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A Study of Tocilizumab as Monotherapy or in Combination With DMARDs in Patients With Moderate to Severe Active Rheumatoid Arthritis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01089023
Recruitment Status : Completed
First Posted : March 18, 2010
Results First Posted : July 22, 2014
Last Update Posted : July 22, 2014
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Rheumatoid Arthritis
Intervention Drug: tocilizumab [RoActemra/Actemra]
Enrollment 95
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Tocilizumab 8 Milligrams Per Kilogram (mg/kg)
Hide Arm/Group Description Participants received tocilizumab 8 mg/kg intravenous (IV) infusion, once every 4 weeks for a total of 6 infusions.
Period Title: Overall Study
Started 95
Completed 88
Not Completed 7
Reason Not Completed
Lost to Follow-up             3
Adverse Event             1
Withdrawal by Subject             1
Protocol Violation             1
Lack of Efficacy             1
Arm/Group Title Tocilizumab 8 mg/kg
Hide Arm/Group Description Participants received tocilizumab 8 mg/kg IV infusion, once every 4 weeks for a total of 6 infusions.
Overall Number of Baseline Participants 95
Hide Baseline Analysis Population Description
All the participants who were administered treatment at each visit were considered during the analysis.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 95 participants
44.89  (13.677)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 95 participants
Female
78
  82.1%
Male
17
  17.9%
1.Primary Outcome
Title Percentage of Participants Reporting Any Adverse Event - Overall Summary of Events
Hide Description Percentage of participants with a serious adverse event (SAE), who died, with an adverse event (AE), or study drug related AE during the study.
Time Frame Baseline and Weeks 2, 4, 8, 12, 16, 20, and 24
Hide Outcome Measure Data
Hide Analysis Population Description
All the participants who were administered treatment at each visit were considered during the analysis.
Arm/Group Title Tocilizumab 8 mg/kg
Hide Arm/Group Description:
Participants received tocilizumab 8 mg/kg IV infusion, once every 4 weeks for a total of 6 infusions.
Overall Number of Participants Analyzed 95
Measure Type: Number
Unit of Measure: percentage of participants
With an SAE 8.4
Who Died 0
With any drug-related AE 38.9
With any AE 45.3
2.Secondary Outcome
Title Percentage of Participants by Disease Activity Score Based on 28-Joint Count (DAS28) Category
Hide Description 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/hr]) and global health assessment (participant rated global assessment of disease activity using 10-mm Visual analog scale - VAS); DAS28 score ranged from 0 to 10, where higher scores correspond to greater disease activity. A DAS28 score of greater than (>)5.1 indicated high disease activity, a score of >3.2 but less than or equal to (≤)5.1 indicated moderate disease activity, a score of greater than or equal to (≥)2.6 but ≤3.2 indicated low disease activity, and a score of less than <2.6 indicated disease remission. Week 24 is the Follow-Up visit.
Time Frame Baseline and Weeks 4, 8, 12, 16, 20, and 24
Hide Outcome Measure Data
Hide Analysis Population Description

All the participants who were administered treatment at each visit were considered during the analysis.

n (number) at Week 24 equals (=) number of participants in that visit; n at Other Visits = number of participants with treatment administered

Arm/Group Title Tocilizumab 8 mg/kg
Hide Arm/Group Description:
Participants received tocilizumab 8 mg/kg IV infusion, once every 4 weeks for a total of 6 infusions.
Overall Number of Participants Analyzed 95
Measure Type: Number
Unit of Measure: percentage of participants
High Disease Activity, Baseline (n=95) 66.3
High Disease Activity, Week 4 (n=93) 15.1
High Disease Activity, Week 8 (n=91) 5.5
High Disease Activity, Week 12 (n=89) 2.2
High Disease Activity, Week 16 (n=89) 3.4
High Disease Activity, Week 20 (n=88) 1.1
High Disease Activity, Week 24 (n=95) 0
Moderate Disease Activity, Baseline (n=95) 33.7
Moderate Disease Activity, Week 4 (n=93) 48.4
Moderate Disease Activity, Week 8 (n=91) 36.3
Moderate Disease Activity, Week 12 (n=89) 23.6
Moderate Disease Activity, Week 16 (n=89) 11.2
Moderate Disease Activity, Week 20 (n=88) 10.2
Moderate Disease Activity, Week 24 (n=95) 7.4
Low Disease Activity, Baseline (n=95) 0.0
Low Disease Activity, Week 4 (n=93) 26.9
Low Disease Activity, Week 8 (n=91) 26.4
Low Disease Activity, Week 12 (n=89) 36.0
Low Disease Activity, Week 16 (n=89) 16.9
Low Disease Activity Week 20 (n=88) 15.9
Low Disease Activity Week 24 (n=95) 23.2
Remission Baseline (n=95) 0
Remission Week 4 (n=93) 9.7
Remission Week 8 (n=91) 31.9
Remission Week 12 (n=89) 38.2
Remission Week 16 (n=89) 67.4
Remission Week 20 (n=88) 67.4
Remission Week 24 (n=95) 64.2
3.Secondary Outcome
Title Percentage of Participants Achieving a Clinically Meaningful Improvement as Measured by DAS28
Hide Description DAS28 was calculated from the number of swollen joints and tender joints using the 28-joint count, the ESR (mm/hr) and global health assessment (participant rated global assessment of disease activity using 10-mm VAS); DAS28 score ranged from 0 to 10, where higher scores correspond to greater disease activity. Participants achieved a clinically meaningful improvement in DAS28 if there was a reduction of at least 1.2 units from baseline.
Time Frame Weeks 4, 8, 12, 16, 20, and 24
Hide Outcome Measure Data
Hide Analysis Population Description

All the participants who were administered treatment at each visit were considered during the analysis.

n at Week 24 = number of participants in that visit; n at Other Visits = number of participants with treatment administered

Arm/Group Title Tocilizumab 8 mg/kg
Hide Arm/Group Description:
Participants received tocilizumab 8 mg/kg IV infusion, once every 4 weeks for a total of 6 infusions.
Overall Number of Participants Analyzed 95
Measure Type: Number
Unit of Measure: percentage of participants
Week 4 (n=93) 82.8
Week 8 (n=91) 92.3
Week 12 (n=89) 95.5
Week 16 (n=89) 95.5
Week 20 (n=88) 94.3
Week 24 (n=95) 91.6
4.Secondary Outcome
Title Time to DAS28 Response by DAS28 Category
Hide Description Time to response is the number of days from date of first infusion to date of event. DAS28 response was defined as achievement of Low Disease Activity (DAS28 ≥2.6 to ≤3.2), Remission (DAS28 <2.6), or Clinically Meaningful Improvement (change of >1.2 from baseline).
Time Frame Weeks 4, 8, 12, 16, 20, and 24
Hide Outcome Measure Data
Hide Analysis Population Description
All the participants who were administered treatment at each visit were considered during the analysis.
Arm/Group Title Tocilizumab 8 mg/kg
Hide Arm/Group Description:
Participants received tocilizumab 8 mg/kg IV infusion, once every 4 weeks for a total of 6 infusions.
Overall Number of Participants Analyzed 95
Mean (Standard Error)
Unit of Measure: days
Clinically meaningful Improvement in DAS28 36.430  (2.355)
Low disease activity (≥2.6 to ≤3.2) 75.261  (5.587)
Remission (<2.6) 89.945  (4.395)
5.Secondary Outcome
Title Percentage of Participants With a Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) of at Least 0.22 Units
Hide Description HAQ includes 20 questions concerning participant's activities of daily life, grouped in 8 scales of 2 to 3 questions for each activity. To respond to each question, a four-level response (score of 0 to 3 points), with higher scores showing larger functional limitations, was chosen. Scoring was as follows with respect to performance of participant's everyday activities: 0=without difficulties; 1= with some difficulties; 2=with great difficulties; and 3=unable to perform these actions at all. Minimum score was 0, maximum score was 3.
Time Frame Weeks 4, 8, 12, 16, 20, and 24
Hide Outcome Measure Data
Hide Analysis Population Description

All the participants who were administered treatment at each visit were considered during the analysis.

n at Week 24 = number of participants in that visit; n at Other Visits = number of participants with treatment administered

Arm/Group Title Tocilizumab 8 mg/kg
Hide Arm/Group Description:
Participants received tocilizumab 8 mg/kg IV infusion, once every 4 weeks for a total of 6 infusions.
Overall Number of Participants Analyzed 95
Measure Type: Number
Unit of Measure: percentage of participants
Week 4 (n=93) 61.3
Week 8 (n=91) 72.5
Week 12 (n=89) 87.6
Week 16 (n=89) 93.3
Week 20 (n=88) 92.0
Week 24 (n=95) 83.2
6.Secondary Outcome
Title Percentage of Participants With Improvement in Physical Function by HAQ-DI Category
Hide Description Physical function scoring was as follows with respect to performance of participant's everyday activities: 0=without difficulties; 1= with some difficulties; 2=with great difficulties; and 3=unable to perform these actions at all. Minimum score was 0, maximum score was 3. The HAQ-DI score at every visit was categorized into none to mild disability (HAQ-DI <1), moderate disability (1≤ HAQ-DI <2) and severe disability (HAQ-DI ≥2). The percentages of the participants falling in each of these categories with respect to the visits were determined.
Time Frame Baseline, Weeks 4, 8, 12, 16, 20, and 24
Hide Outcome Measure Data
Hide Analysis Population Description

All the participants who were administered treatment at each visit were considered during the analysis.

n at Week 24 = number of participants in that visit; n at Other Visits = number of participants with treatment administered

Arm/Group Title Tocilizumab 8 mg/kg
Hide Arm/Group Description:
Participants received tocilizumab 8 mg/kg IV infusion, once every 4 weeks for a total of 6 infusions.
Overall Number of Participants Analyzed 95
Measure Type: Number
Unit of Measure: percentage of participants
HAQ-DI <1 Baseline (n=95) 13.7
HAQ-DI <1 Week 4 (n=93) 36.6
HAQ-DI <1 Week 8 (n=91) 50.5
HAQ-DI <1 Week 12 (n=89) 60.7
HAQ-DI <1 Week 16 (n=89) 73.0
HAQ-DI <1 Week 20 (n=88) 80.7
HAQ-DI <1 Week 24 (n=95) 71.6
≤1 HAQ-DI <2 Baseline (n=95) 61.1
≤1 HAQ-DI <2 Week 4 (n=93) 46.2
≤1 HAQ-DI <2 Week 8 (n=91) 39.6
≤1 HAQ-DI <2 Week 12 (n=89) 34.8
≤1 HAQ-DI <2 Week 16 (n=89) 25.8
≤1 HAQ-DI <2 Week 20 (n=88) 15.9
≤1 HAQ-DI <2 Week 24 (n=95) 15.8
HAQ-DI ≥2 Baseline (n=95) 24.2
HAQ-DI ≥2 Week 4 (n=93) 17.2
HAQ-DI ≥2 Week 8 (n=91) 9.9
HAQ-DI ≥2 Week 12 (n=89) 4.5
HAQ-DI ≥2 Week 16 (n=89) 1.1
HAQ-DI ≥2 Week 20 (n=88) 2.3
HAQ-DI ≥2 Week 24 (n=95) 3.2
7.Secondary Outcome
Title HAQ-DI Score by Visit
Hide Description HAQ includes 20 questions concerning participant's activities of daily life, grouped in 8 scales of 2 to 3 questions for each activity. To respond to each question, a four-level response (score of 0 to 3 points), with higher scores showing larger functional limitations, was chosen. Scoring was as follows with respect to performance of participant's everyday activities: 0=without difficulties; 1= with some difficulties; 2=with great difficulties; and 3=unable to perform these actions at all. Minimum score was 0, maximum score was 3..
Time Frame Baseline and Weeks 4, 8, 12, 16, 20, and 24
Hide Outcome Measure Data
Hide Analysis Population Description

All the participants who were administered treatment at each visit were considered during the analysis.

n at Week 24 = number of participants in that visit; n at Other Visits = number of participants with treatment administered

Arm/Group Title Tocilizumab 8 mg/kg
Hide Arm/Group Description:
Participants received tocilizumab 8 mg/kg IV infusion, once every 4 weeks for a total of 6 infusions.
Overall Number of Participants Analyzed 95
Mean (Standard Deviation)
Unit of Measure: scores on a scale
Baseline (n=95) 1.570  (0.6157)
Week 4 (n=93) 1.185  (0.7092)
Week 8 (n=91) 0.972  (0.6236)
Week 12 (n=89) 0.805  (0.5634)
Week 16 (n=89) 0.680  (0.4804)
Week 20 (n=88) 0.576  (0.4812)
Week 24 (n=95) 0.551  (0.5139)
8.Secondary Outcome
Title C-Reactive Protein (CRP) Values by Study Visit
Hide Description CRP is an acute phase inflammatory marker. The serum concentration of CRP is measured in milligrams per liter (mg/L). A reduction in the level is considered an improvement.
Time Frame Baseline and Weeks 4, 8, 12, 16, 20, and 24
Hide Outcome Measure Data
Hide Analysis Population Description
All the participants who were administered treatment at each visit were considered during the analysis.
Arm/Group Title Tocilizumab 8 mg/kg
Hide Arm/Group Description:
Participants received tocilizumab 8 mg/kg IV infusion, once every 4 weeks for a total of 6 infusions.
Overall Number of Participants Analyzed 95
Mean (Standard Deviation)
Unit of Measure: mg/L
Baseline 26.90  (34.406)
Week 4 8.49  (29.074)
Week 8 7.84  (23.116)
Week 12 5.32  (10.614)
Week 16 5.18  (8.105)
Week 20 5.62  (8.618)
Week 24 8.59  (21.702)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab 8 mg/kg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments p-value measures the significance between each visit using analysis of variance
Method ANOVA
Comments [Not Specified]
9.Secondary Outcome
Title Erythrocyte Sedimentation Rate
Hide Description ESR (measured in mm/hr) is an inflammation marker used to determine acute phase response.
Time Frame Baseline and Weeks 4, 8, 12, 16, 20, and 24
Hide Outcome Measure Data
Hide Analysis Population Description
All the participants who were administered treatment at each visit were considered during the analysis.
Arm/Group Title Tocilizumab 8 mg/kg
Hide Arm/Group Description:
Participants received tocilizumab 8 mg/kg IV infusion, once every 4 weeks for a total of 6 infusions.
Overall Number of Participants Analyzed 95
Mean (Standard Deviation)
Unit of Measure: mm/hr
Baseline 45.27  (29.227)
Week 4 10.61  (14.118)
Week 8 7.66  (11.554)
Week 12 7.52  (10.361)
Week 16 5.83  (6.386)
Week 20 6.60  (8.576)
Week 24 9.17  (12.311)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tocilizumab 8 mg/kg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments p-value measures the significance between each visit using analysis of variance
Method ANOVA
Comments [Not Specified]
Time Frame Adverse events data were collected from the date of first dose of study drug administration to the end of study at Week 24.
Adverse Event Reporting Description Nonserious adverse events presented in this record include all adverse events reported during the study, not just nonserious events. Note that available data included a summary of events by system organ class only, no data provided by preferred term.
 
Arm/Group Title Tocilizumab
Hide Arm/Group Description Participants received tocilizumab 8 mg/kg iv infusion, every 4 weeks for a total of 6 infusions.
All-Cause Mortality
Tocilizumab
Affected / at Risk (%)
Total   --/-- 
Hide Serious Adverse Events
Tocilizumab
Affected / at Risk (%)
Total   8/95 (8.42%) 
Infections and infestations   
Infection and infestation  1  1/95 (1.05%) 
Investigations   
Investigations  1  2/95 (2.11%) 
Metabolism and nutrition disorders   
Metabolism and nutrition disorders  1  3/95 (3.16%) 
Musculoskeletal and connective tissue disorders   
Musculoskeletal and connective tissue disorder  1  2/95 (2.11%) 
Renal and urinary disorders   
Renal and urinary disorders  1  1/95 (1.05%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Tocilizumab
Affected / at Risk (%)
Total   43/95 (45.26%) 
Blood and lymphatic system disorders   
Blood and lymphatic system disorders * 1  7/95 (7.37%) 
Cardiac disorders   
Cardiac disorders * 1  1/95 (1.05%) 
Gastrointestinal disorders   
Gastrointestinal disorders * 1  4/95 (4.21%) 
General disorders   
General disorders and administration site conditions * 1  3/95 (3.16%) 
Infections and infestations   
Infections and infestations * 1  7/95 (7.37%) 
Injury, poisoning and procedural complications   
Injury, poisoning, and procedural complications * 1  1/95 (1.05%) 
Investigations   
Investigations * 1  29/95 (30.53%) 
Metabolism and nutrition disorders   
Metabolism and nutrition disorders * 1  7/95 (7.37%) 
Musculoskeletal and connective tissue disorders   
Musculoskeletal and connective tissue disorders * 1  4/95 (4.21%) 
Nervous system disorders   
Nervous system disorders * 1  3/95 (3.16%) 
Renal and urinary disorders   
Renal and urinary disorders * 1  1/95 (1.05%) 
Respiratory, thoracic and mediastinal disorders   
Respiratory, thoracic, and mediastinal disorders * 1  3/95 (3.16%) 
Skin and subcutaneous tissue disorders   
Skin and subcutaneous tissue disorders * 1  5/95 (5.26%) 
Vascular disorders   
Vascular disorders * 1  1/95 (1.05%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA
Nonserious adverse events presented in this record include all adverse events reported during the study, not just nonserious events.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Communications
Organization: Hoffmann- LaRoche
Phone: 800-821-8590
EMail: genentech@druginfo.com
Layout table for additonal information
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01089023    
Other Study ID Numbers: ML22440
First Submitted: March 8, 2010
First Posted: March 18, 2010
Results First Submitted: June 23, 2014
Results First Posted: July 22, 2014
Last Update Posted: July 22, 2014