Trial Outcomes & Findings for A Study to Evaluate Drug-Drug Interaction of TAK-788 With Itraconazole and Rifampin in Healthy Adult Participants (NCT NCT03928327)

Last Updated: 2020-08-21

Results Overview

The combined molar exposure Cmax for TAK-788 and its metabolites AP32960 and AP3914 value was calculated as the sum of each molar Cmax which was multiplied by 1000 and divided by molecular weight of each analyte, TAK-788, AP32960, and AP32914 respectively. The combined molar exposure was presented in nanomolar.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

24 participants

Primary outcome timeframe

Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose

Results posted on

2020-08-21

Participant Flow

Participants took part in the study in the United States from 02 May 2019 to 16 August 2019.

Healthy participants were enrolled in this 2-period study to receive: TAK-788 20 mg (Treatment A) along with itraconazole 200 mg (Treatment B) and TAK-788 160 mg (Treatment C) with rifampin 600 mg (Treatment D) in sequential manner to evaluate drug-drug interaction.

Participant milestones

Participant milestones
Measure	Part 1, Treatment Sequence AB TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast (Treatment A). Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 (Treatment B). There was a washout period of 7 days between the two treatments.	Part 2, Treatment Sequence CD TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast (Treatment C). Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 (Treatment D). There was a washout period of 7 days between the two treatments.
Period 1 STARTED	12	12
Period 1 COMPLETED	12	12
Period 1 NOT COMPLETED	0	0
Washout Period STARTED	12	12
Washout Period COMPLETED	12	12
Washout Period NOT COMPLETED	0	0
Period 2 STARTED	12	12
Period 2 COMPLETED	12	12
Period 2 NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Study to Evaluate Drug-Drug Interaction of TAK-788 With Itraconazole and Rifampin in Healthy Adult Participants

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1, Treatment Sequence AB n=12 Participants TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast (Treatment A). Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 (Treatment B). There was a washout period of 7 days between the two treatments.	Part 2, Treatment Sequence CD n=12 Participants TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast (Treatment C). Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 (Treatment D). There was a washout period of 7 days between the two treatments.	Total n=24 Participants Total of all reporting groups
Age, Continuous	37.7 years n=5 Participants	40.3 years n=7 Participants	39 years n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	8 Participants n=7 Participants	12 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	4 Participants n=7 Participants	12 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	9 Participants n=5 Participants	10 Participants n=7 Participants	19 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	10 Participants n=5 Participants	12 Participants n=7 Participants	22 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	12 Participants n=5 Participants	12 Participants n=7 Participants	24 Participants n=5 Participants
Weight	85.53 Kg n=5 Participants	79.78 Kg n=7 Participants	82.65 Kg n=5 Participants
Height	172.8 cm n=5 Participants	165.8 cm n=7 Participants	169.3 cm n=5 Participants
Body Mass Index (BMI)	28.573 kg/m^2 n=5 Participants	28.955 kg/m^2 n=7 Participants	28.764 kg/m^2 n=5 Participants

PRIMARY outcome

Timeframe: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose

Population: Pharmacokinetic (PK) Set included participants who complied sufficiently with the protocol and display an evaluable PK profile.

Outcome measures

Outcome measures
Measure	Part 1, Treatment A n=12 Participants TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast in Period 1.	Part 1, Treatment B n=12 Participants Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 in Period 2.	Part 2, Treatment C TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast in Period 1.	Part 2, Treatment D Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 in Period 2.
Treatment B vs Treatment A (Part 1), Combined Molar Exposure for Cmax: Maximum Observed Plasma Concentration of TAK-788, AP32960, and AP32914	13.7 nM Geometric Coefficient of Variation 30.7	39.2 nM Geometric Coefficient of Variation 21.1	—	—

PRIMARY outcome

Timeframe: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose

Population: PK Set included participants who complied sufficiently with the protocol and display an evaluable PK profile.

Outcome measures

Outcome measures
Measure	Part 1, Treatment A n=12 Participants TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast in Period 1.	Part 1, Treatment B n=12 Participants Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 in Period 2.	Part 2, Treatment C TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast in Period 1.	Part 2, Treatment D Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 in Period 2.
Treatment D Vs Treatment C (Part 2), Combined Molar Exposure for Cmax: Maximum Observed Plasma Concentration of TAK-788, AP32960, and AP32914	177 nM Geometric Coefficient of Variation 34.1	14.9 nM Geometric Coefficient of Variation 68.0	—	—

PRIMARY outcome

Timeframe: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose

Population: PK Set included participants who complied sufficiently with the protocol and display an evaluable PK profile. Overall number analyzed is the number of participants with data available for analyses.

The combined molar exposure AUC∞ for TAK-788 and its metabolites AP32960 and AP3914 value was calculated as the sum of each molar AUC∞ which was multiplied by 1000 and divided by molecular weight of each analyte, TAK-788, AP32960, and AP32914 respectively. The combined molar exposure was presented in hour\*nanomolar.

