E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Spinal Muscular Atrophy (SMA) |
|
E.1.1.1 | Medical 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.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10041582 |
E.1.2 | Term | Spinal muscular atrophy |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
•To evaluate the safety and tolerability of Risdiplam
•To investigate the pharmacokinetics (PK) of Risdiplam and metabolites as appropriate
|
|
E.2.2 | Secondary objectives of the trial |
•To investigate the PK/ pharmacodynamics (PD) relationship of Risdiplam. The PD investigations will include analyses of Survival of motor neuron (SMN) mRNA splice forms and SMN protein |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Males and females 6 months to 60 years of age inclusive (at screening)
- Confirmed diagnosis of 5q-autosomal recessive SMA, including:
•Genetic confirmation of homozygous deletion or heterozygosity predictive of loss of function of the SMN1 gene.
•Clinical history, signs, or symptoms attributable to SMA
- Previous enrollment in Study BP29420 (Moonfish) with the splicing modifier RO6885247 or previous treatment with nusinersen (defined as having received >= 4 doses of nusinersen, provided that the last dose was received >=90 days prior to screening), olesoxime (provided that the last dose was received <=12 months and >= 90 days prior to screening) or AVXS-101 (provided that the time of treatment was >=12 months prior to screening)
- Adequately recovered from any acute illness at the time of screening and considered well enough to participate in the opinion of the Investigator
- Women of childbearing potential: Negative blood pregnancy test at screening, agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating eggs for at least 28 days after the final dose of study drug For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm
-For patients aged 2 years or younger at screening:
•Receiving adequate nutrition and hydration (with or without gastrostomy) at the time of screening, in the opinion of the Investigator
•Medical care meets local accepted standard of care, in the opinion of the Investigator
•Would be able to complete all study procedures, measurements and visits, and the parent or caregiver of the patient has adequately supportive psychosocial circumstances, in the opinion of the Investigator
•Parent or caregiver of patient is willing to consider nasogastric, naso-jejunal or gastrostomy tube placement, as recommended by the Investigator, during the study to maintain safe hydration, nutrition and treatment delivery
•Parent or caregiver of patient is willing to consider the use of non-invasive ventilation, as recommended by the Investigator during the study
|
|
E.4 | Principal exclusion criteria |
-Inability to meet study requirements
-Concomitant participation in any investigational drug or device study
- With the exception of studies with Olesoxime, AVXS101 or nusinersen: 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
-Any history of gene or cell therapy, with the exception of AVXS-101
-Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system diseases as considered to be clinically significant by the Investigator
-Inadequate venous or capillary blood access for the study procedures, in the opinion of the Investigator
-For patients aged < 2 years, hospitalization for a pulmonary event within 2 months prior to screening and pulmonary function not fully recovered at the time of screening
-Lactating women
-Suspicion of regular consumption of drugs of abuse
-For adults and adolescents only, i.e., aged > 12 years, positive urine test for drugs of abuse or alcohol at the screening or Day − 1 visit
-Presence of clinically significant ECG abnormalities before study drug administration
-Presence of clinically significant cardiovascular, blood pressure, and heart rate measures
-History of malignancy if not considered cured
-For patients aged > 6 years, significant risk for suicidal behavior, in the opinion of the Investigator as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)
-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
-Use of any OCT-2 and MATE substrates within 2-weeks before dosing including the mother, if breastfeeding the patient
-Use of the following medications within 90 days prior to enrollment: 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 (e.g., oral retinoids including over-the-counter formulations, amiodarone. Use of inhaled corticosteroids is allowed
-Recently initiated treatment for SMA (within < 6 weeks prior to enrollment) with oral salbutamol or another β2-adrenergic agonist taken orally is not allowed. Patients who have been on oral salbutamol (or another β2-adrenergic agonist) for >= 6 weeks before enrollment and have shown good tolerance are allowed. The dose of β2-adrenergic agonist should remain stable as much as possible for the duration of the study. Use of inhaled β2-adrenergic agonists (e.g., for the treatment of asthma) is allowed
-Any prior use of chloroquine, hydroxychloroquine, retigabin, vigabatrin or thioridazine is not allowed. Use of other medications known to or suspected of causing retinal toxicity within one year prior to enrollment 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
-Concomitant disease or condition that could interfere with, or treatment of which might interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the patient in this study
-Recent history (less than one year) of ophthalmological diseases
-Any prior use of an inhibitor or inducer of FMO1 or FMO3 taken within 2 weeks (or within 5 elimination half-lives, whichever is longer) prior to dosing. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1.Incidence and severity of adverse events and serious adverse events with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events scale, Version 4.0
2.Incidence of treatment discontinuations due to adverse events
3.Incidence of abnormal vital sign, laboratory, and ECG abnormalities
4.Incidence of clinically significant findings on ophthalmological examination
5.Incidence of clinically significant findings on neurological examination
6.Physical examination
7.Incidence of emergence or worsening of symptoms as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) (adult version for adults and adolescents, pediatric version for patients aged 6-11 years)
8.Mean plasma concentrations of Risdiplam and metabolites
9.Peak plasma concentration (Cmax)
10.Area under the curve (AUC)
11.Concentration at the end of a dosing interval (Ctrough) to assess steady-state
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-7. Up to 5 years
8.-11. Aged 2 to 60 Years: Days 1, 14, 28, 91, 183, 273, 365, 456, 637, 729, and at completion/early withdrawal;
Aged 6 month to 2 Years: Days 1, 14, 28, 91, 182, 273,364, 456, 546, 637, 728, every 26 weeks during the extension phase and at completion/early withdrawal |
|
E.5.2 | Secondary end point(s) |
1.SMN mRNA in blood
2.SMN protein levels in blood |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Aged 2 to 60 Years: Days -1, 1, 28, 91, 183, 365, 729, and at completion/early withdrawal; Patients Aged 6 Months to <2 Years: Day 1, 28, 182, 364 and 728 and at completion/early withdrawal
2.Aged 2 to 60 Years: Day -1, Day 28, 91, 183, 365, 729, and at completion/early withdrawal; Patients Aged 6 Months to <2 Years: Day 1, 28, 182, 364 and 728 and at completion/early withdrawal |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United States |
Belgium |
France |
Germany |
Italy |
Netherlands |
Poland |
Switzerland |
United Kingdom |
|
E.8.7 | Trial 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 (completion of 24 months treatment phase and 3 years extension phase). |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 10 |