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

• Register: EUCTR
• Last refreshed on: 2 September 2024
• Main ID: EUCTR2021-003417-19-BE
• Date of registration: 15/12/2021
• Prospective Registration: Yes
• Primary sponsor: F.Hoffmann-La Roche Ltd
• Public title: A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of RO7204239 in Combination with Risdiplam (RO7034067) in Patients with Spinal Muscular Atrophy
• Scientific 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 PATIENTS WITH SPINAL MUSCULAR ATROPHY
• Date of first enrolment: 08/03/2022
• Target sample size: 180
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2021-003417-19
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: yes Other: yes Other specify the comparator: Placebo + Risdiplam Number of treatment arms in the trial: 8
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Germany, Italy, Netherlands, Poland, Portugal, Spain, United Kingdom, United States

Contacts

• Name: Trial Information Support Line-TISL
• Affiliation: F. Hoffmann-La Roche Ltd

• Name: Trial Information Support Line-TISL
• Affiliation: F. Hoffmann-La Roche Ltd

Key inclusion & exclusion criteria

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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Spinal Muscular Atrophy (SMA)
MedDRA version: 20.1 Level: LLT Classification code 10051203 Term: Spinal muscular atrophy congenital System Organ Class: 100000004850
MedDRA version: 20.1 Level: LLT Classification code 10041583 Term: Spinal muscular atrophy, unspecified System Organ Class: 100000004850
MedDRA version: 20.0 Level: LLT Classification code 10079413 Term: Spinal muscular atrophy type I System Organ Class: 100000004850
MedDRA version: 20.0 Level: LLT Classification code 10079415 Term: Spinal muscular atrophy type III System Organ Class: 100000004850
MedDRA version: 20.0 Level: LLT Classification code 10079416 Term: Spinal muscular atrophy type II System Organ Class: 100000004850
MedDRA version: 20.0 Level: LLT Classification code 10079417 Term: Spinal muscular atrophy infantile onset System Organ Class: 100000004850
MedDRA version: 20.0 Level: LLT Classification code 10079418 Term: Spinal muscular atrophy later onset System Organ Class: 100000004850
MedDRA version: 20.0 Level: LLT Classification code 10079419 Term: Spinal muscular atrophy pre-symptomatic System Organ Class: 100000004850

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Intervention(s)

Product Name: N/A
Product Code: RO7204239/F01-01
Pharmaceutical Form: Solution for injection
INN or Proposed INN: N/A
CAS Number: N/A
Current Sponsor code: RO7204239
Other descriptive name: GYM329
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 80-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Trade Name: Evrysdi
Pharmaceutical Form: Powder for oral solution
INN or Proposed INN: Risdiplam
Current Sponsor code: RO7034067
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 60-

Product Name: N/A
Product Code: RO7204239/F03-01
Pharmaceutical Form: Solution for injection
INN or Proposed INN: N/A
CAS Number: N/A
Current Sponsor code: RO7204239
Other descriptive name: GYM329
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 90-0.75
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Main Objective: Part 1 Ambulant Cohorts A-C
• Evaluation of the safety of RO7204239 in combination with risdiplam compared with placebo in combination with risdiplam
• Evaluation of pharmacokinetic (PK) parameters for RO7204239 when administered in combination with risdiplam
• Evaluation of PK parameters for risdiplam when administered in combination with RO7204239
• Evaluation of the immune response to RO7204239 in combination with risdiplam
• Evaluation of the pharmacodynamic (PD) effects of RO7204239 in combination with risdiplam compared with placebo in combination with risdiplam
• Evaluation of RO7204239 PK/PD effects
Part 2
• Evaluation of the efficacy of RO7204239 in combination with risdiplam compared with placebo in combination with risdiplam

Primary end point(s): Part 1 Ambulant Cohorts A-C
1. Incidence, severity, and causal relationship of adverse events (AEs), with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0)
2. Change from baseline in vital signs, physical findings, ECG, echocardiogram, relevant echocardiographic parameters and clinical laboratory results
3. Incidence of local and systemic injection reactions
4. Incidence of abnormal laboratory findings
5. Incidence of abnormal ECG parameters
6. Incidence of relevant echocardiographic parameter z scores >2
7. Incidence of abnormal vital signs
8. Serum concentration of RO7204239 at specified timepoints
9. Maximum observed concentration (Cmax) of RO7204239 at specified timepoints
10. Area under the concentration-time curve (AUC) of RO7204239 at specified timepoints
11. Trough concentration (Ctrough) of RO7204239 at specified timepoints
12. Plasma concentration of risdiplam (and its metabolite M1) at specified timepoints
13. Cmax of risdiplam (and its metabolite M1) at specified timepoints
14. AUC of risdiplam (and its metabolite M1) at specified timepoints
15. Ctrough of risdiplam (and its metabolite M1) at specified timepoints
16. Prevalence of anti-drug antibodies (ADAs) against RO7204239 at baseline and incidence of ADAs during the study
17. Change from baseline in serum concentrations of total and free latent myostatin, and mature myostatin
18. Percentage change from baseline in the contractile area of skeletal muscle in the dominant thigh as assessed by MRI (participants >=5 years) at Week 24 of combination treatment
19. Percentage change from baseline in the contractile area of skeletal muscle in the dominant calf as assessed by MRI (participants >=5 years) at Week 24 of combination treatment
20. Relationship between PK/PD endpoints, ADA status, and safety or efficacy
Part 2
21. Change from baseline in the Revised Hammersmith Scale (RHS) total score at Week 72 of combination treatment (Study Week 80)

Secondary Objective: Part 2
• Evaluation of the efficacy and PD of RO7204239 in combination with risdiplam compared with placebo in combination with risdiplam
• Evaluation of the safety of RO7204239 in combination with risdiplam compared with placebo in combination with risdiplam
• Evaluation of PK parameters for RO7204239 when administered in combination with risdiplam
• Evaluation of PK parameters for risdiplam when administered in combination with RO7204239
• Evaluation of immune response to RO7204239 in combination with risdiplam

Timepoint(s) of evaluation of this end point: 1-11. Throughout the study at specified timepoints
12-15. At Week 21
16. Throughout the study at specified timepoints
17. Up to Week 85
18-19. At Week 24
20. Up to Week 96
21. At Week 72

Secondary Outcome(s)

Secondary end point(s): Part 2
1. Change from baseline in MFM Domain 1 + Domain 2 (D1 + D2) score at Week 72 of combination treatment (Study Week 80)
2. Change from baseline in MFM-32 item total score at Week 72 of combination treatment (Study Week 80)
3. Change from baseline in the time taken to rise from floor as measured by RHS Item 25 at Week 72 of combination treatment (Study Week 80)
4. Change from baseline in the time taken to walk/run 10 meters as measured by RHS Item 19 at Week 72 of combination treatment (Study Week 80)
5. Percent change from baseline in lean mass as assessed by full-body DXA scan (participants >=5 years) at Week 72 of combination treatment (Study Week 80)
6. Incidence, severity, and causal relationship of AEs, with severity determined according to NCI CTCAE v5.0
7. Change from baseline in vital signs, physical findings, ECG, echocardiogram, relevant echocardiographic parameters and clinical laboratory results
8. Incidence of local and systemic injection reactions
9. Incidence of abnormal laboratory findings
10. Incidence of abnormal ECG parameters
11. Incidence of relevant echocardiographic parameter z scores >2
12. Incidence of abnormal vital signs
13. Serum concentration of RO7204239 at specified timepoints
14. Cmax of RO7204239 at specified timepoints
15. AUC of RO7204239 at specified timepoints
16. Ctrough of RO7204239 at specified timepoints
17. Plasma concentration of risdiplam (and its metabolite M1) at specified timepoints
18. Cmax of risdiplam (and its metabolite M1) at specified timepoints
19. AUC of risdiplam (and its metabolite M1) at specified timepoints
20. Ctrough of risdiplam (and its metabolite M1) at specified timepoints
21. Prevalence of ADAs at baseline and incidence of ADAs during the study; Impact of ADA on PK, PD, safety and efficacy parameters

Timepoint(s) of evaluation of this end point: 1-5. At week 72
6-16. Throughout the study at specified timepoints
17-20. At week 24
21. Throughout the study at specified timepoints

Secondary ID(s)

2021-003417-19-IT

BN42644

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd

Ethics review

Status: Approved
Approval date: 08/03/2022
Contact: