Clinical trial NCT01995201: A Study of Subcutaneous RoActemra/Actemra (Tocilizumab) as Monotherapy or in Combination With Methotrexate or Other Non-Biologic DMARDs in Patients With Active Rheumatoid Arthritis
Official title: A Phase IIIb Study to Evaluate the Efficacy, Safety and Tolerability of Subcutaneous (SC) Tocilizumab (TCZ) Given as Monotherapy or in Combination With Methotrexate (MTX) or Other Non Biologics DMARDs in Subjects With Rheumatoid Arthritis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2013-11-26
Enrollment: 401
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This multicenter, open-label study will evaluate the efficacy and safety of subcutaneously administered RoActemra/Actemra (tocilizumab) as monotherapy or in combination with methotrexate or other non-biologic DMARDs in patients with active rheumatoid arthritis and an inadequate response to non-biologic DMARDs or to one anti-TNF. In Phase 1, all patients will receive RoActemra/Actemra 162 mg subcutaneously (sc) weekly for Weeks 1 to 24, with or without methotrexate or other non-biologic DMARDs. For Part 2, patients who achieve sustained clinical DAS28-ESR remission at Weeks 20 and 24 will be randomized to receive RoActemra/Actemra 162 mg sc either weekly or every 2 weeks for Weeks 24 to 48, with or without methotrexate or other non-biologic DMARDs. Patients who do not achieve sustained clinical remission but achieve low disease activity (DAS-ESR \</= 3.2) will continue the initial treatment of RoActemra/Actemra 162 mg sc weekly for Weeks 24 to 48, with or without methotrexate or other non-biologic DMARDs.


Eligibility criteria: Inclusion Criteria:

* Adult patients, \>/= 18 years of age
* Active rheumatoid arthritis (DAS28-ESR \> 3.2), according to the revised (1987) ACR criteria or EULAR/ACR (2010) criteria of \> 6 months duration
* Patients with intolerance or inadequate response to methotrexate or other non-biologic DMRADs or inadequate response to a first ant-TNF agent
* Oral corticosteroids (\</= 10 mg/day prednisone or equivalent) and non-steroidal anti-inflammatory drugs (NSAIDs; up to the maximum recommended dose) are permitted if on a stable dose regimen for \>/= 4 weeks prior to baseline
* Permitted non-biologic DMRAD is allowed if at stable dose for at least 4 weeks prior to baseline
* Females of childbearing potential and males with female partners of childbearing potential must be using a reliable means of contraception as defined by protocol during the study and for at least 3 months following the last dose of RoActemra/Actemra
* Patients with intolerance or inadequate response to methotrexate or other non-biologic DMARDs or inadequate response to first anti-TNF agent

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 RA or significant systemic involvement secondary to RA; 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 intravenous \[IV\] or SC) at any time prior to baseline
* Treatment with any investigational agent with four weeks (or five-half lives of the investigational drug, whichever is longer) of screening
* Intra-articular or parenteral corticosteroids within 4 weeks prior to baseline
* Previous treatment with Abatacept
* History of severe allergic of anaphylactic reactions to human, humanized, or murine monoclonal antibodies
* Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary, renal, hepatic, endocrine, or gastrointestinal (GI) disease
* History of diverticulitis, diverticulitis requiring antibiotic treatment, or chronic ulcerative lower GI disease such as Crohn's disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose to perforation
* Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to tuberculosis \[TB\] and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections or nail beds)
* Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks of screening
* Active TB requiring treatment within the previous 3 years
* Positive hepatitis B or hepatitis C
* Primary or secondary immunodeficiency (history of or currently active)
* Evidence of active malignant disease, malignancies diagnosed with the previous 10 years (including hematological malignancies and solid tumors, except basal of squamous cell carcinoma of the skin diagnosed within the previous 20 years
* Pregnant and lactating women
* History of alcohol, drug, or chemical abuse within 1 year prior to screening
* Neuropathies or other conditions that might interfere with pain evaluation
* Inadequate hematological, real of liver function

Primary outcomes:
measure: Percentage of Participants Achieving Sustained Clinical Remission, Disease Activity Scale 28 - Erythrocyte Sedimentation Rate <26 (DAS28-ESR <2.6) at Week 20 and Week 24
timeFrame: Week 20 and Week 24
Secondary outcomes:
measure: Mean Change in Disease Activity Score 28 - Erythrocyte Sedimentation Rate(DAS28-ESR)
timeFrame: From week 24 up to week 48
measure: Percentage of Patients Allocated in Groups A1 and A2 Who Remain With Clinical Remission Activity (DAS 28 ESR <2.6) up to Week 48
timeFrame: From week 28 up to week 48
measure: Percentage of Patients Reporting Change in DAS 28 ESR >1.2 Until Week 48
timeFrame: From week 28 up to week 48
measure: Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24
timeFrame: From week 2 until week 24
measure: Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48
timeFrame: From week 28 until week 48
measure: Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24
timeFrame: From week 2 until week 24
measure: Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48
timeFrame: From week 28 until week 48
measure: Mean Change in Clinical Disease Activity Index (CDAI) From Baseline up to Week 24
timeFrame: From baseline to Week 24
measure: Mean Change From Baseline in Clinical Disease Activity Index (CDAI) up to Week 48
timeFrame: From week 24 until week 48
measure: Mean Change in Simplified Disease Activity Index (SDAI) From Baseline up to Week 24
timeFrame: From baseline to Week 24
measure: Mean Change in Simplified Disease Activity Index (SDAI) From Week 24 up to Week 48
timeFrame: From week 24 until week 48
measure: Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 24
timeFrame: From baseline to Week 24
measure: Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 48
timeFrame: From week 24 until week 48
measure: Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 24
timeFrame: From baseline to Week 24
measure: Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 48
timeFrame: From week 24 until week 48
measure: Percentages of Patients Who Achieve DAS28-ESR Remission (DAS28 < 2.6) up to Week 48
timeFrame: Week 48
measure: Percentages of Patients With Remission (CDAI<2.8) Until Week 24
timeFrame: From baseline to Week 24
measure: Percentages of Patients With Remission (CDAI<2.8) Until Week 48
timeFrame: From week 28 until week 48
measure: Percentages of Patients With Remission (SDAI<3.3) Until Week 24
timeFrame: From baseline to Week 24
measure: Percentages of Patients With Remission (SDAI<3.3) Until Week 48
timeFrame: From week 28 until week 48
measure: Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 24
timeFrame: From baseline to Week 24
measure: Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 48
timeFrame: From week 28 until week 48
measure: Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 24
timeFrame: From baseline to Week 24
measure: Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 48
timeFrame: From week 28 until week 48
measure: Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 24
timeFrame: From baseline to Week 24
measure: Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 48
timeFrame: From week 28 until week 48
measure: Safety: Number of Patients Reporting Adverse Events up to Week 24
timeFrame: From baseline to Week 24
measure: Safety: Number of Patients Reporting Adverse Events up to Week 48
timeFrame: From week 24 until week 48
measure: Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 24
timeFrame: From baseline to Week 24
measure: Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 48
timeFrame: From week 24 until week 48
measure: Immunogenicity: TCZ Levels up to Week 24
timeFrame: From baseline to Week 24
measure: Immunogenicity: TCZ Levels at Week 36 and Early Withdrawal Visit
timeFrame: week 36 and early withdrawal visit
measure: Immunogenicity: SIL-6R Levels up to Week 24
timeFrame: From baseline to Week 24
measure: Immunogenicity: SIL-6R Levels at Week 36 and Early Withdrawal Visit
timeFrame: Baseline, Week 36 and Early Withdrawal Visit
measure: Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 24
timeFrame: From baseline to Week 24
measure: Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 48
timeFrame: Baseline, from week 28 until week 48
measure: Assessment of Pain Reported by the Patient (VAS) Until Week 24
timeFrame: From baseline to Week 24
measure: Assessment of Pain Reported by the Patient (VAS) Until Week 48
timeFrame: Baseline, from week 28 until week 48
measure: Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 24
timeFrame: From baseline to Week 24
measure: Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 48
timeFrame: Baseline, from week 28 until week 48
measure: Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 24
timeFrame: From baseline to Week 24
measure: Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 48
timeFrame: Baseline, from week 28 until week 48
Other outcomes:
Locations:
city: Co Leitrim
country: Ireland
city: Cork
country: Ireland
city: Dublin 4
country: Ireland
city: Dublin
country: Ireland
city: Limerick
country: Ireland
city: Waterford
country: Ireland
city: Almada
country: Portugal
city: Amadora
country: Portugal
city: Lisboa
country: Portugal
city: Lisboa
country: Portugal
city: Porto
country: Portugal
city: Porto
country: Portugal
city: Elche
country: Spain
state: Alicante
city: Merida
country: Spain
state: Badajoz
city: Sabadell
country: Spain
state: Barcelona
city: Sant Joan Despi
country: Spain
state: Barcelona
city: Terrassa
country: Spain
state: Barcelona
city: Jerez de La Frontera
country: Spain
state: Cadiz
city: Torrelavega
country: Spain
state: Cantabria
city: San Sebastian
country: Spain
state: Guipuzcoa
city: Palma de Mallorca
country: Spain
state: Islas Baleares
city: La Coruna
country: Spain
state: La Coruña
city: Santiago De Compostela
country: Spain
state: La Coruña
city: Las Palmas de Gran Canaria
country: Spain
state: Las Palmas
city: Fuenlabrada
country: Spain
state: Madrid
city: Cartagena
country: Spain
state: Murcia
city: El Palmar
country: Spain
state: Murcia
city: Valenica
country: Spain
state: Valencia
city: Bilbao
country: Spain
state: Vizcaya
city: Alicante
country: Spain
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Burgos
country: Spain
city: Cordoba
country: Spain
city: Granada
country: Spain
city: Guadalajara
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Malaga
country: Spain
city: Salamanca
country: Spain
city: Sevilla
country: Spain
city: Sevilla
country: Spain
city: Sevilla
country: Spain
city: Tarragona
country: Spain
city: Tenerife
country: Spain
city: Toledo
country: Spain
city: Valencia
country: Spain
city: Zaragoza
country: Spain
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Sanmarti R, Veale DJ, Martin-Mola E, Escudero-Contreras A, Gonzalez C, Ercole L, Alonso R, Fonseca JE; ToSpace Study Group. Reducing or Maintaining the Dose of Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis in Clinical Remission: A Randomized, Open-Label Trial. Arthritis Rheumatol. 2019 Oct;71(10):1616-1625. doi: 10.1002/art.40905. Epub 2019 Sep 24.
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.