Outcome measures

Outcome measures
Measure	Part 1, Treatment A n=8 Participants TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast in Period 1.	Part 1, Treatment B n=10 Participants Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 in Period 2.	Part 2, Treatment C TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast in Period 1.	Part 2, Treatment D Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 in Period 2.
Treatment B Vs Treatment A (Part 1), Combined Molar Exposure for AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration of TAK-788, AP32960, and AP32914	298 hr*nM Geometric Coefficient of Variation 35.2	1820 hr*nM Geometric Coefficient of Variation 18.0	—	—

PRIMARY outcome

Timeframe: Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose

Outcome measures

Outcome measures
Measure	Part 1, Treatment A n=12 Participants TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast in Period 1.	Part 1, Treatment B n=11 Participants Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 in Period 2.	Part 2, Treatment C TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast in Period 1.	Part 2, Treatment D Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 in Period 2.
Treatment D Vs Treatment C (Part 2), Combined Molar Exposure for AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration of TAK-788, AP32960, and AP32914	3610 hr*nM Geometric Coefficient of Variation 43.2	194 hr*nM Geometric Coefficient of Variation 70.2	—	—

PRIMARY outcome

Timeframe: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose

Population: PK Set included participants who complied sufficiently with the protocol and display an evaluable PK profile.

Outcome measures

Outcome measures
Measure	Part 1, Treatment A n=12 Participants TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast in Period 1.	Part 1, Treatment B n=12 Participants Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 in Period 2.	Part 2, Treatment C n=12 Participants TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast in Period 1.	Part 2, Treatment D n=12 Participants Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 in Period 2.
Tmax - Time to Reach the Maximum Plasma Concentration (Cmax) of TAK-788	6.00 hr Interval 2.0 to 8.0	8.00 hr Interval 5.99 to 12.0	6.00 hr Interval 4.0 to 8.0	4.00 hr Interval 1.03 to 6.0

PRIMARY outcome

Timeframe: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose

Population: PK Set included participants who complied sufficiently with the protocol and display an evaluable PK profile.

Outcome measures

Outcome measures
Measure	Part 1, Treatment A n=12 Participants TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast in Period 1.	Part 1, Treatment B n=12 Participants Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 in Period 2.	Part 2, Treatment C n=12 Participants TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast in Period 1.	Part 2, Treatment D n=12 Participants Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 in Period 2.
Tmax - Time to Reach the Maximum Plasma Concentration (Cmax) of AP32960	6.00 hr Interval 2.0 to 6.01	8.00 hr Interval 6.0 to 12.0	6.00 hr Interval 2.01 to 6.0	2.00 hr Interval 1.03 to 6.0

PRIMARY outcome

Timeframe: Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose

Outcome measures

Outcome measures
Measure	Part 1, Treatment A n=9 Participants TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast in Period 1.	Part 1, Treatment B n=8 Participants Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 in Period 2.	Part 2, Treatment C n=12 Participants TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast in Period 1.	Part 2, Treatment D n=8 Participants Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 in Period 2.
Tmax - Time to Reach the Maximum Plasma Concentration (Cmax) of AP32914	6.00 hr Interval 2.0 to 8.0	8.00 hr Interval 6.0 to 12.0	6.00 hr Interval 4.0 to 6.01	4.00 hr Interval 1.03 to 119.92

Adverse Events

Part 1, Treatment A

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Part 1, Treatment B

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Part 2, Treatment C

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Part 2, Treatment D

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Medical director

Takeda

Phone: +1-877-825-3327

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.
Publication restrictions are in place

Restriction type: OTHER

Other adverse events
Measure	Part 1, Treatment A n=12 participants at risk TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast in Period 1.	Part 1, Treatment B n=12 participants at risk Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 in Period 2.	Part 2, Treatment C n=12 participants at risk TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast in Period 1.	Part 2, Treatment D n=12 participants at risk Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 in Period 2.
Ear and labyrinth disorders Ear pain	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Abdominal distension	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Abdominal pain	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Abdominal pain lower	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Diarrhoea	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	16.7% 2/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	16.7% 2/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	25.0% 3/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Flatulence	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Lip dry	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Nausea	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	16.7% 2/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Oral discomfort	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Urinary tract infection	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Vomiting	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Chest discomfort	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	16.7% 2/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Chills	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Feeling hot	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Limb injury	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Burning sensation	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Dizziness	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Dysgeusia	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Headache	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	16.7% 2/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Paraesthesia	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Sensory disturbance	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Renal and urinary disorders Micturition urgency	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Reproductive system and breast disorders Menstruation delayed	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Respiratory, thoracic and mediastinal disorders Dry throat	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	16.7% 2/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	16.7% 2/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Skin and subcutaneous tissue disorders Dry skin	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	25.0% 3/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Skin and subcutaneous tissue disorders Generalised erythema	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	16.7% 2/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Skin and subcutaneous tissue disorders Pruritus generalised	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	16.7% 2/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Skin and subcutaneous tissue disorders Rash	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	16.7% 2/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Skin and subcutaneous tissue disorders Rash papular	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Flushing	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	8.3% 1/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/12 • From first dose up to 30 days post last dose of study drug (Up to 45 days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.