NCT01941940

A Study to Evaluate Efficacy of Tocilizumab Administered as Monotherapy or in Combination With Methotrexate and/or Other Disease Modifying Antirheumatic Drugs (DMARDs) in Rheumatoid Arthritis (RA) Participants

Completed Phase 3 Results posted Last updated 11 July 2017

What this trial tests

Phase 3 trial testing Tocilizumab in Rheumatoid Arthritis in 227 participants. Completed in 5 July 2016.

Timeline

5 September 2013

Primary endpoint
9 September 2015

5 July 2016

Quick facts

Lead sponsor	Hoffmann-La Roche
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	227
Start date	5 September 2013
Primary completion	9 September 2015
Estimated completion	5 July 2016
Sites	49 locations across Italy

Drugs / interventions tested

• Tocilizumab (tocilizumab) — full drug profile →
• DMARDs — full drug profile →

Conditions studied

• Rheumatoid Arthritis — all drugs for Rheumatoid Arthritis →

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.

Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 24 Primary · Baseline, Week 24

The CDAI is a numerical sum of 4 outcome parameters: tender joint count (TJC) and swollen joint count (SJC) based on a 28-joint assessment, patient's global assessment of disease activity (PtGDA) and physician global assessment of disease activity (PGDA) assessed on 0-10 centimeters (cm) visual analogue scale (VAS). Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score less than or equal to (\</=) 2.8 indicates disease remission, greater than (\>) 2.8 to 10 indicates low disease activity, \>10 to 22 indicates moderate disease activity, and \>2

Group	Value	95% CI
Tocilizumab	-21.6	± 13.25

Change From Baseline in CDAI at Week 20 Primary · Baseline, Week 20

The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score \</=2.8 indicates disease remission, \>2.8 to 10 indicates low disease activity, \>10 to 22 indicates moderate disease activity, and \>22 indicates high disease activity.

Group	Value	95% CI
Tocilizumab	-21.3	± 12.87

Change From Baseline in CDAI at Week 16 Primary · Baseline, Week 16

The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score \</=2.8 indicates disease remission, \>2.8 to 10 indicates low disease activity, \>10 to 22 indicates moderate disease activity, and \>22 indicates high disease activity.

Group	Value	95% CI
Tocilizumab	-20.2	± 12.53

Change From Baseline in CDAI at Week 12 Primary · Baseline, Week 12

The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score \</=2.8 indicates disease remission, \>2.8 to 10 indicates low disease activity, \>10 to 22 indicates moderate disease activity, and \>22 indicates high disease activity.

Group	Value	95% CI
Tocilizumab	-19.1	± 12.46

Change From Baseline in CDAI at Week 8 Primary · Baseline, Week 8

The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score \</=2.8 indicates disease remission, \>2.8 to 10 indicates low disease activity, \>10 to 22 indicates moderate disease activity, and \>22 indicates high disease activity.

Group	Value	95% CI
Tocilizumab	-17.7	± 12.07

Change From Baseline in CDAI at Week 4 Primary · Baseline, Week 4

The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score \</=2.8 indicates disease remission, \>2.8 to 10 indicates low disease activity, \>10 to 22 indicates moderate disease activity, and \>22 indicates high disease activity.

Group	Value	95% CI
Tocilizumab	-14.0	± 11.57

Change From Baseline in CDAI at Week 2 Primary · Baseline, Week 2

The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score \</=2.8 indicates disease remission, \>2.8 to 10 indicates low disease activity, \>10 to 22 indicates moderate disease activity, and \>22 indicates high disease activity.

Group	Value	95% CI
Tocilizumab	-9.1	± 9.71

Number of Participants Achieving Clinical Remission According to CDAI up to Week 52 Secondary · Baseline up to Week 52 (Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 38, and 52)

The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score \</=2.8 during any two consecutive visits, not including the baseline visit indicates disease remission.

Group	Value	95% CI
Tocilizumab	10

Change From Baseline in Disease Activity Score Based on 28-Joints Count and Erythrocyte Sedimentation Rate (DAS28-ESR) at Weeks 2, 24, and 52 Secondary · Baseline, Weeks 2, 24, and 52

DAS28-ESR is calculated from the TJC and SJC based on a 28-joint assessment, the erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/hour) and PtGDA assessed on 0-10 cm VAS. Higher scores indicate greater affectation due to disease activity. DAS28-ESR total score= 0-9.4. DAS28-ESR \</=3.2 indicates low disease activity, DAS28-ESR \>3.2 to 5.1 indicates moderate to high disease activity, and DAS28-ESR \</=3.2 indicates remission.

Baseline (n=216)

Group	Value	95% CI
Tocilizumab	5.81	± 1.080

Change at Week 2 (n=208)

Group	Value	95% CI
Tocilizumab	-1.5	± 1.04

Change at Week 24 (n=174)

Group	Value	95% CI
Tocilizumab	-3.2	± 1.47

Change at Week 52 (n=31)

Group	Value	95% CI
Tocilizumab	-3.6	± 1.18

Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 24, and 52 Secondary · Baseline, Weeks 2, 24, and 52

SDAI is a numerical sum of five outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS and C-reactive protein (CRP) in milligrams per deciliter (mg/dL). Higher scores indicate greater affectation due to disease activity. SDAI total score = 0-86. SDAI \</=3.3 indicates disease remission, \>3.4 to 11 indicates low disease activity, \>11 to 26 indicates moderate disease activity, and \>26 indicates high disease activity.

Baseline (n=215)

Group	Value	95% CI
Tocilizumab	48.70	± 45.790

Change at Week 2 (n=203)

Group	Value	95% CI
Tocilizumab	-26.5	± 44.04

Change at Week 24 (n=176)

Group	Value	95% CI
Tocilizumab	-38.9	± 48.75

Change at Week 52 (n=29)

Group	Value	95% CI
Tocilizumab	-39.3	± 26.82

Percentage of Participants With an American College of Rheumatology 20% (ACR20), 50% (ACR50), and 70% (ACR70) Response Secondary · Weeks 2, 24, and 52

The ACR 20, 50, and 70 responses: greater than or equal to (\>/=) 20 percent (%), 50%, and 70% improvement in TJC and SJC (28 assessed joints), and 20%, 50%, 70% improvement in 3 of the following 5 criteria, respectively: 1) PGDA, 2) PtGDA, 3) participant's assessment of pain, 4) participant's assessment of functional disability via a health assessment questionnaire, and 5) CRP or ESR at each visit.

Week 2: ACR 20 (n=222)

Group	Value	95% CI
Tocilizumab	18.5

Week 2: ACR 50 (n=222)

Group	Value	95% CI
Tocilizumab	6.3

Week 2: ACR 70 (n=222)

Group	Value	95% CI
Tocilizumab	11.7

Week 24: ACR 20 (n=192)

Group	Value	95% CI
Tocilizumab	8.3

Week 24: ACR 50 (n=192)

Group	Value	95% CI
Tocilizumab	4.7

Week 24: ACR 70 (n=192)

Group	Value	95% CI
Tocilizumab	65.6

Week 52: ACR 20 (n=70)

Group	Value	95% CI
Tocilizumab	0.0

Week 52: ACR 50 (n=70)

Group	Value	95% CI
Tocilizumab	0.0

Percentage of Participants With European League Against Rheumatism (EULAR) Response Based on DAS28 Secondary · Baseline, Weeks 2, 24, and 52

The 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 responders: change from baseline \>1.2 with DAS28 \</=3.2; moderate responders: 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; non-responders: change from baseline \</=0.6 or change from baseline \>0.6 and \</=1.2 with DAS28 \>5.1.

Week 2: No Response (n=222)

Group	Value	95% CI
Tocilizumab	32.4

Week 2: Moderate Response (n=222)

Group	Value	95% CI
Tocilizumab	50.5

Week 2: Good Response (n=222)

Group	Value	95% CI
Tocilizumab	17.1

Week 24: No Response (n=192)

Group	Value	95% CI
Tocilizumab	13.5

Week 24: Moderate Response (n=192)

Group	Value	95% CI
Tocilizumab	25.0

Week 24: Good Response (n=192)

Group	Value	95% CI
Tocilizumab	61.5

Week 52: No Response (n=70)

Group	Value	95% CI
Tocilizumab	55.7

Week 52: Moderate Response (n=70)

Group	Value	95% CI
Tocilizumab	8.6

Adverse events — posted to ClinicalTrials.gov

Time frame: Day 1 up to approximately 95 weeks. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Tocilizumab

Serious: 17/227 (7%)

Deaths: —

Serious adverse events (18 terms)

Reaction	System	Tocilizumab
Stress cardiomyopathy	Cardiac disorders	—
Pneumonia	Infections and infestations	—
Skin infection	Infections and infestations	—
Humerus fracture	Injury, poisoning and procedural complications	—
Wrist fracture	Injury, poisoning and procedural complications	—
Carcinoembryonic antigen increased	Investigations	—
Hepatic enzyme increased	Investigations	—
Intervertebral disc protrusion	Musculoskeletal and connective tissue disorders	—
Ovarian cyst	Reproductive system and breast disorders	—
Pleurisy	Respiratory, thoracic and mediastinal disorders	—
Aneurysm	Vascular disorders	—
Gastrointestinal perforation	Gastrointestinal disorders	—
Anaphylactic reaction	Immune system disorders	—
Cellulitis	Infections and infestations	—
Diverticulitis	Infections and infestations	—
Klebsiella infection	Infections and infestations	—
Device breakage	Product Issues	—
Bladder neoplasm surgery	Surgical and medical procedures	—

Other adverse events (5 terms — click to expand)

Reaction	System	Tocilizumab
Influenza	Infections and infestations	—
Cough	Respiratory, thoracic and mediastinal disorders	—
Transaminases increased	Investigations	—
Bronchitis	Infections and infestations	—
Urinary tract infection	Infections and infestations	—

Most-reported serious reactions: Stress cardiomyopathy, Pneumonia, Skin infection, Humerus fracture, Wrist fracture, Carcinoembryonic antigen increased, Hepatic enzyme increased, Intervertebral disc protrusion.

Data from ClinicalTrials.gov NCT01941940 adverse events section.

Sponsor's own description

This open-label, single arm, Phase 3b study will evaluate the efficacy of tocilizumab (RoActemra), administered as monotherapy or in combination with methotrexate and/or other DMARDs, in participants with moderate to severe active RA.

Publications & conference data

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

1. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases.
   Al-Bari MA. · · 2015 · cited 293× · PMID 25693996 · DOI 10.1093/jac/dkv018
2. 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
3. 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
4. Subcutaneous tocilizumab in rheumatoid arthritis: findings from the common-framework phase 4 study programme TOZURA conducted in 22 countries.
   Choy E, Caporali R, Xavier R, Fautrel B, et al · · 2018 · cited 28× · PMID 29244149 · DOI 10.1093/rheumatology/kex443
5. Effects of concomitant glucocorticoids in TOZURA, a common-framework study programme of subcutaneous tocilizumab in rheumatoid arthritis.
   Choy E, Caporali R, Xavier R, Fautrel B, et al · · 2019 · cited 7× · PMID 30649524 · DOI 10.1093/rheumatology/key393