A study to assess the efficacy and safety of tocilizumab versus placebo in patients with Systemic Sclerosis.

• Register: EUCTR
• Last refreshed on: 28 February 2019
• Main ID: EUCTR2015-000424-28-BE
• Date of registration: 28/07/2015
• Prospective Registration: Yes
• Primary sponsor: F. Hoffmann-La Roche Ltd
• Public title: A study to assess the efficacy and safety of tocilizumab versus placebo in patients with Systemic Sclerosis.
• Scientific title: A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY TO ASSESS THE EFFICACY AND SAFETY OF TOCILIZUMAB VERSUS PLACEBO IN PATIENTS WITH SYSTEMIC SCLEROSIS
• Date of first enrolment: 07/09/2015
• Target sample size: 210
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-000424-28
• 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): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Belgium, Brazil, Bulgaria, Canada, China, Croatia, Denmark, France, Germany, Greece, Hungary, Ireland, Italy, Japan, Lithuania, Mexico, Netherlands, Poland, Portugal, Romania, South Africa, Spain, Switzerland, United Kingdom, United States

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 at baseline (Day 1)
- Diagnosis of SSc, as defined using the American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) criteria (2013)
- SSc disease duration of <=60 months (defined as time from the first non-Raynaud phenomenon manifestation)
- mRSS of >=10 and <=35 units at screening
- Active disease that meets at least one of the following criteria at screening: Disease duration of <=18 months defined as time from the first non-Raynaud phenomenon manifestation; Increase in mRSS of >=3 units compared with the most recent assessment performed within the previous 6 months; Involvement of one new body area and an increase in mRSS of >=2 units compared with the most recent assessment performed within the previous 6 months; Involvement of two new body areas within the previous 6 months; Presence of at least one tendon friction rub
- Presence of at least one of the following at screening: C reactive protein (CRP)>=0.6 milligrams (mg) per deciliter (dL) (>=6 mg/Liter [L]); erythrocyte sedimentation rate (ESR)>=28 millimeter per hour (mm/hr); Platelet count>=330 x 10^9/L (330,000/microliter)
- Uninvolved or mildly thickened skin at one of the following possible injection site locations: Front, middle region of the thigh; Abdomen, except for the 2-inch area directly around the navel; Outer area of the upper arm (if a patient caregiver is giving the injection)
- For women who are not postmenopausal (>=12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use single or combined non-hormonal contraceptive methods that result in a failure rate of <1% per year during the treatment period and for up to 3 months after the last dose of study drug
- For men: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating sperm during the treatment period and for at least 8 weeks after the last dose of study drug

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 140
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 70

Exclusion criteria:
- Pregnant or lactating, or intending to become pregnant during the study
- Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 12 months following randomization
- Skin thickening (scleroderma) limited to the face or areas distal to the elbows or knees at screening
- Rheumatic autoimmune disease other than SSc, including but not limited to rheumatoid arthritis (RA) (diagnosed using ACR/EULAR criteria), systemic lupus erythematosus, mixed connective tissue disorder, polymyositis, dermatomyositis, eosinophilic fasciitis, primary Sjögren's syndrome, and eosinophilic myalgia syndrome, as determined by the investigator
- History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
- Evidence of moderately severe concurrent nervous system, renal, endocrine, or gastrointestinal (GI) disease not related to SSc, as determined by the investigator
Pulmonary disease with FVC <=55% of predicted (best of three measurements) or diffusion capacity of the lung for carbon monoxide [DLCO] (hemoglobin corrected) <=45% of predicted (best of three measurements)
- Class II or higher pulmonary arterial hypertension (PAH), as defined by the World Health Organization
- Evidence of other moderately severe pulmonary disease (e.g., asthma, emphysema), as determined by the investigator
- Cardiovascular disease with significant arrhythmia, congestive heart failure (New York Heart Association Class II-IV), unstable angina, uncontrolled hypertension, cor pulmonale, or symptomatic pericardial effusion
- History of myocardial infarction in the last 6 months prior to screening
- Current liver disease, as determined by the investigator
- History of diverticulitis or chronic ulcerative lower GI disease, such as Crohn disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose a patient to perforations
- Known active current or significant history of recurrent bacterial, viral, fungal, mycobacterial, or other infections, including but not limited to atypical mycobacterial disease, hepatitis B or C, herpes zoster, infected digital ulcers, and osteomyelitis
- Any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks prior to screening or oral antibiotics within 2 weeks prior to screening
- Significant history of recurrent tuberculosis (TB), active TB requiring treatment within the previous 3 years, or untreated latent TB, Patients should be screened for latent TB, and, if positive, will be eligible for the study after treatment per local standard practices
- History of or currently active primary or secondary immunodeficiency
- Evidence of malignant disease, or malignancies diagnosed within the previous 5 years (with the exception of local basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured)
- Neuropathies or other conditions that might interfere with pain evaluation, as determined by the investigator



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

Health Condition(s) or Problem(s) studied

Systemic Sclerosis
MedDRA version: 20.0 Level: LLT Classification code 10042953 Term: Systemic sclerosis System Organ Class: 100000004859

Therapeutic area: Diseases [C] - Skin and Connective Tissue Diseases [C17]

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-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Main Objective: To evaluate the efficacy of tocilizumab (TCZ) compared with placebo on skin sclerosis, as measured by modified Rodnan Skin Score (mRSS) at Week 48

Secondary Objective: •To evaluate the efficacy of TCZ on pulmonary function, patient-reported outcomes, Physician's Global Assessment and time to treatment failure up to Week 48
•To evaluate the safety of TCZ, focusing on the nature, frequency, and severity of serious and non-serious adverse events, the frequency of SSc-related complications, and effects on vital signs, physical findings, and clinical laboratory results, and by assessing the number of digital ulcers
•To assess the long-term safety of TCZ
•To characterize the immunogenic potential of TCZ and to assess the potential relationship between development of anti TCZ antibodies and efficacy, safety, or pharmacokinetic (PK) outcome measures
•To compare changes in levels of pharmacodynamic biomarkers following treatment with TCZ versus placebo
•To characterize the pharmacokinetics of TCZ and evaluate potential relationships between PK parameters for TCZ and efficacy, safety, or immunogenicity outcome measures

Primary end point(s): Change in mRSS from baseline to Week 48

Timepoint(s) of evaluation of this end point: Baseline and up to Week 48

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 1. Baseline and Week 48
2-5. Baseline until Week 48
6. Up to Week 48
7-12. Up to 2 years
13. Baseline (BL), Week (WK) 4, WK 8, WK 16, WK 24, WK 36, WK 48 and WK 96 (for IL-6 and sIL-6R) or at treatment discontinuation [TD] (only sIL-6R) and within 8 weeks of TD (only sIL-6R); BL, WK 4, WK 24, WK 48, WK 72 and WK 96 or at TD (for ESR and CRP)
14. Baseline, Week 4, Week 8, Week 16, Week 24, Week 36, Week 48 and Week 96 or at treatment discontinuation and within 8 weeks of treatment discontinuation.
15. Up to 2 years

Secondary end point(s): 1. Proportions of patients with >= 20%, >= 40%, and >= 60% improvement in mRSS at Week 48 compared with baseline
2. Change in FVC from baseline to Week 48
3. Change in HAQ-DI from baseline to Week 48
4. Change in Patient's Global Assessment from baseline to Week 48
5. Change in Physician's Global Assessment from baseline to Week 48
6. Time to treatment failure, defined as the time from randomization to the time of one of the following events (whichever occurs first) during the 48-week double-blind treatment period: death, decline in percent-predicted FVC > 10% relative to baseline, or > 20% increase in mRSS and an increase in mRSS of >= 5 points occurrence of a predefined SSc-related complication as adjudicated by the Clinical Adjudication Committee
7. Frequency of deaths
8. Nature, frequency, and severity of adverse events
9. Incidence of specific laboratory abnormalities
10. Change from baseline in digital ulcer count
11. Incidence of anti-TCZ antibodies during the study relative to the prevalence of anti TCZ antibodies at baseline
12. Correlation between anti-TCZ antibody status and efficacy, safety, or PK outcome measures
13. Predose ESR and serum IL-6, sIL-6R, and CRP levels at baseline and at subsequent timepoints after initiation of study drug
14. Predose serum TCZ concentration at baseline and at specified timepoints thereafter
15. Correlation between PK parameters for TCZ and efficacy, safety, or immunogenicity outcome measures

Secondary ID(s)

WA29767

2015-000424-28-DK

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd.

Ethics review

Status: Approved
Approval date:
Contact: