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    Summary
    EudraCT Number:2015-000424-28
    Sponsor's Protocol Code Number:WA29767
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-08-11
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2015-000424-28
    A.3Full title of the trial
    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
    III. FÁZISÚ, MULTICENTRIKUS, RANDOMIZÁLT, KETTŐS VAK, PLACEBO KONTROLLÁLT, PÁRHUZAMOS CSOPORTOS VIZSGÁLAT A TOCILIZUMAB HATÁSOSSÁGÁNAK ÉS BIZTONSÁGOSSÁGÁNAK ÉRTÉKELÉSÉRE PLACEBÓVAL ÖSSZEHASONLÍTVA, SZISZTÉMÁS SCLEROSISBAN SZENVEDŐ BETEGEK ESETÉBEN
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess the efficacy and safety of tocilizumab versus placebo in patients with Systemic Sclerosis.
    A.3.2Name or abbreviated title of the trial where available
    FOCUSSCED
    A.4.1Sponsor's protocol code numberWA29767
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF. Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF. Hoffmann-La Roche Ltd.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF. Hoffmann-La Roche Ltd.
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.6E-mailglobal.rochegenentechtrials@roche.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name RoActemra 162 mg
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code RO487-7533/F10-04
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTocilizumab
    D.3.9.1CAS number 375823-41-9
    D.3.9.3Other descriptive nameTOCILIZUMAB
    D.3.9.4EV Substance CodeSUB20313
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number180
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Systemic Sclerosis
    E.1.1.1Medical condition in easily understood language
    Systemic Sclerosis is a rare connective tissue disease involving the skin, underlying tissue, blood vessels, and major organs.
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10042953
    E.1.2Term Systemic sclerosis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of tocilizumab (TCZ) compared with placebo on skin sclerosis, as measured by modified Rodnan Skin Score (mRSS) at Week 48
    E.2.2Secondary objectives of the trial
    •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
    E.2.3Trial contains a sub-study No
    E.3Principal 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
    - 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 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
    E.4Principal 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 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
    E.5 End points
    E.5.1Primary end point(s)
    Change in mRSS from baseline to Week 48
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline and up to Week 48
    E.5.2Secondary 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
    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
    E.5.2.1Timepoint(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
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity.
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA58
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Belgium
    Brazil
    Bulgaria
    Canada
    Croatia
    Denmark
    France
    Germany
    Greece
    Hungary
    Italy
    Japan
    Lithuania
    Mexico
    Netherlands
    Poland
    Portugal
    Romania
    South Africa
    Spain
    Switzerland
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study will occur when the last participating patient completes the last scheduled visit of the follow-up period. This is expected to occur 2 years after the last patient is enrolled.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 140
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 116
    F.4.2.2In the whole clinical trial 210
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The Sponsor will offer post-trial access to tocilizumab free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product. Please see section 4.3.5 of the protocol for further details.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-09-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-02-04
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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