Trial Outcomes & Findings for Study to Demonstrate Equivalent Efficacy and to Compare Safety of Biosimilar Etanercept (GP2015) and Enbrel (NCT NCT01891864)

Last Updated: 2017-03-27

Results Overview

The 95% CI for the Psoriasis Area and Severity Index (PASI) 75 response rate differences at Week12 between GP2015 Etanercept and Enbrel ® Etanercept. PASI 75 response: patients who achieved ≥ 75% improvement (reduction) in PASI score compared to baseline were defined as PASI 75 responders. PASI scores can range from 0, corresponding to no signs of psoriasis up to theoretic maximum of 72.0, which means a higher PASI score reflects a higher psoriasis activity.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

531 participants

Primary outcome timeframe

Week 12

Results posted on

2017-03-27

Participant Flow

Participant milestones

Participant milestones
Measure	GP2015 Etanercept Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter GP2015 Etanercept	Enbrel ® Etanercept Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter Enbrel ® Etanercept	GP2015 Etanercept Continued GP2015 50 mg subcutaneous (s.c.) injection of study drug from week 13 until Week 30 (Treatment Period 2). GP2015 50 mg subcutaneous (s.c.) injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2	Enbrel ® Etanercept Continued Enbrel ® 50 mg subcutaneous (s.c.) injection of study drug from week 13 until Week 30 (Treatment Period 2) Enbrel ® 50 mg subcutaneous (s.c.) injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.	GP2015 Etanercept Switched GP2015/Enbrel ® 50 mg subcutaneous (s.c.) injection of study drug until Week 30. Three periods of 6 weeks alternating between Enbrel/GP2015/Enbrel (Treatment Period 2). Enbrel ® 50 mg subcutaneous (s.c.) injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.	Enbrel ® Etanercept Switched Enbrel ®/GP2015 50 mg subcutaneous (s.c.) injection of study drug until Week 30. Three periods of 6 weeks alternating between GP2015/Enbrel/GP2015 (Treatment Period 2). GP2015 50 mg subcutaneous (s.c.) injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.
Treatment Period 1 STARTED	264	267	0	0	0	0
Treatment Period 1 COMPLETED	256	255	0	0	0	0
Treatment Period 1 NOT COMPLETED	8	12	0	0	0	0
Treatment Period 2 STARTED	0	0	150	151	100	96
Treatment Period 2 COMPLETED	0	0	143	142	96	91
Treatment Period 2 NOT COMPLETED	0	0	7	9	4	5
Extension Period STARTED	0	0	140	142	95	90
Extension Period COMPLETED	0	0	132	137	88	90
Extension Period NOT COMPLETED	0	0	8	5	7	0

Reasons for withdrawal

Reasons for withdrawal
Measure	GP2015 Etanercept Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter GP2015 Etanercept	Enbrel ® Etanercept Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter Enbrel ® Etanercept	GP2015 Etanercept Continued GP2015 50 mg subcutaneous (s.c.) injection of study drug from week 13 until Week 30 (Treatment Period 2). GP2015 50 mg subcutaneous (s.c.) injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2	Enbrel ® Etanercept Continued Enbrel ® 50 mg subcutaneous (s.c.) injection of study drug from week 13 until Week 30 (Treatment Period 2) Enbrel ® 50 mg subcutaneous (s.c.) injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.	GP2015 Etanercept Switched GP2015/Enbrel ® 50 mg subcutaneous (s.c.) injection of study drug until Week 30. Three periods of 6 weeks alternating between Enbrel/GP2015/Enbrel (Treatment Period 2). Enbrel ® 50 mg subcutaneous (s.c.) injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.	Enbrel ® Etanercept Switched Enbrel ®/GP2015 50 mg subcutaneous (s.c.) injection of study drug until Week 30. Three periods of 6 weeks alternating between GP2015/Enbrel/GP2015 (Treatment Period 2). GP2015 50 mg subcutaneous (s.c.) injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.
Treatment Period 1 Protocol Violation / IMP non-compliance	1	1	0	0	0	0
Treatment Period 1 Physician Decision	0	1	0	0	0	0
Treatment Period 1 Adverse Event, Serious, Fatal	0	1	0	0	0	0
Treatment Period 1 Adverse Event / Injection Site Reaction	4	4	0	0	0	0
Treatment Period 1 Withdrawal by Subject	2	5	0	0	0	0
Treatment Period 1 Lost to Follow-up	1	0	0	0	0	0
Treatment Period 2 Protocol Violation	0	0	0	1	0	0
Treatment Period 2 Physician Decision	0	0	1	0	0	0
Treatment Period 2 Site Termination	0	0	1	2	0	0
Treatment Period 2 Lack of Efficacy	0	0	1	0	1	0
Treatment Period 2 Adverse Event	0	0	1	2	0	4
Treatment Period 2 Termination of Site	0	0	0	0	2	0
Treatment Period 2 Withdrawal by Subject	0	0	3	4	1	1
Extension Period Lack of Efficacy	0	0	0	1	1	0
Extension Period Pregnancy	0	0	1	0	0	0
Extension Period Adverse Event	0	0	4	2	2	0
Extension Period Withdrawal by Subject	0	0	1	2	4	0
Extension Period Lost to Follow-up	0	0	2	0	0	0

Baseline Characteristics

Study to Demonstrate Equivalent Efficacy and to Compare Safety of Biosimilar Etanercept (GP2015) and Enbrel

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	GP2015 Etanercept n=264 Participants Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter GP2015 Etanercept	Enbrel ® Etanercept n=267 Participants Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter Enbrel ® Etanercept	Total n=531 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	254 Participants n=5 Participants	249 Participants n=7 Participants	503 Participants n=5 Participants
Age, Categorical >=65 years	10 Participants n=5 Participants	18 Participants n=7 Participants	28 Participants n=5 Participants
Age, Continuous	42.1 years STANDARD_DEVIATION 12.29 • n=5 Participants	42.7 years STANDARD_DEVIATION 12.86 • n=7 Participants	42.4 years STANDARD_DEVIATION 12.57 • n=5 Participants
Sex: Female, Male Female	107 Participants n=5 Participants	95 Participants n=7 Participants	202 Participants n=5 Participants
Sex: Female, Male Male	157 Participants n=5 Participants	172 Participants n=7 Participants	329 Participants n=5 Participants
Region of Enrollment Czech Republic	25 participants n=5 Participants	16 participants n=7 Participants	41 participants n=5 Participants
Region of Enrollment Russian Federation	9 participants n=5 Participants	8 participants n=7 Participants	17 participants n=5 Participants
Region of Enrollment Romania	9 participants n=5 Participants	24 participants n=7 Participants	33 participants n=5 Participants
Region of Enrollment Hungary	9 participants n=5 Participants	12 participants n=7 Participants	21 participants n=5 Participants
Region of Enrollment Ukraine	19 participants n=5 Participants	23 participants n=7 Participants	42 participants n=5 Participants
Region of Enrollment Poland	96 participants n=5 Participants	94 participants n=7 Participants	190 participants n=5 Participants
Region of Enrollment South Africa	4 participants n=5 Participants	1 participants n=7 Participants	5 participants n=5 Participants
Region of Enrollment United Kingdom	10 participants n=5 Participants	4 participants n=7 Participants	14 participants n=5 Participants
Region of Enrollment Slovakia	17 participants n=5 Participants	20 participants n=7 Participants	37 participants n=5 Participants
Region of Enrollment Bulgaria	13 participants n=5 Participants	8 participants n=7 Participants	21 participants n=5 Participants
Region of Enrollment Germany	12 participants n=5 Participants	17 participants n=7 Participants	29 participants n=5 Participants
Region of Enrollment Estonia	41 participants n=5 Participants	40 participants n=7 Participants	81 participants n=5 Participants

PRIMARY outcome

Timeframe: Week 12

Population: The analysis of the primary outcome measure was based on the per-protocol set (PPS) consisting of patients who completed study until 12 weeks without any major protocol deviation.

Outcome measures

Outcome measures
Measure	GP2015 Etanercept n=239 Participants Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter GP2015 Etanercept	Enbrel ® Etanercept n=241 Participants Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter Enbrel ® Etanercept	GP2015 Etanercept Switched GP2015 Etanercept (s.c.) injection administered in a dose of 50 mg twice weekly for the first 12 weeks. GP2015 Etanercept /Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug until Week 30. Three periods of 6 weeks alternating between Enbrel/GP2015/Enbrel (Treatment Period 2). Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.	Enbrel ® Etanercept Continued Enbrel ® Etanercept (s.c.) injection administered in a dose of 50 mg twice weekly for the first 12 weeks. Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 13 until Week 30 (Treatment Period 2). Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.
PASI 75 Response Rate at Week 12 - GP2015 Etanercept vs. Enbrel ® Etanercept	73.4 % of patients achieving PASI75 response	75.7 % of patients achieving PASI75 response	—	—

SECONDARY outcome

Timeframe: 12 weeks

Population: The analysis was based on the per-protocol set (PPS) consisting of patients who completed study until 12 weeks without any major protocol deviation.

The key secondary efficacy endpoint was the % change from baseline in PASI score up to Week 12. PASI scores can range from 0, corresponding to no signs of psoriasis up to theoretic maximum of 72.0, which means a higher PASI score reflects a higher psoriasis activity. Two approaches (longitudinal approach applying a Mixed Model Repeated Measures and Averaged Treatment Effect approach applying an ANCOVA model) were employed in order to calculate 2-sided 95% confidence intervals (CI) for the difference between the treatment groups.

Outcome measures

Outcome measures
Measure	GP2015 Etanercept n=239 Participants Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter GP2015 Etanercept	Enbrel ® Etanercept n=241 Participants Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter Enbrel ® Etanercept	GP2015 Etanercept Switched GP2015 Etanercept (s.c.) injection administered in a dose of 50 mg twice weekly for the first 12 weeks. GP2015 Etanercept /Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug until Week 30. Three periods of 6 weeks alternating between Enbrel/GP2015/Enbrel (Treatment Period 2). Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.	Enbrel ® Etanercept Continued Enbrel ® Etanercept (s.c.) injection administered in a dose of 50 mg twice weekly for the first 12 weeks. Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 13 until Week 30 (Treatment Period 2). Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.
Percent Change From Baseline in PASI Score up to Week 12	-56.11 percentage difference Standard Error 1.0578	-55.48 percentage difference Standard Error 1.0511	—	—

SECONDARY outcome

Timeframe: Week12

Population: The analysis of this secondary outcome measure was based on the per-protocol set (PPS) consisting of patients who completed study until 12 weeks without any major protocol deviation.

Percentage of patients achieving Psoriasis Area and Severity Index (PASI) 50, PASI 75, and PASI 90 responses at Week 12. PASI 50 response: patients who achieved ≥ 50% improvement (reduction) in PASI score compared to baseline were defined as PASI 50 responders .PASI 90 response: patients who achieved ≥ 90% improvement (reduction) in PASI score compared to baseline were defined as PASI 90 responders .

Outcome measures

Outcome measures
Measure	GP2015 Etanercept n=239 Participants Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter GP2015 Etanercept	Enbrel ® Etanercept n=241 Participants Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter Enbrel ® Etanercept	GP2015 Etanercept Switched GP2015 Etanercept (s.c.) injection administered in a dose of 50 mg twice weekly for the first 12 weeks. GP2015 Etanercept /Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug until Week 30. Three periods of 6 weeks alternating between Enbrel/GP2015/Enbrel (Treatment Period 2). Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.	Enbrel ® Etanercept Continued Enbrel ® Etanercept (s.c.) injection administered in a dose of 50 mg twice weekly for the first 12 weeks. Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 13 until Week 30 (Treatment Period 2). Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.
PASI 50, 75 and 90 Response Rates % of patients achieving PASI50 response at Week 12	99.2 percentage of patients	97.9 percentage of patients	—	—
PASI 50, 75 and 90 Response Rates % of patients achieving PASI75 response at Week 12	73.4 percentage of patients	75.7 percentage of patients	—	—
PASI 50, 75 and 90 Response Rates % of patients achieving PASI90 response at Week 12	39.2 percentage of patients	34.1 percentage of patients	—	—

SECONDARY outcome

Timeframe: Week52

Population: The analysis was performed on safety set including all patients who took at least 1 dose of study treatment

Percentage of patients with injection site reactions up to Week 52

Outcome measures

Outcome measures
Measure	GP2015 Etanercept n=164 Participants Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter GP2015 Etanercept	Enbrel ® Etanercept n=96 Participants Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter Enbrel ® Etanercept	GP2015 Etanercept Switched n=100 Participants GP2015 Etanercept (s.c.) injection administered in a dose of 50 mg twice weekly for the first 12 weeks. GP2015 Etanercept /Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug until Week 30. Three periods of 6 weeks alternating between Enbrel/GP2015/Enbrel (Treatment Period 2). Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.	Enbrel ® Etanercept Continued n=171 Participants Enbrel ® Etanercept (s.c.) injection administered in a dose of 50 mg twice weekly for the first 12 weeks. Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 13 until Week 30 (Treatment Period 2). Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.
Injection Site Reactions	8.5 percentage of patients with ISRs	16.7 percentage of patients with ISRs	9.0 percentage of patients with ISRs	15.8 percentage of patients with ISRs

SECONDARY outcome

Timeframe: Week 52

Population: The analysis was performed on immunogenicity set consisting of patients who provided data for ADA assessment of etanercept at baseline visit.

Immunogenicity was analyzed by the percentage of patients with positive anti-drug antibodies (ADA) to either GP2015 Etanercept or Enbrel ® up to Week 52.

Outcome measures

Outcome measures
Measure	GP2015 Etanercept n=140 Participants Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter GP2015 Etanercept	Enbrel ® Etanercept n=90 Participants Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter Enbrel ® Etanercept	GP2015 Etanercept Switched n=95 Participants GP2015 Etanercept (s.c.) injection administered in a dose of 50 mg twice weekly for the first 12 weeks. GP2015 Etanercept /Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug until Week 30. Three periods of 6 weeks alternating between Enbrel/GP2015/Enbrel (Treatment Period 2). Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.	Enbrel ® Etanercept Continued n=142 Participants Enbrel ® Etanercept (s.c.) injection administered in a dose of 50 mg twice weekly for the first 12 weeks. Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 13 until Week 30 (Treatment Period 2). Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.
Immunogenicity: Measurement of Rate of ADA Formations Against GP2015 Etanercept and Enbrel ® Etanercept	0 percentage patients with positive ADA	1.1 percentage patients with positive ADA	0 percentage patients with positive ADA	3.5 percentage patients with positive ADA

Adverse Events

GP2015 Etanercept Continued

Serious events: 7 serious events

Other events: 97 other events

Deaths: 0 deaths

Enbrel ® Etanercept Switched

Serious events: 6 serious events

Other events: 57 other events

Deaths: 0 deaths

GP2015 Etanercept Switched

Serious events: 6 serious events

Other events: 60 other events

Deaths: 0 deaths

Enbrel ® Etanercept Continued

Serious events: 7 serious events

Other events: 94 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Dr Guido Wuerth - Global Program Medical Director

Sandoz

Phone: +4980244762925

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee At least sixty days prior to submitting/presenting manuscript or other materials relating to the study a copy should be provided to Sandoz and Sandoz has sixty days to review and comment. Sandoz has the right to require amendments to any such proposed presentation or publication on reasonable grounds. Sandoz may require any proposed publication or presentation to be delayed for up to four months to enable a patent application to be prepared and filed.
Publication restrictions are in place

Restriction type: OTHER

Measure	GP2015 Etanercept Continued n=164 participants at risk GP2015 Etanercept (s.c.) injection administered in a dose of 50 mg twice weekly for the first 12 weeks. GP2015 Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 13 until Week 30 (Treatment Period 2). GP2015 Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.	Enbrel ® Etanercept Switched n=96 participants at risk Enbrel ® Etanercept (s.c.) injection administered in a dose of 50 mg twice weekly for the first 12 weeks. Enbrel ® Etanercept /GP2015 Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug until Week 30. Three periods of 6 weeks alternating between GP2015/Enbrel/GP2015 (Treatment Period 2). GP2015 Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.	GP2015 Etanercept Switched n=100 participants at risk GP2015 Etanercept (s.c.) injection administered in a dose of 50 mg twice weekly for the first 12 weeks. GP2015 Etanercept /Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug until Week 30. Three periods of 6 weeks alternating between Enbrel/GP2015/Enbrel (Treatment Period 2). Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.	Enbrel ® Etanercept Continued n=171 participants at risk Enbrel ® Etanercept (s.c.) injection administered in a dose of 50 mg twice weekly for the first 12 weeks. Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 13 until Week 30 (Treatment Period 2). Enbrel ® Etanercept 50 mg subcutaneous (s.c.) weekly injection of study drug from week 31 until Week 52 (Extension Period) in patients who had completed Treatment Period 2.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma in situ	0.61% 1/164 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of the cervix	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	1.0% 1/100 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Immune system disorders Milk allergy	0.61% 1/164 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	0.61% 1/164 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
General disorders Fatigue	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	1.0% 1/100 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Injury, poisoning and procedural complications Meniscus injury	0.61% 1/164 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Injury, poisoning and procedural complications Upper limb fracture	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.58% 1/171 • Number of events 1 • Adverse events are reported until the end of the study (week 52).
Injury, poisoning and procedural complications Lower limb fracture	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	1.0% 1/100 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Cardiac disorders Cardiopulmonary failure	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.58% 1/171 • Number of events 1 • Adverse events are reported until the end of the study (week 52).
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.61% 1/164 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	1.0% 1/100 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.58% 1/171 • Number of events 1 • Adverse events are reported until the end of the study (week 52).
Respiratory, thoracic and mediastinal disorders Pulmonary sarcoidosis	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	1.0% 1/96 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.61% 1/164 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Nervous system disorders Cerebral infarction	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	1.0% 1/96 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Nervous system disorders Multiple sclerosis	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	1.0% 1/100 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Eye disorders Retinal detachment	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	1.0% 1/96 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Gastrointestinal disorders Umbilical hernia	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	1.0% 1/100 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Gastrointestinal disorders Mesenteric vascular insufficiency	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.58% 1/171 • Number of events 1 • Adverse events are reported until the end of the study (week 52).
Hepatobiliary disorders Drug-induced liver injury	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.58% 1/171 • Number of events 1 • Adverse events are reported until the end of the study (week 52).
Hepatobiliary disorders Cholelithiasis	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	1.0% 1/100 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Renal and urinary disorders Renal failure acute	0.61% 1/164 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	1.0% 1/100 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Skin and subcutaneous tissue disorders Psoriasis	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	1.0% 1/100 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Musculoskeletal and connective tissue disorders Psoriatic arthropathy	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	1.0% 1/100 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Metabolism and nutrition disorders Acid-base balance disorder mixed	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	1.0% 1/100 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Infections and infestations Appendicitis	0.61% 1/164 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Infections and infestations Pneumonia	0.61% 1/164 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.58% 1/171 • Number of events 1 • Adverse events are reported until the end of the study (week 52).
Infections and infestations Brain abscess	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.58% 1/171 • Number of events 1 • Adverse events are reported until the end of the study (week 52).
Infections and infestations Lobar pneumonia	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.58% 1/171 • Number of events 1 • Adverse events are reported until the end of the study (week 52).
Infections and infestations Sepsis	0.61% 1/164 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Infections and infestations Diverticulitis	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	1.0% 1/96 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Infections and infestations Tonsillitis	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	1.0% 1/96 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Infections and infestations Eczema infected	0.61% 1/164 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/96 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).
Vascular disorders Thrombophlebitis	0.00% 0/164 • Adverse events are reported until the end of the study (week 52).	1.0% 1/96 • Number of events 1 • Adverse events are reported until the end of the study (week 52).	0.00% 0/100 • Adverse events are reported until the end of the study (week 52).	0.00% 0/171 • Adverse events are reported until the end of the study (week 52).