Trial Outcomes & Findings for An Observational Study on the Safety and Effectiveness of Rituximab in Patients With Severe Active Rheumatoid Arthritis (NCT NCT01071798)

Last Updated: 2016-02-22

Results Overview

The DAS28 consists of swollen joint count (SJC) and tender joint count (TJC) measurements, the erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/hr), and the Patient's Global Assessment of Disease Activity (participant-rated rheumatoid arthritis \[RA\] activity assessment) with transformed scores ranging 0 to 10; higher scores indicate greater affectation due to disease activity.

Recruitment status

COMPLETED

Target enrollment

1653 participants

Primary outcome timeframe

at baseline of each cycle and approximately 15 days, 6 weeks (only cycle 1), 12 weeks (3 months), 18 weeks (only cycle 1), and 24 weeks (6 months) after the start of the respective cycle

Results posted on

2016-02-22

Participant Flow

Data were recorded throughout Germany in 264 study centers.

Participant milestones

Participant milestones
Measure	Main Analysis Set Participants who received at least one cycle of rituximab
Participants Who Received One Cycle STARTED	1653
Participants Who Received One Cycle Baseline and Safety Analysis Set	1653
Participants Who Received One Cycle COMPLETED	1588
Participants Who Received One Cycle NOT COMPLETED	65
Subpopulation Who Received Two Cycles STARTED	820
Subpopulation Who Received Two Cycles Baseline and Safety Analysis Set	820
Subpopulation Who Received Two Cycles COMPLETED	805
Subpopulation Who Received Two Cycles NOT COMPLETED	15

Reasons for withdrawal

Reasons for withdrawal
Measure	Main Analysis Set Participants who received at least one cycle of rituximab
Participants Who Received One Cycle Lack of Efficacy	18
Participants Who Received One Cycle Lack of tolerability	14
Participants Who Received One Cycle Patient requirement	20
Participants Who Received One Cycle Death	5
Participants Who Received One Cycle Change of therapy	6
Participants Who Received One Cycle Severe concomitant disease	2
Subpopulation Who Received Two Cycles Remission	1
Subpopulation Who Received Two Cycles Lack of Efficacy	3
Subpopulation Who Received Two Cycles Lack of Tolerability	4
Subpopulation Who Received Two Cycles Patient Requirement	7

Baseline Characteristics

An Observational Study on the Safety and Effectiveness of Rituximab in Patients With Severe Active Rheumatoid Arthritis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Main Analysis Set n=1653 Participants Participants who received at least one cycle of rituximab
Age, Continuous	60.0 years n=5 Participants
Sex: Female, Male Female	1199 Participants n=5 Participants
Sex: Female, Male Male	454 Participants n=5 Participants

PRIMARY outcome

Timeframe: at baseline of each cycle and approximately 15 days, 6 weeks (only cycle 1), 12 weeks (3 months), 18 weeks (only cycle 1), and 24 weeks (6 months) after the start of the respective cycle

Outcome measures

Outcome measures
Measure	Main Analysis Set n=1653 Participants Participants who received at least one cycle of rituximab	Seronegative Participants n=150 Participants Subgroup of seronegative participants	Seropositive Participants n=1186 Participants Subgroup of seropositive participants
DAS28 Score Baseline (n=1396,150,1186)	5.3 units on a scale Standard Deviation 1.4	5.0 units on a scale Standard Deviation 1.4	5.4 units on a scale Standard Deviation 1.4
DAS28 Score 15 days (n=1133,120,957)	4.8 units on a scale Standard Deviation 1.4	4.6 units on a scale Standard Deviation 1.4	4.9 units on a scale Standard Deviation 1.4
DAS28 Score 18 weeks (n=601,57,520)	3.8 units on a scale Standard Deviation 1.3	4.1 units on a scale Standard Deviation 1.4	3.8 units on a scale Standard Deviation 1.3
DAS28 Score 24 weeks (n=641,60,553)	3.8 units on a scale Standard Deviation 1.4	4.1 units on a scale Standard Deviation 1.3	3.8 units on a scale Standard Deviation 1.4
DAS28 Score Start 2nd cycle (n=588,47,517)	4.1 units on a scale Standard Deviation 1.4	4.2 units on a scale Standard Deviation 1.5	4.1 units on a scale Standard Deviation 1.4
DAS28 Score 6 weeks (n=778,73,670)	4.4 units on a scale Standard Deviation 1.4	4.3 units on a scale Standard Deviation 1.4	4.4 units on a scale Standard Deviation 1.4
DAS28 Score 12 weeks (n=785,75,666)	4.0 units on a scale Standard Deviation 1.3	4.0 units on a scale Standard Deviation 1.3	4.0 units on a scale Standard Deviation 1.3
DAS28 Score 15 days (n=525,43,460)	3.9 units on a scale Standard Deviation 1.4	4.0 units on a scale Standard Deviation 1.5	3.8 units on a scale Standard Deviation 1.4
DAS28 Score 3 months (n=451,37,393)	3.5 units on a scale Standard Deviation 1.3	3.7 units on a scale Standard Deviation 1.5	3.5 units on a scale Standard Deviation 1.3
DAS28 Score 6 months (n=491,34,438)	3.5 units on a scale Standard Deviation 1.4	3.9 units on a scale Standard Deviation 1.6	3.5 units on a scale Standard Deviation 1.3

PRIMARY outcome

Timeframe: at baseline of each cycle and approximately 15 days, 6 weeks (only cycle 1), 12 weeks (3 months), 18 weeks (only cycle 1), and 24 weeks (6 months) after the start of the respective cycle

The HAQ-DI score consists of questions referring to 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities. For each of the categories, participants reported the amount of difficulty they had in performing 2 or 3 specific subcategory items. The standard disability score is calculated from the 8 categories by dividing the sum of the individual categories by the number of categories answered, yielding a score from 0 (without any difficulty) to 3 (unable to do).

Outcome measures

Outcome measures
Measure	Main Analysis Set n=1653 Participants Participants who received at least one cycle of rituximab	Seronegative Participants n=174 Participants Subgroup of seronegative participants	Seropositive Participants n=1326 Participants Subgroup of seropositive participants
HAQ Disability Index (HAQ-DI) Baseline (n=1579,174,1326)	1.5 units on a scale Standard Deviation 0.7	1.5 units on a scale Standard Deviation 0.7	1.5 units on a scale Standard Deviation 0.7
HAQ Disability Index (HAQ-DI) 6 weeks (n=983,0,0)	1.3 units on a scale Standard Deviation 0.7	NA units on a scale Standard Deviation NA These data were not collected	NA units on a scale Standard Deviation NA These data were not collected
HAQ Disability Index (HAQ-DI) 18 weeks (n=784,0,0)	1.2 units on a scale Standard Deviation 0.7	NA units on a scale Standard Deviation NA These data were not collected	NA units on a scale Standard Deviation NA These data were not collected
HAQ Disability Index (HAQ-DI) Start 2nd cycle (n=768,68,669)	1.2 units on a scale Standard Deviation 0.7	1.4 units on a scale Standard Deviation 0.8	1.2 units on a scale Standard Deviation 0.7
HAQ Disability Index (HAQ-DI) 3 months (n=594,59,508)	1.1 units on a scale Standard Deviation 0.7	1.3 units on a scale Standard Deviation 0.7	1.1 units on a scale Standard Deviation 0.7
HAQ Disability Index (HAQ-DI) 6 months (n=626,56,546)	1.2 units on a scale Standard Deviation 0.7	1.3 units on a scale Standard Deviation 0.8	1.1 units on a scale Standard Deviation 0.7
HAQ Disability Index (HAQ-DI) 15 days (n=1514,169,1270)	1.4 units on a scale Standard Deviation 0.7	1.4 units on a scale Standard Deviation 0.8	1.4 units on a scale Standard Deviation 0.7
HAQ Disability Index (HAQ-DI) 12 weeks (n=1015,116,848)	1.2 units on a scale Standard Deviation 0.7	1.3 units on a scale Standard Deviation 0.8	1.2 units on a scale Standard Deviation 0.7
HAQ Disability Index (HAQ-DI) 24 weeks (n=810,90,681)	1.2 units on a scale Standard Deviation 0.7	1.3 units on a scale Standard Deviation 0.8	1.2 units on a scale Standard Deviation 0.7
HAQ Disability Index (HAQ-DI) 15 days (n=706,67,610)	1.2 units on a scale Standard Deviation 0.7	1.2 units on a scale Standard Deviation 0.7	1.2 units on a scale Standard Deviation 0.7

SECONDARY outcome

Timeframe: during Cycle 1, during Cycle 2, during the trial (within 12 months)

Outcome measures

Outcome measures
Measure	Main Analysis Set n=1653 Participants Participants who received at least one cycle of rituximab	Seronegative Participants n=820 Participants Subgroup of seronegative participants	Seropositive Participants n=1653 Participants Subgroup of seropositive participants
Percentage of Participants With a Treatment-Emergent Adverse Event (TEAE) Any TEAE	28.5 percentage of participants	21.1 percentage of participants	34.8 percentage of participants
Percentage of Participants With a Treatment-Emergent Adverse Event (TEAE) Any serious TEAE	8.7 percentage of participants	5.7 percentage of participants	10.9 percentage of participants
Percentage of Participants With a Treatment-Emergent Adverse Event (TEAE) Any related TEAE	6.1 percentage of participants	6.2 percentage of participants	8.5 percentage of participants
Percentage of Participants With a Treatment-Emergent Adverse Event (TEAE) Any related serious TEAE	2.5 percentage of participants	1.3 percentage of participants	3.0 percentage of participants
Percentage of Participants With a Treatment-Emergent Adverse Event (TEAE) Any severe TEAE	5.5 percentage of participants	4.3 percentage of participants	7.0 percentage of participants
Percentage of Participants With a Treatment-Emergent Adverse Event (TEAE) Any TEAE leading to discontinuation	1.9 percentage of participants	1.3 percentage of participants	2.6 percentage of participants
Percentage of Participants With a Treatment-Emergent Adverse Event (TEAE) Any TEAE leading to death	0.5 percentage of participants	0.2 percentage of participants	0.6 percentage of participants

