A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of RO7204239 in Combination with Risdiplam (RO7034067) in Patients with Spinal Muscular Atrophy

Phase 1

• Conditions: Spinal Muscular Atrophy (SMA); MedDRA version: 20.1Level: LLTClassification code 10051203Term: Spinal muscular atrophy congenitalSystem Organ Class: 10010331 - Congenital, familial and genetic disorders; MedDRA version: 20.1Level: LLTClassification code 10041583Term: Spinal muscular atrophy, unspecifiedSystem Organ Class: 10010331 - Congenital, familial and genetic disorders; MedDRA version: 20.0Level: LLTClassification code 10079413Term: Spinal muscular atrophy type ISystem Organ Class: 10010331 - Congenital, familial and genetic disorders; MedDRA version: 20.0Level: LLTClassification code 10079415Term: Spinal muscular atrophy type IIISystem Organ Class: 10010331 - Congenital, familial and genetic disorders; MedDRA version: 20.0Level: LLTClassification code 10079416Term: Spinal muscular atrophy type IISystem Organ Class: 10010331 - Congenital, familial and genetic disorders; MedDRA version: 20.0Level: LLTClassification code 10079417Term: Spinal muscular atrophy infantile onsetSystem Organ Class: 10010331 - Congenital, familial and genetic disorders; MedDRA version: 20.0Level: LLTClassification code 10079418Term: Spinal muscular atrophy later onsetSystem Organ Class: 10010331 - Congenital, familial and genetic disorders; MedDRA version: 20.0Level: LLTClassification code 10079419Term: Spinal muscular atrophy pre-symptomaticSystem Organ Class: 10010331 - Congenital, familial and genetic disorders; Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

• Registration Number: EUCTR2021-003417-19-PL
• Lead Sponsor: F.Hoffmann-La Roche Ltd

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2021-10-25
• Last Update Posted: 4 December 2023

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 180

Inclusion Criteria

• Confirmed genetic diagnosis of 5q-autosomal recessive SMA
• Part 2 only: available survival of motor neuron 2 gene copy number as previously determined by genetic testing and recorded in the participant's medical history
• Symptomatic SMA disease, as per investigator’s clinical judgement
• Age at screening:
o Part 1 Cohorts A, B, and D: 5-10 years, inclusive
o Part 1 Cohort C: 2-4 years, inclusive
o Part 2: 2-25 years, inclusive
• For Part 1 Cohorts A, B, and C and Part 2 only: Participants who are ambulant, where ambulant is defined as able to walk/run unassisted (i.e., without the use of assistive devices such as canes, walking sticks, crutches, walkers, person/hand held assistance, braces, orthoses, over the malleoli insoles or any other type of support) 10 meters in <= 30 seconds as measured by the Timed 10-Meter Walk/Run Test [10MWRT]) at screening
• For Part 1 Cohort D only: Participants who are able to sit, defined by:
o A score of 3 on Item 9 of the Motor Function Measure-32 item (MFM32)
o A score of at least 2 on Item 10 of the MFM32
• For Part 1 Cohort D only: Participants who are able to raise a standardized plastic cup with a 200 g weight in it to the mouth, using both hands if necessary, defined by a score of 3 on the entry item of the Revised Upper Limb Module (RULM)
• Participants who have received previous SMA disease-modifying therapies may be included provided that
o Onasemnogene abeparvovec was received at least 90 days prior to screening. Participants should be tapered off steroids prior to receiving risdiplam. In addition, participants should have normal levels of liver function tests, coagulation parameters, platelets, and troponin-I at 90 days after administration of onasemnogene abeparvovec or at least 1 month after tapering off corticosteroids, whichever comes later
o Nusinersen last dose was received at least 90 days prior to screening
o Risdiplam is switched to the investigational medicinal product (IMP) provided by the site
• Able and willing to comply with the study protocol and to complete all study procedures, measurements, and visits
• Negative pregnancy test at screening for females of childbearing potential
• Females of childbearing potential or who may reach childbearing potential during the study: must agree to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for both 17 months after the final dose of RO7204239 and 28 days after the final dose of risdiplam
• For males who are expected to reach sexual maturity during the study: participants must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agree to refrain from donating sperm during the treatment period and for 28 days after the final dose of risdiplam and 4 months after the final dose of RO7204239

Are the trial subjects under 18? yes
Number of subjects for this age range: 180
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

• For Part 1 Cohorts A and B only: Participants with contraindications for magnetic resonance imaging (MRI) scan, difficulties maintaining a prolonged supine position, or any other clinical history or examination finding that would pose a potential hazard in combination with MRI
• Part 1 Cohort D only:
o Participants who are unable to adopt the correct position to ensure adequate quality of dual-energy X-ray absorptiometry (DXA) scan acquisition, as determined by the DXA scan technologist
o Participants who have contractures at screening that would interfere with DXA scan acquisition or functional assessments, as confirmed by the DXA scan technologist and clinical evaluator
o For participants able to take steps only: Able to walk unassisted 10 meters in <= 30 seconds as measured by the timed 10MWRT at screening
o Participants who have severe scoliosis (curvature > 40°) at screening based on the participant's most recent X ray as performed per standard of care or scoliosis that would interfere with functional assessments, as confirmed by the clinical evaluator. An X-ray is not required if it is not clinically indicated
o Participants who require invasive ventilation, tracheostomy, or the use of non-invasive ventilation during the daytime
• For Part 2 only: Participants who recently initiated treatment (within 6 months prior to screening) with oral salbutamol or another ß2-adrenergic agonist taken orally
• 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. For those who have completed a risdiplam study, or participated in a nusinersen or onasemnogene abeparvovec study, the same as described under inclusion criteria apply
• Received previous administration of anti-myostatin therapies
• Any history of cell therapy
• Hospitalized for a pulmonary event within the last 2 months or planned hospitalization at the time of screening
• Previous surgery for scoliosis or hip fixation in the 6 months preceding screening or planned within the next 9 months (Part 1) or 21 months (Part 2)
• Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system diseases considered to be clinically significant
• Clinically significant electrocardiography (ECG) abnormalities at screening
• Clinically significant abnormal findings at echocardiography at screening from average of triplicate measurement or cardiovascular disease indicating a safety risk for participants
• Any major illness within 1 month before screening
• Received any multidrug and toxin extrusion1/2K (MATE) substrates within 2 weeks before screening
• Hereditary fructose intolerance
• Use of any of the following medications within 90 days prior to screening: riluzole, valproic acid, hydroxyurea, sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, growth hormone, anabolic steroids, probenecid, acetyl cholinesterase inhibitors, agents that could potentially increase or decrease muscle strength, and agents with known or presumed histone deacetylase (HDAC) inhibitory effect
• Clinically significant abnormalities in laboratory test results
• Ascertained or presumptive hypersensitivity to RO7204239 or risdiplam, or to the constituents of their formulations
• Concomitant disease or a condition that could interfere with, or treatment of which might interfere with, the conduct of the study, or that would pose an unacceptable risk to the participant in this st

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified