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NCT01007435

A Study of Tocilizumab as Monotherapy and in Combination With Methotrexate Versus Methotrexate in Patients With Early Moderate to Severe Rheumatoid Arthritis

Completed Phase 3 Results posted Last updated 26 July 2017
What this trial tests

Phase 3 trial testing Tocilizumab in Rheumatoid Arthritis in 1,162 participants. Completed in 28 January 2014.

Timeline
31 October 2009
Primary endpoint
31 May 2012
28 January 2014

Quick facts

Lead sponsorHoffmann-La Roche
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingdouble
Primary purposetreatment
Enrollment1,162
Start date31 October 2009
Primary completion31 May 2012
Estimated completion28 January 2014
Sites236 locations across Hong Kong, Colombia, Finland, Italy, Panama, Ireland, Poland, Philippines

Drugs / interventions tested

Conditions studied

Sponsor

Hoffmann-La Roche — full company profile →

Who can join

18 and older, any sex, with Rheumatoid Arthritis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants With a Disease Activity Score 28 (DAS28) Remission Response at Week 24 Primary · Week 24

A participant has a DAS28 remission response if their DAS28 \< 2.6. The DAS28 is a combined index for measuring disease activity in rheumatic arthritis (RA) and includes swollen and tender joint counts, erythrocyte sedimentation rate (ESR), and general health (GH) status. The index is calculated with the following formula: DAS28 = (0.56 × √(TJC28)) + (0.28 × √(SJC28)) + (0.7 × log(ESR)) + (0.014 × GH), where TJC28 = tender joint count and SJC28 = swollen joint count, each on 28 joints. GH = a patient's global assessment of disease activity in the previous 24 hours on a 100 mm visual analog sca

GroupValue95% CI
Placebo to Tocilizumab + Methotrexate15.010.9 – 19.1
Tocilizumab 4 mg/kg + Methotrexate31.926.6 – 37.3
Tocilizumab 8 mg/kg + Methotrexate44.839.1 – 50.6
Tocilizumab 8 mg/kg + Placebo to Methotrexate38.733.1 – 44.3
Percentage of Participants With a Disease Activity Score 28 (DAS28) Remission Response at Week 52 Secondary · Week 52
GroupValue95% CI
Placebo to Tocilizumab + Methotrexate19.5
Tocilizumab 4 mg/kg + Methotrexate34.0
Tocilizumab 8 mg/kg + Methotrexate49.0
Tocilizumab 8 mg/kg + Placebo to Methotrexate39.4
Percentage of Patients With an Improvement ≥ 20%, 50%, or 70% in American College of Rheumatology (ACR) Score (ACR20/50/70) From Baseline to Weeks 24 and 52 Secondary · Baseline to Weeks 24 and 52

Improvement must be seen in tender (68) and swollen (66) joint counts. Joints were assessed and classified as swollen/not swollen and tender/not tender by pressure and joint manipulation. Improvement must also be seen in at least 3 of the following 5 parameters: Separate patient and physician assessments of patient disease activity in the previous 24 hours on a visual analog scale (VAS, the extreme left end of the line "no disease activity" \[symptom-free and no arthritis symptoms\] and the extreme right end "maximum disease activity"; patient assessment of pain in previous the 24 hours on a V

Week 24: ACR 20
GroupValue95% CI
Placebo to Tocilizumab + Methotrexate65.2
Tocilizumab 4 mg/kg + Methotrexate73.6
Tocilizumab 8 mg/kg + Methotrexate74.5
Tocilizumab 8 mg/kg + Placebo to Methotrexate70.2
Week 24: ACR 50
GroupValue95% CI
Placebo to Tocilizumab + Methotrexate43.2
Tocilizumab 4 mg/kg + Methotrexate47.9
Tocilizumab 8 mg/kg + Methotrexate56.9
Tocilizumab 8 mg/kg + Placebo to Methotrexate47.6
Week 24: ACR 70
GroupValue95% CI
Placebo to Tocilizumab + Methotrexate25.4
Tocilizumab 4 mg/kg + Methotrexate34.7
Tocilizumab 8 mg/kg + Methotrexate38.6
Tocilizumab 8 mg/kg + Placebo to Methotrexate30.1
Week 52: ACR 20
GroupValue95% CI
Placebo to Tocilizumab + Methotrexate57.1
Tocilizumab 4 mg/kg + Methotrexate62.8
Tocilizumab 8 mg/kg + Methotrexate67.2
Tocilizumab 8 mg/kg + Placebo to Methotrexate63.0
Week 52: ACR 50
GroupValue95% CI
Placebo to Tocilizumab + Methotrexate40.8
Tocilizumab 4 mg/kg + Methotrexate52.4
Tocilizumab 8 mg/kg + Methotrexate55.9
Tocilizumab 8 mg/kg + Placebo to Methotrexate49.3
Week 52: ACR 70
GroupValue95% CI
Placebo to Tocilizumab + Methotrexate28.9
Tocilizumab 4 mg/kg + Methotrexate37.2
Tocilizumab 8 mg/kg + Methotrexate43.1
Tocilizumab 8 mg/kg + Placebo to Methotrexate36.0
Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52 Secondary · Baseline to Week 52

The mTSS is a measure of joint damage and includes measures of joint erosion (JE) and joint space narrowing (JSN). The JE score, using the van der Heijde modification, measures erosion severity in 32 hand joints and 12 foot joints. Each hand joint is scored from 0 to 5 and each foot joint is scored from 0 to 10; the total score ranges from 0 to 280. Each joint is scored according to the surface area involved. A score of 10 indicates extensive loss of bone from more than one-half of the articulating bone; a score of 0 indicates no erosion. The JSN score measures the severity of JSN in 30 hand j

GroupValue95% CI
Placebo to Tocilizumab + Methotrexate1.14± 4.297
Tocilizumab 4 mg/kg + Methotrexate0.42± 2.929
Tocilizumab 8 mg/kg + Methotrexate0.08± 2.090
Tocilizumab 8 mg/kg + Placebo to Methotrexate0.26± 1.876
Change From Baseline in Modified Sharp Erosion Score at Week 52 Secondary · Baseline to Week 52
GroupValue95% CI
Placebo to Tocilizumab + Methotrexate0.63± 2.556
Tocilizumab 4 mg/kg + Methotrexate0.25± 1.686
Tocilizumab 8 mg/kg + Methotrexate0.05± 1.736
Tocilizumab 8 mg/kg + Placebo to Methotrexate0.15± 1.544
Change From Baseline in Sharp Joint Space Narrowing Score at Week 52 Secondary · Baseline to Week 52
GroupValue95% CI
Placebo to Tocilizumab + Methotrexate0.51± 2.362
Tocilizumab 4 mg/kg + Methotrexate0.17± 1.645
Tocilizumab 8 mg/kg + Methotrexate0.03± 0.751
Tocilizumab 8 mg/kg + Placebo to Methotrexate0.11± 1.046
Percentage of Participants With a Major Clinical Response at Week 52 Secondary · Baseline to Week 52

A major clinical response is defined as an ACR70 response that is maintained for 6 consecutive months (24 weeks) for any 24-week period between Week 2 and Week 52.

GroupValue95% CI
Placebo to Tocilizumab + Methotrexate16
Tocilizumab 4 mg/kg + Methotrexate22
Tocilizumab 8 mg/kg + Methotrexate31
Tocilizumab 8 mg/kg + Placebo to Methotrexate22
Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Weeks 24 and 52 Secondary · Baseline to Weeks 24 and 52

The Stanford HAQ-DI is a patient completed questionnaire specific for rheumatoid arthritis. The HAQ-DI assesses how well the patient is able to perform 8 activities: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. The patient answers 20 questions with 1 of 4 responses with the past week as the time frame: 0=without difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. The highest score for any question in a category determines the category score. The total score ranges from 0 (no disability) to 3 (completely disabled). A negative cha

Week 24 (n=246, 255, 250, 265)
GroupValue95% CI
Placebo to Tocilizumab + Methotrexate-0.71± 0.718
Tocilizumab 4 mg/kg + Methotrexate-0.92± 0.736
Tocilizumab 8 mg/kg + Methotrexate-0.91± 0.695
Tocilizumab 8 mg/kg + Placebo to Methotrexate-0.82± 0.739
Week 52 (n=214, 227, 228, 230)
GroupValue95% CI
Placebo to Tocilizumab + Methotrexate-0.76± 0.800
Tocilizumab 4 mg/kg + Methotrexate-1.00± 0.795
Tocilizumab 8 mg/kg + Methotrexate-0.97± 0.700
Tocilizumab 8 mg/kg + Placebo to Methotrexate-0.87± 0.776
Change From Baseline in Short Form 36 (SF-36) Physical Component Summary (PCS) Scores at Weeks 24 and 52 Secondary · Baseline to Weeks 24 and 52

The SF-36 Health Survey (Version 2) is a standardized questionnaire consisting of 36 questions that measures patient-reported symptoms on 8 dimensions; it is used to assess health-related quality of life (HRQoL). The Physical Component Summary (PCS) score summarizes the subscales Physical Functioning, Role-Physical, Bodily Pain, and General Health. The Mental Component Summary (MCS) score summarizes the subscales Vitality, Social Functioning, Role-Emotional, and Mental Health. Each score was scaled from 0 to 100. A positive change score indicates better HRQoL.

Week 24 (n=237, 247, 246, 255)
GroupValue95% CI
Placebo to Tocilizumab + Methotrexate9.35± 9.763
Tocilizumab 4 mg/kg + Methotrexate11.33± 9.282
Tocilizumab 8 mg/kg + Methotrexate12.13± 9.263
Tocilizumab 8 mg/kg + Placebo to Methotrexate10.75± 10.055
Week 52 (n=204, 225, 221, 224)
GroupValue95% CI
Placebo to Tocilizumab + Methotrexate10.72± 10.389
Tocilizumab 4 mg/kg + Methotrexate12.27± 10.509
Tocilizumab 8 mg/kg + Methotrexate13.52± 9.848
Tocilizumab 8 mg/kg + Placebo to Methotrexate11.73± 10.691

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events were reported from Baseline through Week 52.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo to Tocilizumab + Methotrexate
Serious: 24/282 (9%)
Deaths:
Tocilizumab 4 mg/kg + Methotrexate
Serious: 29/289 (10%)
Deaths:
Tocilizumab 8 mg/kg + Methotrexate
Serious: 31/290 (11%)
Deaths:
Tocilizumab 8 mg/kg + Placebo to Methotrexate
Serious: 25/292 (9%)
Deaths:

Serious adverse events (99 terms)

ReactionSystemPlacebo to Tocilizumab + M…Tocilizumab 4 mg/kg + Meth…Tocilizumab 8 mg/kg + Meth…Tocilizumab 8 mg/kg + Plac…
PneumoniaInfections and infestations
PregnancyPregnancy, puerperium and perinatal conditions
AppendicitisInfections and infestations
CellulitisInfections and infestations
AsthmaRespiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary diseaseRespiratory, thoracic and mediastinal disorders
Rheumatoid arthritisMusculoskeletal and connective tissue disorders
BronchopneumoniaInfections and infestations
Urinary tract infectionInfections and infestations
Appendicitis perforatedInfections and infestations
Arthritis bacterialInfections and infestations
ErysipelasInfections and infestations
GastroenteritisInfections and infestations
Herpes zosterInfections and infestations
Lower respiratory tract infectionInfections and infestations
Lung infectionInfections and infestations
Lyme diseaseInfections and infestations
Pneumococcal infectionInfections and infestations
Pneumonia bacterialInfections and infestations
Pneumonia influenzalInfections and infestations
SepsisInfections and infestations
Staphylococcal infectionInfections and infestations
TuberculosisInfections and infestations
Upper respiratory tract infectionInfections and infestations
Viral infectionInfections and infestations
Other adverse events (15 terms — click to expand)

ReactionSystemPlacebo to Tocilizumab + M…Tocilizumab 4 mg/kg + Meth…Tocilizumab 8 mg/kg + Meth…Tocilizumab 8 mg/kg + Plac…
Alanine aminotransferase increasedInvestigations
NauseaGastrointestinal disorders
Upper respiratory tract infectionInfections and infestations
NasopharyngitisInfections and infestations
Transaminases increasedInvestigations
HypertensionVascular disorders
Rheumatoid arthritisMusculoskeletal and connective tissue disorders
BronchitisInfections and infestations
HeadacheNervous system disorders
DiarrhoeaGastrointestinal disorders
Back painMusculoskeletal and connective tissue disorders
Urinary tract infectionInfections and infestations
RashSkin and subcutaneous tissue disorders
Aspartate aminotransferase increasedInvestigations
DyspepsiaGastrointestinal disorders

Most-reported serious reactions: Pneumonia, Pregnancy, Appendicitis, Cellulitis, Asthma, Chronic obstructive pulmonary disease, Rheumatoid arthritis, Bronchopneumonia.

Data from ClinicalTrials.gov NCT01007435 adverse events section.

Sponsor's own description

This randomized, double-blind, parallel group study will assess the safety, disease remission, and prevention of structural joint damage in patients with early moderate to severe rheumatoid arthritis treated with tocilizumab as monotherapy or in combination with methotrexate, versus methotrexate alone. Patients will be randomized to receive either (A) tocilizumab (8 mg/kg iv every 4 weeks) plus placebo, (B) tocilizumab (8 mg/kg iv every 4 weeks) plus methotrexate (7.5-20 mg po weekly), (C) tocilizumab (4 mg/kg iv every 4 weeks) plus methotrexate (7.5-20 mg po weekly), or (D) placebo plus methotrexate (7.5-20 mg po weekly). Patients in groups C and D who have not achieved low disease activity at week 52 can receive tocilizumab 8 mg/kg iv every 4 weeks. Anticipated time on study treatment is 104 weeks.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial.
    Burmester GR, Rigby WF, van Vollenhoven RF, Kay J, et al · · 2016 · cited 134× · PMID 26511996 · DOI 10.1136/annrheumdis-2015-207628
  2. Understanding the Role of Interleukin-6 (IL-6) in the Joint and Beyond: A Comprehensive Review of IL-6 Inhibition for the Management of Rheumatoid Arthritis.
    Favalli EG. · · 2020 · cited 90× · PMID 32734482 · DOI 10.1007/s40744-020-00219-2
  3. Tocilizumab combination therapy or monotherapy or methotrexate monotherapy in methotrexate-naive patients with early rheumatoid arthritis: 2-year clinical and radiographic results from the randomised, placebo-controlled FUNCTION trial.
    Burmester GR, Rigby WF, van Vollenhoven RF, Kay J, et al · · 2017 · cited 63× · PMID 28389552 · DOI 10.1136/annrheumdis-2016-210561
  4. Biologics or tofacitinib for people with rheumatoid arthritis naive to methotrexate: a systematic review and network meta-analysis.
    Singh JA, Hossain A, Mudano AS, Tanjong Ghogomu E, et al · · 2017 · cited 44× · PMID 28481462 · DOI 10.1002/14651858.cd012657
  5. Tocilizumab as monotherapy or combination therapy for treating active rheumatoid arthritis: a meta-analysis of efficacy and safety reported in randomized controlled trials.
    Teitsma XM, Marijnissen AK, Bijlsma JW, Lafeber FP, et al · · 2016 · cited 40× · PMID 27658491 · DOI 10.1186/s13075-016-1108-9
  6. Biologics or tofacitinib for people with rheumatoid arthritis unsuccessfully treated with biologics: a systematic review and network meta-analysis.
    Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, et al · · 2017 · cited 38× · PMID 28282491 · DOI 10.1002/14651858.cd012591
  7. Identifying frailty in trials: an analysis of individual participant data from trials of novel pharmacological interventions.
    Hanlon P, Butterly E, Lewsey J, Siebert S, et al · · 2020 · cited 36× · PMID 33087107 · DOI 10.1186/s12916-020-01752-1
  8. Comparative effectiveness of improvement in pain and physical function for baricitinib versus adalimumab, tocilizumab and tofacitinib monotherapies in rheumatoid arthritis patients who are naïve to treatment with biologic or conventional synthetic disease-modifying antirheumatic
    Fautrel B, Zhu B, Taylor PC, van de Laar M, et al · · 2020 · cited 31× · PMID 32371431 · DOI 10.1136/rmdopen-2019-001131

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