Trial Outcomes & Findings for A Phase 2 Dose-finding Study of Atacicept in Subjects With Rheumatoid Arthritis (AUGUST I) (NCT NCT00430495)

Last Updated: 2016-02-17

Results Overview

ACR20-CRP response is defined as greater than or equal to (\>=) 20 percent (%) improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with \>=20% improvement in at least 3 of the following 5 measures: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function; and 5) acute-phase marker (CRP).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

256 participants

Primary outcome timeframe

Week 26

Results posted on

2016-02-17

Participant Flow

A total of 456 subjects were screened, of whom 256 were enrolled and randomized of which 254 received the trial medication and included in Intention to Treat (ITT) population.

Participant milestones

Participant milestones
Measure	Placebo Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 21 weeks.	Atacicept 25 mg Atacicept was administered subcutaneously at a dose of 25 milligram (mg) twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 21 weeks.	Atacicept 75 mg Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 21 weeks.	Atacicept 150 mg Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 21 weeks.
Overall Study STARTED	64	66	62	64
Overall Study Treated	62	66	62	64
Overall Study COMPLETED	50	59	49	60
Overall Study NOT COMPLETED	14	7	13	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 21 weeks.	Atacicept 25 mg Atacicept was administered subcutaneously at a dose of 25 milligram (mg) twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 21 weeks.	Atacicept 75 mg Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 21 weeks.	Atacicept 150 mg Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 21 weeks.
Overall Study Adverse Event	2	3	2	0
Overall Study Death	0	0	1	0
Overall Study Lost to Follow-up	0	1	4	0
Overall Study Protocol Violation	1	0	1	0
Overall Study Disease Progression	1	1	0	0
Overall Study Other	8	2	5	4
Overall Study Randomized but not Treated	2	0	0	0

Baseline Characteristics

A Phase 2 Dose-finding Study of Atacicept in Subjects With Rheumatoid Arthritis (AUGUST I)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=62 Participants Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 21 weeks.	Atacicept 25 mg n=66 Participants Atacicept was administered subcutaneously at a dose of 25 mg twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 21 weeks.	Atacicept 75 mg n=62 Participants Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 21 weeks.	Atacicept 150 mg n=64 Participants Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 21 weeks.	Total n=254 Participants Total of all reporting groups
Age, Continuous	53.1 years STANDARD_DEVIATION 12.5 • n=5 Participants	53.4 years STANDARD_DEVIATION 13.1 • n=7 Participants	55.3 years STANDARD_DEVIATION 12.0 • n=5 Participants	53.5 years STANDARD_DEVIATION 10.1 • n=4 Participants	53.8 years STANDARD_DEVIATION 11.9 • n=21 Participants
Sex: Female, Male Female	51 Participants n=5 Participants	54 Participants n=7 Participants	53 Participants n=5 Participants	53 Participants n=4 Participants	211 Participants n=21 Participants
Sex: Female, Male Male	11 Participants n=5 Participants	12 Participants n=7 Participants	9 Participants n=5 Participants	11 Participants n=4 Participants	43 Participants n=21 Participants

PRIMARY outcome

Timeframe: Week 26

Population: ITT population included all randomized participants who received at least 1 treatment dose.

Outcome measures

Outcome measures
Measure	Placebo n=62 Participants Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 21 weeks.	Atacicept 25 mg n=66 Participants Atacicept was administered subcutaneously at a dose of 25 mg twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 21 weeks.	Atacicept 75 mg n=62 Participants Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 21 weeks.	Atacicept 150 mg n=64 Participants Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 21 weeks.
Percentage of Participants Achieving American College of Rheumatology 20 Response Based on C-reactive Protein (ACR20-CRP) at Week 26	29.0 percentage of participants	30.3 percentage of participants	27.4 percentage of participants	39.1 percentage of participants

SECONDARY outcome

Timeframe: Week 26

Population: ITT population included all randomized participants who received at least 1 treatment dose.

ACR50-CRP response is defined as \>=50% improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with \>=50% improvement in at least 3 of the following 5 measures: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function; and 5) acute-phase marker (CRP).

Outcome measures

Outcome measures
Measure	Placebo n=62 Participants Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 21 weeks.	Atacicept 25 mg n=66 Participants Atacicept was administered subcutaneously at a dose of 25 mg twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 21 weeks.	Atacicept 75 mg n=62 Participants Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 21 weeks.	Atacicept 150 mg n=64 Participants Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 21 weeks.
Percentage of Participants Achieving American College of Rheumatology 50 Response Based on CRP (ACR50-CRP) at Week 26	6.5 percentage of participants	13.6 percentage of participants	11.3 percentage of participants	10.9 percentage of participants

SECONDARY outcome

Timeframe: Week 26

Population: ITT population included all randomized participants who received at least 1 treatment dose.

ACR70-CRP response is defined as \>=70% improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with \>=70% improvement in at least 3 of the following 5 measures: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function; and 5) acute-phase marker (CRP).

Outcome measures

Outcome measures
Measure	Placebo n=62 Participants Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 21 weeks.	Atacicept 25 mg n=66 Participants Atacicept was administered subcutaneously at a dose of 25 mg twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 21 weeks.	Atacicept 75 mg n=62 Participants Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 21 weeks.	Atacicept 150 mg n=64 Participants Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 21 weeks.
Percentage of Participants Achieving American College of Rheumatology 70 Response Based on CRP (ACR70-CRP) at Week 26	0.0 percentage of participants	6.1 percentage of participants	4.8 percentage of participants	0.0 percentage of participants

SECONDARY outcome

Timeframe: Week 26

Population: ITT population included all randomized participants who received at least 1 treatment dose.

DAS28-CRP incorporates non-graded joint counts for tenderness and swelling based on a total of 28 joints, CRP as a marker of inflammation, and a general health assessment using a 100-millimeter (mm) visual analog scale (the participant's global assessment of disease activity). DAS28 ranges between 0 and 10 representing current disease activity. A value above 5.1 represents high disease activity, a value below 3.2 represents low disease activity, and a value below 2.6 represents remission.

Outcome measures

Outcome measures
Measure	Placebo n=62 Participants Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 21 weeks.	Atacicept 25 mg n=66 Participants Atacicept was administered subcutaneously at a dose of 25 mg twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 21 weeks.	Atacicept 75 mg n=62 Participants Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 21 weeks.	Atacicept 150 mg n=64 Participants Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 21 weeks.
Percentage of Participants Achieving Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) of Less Than or Equal to (<=) 3.2 at Week 26	9.7 percentage of participants 0.95	10.6 percentage of participants 0.84	9.7 percentage of participants 0.88	12.5 percentage of participants 0.84

SECONDARY outcome

Timeframe: Week 26

Population: ITT population included all randomized participants who received at least 1 treatment dose.

DAS28-CRP incorporates non-graded joint counts for tenderness and swelling based on a total of 28 joints, CRP as a marker of inflammation, and a general health assessment using a 100 mm visual analog scale (the participant's global assessment of disease activity). DAS28 ranges between 0 and 10 representing current disease activity. A value above 5.1 represents high disease activity, a value below 3.2 represents low disease activity, and a value below 2.6 represents remission.

Outcome measures

Outcome measures
Measure	Placebo n=62 Participants Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 21 weeks.	Atacicept 25 mg n=66 Participants Atacicept was administered subcutaneously at a dose of 25 mg twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 21 weeks.	Atacicept 75 mg n=62 Participants Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 21 weeks.	Atacicept 150 mg n=64 Participants Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 21 weeks.
Percentage of Participants Achieving Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) of <=2.6 at Week 26	1.6 percentage of participants	6.1 percentage of participants	4.8 percentage of participants	4.7 percentage of participants

SECONDARY outcome

Timeframe: Week 26

Population: ITT population included all randomized participants who received at least 1 treatment dose. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.

The HAQ-DI is a participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item was scored on 4-point scale from 0 to 3: 0 = no difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range is 0 to 3 where 0 = least difficulty and 3 = extreme difficulty. Percentage of participants achieving improvement in HAQ-DI of at least 0.3 from baseline at Week 26 was reported.

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 21 weeks.	Atacicept 25 mg n=41 Participants Atacicept was administered subcutaneously at a dose of 25 mg twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 21 weeks.	Atacicept 75 mg n=34 Participants Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 21 weeks.	Atacicept 150 mg n=48 Participants Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 21 weeks.
Percentage of Participants Achieving Improvement in Health Assessment Questionnaire Disability Index (HAQ-DI) of at Least 0.3 From Baseline at Week 26	47.4 percentage of participants	48.8 percentage of participants	55.9 percentage of participants	37.5 percentage of participants

SECONDARY outcome

Timeframe: Week 26

Population: ITT population included all randomized participants who received at least 1 treatment dose.

The EULAR response criteria evaluate change in DAS28 scores represented as "good response", "moderate response", or "no response" considering both the current DAS28 score and the observed improvement from baseline. Participants were considered to have "good" or "moderate" EULAR response if at the time of assessment, their DAS28 score was \<=5.1 and the improvement from baseline in their DAS28 score was greater than (\>) 0.6; or if at the time of assessment, their DAS28 score was \>5.1 and improvement from baseline in their DAS28 score was \>1.2.

Outcome measures

Outcome measures
Measure	Placebo n=62 Participants Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 21 weeks.	Atacicept 25 mg n=66 Participants Atacicept was administered subcutaneously at a dose of 25 mg twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 21 weeks.	Atacicept 75 mg n=62 Participants Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 21 weeks.	Atacicept 150 mg n=64 Participants Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 21 weeks.
Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) Response at Week 26	41.9 percentage of participants	31.8 percentage of participants	35.5 percentage of participants	53.1 percentage of participants

SECONDARY outcome

Timeframe: Baseline up to Week 38

Population: Safety population included all randomized participants who received at least 1 treatment dose and had safety data following their first dose.

An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.

Outcome measures

Outcome measures
Measure	Placebo n=62 Participants Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 21 weeks.	Atacicept 25 mg n=66 Participants Atacicept was administered subcutaneously at a dose of 25 mg twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 21 weeks.	Atacicept 75 mg n=62 Participants Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 21 weeks.	Atacicept 150 mg n=64 Participants Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 21 weeks.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) AEs	41 participants	49 participants	42 participants	46 participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) SAEs	3 participants	9 participants	8 participants	5 participants

Adverse Events

Placebo

Serious events: 3 serious events

Other events: 15 other events

Deaths: 0 deaths

Atacicept 25 mg

Serious events: 9 serious events

Other events: 25 other events

Deaths: 0 deaths

Atacicept 75 mg

Serious events: 8 serious events

Other events: 16 other events

Deaths: 0 deaths

Atacicept 150 mg

Serious events: 5 serious events

Other events: 26 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=62 participants at risk Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 21 weeks.	Atacicept 25 mg n=66 participants at risk Atacicept was administered subcutaneously at a dose of 25 mg twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 21 weeks.	Atacicept 75 mg n=62 participants at risk Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 21 weeks.	Atacicept 150 mg n=64 participants at risk Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 21 weeks.
Infections and infestations Upper respiratory tract infection	6.5% 4/62 • Baseline up to Week 38	4.5% 3/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	12.5% 8/64 • Baseline up to Week 38
Infections and infestations Urinary tract infection	4.8% 3/62 • Baseline up to Week 38	6.1% 4/66 • Baseline up to Week 38	4.8% 3/62 • Baseline up to Week 38	7.8% 5/64 • Baseline up to Week 38
Infections and infestations Nasopharyngitis	1.6% 1/62 • Baseline up to Week 38	4.5% 3/66 • Baseline up to Week 38	1.6% 1/62 • Baseline up to Week 38	6.2% 4/64 • Baseline up to Week 38
Gastrointestinal disorders Diarrhoea	1.6% 1/62 • Baseline up to Week 38	6.1% 4/66 • Baseline up to Week 38	9.7% 6/62 • Baseline up to Week 38	7.8% 5/64 • Baseline up to Week 38
Gastrointestinal disorders Nausea	1.6% 1/62 • Baseline up to Week 38	7.6% 5/66 • Baseline up to Week 38	6.5% 4/62 • Baseline up to Week 38	1.6% 1/64 • Baseline up to Week 38
Gastrointestinal disorders Constipation	1.6% 1/62 • Baseline up to Week 38	6.1% 4/66 • Baseline up to Week 38	1.6% 1/62 • Baseline up to Week 38	3.1% 2/64 • Baseline up to Week 38
Nervous system disorders Headache	6.5% 4/62 • Baseline up to Week 38	18.2% 12/66 • Baseline up to Week 38	8.1% 5/62 • Baseline up to Week 38	4.7% 3/64 • Baseline up to Week 38
Vascular disorders Hypertension	8.1% 5/62 • Baseline up to Week 38	4.5% 3/66 • Baseline up to Week 38	4.8% 3/62 • Baseline up to Week 38	3.1% 2/64 • Baseline up to Week 38
Blood and lymphatic system disorders Iron deficiency anaemia	0.00% 0/62 • Baseline up to Week 38	1.5% 1/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	6.2% 4/64 • Baseline up to Week 38

Additional Information

Merck KGaA Communication Center

Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany

Phone: +49-6151-72-5200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Prior to publishing results, Institution and Principal Investigator (PI) must first provide Sponsor with a copy of proposed publication for review at least 30 days prior to submission. If Institution and PI do not agree to modification, they shall so notify Sponsor and postpone submission for additional 60 days to allow Sponsor to seek legal remedies or file patent applications. There is a need for coordinated approach to any publication of results from sites for any multi-site study.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=62 participants at risk Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 21 weeks.	Atacicept 25 mg n=66 participants at risk Atacicept was administered subcutaneously at a dose of 25 mg twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 21 weeks.	Atacicept 75 mg n=62 participants at risk Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 21 weeks.	Atacicept 150 mg n=64 participants at risk Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 21 weeks.
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	0.00% 0/62 • Baseline up to Week 38	3.0% 2/66 • Baseline up to Week 38	3.2% 2/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Musculoskeletal and connective tissue disorders Back pain	1.6% 1/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Musculoskeletal and connective tissue disorders Osteonecrosis	0.00% 0/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	1.6% 1/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Injury, poisoning and procedural complications Femur fracture	1.6% 1/62 • Baseline up to Week 38	1.5% 1/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Injury, poisoning and procedural complications Hip fracture	0.00% 0/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	3.2% 2/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Injury, poisoning and procedural complications Humerus fracture	0.00% 0/62 • Baseline up to Week 38	1.5% 1/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Injury, poisoning and procedural complications Pelvic fracture	0.00% 0/62 • Baseline up to Week 38	1.5% 1/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Injury, poisoning and procedural complications Upper limb fracture	0.00% 0/62 • Baseline up to Week 38	1.5% 1/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Cardiac disorders Acute myocardial infarction	0.00% 0/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	1.6% 1/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Cardiac disorders Angina pectoris	0.00% 0/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	1.6% 1/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Cardiac disorders Cardio-respiratory arrest	0.00% 0/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	1.6% 1/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Cardiac disorders Right ventricular failure	0.00% 0/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	1.6% 1/64 • Baseline up to Week 38
Infections and infestations Bronchitis	0.00% 0/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	1.6% 1/64 • Baseline up to Week 38
Infections and infestations Pyopneumothorax	0.00% 0/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	1.6% 1/64 • Baseline up to Week 38
Infections and infestations Relapsing fever	0.00% 0/62 • Baseline up to Week 38	1.5% 1/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Infections and infestations Stenotrophomonas infection	0.00% 0/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	1.6% 1/64 • Baseline up to Week 38
Gastrointestinal disorders Diverticular perforation	0.00% 0/62 • Baseline up to Week 38	1.5% 1/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Gastrointestinal disorders Inguinal hernia	0.00% 0/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	1.6% 1/64 • Baseline up to Week 38
Gastrointestinal disorders Intestinal obstruction	0.00% 0/62 • Baseline up to Week 38	1.5% 1/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Endocrine disorders Basedow's disease	1.6% 1/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Endocrine disorders Hyperthyroidism	0.00% 0/62 • Baseline up to Week 38	1.5% 1/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
General disorders Non-cardiac chest pain	0.00% 0/62 • Baseline up to Week 38	1.5% 1/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
General disorders Pyrexia	0.00% 0/62 • Baseline up to Week 38	1.5% 1/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Nervous system disorders Migraine	1.6% 1/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Nervous system disorders Vasculitis cerebral	0.00% 0/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	1.6% 1/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Investigations Fibrin D dimer increased	0.00% 0/62 • Baseline up to Week 38	1.5% 1/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Investigations Gamma-glutamyltransferase increased	0.00% 0/62 • Baseline up to Week 38	1.5% 1/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Blood and lymphatic system disorders Anaemia	0.00% 0/62 • Baseline up to Week 38	1.5% 1/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Immune system disorders Drug hypersensitivity	0.00% 0/62 • Baseline up to Week 38	1.5% 1/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	0.00% 0/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	1.6% 1/64 • Baseline up to Week 38
Reproductive system and breast disorders Fallopian tube cyst	0.00% 0/62 • Baseline up to Week 38	1.5% 1/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	1.6% 1/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Skin and subcutaneous tissue disorders Angioedema	0.00% 0/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	1.6% 1/62 • Baseline up to Week 38	0.00% 0/64 • Baseline up to Week 38
Surgical and medical procedures Prostatic operation	0.00% 0/62 • Baseline up to Week 38	0.00% 0/66 • Baseline up to Week 38	0.00% 0/62 • Baseline up to Week 38	1.6% 1/64 • Baseline up to Week 38