E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Spinal Muscular Atrophy (SMA) |
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E.1.1.1 | Medical condition in easily understood language |
SMA is a group of hereditary diseases that destroys nerve cells in the spinal cord that control essential skeletal muscle activity such as speaking, walking, breathing, and swallowing. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10051203 |
E.1.2 | Term | Spinal muscular atrophy congenital |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10041583 |
E.1.2 | Term | Spinal muscular atrophy, unspecified |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10079413 |
E.1.2 | Term | Spinal muscular atrophy type I |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10079415 |
E.1.2 | Term | Spinal muscular atrophy type III |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10079416 |
E.1.2 | Term | Spinal muscular atrophy type II |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10079417 |
E.1.2 | Term | Spinal muscular atrophy infantile onset |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10079418 |
E.1.2 | Term | Spinal muscular atrophy later onset |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10079419 |
E.1.2 | Term | Spinal muscular atrophy pre-symptomatic |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Part 1 • 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
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E.2.2 | Secondary objectives of the trial |
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
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 seconds as measured by the Timed 10-Meter Walk/Run Test [10MWRT]) at screening • 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 • Participants who have a legally authorized representative able to consent for the participant • Participants who are 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
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E.4 | Principal exclusion criteria |
• Participants with 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 • Participants who are receiving or have received previous administration of anti-myostatin therapies • For Part 1 participants aged 5-10 years only: Participants who have contraindications for magnetic resonance imaging (MRI) scans, difficulties maintaining a prolonged supine position, or any other clinical history or examination finding that would pose a potential hazard in combination with MRI • Participants with any history of cell therapy • Participants who have been hospitalized for a pulmonary event within the last 2 months or planned hospitalization at the time of screening • Participants who have had 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) • Participants who have unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system diseases considered to be clinically significant • Participants who have clinically significant electrocardiography (ECG) abnormalities at screening • Participants with clinically significant abnormal findings at echocardiography at screening from average of triplicate measurement or cardiovascular disease indicating a safety risk for participants • Participants who have had any major illness within 1 month before screening • Participants who have received any MATE1/2K substrates within 2 weeks before screening • Participants with hereditary fructose intolerance • Participants who have 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 • For Part 2 only: Participants who have recently initiated treatment (within <6 months prior to screening) with oral salbutamol or another β2-adrenergic agonist taken orally is not allowed • Participants who have clinically significant abnormalities in laboratory test results • Participants who have ascertained or presumptive hypersensitivity to RO7204239 or risdiplam, or to the constituents of their formulations • Participants with 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 study • Participants who have a history of any malignancy • Participants who have any clinically relevant history of anaphylactic reaction requiring inotropic support • Participants who have any abnormal skin conditions, pigmentation or lesions in the area intended for subcutaneous (SC) injection (abdomen) and that would prevent visualization of potential injection site reactions to RO7204239 • Participants with immobilization, surgical procedures, fracture, or trauma to the upper or lower limbs within 90 days prior to screening • Female participants who are pregnant or breastfeeding, or intending to become pregnant during the study or within either 17 months after the final dose of RO7204239 or 28 days after the final dose of risdiplam
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1 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 RHS total score at Week 72 of combination treatment (Study Week 80)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to Week 96 2. Baseline to Week 96 3-7. Up to Week 96 8-11. At Weeks 1, 2, 3, 5, 9, 13, 17, 21, 22, 23, 24, 29, 41, 53, 65, 72, 85 and 96 12-15. At Week 21 16. At Weeks 1, 9, 17, 24, 29, 41, 53, 65, 72, 85 and 96 17. Baseline to Week 85 18-19. Baseline to Week 24 20. Up to Week 96 21. Baseline to Week 72
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E.5.2 | Secondary end point(s) |
Part 2 1. Change from baseline in Motor Function Measure (MFM) Domain 1 + Domain 2 (D1 + D2) score at Week 72 of combination treatment (Study Week 80) 2. Change from baseline in Motor Function Measure-32 item (MFM32) 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 Revised Hammersmith Scale (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. Change from baseline in lean muscle mass as assessed by full-body dual-energy X-ray absorptiometry (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. Impact of ADA on PK, PD, safety and efficacy parameters
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-5. Baseline to Week 72 of combination treatment (Study Week 80) 6. Up to Week 72 of combination treatment (Study Week 80) 7. Baseline to Week 72 of combination treatment (Study Week 80) 8-12. Up to Week 72 of combination treatment (Study Week 80) 13-16. At Weeks 1, 5, 9, 13, 17, 21, 24, 37, 48, 61 and 72 (of combination treatment) 17-20. At Week 24 21. Up to Week 72 of combination treatment (Study Week 80)
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 8 |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 |
France |
Poland |
Netherlands |
Spain |
Germany |
Italy |
Belgium |
Croatia |
United Kingdom |
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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
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The end of this study is defined as the date of the last visit of the last participant in the study or the date at which the last data point required for statistical analysis (i.e., for the final analysis) or safety follow-up is received from the last participant in the study, whichever occurs later. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |