51
Percentage of Participants With Progression-free Survival (PFS) Events PFS2	57.1 Percentage of participants Interval 33.44 to 82.86	31.9 Percentage of participants Interval 18.04 to 52.51

SECONDARY outcome

Timeframe: Up to 48 weeks post first dose of study treatment

Population: PD analysis set including participants with available PD data and no protocol deviations with relevant impact on PD data.

The following disease progression events were considered: a) relative reduction in FVC ≥ 10%; b) relative reduction in Diffusing Capacity of the Lungs (DLCO) ≥ 15%; c) absolute reduction in Six Minute Walk Distance (6MWD) ≥ 50 m. Kaplan-Meier estimates of the percentage of participants with the event of interest along with 80% two-sided confidence intervals using Greenwood's formula are provided.

Outcome measures

Measure	VAY736 n=12 Participants Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo n=16 Participants Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Percentage of Participants With Disease Progression Events FVC	57.1 Percentage of participants Interval 33.44 to 82.86	31.9 Percentage of participants Interval 18.04 to 52.51
Percentage of Participants With Disease Progression Events DLCO	73.8 Percentage of participants Interval 46.56 to 94.24	56.1 Percentage of participants Interval 38.65 to 75.1
Percentage of Participants With Disease Progression Events 6MWD	38.3 Percentage of participants Interval 19.96 to 64.88	75.0 Percentage of participants Interval 58.52 to 88.74

SECONDARY outcome

Timeframe: Up to 48 weeks post first dose of study treatment

Population: PD analysis set including participants with available PD data and no protocol deviations with relevant impact on PD data.

Composite events were defined as: 1) death (all-cause mortality), or relative reduction in FVC ≥ 10%, or relative reduction in DLCO ≥ 15%, or relative reduction in 6MWD ≥ 50 m (composite endpoint 1); and 2) Death (IPF-related mortality), or relative reduction in FVC ≥ 10%, or relative reduction in DLCO ≥ 15%, or relative reduction in 6MWD ≥ 50 m (composite endpoint 2). Kaplan-Meier estimates of the percentage of participants with the event of interest along with 80% two-sided confidence intervals using Greenwood's formula are provided.

Outcome measures

Measure	VAY736 n=12 Participants Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo n=16 Participants Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Percentage of Participants With Composite Events Composite Endpoint 1	81.0 Percentage of participants Interval 63.86 to 93.29	66.3 Percentage of participants Interval 50.84 to 81.18
Percentage of Participants With Composite Events Composite Endpoint 2	79.2 Percentage of participants Interval 61.07 to 92.7	66.3 Percentage of participants Interval 50.84 to 81.18

SECONDARY outcome

Timeframe: From baseline up to 48 weeks post first dose of study treatment

Population: Pharmacodynamic (PD) analysis set including participants with available PD data and no protocol deviations with relevant impact on PD data. Only participants with a value at both Baseline and end of treatment (48 weeks post-first dose of treatment) were included in the analysis.

DLCO is a measurement to assess the lungs' ability to transfer gas from inspired air to the bloodstream. DLCO was determined according to ATS guidelines. Change from baseline to end of treatment epoch (48 weeks of treatment) in diffusing capacity of the lung for carbon monoxide (DLCO) was analyzed using a Mixed Effects Model for Repeated Measures (MMRM) and considering all assessments collected during the treatment epoch. The model included treatment and visit as fixed effects, standard of care treatment (Nintedanib, Pirfenidone, or no treatment) as factor and baseline value as a covariate, treatment-by-visit and baseline-by-visit as interaction terms. A positive change from baseline indicates improvement.

Baseline was defined as the last available assessment pre-dose before or on randomization date.

Outcome measures

Measure	VAY736 n=3 Participants Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo n=7 Participants Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Change From Baseline to End of Treatment Epoch (48 Weeks of Treatment) in Diffusing Capacity of the Lungs	-1.954 mililiter/minute/millimeter Mercury Standard Error 1.0816	-1.033 mililiter/minute/millimeter Mercury Standard Error 0.7244

SECONDARY outcome

Timeframe: From baseline up to 48 weeks post first dose of study treatment

Population: Pharmacodynamic (PD) analysis set including participants with available PD data and no protocol deviations with relevant impact on PD data. Only participants with a value at both Baseline and end of treatment (48 weeks post-first dose of treatment) were included in the analysis.

A standardized 6-minute walk test (6MWT) was performed in accordance with the guidelines of the American Thoracic Society 2002. The distance walked in six minutes (6MWD) was recorded. Change from baseline to end of treatment epoch (48 weeks of treatment) in 6MWD was analyzed using a Mixed Effects Model for Repeated Measures (MMRM) and considering all assessments collected during the treatment epoch. The model included treatment and visit as fixed effects, standard of care treatment (Nintedanib, Pirfenidone, or no treatment) as factor and baseline value as a covariate, treatment-by-visit and baseline-by-visit as interaction terms. A positive change from baseline indicates improvement. Baseline was defined as the last available assessment pre-dose before or on randomization date.

Outcome measures

Measure	VAY736 n=2 Participants Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo n=7 Participants Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Change From Baseline to the End of Treatment Epoch (48 Weeks of Treatment) in 6-minute Walk Distance (6MWD)	19.743 Meter (m) Standard Error 53.5268	-12.479 Meter (m) Standard Error 28.9400

SECONDARY outcome

Timeframe: From baseline up to 48 weeks post first dose of study treatment

Population: Pharmacodynamic (PD) analysis set including participants with available PD data and no protocol deviations with relevant impact on PD data. Only participants with a value at both Baseline and end of treatment (48 weeks post-first dose of treatment) were included in the analysis.

Distance saturation product is the product of distance walked and lowest oxygen saturation during the 6-min walk test. Change from baseline to end of treatment epoch (48 weeks of treatment) in distance saturation product was analyzed using a Mixed Effects Model for Repeated Measures (MMRM) and considering all assessments collected during the treatment epoch. The model included treatment and visit as fixed effects, standard of care treatment (Nintedanib, Pirfenidone, or no treatment) as factor and baseline value as a covariate, treatment-by-visit and baseline-by-visit as interaction terms. A positive change from baseline indicates improvement. Baseline was defined as the last available assessment pre-dose before or on randomization date.

Outcome measures

Measure	VAY736 n=2 Participants Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo n=7 Participants Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Change From Baseline to the End of Treatment Epoch (48 Weeks of Treatment) in Distance Saturation Product	9.746 Meter% (m%) Standard Error 52.2985	-19.420 Meter% (m%) Standard Error 28.3755

SECONDARY outcome

Timeframe: From baseline up to 48 weeks post first dose of study treatment

Population: Pharmacodynamic (PD) analysis set including participants with available PD data and no protocol deviations with relevant impact on PD data. Only participants with a value at both Baseline and end of treatment (48 weeks post-first dose of treatment) were included in the analysis.

Change from baseline to end of treatment epoch (48 weeks of treatment) in resting oxygen saturation (on room air) was analyzed using a Mixed Effects Model for Repeated Measures (MMRM) and considering all assessments collected during the treatment epoch. The model included treatment and visit as fixed effects, standard of care treatment (Nintedanib, Pirfenidone, or no treatment) as factor and baseline value as a covariate, treatment-by-visit and baseline-by-visit as interaction terms. A positive change from baseline indicates improvement. Baseline was defined as the last available assessment pre-dose before or on randomization date.

Outcome measures

Measure	VAY736 n=5 Participants Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo n=7 Participants Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Change From Baseline to the End of Treatment Epoch (48 Weeks of Treatment) in Resting Oxygen Saturation Level (on Room Air)	-0.117 Percentage (%) Standard Error 1.0179	-1.887 Percentage (%) Standard Error 0.9415

SECONDARY outcome

Timeframe: Day 1, 29, 85, 169, 253 and 337

Population: Immunogenicity (IG) analysis set including all participants with at least one available valid (i.e. not flagged for exclusion) IG concentration measurement, who received any study drug and with no protocol deviations that impact on IG data.

Number of participants with positive serum anti-VAY736 antibodies. A bridging ELISA method that is designed to detect the presence of anti-VAY736 antibodies in human serum was used.

Outcome measures

Measure	VAY736 n=10 Participants Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo n=15 Participants Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Number of Participants With Positive Serum Anti-VAY736 Antibodies Day 1	1 Participants	3 Participants
Number of Participants With Positive Serum Anti-VAY736 Antibodies Day 29	1 Participants	2 Participants
Number of Participants With Positive Serum Anti-VAY736 Antibodies Day 85	1 Participants	1 Participants
Number of Participants With Positive Serum Anti-VAY736 Antibodies Day 169	0 Participants	2 Participants
Number of Participants With Positive Serum Anti-VAY736 Antibodies Day 253	2 Participants	1 Participants
Number of Participants With Positive Serum Anti-VAY736 Antibodies Day 337	0 Participants	0 Participants

SECONDARY outcome

Timeframe: At pre-dose on Day 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309 and 337

Population: Overall number of participants analyzed represents the Pharmacokinetic (PK) analysis set including all participants with at least one available valid (i.e. not flagged for exclusion) PK concentration measurement who received at least one dose of VAY736 and with no protocol deviations that impact on PK data. The number of participants analyzed in each row represents the number of participants with a valid value in the corresponding time point.

The lowest serum concentration of VAY736 observed during a dosing interval at steady state (Ctrough) was determined

Outcome measures

Measure	VAY736 n=11 Participants Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Ctrough of VAY736 From the Serum Concentration-time Data Day 225	1271.10 nanogram (ng) / mililiter (mL) Standard Deviation 863.055	—
Ctrough of VAY736 From the Serum Concentration-time Data Day 1	0.00 nanogram (ng) / mililiter (mL) Standard Deviation 0.000	—
Ctrough of VAY736 From the Serum Concentration-time Data Day 29	676.79 nanogram (ng) / mililiter (mL) Standard Deviation 499.931	—
Ctrough of VAY736 From the Serum Concentration-time Data Day 57	779.89 nanogram (ng) / mililiter (mL) Standard Deviation 645.363	—
Ctrough of VAY736 From the Serum Concentration-time Data Day 85	786.63 nanogram (ng) / mililiter (mL) Standard Deviation 501.225	—
Ctrough of VAY736 From the Serum Concentration-time Data Day 113	771.88 nanogram (ng) / mililiter (mL) Standard Deviation 623.268	—
Ctrough of VAY736 From the Serum Concentration-time Data Day 141	1316.05 nanogram (ng) / mililiter (mL) Standard Deviation 877.240	—
Ctrough of VAY736 From the Serum Concentration-time Data Day 169	1019.00 nanogram (ng) / mililiter (mL) Standard Deviation 587.097	—
Ctrough of VAY736 From the Serum Concentration-time Data Day 197	985.50 nanogram (ng) / mililiter (mL) Standard Deviation 495.652	—
Ctrough of VAY736 From the Serum Concentration-time Data Day 253	998.57 nanogram (ng) / mililiter (mL) Standard Deviation 947.343	—
Ctrough of VAY736 From the Serum Concentration-time Data Day 281	705.00 nanogram (ng) / mililiter (mL) Standard Deviation 997.021	—
Ctrough of VAY736 From the Serum Concentration-time Data Day 309	827.40 nanogram (ng) / mililiter (mL) Standard Deviation 678.836	—
Ctrough of VAY736 From the Serum Concentration-time Data Day 337	688.50 nanogram (ng) / mililiter (mL) Standard Deviation 1172.124	—

Adverse Events

VAY736

Serious events: 5 serious events

Other events: 13 other events

Deaths: 1 deaths

Placebo

Serious events: 9 serious events

Other events: 15 other events

Deaths: 0 deaths

Total

Serious events: 14 serious events

Other events: 28 other events

Deaths: 1 deaths

Serious adverse events

Measure	VAY736 n=13 participants at risk Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo n=16 participants at risk Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Total n=29 participants at risk Total
Cardiac disorders Aortic valve incompetence	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Cardiac disorders Myocardial infarction	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Ear and labyrinth disorders Vertigo	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Eye disorders Retinal vein occlusion	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Gastrointestinal disorders Pancreatitis	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Infections and infestations Bronchitis	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Infections and infestations Lower respiratory tract infection	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Infections and infestations Pneumonia	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	18.8% 3/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	10.3% 3/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Metabolism and nutrition disorders Dehydration	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Respiratory, thoracic and mediastinal disorders Hypoxia	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Respiratory, thoracic and mediastinal disorders Idiopathic pulmonary fibrosis	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Vascular disorders Vasculitis	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug

Other adverse events

Measure	VAY736 n=13 participants at risk Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Placebo n=16 participants at risk Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy	Total n=29 participants at risk Total
Renal and urinary disorders Pollakiuria	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Blood and lymphatic system disorders Anaemia	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Blood and lymphatic system disorders Eosinophilia	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Cardiac disorders Aortic valve incompetence	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Cardiac disorders Arteriosclerosis coronary artery	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Cardiac disorders Palpitations	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Cardiac disorders Tachycardia	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Ear and labyrinth disorders Eustachian tube dysfunction	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Ear and labyrinth disorders Tinnitus	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Eye disorders Cataract	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Eye disorders Corneal degeneration	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Eye disorders Ocular hyperaemia	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Gastrointestinal disorders Abdominal pain	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Gastrointestinal disorders Abdominal pain upper	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Gastrointestinal disorders Diarrhoea	23.1% 3/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	13.8% 4/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Gastrointestinal disorders Dyspepsia	15.4% 2/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Gastrointestinal disorders Enteritis	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Gastrointestinal disorders Flatulence	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Gastrointestinal disorders Frequent bowel movements	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Gastrointestinal disorders Nausea	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	12.5% 2/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	10.3% 3/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Gastrointestinal disorders Vomiting	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	12.5% 2/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	10.3% 3/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
General disorders Asthenia	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
General disorders Chest discomfort	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
General disorders Chest pain	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
General disorders Fatigue	15.4% 2/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	10.3% 3/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
General disorders Injection site bruising	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
General disorders Injection site dermatitis	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
General disorders Injection site erythema	15.4% 2/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	10.3% 3/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
General disorders Injection site inflammation	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
General disorders Injection site pain	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
General disorders Injection site pruritus	23.1% 3/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	12.5% 2/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	17.2% 5/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
General disorders Injection site rash	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
General disorders Injection site warmth	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
General disorders Non-cardiac chest pain	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Immune system disorders Seasonal allergy	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Infections and infestations Bronchitis	15.4% 2/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	12.5% 2/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	13.8% 4/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Infections and infestations Conjunctivitis	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Infections and infestations Influenza	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Infections and infestations Lower respiratory tract infection	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Infections and infestations Respiratory tract infection	15.4% 2/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	10.3% 3/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Infections and infestations Rhinitis	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Infections and infestations Tooth infection	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Infections and infestations Upper respiratory tract infection	15.4% 2/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	12.5% 2/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	13.8% 4/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Infections and infestations Urinary tract infection	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Infections and infestations Viral upper respiratory tract infection	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Renal and urinary disorders Proteinuria	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Injury, poisoning and procedural complications Contusion	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Injury, poisoning and procedural complications Facial bones fracture	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Injury, poisoning and procedural complications Heat stroke	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Injury, poisoning and procedural complications Injection related reaction	15.4% 2/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Injury, poisoning and procedural complications Sunburn	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	12.5% 2/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Alanine aminotransferase increased	15.4% 2/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Antinuclear antibody increased	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Blood creatine phosphokinase decreased	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Blood creatinine increased	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Blood glucose increased	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Blood parathyroid hormone decreased	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Blood potassium increased	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Blood triglycerides increased	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Blood urea increased	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Blood urine present	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Escherichia test positive	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Gamma-glutamyltransferase increased	15.4% 2/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Glucose urine present	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Hepatic enzyme increased	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Lymphocyte count decreased	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Mean cell volume increased	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Monocyte count increased	15.4% 2/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Neutrophil count increased	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Protein urine present	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Urine albumin/creatinine ratio increased	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Urine analysis abnormal	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Urine protein/creatinine ratio increased	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations Weight decreased	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	25.0% 4/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	17.2% 5/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Investigations White blood cell count increased	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Metabolism and nutrition disorders Decreased appetite	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Metabolism and nutrition disorders Hyperkalaemia	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Metabolism and nutrition disorders Vitamin D deficiency	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Musculoskeletal and connective tissue disorders Arthralgia	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Musculoskeletal and connective tissue disorders Limb discomfort	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Musculoskeletal and connective tissue disorders Musculoskeletal pain	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Musculoskeletal and connective tissue disorders Osteoporosis	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Musculoskeletal and connective tissue disorders Pain in extremity	15.4% 2/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Dysplastic naevus	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Keratoacanthoma	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Nervous system disorders Carotid artery stenosis	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Nervous system disorders Cervical radiculopathy	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Nervous system disorders Cognitive disorder	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Nervous system disorders Dizziness	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Nervous system disorders Headache	15.4% 2/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	12.5% 2/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	13.8% 4/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Nervous system disorders Memory impairment	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Nervous system disorders Paraesthesia	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Nervous system disorders Tremor	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Psychiatric disorders Depression	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Psychiatric disorders Insomnia	15.4% 2/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	10.3% 3/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Renal and urinary disorders Haematuria	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Renal and urinary disorders Urinary incontinence	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Respiratory, thoracic and mediastinal disorders Cough	23.1% 3/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	13.8% 4/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Respiratory, thoracic and mediastinal disorders Dysphonia	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Respiratory, thoracic and mediastinal disorders Dyspnoea	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Respiratory, thoracic and mediastinal disorders Idiopathic pulmonary fibrosis	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	18.8% 3/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	13.8% 4/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Respiratory, thoracic and mediastinal disorders Nasal congestion	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Skin and subcutaneous tissue disorders Alopecia	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Skin and subcutaneous tissue disorders Dermatitis atopic	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Skin and subcutaneous tissue disorders Drug eruption	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Skin and subcutaneous tissue disorders Hyperhidrosis	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Skin and subcutaneous tissue disorders Keloid scar	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Skin and subcutaneous tissue disorders Photosensitivity reaction	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.2% 1/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Skin and subcutaneous tissue disorders Rash	0.00% 0/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	12.5% 2/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Skin and subcutaneous tissue disorders Rash erythematous	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Skin and subcutaneous tissue disorders Skin lesion	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Vascular disorders Hot flush	15.4% 2/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	6.9% 2/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug
Vascular disorders Hypertension	7.7% 1/13 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	0.00% 0/16 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug	3.4% 1/29 • From baseline up to end of study, assessed up to approximately 2.4 years Safety analyses were performed in the safety set including all participants who received at least one dose of any study drug

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