Clinical trial NCT02001987: A Study of Tocilizumab (RoActemra) in Tocilizumab-Naive Participants With Rheumatoid Arthritis and Inadequate Response to Non-Biologic Disease-Modifying Antirheumatic Drugs (DMARDs) and/or Biologic Therapy
Official title: A Multi-Center Open-Label Study to Evaluate the Efficacy, Safety and Tolerability of Subcutaneous Tocilizumab in Tocilizumab-Naive Patients With Active Rheumatoid Arthritis Who Have an Inadequate Response to Current Non-Biologic DMARD and/or Biologic Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2013-12-05
Enrollment: 139
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This two part, multi-center, open-label, single-arm study will evaluate the efficacy and safety of tocilizumab as a monotherapy or in combination with methotrexate or other conventional synthetic disease modifying antirheumatic drugs (csDMARDs) in participants with moderate to severe active rheumatoid arthritis who have an inadequate response or are intolerant to non-biologic csDMARDs and/or biologic therapy.


Eligibility criteria: Inclusion Criteria:

* Participants with a diagnosis of active rheumatoid arthritis according to the revised (1987) ACR criteria or EULAR/ACR (2010) criteria and receiving outpatient treatment
* Oral corticosteroids (\</= 10 mg/day prednisone or equivalent), nonsteroidal anti-inflammatory drugs (NSAIDs), and permitted csDMARDs are allowed at a stable dose for at least 4 weeks prior to Baseline
* At Screening either CRP \>/=10 mg/L or ESR \>/=20 mm/h and SJC \>/=3 (based on 44 joints)
* Inadequate response (IR) to tumor necrosis factor, abatacept and/or non-biological DMARDs

Exclusion Criteria:

* 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 rheumatoid arthritis; Secondary Sjögren's syndrome with rheumatoid arthritis is permitted
* Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis
* Diagnosis of juvenile idiopathic arthritis or juvenile rheumatoid arthritis and/or rheumatoid arthritis before the age of 16
* Prior history of or current inflammatory joint disease other than rheumatoid arthritis
* Exposure to tocilizumab at any time prior to Baseline
* Treatment with any investigational agent within 4 weeks (or five half-lives of the investigational drug, whichever was longer) of Screening
* Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies or any alkylating agents such as chlorambucil, or with total lymphoid irradiation
* Treatment with IV gamma globulin, plasmapheresis within 6 months of Baseline
* Intraarticular or parenteral corticosteroids within 4 weeks prior to Baseline
* Immunization with a live/attenuated vaccine within 4 weeks prior to Baseline
* History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
* Serious uncontrolled concomitant disease or other significant condition
* History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower gastrointestinal disease
* Current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections
* Any infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of Screening or oral antibiotics within 2 weeks of Screening
* Active tuberculosis requiring treatment within the previous 3 years
* Positive for hepatitis B or C
* Primary or secondary immunodeficiency disorder
* Active cancer, or cancer diagnosed within the previous 10 years (except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised or cured), 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

Primary outcomes:
measure: Change From Baseline in Disease Activity Score Based on 28-joints Count and Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 24
timeFrame: Baseline, Week 24
Secondary outcomes:
measure: Change From Baseline in DAS28-ESR at Weeks 2, 4, 8, 12, 16, 20, and 24
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, and 24
measure: Percentage of Participants With DAS28-ESR Low Disease Activity (LDA) and Remission at Week 24
timeFrame: Week 24
measure: Change From Baseline in DAS28-ESR at Week 24 and at Last Assessment
timeFrame: Baseline, Week 24, last assessment (up to Week 76)
measure: Percentage of Participants With DAS28-ESR LDA and Remission at Week 24 and at Last Assessment
timeFrame: Week 24, last assessment (up to Week 76)
measure: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20), 50% (ACR50), and 70% (ACR70) Response at Week 24
timeFrame: Baseline, Week 24
measure: Percentage of Participants Achieving ACR20, ACR50, and ACR70 Response at Week 24 and at Last Assessment
timeFrame: Baseline, Week 24, last assessment (up to Week 76)
measure: Percentage of Participants With European League Against Rheumatism (EULAR) Response Based on DAS28-ESR at Week 24
timeFrame: Baseline, Week 24
measure: Percentage of Participants With EULAR Response Based on DAS28-ESR at Week 24 and at Last Assessment
timeFrame: Baseline, Week 24, last assessment (up to Week 76)
measure: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4, 8, 12, 16, 20, and 24
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, and 24
measure: Percentage of Participants With SDAI LDA and Remission at Week 24
timeFrame: Week 24
measure: Change From Baseline in SDAI at Week 24 and at Last Assessment
timeFrame: Baseline, Week 24, last assessment (up to Week 76)
measure: Percentage of Participants With SDAI LDA and Remission at Week 24 and at Last Assessment
timeFrame: Week 24, last assessment (up to Week 76)
measure: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4, 8, 12, 16, 20, and 24
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, and 24
measure: Percentage of Participants With CDAI LDA and Remission at Week 24
timeFrame: Week 24
measure: Change From Baseline in CDAI at Week 24 and at Last Assessment
timeFrame: Baseline, Week 24, last assessment (up to Week 76)
measure: Percentage of Participants With CDAI LDA and Remission at Week 24 and at Last Assessment
timeFrame: Week 24, last assessment (up to Week 76)
measure: Change From Baseline in SJC at Weeks 2, 4, 8, 12, 16, 20, and 24
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, and 24
measure: Change From Baseline in SJC at Week 24 and at Last Assessment
timeFrame: Baseline, Week 24, last assessment (up to Week 76)
measure: Change From Baseline in TJC at Weeks 2, 4, 8, 12, 16, 20, and 24
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, and 24
measure: Change From Baseline in TJC at Week 24 and at Last Assessment
timeFrame: Baseline, Week 24, last assessment (up to Week 76)
measure: Change From Baseline in Physician's Global Assessment of Disease Activity at Weeks 2, 4, 8, 12, 16, 20, and 24
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, and 24
measure: Change From Baseline in PGA at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64
measure: Change From Baseline in Pain VAS Score at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64
measure: Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Score at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64
measure: Percentage of Participants With Health Assessment Questionnaire-Disability Index (HAQ-DI) Remission at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64
measure: Percentage of Participants With HAQ-DI Clinically Meaningful Improvement at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, and 64
measure: Treatment Compliance From Baseline up to Week 24
timeFrame: Baseline up to Week 24
measure: Change From Baseline in Rheumatoid Arthritis Impact of Disease (RAID) Score at Weeks 12, 24, 28, 40, 52, and 64
timeFrame: Baseline, Weeks 12, 24, 28, 40, 52, and 64
measure: Change From Baseline in Routine Assessment of Patient Index Data 3 (RAPID-3) at Weeks 2, 4, 12, 24, 28, 40, 52, and 64
timeFrame: Baseline, Weeks 2, 4, 12, 24, 28, 40, 52, and 64
measure: Number of Participants With Patient Acceptable Symptom State (PASS) Score
timeFrame: Baseline, Weeks 24, 52, and last assessment (up to Week 76)
measure: Change From Baseline in Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAF-MDQ) Total Score at Weeks 24 and 52
timeFrame: Baseline, Weeks 24 and 52
measure: Change From Baseline in Bristol Rheumatoid Arthritis Fatigue (BRAF)-NRS Score at Weeks 24 and 52
timeFrame: Baseline, Weeks 24 and 52
measure: Change From Baseline in Medical Outcome Study (MOS) Sleep Questionnaire Score at Weeks 12, 24, 28, 40, 52, and 64
timeFrame: Baseline, Weeks 12, 24, 28, 40, 52, and 64
measure: Change From Baseline in Fluctuations of Disease Activity in Rheumatoid Arthritis (FLARE) Questionnaire Score at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 40, 52, and 64
timeFrame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 40, 52, and 64
measure: Change From Baseline in BioSecure Questionnaire Score at Week 24
timeFrame: Baseline, Week 24
measure: Percentage of Participants With Discontinuations of Corticosteroid Dosage During Core Study Period
timeFrame: Screening up to 8 weeks after last dose in core study period (overall up to 36 weeks)
measure: Time to Permanent Discontinuation of Corticosteroid Dosage During Core Study Period
timeFrame: Screening up to 8 weeks after last dose in core study period (overall up to 36 weeks)
measure: Time to First Temporary Discontinuation of Corticosteroid Dosage During Core Study Period
timeFrame: Screening up to 8 weeks after last dose in core study period (overall up to 36 weeks)
measure: Percentage of Participants With Change in Corticosteroid Dosage During Core Study Period
timeFrame: Screening up to 8 weeks after last dose in core study period (overall up to 36 weeks)
measure: Time to Change in Corticosteroid Dosage During Core Study Period
timeFrame: Screening up to 8 weeks after last dose in core study period (overall up to 36 weeks)
measure: Number of Participants According to Reasons for Change in Corticosteroid Dosage During Core Study Period
timeFrame: Screening up to 8 weeks after last dose in core study period (overall up to 36 weeks)
measure: Percentage of Participants With Discontinuations of Corticosteroid Dosage During Study
timeFrame: Screening up to 8 weeks after last dose (overall up to 88 weeks)
measure: Time to Permanent Discontinuation of Corticosteroid Dosage During Study
timeFrame: Screening up to 8 weeks after last dose (overall up to 88 weeks)
measure: Time to First Temporary Discontinuation of Corticosteroid Dosage During Study
timeFrame: Screening up to 8 weeks after last dose (overall up to 88 weeks)
measure: Percentage of Participants With Change in Corticosteroid Dosage During Study
timeFrame: Screening up to 8 weeks after last dose (overall up to 88 weeks)
measure: Time to Change in Corticosteroid Dosage During Study
timeFrame: Screening up to 8 weeks after last dose (overall up to 88 weeks)
measure: Number of Participants According to Reasons for Change in Corticosteroid Dosage During Study
timeFrame: Screening up to 8 weeks after last dose (overall up to 88 weeks)
measure: Number of Participants According to Reasons for Changes in csDMARDs Treatment During Core Study Period
timeFrame: Screening up to 8 weeks after last dose in core study period (overall up to 36 weeks)
measure: Number of Participants According to Reasons for Changes in csDMARDs Treatment During Study
timeFrame: Screening up to 8 weeks after last dose (overall up to 88 weeks)
measure: Change From Baseline in Synovitis Ultrasound B-Mode Score at Week 24
timeFrame: Baseline, Weeks 24
measure: Change From Baseline in Synovitis Ultrasound Power-Doppler Mode Score at Week 24
timeFrame: Baseline, Weeks 24
measure: Percentage of Participants With Anti-Therapeutic Antibodies to Tocilizumab
timeFrame: Baseline up to 8 weeks after last study drug administration (up to Week 84)
Other outcomes:
Locations:
city: Amiens
country: France
city: Bordeaux
country: France
city: Brest
country: France
city: Caen
country: France
city: Cahors
country: France
city: Clermont-ferrand
country: France
city: Echirolles
country: France
city: La Source
country: France
city: Le Mans
country: France
city: Lille
country: France
city: Limoges
country: France
city: Lomme
country: France
city: Lyon cedex 3
country: France
city: Marseille
country: France
city: Marseille
country: France
city: Metz Tessy
country: France
city: Monaco
country: France
city: Montpellier
country: France
city: Mulhouse
country: France
city: Paris
country: France
city: Paris
country: France
city: Paris
country: France
city: Paris
country: France
city: Paris
country: France
city: Rennes
country: France
city: Rouen
country: France
city: St Mande
country: France
city: St Priest En Jarez
country: France
city: Strasbourg
country: France
city: Thonon Les Bains
country: France
city: Toulouse
country: France
city: Vandoeuvre-les-nancy
country: France
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.