NCT01668966

A Long Term Extension Study of WA19926 (NCT01007435) of Tocilizumab (RoActemra/Actemra) in Participants With Early, Moderate to Severe Rheumatoid Arthritis (RA)

Completed Phase 3 Results posted Last updated 13 May 2019

What this trial tests

Phase 3 trial testing Tocilizumab in Rheumatoid Arthritis in 23 participants. Completed in 11 May 2016.

Timeline

9 December 2013

Primary endpoint
11 May 2016

11 May 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	23
Start date	9 December 2013
Primary completion	11 May 2016
Estimated completion	11 May 2016
Sites	6 locations across Brazil

Drugs / interventions tested

• Tocilizumab (tocilizumab) — full drug profile →

Conditions studied

• Rheumatoid Arthritis — all drugs for Rheumatoid Arthritis →

Sponsor

Hoffmann-La Roche — full company profile →

Who can join

18 Months 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 Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Primary · Baseline up to approximately 104 weeks

An adverse event (AE) is any unfavorable or unintended sign (including an abnormal laboratory finding), symptom or disease temporarily associated with use of study drug, regardless of its relation to study drug. A TEAE is an AE that occurs only once treatment has started. An SAE can be a) fatal, b) life-threatening, c) requires/prolongs hospitalization, d) results in persistent/significant incapacity/disability, e) results in congenital anomaly/birth defect or f) is considered as a significant medical event by the investigator.

TEAEs

Group	Value	95% CI
Tocilizumab	95.2

SAEs

Group	Value	95% CI
Tocilizumab	9.5

Percentage of Participants With TEAEs of Special Interest Primary · Baseline up to approximately 104 weeks

An AE is any unfavorable or unintended sign (including an abnormal laboratory finding), symptom or disease temporarily associated with use of study drug, regardless of its relation to study drug. A TEAE is an AE that occurs only once treatment has started. Nine categories of AE of special interest are identified for tocilizumab which includes a) serious/medically significant infections, b) myocardial infarction/acute coronary syndrome, c) gastrointestinal perforations, d) malignancies, e) anaphylaxis/hypersensitivity reactions, f) demyelinating disorders, g) stroke, h) serious and/or medically

Group	Value	95% CI
Tocilizumab	95.2

Percentage of Participants With TEAEs Leading to Change in Dose or Study Drug Discontinuation Primary · Baseline up to approximately 104 weeks

An AE is any unfavorable or unintended sign (including an abnormal laboratory finding), symptom or disease temporarily associated with use of study drug, regardless of its relation to study drug. A TEAE is an AE that occurs only once treatment has started.

TEAEs leading to study drug discontinuation

Group	Value	95% CI
Tocilizumab	4.8

TEAEs leading to dose modification

Group	Value	95% CI
Tocilizumab	28.6

Change From Baseline (CFB) in Disease Activity Score 28 Using Erythrocyte Sedimentation Rate (DAS28-ESR) at Specified Time Points Secondary · Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, early withdrawal (up to 104 weeks), follow-up 1 (8 weeks after the last visit or discontinuation; 112 weeks), follow-up 2 (16 weeks after the last visit or discontinuation; 120 weeks)

The DAS28-ESR is a combined index for measuring disease activity in rheumatoid arthritis (RA). The index includes swollen joint counts (SJC) and tender joint counts (TJC), both scored 0-28 (higher scores indicate higher disease activity), as well as acute phase response (APR) determined as erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/hr), and general health (GH) (patient global assessment of disease activity \[PGA\] using visual analog scale \[VAS\], range 1-100 millimeters \[mm\]) (higher scores indicate higher disease activity). DAS28-ESR is calculated according to the fo

Baseline (n=21)

Group	Value	95% CI
Tocilizumab	2.4	± 1.76

CFB at Week 12 (n=19)

Group	Value	95% CI
Tocilizumab	-0.6	± 1.6

CFB at Week 24 (n=21)

Group	Value	95% CI
Tocilizumab	-0.6	± 1.7

CFB at Week 36 (n=19)

Group	Value	95% CI
Tocilizumab	-0.5	± 1.3

CFB at Week 48 (n=20)

Group	Value	95% CI
Tocilizumab	-0.6	± 1.9

CFB at Week 56 (n=19)

Group	Value	95% CI
Tocilizumab	-0.5	± 1.7

CFB at Week 68 (n=20)

Group	Value	95% CI
Tocilizumab	-0.4	± 2.0

CFB at Week 80 (n=21)

Group	Value	95% CI
Tocilizumab	0.3	± 1.9

CFB in Simplified Disease Activity Index (SDAI) Score at Specified Time Points Secondary · Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, early withdrawal (up to 104 weeks), follow-up 1 (8 weeks after the last visit or discontinuation; 112 weeks), follow-up 2 (16 weeks after the last visit or discontinuation; 120 weeks)

The SDAI is a combined index for measuring disease activity. SDAI is the sum of TJC and SJC, both scored 0-28 (higher scores indicate higher disease activity), physician global assessment (PhGA) and PGA of disease activity, both scored 0 to 10 centimeters (cm) as assessed by VAS, and C-reactive protein level (CRP) in milligrams per deciliter (mg/dL) where normal is less than (\<) 1 mg/dL. SDAI is calculated according to the following formula: SDAI = TJC + SJC + PhGA + PGA + CRP. SDAI ranges from 0 to 86. A negative CFB indicated improvement.

Baseline (n=21)

Group	Value	95% CI
Tocilizumab	9.5	± 11.84

CFB at Week 12 (n=20)

Group	Value	95% CI
Tocilizumab	-2.4	± 7.75

CFB at Week 24 (n=21)

Group	Value	95% CI
Tocilizumab	-2.7	± 11.46

CFB at Week 36 (n=20)

Group	Value	95% CI
Tocilizumab	-2.8	± 9.85

CFB at Week 48 (n=20)

Group	Value	95% CI
Tocilizumab	-3.0	± 12.71

CFB at Week 56 (n=20)

Group	Value	95% CI
Tocilizumab	-3.2	± 11.09

CFB at Week 68 (n=20)

Group	Value	95% CI
Tocilizumab	-0.6	± 18.1

CFB at Week 80 (n=21)

Group	Value	95% CI
Tocilizumab	0.9	± 13.92

CFB in Swollen Joint Count (SJC) at Specified Time Points Secondary · Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, follow-up 1 (8 weeks after the last visit or discontinuation; 112 weeks), follow-up 2 (16 weeks after the last visit or discontinuation; 120 weeks)

For SJC, a total of 66 joints are assessed. The presence of a swollen joint is scored as 1 and absence as 0. Total score is calculated by adding the scores, which ranges from 0 (best possible score or no swollen joint) to 66 (worse possible score or all swollen joints). Lower scores indicated no swollen joint and higher scores indicated worsening swollen joints.

Baseline (n=21)

Group	Value	95% CI
Tocilizumab	0.8	± 1.7

CFB at Week 12 (n=6)

Group	Value	95% CI
Tocilizumab	-1.3	± 1.37

CFB at Week 24 (n=7)

Group	Value	95% CI
Tocilizumab	-1.6	± 1.81

CFB at Week 36 (n=6)

Group	Value	95% CI
Tocilizumab	-1.5	± 2.81

CFB at Week 48 (n=7)

Group	Value	95% CI
Tocilizumab	-0.9	± 3.48

CFB at Week 56 (n=6)

Group	Value	95% CI
Tocilizumab	-1.8	± 2.56

CFB at Week 68 (n=7)

Group	Value	95% CI
Tocilizumab	-2.0	± 2.38

CFB at Week 80 (n=7)

Group	Value	95% CI
Tocilizumab	1.1	± 5.49

CFB in Tender Joint Count (TJC) at Specified Time Points Secondary · Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, early withdrawal (up to 104 weeks), follow-up 1 (8 weeks after the last visit or discontinuation; 112 weeks), follow-up 2 (16 weeks after the last visit or discontinuation; 120 weeks)

The number of tender joints is recorded on the joint assessment form, no tenderness = 0, tenderness = 1, for 68 joints and joints were classified as tender/not tender giving a total possible tender joint count score of 0 to 68.

Baseline (n=21)

Group	Value	95% CI
Tocilizumab	5.8	± 8.57

CFB at Week 12 (n=13)

Group	Value	95% CI
Tocilizumab	-3.1	± 8.95

CFB at Week 24 (n=14)

Group	Value	95% CI
Tocilizumab	-4.8	± 10.39

CFB at Week 36 (n=14)

Group	Value	95% CI
Tocilizumab	-5.4	± 8.35

CFB at Week 48 (n=14)

Group	Value	95% CI
Tocilizumab	-5.9	± 8.4

CFB at Week 56 (n=14)

Group	Value	95% CI
Tocilizumab	-6.0	± 8.41

CFB at Week 68 (n=13)

Group	Value	95% CI
Tocilizumab	-2.3	± 16.51

CFB at Week 80 (n=14)

Group	Value	95% CI
Tocilizumab	-3.5	± 11.65

Percentage of Participants Reaching Clinical Remission (DAS28-ESR Score Less Than [<] 2.6 and/or SDAI Score Less Than or Equal to [</=] 3.3) Among Participants for Whom Tocilizumab Treatment Was Discontinued Secondary · Baseline up to approximately 104 weeks

Remission: DAS28-ESR score \<2.6 and SDAI score \</=3.3. DAS28-ESR index included SJC and TJC, both scored 0-28, as well as APR determined as ESR in mm/hr, and GH (ranges 1-100 mm; higher scores=higher disease activity). DAS28=(0.56\*√TJC)+(0.28\*√SJC) +(0.70\*ln ESR) +(0.014\*GH). DAS28-ESR scale is transformed and ranges from 0 to 10. Negative CFB indicated improvement. DAS28 \>2.6 (clinical remission); DAS28 2.6 to 3.2 (low disease activity); DAS28 \>3.2 to 5.1 = moderate to high disease activity. SDAI is sum of TJC and SJC (both scored 0-28), PhGA and PGA of disease activity (both scored 0

Percentage of participants achieved DAS28-ESR <2.6

Group	Value	95% CI
Tocilizumab	100

Percentage of participants achieved SDAI</=3.3

Group	Value	95% CI
Tocilizumab	100

Time to RA Crisis Among Participants Who Discontinued After Clinical Remission Secondary · Baseline up to approximately 104 weeks

RA crisis is any worsening of participant disease acitivity that, in the opinion of the investigator, required intensified treatment other than supportive therapy, and may have included restart of the treatment with the study drug. Time to RA crisis is defined as the period of remission without drug until the RA crisis documentation.

Group	Value	95% CI
Tocilizumab	135.3	± 53.73

CFB in PGA of Disease Activity Using VAS Score at Specified Time Points Secondary · Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, early withdrawal (up to 104 weeks), follow-up 1 (8 weeks after the last visit or discontinuation; 112 weeks), follow-up 2 (16 weeks after the last visit or discontinuation; 120 weeks)

PGA 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 negative CFB indicated improvement.

Baseline (n=21)

Group	Value	95% CI
Tocilizumab	26.5	± 19.90

CFB at Week 12 (n=20)

Group	Value	95% CI
Tocilizumab	-0.3	± 16.1

CFB at Week 24 (n=21)

Group	Value	95% CI
Tocilizumab	2.5	± 23.2

CFB at Week 36 (n=20)

Group	Value	95% CI
Tocilizumab	2.0	± 18.5

CFB at Week 48 (n=20)

Group	Value	95% CI
Tocilizumab	0.4	± 25.8

CFB at Week 56 (n=20)

Group	Value	95% CI
Tocilizumab	-0.5	± 22.1

CFB at Week 68 (n=20)

Group	Value	95% CI
Tocilizumab	1.3	± 27.0

CFB at Week 80 (n=21)

Group	Value	95% CI
Tocilizumab	6.2	± 27.5

CFB in PGA of Pain Using VAS Score at Specified Time Points Secondary · Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, early withdrawal (up to 104 weeks), follow-up 1 (8 weeks after the last visit or discontinuation; 112 weeks), follow-up 2 (16 weeks after the last visit or discontinuation; 120 weeks)

PGA of pain is assessed on a 0 to 100 mm horizontal 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, and is described as "unbearable pain". A negative change indicated improvement.

Baseline (n=21)

Group	Value	95% CI
Tocilizumab	22.3	± 21.76

CFB at Week 12 (n=20)

Group	Value	95% CI
Tocilizumab	2.5	± 14.1

CFB at Week 24 (n=21)

Group	Value	95% CI
Tocilizumab	5.0	± 27.7

CFB at Week 36 (n=20)

Group	Value	95% CI
Tocilizumab	3.6	± 18.5

CFB at Week 48 (n=20)

Group	Value	95% CI
Tocilizumab	0.6	± 26.4

CFB at Week 56 (n=20)

Group	Value	95% CI
Tocilizumab	1.0	± 20.0

CFB at Week 68 (n=20)

Group	Value	95% CI
Tocilizumab	3.7	± 26.4

CFB at Week 80 (n=21)

Group	Value	95% CI
Tocilizumab	7.5	± 28.9

CFB in PhGA of Disease Activity Using VAS Score at Specified Time Points Secondary · Baseline, Weeks 12, 24, 36, 48, 56, 68, 80, 92, 104, early withdrawal (up to 104 weeks), follow-up 1 (8 weeks after the last visit or discontinuation; 112 weeks), follow-up 2 (16 weeks after the last visit or discontinuation; 120 weeks)

PhGA of disease activity is assessed on a 0 to 100 mm horizontal 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).

Baseline (n=21)

Group	Value	95% CI
Tocilizumab	7.9	± 11.13

CFB at Week 12 (n=20)

Group	Value	95% CI
Tocilizumab	-1.0	± 7.3

CFB at Week 24 (n=21)

Group	Value	95% CI
Tocilizumab	-0.8	± 7.7

CFB at Week 36 (n=20)

Group	Value	95% CI
Tocilizumab	-1.0	± 8.3

CFB at Week 48 (n=20)

Group	Value	95% CI
Tocilizumab	0.8	± 13.1

CFB at Week 56 (n=20)

Group	Value	95% CI
Tocilizumab	-2.2	± 9.6

CFB at Week 68 (n=20)

Group	Value	95% CI
Tocilizumab	1.5	± 18.1

CFB at Week 80 (n=21)

Group	Value	95% CI
Tocilizumab	7.6	± 21.3

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline up to approximately 104 weeks. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Tocilizumab

Serious: 2/21 (10%)

Deaths: —

Serious adverse events (3 terms)

Reaction	System	Tocilizumab
Vaginal bleeding	Reproductive system and breast disorders	—
Bronchopneumonia	Respiratory, thoracic and mediastinal disorders	—
Cardiac arrhythimia	Cardiac disorders	—

Other adverse events (52 terms — click to expand)

Reaction	System	Tocilizumab
Upper Respiratory Tract Infection	Respiratory, thoracic and mediastinal disorders	—
Dyslipidaemia	Metabolism and nutrition disorders	—
Upper respiratory tract infection	Infections and infestations	—
Tracheobronchitis	Respiratory, thoracic and mediastinal disorders	—
Vaginitis Bacterial	Infections and infestations	—
Transaminases Increased	Investigations	—
Urinary Tract Infection	Renal and urinary disorders	—
Cough	Respiratory, thoracic and mediastinal disorders	—
Nasopharyngitis	Respiratory, thoracic and mediastinal disorders	—
Sinusitis	Respiratory, thoracic and mediastinal disorders	—
Leukopenia	Blood and lymphatic system disorders	—
Neutropenia	Blood and lymphatic system disorders	—
Dizziness	Cardiac disorders	—
Tachycardia	Cardiac disorders	—
Diabetes mellitus	Endocrine disorders	—
Menstruation irregular	Endocrine disorders	—
Ulcerative keratitis	Eye disorders	—
Conjunctivitis	Eye disorders	—
Scleritis	Eye disorders	—
Abdominal pain	Gastrointestinal disorders	—
Diarrhoea	Gastrointestinal disorders	—
Dyspepsia	Gastrointestinal disorders	—
Impaired healing	General disorders	—
Drug intolerance	General disorders	—
Cholestasis	Hepatobiliary disorders	—
Hepatic steatosis	Hepatobiliary disorders	—
Rheumatoid arthritis	Immune system disorders	—
Cellulitis	Infections and infestations	—
Labyrinthitis	Infections and infestations	—
Nasopharyngitis	Infections and infestations	—
Viraemia	Infections and infestations	—
Urinary tract infection	Infections and infestations	—
Chest injury	Injury, poisoning and procedural complications	—
Hypercholesterolaemia	Metabolism and nutrition disorders	—
Hyperkalaemia	Metabolism and nutrition disorders	—
Vitamin D Deficiency	Metabolism and nutrition disorders	—
Arthralgia	Musculoskeletal and connective tissue disorders	—
Arthritis	Musculoskeletal and connective tissue disorders	—
Sciatica	Musculoskeletal and connective tissue disorders	—
Tendonitis	Musculoskeletal and connective tissue disorders	—

Most-reported serious reactions: Vaginal bleeding, Bronchopneumonia, Cardiac arrhythimia.

Data from ClinicalTrials.gov NCT01668966 adverse events section.

Sponsor's own description

This open-label, single arm, multicenter long-term extension study of WA19926 (NCT01007435) will evaluate the safety and efficacy of tocilizumab in participants with early, moderate to severe RA who have completed the 104-week WA19926 (NCT01007435) core study. Eligible participants will be those who are expected to benefit from the study medicine based on the investigator's discretion.

Publications & conference data

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

1. 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
2. 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