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    Summary
    EudraCT Number:2016-000750-35
    Sponsor's Protocol Code Number:BP39055
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-07-12
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2016-000750-35
    A.3Full title of the trial
    A TWO-PART SEAMLESS, MULTI-CENTER RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE BLIND STUDY TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS AND EFFICACY OF RO7034067 IN TYPE 2 AND 3 SPINAL MUSCULAR ATROPHY PATIENTS.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of Risdiplam (RO7034067) in type 2 and 3 spinal muscular atrophy patients
    A.4.1Sponsor's protocol code numberBP39055
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/089/2020
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/19/2145
    D.3 Description of the IMP
    D.3.1Product nameRO7034067
    D.3.2Product code RO7034067/F12
    D.3.4Pharmaceutical form Powder for oral solution
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNrisdiplam
    D.3.9.1CAS number 1825352-65-5
    D.3.9.2Current sponsor codeRO7034067
    D.3.9.4EV Substance CodeSUB179686
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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.IMP: 2
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/19/2145
    D.3 Description of the IMP
    D.3.1Product nameRO7034067
    D.3.2Product code RO7034067/F13
    D.3.4Pharmaceutical form Powder for oral solution
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNrisdiplam
    D.3.9.1CAS number 1825352-65-5
    D.3.9.2Current sponsor codeRO7034067
    D.3.9.4EV Substance CodeSUB179686
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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 placeboPowder for oral solution
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboPowder for oral solution
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Spinal Muscular Atrophy (SMA) Type 2 and 3
    E.1.1.1Medical condition in easily understood language
    Spinal Muscular Atrophy, a genetic progressive neuromuscular disease characterized by profound weakness and muscle atrophy that is the leading genetic cause of death in babies and toddlers.
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10041582
    E.1.2Term Spinal muscular atrophy
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part 1:
    •To evaluate the safety, tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of risdiplam in patients with Type 2 and Type 3 (ambulant or non-ambulant) SMA, and to select the dose for Part 2 of the study

    Part 2:
    •To evaluate efficacy of risdiplam compared to placebo in terms of motor function in Type 2 and non-ambulant Type 3 SMA patients, as assessed by the change from baseline in the total score of the Motor Function Measure (MFM) at 12 months
    E.2.2Secondary objectives of the trial
    Part 2:To investigate
    •PK/PD relationship of risdiplam by PK/PD modeling
    •efficacy of 12 month treatment with risdiplam in terms of motor function as assessed by the Hammersmith Functional Motor Scale Expanded (HFMSE) and the revised upper limb module (RULM)
    •efficacy of 12 month treatment with risdiplam in terms of responder analyses of the MFM,HFMSE,RULM
    •efficacy of 12 month treatment with risdiplam in terms of respiratory function as assessed by Sniff nasal inspiratory pressure and, in patients aged 6 years and older,by Maximal Inspiratory Pressure,Maximal Expiratory Pressure,Forced vital capacity,Forced expiratory volume (FEV1) and Peak cough flow
    •proportion of patients who experience a pre-specified disease related adverse event by Month 12
    •efficacy of 12 month treatment with risdiplam in terms of global health status as assessed by the Clinical Global Impression of Change and independence as measured by the SMA Independence Scale
    •safety and tolerability of risdiplam
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Males and females 2 to 25 years of age inclusive
    - For Part 1: Type 2 or 3 SMA ambulant or non-ambulant. For Part 2: Type 2 or 3 SMA non-ambulant.
    Non-ambulant is defined as not having the ability to walk unassisted for 10 m or more
    - Confirmed diagnosis of 5q-autosomal recessive SMA
    - Negative blood pregnancy test at screening and agreement to comply with measures to prevent pregnancy and restrictions on sperm donation
    E.4Principal exclusion criteria
    - Concomitant or previous participation in any investigational drug or device study within 90 days
    prior to screening, or 5 half-lives of the drug, whichever is longer
    - Concomitant or previous administration of a SMN2 targeting antisense oligonucleotide, SMN2 splicing modifier or gene therapy either in a clinical study or as part of medical care.
    - Any history of cell therapy
    - Hospitalization for a pulmonary event within the last 2 months or planned at time of screening
    - Surgery for scoliosis or hip fixation in the one year preceding screening or planned within the next 18 months
    - Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system diseases as considered to be clinically significant by the Investigator
    - Presence of clinically significant ECG abnormalities before study drug administration from average of triplicate measurement or cardiovascular disease indicating a safety risk for patients as determined by the Investigator
    - History of malignancy if not considered cured
    - Significant risk for suicidal behavior, in the opinion of the Investigator as assessed by the C-SSRS (>6 years of age)
    - Any major illness within one month before the screening examination or any febrile illness within one week prior to screening and up to first dose administration
    - Any Organic cation transporter (OCT)-2 and multidrug and toxin extrusion (MATE) substrates within 2 weeks before dosing
    - Use of the following medications within 90 days prior to randomization: riluzole, valproic acid, hydroxyurea, sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, growth hormone, anabolic steroids, probenecid, agents anticipated to increase or decrease muscle strength, agents with known or presumed histone deacetylase (HDAC) inhibitory effect, and medications with known phototoxicity liabilities
    - Recently initiated treatment (within < 6 months prior to randomization) with oral salbutamol or another 2-adrenergic agonist taken orally
    - Any prior use of chloroquine, hydroxychloroquine, retigabin, vigabatrin or thioridazine, is not allowed.
    - Clinically significant abnormalities in laboratory test results
    - Donation or loss of blood >= 10% of blood volume within three months prior to screening
    - Ascertained or presumptive hypersensitivity (e.g., anaphylactic reaction) to risdiplam or to the constituents of its formulation
    - Recent history (less than one year) of ophthalmological diseases
    - Patients requiring invasive ventilation or tracheostomy
    - Any inhibitor or inducer of FMO1 or FMO3 taken within 2 weeks (or within 5 times the elimination half-life, whichever is longer) prior to dosing.
    E.5 End points
    E.5.1Primary end point(s)
    Part 1
    1. Incidence of adverse events and serious adverse events
    2. Maximum plasma concentration (Cmax) of risdiplam
    3. Area under the curve (AUC) of risdiplam
    4. Concentration at the end of a dosing interval (Ctrough) of risdiplam

    Part 2
    5. Change from baseline in the total MFM 32 score at Month 12
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to 24 months
    2-4. Days 1, 7, 14, 28, 56, 120, 246, 365, 490, 609, and 729
    5. Baseline (Day -1) and Month 12
    E.5.2Secondary end point(s)
    Part 2
    1.SMN2 mRNA in blood
    2.SMN protein levels in blood
    3.Change from baseline in total score of HFMSE at Month 12
    4.Change from baseline in the total score of the revised upper limb module (RULM) at Month 12
    5.Proportion of patients who achieve stabilization or improvement (i.e., a change from baseline >= 0) on the total MFM score at Month 12
    6.Proportion of patients who achieve an improvement of at least one standard error of measurement (SEM calculated at baseline) on the total MFM score at Month 12.
    7.Proportion of patients who achieve stabilization or improvement (i.e., a change from baseline >= 0) on the total HFMSE score at Month 12.
    8.Proportion of patients who achieve stabilization or improvement (i.e., a change from baseline >= 0) on the total RULM score at Month 12.
    9.Change from baseline in the MFM domain scores of D1, D2, D3 and the total combined score of (D1 + D2) at Month 12.
    10.Change from baseline in the best SNIP (expressed as a percentage of the predicted value) at Month 12.
    11.Change from baseline in the best MIP at Month 12.
    12.Change from baseline in the best MEP at Month 12
    13.Change from baseline in FEV1 in patients aged 6 to 25 years at Month 12
    14.Change from baseline in FVC in patients aged 6 to 25 years at Month 12.
    15.Change from baseline in the peak cough flow (PCF) in patients aged 6 to 25 years at Month 12.
    16.Change from baseline in the Total Score of the caregiver-reported SMA independence Scale (SMAIS) at Month 12.
    17.Change from baseline in the Total score of the patient-reported SMA independence scale (SMAIS) at Month 12
    18.Proportion of patients rated by clinicians as no change or improved in the Clinical Global Impression of Change (CGI-C) Scale at Month 12 (Part 2 only).
    19.Proportion of patients rated by clinicians as improved in the Clinical Global Impression of Change (CGI-C) Scale at Month 12.
    20.Proportion of patients who experience at least one disease related adverse event by Month 12
    21.Number of disease-related adverse events per patient-year at Month 12
    22.PedsQL 4.0 Generic Core scale(Part 1 only)
    23.PedsQL 3.0 Neuromuscular module (Part 1 only)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Part 1: Days -1, 1, 7, 14, 28, 120, 246, 365, 729; Part 2: Days -1, 1, 7, 28, 120, 246, 365, 729
    2. Part 1: Days -1, 7, 14, 28, 120, 246, 365, 729; Part 2: Days -1, 7, 28, 120, 246, 365, 729, every 26 weeks thereafter
    3-18. Baseline (Day-1) and Month 12
    19-21. Up to Month 12
    22-23. Week 35, Week 62, at early withdrawal
    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 Yes
    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
    genetic testing
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 Yes
    E.8.1.7.1Other trial design description
    2 part design
    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.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA31
    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
    China
    Croatia
    France
    Germany
    Hungary
    Italy
    Japan
    Mexico
    Poland
    Romania
    Russian Federation
    Serbia
    Spain
    Switzerland
    Turkey
    Ukraine
    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 this study is defined as the date when the last patient last visit (LPLV) occurs.LPLV is expected to occur approximately 5 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 Yes
    F.1.1Number of subjects for this age range: 185
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 123
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 62
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 34
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Pediatric patients may provide according to local regulation informed assent
    informed consent for study participation will be obtained from parents or legal guardian
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 219
    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)
    A patient will be eligible to receive study drug after completing the study if all of the following conditions are met: The patient has a life-threatening or severe medical condition and requires continued study drug treatment for his or her well-being/There are no appropriate alternative treatments available to the patient/The patient and his/her doctor comply with and satisfy any legal or regulatory requirements that apply to them. See furher details in section 4.4.4 of the protocol.
    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 Decision2016-09-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-02-17
    P. End of Trial
    P.End of Trial StatusOngoing
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