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    Summary
    EudraCT Number:2018-002087-12
    Sponsor's Protocol Code Number:BN40703
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2018-12-05
    Trial 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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2018-002087-12
    A.3Full title of the trial
    AN OPEN-LABEL STUDY OF RISDIPLAM IN INFANTS WITH GENETICALLY DIAGNOSED AND PRESYMPTOMATIC SPINAL MUSCULAR ATROPHY
    PROWADZONE METODĄ OTWARTEJ PRÓBY BADANIE RISDIPLAMU U NIEMOWLĄT Z ROZPOZNANYM GENETYCZNIE RDZENIOWYM ZANIKIEM MIĘŚNI W FAZIE PRZEDOBJAWOWEJ
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Risdiplam in Infants with Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy
    Badanie risdiplamu u niemowląt z rozpoznanym genetycznie rdzeniowym zanikiem mięśni w fazie przedobjawowej
    A.4.1Sponsor's protocol code numberBN40703
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/284/2017
    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
    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 No
    D.2.5.1Orphan drug designation number
    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/F13
    D.3.9.3Other descriptive nameRO7034067
    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.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 No
    D.2.5.1Orphan drug designation number
    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/F12
    D.3.9.3Other descriptive nameRO7034067
    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.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
    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)
    E.1.1.1Medical condition in easily understood language
    SMA is a genetic disorder that affects the control of muscle movement. It is caused by a loss of motor neurons, in the spinal cord and the part of the brain that is connected to the spinal cord
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10079419
    E.1.2Term Spinal muscular atrophy pre-symptomatic
    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
    •To evaluate the efficacy of risdiplam in patients with two copies of the survival motor neuron (SMN)2 gene (excluding the known SMN2 gene modifier mutation c.859G> C) and baseline compound muscle action potential (CMAP) ≥ 1.5 mV, as determined by the proportion of patients who are sitting without support after 12 months of treatment
    E.2.2Secondary objectives of the trial
    •To evaluate the efficacy of risdiplam on the development of clinical symptoms of SMA
    •To evaluate the efficacy of risdiplam on survival and permanent ventilation
    •To evaluate the efficacy of risdiplam on achievement of motor milestones
    •To evaluate the efficacy of risdiplam on motor function
    •To evaluate the efficacy of risdiplam on growth measures
    •To evaluate the efficacy of risdiplam on nutritional status of the patients
    •To evaluate the efficacy of risdiplam on the degree of innervation upon treatment with risdiplam
    •To evaluate the pharmacodynamic effects of risdiplam
    •To evaluate the respiratory effects of risdiplam
    •To evaluate the safety of risdiplam
    •To characterize the pharmacokinetics profile of risdiplam
    •To identify biomarkers that are predictive of response to risdiplam
    •To evaluate parent (or caregiver)-rated health status and health-related quality of life
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Males and females aged from birth (1 day) to 6 weeks (42 days) of age at the time of first dose (Day 1); a minimum age of 7 days at first dose is required for the first infant to be enrolled
    - Gestational age of 37-42 weeks for singleton births; gestational age of 34-42 weeks for twins
    - Body weight >= 3rd percentile for age, using appropriate country-specific guidelines
    - Genetic diagnosis of 5q-autosomal recessive SMA, including confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of the SMN1 gene
    - Absence of clinical signs or symptoms at screening (Day -30 to Day -2) or at baseline (Day -1) that are, in the opinion of the investigator, strongly suggestive of SMA
    - Receiving adequate nutrition and hydration at the time of screening, in the opinion of the investigator
    - Adequately recovered from any acute illness at baseline and considered well enough to participate in the study, in the opinion of the investigator
    - Able and expected to be able to safely travel to the study site for the entire duration of the study and in accordance to the frequency of required study visits, in the opinion of the investigator
    - Able to complete all study procedures, measurements, and visits, and the parent (or caregiver), in the opinion of the investigator, has adequately supportive psychosocial circumstances
    - Parent (or caregiver) is willing to consider nasogastric, naso-jejunal, or gastrostomy tube placement during the study to maintain safe hydration, nutrition, and treatment delivery, if recommended by the investigator
    - Parent (or caregiver) is willing to consider the use of non-invasive ventilation during the study, if recommended by the investigator
    E.4Principal exclusion criteria
    - Concomitant or previous participation in any investigational drug or device study at any time
    - Concomitant or previous administration of an SMN2-targeting antisense oligonucleotide, SMN2-splicing modifier, or gene therapy either in a clinical study or as part of medical care
    - Presence of significant concurrent syndromes or diseases
    - In the opinion of the investigator, inadequate venous or capillary blood access for the study procedures
    - Requiring invasive ventilation, tracheostomy or awake non-invasive ventilation
    - Awake hypoxemia (SaO2 < 95%) with or without ventilator support
    - Multiple or fixed contractures and/or hip subluxation or dislocation at birth
    - Systolic blood pressure or diastolic blood pressure or heart rate considered to be clinically significant by the investigator
    - Presence of clinically relevant ECG abnormalities before study drug administration; corrected QT interval using Bazett’s method > 460 ms; personal or family history (first degree relatives) of congenital long QT syndrome indicating a safety risk for patients as determined by the investigator. First-degree atrioventricular block or isolated right bundle branch block are allowed
    - The infant taking any nutrients known to modulate CYP3A activity (e.g., grapefruit juice; Seville orange) within 2 weeks prior to dosing (Day 1)
    - The infant (and the mother, if breastfeeding the infant) taking any inhibitor of CYP3A4 taken within 2 weeks, any inducer of CYP3A4 taken within 4 weeks, any OCT 2 and MATE substrates and known FMO1 or FMO3 inhibitors or substrates
    - Clinically significant abnormalities in laboratory test results
    - Ascertained or presumptive hypersensitivity to risdiplam or to the constituents of its formulation
    - Treatment with oral salbutamol or another beta-2 adrenergic agonist taken orally for SMA is not allowed. Use of inhaled beta-2 adrenergic agonists is allowed
    - Infants exposed to drugs with known retinal toxicity given to mothers during pregnancy (and lactation) should not be enrolled. Anticipated need for drugs known to cause retinal toxicity during the study.
    - Diagnosis of ophthalmic diseases
    E.5 End points
    E.5.1Primary end point(s)
    1.The proportion of infants with two copies of the survival motor neuron (SMN) 2 gene (excluding the known SMN2 gene modifier mutation c.859G> C) and baseline compound muscle action potential (CMAP) >=1.5 mV who are sitting without support. Sitting is defined as “sits without support for 5 seconds” as assessed in Item 22 of the Bayley Scales
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. At Month 12
    E.5.2Secondary end point(s)
    1.Proportion of infants developing clinically manifested SMA by month 12 and 24
    2.Time to death or permanent ventilation
    3.Proportion of infants who are alive without permanent ventilation at Month 12 and 24
    4.Proportion of infants who achieve the attainment level of the motor milestones as assessed in the Hammersmith Infant Neurological Examination-2 (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) at Month 12 and 24
    5.Proportion of infants sitting without support at Month 24 (as assessed in Item 22 of Bayley Scales of Infant and Toddler Development®, Third Edition [BSID-III] Gross Motor Scale) for 5 seconds
    6.Proportion of infants sitting without support at Month 24 (as assessed in Item 26 of BSID-III Gross Motor Scale) for 30 seconds
    7.Proportion of infants standing at Month 24 (defined as “Stands Alone” for at least 3 seconds as assessed in Item 40 and 42 of the BSID-III Gross Motor Scale)
    8.Proportion of infants walking at Month 24 (defined as “Walks Alone” takes at least 3 steps as assessed in Item 42 of the BSID-III Gross Motor Scale)
    9.Change from baseline score in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) motor function scale at Month 12 and 24
    10.Proportion of infants who achieve a score of 40 and 50 or higher in the CHOP INTEND motor function scale at Month 12 and 24
    11.Proportion of infants who achieve a score of 64 in the CHOP INTEND motor function scale at Month 12 and 24
    12.Number and proportion of infants within 3rd percentile of normal range for weight-for-age, length/height-for-age, weight-for-length/height, and head circumference-for-age (from enrollment) at Month 12 and 24
    13.Change from baseline percentiles at each timepoint for weight-for-age, length/height-for-age, weight-for-length/height, and head circumference-for-age
    14.Change from baseline in chest circumference at Month 12 and 24
    15.Ratio between chest and head circumferences at Month 12 and 24
    16.Proportion of infants with phase angle of < 20 degrees, as measured by respiratory plethysmography, at Month 12 and 24
    17.Proportion of infants with the ability to swallow at Month 12 and 24
    18.Level of food intake at Month 12 and 24
    19.Change from baseline in CMAP at Month 12 and 24
    20.SMN mRNA and SMN protein levels in blood
    21.Incidence and severity of adverse events with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE) v5
    22.Incidence and severity of serious adverse events
    23.Incidence of treatment discontinuation due to adverse events
    24.Incidence of abnormal laboratory, ECG values and vital signs abnormalities
    25.Incidence of clinically significant findings on ophthalmological examination
    26.Anthropometric examination including weight, height, and head and chest circumferences
    27.Plasma concentration of risdiplam and its metabolites
    28.Area under curve of risdiplam
    29.Concentration at the end of a dosing interval to assess steady-state
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. At Month 12 and 24
    2. Up to 7 years
    3-4. At Month 12 and 24
    5-8. At Month 24
    9. Baseline (Day -1) to Month 12 and 24
    10-12. At Month 12 and 24
    13. Baseline to 7 years
    14. Baseline to Month 12 and 24
    15-18. At Month 12 and 24
    19. Baseline to Month 12 and 24
    20. Day 1, 56, 196, 364, 728 and at early withdrawal
    21-26. Up to 7 years
    27-29. Up to 7 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 No
    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 No
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    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
    Australia
    Belgium
    Brazil
    China
    Italy
    Poland
    Russian Federation
    Saudi Arabia
    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 occurs.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    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 years6
    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: 25
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 15
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 10
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    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 No
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 6
    F.4.2.2In the whole clinical trial 25
    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)
    Study will continue until risdiplam is commercially available in the country of the site as per local regulation or per the Sponsors decision to terminate risdiplam development.After completion of 2 years treatment each patient will be offered treatment in the OLE phase for at least 3 years.The Sponsor will offer continued access to risdiplam free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product as per 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 Decision2019-03-21
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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