A Study to Assess Efficacy With Respect to Clinical Improvement in Disease Activity and Safety of Tocilizumab in Patients Wtih Active Rheumatoid Arthritis.

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00754559
• Collaborator: (none)
• Enrollment: 286
• Locations: 81
• Arm: 1
• Duration (Months): 15
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This single arm study will assess the effectiveness of tocilizumab in combination with traditional DMARDs with regard to the clinical improvement in disease activity (achievement of LDAS) after 24 weeks' treatment in patients with active rheumatoid arthritis (RA) who have had an inadequate response to current traditional DMARD and/or anti-TNF therapy. Patients will receive tocilizumab 8mg/kg iv every 4 weeks, in addition to ongoing DMARDs at the stable pre-entry dose prescribed by the physician, for a total of 6 infusions during the regular treatment period and a further 6 infusions during an optional extension phase. The anticipated time on study treatment is 6 to 12 months, and the target sample size is <500 individuals.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Tocilizumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 286 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: "Effectiveness After Four and Twentyfour Weeks and Safety of Tocilizumab in Patients With Active RA"
• Study Start Date: Aug 1, 2008
• Actual Primary Completion Date: Nov 1, 2009
• Actual Study Completion Date: Nov 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tocilizumab	Drug: Tocilizumab; 8mg/kg iv every 4 weeks

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Low Disease Activity Score at Week 24 [Week 24]

   Low Disease Activity Score (LDAS) is defined as Disease Activity score less than or equal to (≤ ) 3.2. Disease activity score 28 (DAS28) was calculated from the number of swollen joints and tender joints using the 28-joint count, the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]) and global health assessment (participant rated global assessment of disease activity using 100-mm Visual analog scale [VAS]); DAS28 score ranged from 0 to 10, where higher scores correspond to greater disease activity.

Secondary Outcome Measures

1. Absolute Changes in DAS28 From Baseline [Weeks 1, 2, 4, 8, 12, 16, 20 and 24]

   DAS28 calculated from the number of swollen joints and tender joints using the 28-joint count, the ESR (mm/hour) and global health assessment (participant rated global assessment of disease activity using 100-mm VAS); DAS28 score ranged from 0 to 10, where higher scores correspond to greater disease activity. DAS28 ≤3.2 = low disease activity, DAS28 greater than (>)3.2 to 5.1 = moderate to high disease activity.

2. Percentage of Participants With a Response at Week 24 by European League Against Rheumatism (EULAR) Category [Week 24]

   The DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline >1.2 with DAS28 ≤3.2; moderate responders: change from baseline >1.2 with DAS28 >3.2 to ≤5.1 or change from baseline >0.6 to ≤1.2 with DAS28 ≤5.1; non-responders: change from baseline ≤ 0.6 or change from baseline >0.6 and ≤1.2 with DAS28 >5.1.

3. Percentage of Participants With a DAS28 Response at Weeks 4 and 24 [Weeks 4 and 24]

   DAS28 calculated from the number of swollen joints and painful joints using the 28-joint count, the ESR and participant's global assessment (PGA) of disease activity (participant rated arthritis activity assessment using VAS) with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity. DAS28 ≤3.2 = low disease activity, DAS28 <2.6 = remission and a clinically significant (CS) reduction was defined as ≥1.2.

4. Percentage of Participants With an American College of Rheumatology 20%, 50%, or 70% (ACR20/ACR50/ACR70) Response [Weeks 1, 2, 4, 8, 12, 16, 20 and 24]

   ACR20/50/70 response: ≥20%, 50%, or 70% improvement, respectively, in swollen and tender joint count; and ≥20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ-DI]); and C-Reactive Protein (CRP).

5. Change From Baseline in Swollen and Tender Joint Counts at Week 24 [Week 24]

   Swollen joint count: 66 joints were assessed for swelling and joints were classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66. Tender joint counts: 68 joints were assessed for tenderness and joints were classified as tender/not tender giving a total possible tender joint count score of 0 to 68.

6. Change From Baseline in the Levels of C-Reactive Protein at Week 24 [Week 24]

   The serum concentration of CRP is measured in mg/L. A reduction in the level was considered an improvement.

7. Change From Baseline in Participant's Global Assessment of Pain (VAS) at Week 24 [Week 24]

   Participant's global assessment of pain was assessed using a 100-mm horizontal VAS (0 to 100 mm) with 0=pain absent and 100=unbearable pain. Participants responded by placing a mark on the line to indicate their current level of pain.

8. Change From Baseline in Participant and Physician Assessment of Global Disease Activity (VAS) at Week 24 [Week 24]

   Participant's global assessment of disease activity was an overall assessment of their current disease activity on a 100-mm horizontal VAS scale (left-hand extreme: "no disease activity"; right-hand extreme: "maximum disease activity"). Physician's global assessment of disease activity was measured as participant's current disease activity on a 100-mm horizontal VAS scale (left hand extreme: "no disease activity"; right-hand extreme: "maximum disease activity").

9. Change From Baseline in Clinical Disease Activity Index (CDAI) Score [Weeks 1, 2, 4, 8, 12, 16, 20 and 24]

   CDAI was calculated according to the following formula: CDAI = Number of swollen joints (plus) + Number of tender joints + VAS disease activity participant assessment + VAS disease activity investigator assessment. The maximum score was 334 (66 joints + 68 joints + 100 mm + 100 mm); higher scores indicated higher disease activity.

10. Change From Baseline in HAQ-DI at Week 24 [Week 24]

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

11. Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 24 [Week 24]

    FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the participant's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). A higher score reflects an improvement in the participant's health status.

12. Change From Baseline in Short Form-36 (SF-36) Score at Week 24 [Week 24]

    SF-36 is a standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). Absolute change was defined as the change from baseline to Week 24.

13. Participant's Global Assessment of Pain as Assessed by Patient Take Home Form (PTHF) [Baseline and Weeks 1, 2, and 4]

    Participant's were asked to state the worst level of pain felt in the past 24 hours using a 100-mm horizontal VAS (0 to 100 mm) with 0=no pain and 100=unbearable pain. Participants responded by placing a mark on the line to indicate their level of pain. Participants were asked to document their response during the first 4 treatment weeks at approximately the same time every day.

14. Duration of Morning Stiffness as Assessed Using PTHF [Baseline, Weeks 1, 2, and 4]

    Duration of morning stiffness: participants were asked 'how long did your morning stiffness last from the time you woke up yesterday' and the response was provided in minutes and hours. Participants were asked to document their response during the first 4 treatment weeks at approximately the same time every day.

15. Participant Assessment of Fatigue/Tiredness as Assessed Using PTHF [Baseline and Weeks 1, 2 and 4]

    Participants were asked to assess their overall level of fatigue/tiredness during the previous 24 hours using a 100-mm horizontal VAS with 0=none and 100=very severe. Participants responded by placing a mark on the line to indicate their current level of fatigue. Participants were asked to document their response during the first 4 treatment weeks at approximately the same time every day.

16. Treatment Satisfaction Questionnaire for Medication (TSQM) Score [Week 24]

    The TSQM is a general measure of participants treatment satisfaction and consists of 14 questions that result in 4 subscales: "effectiveness", "side-effects", "convenience" and "global satisfaction". All subscale scores range from 0 to 100%, with 100% being the best possible result.

17. Changes in Hemoglobin [Baseline, Weeks 1, 2, 4 and 24]

    Hemoglobin levels were determined as a hematology parameter to measure changes in disease related anemia.

18. Changes in C-Reactive Protein [Baseline, Weeks 1, 2 ,4 and 24]

    CRP is an acute phase inflammatory marker used as a measure of inflammation. A reduction in CRP is considered to be an improvement.

19. Changes in Erythrocyte Sedimentation Rate (ESR) [Baseline, Weeks 1, 2, 4 and 24]

    ESR is an inflammation marker used to determine acute phase response.

20. Percentage of Participants Withdrawing From Study Treatment Because of Insufficient Therapeutic Response [Weeks 1, 2, 4, 8, 12, 16, 20 and 24]

    Participants who withdrew from study drug due to other reasons were not taken into account.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• adult patients, >=18 years of age;

• rheumatoid arthritis of >=6 months duration diagnosed according to the revised 1987 ACR criteria;

• DAS28 of >3.2;

• At screening either ESR >=28 mm/h or CRP >=1 mg/dL;

• Having received permitted DMARDs, 1 or more; current DMARD therapy must have been at a stable dose for at least 8 weeks prior to baseline.

Exclusion Criteria:

• major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following screening;

• functional class IV as identified by the ACR classification of functional status in RA;

• rheumatoid autoimmune disease other than RA;

• prior history of or current inflammatory joint disease other than RA.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Aachen		Germany	52064
2		Bad Abbach		Germany	93077
3		Bad Aibling		Germany	83043
4		Bad Bramstedt		Germany	24576
5		Bad Nauheim		Germany	61231
6		Baden-baden		Germany	76530
7		Bayreuth		Germany	95445
8		Berlin		Germany	10117
9		Berlin		Germany	12161
10		Berlin		Germany	12435
11		Berlin		Germany	13055
12		Berlin		Germany	13125
13		Berlin		Germany	14109
14		Berlin		Germany	14163
15		Bremen		Germany	28199
16		Cuxhaven		Germany	27476
17		Damp		Germany	24351
18		Donaueschingen		Germany	78166
19		Dresden		Germany	01067
20		Dresden		Germany	01109
21		Dresden		Germany	01307
22		Düsseldorf		Germany	40217
23		Düsseldorf		Germany	40225
24		Erfurt		Germany	99096
25		Erlangen		Germany	91054
26		Erlangen		Germany	91056
27		Essen		Germany	45239
28		Frankfurt Am Main		Germany	60590
29		Frankfurt		Germany	60596
30		Fulda		Germany	36039
31		Gommern		Germany	39245
32		Goslar		Germany	38642
33		Grafschaft		Germany	53501
34		Göttingen		Germany	37075
35		Hagen		Germany	58135
36		Halle		Germany	06108
37		Halle		Germany	06120
38		Hamburg		Germany	22081
39		Hamburg		Germany	22147
40		Hamburg		Germany	22609
41		Hamburg		Germany	22767
42		Hannover		Germany	30625
43		Heidelberg		Germany	69120
44		Herne		Germany	44652
45		Hildesheim		Germany	31134
46		Hofheim		Germany	65719
47		Homburg/saar		Germany	66424
48		Hoyerswerda		Germany	02977
49		Köln		Germany	50679
50		Köln		Germany	50924
51		Leipzig		Germany	04103
52		Ludwigsfelde		Germany	14974
53		Ludwigshafen		Germany	67063
54		Lüneburg		Germany	21335
55		Mainz		Germany	55122
56		Mainz		Germany	55131
57		Marburg		Germany	35037
58		Muenchen		Germany	80336
59		München		Germany	80335
60		München		Germany	81541
61		München		Germany	81925
62		Münster		Germany	48149
63		Naunhof		Germany	04683
64		Neuss		Germany	41460
65		Nürnberg		Germany	90402
66		Oberammergau		Germany	82487
67		Osnabrück		Germany	49074
68		Pirna		Germany	01796
69		Plochingen		Germany	73207
70		Potsdam		Germany	14469
71		Ratingen		Germany	40882
72		Rostock		Germany	18059
73		Sendenhorst		Germany	48324
74		Stuttgart		Germany	70178
75		Stuttgart		Germany	70372
76		Treuenbrietzen		Germany	14929
77		Tübingen		Germany	72076
78		ULM		Germany	89081
79		Wiesbaden		Germany	65189
80		Würselen		Germany	52146
81		Zeven		Germany	27404

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT00754559
• Other Study ID Numbers: ML21469; 2008-000105-11
• First Posted: Sep 18, 2008
• Last Update Posted: Feb 8, 2016
• Last Verified: Jan 1, 2016

• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid

Study Results

Participant Flow

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 milligrams/kilogram (mg/kg) intravenously (iv) every 4 weeks for a total of 6 infusions.
Period Title: Overall Study
STARTED	286
COMPLETED	239
NOT COMPLETED	47

Baseline Characteristics

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks for a total of 6 infusions.
Overall Participants	286
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.9 (12.2)
Sex: Female, Male (Count of Participants)
Female	216 75.5%
Male	70 24.5%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Low Disease Activity Score at Week 24
Description	Low Disease Activity Score (LDAS) is defined as Disease Activity score less than or equal to (≤ ) 3.2. Disease activity score 28 (DAS28) was calculated from the number of swollen joints and tender joints using the 28-joint count, the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]) and global health assessment (participant rated global assessment of disease activity using 100-mm Visual analog scale [VAS]); DAS28 score ranged from 0 to 10, where higher scores correspond to greater disease activity.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks for a total of 6 infusions.
Measure Participants	286
Number (95% Confidence Interval) [Percentage of Participants]	57 19.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tocilizumab
	Comments	Null hypothesis: Proportion of participants reaching LDAS (≤ 3.2) at Week 24 equals (=) expected proportion of 42%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Exact Binomial Test
	Comments

2. Secondary Outcome

Title	Absolute Changes in DAS28 From Baseline
Description	DAS28 calculated from the number of swollen joints and tender joints using the 28-joint count, the ESR (mm/hour) and global health assessment (participant rated global assessment of disease activity using 100-mm VAS); DAS28 score ranged from 0 to 10, where higher scores correspond to greater disease activity. DAS28 ≤3.2 = low disease activity, DAS28 greater than (>)3.2 to 5.1 = moderate to high disease activity.
Time Frame	Weeks 1, 2, 4, 8, 12, 16, 20 and 24

Outcome Measure Data

Analysis Population Description

ITT Population; only participants with a DAS28 value at baseline were included in the analysis.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks for a total of 6 infusions.
Measure Participants	274
Week 1	-1.31 (1.1)
Week 2	-2.1 (1.2)
Week 4	-2.4 (1.2)
Week 8	-2.8 (1.3)
Week 12	-3.2 (1.4)
Week 16	-3.2 (1.4)
Week 20	-3.3 (1.4)
Week 24	-3.4 (1.4)

3. Secondary Outcome

Title	Percentage of Participants With a Response at Week 24 by European League Against Rheumatism (EULAR) Category
Description	The DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline >1.2 with DAS28 ≤3.2; moderate responders: change from baseline >1.2 with DAS28 >3.2 to ≤5.1 or change from baseline >0.6 to ≤1.2 with DAS28 ≤5.1; non-responders: change from baseline ≤ 0.6 or change from baseline >0.6 and ≤1.2 with DAS28 >5.1.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks for a total of 6 infusions.
Measure Participants	286
Good	54.9 19.2%
Moderate	20.3 7.1%
None	24.8 8.7%

4. Secondary Outcome

Title	Percentage of Participants With a DAS28 Response at Weeks 4 and 24
Description	DAS28 calculated from the number of swollen joints and painful joints using the 28-joint count, the ESR and participant's global assessment (PGA) of disease activity (participant rated arthritis activity assessment using VAS) with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity. DAS28 ≤3.2 = low disease activity, DAS28 <2.6 = remission and a clinically significant (CS) reduction was defined as ≥1.2.
Time Frame	Weeks 4 and 24

Outcome Measure Data

Analysis Population Description

ITT Population;

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks for a total of 6 infusions.
Measure Participants	286
Week 4, CS reduction	75.2 26.3%
Week 4, Remission	23.1 8.1%
Week 4, CS reduction or remission	76.6 26.8%
Week 4, LDAS	40.9 14.3%
Week 24, CS reduction	74.5 26%
Week 24, Remission	47.6 16.6%
Week 24, CS reduction or remission	76.6 26.8%
Week 24, LDAS	57.0 19.9%

5. Secondary Outcome

Title	Percentage of Participants With an American College of Rheumatology 20%, 50%, or 70% (ACR20/ACR50/ACR70) Response
Description	ACR20/50/70 response: ≥20%, 50%, or 70% improvement, respectively, in swollen and tender joint count; and ≥20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ-DI]); and C-Reactive Protein (CRP).
Time Frame	Weeks 1, 2, 4, 8, 12, 16, 20 and 24

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks for a total of 6 infusions.
Measure Participants	286
Week 1 ACR20	25.2 8.8%
Week 1 ACR50	7.0 2.4%
Week 1 ACR70	2.4 0.8%
Week 2 ACR20	41.3 14.4%
Week 2 ACR50	14.7 5.1%
Week 2 ACR70	4.9 1.7%
Week 4 ACR20	50.0 17.5%
Week 4 ACR50	25.5 8.9%
Week 4 ACR70	12.2 4.3%
Week 8 ACR20	64.3 22.5%
Week 8 ACR50	37.4 13.1%
Week 8 ACR70	17.1 6%
Week 12 ACR20	69.6 24.3%
Week 12 ACR50	48.6 17%
Week 12 ACR70	26.2 9.2%
Week 16 ACR20	67.5 23.6%
Week 16 ACR50	49.0 17.1%
Week 16 ACR70	29.4 10.3%
Week 20 ACR20	67.8 23.7%
Week 20 ACR50	49.7 17.4%
Week 20 ACR70	33.9 11.9%
Week 24 ACR20	65.0 22.7%
Week 24 ACR50	50.7 17.7%
Week 24 ACR70	33.9 11.9%

6. Secondary Outcome

Title	Change From Baseline in Swollen and Tender Joint Counts at Week 24
Description	Swollen joint count: 66 joints were assessed for swelling and joints were classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66. Tender joint counts: 68 joints were assessed for tenderness and joints were classified as tender/not tender giving a total possible tender joint count score of 0 to 68.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

ITT Population; missing data were imputed using last observation carried forward (LOCF).

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks up to week 20 for a total of 6 infusions.
Measure Participants	286
Number of swollen joints	-9.6
Number of tender joints	-13.4

7. Secondary Outcome

Title	Change From Baseline in the Levels of C-Reactive Protein at Week 24
Description	The serum concentration of CRP is measured in mg/L. A reduction in the level was considered an improvement.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

ITT Population; missing data were imputed using LOCF.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks up to week 20 for a total of 6 infusions.
Measure Participants	286
Mean (95% Confidence Interval) [mg/L]	-20.1

8. Secondary Outcome

Title	Change From Baseline in Participant's Global Assessment of Pain (VAS) at Week 24
Description	Participant's global assessment of pain was assessed using a 100-mm horizontal VAS (0 to 100 mm) with 0=pain absent and 100=unbearable pain. Participants responded by placing a mark on the line to indicate their current level of pain.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

ITT Population; missing data were imputed using LOCF.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks up to week 20 for a total of 6 infusions.
Measure Participants	286
Mean (95% Confidence Interval) [mm]	-36.2

9. Secondary Outcome

Title	Change From Baseline in Participant and Physician Assessment of Global Disease Activity (VAS) at Week 24
Description	Participant's global assessment of disease activity was an overall assessment of their current disease activity on a 100-mm horizontal VAS scale (left-hand extreme: "no disease activity"; right-hand extreme: "maximum disease activity"). Physician's global assessment of disease activity was measured as participant's current disease activity on a 100-mm horizontal VAS scale (left hand extreme: "no disease activity"; right-hand extreme: "maximum disease activity").
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

ITT Population; missing data were imputed using LOCF.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks up to week 20 for a total of 6 infusions.
Measure Participants	286
Participant's assessment	-35.9
Physician's assessment	-44.9

10. Secondary Outcome

Title	Change From Baseline in Clinical Disease Activity Index (CDAI) Score
Description	CDAI was calculated according to the following formula: CDAI = Number of swollen joints (plus) + Number of tender joints + VAS disease activity participant assessment + VAS disease activity investigator assessment. The maximum score was 334 (66 joints + 68 joints + 100 mm + 100 mm); higher scores indicated higher disease activity.
Time Frame	Weeks 1, 2, 4, 8, 12, 16, 20 and 24

Outcome Measure Data

Analysis Population Description

ITT population; only participants with values for CDAI at baseline and the respective visit were included in the analysis.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks for a total of 6 infusions.
Measure Participants	286
Week 1	-8.4 (12.1)
Week 2	-13.3 (12.4)
Week 4	-15.6 (13.4)
Week 8	-19.7 (13.2)
Week 12	-22.4 (13.4)
Week 16	-22.4 (13.8)
Week 20	-22.7 (13.3)
Week 24	-24.2 (12.9)

11. Secondary Outcome

Title	Change From Baseline in HAQ-DI at Week 24
Description	HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

ITT Population; Missing data were imputed using LOCF.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks up to week 20 for a total of 6 infusions.
Measure Participants	286
Mean (Standard Deviation) [units on a scale]	-0.48 (0.60)

12. Secondary Outcome

Title	Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 24
Description	FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the participant's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). A higher score reflects an improvement in the participant's health status.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

ITT Population; Missing data were imputed using LOCF.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks up to week 20 for a total of 6 infusions.
Measure Participants	286
Mean (Standard Deviation) [units on a scale]	8.6 (11.1)

13. Secondary Outcome

Title	Change From Baseline in Short Form-36 (SF-36) Score at Week 24
Description	SF-36 is a standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). Absolute change was defined as the change from baseline to Week 24.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

ITT Population; Missing data were imputed using LOCF.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8mg/kg iv every 4 weeks up to week 20 for a total of 6 infusions.
Measure Participants	286
Physical functioning	18.4 (24.6)
Role physical	16.5 (21.6)
Bodily pain	25.0 (22.3)
General health perception	11.9 (18.7)
Vitality	18.0 (20.2)
Social functioning	13.8 (27.2)
Role emotional	13.9 (50.1)
Mental health	10.3 (19.1)

14. Secondary Outcome

Title	Participant's Global Assessment of Pain as Assessed by Patient Take Home Form (PTHF)
Description	Participant's were asked to state the worst level of pain felt in the past 24 hours using a 100-mm horizontal VAS (0 to 100 mm) with 0=no pain and 100=unbearable pain. Participants responded by placing a mark on the line to indicate their level of pain. Participants were asked to document their response during the first 4 treatment weeks at approximately the same time every day.
Time Frame	Baseline and Weeks 1, 2, and 4

Outcome Measure Data

Analysis Population Description

ITT Population; Missing data were imputed using LOCF.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks for a total of 6 infusions.
Measure Participants	286
Baseline	60.7 (23.1)
Week 1	48.6 (25.2)
Week 2	41.9 (25.4)
Week 4	36.3 (26.7)
Change at Week 1	-12.0 (22.3)
Change at Week 2	-18.7 (24.9)
Change at Week 4	-24.4 (27.4)

15. Secondary Outcome

Title	Duration of Morning Stiffness as Assessed Using PTHF
Description	Duration of morning stiffness: participants were asked 'how long did your morning stiffness last from the time you woke up yesterday' and the response was provided in minutes and hours. Participants were asked to document their response during the first 4 treatment weeks at approximately the same time every day.
Time Frame	Baseline, Weeks 1, 2, and 4

Outcome Measure Data

Analysis Population Description

ITT Population; Missing data were imputed using LOCF.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks for a total of 6 infusions.
Measure Participants	286
Baseline	2.4 (2.8)
Week 1	1.8 (2.3)
Week 2	1.5 (1.8)
Week 4	1.2 (1.5)
Change at Week 1	-0.6 (1.8)
Change at Week 2	-0.9 (2.1)
Change at Week 4	-1.2 (2.3)

16. Secondary Outcome

Title	Participant Assessment of Fatigue/Tiredness as Assessed Using PTHF
Description	Participants were asked to assess their overall level of fatigue/tiredness during the previous 24 hours using a 100-mm horizontal VAS with 0=none and 100=very severe. Participants responded by placing a mark on the line to indicate their current level of fatigue. Participants were asked to document their response during the first 4 treatment weeks at approximately the same time every day.
Time Frame	Baseline and Weeks 1, 2 and 4

Outcome Measure Data

Analysis Population Description

ITT Population; Missing data were imputed using LOCF.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks for a total of 6 infusions.
Measure Participants	286
Baseline	52.9 (26.9)
Week 1	42.2 (26.2)
Week 2	36.3 (26.5)
Week 4	30.6 (26.0)
Change at Week 1	-10.6 (22.0)
Change at Week 2	-16.6 (24.1)
Change at Week 4	-22.2 (26.5)

17. Secondary Outcome

Title	Treatment Satisfaction Questionnaire for Medication (TSQM) Score
Description	The TSQM is a general measure of participants treatment satisfaction and consists of 14 questions that result in 4 subscales: "effectiveness", "side-effects", "convenience" and "global satisfaction". All subscale scores range from 0 to 100%, with 100% being the best possible result.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks for a total of 6 infusions.
Measure Participants	286
Percent Effectiveness	69.4 (28.3)
Percent Side-effects	88.7 (21.7)
Percent Convenience	72.4 (20.8)
Percent Global satisfaction	74.7 (25.9)

18. Secondary Outcome

Title	Changes in Hemoglobin
Description	Hemoglobin levels were determined as a hematology parameter to measure changes in disease related anemia.
Time Frame	Baseline, Weeks 1, 2, 4 and 24

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks up to week 20 for a total of 6 infusions.
Measure Participants	286
Baseline	128.6 (13.1)
Week 1	132.2 (13.4)
Week 2	133.5 (13.1)
Week 4	133.5 (13.6)
Week 24	136.1 (13.7)
Change at Week 1	3.5 (6.8)
Change at Week 2	4.8 (6.5)
Change at Week 4	4.3 (8.0)
Change at Week 24	7.5 (9.7)

19. Secondary Outcome

Title	Changes in C-Reactive Protein
Description	CRP is an acute phase inflammatory marker used as a measure of inflammation. A reduction in CRP is considered to be an improvement.
Time Frame	Baseline, Weeks 1, 2 ,4 and 24

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks for a total of 6 infusions.
Measure Participants	286
Baseline	23.1 (30.7)
Week 1	3.5 (6.6)
Week 2	2.4 (4.4)
Week 4	5.5 (14.8)
Week 24	3.0 (7.7)
Change at Week 1	-19.6 (29.4)
Change at Week 2	-20.7 (29.8)
Change at Week 4	-17.5 (27.7)
Change at Week 24	-20.1 (29.9)

20. Secondary Outcome

Title	Changes in Erythrocyte Sedimentation Rate (ESR)
Description	ESR is an inflammation marker used to determine acute phase response.
Time Frame	Baseline, Weeks 1, 2, 4 and 24

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks for a total of 6 infusions.
Measure Participants	286
Baseline	37.4 (22.1)
Week 1	16.7 (14.2)
Week 2	10.6 (11.0)
Week 4	10.3 (13.5)
Week 24	7.1 (9.5)
Change at Week 1	-20.6 (17.9)
Change at Week 2	-26.7 (19.0)
Change at Week 4	-27.2 (18.6)
Change at Week 24	-30.3 (21.7)

21. Secondary Outcome

Title	Percentage of Participants Withdrawing From Study Treatment Because of Insufficient Therapeutic Response
Description	Participants who withdrew from study drug due to other reasons were not taken into account.
Time Frame	Weeks 1, 2, 4, 8, 12, 16, 20 and 24

Outcome Measure Data

Analysis Population Description

ITT Population; participants who withdrew from study drug due to other reaasons were not included in the analysis.

Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8mg /kg iv every 4 weeks for a total of 6 infusions.
Measure Participants	249
Number (95% Confidence Interval) [percentage of participants]	4.0 1.4%

Adverse Events

Time Frame	Adverse events were reported throughout the study including any reactions that occurred within 24 hours after infusion.
Adverse Event Reporting Description	An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Arm/Group Title	Tocilizumab
Arm/Group Description	Participants received tocilizumab 8 mg/kg iv every 4 weeks for a total of 6 infusions.
All Cause Mortality
	Tocilizumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Tocilizumab
	Affected / at Risk (%)	# Events
Total	32/286 (11.2%)
Ear and labyrinth disorders
Vertigo	1/286 (0.3%)
Endocrine disorders
Hypothyroidism	1/286 (0.3%)
Gastrointestinal disorders
Periodontitis	1/286 (0.3%)
Vomiting	1/286 (0.3%)
General disorders
General physical health deterioration	1/286 (0.3%)
Chest pain	1/286 (0.3%)
Infections and infestations
Pneumonia	2/286 (0.7%)
Abscess jaw	1/286 (0.3%)
Bronchopneumonia	1/286 (0.3%)
Herpes zoster	1/286 (0.3%)
Osteomyelitis	1/286 (0.3%)
Pharyngeal abscess	1/286 (0.3%)
Postoperative wound infection	1/286 (0.3%)
Septic shock	1/286 (0.3%)
Injury, poisoning and procedural complications
Lower limb fracture	1/286 (0.3%)
Overdose	8/286 (2.8%)
Investigations
Low density lipoprotein increased	1/286 (0.3%)
Alanine aminotransferase increased	1/286 (0.3%)
Aspartate aminotransferase increased	1/286 (0.3%)
Musculoskeletal and connective tissue disorders
Bursitis	1/286 (0.3%)
Tendonitis	1/286 (0.3%)
Back pain	1/286 (0.3%)
Rheumatoid arthritis	1/286 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Non-Hodgkin's lymphoma	1/286 (0.3%)
Bladder transitional cell carcinoma	1/286 (0.3%)
Nervous system disorders
Multiple sclerosis relapse	1/286 (0.3%)
Headache	1/286 (0.3%)
Pregnancy, puerperium and perinatal conditions
Abortion	1/286 (0.3%)
Psychiatric disorders
Post-traumatic stress disorder	1/286 (0.3%)
Renal and urinary disorders
Renal failure acute	1/286 (0.3%)
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease	1/286 (0.3%)
Other (Not Including Serious) Adverse Events
	Tocilizumab
	Affected / at Risk (%)	# Events
Total	242/286 (84.6%)
Blood and lymphatic system disorders
Eosinophilia	1/286 (0.3%)
Haemolysis	2/286 (0.7%)
Intravascular haemolysis	2/286 (0.7%)
Leukopenia	19/286 (6.6%)
Neutropenia	5/286 (1.7%)
Thrombocytopenia	5/286 (1.7%)
Cardiac disorders
Extrasystoles	1/286 (0.3%)
Palpitations	2/286 (0.7%)
Tachyarrhythmia	1/286 (0.3%)
Ear and labyrinth disorders
Ear pain	1/286 (0.3%)
Tinnitus	2/286 (0.7%)
Vertigo	4/286 (1.4%)
Endocrine disorders
Cushingoid	1/286 (0.3%)
Goitre	2/286 (0.7%)
Hypothyroidism	1/286 (0.3%)
Eye disorders
Conjunctival haemorrhage	2/286 (0.7%)
Conjunctivitis	6/286 (2.1%)
Dry eye	1/286 (0.3%)
Eye inflammation	1/286 (0.3%)
Eyelid oedema	1/286 (0.3%)
Visual acuity reduced	1/286 (0.3%)
Gastrointestinal disorders
Abdominal discomfort	1/286 (0.3%)
Abdominal distension	1/286 (0.3%)
Abdominal pain	2/286 (0.7%)
Abdominal pain upper	4/286 (1.4%)
Aphthous stomatitis	3/286 (1%)
Constipation	2/286 (0.7%)
Dental caries	2/286 (0.7%)
Diarrhoea	16/286 (5.6%)
Diarrhoea haemorrhagic	1/286 (0.3%)
Dry mouth	1/286 (0.3%)
Dyspepsia	4/286 (1.4%)
Enteritis	2/286 (0.7%)
Eructation	1/286 (0.3%)
Flatulence	1/286 (0.3%)
Gastric ulcer	1/286 (0.3%)
Gastritis	2/286 (0.7%)
Gastrooesophageal reflux disease	1/286 (0.3%)
Gingival bleeding	1/286 (0.3%)
Gingival erythema	1/286 (0.3%)
Loose tooth	1/286 (0.3%)
Nausea	9/286 (3.1%)
Periodontitis	5/286 (1.7%)
Stomatitis	3/286 (1%)
Toothache	1/286 (0.3%)
Vomiting	5/286 (1.7%)
General disorders
Chest pain	2/286 (0.7%)
Chills	2/286 (0.7%)
Discomfort	3/286 (1%)
Drug intolerance	3/286 (1%)
Fatigue	13/286 (4.5%)
General physical health deterioration	1/286 (0.3%)
Local swelling	1/286 (0.3%)
Malaise	1/286 (0.3%)
Mucosal inflammation	1/286 (0.3%)
Oedema	1/286 (0.3%)
Oedema peripheral	6/286 (2.1%)
Pitting oedema	1/286 (0.3%)
Thirst	1/286 (0.3%)
Hepatobiliary disorders
Hepatotoxicity	1/286 (0.3%)
Immune system disorders
Food allergy	1/286 (0.3%)
Hypersensitivity	5/286 (1.7%)
Seasonal allergy	2/286 (0.7%)
Infections and infestations
Abscess jaw	1/286 (0.3%)
Abscess limb	1/286 (0.3%)
Acute tonsillitis	1/286 (0.3%)
Anal abscess	1/286 (0.3%)
Bacterial disease carrier	1/286 (0.3%)
Bacteriuria	1/286 (0.3%)
Bronchitis	16/286 (5.6%)
Bronchopneumonia	2/286 (0.7%)
Cellulitis	1/286 (0.3%)
Cystitis	5/286 (1.7%)
Eyelid infection	1/286 (0.3%)
Folliculitis	3/286 (1%)
Fungal skin infection	1/286 (0.3%)
Furuncle	1/286 (0.3%)
Gastroenteritis	5/286 (1.7%)
Gastrointestinal infection	1/286 (0.3%)
Herpes simplex	1/286 (0.3%)
Herpes virus infection	1/286 (0.3%)
Herpes zoster	2/286 (0.7%)
Herpes zoster ophthalmic	1/286 (0.3%)
Influenza	3/286 (1%)
Lower respiratory tract infection viral	1/286 (0.3%)
Nasopharyngitis	54/286 (18.9%)
Onychomycosis	2/286 (0.7%)
Oral herpes	6/286 (2.1%)
Osteomyelitis	1/286 (0.3%)
Otitis media	3/286 (1%)
Paronychia	1/286 (0.3%)
Parotitis	1/286 (0.3%)
Peritonsillar abscess	1/286 (0.3%)
Pharyngeal abscess	1/286 (0.3%)
Pharyngitis	4/286 (1.4%)
Pneumonia	2/286 (0.7%)
Post procedural infection	1/286 (0.3%)
Postoperative wound infection	1/286 (0.3%)
Prostate infection	1/286 (0.3%)
Pulpitis dental	2/286 (0.7%)
Respiratory tract infection	4/286 (1.4%)
Rhinitis	15/286 (5.2%)
Septic shock	1/286 (0.3%)
Sinobronchitis	1/286 (0.3%)
Sinusitis	8/286 (2.8%)
Skin bacterial infection	1/286 (0.3%)
Tinea pedis	1/286 (0.3%)
Tinea versicolour	1/286 (0.3%)
Tonsillitis	1/286 (0.3%)
Tooth abscess	2/286 (0.7%)
Tooth infection	1/286 (0.3%)
Tracheobronchitis	2/286 (0.7%)
Upper respiratory tract infection	9/286 (3.1%)
Upper respiratory tract infection bacterial	1/286 (0.3%)
Urethritis	1/286 (0.3%)
Urinary tract infection	15/286 (5.2%)
Urinary tract infection bacterial	1/286 (0.3%)
Vaginal infection	1/286 (0.3%)
Viral infection	4/286 (1.4%)
Vulvitis	1/286 (0.3%)
Vulvovaginal mycotic infection	3/286 (1%)
Injury, poisoning and procedural complications
Contusion	2/286 (0.7%)
Excoriation	1/286 (0.3%)
Fall	1/286 (0.3%)
Foot fracture	2/286 (0.7%)
Humerus fracture	1/286 (0.3%)
Joint sprain	2/286 (0.7%)
Lower limb fracture	1/286 (0.3%)
Meniscus lesion	1/286 (0.3%)
Nail injury	1/286 (0.3%)
Overdose	8/286 (2.8%)
Radius fracture	1/286 (0.3%)
Skeletal injury	1/286 (0.3%)
Tendon rupture	1/286 (0.3%)
Wound	1/286 (0.3%)
Wrist fracture	1/286 (0.3%)
Investigations
Alanine aminotransferase increased	24/286 (8.4%)
Aspartate aminotransferase increased	14/286 (4.9%)
Basophil count increased	1/286 (0.3%)
Blood bilirubin increased	4/286 (1.4%)
Blood cholesterol increased	5/286 (1.7%)
Blood creatinine increased	1/286 (0.3%)
Blood lactate dehydrogenase increased	2/286 (0.7%)
Blood triglycerides increased	2/286 (0.7%)
Blood uric acid increased	2/286 (0.7%)
Body temperature increased	2/286 (0.7%)
Haematocrit increased	1/286 (0.3%)
Haemoglobin increased	1/286 (0.3%)
Hepatic enzyme increased	2/286 (0.7%)
Low density lipoprotein increased	79/286 (27.6%)
Lymphocyte count increased	1/286 (0.3%)
Neutrophil count decreased	4/286 (1.4%)
Transaminases increased	2/286 (0.7%)
Weight decreased	1/286 (0.3%)
Weight increased	7/286 (2.4%)
Metabolism and nutrition disorders
Anorexia	1/286 (0.3%)
Hypercholesterolaemia	5/286 (1.7%)
Hyperglycaemia	1/286 (0.3%)
Hyperlipidaemia	6/286 (2.1%)
Hyperureicaemia	1/286 (0.3%)
Hypokalaemia	1/286 (0.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	8/286 (2.8%)
Arthritis	1/286 (0.3%)
Back pain	9/286 (3.1%)
Bursitis	2/286 (0.7%)
Facit joint syndrome	1/286 (0.3%)
Groin pain	1/286 (0.3%)
Haemarthrosis	1/286 (0.3%)
Intervertebral disc protrusion	1/286 (0.3%)
Jaw cyst	1/286 (0.3%)
Joint range of motion decreased	1/286 (0.3%)
Ligament disorder	1/286 (0.3%)
Muscle spasms	1/286 (0.3%)
Muscle tightness	2/286 (0.7%)
Musculoskeletal chest pain	1/286 (0.3%)
Musculoskeletal pain	2/286 (0.7%)
Myalgia	2/286 (0.7%)
Osteoarthritis	1/286 (0.3%)
Osteoporosis	1/286 (0.3%)
Pain in extremity	2/286 (0.7%)
Rheumatoid arthritis	25/286 (8.7%)
Sacroiliitis	1/286 (0.3%)
Synovial cyst	1/286 (0.3%)
Tendonitis	1/286 (0.3%)
Tenosynovitis	2/286 (0.7%)
Tenosynovitis stenosans	1/286 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign bone neoplasm	1/286 (0.3%)
Bladder transitional cell carcinoma	1/286 (0.3%)
Non-Hodgkin's lymphoma	1/286 (0.3%)
Uterine leiomyoma	1/286 (0.3%)
Nervous system disorders
Aphasia	1/286 (0.3%)
Carpal tunnel syndrome	1/286 (0.3%)
Cervicobrachial syndrome	1/286 (0.3%)
Dizziness	3/286 (1%)
Dysaesthesia	1/286 (0.3%)
Dysgeusia	1/286 (0.3%)
Facial neuralgia	1/286 (0.3%)
Headache	27/286 (9.4%)
Migraine	4/286 (1.4%)
Multiple sclerosis relapse	1/286 (0.3%)
Paraesthesia	1/286 (0.3%)
Restless legs syndrome	2/286 (0.7%)
Sciatica	3/286 (1%)
Somnolence	1/286 (0.3%)
Synope	1/286 (0.3%)
Tremor	1/286 (0.3%)
Pregnancy, puerperium and perinatal conditions
Abortion	1/286 (0.3%)
Psychiatric disorders
Depression	2/286 (0.7%)
Food aversion	1/286 (0.3%)
Insomnia	2/286 (0.7%)
Mood altered	1/286 (0.3%)
Post-traumatic stress disorder	1/286 (0.3%)
Sleep disorder	3/286 (1%)
Renal and urinary disorders
Haematuria	3/286 (1%)
Leukocyturia	2/286 (0.7%)
Nocturia	1/286 (0.3%)
Renal failure acute	1/286 (0.3%)
Urethral stenosis	1/286 (0.3%)
Reproductive system and breast disorders
Breast disorder	1/286 (0.3%)
Breast pain	1/286 (0.3%)
Genital cyst	1/286 (0.3%)
Menopausal symptoms	2/286 (0.7%)
Vulvovaginal dryness	1/286 (0.3%)
Respiratory, thoracic and mediastinal disorders
Allergic cough	1/286 (0.3%)
Asthma	2/286 (0.7%)
Cough	9/286 (3.1%)
Dysphonia	2/286 (0.7%)
Dyspnoea	3/286 (1%)
Dyspnoea exertional	1/286 (0.3%)
Epistaxis	3/286 (1%)
Interstitial lung disease	1/286 (0.3%)
Nasal dryness	1/286 (0.3%)
Nasal mucosal disorder	1/286 (0.3%)
Oropharyngeal blistering	1/286 (0.3%)
Oropharyngeal pain	3/286 (1%)
Pleurisy	2/286 (0.7%)
Rales	1/286 (0.3%)
Rhinitis allergic	2/286 (0.7%)
Rhinorrhoea	1/286 (0.3%)
Skin and subcutaneous tissue disorders
Acne	2/286 (0.7%)
Alopecia	5/286 (1.7%)
Blister	1/286 (0.3%)
Dermatitis allergic	1/286 (0.3%)
Drug eruption	1/286 (0.3%)
Dry skin	1/286 (0.3%)
Eczema	8/286 (2.8%)
Erythema	1/286 (0.3%)
Hyperhidrosis	3/286 (1%)
Pruritus	7/286 (2.4%)
Pruritus generalised	1/286 (0.3%)
Psoriasis	2/286 (0.7%)
Rash	3/286 (1%)
Rash macular	1/286 (0.3%)
Rash pruritic	1/286 (0.3%)
Skin chapped	1/286 (0.3%)
Skin exfoliation	1/286 (0.3%)
Skin fissures	1/286 (0.3%)
Skin irritation	2/286 (0.7%)
Skin reaction	1/286 (0.3%)
Skin ulcer	1/286 (0.3%)
Urticaria	2/286 (0.7%)
Vascular disorders
Haematoma	2/286 (0.7%)
Hypertension	16/286 (5.6%)
Lymphoedema	1/286 (0.3%)
Thrombosis	1/286 (0.3%)

Limitations/Caveats

Nonserious adverse events presented in this record include all adverse events reported during the study, not just nonserious events.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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 after the first publication or presentation that involves the overall study. Sponsor may request that confidential information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights