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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

F. Hoffmann-La Roche AG

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

8 Apr 2022 → ongoing

Decision date (initial)

2024-08-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

F. Hoffmann-La Roche AG

External identifiers

EU CT number

2023-506761-65-00

EudraCT number

2021-003417-19

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Pharmacodynamic, Safety, Others

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

Secondary objectives 5

1. Part 2: Evaluation of the efficacy and PD of RO7204239 in combination with risdiplam compared with placebo in combination with risdiplam
2. Part 2: Evaluation of the safety of RO7204239 in combination with risdiplam compared with placebo in combination with risdiplam
3. Part 2: Evaluation of PK parameters for RO7204239 when administered in combination with risdiplam
4. Part 2: Evaluation of PK parameters for risdiplam when administered in combination with RO7204239
5. Part 2: Evaluation of the immune response to RO7204239 in combination with risdiplam

Conditions and MedDRA coding

Spinal Muscular Atrophy (SMA)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

IPD plan description

N/A

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Age at screening: - Part 1 Cohorts A (ambulant participants), B (ambulant participants), and D (non-ambulant participants): 5-10 years, inclusive; - Part 1 Cohort C (ambulant participants): 2-4 years, inclusive; - Part 2 (ambulant participants): 2-25 years, inclusive
2. Participants who have a confirmed genetic diagnosis of 5q-autosomal recessive SMA
3. 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
4. Inclusion Criteria 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 measures by the Timed 10-Meter Walk/Run Test [10MWRT] at screening
5. Inclusion Criteria for Part 1 Cohort D only: Participants who are able to sit, defined by: - A score of 3 on Item 9 of the MFM32 (sitting without upper limb support while maintaining contact between the two hands for 5 seconds); - A score of at least 2 on Item 10 of the MFM32 (while seated, leaning forward to touch a tennis ball and sitting back again, either with or without upper limb support)
6. Inclusion Criteria for Part 1 Cohort D only: Participants who are able to raise a standardized plastic cup with a 200g 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)

Exclusion criteria 6

1. 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
2. Receiving or have received previous administration of anti-myostatin therapies
3. Exclusion Criteria for Part 1 Cohort D only: 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 (e.g., in participants with mild scoliosis)
4. Exclusion Criteria for Part 1 Cohorts A and B only: Participants with contraindications for MRI scan (including, but not restricted to, claustrophobia, pacemaker, artificial heart valves, cochlear implants, presence of foreign metal objects in heart or body, including spinal rods, intracranial vascular clips, insulin pumps, etc.), difficulties maintaining a prolonged supine position, or any other clinical history or examination finding that would pose a potential hazard in combination with MRI
5. Exclusion Criteria for Part 1 Cohort D only: Participants who are unable to adopt the correct position to ensure adequate quality of DXA scan acquisition, as determined by the DXA scan technologist
6. Exclusion Criteria for Part 1 Cohort D only: For participants able to take steps only: Able to walk 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 10MWRT at screening

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 21

1. 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. Part 1 Ambulant Cohorts A-C: 2. Change from baseline in vital signs, physical findings, ECG, echocardiogram, relevant echocardiographic parameters, and clinical laboratory results
3. Part 1 Ambulant Cohorts A-C: 3. Incidence of local and systemic injection reactions
4. Part 1 Ambulant Cohorts A-C: 4. Incidence of abnormal laboratory findings
5. Part 1 Ambulant Cohorts A-C: 5. Incidence of abnormal ECG parameters
6. Part 1 Ambulant Cohorts A-C: 6. Incidence of relevant echocardiographic parameter z scores > 2
7. Part 1 Ambulant Cohorts A-C: 7. Incidence of abnormal vital signs
8. Part 1 Ambulant Cohorts A-C: 8. Serum concentration of RO7204239 at specified timepoints
9. Part 1 Ambulant Cohorts A-C: 9. Maximum observed concentration (Cmax) of RO7204239 at specified timepoints
10. Part 1 Ambulant Cohorts A-C: 10. Area under the concentration-time curve (AUC) of RO7204239 at specified timepoints
11. Part 1 Ambulant Cohorts A-C: 11.Trough concentration (Ctrough) of RO7204239 at specified timepoints
12. Part 1 Ambulant Cohorts A-C: 12. Plasma concentration of risdiplam (and its metabolite M1) at specified timepoints
13. Part 1 Ambulant Cohorts A-C: 13. Cmax of risdiplam (and its metabolite M1) at specified timepoints
14. Part 1 Ambulant Cohorts A-C: 14. AUC of risdiplam (and its metabolite M1) at specified timepoints
15. Part 1 Ambulant Cohorts A-C: 15. Ctrough of risdiplam (and its metabolite M1) at specified timepoints
16. Part 1 Ambulant Cohorts A-C: 16. Prevalence of anti-drug antibodies (ADAs) against RO7204239 at baseline and incidence of ADAs during the study
17. Part 1 Ambulant Cohorts A-C: 17. Change from baseline in serum concentrations of total and free latent myostatin, and mature myostatin
18. Part 1 Ambulant Cohorts A-C: 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. Part 1 Ambulant Cohorts A-C: 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. Part 1 Ambulant Cohorts A-C: 20. Relationship between PK and PD endpoints, ADA status, safety, or efficacy
21. Part 2: 21. Change from baseline in the Revised Hammersmith Scale (RHS) total score at Week 72 of combination treatment (Study Week 80)

Secondary endpoints 21

1. 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. Part 2: 2. Change from baseline in MFM-32 item total score at Week 72 of combination treatment (Study Week 80)
3. Part 2: 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. Part 2: 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. Part 2: 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. Part 2: 6. Incidence, severity, and causal relationship of AEs, with severity determined according to NCI CTCAE v5.0
7. Part 2: 7. Change from baseline in vital signs, physical findings, ECG, echocardiogram, relevant echocardiographic parameters and clinical laboratory results
8. Part 2: 8. Incidence of local and systemic injection reactions
9. Part 2: 9. Incidence of abnormal laboratory findings
10. Part 2: 10. Incidence of abnormal ECG parameters
11. Part 2: 11. Incidence of relevant echocardiographic parameter z scores >2
12. Part 2: 12. Incidence of abnormal vital signs
13. Part 2: 13. Serum concentration of RO7204239 at specified timepoints
14. Part 2: 14. Cmax of RO7204239 at specified timepoints
15. Part 2: 15. AUC of RO7204239 at specified timepoints
16. Part 2: 16. Ctrough of RO7204239 at specified timepoints
17. Part 2: 17. Plasma concentration of risdiplam (and its metabolite M1) at specified timepoints
18. Part 2: 18. Cmax of risdiplam (and its metabolite M1) at specified timepoints
19. Part 2: 19. AUC of risdiplam (and its metabolite M1) at specified timepoints
20. Part 2: 20. Ctrough of risdiplam (and its metabolite M1) at specified timepoints
21. Part 2: 21. Prevalence of ADAs at baseline and incidence of ADAs during the study; Impact of ADA on PK, PD, safety and efficacy parameters

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

F. Hoffmann-La Roche AG

Sponsor organisation

F. Hoffmann-La Roche AG

Address

Grenzacherstrasse 124

City

Basel

Postcode

4058

Country

Switzerland

Scientific contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Public contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Third parties 16

Locations

9 EU/EEA countries · 26 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 144 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications