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    Summary
    EudraCT Number:2016-000778-40
    Sponsor's Protocol Code Number:BP39056
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-08-16
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-000778-40
    A.3Full title of the trial
    A TWO PART SEAMLESS, OPEN-LABEL, MULTICENTER STUDY TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS AND EFFICACY OF RO7034067 IN INFANTS WITH TYPE1 SPINAL MUSCULAR ATROPHY
    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 RO7034067 in Infants With Type1 Spinal Muscular Atrophy
    A.4.1Sponsor's protocol code numberBP39056
    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 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/F06 with solvent (RO7034067/F08)
    D.3.4Pharmaceutical form Powder and solvent 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 INNn/a
    D.3.9.2Current sponsor codeRO7034067/F06
    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.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/F07 with solvent (RO7034067/F09)
    D.3.4Pharmaceutical form Powder and solvent 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 INNn/a
    D.3.9.2Current sponsor codeRO7034067/F07
    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 number120
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Type 1 Spinal Muscular Atrophy (SMA)
    E.1.1.1Medical condition in easily understood language
    SMA is a muscular disease that affects child's muscular development leading to muscle weakness and progressive loss of movement. Type 1 children are usually diagnosed before 6 months of age.
    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 19.0
    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 and pharmacodynamics of RO7034067 in infants with Type 1 SMA and to select the dose for Part 2

    Part 2
    •To assess the efficacy of RO7034067 measured as the proportion of infants sitting without support after 12 months of treatment
    E.2.2Secondary objectives of the trial
    •To assess:Safety and tolerability of RO7034067,Pharmacokinetics of RO7034067,Pharmacodynamic effects of RO7034067
    •To assess at 12 months of treatment with RO7034067 the effect on motor development milestones
    •To assess at 24 months of treatment with RO7034067 the effect on sitting without support and further motor development milestones
    •To assess the proportion of infants who achieve a score of 40 or higher in the Childrens Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale at 12 months of treatment
    •To assess the proportion of infants who achieve a reduction of 30 degrees in phase angle (respiratory inductance plethysmography) at 12 months of treatment
    •To assess at 12 and 24 months of treatment the proportion of infants who are alive without permanent ventilation
    •To assess the impact of treatment with RO7034067 on time to event (death, permanent ventilation)
    •To assess the effect at 12 and 24 months of treatment with RO7034067 on muscle electrophysiology
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Males and females aged between 28 days (1 month) of life and 210 days (7 months) (inclusive) at enrollment
    - A legally authorized representative must be able to consent for the patient according to International Conference on Harmonisation and local regulations
    - Gestational age of 37 to 42 weeks
    - Confirmed diagnosis of 5q-autosomal recessive SMA, including:
    •Genetic confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of the survival motor neuron 1 (SMN1) gene
    •Clinical history, signs or symptoms attributable to Type 1 SMA, i.e., hypotonia, absent deep tendon reflexes and/or tongue fasciculations with onset after the age of 28 days, but prior to the age of 3 months (inclusive), and inability to sit independently (without support) at the time of screening
    - Patient has two SMN2 gene copies, as confirmed by central testing
    - Body weight >= 3rd percentile for age, using appropriate country-specific guidelines (for the first infant only > 7 kg)
    - Receiving adequate nutrition and hydration (with or without gastrostomy) at the time of screening, in the opinion of the Investigator
    - Adequately recovered from any acute illness at the time of screening and considered well-enough to participate in the opinion of the Investigator
    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, whichever is longer
    - Concomitant or previous participation in a SMN2 targeting antisense oligonucleotide or SMN2 splicing modifier or gene therapy study
    - Any history of cell therapy
    - Hospitalization for pulmonary event within the last 2 months, or planned at the time of screening
    - Unstable gastrointestinal, renal, hepatic, endocrine or cardiovascular system diseases
    - Inadequate venous or capillary blood access for the study procedures
    - Patients requiring invasive ventilation or tracheostomy
    - Patients requiring awake non-invasive ventilation or with awake hypoxemia (arterial oxygen saturation < 95%) with or without ventilator support
    - Patients with a history of respiratory failure or severe pneumonia, and have not fully recovered their pulmonary function at the time of screening
    - Multiple or fixed contractures and/or hip subluxation or dislocation at birth
    - Presence of non-SMA related concurrent syndromes or diseases
    - Confirmed (2 consecutive measurements) systolic blood pressure or diastolic blood pressure outside the 95th percentile for age; resting heart rate < 70 bpm or > 170 bpm
    - Presence of clinically relevant electrocardiogram (ECG) abnormalities before study drug administration
    - History of malignancy if not considered cured
    - 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
    - Taking any nutrients known to modulate cytochrome [CYP] 3A activity within 2 weeks prior to administration of study drugs
    - The infant (and the mother, if breastfeeding the infant):
    • Any inhibitor of CYP3A4 taken within 2 weeks (or within 5 times the elimination half life, whichever is longer) prior to dosing, including but not limited to ketoconazole, miconazole, itraconazole, fluconazole, erythromycin, clarithromycin, ranitidine, cimetidine
    • Any inducer of CYP3A4 taken within 4 weeks (or within 5 times the elimination half-life, whichever is longer) prior to dosing, including but not limited to rifampicin, rifabutin, glucocorticoids, carbamazepine, phenytoin, phenobarbital, St. John's wort
    • Any organic cation transporter-2 and multidrug and toxic compound extrusion substrates shall be avoided
    • Any known flavin containing monooxygenase (FMO) 1 or FMO3 inhibitors or substrates
    - Clinically significant abnormalities in laboratory test results
    - Ascertained or presumptive hypersensitivity to RO7034067 or the constituents of its formulation
    - Prior use, anticipated need for hydroxychloroquine, vigabatrin, retigabine, or any other drug known to cause retinal toxicity during the study
    - Recent history (less than 6 months) of ophthalmic disease that would interfere with the conduct of the study as assessed by an ophthalmologist
    E.5 End points
    E.5.1Primary end point(s)
    Part 1 and 2: Safety
    1. Incidence and severity of adverse events (AE) and serious adverse events
    2. Incidence of treatment discontinuations due to AE
    3. Incidence of abnormal laboratory and ECG values
    4. Clinically significant vital signs abnormalities
    5. Anthropometric and ophthalmological examination

    Pharmacokinetics
    6.Plasma concentrations of RO7034067, and its metabolite(s)

    Pharmacodynamic
    7. Assessment of SMN protein in blood
    8.Assessment of SMN messenger ribonucleic acid (mRNA) in blood

    Part 2: Efficacy
    9.Proportion of infants who are sitting without support at 12 months of treatment assessed by the Gross Motor Scale of the Bayley Scales of Infant and Toddler development – Third Edition (BSID-III)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1-4. Up to 2 years
    5. Screening (D [Day] -30 to D -2), D56, D119, D182, D245, D301, D364, D427, D490, D546, D609, D672, D728
    6. D1, D2, D7, D14, D28, D56, D84, D119, D182, D245, D301, D364, D427, D490, D546, D609, D672, D728
    7. D1, D14, D28, D119, D245, D364, D609, D728
    8. D1, D14, D28, D245, D364, D609, D728
    9. At Month 12
    E.5.2Secondary end point(s)
    Part 2
    1. Plasma concentrations of RO7034067 and its metabolite(s)
    2. Assessment of SMN protein in blood
    3. Assessment of SMN mRNA in blood
    4. Change from baseline in the Total Raw Score of the BSID-III gross motor scale at Month 12 and 24
    5. Proportion of infants who achieve the attainment levels of the motor milestones assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 and 24
    6. Proportion of infants who achieve a score of 40 or higher in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) at Month 12
    7. Proportion of infants who achieve a reduction of 30 degrees in their phase angle from baseline, as measured by respiratory inductance plethysmography, at Month 12
    8. Proportion of infants who achieve an increase of at least 0.3 millivolt from baseline in their compound muscle action potential negative peak amplitude at Month 12 and 24
    9. Time to permanent ventilation (from enrollment)
    10. Proportion of infants who are alive without permanent ventilation at Month 12 and 24
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. D1, D2, D14, D28, D56, D119, D182, D245, D301, D364, D427, D490, D546, D609, D672, D728
    2. D1, D28, D119, D245, D364, D609, D728
    3. D1, D28, D245, D364, D609, D728
    4. Baseline, Month 12 and 24
    5. Month 12 and 24
    6. Month 12
    7. Baseline and Month 12
    8. Baseline, Month 12 and 24
    9. Up to 2 years
    10. At Month 12 and 24
    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 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 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 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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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
    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.
    The study will continue until RO7034067 is commercially available in the infant’s country, or as per local regulation, or per the Sponsor’s decision to terminate RO7034067 development. However, the study will not exceed 4 years (or less as per country specific requirements) after the last infant is enrolled in the study.
    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: 64
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 64
    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
    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 44
    F.4.2.2In the whole clinical trial 64
    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)
    Post-trial access to study drug (SD) to eligible patients is offered free of charge according to the Roche Global Policy. A patient will be eligible to receive SD after the end of study if all of these conditions are met:patient has a life-threatening or severe medical condition and requires continued SD treatment for his or her well-being/no appropriate alternative treatments available/patient and his or her doctor comply with and satisfy any legal or regulatory requirements that apply to them
    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 Decision2016-10-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-09-15
    P. End of Trial
    P.End of Trial StatusOngoing
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