A Study of Risdiplam in Infants with Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

F. Hoffmann-La Roche AG

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

29 Mar 2019 → ongoing

Decision date (initial)

2023-11-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

F. Hoffmann-La Roche Ltd

External identifiers

EU CT number

2023-506009-20-00

EudraCT number

2018-002087-12

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacokinetic, Efficacy, Safety

1. To evaluate the efficacy of risdiplam in patients with two copies of the survival motor neuron (SMN)2 gene (excluding the known SMN2 gene modifier mutation c.859G> C) and baseline compound muscle action potential (CMAP) amplitude ≥ 1.5mV, as determined by the proportion of patients who are sitting without support after 12 months of treatment

Secondary objectives 10

1. 1. To evaluate the efficacy of risdiplam on the development of clinically manifested SMA
2. 2. To evaluate the efficacy of risdiplam on survival and permanent ventilation
3. 3. To evaluate the efficacy of risdiplam on achievement of motor milestones
4. 4. To evaluate the efficacy of risdiplam on motor function
5. 5. To evaluate the efficacy of risdiplam on growth measures
6. 6. To evaluate the efficacy of risdiplam on nutritional status of the patients
7. 7. To evaluate the efficacy of risdiplam on the degree of innervation upon treatment with risdiplam
8. 8. To evaluate the pharmacodynamic effects of risdiplam
9. 9. To evaluate the safety of risdiplam
10. 10. To characterize the pharmacokinetics profile of risdiplam

Conditions and MedDRA coding

Spinal Muscular Atrophy (SMA)

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002070-PIP01-16

Plan to share IPD

No

IPD plan description

n/a

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 1. Males and females aged from birth (1 day) to 6 weeks (42 days) of age at the time of first dose (Day 1); a minimum age of 7 days at first dose is required for the first infant to be enrolled
2. 2. Gestational age of 37-42 weeks for singleton births; gestational age of 34-42 weeks for twins
3. 3. Body weight ≥ 3rd percentile for age, using appropriate country specific guidelines
4. 4. Genetic diagnosis of 5q-autosomal recessive SMA, including confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of the SMN1 gene
5. 5. Absence of clinical signs or symptoms at screening (Day -42 to Day -2) or at baseline (Day -1) that are, in the opinion of the investigator, strongly suggestive of SMA
6. 6. Receiving adequate nutrition and hydration at the time of screening, in the opinion of the investigator

Exclusion criteria 6

1. 1. Concomitant or previous participation in any investigational drug or device study at any time
2. 2. Concomitant or previous administration of an SMN2-targeting antisense oligonucleotide, SMN2-splicing modifier, or gene therapy either in a clinical study or as part of medical care
3. 3. Presence of significant concurrent syndromes or diseases
4. 4. In the opinion of the investigator, inadequate venous or capillary blood access for the study procedures
5. 5. Requiring invasive ventilation, tracheostomy or awake non-invasive ventilation
6. 6. Awake hypoxemia (SaO2 < 95%) with or without ventilator support

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1. The proportion of infants with two copies of the SMN 2 gene (excluding the known SMN2 gene modifier mutation c.859G> C) and baseline CMAP amplitude ≥1.5 mV who are sitting without support after 12 months of treatment. Sitting is defined as “sits without support for 5 seconds” as assessed in Item 22 of the Bayley Scales of Infant and Toddler Development®, Third Edition [BSIDIII] Gross Motor Scale.

Secondary endpoints 35

1. 1. Proportion of patients developing clinically manifested SMA at month 12 and 24 of treatment
2. 2. Time to death or permanent ventilation
3. 3. Proportion of patients who are alive without permanent ventilation at Month12 and 24 of treatment
4. 4. Proportion of patients alive (at Month 12 and Month 24 of treatment)
5. 5. Proportion of patients who achieve the attainment level of the motor milestones as assessed in the Hammersmith Infant Neurological Examination-2 (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) at Month 12 and 24 of treatment
6. 6. Proportion of patients sitting without support at Month 24 of treatment (as assessed in Item 22 of the BSID-III Gross Motor Scale) for 5 seconds
7. 7. Proportion of patients with two copies of the SMN2 gene sitting without support at Month 12 of treatment (as assessed in Item 22 of BSID-III Gross Motor Scale) for 5 seconds (independent of the CMAP value at baseline)
8. 8. Proportion of patients sitting without support at Month 12 and 24 of treatment (as assessed in Item 26 of the BSID-III Gross Motor Scale) for 30 seconds
9. 9. Proportion of patients standing at Month 24 of treatment (defined as “Stands Alone” for at least 3 seconds as assessed in Item 40 of the BSID-III Gross Motor Scale)
10. 10. Proportion of patients walking at Month 24 of treatment (defined as “Walks Alone” takes at least 3 steps as assessed in Item 42 of the BSID-III Gross Motor Scale)
11. 11. Proportion of patients demonstrating the ability to achieve a scaled score within 1.5 standard deviations of the chronological reference standard (at Months 24 and 42 of treatment [as assessed through the use of the BSID-III Gross Motor Scale])
12. 12. Change from baseline score in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) motor function scale at Month 12 of treatment
13. 13. Proportion of patients who achieve a score of 40 or higher, 50 or higher and 60 or higher in the CHOP INTEND motor function scale at Month 12 of treatment
14. 14. Proportion of patients who meet CHOP INTEND stopping criteria at any point up to Month 24 of treatment
15. 15. Change from baseline (Month 24) in the Hammersmith Functional Motor Scale Expanded (HFMSE) (at Month 60 of treatment).
16. 16. Number and proportion of patients within 3rd percentile of normal range for weight-for-age, length/height-for-age, and weight-for-length/ height, (from enrollment) at Month 12, 24, 36, 48, and 60 of treatment
17. 17. Number and proportion of patients within 3rd percentile of normal range for head circumference for age at Month 12 and 24 of treatment
18. 18. Change from baseline percentiles for weight-for-age, length/height-for-age, and weight-for-length/height at Months 12, 24, 36, 48 and 60 of treatment
19. 19. Change from baseline percentiles for head circumference for age at Month 12 and Month 24 of treatment
20. 20. Change from baseline in chest circumference at Month 12 and 24 of treatment
21. 21. Ratio between chest and head circumferences at Month 12 and 24 of treatment
22. 22. Ability to swallow at Month 12, 24, 36, 48 and 60 of treatment
23. 23. Ability to feed orally at Month 12, 24, 36, 48 and 60 of treatment
24. 24. Change from baseline in CMAP amplitude at Month 12 and 24 of treatment
25. 25. SMN mRNA levels in blood
26. 26. SMN protein levels in blood
27. 27. Incidence and severity of adverse events with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE) v5
28. 28. Incidence and severity of serious adverse events
29. 29. Incidence of treatment discontinuation due to adverse events
30. 30. Incidence of abnormal laboratory, ECG values and vital signs abnormalities
31. 31. Incidence of clinically significant findings on ophthalmological examination
32. 32. Plasma concentration of risdiplam and its metabolites
33. 33. Area under curve of risdiplam
34. 34. Concentration at the end of a dosing interval to assess steady-state
35. 35. Other PK parameters as appropriate

Investigational products

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

Test 3

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 9

Locations

2 EU/EEA countries · 2 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 5 files

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

Application history

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