Trial Outcomes & Findings for Efficacy and Safety of Atacicept in Systemic Lupus Erythematosus (NCT NCT01972568)

NCT ID: NCT01972568

Last Updated: 2018-01-02

Results Overview

SRI response, a composite measure of reduced SLE disease activity, was defined as a reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) disease activity score of greater than or equal to (\>=) 4 points; no significant worsening in Physician's Global Assessment (PGA) score (\<10 % increase, defined as \<0.3 point increase for statistical analyses); no new British Isles Lupus Assessment Group (BILAG) A organ domain scores and \<=1 (defined as no more than one) new BILAG B organ domain score.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

306 participants

Primary outcome timeframe

Week 24

Results posted on

2018-01-02

Participant Flow

The study was conducted at 136 sites in 18 countries in Asia, Europe, North America, Central America, and South America.

Participant milestones

Participant milestones
Measure	Atacicept 75 mg Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.	Atacicept 150 mg Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.	Placebo Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.
Overall Study STARTED	102	104	100
Overall Study COMPLETED	86	92	84
Overall Study NOT COMPLETED	16	12	16

Reasons for withdrawal

Reasons for withdrawal
Measure	Atacicept 75 mg Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.	Atacicept 150 mg Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.	Placebo Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.
Overall Study Other events	3	0	0
Overall Study Lack of Efficacy	0	1	2
Overall Study Protocol Violation	1	2	2
Overall Study Withdrawal by Subject	6	3	7
Overall Study Lost to Follow-up	1	0	0
Overall Study Adverse Event	5	6	5

Baseline Characteristics

Efficacy and Safety of Atacicept in Systemic Lupus Erythematosus

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Atacicept 75 mg n=102 Participants Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.	Atacicept 150 mg n=104 Participants Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.	Placebo n=100 Participants Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.	Total n=306 Participants Total of all reporting groups
Age, Continuous	37 years STANDARD_DEVIATION 11.2 • n=5 Participants	39 years STANDARD_DEVIATION 11.6 • n=7 Participants	40 years STANDARD_DEVIATION 13.0 • n=5 Participants	39 years STANDARD_DEVIATION 11.9 • n=4 Participants
Sex: Female, Male Female	93 Participants n=5 Participants	97 Participants n=7 Participants	90 Participants n=5 Participants	280 Participants n=4 Participants
Sex: Female, Male Male	9 Participants n=5 Participants	7 Participants n=7 Participants	10 Participants n=5 Participants	26 Participants n=4 Participants

PRIMARY outcome

Timeframe: Week 24

Population: mITT analysis set included all randomized subjects who had received at least 1 dose of IMP.

Outcome measures

Outcome measures
Measure	Atacicept 75 mg n=102 Participants Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.	Atacicept 150 mg n=104 Participants Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.	Placebo n=100 Participants Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.
Percentage of Subjects With Systemic Lupus Erythematosus (SLE) Responder Index (SRI) Response at Week 24 Using Screening Visit as Baseline	57.8 percentage of subjects	53.8 percentage of subjects	44.0 percentage of subjects

PRIMARY outcome

Timeframe: Week 24

Population: mITT analysis set included all randomized subjects who had received at least 1 dose of IMP.

Outcome measures

Outcome measures
Measure	Atacicept 75 mg n=102 Participants Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.	Atacicept 150 mg n=104 Participants Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.	Placebo n=100 Participants Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.
Percentage of Subjects With Systemic Lupus Erythematosus (SLE) Responder Index (SRI) Response at Week 24 Using Day 1 as Baseline	55.9 percentage of subjects	55.8 percentage of subjects	41.0 percentage of subjects

SECONDARY outcome

Timeframe: Week 24

Population: mITT analysis set included all randomized subjects who had received at least 1 dose of IMP. Here "Number of Participants Analyzed" signifies those subjects whose CS dose \>=10 mg at Screening.

BILAG A or 2B flare is defined by 1 new BILAG A organ domain score and/or 2 new BILAG B organ domain scores compared to the Screening Visit. The BILAG disease activity index evaluates systemic lupus erythematosus (SLE) activity in 8 organ systems, using a separate alphabetic score (A to E) assigned to each organ system defined as follows. BILAG A: Disease sufficiently active requiring disease-modifying treatment (prednisone \>20 mg daily or immunosuppressants); BILAG B: moderate disease activity requiring treatment with systemic low-dose oral glucocorticoids, intramuscular or intra-articular or soft tissue CS injection, topical CS or immunosuppressants, or symptomatic therapy such as antimalarials or NSAIDs. BILAG C: mild disease; BILAG D: system previously affected but now inactive and BILAG E: system never involved.

Outcome measures

Outcome measures
Measure	Atacicept 75 mg n=56 Participants Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.	Atacicept 150 mg n=53 Participants Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.	Placebo n=53 Participants Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.
Percentage of Subjects at Week 24 Whose Prednisone-Equivalent Corticosteroid (CS) Dose Reduced From Screening by >=25% and to a Dose of =<7.5mg/Day, and no British Isles Lupus Assessment Group (BILAG) A or 2B Flare in Disease Activity	17.9 percentage of subjects	11.3 percentage of subjects	18.9 percentage of subjects

SECONDARY outcome

Timeframe: Week 24

Population: mITT analysis set included all randomized subjects who had received at least 1 dose of IMP.

The PGIC is self-rated scale that asks the subject to describe the change in activity limitations, symptoms, emotions, and overall Quality of life (QoL) related to the subject's painful condition on the following scale: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse) and 7 (very much worse). Percentage of subjects in the PGIC categories of very much or much improved (1 or 2), minimally improved or no change or minimally worse (3 or 4 or 5) and much or very much worse (6 or 7) at Week 24 were presented.

Outcome measures

Outcome measures
Measure	Atacicept 75 mg n=102 Participants Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.	Atacicept 150 mg n=104 Participants Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.	Placebo n=100 Participants Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.
Percentage of Subjects With Patient Global Impression of Change (PGIC) Categories at Week 24 Very much or much improved	57.8 percentage of subjects	53.8 percentage of subjects	46.0 percentage of subjects
Percentage of Subjects With Patient Global Impression of Change (PGIC) Categories at Week 24 Minimally improved or no change or minimally worse	39.2 percentage of subjects	44.2 percentage of subjects	46.0 percentage of subjects
Percentage of Subjects With Patient Global Impression of Change (PGIC) Categories at Week 24 Much or very much worse	2.0 percentage of subjects	1.0 percentage of subjects	6.0 percentage of subjects
Percentage of Subjects With Patient Global Impression of Change (PGIC) Categories at Week 24 Missing	1.0 percentage of subjects	1.0 percentage of subjects	2.0 percentage of subjects

SECONDARY outcome

Timeframe: Screening and Week 24

Population: mITT analysis set included all randomized subjects who had received at least 1 dose of IMP.

Change From screening visit to Week 24 of prednisolone-equivalent CS daily dose was presented.

Outcome measures

Outcome measures
Measure	Atacicept 75 mg n=102 Participants Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.	Atacicept 150 mg n=104 Participants Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.	Placebo n=100 Participants Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.
Change From Screening in Prednisolone-Equivalent Corticosteroid (CS) Daily Dose at Week 24	-2.64 mg per day Standard Deviation 6.106	-1.87 mg per day Standard Deviation 4.653	-1.89 mg per day Standard Deviation 5.588

SECONDARY outcome

Timeframe: Baseline up to 24 Weeks

Population: mITT analysis set included all randomized subjects who had received at least 1 dose of IMP.

Outcome measures

Outcome measures
Measure	Atacicept 75 mg n=102 Participants Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.	Atacicept 150 mg n=104 Participants Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.	Placebo n=100 Participants Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.
Time From Randomization to First SRI Response During Treatment Period	12.4 weeks Interval 12.1 to 16.7	16.1 weeks Interval 12.0 to 16.4	16.1 weeks Interval 12.1 to 20.1

SECONDARY outcome

Timeframe: Week 24

Population: mITT analysis set included all randomized subjects who had received at least 1 dose of IMP. Here "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure.

The BICLA response is defined as BILAG-2004 improvement (all screening visit BILAG A improving to B/C/D, all screening visit BILAG B to C/D, and \<=1 new BILAG B and no new BILAG A); no deterioration in SLEDAI total score; PGA increase by \<10% (defined as \<0.3 point increase for the statistical analyses) and no nonpermitted medication/treatment.

Outcome measures

Outcome measures
Measure	Atacicept 75 mg n=88 Participants Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.	Atacicept 150 mg n=100 Participants Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.	Placebo n=93 Participants Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.
Percentage of Subjects With British Isles Lupus Assessment Group (BILAG)-Based Combined Lupus Assessment (BICLA) Response at Week 24	53.4 percentage of subjects	49.0 percentage of subjects	45.2 percentage of subjects

SECONDARY outcome

Timeframe: Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)

Population: Safety analysis set included all randomized subjects who received at least 1 dose of IMP.

An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE 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 or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug and up to 48 weeks. TEAEs include both Serious TEAEs and non-serious TEAEs.

Outcome measures

Outcome measures
Measure	Atacicept 75 mg n=102 Participants Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.	Atacicept 150 mg n=104 Participants Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.	Placebo n=100 Participants Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.
Percentage of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs TEAEs	81.4 percentage of subjects	80.8 percentage of subjects	72.0 percentage of subjects
Percentage of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Serious TEAEs	8.8 percentage of subjects	5.8 percentage of subjects	12.0 percentage of subjects

SECONDARY outcome

Timeframe: Week 0 (Day 1) and Week 24

Population: mITT analysis set included all randomized subjects who had received at least 1 dose of IMP. Here "Number Analyzed" signifies those subjects who were evaluable for this outcome measure at specified categories.

The 36-Item Short-Form Health Survey (SF-36) is a standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. These 8 aspects can also be summarized as physical and mental component summary scores. Total of 10 variables were analyzed (8 aspects, 2 component summary scores). The score for each of the 8 aspects and 2 component summary scores was scaled from 0 to 100, where 0 = lowest level of functioning and 100 = highest level of functioning.

Outcome measures

Outcome measures
Measure	Atacicept 75 mg n=102 Participants Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.	Atacicept 150 mg n=104 Participants Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.	Placebo n=100 Participants Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.
Change From Week 0 (Day 1) in SF-36 Components at Week 24 Physical Component Summary	4.7 units on a scale Standard Deviation 7.95	3.4 units on a scale Standard Deviation 7.57	3.5 units on a scale Standard Deviation 10.33
Change From Week 0 (Day 1) in SF-36 Components at Week 24 Mental Component Summary	1.9 units on a scale Standard Deviation 12.01	1.8 units on a scale Standard Deviation 9.08	0.7 units on a scale Standard Deviation 11.44
Change From Week 0 (Day 1) in SF-36 Components at Week 24 Physical Functioning	3.5 units on a scale Standard Deviation 9.30	3.8 units on a scale Standard Deviation 8.42	3.3 units on a scale Standard Deviation 8.62
Change From Week 0 (Day 1) in SF-36 Components at Week 24 Role-Physical	4.3 units on a scale Standard Deviation 10.26	2.3 units on a scale Standard Deviation 8.64	3.9 units on a scale Standard Deviation 9.51
Change From Week 0 (Day 1) in SF-36 Components at Week 24 Bodily Pain	6.0 units on a scale Standard Deviation 10.22	4.4 units on a scale Standard Deviation 9.30	5.6 units on a scale Standard Deviation 10.72
Change From Week 0 (Day 1) in SF-36 Components at Week 24 General Health	2.9 units on a scale Standard Deviation 8.43	3.0 units on a scale Standard Deviation 7.72	4.4 units on a scale Standard Deviation 8.00
Change From Week 0 (Day 1) in SF-36 Components at Week 24 Vitality	3.9 units on a scale Standard Deviation 9.86	3.7 units on a scale Standard Deviation 9.76	3.5 units on a scale Standard Deviation 9.57
Change From Week 0 (Day 1) in SF-36 Components at Week 24 Social Functioning	3.8 units on a scale Standard Deviation 11.45	2.2 units on a scale Standard Deviation 10.06	4.3 units on a scale Standard Deviation 11.08
Change From Week 0 (Day 1) in SF-36 Components at Week 24 Role-Emotional	2.5 units on a scale Standard Deviation 12.71	1.0 units on a scale Standard Deviation 10.43	2.3 units on a scale Standard Deviation 10.99
Change From Week 0 (Day 1) in SF-36 Components at Week 24 Mental Health	2.3 units on a scale Standard Deviation 12.30	2.8 units on a scale Standard Deviation 8.87	2.1 units on a scale Standard Deviation 10.60

POST_HOC outcome

Timeframe: Week 24

Population: mITT\_HDA analysis set included mITT population with high disease activity (HDA) defined as screening SLE Disease Activity Index (SLEDAI) \>=10.

SRI-6 response, a composite measure of reduced SLE disease activity, was defined as a reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) disease activity score of greater than or equal to (\>=) 6 points; no significant worsening in Physician's Global Assessment (PGA) score (\<10 % increase, defined as \<0.3 point increase for statistical analyses); no new British Isles Lupus Assessment Group (BILAG) A organ domain scores and \<=1 (defined as no more than one) new BILAG B organ domain score. Logistic regression of number of subjects with SRI-6 response was analyzed by using Logistic regression model.

Outcome measures

Outcome measures
Measure	Atacicept 75 mg n=55 Participants Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.	Atacicept 150 mg n=51 Participants Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.	Placebo n=52 Participants Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.
High Disease Activity Subpopulation (SLEDAI-2K >=10 at Screening): Logistic Regression of Percentage of Subjects With SRI-6 Response at Week 24	43.6 percentage of subjects	54.9 percentage of subjects	28.8 percentage of subjects

Adverse Events

Atacicept 75 mg

Serious events: 9 serious events

Other events: 83 other events

Deaths: 0 deaths

Atacicept 150 mg

Serious events: 6 serious events

Other events: 84 other events

Deaths: 0 deaths

Placebo

Serious events: 12 serious events

Other events: 72 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Atacicept 75 mg n=102 participants at risk Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.	Atacicept 150 mg n=104 participants at risk Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.	Placebo n=100 participants at risk Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.
Gastrointestinal disorders Diarrhoea	7.8% 8/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	11.5% 12/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	5.0% 5/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Gastrointestinal disorders Nausea	8.8% 9/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	4.8% 5/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
General disorders Fatigue	5.9% 6/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	2.9% 3/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	2.0% 2/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
General disorders Injection site pain	11.8% 12/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	13.5% 14/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	7.0% 7/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
General disorders Injection site reaction	41.2% 42/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	41.3% 43/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	19.0% 19/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Nasopharyngitis	5.9% 6/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	6.7% 7/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	5.0% 5/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Upper respiratory tract infection	9.8% 10/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	12.5% 13/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	3.0% 3/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Urinary tract infection	11.8% 12/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	11.5% 12/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	17.0% 17/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Musculoskeletal and connective tissue disorders Back pain	3.9% 4/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	2.9% 3/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	7.0% 7/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Nervous system disorders Headache	10.8% 11/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	14.4% 15/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	8.0% 8/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)

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
Publication restrictions are in place

Restriction type: OTHER

Measure	Atacicept 75 mg n=102 participants at risk Subjects received atacicept 75 milligram (mg) as once-weekly subcutaneous injection for 24 weeks.	Atacicept 150 mg n=104 participants at risk Subjects received atacicept 150 mg as once-weekly subcutaneous injection for 24 weeks.	Placebo n=100 participants at risk Subjects received placebo matched to atacicept as once-weekly subcutaneous injection for 24 weeks.
Blood and lymphatic system disorders Iron deficiency anaemia	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.96% 1/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Cardiac disorders Angina pectoris	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Cardiac disorders Cardiac failure congestive	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Cardiac disorders Mitral valve prolapse	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Cardiac disorders Right ventricular dilatation	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Congenital, familial and genetic disorders Atrial septal defect	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.96% 1/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Gastrointestinal disorders Dyspepsia	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Hepatobiliary disorders Cholecystitis acute	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.96% 1/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Abscess neck	0.98% 1/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Appendicitis	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Arthritis bacterial	0.98% 1/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Bronchitis	0.98% 1/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Cardiac valve vegetation	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.96% 1/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Cellulitis	0.98% 1/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Endocarditis bacterial	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.96% 1/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Gastroenteritis	0.98% 1/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Gastroenteritis viral	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Infective aortitis	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.96% 1/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Lymph node abscess	0.98% 1/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Nasopharyngitis	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Ophthalmic herpes zoster	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Parotitis	0.98% 1/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Peritonitis	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Pharyngitis	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Pneumonia	0.98% 1/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Pyelonephritis	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Sinusitis	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Sinusitis bacterial	0.98% 1/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Streptococcal bacteraemia	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Streptococcal sepsis	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.96% 1/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Infections and infestations Urinary tract infection	0.98% 1/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Injury, poisoning and procedural complications Ligament injury	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Metabolism and nutrition disorders Acidosis	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Musculoskeletal and connective tissue disorders Osteonecrosis	0.98% 1/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Musculoskeletal and connective tissue disorders Systemic lupus erythematosus	0.98% 1/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	2.0% 2/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lipoma	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Nervous system disorders Headache	0.98% 1/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Nervous system disorders Sciatica	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.96% 1/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Nervous system disorders Temporal lobe epilepsy	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Renal and urinary disorders Acute kidney injury	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	2.0% 2/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Reproductive system and breast disorders Metrorrhagia	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Reproductive system and breast disorders Uterine haemorrhage	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Respiratory, thoracic and mediastinal disorders Aspiration	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.96% 1/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	1.0% 1/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Skin and subcutaneous tissue disorders Angioedema	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.96% 1/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Vascular disorders Hypertension	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.96% 1/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)
Vascular disorders Peripheral artery occlusion	0.00% 0/102 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.96% 1/104 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)	0.00% 0/100 • Baseline up to 24 weeks after last dose of study drug (assessed up to maximum of 48 weeks)