A Study to Investigate the Safety and Efficacy of RO7204239 in Combination With Risdiplam (RO7034067) in Ambulatory Children With Spinal Muscular Atrophy

• ClinicalTrials.gov Identifier: NCT05115110
• Recruitment Status: Recruiting
• First Posted: November 10, 2021
• Last Update Posted: January 19, 2023
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: November 1, 2021
• First Posted Date: November 10, 2021
• Last Update Posted Date: January 19, 2023
• Actual Study Start Date: June 2, 2022
• Estimated Primary Completion Date: December 15, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 14, 2022)

• Part 1 - Percentage of participants with adverse events (AEs) [ Time Frame: Up to 4.5 years ]
• Part 1 - Incidence of relevant echocardiographic parameter z scores > 2 [ Time Frame: Up to 4.5 years ]
• Part 1 - Serum concentration of RO7204239 [ Time Frame: Through Week 96 ]
• Part 1 - Time to maximum serum concentration (Cmax) of RO7204239 [ Time Frame: Through Week 96 ]
• Part 1 - Area under the curve (AUC) of RO7204239 [ Time Frame: Through Week 96 ]
• Part 1 - Trough concentration (Ctrough) of RO7204239 [ Time Frame: Through Week 96 ]
• Part 1 - Plasma concentration of risdiplam [ Time Frame: Week 21 ]
• Part 1 - Plasma concentration of risdiplam metabolite (M1) [ Time Frame: Week 21 ]
• Part 1 - Cmax of risdiplam [ Time Frame: Week 21 ]
• Part 1 - AUC of risdiplam [ Time Frame: Week 21 ]
• Part 1 - Ctrough of risdiplam [ Time Frame: Week 21 ]
• Part 1 - Incidence of anti-drug antibodies (ADAs) [ Time Frame: Through Week 96 ]
• Part 1 - Change from baseline in serum concentration of total myostatin [ Time Frame: Through Week 85 ]
• Part 1 - Change from baseline in serum concentration of free latent myostatin [ Time Frame: Through Week 85 ]
• Part 1 - Change from baseline in serum concentration of mature myostatin [ Time Frame: Through Week 85 ]
• Part 1 - Percentage change from baseline in the contractile area of skeletal muscle in the dominant thigh muscles as assessed by magnetic resonance imaging (MRI) in participants aged at least 5 years [ Time Frame: Week 24 of combination treatment ]
• Part 1 - Percentage change from baseline in the contractile area of skeletal muscle in the dominant calf muscles as assessed by MRI in participants aged at least 5 years [ Time Frame: Week 24 of combination treatment ]
• Part 2 - Change from baseline in Revised Hammersmith Scale (RHS) total score [ Time Frame: Week 72 of combination treatment (study Week 80) ]

Original Primary Outcome Measures (submitted: November 1, 2021)

• Part 1 - Percentage of participants with adverse events (AEs) [ Time Frame: Up to 4.5 years ]
• Part 1 - Incidence of relevant echocardiographic parameter z scores > 2 [ Time Frame: Up to 4.5 years ]
• Part 1 - Serum concentration of RO7204239 [ Time Frame: Through Week 96 ]
• Part 1 - Time to maximum serum concentration (Cmax) of RO7204239 [ Time Frame: Through Week 96 ]
• Part 1 - Area under the curve (AUC) of RO7204239 [ Time Frame: Through Week 96 ]
• Part 1 - Trough concentration (Ctrough) of RO7204239 [ Time Frame: Through Week 96 ]
• Part 1 - Plasma concentration of risdiplam [ Time Frame: Week 21 ]
• Part 1 - Plasma concentration of risdiplam metabolite (M1) [ Time Frame: Week 21 ]
• Part 1 - Cmax of risdiplam [ Time Frame: Week 21 ]
• Part 1 - AUC of risdiplam [ Time Frame: Week 21 ]
• Part 1 - Ctrough of risdiplam [ Time Frame: Week 21 ]
• Part 1 - Incidence of anti-drug antibodies (ADAs) [ Time Frame: Through Week 96 ]
• Part 1 - Change from baseline in serum concentration of total myostatin [ Time Frame: Through Week 85 ]
• Part 1 - Change from baseline in serum concentration of free latent myostatin [ Time Frame: Through Week 85 ]
• Part 1 - Change from baseline in serum concentration of mature myostatin [ Time Frame: Through Week 85 ]
• Part 1 - Change from baseline in the contractile area of skeletal muscle in thigh muscles as assessed by magnetic resonance imaging (MRI) in participants aged at least 5 years [ Time Frame: Week 24 of combination treatment ]
• Part 1 - Change from baseline in the contractile area of skeletal muscle in calf muscles as assessed by MRI in participants aged at least 5 years [ Time Frame: Week 24 of combination treatment ]
• Part 2 - Change from baseline in Revised Hammersmith Scale (RHS) total score [ Time Frame: Week 72 of combination treatment (study Week 80) ]

Current Secondary Outcome Measures (submitted: November 1, 2021)

• Part 2 - Change from baseline in Motor Function Measure (MFM) Domain 1 + Domain 2 (D1 + D2) score [ Time Frame: Week 72 of combination treatment (study Week 80) ]
• Part 2 - Change from baseline in MFM-32 total score [ Time Frame: Week 72 of combination treatment (study Week 80) ]
• Part 2 - Change from baseline in time taken to rise from the floor as measured by RHS Item 25 [ Time Frame: Week 72 of combination treatment (study Week 80) ]
• Part 2 - Change from baseline in time taken to walk/run 10 meters as measured by RHS Item 19 [ Time Frame: Week 72 of combination treatment (study Week 80) ]
• Part 2 - Change from baseline in lean muscle mass as assessed by full body dual energy X-ray absorptiometry (DXA) scan in participants aged at least 5 years [ Time Frame: Week 72 of combination treatment (study Week 80) ]
• Part 2 - Percentage of participants with adverse events (AEs) [ Time Frame: Up to 4.5 years ]
• Part 2 - Serum concentration of RO7204239 [ Time Frame: Through Week 80 ]
• Part 2 - Cmax of RO7204239 [ Time Frame: Through Week 80 ]
• Part 2 - AUC of RO7204239 [ Time Frame: Through Week 80 ]
• Part 2 - Ctrough of RO7204239 [ Time Frame: Through Week 80 ]
• Part 2 - Plasma concentration of risdiplam [ Time Frame: Week 32 ]
• Part 2 - Plasma concentration of risdiplam metabolite (M1) [ Time Frame: Week 32 ]
• Part 2 - Cmax of risdiplam [ Time Frame: Week 32 ]
• Part 2 - AUC of risdiplam [ Time Frame: Week 32 ]
• Part 2 - Ctrough of risdiplam [ Time Frame: Week 32 ]
• Part 2 - Incidence of ADAs [ Time Frame: Through Week 80 ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Investigate the Safety and Efficacy of RO7204239 in Combination With Risdiplam (RO7034067) in Ambulatory Children With Spinal Muscular Atrophy
• Official Title: A Two-Part, Seamless, Multi-Center, Randomized, Placebo-Controlled, Double-Blind Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of RO7204239 in Combination With Risdiplam (RO7034067) in Ambulant Patients With Spinal Muscular Atrophy

Brief Summary

Risdiplam works by helping the body produce more survival motor neuron (SMN) protein throughout the body. This means fewer motor neurons - nerve cells that pass impulses from nerves to muscles to cause movement - are lost, which may improve how well muscles work in people with SMA. RO7204239 is an investigational anti-myostatin antibody that is designed to target myostatin. Myostatin plays an important role in the regulation of skeletal muscle size by controlling growth. Inhibiting myostatin may help muscles grow in size and strength. RO7204239 in combination with risdiplam, which is designed to increase the amount of SMN protein throughout the body, has the potential to further improve motor function and clinical outcomes for people living with SMA.

This trial will study the safety and efficacy of RO7204239 in combination with risdiplam in children aged 2-10 years with spinal muscular atrophy (SMA) that are ambulant.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Spinal Muscular Atrophy (SMA)

Intervention

• Drug: RO7204239
  RO7204239 will administered every 4 weeks (Q4W) by subcutaneous (SC) injection into the abdomen.
• Drug: Placebo
  Placebo will be administered Q4W by SC injection into the abdomen.
• Drug: Risdiplam
  Risdiplam will be administered orally once daily (QD) for the duration of the study.
  Other Name: RO7034067

Study Arms

• Experimental: RO7204239 + Risdiplam

  Participants who have not previously been treated with risplidam will receive risdiplam for at least 8 weeks prior to randomization into a treatment group (Part 1 only). Participants that have been treated with risdiplam for at least 8 continuous weeks immediately prior to joining the study may be immediately randomized to combination therapy, or join the study run-in period (the period between screening and randomization to a treatment group) where they will continue to receive risdiplam monotherapy until randomization.

  Participants enrolled in Part 1 will receive RO7204239 + risdiplam for 24 weeks, followed by RO7204239 + risdiplam for 72 weeks.

  Participants enrolled in Part 2 will receive treatment with RO7204239 + risdiplam for 72 weeks.

  Once the treatment period has completed (Part 1 or Part 2), participants will have the option of treatment with RO7204239 + risdiplam for 2 additional years.

  Interventions:

  • Drug: RO7204239
  • Drug: Risdiplam
• Active Comparator: Risdiplam + Placebo

  Participants who have not previously been treated with risplidam will receive risdiplam for at least 8 weeks prior to randomization into a treatment group (Part 1 only). Participants that have been treated with risdiplam for at least 8 continuous weeks immediately prior to joining the study may be immediately randomized to combination therapy, or join the study run-in period (the period between screening and randomization to a treatment group) where they will continue to receive risdiplam monotherapy until randomization.

  Participants enrolled in Part 1 will receive placebo + risdiplam for 24 weeks, followed by RO7204239 + risdiplam for 72 weeks.

  Participants enrolled in Part 2 will receive treatment with placebo + risdiplam for 72 weeks.

  Once the treatment period has completed (Part 1 or Part 2), participants will have the option of treatment with RO7204239 + risdiplam for 2 additional years.

  Interventions:

  • Drug: Placebo
  • Drug: Risdiplam

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 1, 2021): 180
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 15, 2026
• Estimated Primary Completion Date: December 15, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Participants who are 2 to 10 years of age inclusive at screening
• Participants who have a confirmed genetic diagnosis of 5q-autosomal recessive SMA
• Symptomatic SMA disease, as per investigator's clinical judgement
• 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 as measured by the Timed 10-Meter Walk/Run Test [10MWRT] seconds at screening
• Participants who have received previous SMA disease-modifying therapies may be included provided that: 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, coagulatory 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; Nusinersen last dose was received at least 90 days prior to screening; Risdiplam is switched to the investigational medicinal product (IMP) provided by the site

Exclusion Criteria:

• 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, with the exception of those who have completed a risdiplam study, or participated in a nusinersen or onasemnogene abeparvovec study
• Receiving or have received previous administration of anti-myostatin therapies
• For Part 1 participants aged 5 to 10 years only: contraindications for MRI scans including difficulties maintaining a prolonged supine position, or any other clinical history or examination finding that would pose a potential hazard in combination with MRI
• Any history of cell therapy
• Hospitalization for a pulmonary event within the last 2 months or planned hospitalization at the time of screening
• Past 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 ECG abnormalities at screening from average of triplicate measurement, abnormal findings at echocardiography, or cardiovascular disease indicating a safety risk for participants at the time of screening
• Any major illness within 1 month before screening
• Received any multidrug and toxin extrusion (MATE1/2K) substrates within 2 weeks before screening
• Hereditary fructose intolerance
• Used 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 at the time of screening
• Ascertained or presumptive hypersensitivity to RO7204239 or risdiplam, or to the constituents of its formulations
• Clinically relevant history of anaphylactic reaction requiring inotropic support
• Any abnormal skin conditions, pigmentation or lesions in the area intended for SC injection (abdomen) and that would prevent visualization of potential injection site reactions to RO7204239
• Immobilization, surgical procedures, fracture, or trauma to the upper or lower limbs within 90 days prior to screening

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 10 Years (Child)
• Accepts Healthy Volunteers: No

Contacts

Contact: Reference Study ID Number: BN42644 https://forpatients.roche.com/; 888-662-6728; global-roche-genentech-trials@gene.com

• Listed Location Countries: Belgium, Italy, Netherlands, Poland, United Kingdom, United States
• Removed Location Countries: Germany

Administrative Information

• NCT Number: NCT05115110
• Other Study ID Numbers: BN42644
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: January 2023