The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03779334




Registration number
NCT03779334
Ethics application status
Date submitted
17/12/2018
Date registered
18/12/2018
Date last updated
13/08/2019

Titles & IDs
Public title
A Study of Risdiplam in Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy
Scientific title
An Open-Label Study of Risdiplam in Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy
Secondary ID [1] 0 0
BN40703
Universal Trial Number (UTN)
Trial acronym
Rainbowfish
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Muscular Atrophy, Spinal 0 0
Condition category
Condition code
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above
Musculoskeletal 0 0 0 0
Other muscular and skeletal disorders
Neurological 0 0 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Risdiplam

Experimental: Open-label Arm - Participants will be enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range


Treatment: Drugs: Risdiplam
Risdiplam will be administered orally.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Proportion of participants 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) >=1.5 millivolt (mV) who are sitting without support. - 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 (BSID-III) Gross Motor Scale
Timepoint [1] 0 0
At Month 12
Secondary outcome [1] 0 0
Proportion of participants developing clinically manifested SMA
Timepoint [1] 0 0
At Month 12 and 24
Secondary outcome [2] 0 0
Time to permanent ventilation and/or death
Timepoint [2] 0 0
Up to 7 years
Secondary outcome [3] 0 0
Proportion of participants who are alive without permanent ventilation
Timepoint [3] 0 0
At Month 12 and 24
Secondary outcome [4] 0 0
Proportion of participants who achieve the attainment level of the motor milestones as assessed in the Hammersmith Infant Neurological Examination-2 (HINE-2) - HINE-2 assessment includes head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking
Timepoint [4] 0 0
At Month 12 and 24
Secondary outcome [5] 0 0
Proportion of participants sitting without support for 5 seconds - Assessed with BSID-III Gross Motor Scale
Timepoint [5] 0 0
At Month 24
Secondary outcome [6] 0 0
Proportion of participants sitting without support for 30 seconds - Assessed with BSID-III Gross Motor Scale
Timepoint [6] 0 0
At Month 24
Secondary outcome [7] 0 0
Proportion of participants standing for at least 3 seconds - Assessed with BSID-III Gross Motor Scale
Timepoint [7] 0 0
At Month 24
Secondary outcome [8] 0 0
Proportion of participants walking (takes at least 3 steps) - Assessed with BSID-III Gross Motor Scale
Timepoint [8] 0 0
At Month 24
Secondary outcome [9] 0 0
Proportion of participants demonstrating the ability to achieve a scaled score on BSID-III Gross Motor Subtests within 1.5 standard deviations of chronological reference standard - Assessed through BSID-III Gross Motor Scale
Timepoint [9] 0 0
At Month 24 and 42
Secondary outcome [10] 0 0
Change from baseline score in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) motor function scale
Timepoint [10] 0 0
Baseline (Day -1) to Month 12 and 24
Secondary outcome [11] 0 0
Proportion of participants who achieve a score of 40 or higher, 50 or higher and 64 in the CHOP INTEND motor function scale
Timepoint [11] 0 0
At Month 12 and 24
Secondary outcome [12] 0 0
Number and proportion of participants within 3rd percentile of normal range for weight-for-age, length/height-for-age, weight-for-length/height, and head circumference-for-age - Based on the WHO Child Growth Standards (WHO 2019)
Timepoint [12] 0 0
At Month 12 and 24
Secondary outcome [13] 0 0
Change from baseline percentiles at each time point for weight-for-age, length/height-for-age, weight-for-length/height, and head circumference-for-age
Timepoint [13] 0 0
Baseline, at Month 12 and 24
Secondary outcome [14] 0 0
Change from baseline in chest circumference
Timepoint [14] 0 0
Baseline to Month 12 and 24
Secondary outcome [15] 0 0
Ratio between chest and head circumferences
Timepoint [15] 0 0
At Month 12 and 24
Secondary outcome [16] 0 0
Proportion of participants with the ability to swallow and level of solid food intake
Timepoint [16] 0 0
At Month 12 and 24
Secondary outcome [17] 0 0
Change of innervation - Measured by CMAP
Timepoint [17] 0 0
Baseline to Month 12 and 24
Secondary outcome [18] 0 0
Measurement of pharmacodynamic marker levels in blood
Timepoint [18] 0 0
Day 1, 56, 196, 364, 728 and at early withdrawal
Secondary outcome [19] 0 0
Proportion of participants with phase angle of < 20 degrees, as measured by respiratory plethysmography
Timepoint [19] 0 0
At Month 12 and 24
Secondary outcome [20] 0 0
Proportion of participants with adverse events - Adverse event severity is determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE) v5
Timepoint [20] 0 0
Up to 7 years
Secondary outcome [21] 0 0
Plasma concentration of risdiplam and its metabolites to characterize the PK profile
Timepoint [21] 0 0
Up to 7 years

Eligibility
Key inclusion criteria
- 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

- Gestational age of 37-42 weeks for singleton births; gestational age of 34-42 weeks
for twins

- Body weight >= 3rd percentile for age, using appropriate country-specific guidelines

- Genetic diagnosis of 5q-autosomal recessive SMA, including confirmation of homozygous
deletion or compound heterozygosity predictive of loss of function of the SMN1 gene

- Absence of clinical signs or symptoms at screening (Day -30 to Day -2) or at baseline
(Day -1) that are, in the opinion of the investigator, strongly suggestive of SMA

- Receiving adequate nutrition and hydration at the time of screening, in the opinion of
the investigator

- Adequately recovered from any acute illness at baseline and considered well enough to
participate in the study, in the opinion of the investigator

- Able and expected to be able to safely travel to the study site for the entire
duration of the study and in accordance to the frequency of required study visits, in
the opinion of the investigator

- Able to complete all study procedures, measurements, and visits, and the parent (or
caregiver), in the opinion of the investigator, has adequately supportive psychosocial
circumstances

- Parent (or caregiver) is willing to consider nasogastric, naso-jejunal, or gastrostomy
tube placement during the study to maintain safe hydration, nutrition, and treatment
delivery, if recommended by the investigator

- Parent (or caregiver) is willing to consider the use of non-invasive ventilation
during the study, if recommended by the investigator
Minimum age
No limit
Maximum age
6 Weeks
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Concomitant or previous participation in any investigational drug or device study at
any time

- 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

- Presence of significant concurrent syndromes or diseases

- In the opinion of the investigator, inadequate venous or capillary blood access for
the study procedures

- Requiring invasive ventilation, tracheostomy or awake non-invasive ventilation

- Awake hypoxemia (SaO2 < 95%) with or without ventilator support

- Multiple or fixed contractures and/or hip subluxation or dislocation at birth

- Systolic blood pressure or diastolic blood pressure or heart rate considered to be
clinically significant by the investigator

- Presence of clinically relevant ECG abnormalities before study drug administration;
corrected QT interval using Bazett's method > 460 ms; personal or family history
(first degree relatives) of congenital long QT syndrome indicating a safety risk for
patients as determined by the investigator. First-degree atrioventricular block or
isolated right bundle branch block are allowed

- The infant taking any nutrients known to modulate CYP3A activity (e.g., grapefruit
juice; Seville orange) within 2 weeks prior to dosing (Day 1)

- The infant (and the mother, if breastfeeding the infant) taking any inhibitor of
CYP3A4 taken within 2 weeks, any inducer of CYP3A4 taken within 4 weeks, any OCT 2 and
MATE substrates within 2 weeks and known FMO1 or FMO3 inhibitors or substrates

- Clinically significant abnormalities in laboratory test results

- Ascertained or presumptive hypersensitivity to risdiplam or to the constituents of its
formulation

- Treatment with oral salbutamol or another beta-2 adrenergic agonist taken orally for
SMA is not allowed. Use of inhaled beta-2 adrenergic agonists is allowed

- Infants exposed to drugs with known retinal toxicity given to mothers during pregnancy
(and lactation) should not be enrolled. Anticipated need for drugs known to cause
retinal toxicity during the study.

- Diagnosis of ophthalmic diseases

Study design
Purpose of the study
Treatment
Allocation to intervention
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Sydney Children's Hospital; CENTRE FOR CHILD HEALTH RESEARCH & INNOVATION (CHeRI) - Randwick
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Florida
Country [2] 0 0
United States of America
State/province [2] 0 0
New York
Country [3] 0 0
Belgium
State/province [3] 0 0
Liège
Country [4] 0 0
Brazil
State/province [4] 0 0
RJ
Country [5] 0 0
Brazil
State/province [5] 0 0
SP
Country [6] 0 0
China
State/province [6] 0 0
Shanghai
Country [7] 0 0
Italy
State/province [7] 0 0
Lazio
Country [8] 0 0
Poland
State/province [8] 0 0
Gdansk
Country [9] 0 0
Poland
State/province [9] 0 0
Warszawa
Country [10] 0 0
Russian Federation
State/province [10] 0 0
Moskovskaja Oblast
Country [11] 0 0
Saudi Arabia
State/province [11] 0 0
Riyadh

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
A global study of oral risdiplam in pre-symptomatic participants with SMA.
Trial website
https://clinicaltrials.gov/show/NCT03779334
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Reference Study ID Number: BN40703 www.roche.com/about_roche/roche_worldwide.htm
Address 0 0
Country 0 0
Phone 0 0
888-662-6728 (U.S. and Canada)
Fax 0 0
Email 0 0
global-roche-genentech-trials@gene.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03779334