SECONDARY outcome

Timeframe: 24 weeks after starting Cycle 1

Population: Main Analysis Set with HAQ Score

In the Main Analysis Set participants with only one treatment cycle, the HAQ score was categorized for 12 subgroups as Clinically relevant improvement of HAQ-Score ≥0.3, Other or no clinical relevant change of HAQ Score, or Clinically relevant worsening of HAQ Score ≥0.3. Subgroups are defined as Anti-Cyclic citrullinated peptide (CCP) and Rheumatoid factor (RF) negative (-), positive (+), or Non-specified (n.sp.) and Seropositive Non-specified (n.sp.), Seronegative, or Seropositive.

Outcome measures

Outcome measures
Measure	Main Analysis Set n=253 Participants Participants who received at least one cycle of rituximab	Seronegative Participants n=366 Participants Subgroup of seronegative participants	Seropositive Participants n=76 Participants Subgroup of seropositive participants
Number of Participants Who Received Only One Treatment Cycle With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 1: Anti-CCP-/RF- (n=44)	10 participants	28 participants	6 participants
Number of Participants Who Received Only One Treatment Cycle With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 2: Anti-CCP-/RF+ (n=19)	2 participants	17 participants	0 participants
Number of Participants Who Received Only One Treatment Cycle With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 4: Anti-CCP+/RF+ (n=375)	146 participants	185 participants	44 participants
Number of Participants Who Received Only One Treatment Cycle With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 5: Anti-CCP n.sp./RF+ (n=109)	46 participants	57 participants	6 participants
Number of Participants Who Received Only One Treatment Cycle With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 8: Anti-CCP-/RF n.sp. (n=2)	0 participants	1 participants	1 participants
Number of Participants Who Received Only One Treatment Cycle With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 10: Anti-CCP and RF n.sp. (n=36)	12 participants	20 participants	4 participants
Number of Participants Who Received Only One Treatment Cycle With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 1+6+8: seronegative (n=75)	19 participants	42 participants	14 participants
Number of Participants Who Received Only One Treatment Cycle With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 3: Anti-CCP+/RF- (n=45)	14 participants	29 participants	2 participants
Number of Participants Who Received Only One Treatment Cycle With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 6: Anti-CCP n.sp./RF- (n=29)	9 participants	13 participants	7 participants
Number of Participants Who Received Only One Treatment Cycle With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 7: Anti-CCP+/RF n.sp. (n=19)	8 participants	7 participants	4 participants
Number of Participants Who Received Only One Treatment Cycle With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 9: Seropositive n.sp. (n=17)	6 participants	9 participants	2 participants
Number of Participants Who Received Only One Treatment Cycle With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 2+3+4+5+7+9: seropositive (n=584)	222 participants	304 participants	58 participants

SECONDARY outcome

Timeframe: 24 weeks after starting Cycle 2

Population: Subpopulation With Two Cycles with HAQ Score

In the Subpopulation With Two Cycles, the HAQ score was categorized for 12 subgroups as Clinically relevant improvement of HAQ-Score ≥0.3, Other or no clinical relevant change of HAQ Score, or Clinically relevant worsening of HAQ Score ≥0.3. Subgroups are defined as Anti-Cyclic citrullinated peptide (CCP) and Rheumatoid factor (RF) negative (-), positive (+), or Non-specified (n.sp.) and Seropositive Non-specified (n.sp.), Seronegative, or Seropositive.

Outcome measures

Outcome measures
Measure	Main Analysis Set n=233 Participants Participants who received at least one cycle of rituximab	Seronegative Participants n=243 Participants Subgroup of seronegative participants	Seropositive Participants n=83 Participants Subgroup of seropositive participants
Number of Participants Who Received Two Cycles With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 7: Anti-CCP+/RF n.sp. (n=14)	10 participants	3 participants	1 participants
Number of Participants Who Received Two Cycles With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 8: Anti-CCP-/RF n.sp. (n=2)	1 participants	1 participants	0 participants
Number of Participants Who Received Two Cycles With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 9: Seropositive n.sp. (n=10)	5 participants	4 participants	1 participants
Number of Participants Who Received Two Cycles With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 10: Anti-CCP and RF n.sp. (n=22)	6 participants	14 participants	2 participants
Number of Participants Who Received Two Cycles With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 1+6+8: seronegative (n=52)	11 participants	24 participants	17 participants
Number of Participants Who Received Two Cycles With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 1: Anti-CCP-/RF- (n=33)	7 participants	17 participants	9 participants
Number of Participants Who Received Two Cycles With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 2: Anti-CCP-/RF+ (n=11)	4 participants	6 participants	1 participants
Number of Participants Who Received Two Cycles With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 3: Anti-CCP+/RF- (n=36)	8 participants	18 participants	10 participants
Number of Participants Who Received Two Cycles With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 4: Anti-CCP+/RF+ (n=314)	147 participants	130 participants	37 participants
Number of Participants Who Received Two Cycles With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 5: Anti-CCP n.sp./RF+ (n=100)	42 participants	44 participants	14 participants
Number of Participants Who Received Two Cycles With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 6: Anti-CCP n.sp./RF- (n=17)	3 participants	6 participants	8 participants
Number of Participants Who Received Two Cycles With Clinically Relevant Changes in HAQ-Score at Last Visit During Therapy Compared to Baseline (Categorized) Subgroup 2+3+4+5+7+9: seropositive (n=485)	216 participants	205 participants	64 participants

Adverse Events

Cycle 1

Serious events: 144 serious events

Other events: 0 other events

Deaths: 0 deaths

Cycle 2

Serious events: 47 serious events

Other events: 0 other events

Deaths: 0 deaths

Total

Serious events: 180 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Adverse event data not reported

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 1-800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Cycle 1 n=1653 participants at risk During Cycle 1 - Main Analysis Set	Cycle 2 n=820 participants at risk During Cycle 2 - Subpopulation With Two Cycles	Total n=1653 participants at risk During the entire trial
Blood and lymphatic system disorders Anaemia	0.00% 0/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Blood and lymphatic system disorders Leukopenia	0.00% 0/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.12% 2/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Blood and lymphatic system disorders Neutropenia	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Blood and lymphatic system disorders Pancytopenia	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.12% 2/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Blood and lymphatic system disorders Splenomegaly	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Blood and lymphatic system disorders Thrombocytopenia	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Cardiac disorders Acute coronary syndrome	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Cardiac disorders Angina pectoris	0.24% 4/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.24% 4/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Cardiac disorders Atrial fibrillation	0.18% 3/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.18% 3/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Cardiac disorders Cardiac arrest	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Cardiac disorders Cardiac failure	0.24% 4/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.24% 2/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.36% 6/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Cardiac disorders Cardiomyopathy	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Cardiac disorders Cardiovascular disorder	0.00% 0/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.12% 1/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Cardiac disorders Coronary artery disease	0.18% 3/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.18% 3/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Cardiac disorders Coronary artery stenosis	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Cardiac disorders Hypertensive heart disease	0.00% 0/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Cardiac disorders Myocardial infarction	0.12% 2/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.12% 1/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.18% 3/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Cardiac disorders Myocardial ischaemia	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Cardiac disorders Sick sinus syndrome	0.00% 0/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.12% 1/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Cardiac disorders Tachyarrhythmia	0.12% 2/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.12% 2/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Cardiac disorders Tachycardia	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Eye disorders Macular degeneration	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Eye disorders Retinal vein occlusion	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Eye disorders Ulcerative keratitis	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Gastrointestinal disorders Abdominal pain	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Gastrointestinal disorders Anal haemorrhage	0.00% 0/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Gastrointestinal disorders Aphthous stomatitis	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Gastrointestinal disorders Barrett's oesophagus	0.00% 0/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Gastrointestinal disorders Colitis	0.12% 2/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.12% 2/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Gastrointestinal disorders Colitis ulcerative	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Gastrointestinal disorders Crohn's disease	0.00% 0/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Gastrointestinal disorders Diverticulum intestinal	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Gastrointestinal disorders Gastritis	0.00% 0/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.12% 1/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Gastrointestinal disorders Hiatus hernia	0.00% 0/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.12% 1/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Gastrointestinal disorders Large intestine perforation	0.00% 0/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.12% 1/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Gastrointestinal disorders Nausea	0.12% 2/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.12% 1/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.18% 3/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
Gastrointestinal disorders Vomiting	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
General disorders Asthenia	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.06% 1/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
General disorders Chest discomfort	0.12% 2/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.00% 0/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.12% 2/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only
General disorders Chest pain	0.12% 2/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.12% 1/820 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only	0.18% 3/1653 • 3 years, 6 months AEs which cannot be assigned to a Cycle due to missing/incomplete start date are counted in the Total column only