A study to investigate the safety, tolerability, and pharmacokinetics/pharmacodynamics of Risdiplam in adult and pediatric patients with spinal muscular atrophy

Phase 1

Conditions: Spinal Muscular Atrophy (SMA)
MedDRA version: 20.1Level: PTClassification code 10041582Term: Spinal muscular atrophySystem Organ Class: 10010331 - Congenital, familial and genetic disorders
Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Registration Number: EUCTR2016-004184-39-BE

Lead Sponsor: F. Hoffmann-La Roche Ltd

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 180

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

Are the trial subjects under 18? yes
Number of subjects for this age range: 105
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 75
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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 ß2-adrenergic agonist taken orally is not allowed. Patients who have been on oral salbutamol (or another ß2-adrenergic agonist) for >= 6 weeks before enrollment and have shown good tolerance are allowed. The dose of ß2-adrenergic agonist should remain stable as much as possible for the duration of the study. Use of inhaled ß2-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

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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