Randomized, blinded, controlled study to compare the efficacy of treatment with tocilizumab with or without glucocorticoids in rheumatoid arthritis.

• Register: EUCTR
• Last refreshed on: 30 April 2018
• Main ID: EUCTR2014-004673-16-DE
• Date of registration: 15/07/2015
• Prospective Registration: Yes
• Primary sponsor: F. Hoffmann-La Roche Ltd
• Public title: Randomized, blinded, controlled study to compare the efficacy of treatment with tocilizumab with or without glucocorticoids in rheumatoid arthritis.
• Scientific title: Prospective, multicentre, placebo-controlled, double-blind study to compare the efficacy of maintenance treatment with tocilizumab with or without glucocorticoid discontinuation in rheumatoid arthritis patients
• Date of first enrolment: 12/01/2016
• Target sample size: 226
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-004673-16
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Egypt, France, Germany, Italy, Lebanon, Russian Federation, Serbia, Switzerland, Turkey

Contacts

• Name: Trial Information Support Line-TISL
• Affiliation: F. Hoffmann-La Roche Ltd.

• Name: Trial Information Support Line-TISL
• Affiliation: F. Hoffmann-La Roche Ltd.

Key inclusion & exclusion criteria

Inclusion criteria:
- Age >= 18 years
- RA of >= 6 months duration diagnosed according to American College of Rheumatology (ACR)/European League against Rheumatology (EULAR) criteria
Track TCZ-experienced patients:
- Have received tocilizumab (TCZ) either subcutaneous (SC, 162
milligrams [mg] once a week [QW]) or intravenous (IV, 8 mg/kilogram
[kg] every 4 weeks [Q4W]) not exceeding 800 mg/dose for the
treatment of RA for at least 24 weeks prior to randomization
- Have received 5 15 mg/day of prednisone (or glucocorticoids (GCs)
equivalent) for the treatment of RA for at least 20 weeks prior to
screening
- Currently receiving 5 mg/day of oral prednisone (or GC equivalent)
at the screening visit
- Have DAS28 ESR score <=3.2 assessed 4 to 6 weeks prior to
randomization
Track TCZ-naïve patients:
- Have active RA (defined as DAS28 ESR score >3.2)
- Are considered by the investigator as inadequate responders to
conventional synthetic disease-modifying antirheumatic drug
(csDMARDs) or biologic disease-modifying antirheumatic drug
(bDMARDs). Are TCZ treatment naive or last TCZ was >12 months prior
to screening and TCZ was not discontinued due to lack of efficacy, side
effects, or any other safety reasons
- Are receiving 5-15 mg/day prednisone (or GC equivalent) for the
treatment of RA
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 170
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 56

Exclusion criteria:
- Major surgery (including joint surgery) within 8 weeks prior to
screening, or planned major surgery during the study and up to 6
months after randomization
- Pregnant women or nursing (breastfeeding) mothers
- In females of childbearing potential, a positive serum pregnancy test
at screening
- Females of childbearing potential unwilling or unable to use reliable
means of contraception during study treatment and for a minimum of 3
months after the last dose of TCZ
- Body weight of >=150 kg
- Lack of peripheral venous access
- RA of functional class IV, as defined by the ACR Classification of
Functional Status in Rheumatoid Arthritis
- Rheumatic autoimmune disease other than RA, including systemic
lupus erythematosus, mixed connective tissue disease, scleroderma,
polymyositis, or significant systemic involvement secondary to RA (e.g.,
vasculitis, pulmonary fibrosis, or Felty syndrome). Secondary Sjögren
syndrome with RA may be allowed per the discretion of the investigator
- Diagnosed with juvenile idiopathic arthritis or juvenile RA and/or RA
before the age of 16 years
- Prior or current inflammatory joint disease other than RA (e.g., gout,
Lyme disease, sero-negative spondyloarthropathy, including reactive
arthritis, psoriatic arthritis, arthropathy of inflammatory bowel disease),
or prior or current joint infections
- Previous history of primary or secondary adrenal insufficiency
- Treatment with any investigational agent (tocilizumab excepted)
within 4 weeks (or 5 half-lives of the investigational drug, whichever is
longer) of screening. Treatment with csDMARDs, other DMARDS, and/or
biologics for RA which is permanently discontinued within 5 half-lives
prior to randomization
- Previous treatment with any cell-depleting therapies, including
investigational agents or approved therapies
- Treatment with IV gamma globulin, plasmapheresis or Prosorba
column within 6 months of screening
- Intraarticular (IA) or parenteral GCs for the treatment of RA within 6
weeks prior to randomisation (within 12 weeks prior ro randomization
for intra-articular triamcinolone)
- Previous treatment with GCs for conditions other than RA, at any dose
and in any formulation used continuously for > 1 week, during the last 1
year prior to screening. Current treatment with topical GC exceeding
20% of body surface area
- Immunization with a live/attenuated vaccine within 30 days prior to
screening
- Any previous treatment with alkylating agents such as chlorambucil or
with total lymphoid irradiation
- Inadequate haematological, renal and liver functions
- Positive hepatitis B surface antigen (HBsAg) or hepatitis C virus
antibody (HCV Ab)
- History of severe allergic or anaphylactic reactions to human,
humanized, or murine monoclonal antibodies
- Evidence of current serious uncontrolled cardiovascular (including
uncontrolled hyperlipidaemia), nervous system, pulmonary (including
obstructive pulmonary disease), renal, hepatic, endocrine (including
uncontrolled diabetes mellitus) or gastrointestinal (GI) disease
- Current liver disease as determined by the investigator
- History of diverticulitis, peptic ulcer disease, diverticulosis 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 perforations
- Known active current or history of recurrent bacterial, viral, fungal,
mycobacte

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Rheumatoid Arthritis
MedDRA version: 20.0 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Intervention(s)

Trade Name: RoActemra 162 mg
Product Code: RO487-7533/F10-04
Pharmaceutical Form: Solution for injection
INN or Proposed INN: tocilizumab
CAS Number: 375823-41-9
Other descriptive name: TOCILIZUMAB
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 180-

Trade Name: Prednisone Tablets USP, 5 mg
Product Code: RO001-9265/F04
Pharmaceutical Form: Capsule
INN or Proposed INN: Prednisone
Other descriptive name: PREDNISONE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Trade Name: Prednisone Tablets USP, 1 mg
Product Code: RO 001-9265/F02-01
Pharmaceutical Form: Capsule
INN or Proposed INN: Prednisone
Other descriptive name: PREDNISONE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Trade Name: RoActemra
Product Code: L04AC07
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: tocilizumab
CAS Number: 375823-41-9
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Primary Outcome(s)

Primary end point(s): Change in DAS28 ESR between randomization and Week 24 post-randomization

Timepoint(s) of evaluation of this end point: Randomization and Week 24

Main Objective: To compare the impact on disease activity of continued vs. tapered prednisone in RA patients with stable low disease activity (LDA [Disease Activity Score in 28 joints (DAS28) erythrocyte sedimentation rate (ESR) score <= 3.2]) or remission (DAS28 ESR score <= 2.6).

Secondary Objective: -To compare the proportion of patients who continue vs. taper prednisone with LDA at Week 24, who haven't suffered a disease flare and showed no confirmed adrenal insufficiency requiring replacement therapy
-To compare between patients who continue vs. taper prednisone:(1)changes in CDAI and SDAI (2)the proportion of patients with >=1 RA flare; time to first RA flare; number of RA flares; >=1
administration of RA flare rescue medication; time to first administration, and number of administrations of RA flare rescue medication(3)cumulative prednisone exposure(4)the proportion of
patients who maintain LDA and who maintain the baseline disease activity level(5)proportion of patients who permanently discontinue study treatment due to insufficient RA flare control,(6)changes in the ACR core set, (7)identify predictors of successful prednisone dosetapering (8) changes in patient-reported outcomes
-To evaluate the safety and tolerability of TCZ and proposed prednisonetapering scheme

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Week 24
2: From Randomization up to Week 24
3-4: Up to Week 24
5: From Randomization up to Week 24
6: Week 24
7: Up to Week 24
8: From Randomization up to Week 24
9-10: Up to Week 28
11: Up to Week 24 (performed on event driven basis)
12: Up to Week 24
13-14: Enrolment (Track TCZ-naïve patients only), randomization and Week 24
15: Randomization and Week 24

Secondary end point(s): 1 The proportion of patients with LDA (DAS28 ESR score <= 3.2) at Week 24 post-randomization, who have not suffered a disease flare and who showed no confirmed adrenal insufficiency that required
replacement therapy
2 Change in clinical disease activity index (CDAI)/ simplified disease activity index (SDAI) between randomization and Week 24 postrandomization
3 The proportion or patients with >=1 RA flare, the time to first RA flare and the number of RA flares
4 The proportion of patients with >=1 dministration of RA flare rescue medication, the time to first administration, and the number of administrations of RA flare rescue medication
5 Cumulative prednisone exposure (dose) between randomization and Week 24 post-randomization
6 The proportion of patients who maintain LDA (DAS28 ESR score <=3.2) and the proportion of patients who maintain the baseline disease
activity level at Week 24 post-randomization
7 The proportion of patients who permanently discontinue study treatment due to insufficient RA flare control
8 Changes in the ACR core set from randomization to postrandomization Week 24, including: swollen and tender joint counts; patient's assessment of pain and global status; physician's assessment
of global status; Health assessment questionnaire–Disability index (HAQ-DI); and acute phase reactants (high sensitivity C-reactive protein
[hsCRP] and ESR)
9 Incidence of adverse events (AEs) including non-serious and serious AEs, and AEs of special interest
10 Changes in vital signs, physical findings, and clinical laboratory results during and following TCZ administration
11 Assessment of immunogenicity (anti-TCZ antibodies)
12 Proportion of patients with confirmed adrenal insufficiency that required replacement therapy
13 Rheumatoid arthritis impact of disease (RAID) score
14 Work productivity and activity impairment questionnaire: Rheumatoid Arthritis (WPAI: RA)
15 Health assessment questionnaire–Disability index (HAQ-DI) score

Secondary ID(s)

MA29585

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd.