A Study to Assess the Effect of Tocilizumab Plus Methotrexate on Safety and Signs and Symptoms in Patients With Moderate to Severe Active Rheumatoid Arthritis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00754572
First received: September 17, 2008
Last updated: May 13, 2015
Last verified: May 2015
  Purpose

This single arm, open-label study will assess the safety and efficacy with regar d to reduction of signs and symptoms of treatment with tocilizumab in combinatio n with methotrexate, in patients with moderate to severe active rheumatoid arthr itis. Patients will receive tocilizumab 8mg/kg iv, every 4 weeks and methotrexat e 10-25mg weekly. The anticipated time on study treatment is 3-12 months, and th e target sample size is <500 individuals.


Condition Intervention Phase
Rheumatoid Arthritis
Drug: tocilizumab [RoActemra/Actemra]
Drug: methotrexate
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Single-arm, Open-label Study of the Safety and Reduction of Signs and Symptoms During Treatment With Tocilizumab in Combination With Methotrexate, in Patients With Moderate to Severe Active Rheumatoid Arthritis

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Percentage of Participants With American College of Rheumatology (ACR) 50 Response at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]

    ACR50 is defined as 50 percent (%) improvement in: a) Swollen Joints Count (SJC) and Tender Joints Count (TJC) and b) Three of the following 5 assessments:

    1. Participant's global assessment of pain by Visual Analog Scale (VAS)
    2. Participant's global assessment of disease activity (VAS)
    3. Investigator/Physician's global assessment of disease activity (VAS)
    4. Participant's assessment of disability measured by the Health Assessment Questionnaire Disability Index (HAQ-DI)
    5. Acute phase reactant levels - Erythrocyte Sedimentation Rate or C-Reactive Protein (ESR or CRP)


Secondary Outcome Measures:
  • Percentage of Participants With ACR20 and ACR70 Response at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]

    ACR20 and ACR70 are defined as 20 and 70 percent improvement respectively in: a) SJC and TJC and b) Three of the following 5 assessments:

    1. Participant's global assessment of pain by VAS
    2. Participant's global assessment of disease activity (VAS)
    3. Investigator/Physician's global assessment of disease activity (VAS)
    4. Participant's assessment of disability measured by HAQ-DI
    5. Acute phase reactant (ESR or CRP)

  • Time to Onset of ACR20, ACR50, and ACR70 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]

    ACR20, ACR50 and ACR70 are defined as 20, 50 and 70 percent improvement respectively in: a) SJC and TJC and b) Three of the following 5 assessments:

    1. Participant's global assessment of pain by VAS
    2. Participant's global assessment of disease activity (VAS)
    3. Investigator/Physician's global assessment of disease activity (VAS)
    4. Participant's assessment of disability measured by HAQ-DI
    5. Acute phase reactant (ESR or CRP)

  • Change From Baseline in Hemoglobin at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
  • SJC and TJC at Baseline and Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The number of swollen joints (66 joint count) were scored as swollen=1 and not swollen=0, and the number of tender joints (68 joint count ) were scored as tender=1 and not tender=0, and counted. Scores ranged from 0 to 66 for swollen joint counts and from 0 to 68 for tender joint counts. A positive change from baseline represents an improvement (a reduction in the number of swollen or tender joints).

  • Percent Change From Baseline in SJC and TJC at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The number of swollen joints (66 joint count) were scored as swollen=1 and not swollen=0, and the number of tender joints (68 joint count ) were scored as tender=1 and not tender=0, and counted. Scores ranged from 0 to 66 for swollen joint counts and from 0 to 68 for tender joint counts. A positive change from baseline represents an improvement (a reduction in the number of swollen or tender joints).

  • Pain as Assessed by the Participant at Baseline and Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The participants assessed their pain using a 0 to 100 millimeter (mm) VAS. The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". The participants marked the line corresponding to the level of their pain and the distance from the left edge was measured. A positive change from baseline represents an improvement.

  • Percent Change From Baseline in Pain as Assessed by the Participant at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The participants assessed their pain using a 0 to 100 millimeter (mm) VAS. The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". The participants marked the line corresponding to the level of their pain and the distance from the left edge was measured. A positive change from baseline represents an improvement.

  • Participant's Global Assessment of Disease Activity at Baseline and Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The participant's global assessment of disease activity is assessed on a 0 to 100 mm horizontal VAS by the participant. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as "maximum disease activity" (maximum arthritis disease activity). A positive change from baseline represents an improvement (reduced level of disease activity).

  • Percent Change From Baseline in Participant's Global Assessment of Disease Activity at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The participant's global assessment of disease activity is assessed on a 0 to 100 mm horizontal VAS by the participant. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as "maximum disease activity" (maximum arthritis disease activity). A positive change from baseline represents an improvement (reduced level of disease activity).

  • Physician's Global Assessment of Disease Activity at Baseline and Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The physician's global assessment of disease activity is assessed on a 0 to 100 mm VAS by the physician. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as "maximum disease activity" (maximum arthritis disease activity). The physicians marked the line corresponding to their assessment and the distance from the left edge was measured. A positive change from baseline represents an improvement (reduced level of disease activity).

  • Percent Change From Baseline in Physician's Global Assessment of Disease Activity at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    The physician's global assessment of disease activity is assessed on a 0 to 100 mm VAS by the physician. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as "maximum disease activity" (maximum arthritis disease activity). The physicians marked the line corresponding to their assessment and the distance from the left edge was measured. A positive change from baseline represents an improvement (reduced level of disease activity).

  • HAQ-DI at Baseline and Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    HAQ-DI 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. A positive change from baseline represents an improvement (reduced level of impairment).

  • Percent Change From Baseline in HAQ-DI at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    HAQ-DI 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. A positive change from baseline represents an improvement (reduced level of impairment).

  • Area Under The Curve (AUC) of the ACR(n) [ Time Frame: Baseline and Weeks 2, 4, 8, 12, 16, 20 and 24 ] [ Designated as safety issue: No ]
    ACR-n was defined as the lowest of 3 values (the percent change in the swollen joint count, the percent change in the tender joint count, and the median of the other 5 measures in the ACR core data set which included Participant's global assessment of pain (VAS), Participant's global assessment of disease activity (VAS), Investigator/Physician's global assessment of disease activity (VAS), Participant's assessment of disability measured by the HAQ-DI Acute phase reactant levels - ESR or CRP). Therefore, a percentage value was assigned to each participant at each timepoint. AUC was calculated for each participant from baseline to Week 112. Mean and standard deviation values are are provided in percent*years.

  • Percentage of Participants Achieving ACR20 Response [ Time Frame: Week 2 ] [ Designated as safety issue: No ]

    ACR20 is defined as 20% improvement in: a) SJC and TJC and b) Three of the following 5 assessments:

    1. Participant's global assessment of pain (VAS)
    2. Participant's global assessment of disease activity (VAS)
    3. Investigator/Physician's global assessment of disease activity (VAS)
    4. Participant's assessment of disability measured by the HAQ-DI
    5. Acute phase reactant levels - ESR or CRP

  • Odds Estimates for ACR Positive Response in Generalized Estimating Equation (GEE) Models [ Time Frame: Weeks 2, 4, 8, 12, 16, 20, 24 ] [ Designated as safety issue: No ]
    The probability of ACR positive response was determined using the GEE.

  • Change From Baseline in Disease Activity Score Based on 28 Joint Count (DAS28) at Week 24 [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    DAS28 calculated from the number of SJC and TJC using the 28 joints count, the ESR (mm/hour) and participant's global assessment of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 (less than or equal to ) ≤3.2 = low disease activity, DAS28 (greater than) >3.2 to 5.1 = moderate to high disease activity.

  • Percentage of Participants With a Response by Categorical DAS28 Responses According to The European League Against Rheumatism (EULAR Response) at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    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 response: change from baseline >1.2 with DAS28 < 3.2; moderate response: 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; No response: change from baseline < 0.6 or change from baseline >0.6 and <1.2 with DAS28 >5.1.

  • AUC of DAS28 [ Time Frame: Weeks 2, 4, 8, 12, 16, 20 and 24 ] [ Designated as safety issue: No ]
    The AUC was computed using the trapezoidal rule, considering baseline value as 0, through NCSS software. For each participant, AUC for DAS28 units was calculated. Each individual AUC DAS28 value was divided by 52 to have the conversion of AUC DAS28 in unit weeks to AUC DAS28 in unit years, as 1 week is approximately 1/52 years. The set of individual AUC DAS28 was computed as summary statistics.

  • Fatigue as Assessed Using the Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue) Score at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    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. 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.

  • Percentage of Participants Achieving Remission (DAS28 Less Than [<] 2.6) at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    DAS28 calculated from the SJC and TJC using the 28 joints count, the ESR (mm/hour) and participant's global assessment of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 (less than or equal to ) ≤3.2 = low disease activity, DAS28 (greater than) >3.2 to 5.1 = moderate to high disease activity and DAS28<2.6 = remission

  • Quality of Life (QoL) Assessed by Short-Form 36 (SF-36) at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    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, and mental health. Total of 3 variables were analyzed (2 composite subscales and vitality score). The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning).

  • Mean Change in Rheumatoid Factor (RF) at Week 24 in Participants With Positive RF [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]

Enrollment: 418
Study Start Date: February 2009
Study Completion Date: October 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: tocilizumab [RoActemra/Actemra]
8mg/kg iv, every 4 weeks
Drug: methotrexate
10-25mg oral or parenteral weekly.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • patients >=18 years with moderate to severe active RA for at least 6 months;
  • swollen joint count >=6 (66 joint count) and tender joint count >=8 (68 joint count) at screening;
  • inadequate response to stable dose of MTX;
  • patients of reproductive potential must be using a reliable means of contraception.

Exclusion Criteria:

  • rheumatic autoimmune disease other than RA;
  • patients with functional class IV RA;
  • diagnosis of juvenile idiopathic or rheumatoid arthritis before age 16 or a history of current inflammatory joint disease other than RA;
  • prior treatment failure with anti-tumor necrosis factor agent;
  • pregnant or breastfeeding women.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00754572

  Show 70 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

No publications provided

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00754572     History of Changes
Other Study ID Numbers: ML21530
Study First Received: September 17, 2008
Results First Received: June 23, 2014
Last Updated: May 13, 2015
Health Authority: Peru: Amador Vargas Guerra

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Signs and Symptoms
Autoimmune Diseases
Connective Tissue Diseases
Immune System Diseases
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Methotrexate
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Physiological Effects of Drugs
Reproductive Control Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 28, 2015