A Study of the Efficacy and Safety of Tocilizumab in Adults With Rheumatoid Arthritis.

NCT01988012 | Completed Phase 3 Results

• 1 other identifier: ML28698
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 13

Brief Summary

A multi-center, open-label single-arm study to evaluate the efficacy and safety of tocilizumab administered as a single, weekly injection in adults with rheumatoid arthritis. Combination therapy with methotrexate or other non-biologic disease modifying anti-rheumatic drugs (DMARDs) was permitted.

Conditions

Rheumatoid Arthritis

Outcome Measures

Primary Outcomes (14)

• Percentage of Participants With Clinical Disease Activity Index (CDAI) Remission and CDAI Low Disease Activity

  Clinical Disease Activity Index (CDAI) is an index for measuring disease activity in rheumatoid arthritis (RA). The index was calculated using the following formula: CDAI = number of swollen joints using the 28-joint count (SJC28) + number of tender joints using the 28-joint count (TJC28) + patient global assessment of disease (PGA) based on 10 centimeter \[cm\] Visual Analog Scale \[VAS\] + physician global assessment of disease (PhGA) based on 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 0 (no disease activity) to 10 (maximum disease activity). Total CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. Remission is defined as CDAI ≤2.8 and Low Disease Activity (LDA) is defined as 2.8\< CDAI ≤10.

  Week 24

• Change From Baseline in CDAI

  Clinical Disease Activity Index (CDAI) is an index for measuring disease activity in rheumatoid arthritis (RA). The index was calculated using the following formula: CDAI = number of swollen joints using the 28-joint count (SJC28) + number of tender joints using the 28-joint count (TJC28) + patient global assessment of disease (PGA) based on 10 centimeter \[cm\] Visual Analog Scale \[VAS\] + physician global assessment of disease (PhGA) based on 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 0 (no disease activity) to 10 (maximum disease activity). Total CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. A negative change from baseline indicates an improvement.

  Baseline, Week 24

• Percentage of Participants With Simplified Disease Activity Index (SDAI) Remission and SDAI Low Disease Activity

  Simplified Disease Activity Index (SDAI) was an index for measuring disease activity in RA and had a good correlation with the DAS28. The index was calculated using the following formula: SDAI: SJC28 + TJC28 + PGA (10 cm VAS) + PhGA (10 cm VAS + C-Reactive Protein (CRP) in milligram/liter (mg/L). VAS assessments involved a 10 cm horizontal scale from 0 (no disease activity) to 10 (maximum disease activity). Scores ranged from 0 to 86, with higher scores also indicating increased disease activity. An SDAI score of ≤ 3.3 represents clinical remission, a score of ≤ 11.0 represents low disease activity.

  Week 24

• Change From Baseline in SDAI

  Simplified Disease Activity Index (SDAI) was an index for measuring disease activity in RA and had a good correlation with the DAS28. The index was calculated using the following formula: SDAI: SJC28 + TJC28 + PGA (10 cm VAS) + PhGA (10 cm VAS + C-Reactive Protein (CRP) in mg/L. VAS assessments involved a 10 cm horizontal scale from 0 (no disease activity) to 10 (maximum disease activity). Scores ranged from 0 to 86, with higher scores also indicating increased disease activity. A negative change from baseline indicates an improvement.

  Baseline, Week 24

• Change From Baseline in Disease Activity Score 28-Erythrocyte-Sedimentation Rate (DAS28-ESR)

  The DAS28-ESR score is a measure of the patient's disease activity calculated using the tender joint count on 28 joints (TJC28), swollen joint count on 28 joints (SJC28), patient's global assessment (PGA) of disease activity based on visual analog scale (VAS) and the erythrocyte sedimentation rate (ESR) in millimeter/hour (mm/hr). VAS assessments involved a 10 cm horizontal scale from 0 (no disease activity) to 10 (maximum disease activity). Total possible score ranged from 0 to 10. Higher scores represent higher disease activity. A negative change from baseline indicates an improvement.

  Baseline, Week 24

• Percentage of Participants Achieving 20%, 50% and 70% Improvement in American College of Rheumatology (ACR) Response Scores (ACR20, ACR50 and ACR70)

  An ACR20 response requires at least 20% improvement compared to baseline in SJC (based on 66 joints) and TJC (based on 68 joints) as well as at least 20% improvement in 3 of the following 5 assessments: 1) PGA pain VAS, 2) PGA VAS; 3) physician's global assessment of disease activity VAS, 4) Health Assessment Questionnaire-Disability Index (HAQ-DI) with 20 questions consisting of 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do; and 5) CRP in mg/L or ESR in mm/hr. ACR50 and ACR70 responses are defined in a similar way except that they required a 50% and 70% improvement from baseline, respectively. VAS assessments involved a 10 cm horizontal scale from 0 (no disease activity) to 10 (maximum disease activity).

  Week 24

• Percentage of Participants With Good to Moderate European League Against Rheumatism (EULAR) Response

  Response was determined using EULAR criteria based upon DAS28 absolute scores at the assessment visit and the DAS28 reduction from the reference visit. Participants with a score lesser than or equal to (\</=) 3.2 and reduction of greater than (\>) 1.2 points were assessed as having a 'good' response. Participants with a score \>3.2 with reduction of \>1.2 points, or a score \<=5.1 with reduction of \>0.6 to \<=1.2 points, were assessed as having a 'moderate' response. Participants with a score \>5.1 with reduction of \>0.6 to \<=1.2 points, or any score with reduction \<=0.6 points, were assessed as non-responders with response recorded as 'none.'

  Week 24

• Change From Baseline in TJC and SJC

  The number of tender joints (based on 68 joints) and swollen joints (based on 66 joints) were counted at each visit. TJC was determined by identifying the joints that were painful under pressure or to passive motion; no tenderness =0, tenderness =1. SJC was determined by identifying swelling; no swelling =0, swelling =1. A negative change from baseline indicates an improvement.

  Baseline, Week 24

• Change From Baseline in Percentage of Participants on Tocilizumab Monotherapy

  Participants were either on tocilizumab monotherapy or tocilizumab plus non-biologic disease modifying anti-rheumatic drugs (DMARDs). Reported here is the percentage of participants on tocilizumab monotherapy at baseline and the change from baseline at Week 24. A positive change from baseline at Week 24 indicates the percentage of participants, who discontinued DMARDs during the study.

  Baseline, Week 24

• Change From Baseline in Patient Global Assessment of Disease Activity Visual Analog Scale (PGA VAS)

  PGA VAS represents the participant's overall assessment of their current disease activity on a 100 millimeter (mm) horizontal VAS scale from 0 (no disease activity) to 100 (maximum disease activity). A negative change from baseline indicates an improvement.

  Baseline, Week 24

• Change From Baseline in Patient Pain VAS

  Patient Pain VAS represents the participant's assessment of his/her current level of pain on a 100 mm horizontal VAS scale from 0 (no disease activity) to 100 (maximum disease activity). A negative change from baseline indicates an improvement.

  Baseline, Week 24

• Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI)

  The HAQ-DI evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities and 20 questions. Each category contains multiple questions, which were answered using a 4-point scale from 0 (without any difficulty) to 3 (unable to do). The overall index score was an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. A negative change from baseline indicates an improvement.

  Baseline, Week 24

• Change From Baseline in Patient Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F)

  The symptom-specific measure FACIT-F assesses chronic illness therapy with special emphasis on fatigue in the past 7 days and consists of 5 dimensions: 1) physical well- being, 2) social/family well-being, 3) emotional well-being, 4) functional well-being, and 5) additional concerns. Each of the questions is categorically answered using the scales 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very much for a total possible FACIT-F score of 0 to 52. The figures are reversed during score calculations, so that higher score values indicate more favorable conditions. A positive change from baseline indicates an improvement.

  Baseline, Week 24

• Total Scores on Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Scale (HAS)

  The HDRS is a clinician-administered depression assessment and consists of 17 items with a total score range from 0 to 54. A higher score indicates a worse outcome. HAS is a clinician-administered assessment to measure the severity of anxiety symptoms and consists of 14 items with a total score range from 0 to 56. A higher score indicates a worse outcome.

  Baseline, Week 24

Secondary Outcomes (5)

• Percentage of Participants With Adverse Events (AEs) and AEs of Special Interest (AESIs)

  Up to Follow-up Week 32

• Percentage of Participants Who Required Dose Modifications or Discontinued Study Due to AEs

  Up to Week 24

• Immunogenicity: Percentage of Participants With Anti-tocilizumab Antibodies

  Baseline, Week 24, Follow-up Week 32 and Early Withdrawal

• Immunogenicity: Tocilizumab Levels

  Week 12, Week 24, Follow-up Week 32 and Early Withdrawal

• Immunogenicity: Change From Week 1 in Soluble Interleukin-6 Receptor (sIL-6R) Levels

  Week 1, Week 12, Week 24, Follow-up Week 32 and Early Withdrawal

Study Arms (1)

Tocilizumab

EXPERIMENTAL

Adults with rheumatoid arthritis will be treated with tocilizumab for 24 weeks followed by an 8 week follow-up period without treatment.

Biological: tocilizumab

Interventions

tocilizumab BIOLOGICAL

162 milligram (mg) administered subcutaneously once weekly for 24 weeks

Also known as: RoActemra/Actemra

Tocilizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults \>/= 18 years of age
• Diagnosis of active rheumatoid arthritis (RA) according to the revised (1987) American College of Rheumatology (ACR) criteria or European League Against Rheumatism (EULAR)/ACR (2010) criteria
• Previously treated with the following: three non-biologic DMARDs, and not treated with any biologic agent OR one biologic agent (alone or in combination with non-biologic DMARDs), and discontinued that agent for a reason
• Oral corticosteroids (\</= 10 mg/day prednisone or equivalent), non-steroidal anti-inflammatory drug (NSAIDs) and non-biologic DMARDs are permitted if on a stable dose regimen for \>/= 4 weeks prior to Baseline
• Use of effective contraception throughout the study as defined by protocol; female patients of childbearing potential must not be pregnant

You may not qualify if:

• Presence of serious, uncontrolled, clinically significant medical conditions
• History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower gastrointestinal (GI) disease that might predispose to perforation
• Current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections
• Any infection requiring hospitalization or treatment with intravenous (IV) antibiotics within 4 weeks of Screening or oral antibiotics within 2 weeks of Screening
• Clinically significant findings on lab tests and/or hepatitis B or C, or human immunodeficiency virus (HIV) screenings
• Active tuberculosis (TB) requiring treatments within the previous 3 years
• Evidence of active malignant disease, malignancies diagnosed within the previous 10 years, or breast cancer diagnosed within the previous 20 years
• History of alcohol, drug, or chemical abuse within 1 year prior to Screening
• Neuropathies or other conditions that might interfere with pain evaluation
• Major surgery (including joint surgery) within 8 weeks prior to Screening or planned major surgery within 6 months following Baseline
• Rheumatic autoimmune disease other than RA, including systemic lupus erythematosus, mixed connective tissue disorder, scleroderma, polymyositis, or significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis or Felty's syndrome). Secondary Sjögren's syndrome with RA is permitted
• Functional Class IV as defined by the ACR Classification of Functional Status in-Rheumatoid Arthritis
• Diagnosis of juvenile idiopathic arthritis or juvenile RA, and/or RA before the age of 16
• Prior history of current inflammatory joint disease other than RA
• Exposure to tocilizumab (either IV or subcutaneous administration) at any time prior to Baseline

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (13)

Unknown Facility

Beer Yaacov, 6093000, Israel

Location

Unknown Facility

Beersheba, 8410101, Israel

Location

Unknown Facility

Haifa, 3109601, Israel

Location

Unknown Facility

Haifa, 3339419, Israel

Location

Unknown Facility

Haifa, 34362, Israel

Location

Unknown Facility

Jerusalem, 9112001, Israel

Location

Unknown Facility

Jerusalem, 91240, Israel

Location

Unknown Facility

Kfar Saba, 44281, Israel

Location

Unknown Facility

Petah Tikva, 4937211, Israel

Location

Unknown Facility

Petah Tikva, 4941492, Israel

Location

Unknown Facility

Ramat Gan, 5262000, Israel

Location

Unknown Facility

Ramat Gan, 5262100, Israel

Location

Unknown Facility

Tel Aviv, 6423906, Israel

Location

Related Publications (2)

• Choy E, Caporali R, Xavier R, Fautrel B, Sanmarti R, Bao M, Devenport J, Petho-Schramm A. Effects of concomitant glucocorticoids in TOZURA, a common-framework study programme of subcutaneous tocilizumab in rheumatoid arthritis. Rheumatology (Oxford). 2019 Jun 1;58(6):1056-1064. doi: 10.1093/rheumatology/key393.

  PMID: 30649524 DERIVED

• Choy E, Caporali R, Xavier R, Fautrel B, Sanmarti R, Bao M, Bernasconi C, Petho-Schramm A. Subcutaneous tocilizumab in rheumatoid arthritis: findings from the common-framework phase 4 study programme TOZURA conducted in 22 countries. Rheumatology (Oxford). 2018 Mar 1;57(3):499-507. doi: 10.1093/rheumatology/kex443.

  PMID: 29244149 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

tocilizumab

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 31, 2013
• First Posted: November 20, 2013
• Study Start: January 1, 2014
• Primary Completion: July 1, 2015
• Study Completion: July 1, 2015
• Last Updated: March 6, 2017
• Results First Posted: March 6, 2017

Record last verified: 2017-01

Locations

IL (13)