Trial Outcomes & Findings for Safety and Efficacy of APD811 in Pulmonary Arterial Hypertension (NCT NCT02279160)

Last Updated: 2020-07-14

Results Overview

Measurements of PVR from right heart catheterization were obtained prior to Day 1 of the dose titration period and at the end of the maintenance period (Week 22), approximately 4 hours after the last dose of study drug.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

61 participants

Primary outcome timeframe

Baseline and 22 Weeks

Results posted on

2020-07-14

Participant Flow

Participant milestones

Participant milestones
Measure	APD811 Multiple dose titration to maximum tolerated dose. APD811	Placebo Multiple dose titration to maximum tolerated dose. Placebo
Overall Study STARTED	40	21
Overall Study COMPLETED	34	19
Overall Study NOT COMPLETED	6	2

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Safety and Efficacy of APD811 in Pulmonary Arterial Hypertension

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	APD811 n=40 Participants Multiple dose titration to maximum tolerated dose. APD811	Placebo n=21 Participants Multiple dose titration to maximum tolerated dose. Placebo	Total n=61 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	39 Participants n=5 Participants	18 Participants n=7 Participants	57 Participants n=5 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Age, Continuous	46.5 years n=5 Participants	60 years n=7 Participants	51 years n=5 Participants
Sex: Female, Male Female	33 Participants n=5 Participants	20 Participants n=7 Participants	53 Participants n=5 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	1 Participants n=7 Participants	8 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	38 Participants n=5 Participants	19 Participants n=7 Participants	57 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	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 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	38 Participants n=5 Participants	19 Participants n=7 Participants	57 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	2 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment Australia	6 participants n=5 Participants	4 participants n=7 Participants	10 participants n=5 Participants
Region of Enrollment Bulgaria	2 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants
Region of Enrollment Czechia	3 participants n=5 Participants	1 participants n=7 Participants	4 participants n=5 Participants
Region of Enrollment Hungary	0 participants n=5 Participants	3 participants n=7 Participants	3 participants n=5 Participants
Region of Enrollment Poland	1 participants n=5 Participants	3 participants n=7 Participants	4 participants n=5 Participants
Region of Enrollment Romania	3 participants n=5 Participants	3 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment Serbia	8 participants n=5 Participants	3 participants n=7 Participants	11 participants n=5 Participants
Region of Enrollment Spain	7 participants n=5 Participants	2 participants n=7 Participants	9 participants n=5 Participants
Region of Enrollment United States	10 participants n=5 Participants	2 participants n=7 Participants	12 participants n=5 Participants
Weight	73.5 kg n=5 Participants	68 kg n=7 Participants	72.5 kg n=5 Participants
Height	160.5 cm n=5 Participants	162 cm n=7 Participants	161 cm n=5 Participants
BMI	27.18 kg/m^2 n=5 Participants	25.68 kg/m^2 n=7 Participants	27.13 kg/m^2 n=5 Participants
Duration of PAH (Years)	2.22 years n=5 Participants	1.76 years n=7 Participants	2 years n=5 Participants
PAH Treatment Monotherapy (ERA or PDE5-Inhibitor)	14 Participants n=5 Participants	11 Participants n=7 Participants	25 Participants n=5 Participants
PAH Treatment Combination Therapy (ERA + PDE5-Inhibitor/sGCS)	26 Participants n=5 Participants	10 Participants n=7 Participants	36 Participants n=5 Participants
PAH Classification Idiopathic PAH	21 Participants n=5 Participants	11 Participants n=7 Participants	32 Participants n=5 Participants
PAH Classification Heritable PAH	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants
PAH Classification Drugs or Toxin Induced	4 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants
PAH Classification Associated PAH	11 Participants n=5 Participants	9 Participants n=7 Participants	20 Participants n=5 Participants
Baseline WHO/NYHA Functional Class Class I	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Baseline WHO/NYHA Functional Class Class II	22 Participants n=5 Participants	12 Participants n=7 Participants	34 Participants n=5 Participants
Baseline WHO/NYHA Functional Class Class III	17 Participants n=5 Participants	9 Participants n=7 Participants	26 Participants n=5 Participants
Baseline WHO/NYHA Functional Class Class IV	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Baseline Pulmonary Vascular Resistance	704.6 dyn*sec/cm^-5 n=5 Participants	479.7 dyn*sec/cm^-5 n=7 Participants	575.7 dyn*sec/cm^-5 n=5 Participants
Baseline 6MWD	405 meters n=5 Participants	367 meters n=7 Participants	400 meters n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 22 Weeks

Population: Intent-to-Treat Population

Outcome measures

Outcome measures
Measure	APD811 n=40 Participants Multiple dose titration to maximum tolerated dose. APD811	Placebo n=21 Participants Multiple dose titration to maximum tolerated dose. Placebo
Change From Baseline in Pulmonary Vascular Resistance (PVR)	514.6 dyn*sec/cm^5 Standard Deviation 1.85	512.0 dyn*sec/cm^5 Standard Deviation 1.62

PRIMARY outcome

Timeframe: Baseline and 22 Weeks

Population: Modified Intent-to-Treat Population

The 6MWT was conducted according to the modified guidelines issued by the American Thoracic Society prior to Day 1 of the dose titration period and at the end of the maintenance period (Week 22).

Outcome measures

Outcome measures
Measure	APD811 n=38 Participants Multiple dose titration to maximum tolerated dose. APD811	Placebo n=21 Participants Multiple dose titration to maximum tolerated dose. Placebo
Change From Baseline in 6-minute Walk Distance (6MWD) in Patients With PAH	36.2 meters Standard Error 11.79	29.4 meters Standard Error 16.16

Adverse Events

APD811

Serious events: 4 serious events

Other events: 40 other events

Deaths: 0 deaths

Placebo

Serious events: 6 serious events

Other events: 19 other events

Deaths: 2 deaths

Serious adverse events

Other adverse events

Additional Information

Derek Solum, PhD

United Therapeutics

Phone: 919-425-8122

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Serious adverse events
Measure	APD811 n=40 participants at risk Multiple dose titration to maximum tolerated dose. APD811	Placebo n=21 participants at risk Multiple dose titration to maximum tolerated dose. Placebo
Cardiac disorders Bradycardia	2.5% 1/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Cardiac disorders Cardiac arrest	2.5% 1/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Cardiac disorders Cardio-respiratory arrest	0.00% 0/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Cardiac disorders Myocardial infarction	0.00% 0/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	2.5% 1/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
General disorders Drug withdrawal syndrome	2.5% 1/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Hepatobiliary disorders Portal vein thrombosis	2.5% 1/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Infections and infestations Bronchitis	0.00% 0/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Injury, poisoning and procedural complications Fall	0.00% 0/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Injury, poisoning and procedural complications Head injury	0.00% 0/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Investigations Electrocardiogram QT prolonged	2.5% 1/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Musculoskeletal and connective tissue disorders Haemarthrosis	2.5% 1/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Musculoskeletal and connective tissue disorders Myositis	2.5% 1/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Nervous system disorders Loss of consciousness	0.00% 0/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.00% 0/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Respiratory, thoracic and mediastinal disorders Pulmonary arterial hypertension	0.00% 0/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Skin and subcutaneous tissue disorders Toxic skin eruption	0.00% 0/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Vascular disorders Hypovolaemic shock	0.00% 0/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.

Other adverse events
Measure	APD811 n=40 participants at risk Multiple dose titration to maximum tolerated dose. APD811	Placebo n=21 participants at risk Multiple dose titration to maximum tolerated dose. Placebo
Blood and lymphatic system disorders Anaemia	7.5% 3/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Cardiac disorders Bradycardia	5.0% 2/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Nervous system disorders Headache	77.5% 31/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	28.6% 6/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Gastrointestinal disorders Nausea	50.0% 20/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	23.8% 5/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Gastrointestinal disorders Diarrhoea	47.5% 19/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	14.3% 3/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Musculoskeletal and connective tissue disorders Pain in Jaw	35.0% 14/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	14.3% 3/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Vascular disorders Flushing	32.5% 13/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Musculoskeletal and connective tissue disorders Myalgia	27.5% 11/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Gastrointestinal disorders Vomiting	25.0% 10/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	14.3% 3/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Gastrointestinal disorders Abdominal Pain	17.5% 7/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Nervous system disorders Dizziness	17.5% 7/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	14.3% 3/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Musculoskeletal and connective tissue disorders Pain in extremity	17.5% 7/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
General disorders Oedema peripheral	15.0% 6/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Metabolism and nutrition disorders Arthralgia	12.5% 5/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Gastrointestinal disorders Abdominal pain upper	10.0% 4/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Musculoskeletal and connective tissue disorders Neck pain	10.0% 4/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Infections and infestations Urinary tract infection	10.0% 4/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	14.3% 3/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Metabolism and nutrition disorders Decreased appetite	7.5% 3/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Respiratory, thoracic and mediastinal disorders Dyspnoea	7.5% 3/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	4.8% 1/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Infections and infestations Influenza	7.5% 3/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Musculoskeletal and connective tissue disorders Muscle spasms	7.5% 3/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	9.5% 2/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	7.5% 3/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Nervous system disorders Syncope	7.5% 3/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Infections and infestations Upper respiratory tract infection	7.5% 3/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	9.5% 2/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Gastrointestinal disorders Abdominal discomfort	5.0% 2/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
General disorders Asthenia	5.0% 2/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Gastrointestinal disorders Constipation	5.0% 2/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Respiratory, thoracic and mediastinal disorders Cough	5.0% 2/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Investigations Electrocardiogram QT prolonged	5.0% 2/40 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.	0.00% 0/21 • Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks). Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.