A study to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of Risdiplam (RO7034067) in type 2 and 3 spinal muscular atrophy patients

• Register: EUCTR
• Last refreshed on: 13 November 2023
• Main ID: EUCTR2016-000750-35-BE
• Date of registration: 12/07/2016
• Prospective Registration: Yes
• Primary sponsor: F. Hoffmann-La Roche Ltd
• Public title: A study to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of Risdiplam (RO7034067) in type 2 and 3 spinal muscular atrophy patients
• Scientific title: A TWO-PART SEAMLESS, MULTI-CENTER RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE BLIND STUDY TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS AND EFFICACY OF RO7034067 IN TYPE 2 AND 3 SPINAL MUSCULAR ATROPHY PATIENTS.
• Date of first enrolment: 06/09/2016
• Target sample size: 219
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-000750-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: 2 part design If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Belgium, Brazil, Bulgaria, Canada, China, Croatia, France, Germany, Hungary, Italy, Japan, Mexico, Poland, Romania, Russian Federation, Serbia, Spain, Switzerland, Turkey, Ukraine, 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:
- Males and females 2 to 25 years of age inclusive
- For Part 1: Type 2 or 3 SMA ambulant or non-ambulant. For Part 2: Type 2 or 3 SMA non-ambulant.
Non-ambulant is defined as not having the ability to walk unassisted for 10 m or more
- Confirmed diagnosis of 5q-autosomal recessive SMA
- Negative blood pregnancy test at screening and agreement to comply with measures to prevent pregnancy and restrictions on sperm donation

Are the trial subjects under 18? yes
Number of subjects for this age range: 185
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 34
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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
- Concomitant or previous administration of a SMN2 targeting antisense oligonucleotide, SMN2 splicing modifier or gene therapy either in a clinical study or as part of medical care.
- Any history of cell therapy
- Hospitalization for a pulmonary event within the last 2 months or planned at time of screening
- Surgery for scoliosis or hip fixation in the one year preceding screening or planned within the next 18 months
- Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system diseases as considered to be clinically significant by the Investigator
- Presence of clinically significant ECG abnormalities before study drug administration from average of triplicate measurement or cardiovascular disease indicating a safety risk for patients as determined by the Investigator
- History of malignancy if not considered cured
- Significant risk for suicidal behavior, in the opinion of the Investigator as assessed by the C-SSRS (>6 years of age)
- Any major illness within one month before the screening examination or any febrile illness within one week prior to screening and up to first dose administration
- Any Organic cation transporter (OCT)-2 and multidrug and toxin extrusion (MATE) substrates within 2 weeks before dosing
- Use of the following medications within 90 days prior to randomization: riluzole, valproic acid, hydroxyurea, sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, growth hormone, anabolic steroids, probenecid, agents anticipated to increase or decrease muscle strength, agents with known or presumed histone deacetylase (HDAC) inhibitory effect, and medications with known phototoxicity liabilities
- Recently initiated treatment (within < 6 months prior to randomization) with oral salbutamol or another 2-adrenergic agonist taken orally
- Any prior use of chloroquine, hydroxychloroquine, retigabin, vigabatrin or thioridazine, is not allowed.
- Clinically significant abnormalities in laboratory test results
- Donation or loss of blood >= 10% of blood volume within three months prior to screening
- Ascertained or presumptive hypersensitivity (e.g., anaphylactic reaction) to risdiplam or to the constituents of its formulation
- Recent history (less than one year) of ophthalmological diseases
- Patients requiring invasive ventilation or tracheostomy
- Any inhibitor or inducer of FMO1 or FMO3 taken within 2 weeks (or within 5 times the elimination half-life, whichever is longer) prior to dosing.


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

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Spinal Muscular Atrophy (SMA) Type 2 and 3
MedDRA version: 20.1 Level: PT Classification code 10041582 Term: Spinal muscular atrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Product Name: RO7034067
Product Code: RO7034067/F12
Pharmaceutical Form: Powder for oral solution
INN or Proposed INN: risdiplam
CAS Number: 1825352-65-5
Current Sponsor code: RO7034067
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Powder for oral solution
Route of administration of the placebo: Oral use

Product Name: RO7034067
Product Code: RO7034067/F13
Pharmaceutical Form: Powder for oral solution
INN or Proposed INN: risdiplam
CAS Number: 1825352-65-5
Current Sponsor code: RO7034067
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 60-
Pharmaceutical form of the placebo: Powder for oral solution
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): Part 1
1. Incidence of adverse events and serious adverse events
2. Maximum plasma concentration (Cmax) of risdiplam
3. Area under the curve (AUC) of risdiplam
4. Concentration at the end of a dosing interval (Ctrough) of risdiplam

Part 2
5. Change from baseline in the total MFM 32 score at Month 12

Main Objective: Part 1:
•To evaluate the safety, tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of risdiplam in patients with Type 2 and Type 3 (ambulant or non-ambulant) SMA, and to select the dose for Part 2 of the study

Part 2:
•To evaluate efficacy of risdiplam compared to placebo in terms of motor function in Type 2 and non-ambulant Type 3 SMA patients, as assessed by the change from baseline in the total score of the Motor Function Measure (MFM) at 12 months

Secondary Objective: Part 2:To investigate
•PK/PD relationship of risdiplam by PK/PD modeling
•efficacy of 12 month treatment with risdiplam in terms of motor function as assessed by the Hammersmith Functional Motor Scale Expanded (HFMSE) and the revised upper limb module (RULM)
•efficacy of 12 month treatment with risdiplam in terms of responder analyses of the MFM,HFMSE,RULM
•efficacy of 12 month treatment with risdiplam in terms of respiratory function as assessed by Sniff nasal inspiratory pressure and, in patients aged 6 years and older,by Maximal Inspiratory Pressure,Maximal Expiratory Pressure,Forced vital capacity,Forced expiratory volume (FEV1) and Peak cough flow
•proportion of patients who experience a pre-specified disease related adverse event by Month 12
•efficacy of 12 month treatment with risdiplam in terms of global health status as assessed by the Clinical Global Impression of Change and independence as measured by the SMA Independence Scale
•safety and tolerability of risdiplam

Timepoint(s) of evaluation of this end point: 1. Up to 24 months
2-4. Days 1, 7, 14, 28, 56, 120, 246, 365, 490, 609, and 729
5. Baseline (Day -1) and Month 12

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 1. Part 1: Days -1, 1, 7, 14, 28, 120, 246, 365, 729; Part 2: Days -1, 1, 7, 28, 120, 246, 365, 729
2. Part 1: Days -1, 7, 14, 28, 120, 246, 365, 729; Part 2: Days -1, 7, 28, 120, 246, 365, 729, every 26 weeks thereafter
3-18. Baseline (Day-1) and Month 12
19-21. Up to Month 12
22-23. Week 35, Week 62, at early withdrawal

Secondary end point(s): Part 2
1.SMN2 mRNA in blood
2.SMN protein levels in blood
3.Change from baseline in total score of HFMSE at Month 12
4.Change from baseline in the total score of the revised upper limb module (RULM) at Month 12
5.Proportion of patients who achieve stabilization or improvement (i.e., a change from baseline >= 0) on the total MFM score at Month 12
6.Proportion of patients who achieve an improvement of at least one standard error of measurement (SEM calculated at baseline) on the total MFM score at Month 12.
7.Proportion of patients who achieve stabilization or improvement (i.e., a change from baseline >= 0) on the total HFMSE score at Month 12.
8.Proportion of patients who achieve stabilization or improvement (i.e., a change from baseline >= 0) on the total RULM score at Month 12.
9.Change from baseline in the MFM domain scores of D1, D2, D3 and the total combined score of (D1 + D2) at Month 12.
10.Change from baseline in the best SNIP (expressed as a percentage of the predicted value) at Month 12.
11.Change from baseline in the best MIP at Month 12.
12.Change from baseline in the best MEP at Month 12
13.Change from baseline in FEV1 in patients aged 6 to 25 years at Month 12
14.Change from baseline in FVC in patients aged 6 to 25 years at Month 12.
15.Change from baseline in the peak cough flow (PCF) in patients aged 6 to 25 years at Month 12.
16.Change from baseline in the Total Score of the caregiver-reported SMA independence Scale (SMAIS) at Month 12.
17.Change from baseline in the Total score of the patient-reported SMA independence scale (SMAIS) at Month 12
18.Proportion of patients rated by clinicians as no change or improved in the Clinical Global Impression of Change (CGI-C) Scale at Month 12 (Part 2 only).
19.Proportion of patients rated by clinicians as improved in the Clinical Global Impression of Change (CGI-C) Scale at Month 12.
20.Proportion of patients who experience at least one disease related adverse event by Month 12
21.Number of disease-related adverse events per patient-year at Month 12
22.PedsQL 4.0 Generic Core scale(Part 1 only)
23.PedsQL 3.0 Neuromuscular module (Part 1 only)

Secondary ID(s)

2016-000750-35-ES

BP39055

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd

Ethics review

Status: Approved
Approval date: 01/12/2016
Contact:

Results

• Results available: Yes
• Date Posted: 13/09/2020
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-000750-35/results