Trial Outcomes & Findings for Efficacy Confirmation Study of CDP870 in Early Rheumatoid Arthritis (NCT NCT01451203)

Last Updated: 2024-12-09

Results Overview

Radiographs/X-rays of hands and feet (posteroanterior views of both hands and dorsoplantar views of both feet) were independently assessed by two radiographic readers. The degree of joint damage was graded by assessing bone erosion in 44 joints and joint space narrowing (JSN) in 42 joints. The bone erosion score is a summary of erosion severity in 32 joints of the hands and 12 joints in the feet. Each joint was scored, according to the surface area involved, from 0 (no erosion) to 5 (complete collapse of bone). The score for erosion ranges from 0 to 160 in the hands and from 0 to 120 in the feet (the maximum erosion score for a joint in the foot is 10). The JSN score summarizes the severity of JSN in 30 joints of the hands and 12 joints of the feet. JSN, including subluxation, was scored from 0 (normal) to 4 (complete loss of joint space, bony ankylosis, or luxation), with a maximum JSN score of 168. The mTSS ranges from 0 (normal) to 448 (worst).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

319 participants

Primary outcome timeframe

Baseline and Week 52

Results posted on

2024-12-09

Participant Flow

Participants with early rheumatoid arthritis (RA), methotrexate (MTX)-naïve and had poor prognostic factors were recruited for this study.

Participant milestones

Participant milestones
Measure	PBO + MTX Participants who received placebo subcutaneously every two weeks (Q2W) at Weeks 0, 2, and 4; followed by placebo subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards	CZP + MTX Participants who received certolizumab pegol (CZP) subcutaneously at a loading dose of CZP 400 mg every 2 weeks (Q2W) at Weeks 0, 2, and 4; followed by a dose of CZP 200 mg subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards
Double-blind Treatment Period STARTED	158	161
Double-blind Treatment Period Received Treatment	157	159
Double-blind Treatment Period Received Rescue Treatment	70	36
Double-blind Treatment Period COMPLETED	73	111
Double-blind Treatment Period NOT COMPLETED	85	50
Post-treatment Period STARTED	71	108
Post-treatment Period Received Rescue Treatment	12	28
Post-treatment Period COMPLETED	57	74
Post-treatment Period NOT COMPLETED	14	34

Reasons for withdrawal

Reasons for withdrawal
Measure	PBO + MTX Participants who received placebo subcutaneously every two weeks (Q2W) at Weeks 0, 2, and 4; followed by placebo subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards	CZP + MTX Participants who received certolizumab pegol (CZP) subcutaneously at a loading dose of CZP 400 mg every 2 weeks (Q2W) at Weeks 0, 2, and 4; followed by a dose of CZP 200 mg subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards
Double-blind Treatment Period Did not receive treatment	1	2
Double-blind Treatment Period Consent Withdrawn	3	2
Double-blind Treatment Period Lack of Efficacy	71	36
Double-blind Treatment Period HBV-DNA positive (during the DB Period)	0	1
Double-blind Treatment Period Adverse Event	6	9
Double-blind Treatment Period Missing study medication ≥6 times	1	0
Double-blind Treatment Period Violation of eligibility criteria	1	0
Double-blind Treatment Period Investigator decision	2	0
Post-treatment Period Consent withdrawn	2	4
Post-treatment Period Lack of Efficacy	12	28
Post-treatment Period Adverse Event	0	1
Post-treatment Period Investigator decision	0	1

Baseline Characteristics

Efficacy Confirmation Study of CDP870 in Early Rheumatoid Arthritis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	PBO + MTX n=157 Participants Participants who received placebo subcutaneously every two weeks (Q2W) at Weeks 0, 2, and 4; followed by placebo subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards	CZP + MTX n=159 Participants Participants who received certolizumab pegol (CZP) subcutaneously at a loading dose of CZP 400 mg every 2 weeks (Q2W) at Weeks 0, 2, and 4; followed by a dose of CZP 200 mg subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards	Total n=316 Participants Total of all reporting groups
Age, Continuous	49.0 years STANDARD_DEVIATION 10.3 • n=5 Participants	49.4 years STANDARD_DEVIATION 10.6 • n=7 Participants	49.2 years STANDARD_DEVIATION 10.5 • n=5 Participants
Sex: Female, Male Female	127 Participants n=5 Participants	129 Participants n=7 Participants	256 Participants n=5 Participants
Sex: Female, Male Male	30 Participants n=5 Participants	30 Participants n=7 Participants	60 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Week 52

Population: FAS with available data.

Outcome measures

Outcome measures
Measure	PBO + MTX n=157 Participants Participants who received placebo subcutaneously every two weeks (Q2W) at Weeks 0, 2, and 4; followed by placebo subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards	CZP + MTX n=158 Participants Participants who received certolizumab pegol (CZP) subcutaneously at a loading dose of CZP 400 mg every 2 weeks (Q2W) at Weeks 0, 2, and 4; followed by a dose of CZP 200 mg subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards
Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52	1.58 units on a scale Standard Deviation 4.86	0.36 units on a scale Standard Deviation 2.70

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: FAS with available data.

Outcome measures

Outcome measures
Measure	PBO + MTX n=157 Participants Participants who received placebo subcutaneously every two weeks (Q2W) at Weeks 0, 2, and 4; followed by placebo subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards	CZP + MTX n=158 Participants Participants who received certolizumab pegol (CZP) subcutaneously at a loading dose of CZP 400 mg every 2 weeks (Q2W) at Weeks 0, 2, and 4; followed by a dose of CZP 200 mg subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards
Change From Baseline in mTSS at Week 24	0.86 units on a scale Standard Deviation 2.37	0.26 units on a scale Standard Deviation 1.55

SECONDARY outcome

Timeframe: Week 24 and Week 52

Population: FAS

The DAS28(ESR) measures the severity of disease at a specific time and is derived from the following variables: •28 tender joint count (TJC); •28 swollen joint count (SJC); •ESR; •Patient's global assessment of disease activity (PtGADA). To obtain the tender joint count and swollen joint count, 28 joints of the shoulder, elbow, wrist, metacarpophalangeal joints, thumb interphalangeal joints, proximal interphalangeal joints, and knee joints were examined. DAS28(ESR) scores range from 0 to approximately 10, with the upper bound dependent on the highest possible ESR. A participant was considered to be in remission if DAS28(ESR) \<2.6. Last Observation Carried Forward" (LOCF) was applied.

Outcome measures

Outcome measures
Measure	PBO + MTX n=157 Participants Participants who received placebo subcutaneously every two weeks (Q2W) at Weeks 0, 2, and 4; followed by placebo subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards	CZP + MTX n=159 Participants Participants who received certolizumab pegol (CZP) subcutaneously at a loading dose of CZP 400 mg every 2 weeks (Q2W) at Weeks 0, 2, and 4; followed by a dose of CZP 200 mg subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards
Clinical Remission Rate: Percentage of Participants Meeting the Disease Activity Score-28 Joint Count (DAS28) Erythrocyte Sedimentation Rate (ESR) (DAS28[ESR]) Remission Criteria at Weeks 24 and 52 Week 24	30.6 percentage of participants Interval 23.5 to 38.4	52.8 percentage of participants Interval 44.8 to 60.8
Clinical Remission Rate: Percentage of Participants Meeting the Disease Activity Score-28 Joint Count (DAS28) Erythrocyte Sedimentation Rate (ESR) (DAS28[ESR]) Remission Criteria at Weeks 24 and 52 Week 52	36.9 percentage of participants Interval 29.4 to 45.0	57.2 percentage of participants Interval 49.2 to 65.0

SECONDARY outcome

Timeframe: Week 24 and Week 52

Population: FAS

The ACR/EULAR SDAI remission rate measures the severity of disease at a specific time and is derived from the following variables: •28 tender joint count (TJC); •28 swollen joint count (SJC); •Patient's global assessment of disease activity (PtGADA); •Physician's Global Assessment of Disease Activity (PhGADA); •C-reactive protein (CRP) To obtain the tender joint count and swollen joint count, 28 joints of the shoulder, elbow, wrist, metacarpophalangeal joints, thumb interphalangeal joints, proximal interphalangeal joints, and knee joints were examined. A participant was considered to be in remission if SDAI ≤3.3. Last Observation Carried Forward (LOCF) was applied.

Outcome measures

Outcome measures
Measure	PBO + MTX n=157 Participants Participants who received placebo subcutaneously every two weeks (Q2W) at Weeks 0, 2, and 4; followed by placebo subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards	CZP + MTX n=159 Participants Participants who received certolizumab pegol (CZP) subcutaneously at a loading dose of CZP 400 mg every 2 weeks (Q2W) at Weeks 0, 2, and 4; followed by a dose of CZP 200 mg subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards
Clinical Remission Rate: Percentage of Participants Meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Simplified Disease Activity Index (SDAI)-Based Remission Criteria at Weeks 24 and 52 Week 24	29.3 percentage of participants Interval 22.3 to 37.1	48.4 percentage of participants Interval 40.4 to 56.5
Clinical Remission Rate: Percentage of Participants Meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Simplified Disease Activity Index (SDAI)-Based Remission Criteria at Weeks 24 and 52 Week 52	33.8 percentage of participants Interval 26.4 to 41.7	57.9 percentage of participants Interval 49.8 to 65.6

SECONDARY outcome

Timeframe: Week 24 and Week 52

Population: FAS

The ACR/EULAR Boolean-based remission rate measures the severity of disease at a specific time and is derived from the following variables: •28 tender joint count (TJC); •28 swollen joint count (SJC); •Patient's global assessment of disease activity (PtGADA); •C-reactive protein (CRP) To obtain the tender joint count and swollen joint count, 28 joints of the shoulder, elbow, wrist, metacarpophalangeal joints, thumb interphalangeal joints, proximal interphalangeal joints, and knee joints were examined. A participant was considered to be in remission if all the criteria for each variable was met:TJC (in 28 joints) ≤1; SJC (in 28 joints) ≤1; CRP ≤1 mg/dl; PtGADA ≤1. Last Observation Carried Forward (LOCF) was applied

Outcome measures

Outcome measures
Measure	PBO + MTX n=157 Participants Participants who received placebo subcutaneously every two weeks (Q2W) at Weeks 0, 2, and 4; followed by placebo subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards	CZP + MTX n=159 Participants Participants who received certolizumab pegol (CZP) subcutaneously at a loading dose of CZP 400 mg every 2 weeks (Q2W) at Weeks 0, 2, and 4; followed by a dose of CZP 200 mg subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards
Percentage of Participants Meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean-based Remission Criteria at Weeks 24 and 52 Week 24	22.3 percentage of participants Interval 16.0 to 29.6	36.5 percentage of participants Interval 29.0 to 44.5
Percentage of Participants Meeting the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean-based Remission Criteria at Weeks 24 and 52 Week 52	28.0 percentage of participants Interval 21.2 to 35.7	45.3 percentage of participants Interval 37.4 to 53.4

Adverse Events

PBO + MTX

Serious events: 18 serious events

Other events: 139 other events

Deaths: 0 deaths

CZP + MTX

Serious events: 17 serious events

Other events: 146 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Vice President, Japan/Asia Clinical Development

Astellas Pharma Inc

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data. Sponsor must receive a site's manuscript prior to publication to ensure that no confidential information of Sponsor is included in the document. Sponsor may delay the publication for to seek patent protection.
Publication restrictions are in place

Restriction type: OTHER

Measure	PBO + MTX n=157 participants at risk Participants who received placebo subcutaneously every two weeks (Q2W) at Weeks 0, 2, and 4; followed by placebo subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards	CZP + MTX n=159 participants at risk Participants who received certolizumab pegol (CZP) subcutaneously at a loading dose of CZP 400 mg every 2 weeks (Q2W) at Weeks 0, 2, and 4; followed by a dose of CZP 200 mg subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards
Cardiac disorders Coronary artery stenosis	0.00% 0/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.63% 1/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Ear and labyrinth disorders Meniere's disease	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.00% 0/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Gastrointestinal disorders Crohn's disease	0.00% 0/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.63% 1/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Gastrointestinal disorders Colitis ischaemic	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.00% 0/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Gastrointestinal disorders Enterocolitis	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.00% 0/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Hepatobiliary disorders Hepatic function abnormal	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.00% 0/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Infections and infestations Pneumocystis jiroveci pneumonia	1.3% 2/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	1.9% 3/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Infections and infestations Bronchitis	0.00% 0/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.63% 1/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Infections and infestations Meningitis fungal	0.00% 0/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.63% 1/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Infections and infestations Pneumonia bacterial	1.3% 2/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.63% 1/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Infections and infestations Pneumonia	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.00% 0/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Infections and infestations Pneumonia chlamydial	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.00% 0/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Infections and infestations Pneumonia mycoplasmal	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.00% 0/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Infections and infestations Pyelonephritis acute	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.00% 0/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Injury, poisoning and procedural complications Crush injury	0.00% 0/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.63% 1/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Injury, poisoning and procedural complications Tendon injury	0.00% 0/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.63% 1/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Injury, poisoning and procedural complications Tendon rupture	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.00% 0/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.00% 0/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.63% 1/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cervix carcinoma	0.00% 0/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	1.3% 2/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign anorectal neoplasm	0.00% 0/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.63% 1/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign lung neoplasm	0.00% 0/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.63% 1/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Glomus tumour	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.00% 0/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Nervous system disorders Migraine	0.00% 0/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.63% 1/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Nervous system disorders Altered state of consciousness	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.00% 0/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Nervous system disorders Subarachnoid haemorrhage	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.00% 0/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Psychiatric disorders Depression	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.00% 0/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Renal and urinary disorders Nephrolithiasis	0.00% 0/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.63% 1/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Renal and urinary disorders Renal artery stenosis	0.00% 0/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.63% 1/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	1.3% 2/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Respiratory, thoracic and mediastinal disorders Pulmonary fibrosis	0.00% 0/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.63% 1/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Respiratory, thoracic and mediastinal disorders Pleurisy	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	0.00% 0/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)

Measure	PBO + MTX n=157 participants at risk Participants who received placebo subcutaneously every two weeks (Q2W) at Weeks 0, 2, and 4; followed by placebo subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards	CZP + MTX n=159 participants at risk Participants who received certolizumab pegol (CZP) subcutaneously at a loading dose of CZP 400 mg every 2 weeks (Q2W) at Weeks 0, 2, and 4; followed by a dose of CZP 200 mg subcutaneously Q2W from Week 6 to Week 50 and an oral dose of MTX administered from Week 0 onwards
Blood and lymphatic system disorders Iron deficiency anaemia	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	5.7% 9/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Gastrointestinal disorders Nausea	19.1% 30/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	24.5% 39/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Gastrointestinal disorders Stomatitis	17.2% 27/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	17.0% 27/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Gastrointestinal disorders Abdominal discomfort	5.7% 9/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	10.1% 16/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Gastrointestinal disorders Dental caries	6.4% 10/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	8.8% 14/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Gastrointestinal disorders Constipation	1.9% 3/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	6.3% 10/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Gastrointestinal disorders Abdominal pain upper	1.9% 3/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	5.7% 9/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Gastrointestinal disorders Vomiting	5.7% 9/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	5.7% 9/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Gastrointestinal disorders Diarrhoea	6.4% 10/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	3.8% 6/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Gastrointestinal disorders Gastritis	6.4% 10/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	2.5% 4/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
General disorders Malaise	7.0% 11/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	8.8% 14/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Hepatobiliary disorders Hepatic function abnormal	30.6% 48/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	32.1% 51/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Hepatobiliary disorders Liver disorder	5.7% 9/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	5.7% 9/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Infections and infestations Nasopharyngitis	34.4% 54/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	44.0% 70/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Infections and infestations Pharyngitis	8.3% 13/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	15.1% 24/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Infections and infestations Gastroenteritis	6.4% 10/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	11.9% 19/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Infections and infestations Bronchitis	8.3% 13/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	7.5% 12/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Infections and infestations Upper respiratory tract infection	7.0% 11/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	6.3% 10/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Infections and infestations Oral herpes	5.1% 8/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	3.8% 6/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Investigations White blood cell count decreased	4.5% 7/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	6.3% 10/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Investigations Cell marker increased	0.64% 1/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	5.0% 8/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Musculoskeletal and connective tissue disorders Back pain	7.6% 12/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	1.9% 3/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Nervous system disorders Headache	5.1% 8/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	5.7% 9/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Respiratory, thoracic and mediastinal disorders Upper respiratory tract inflammation	9.6% 15/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	7.5% 12/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Skin and subcutaneous tissue disorders Eczema	4.5% 7/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	8.2% 13/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)
Skin and subcutaneous tissue disorders Rash	1.9% 3/157 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)	8.2% 13/159 • From the first dose of study drug up to last dose of study drug (up to 104 weeks)