Clinical Trial Results:
A Two Part Seamless, Open-Label, Multi-center Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Infants with Type 1 Spinal Muscular Atrophy
Summary
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EudraCT number |
2016-000778-40 |
Trial protocol |
DE ES IT BE FR PL HR |
Global end of trial date |
22 Dec 2023
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Results information
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Results version number |
v4(current) |
This version publication date |
06 Jul 2024
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First version publication date |
26 Nov 2020
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Other versions |
v1 , v2 , v3 |
Version creation reason |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
BP39056
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02913482 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
F. Hoffmann-La Roche AG
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Sponsor organisation address |
Grenzacherstrasse 124., Basel, Switzerland, 4058
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Public contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
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Scientific contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-002070-PIP01-16 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
22 Dec 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
22 Dec 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Part 1: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of risdiplam in infants with Type 1 spinal muscular atrophy (SMA) and to select the dose for Part 2.
Part 2: To assess the efficacy of risdiplam measured as the percentage of infants with SMA who are sitting without support after 12 months of treatment, as assessed in the gross motor scale of the Bayley Scales of Infant and Toddler Development -Third Edition (BSID-III) (defined as sitting without support for 5 seconds).
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Protection of trial subjects |
All study subjects, parent or legal guardian were required to read and sign an Informed Consent Form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Dec 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Belgium: 2
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Country: Number of subjects enrolled |
Switzerland: 1
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Country: Number of subjects enrolled |
France: 8
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Country: Number of subjects enrolled |
Italy: 21
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Country: Number of subjects enrolled |
United States: 4
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Country: Number of subjects enrolled |
Brazil: 3
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Country: Number of subjects enrolled |
China: 11
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Country: Number of subjects enrolled |
Croatia: 1
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Country: Number of subjects enrolled |
Japan: 1
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Country: Number of subjects enrolled |
Poland: 4
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Country: Number of subjects enrolled |
Russian Federation: 5
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Country: Number of subjects enrolled |
Türkiye: 1
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Worldwide total number of subjects |
62
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EEA total number of subjects |
36
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
62
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Part 1 was conducted at 7 investigational sites across 5 countries; Part 2 was conducted at 14 investigational sites across 10 countries. | ||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Infants with type 1 spinal muscular atrophy (SMA) were screened for this study. Screening in both Part 1 and 2 was up to 30 days prior to first dose. | ||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Exploratory Part 1 - Cohort 1 | ||||||||||||||||||||||||||||||||
Arm description |
Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 1 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 1 was targeting an exposure of mean AUC0-24h,ss 700 ng*h/mL. | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
risdiplam
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Investigational medicinal product code |
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Other name |
Evrysdi
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Pharmaceutical forms |
Powder and solvent for oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Throughout the study, risdiplam should be taken orally once daily. In the case of breastfeeding, the subject should be fed prior to dosing, winded, and risdiplam administered.
In subjects able to swallow, risdiplam is administered with a syringe inserted between baby's gum and cheek. Thereafter, water (approx. 10–20 mL) should be administered with a baby’s bottle to prevent prolonged contact of study drug with buccal mucosa. Similarly, the peribuccal- area of the SMA infant is washed with water in case of drug drooling or spitting. Subjects unable to swallow the study medication and who have a naso-gastric or gastrostomy tube in situ should receive the study medication by bolus via the tube. This should be followed by a bolus flush of water through the tube.
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Arm title
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Exploratory Part 1 - Cohort 2 | ||||||||||||||||||||||||||||||||
Arm description |
Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 2 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 2 was targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL. | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
risdiplam
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Investigational medicinal product code |
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Other name |
Evrysdi
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Pharmaceutical forms |
Powder and solvent for oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Throughout the study, risdiplam should be taken orally once daily. In the case of breastfeeding, the subject should be fed prior to dosing, winded, and risdiplam administered. In subjects able to swallow, risdiplam is administered with a syringe inserted between baby's gum and cheek. Thereafter, water (approx. 10–20 mL) should be administered with a baby’s bottle to prevent prolonged contact of study drug with buccal mucosa. Similarly, the peribuccal- area of the SMA infant is washed with water in case of drug drooling or spitting. Subjects unable to swallow the study medication and who have a naso-gastric or gastrostomy tube in situ should receive the study medication by bolus via the tube. This should be followed by a bolus flush of water through the tube.
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Arm title
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Confirmatory Part 2 - Risdiplam | ||||||||||||||||||||||||||||||||
Arm description |
Subjects received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the subject’s age. All subjects had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 5 mg when the subject reached 20 kg body weight. | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
risdiplam
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Investigational medicinal product code |
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Other name |
Evrysdi
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Pharmaceutical forms |
Powder and solvent for oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Throughout the study, risdiplam should be taken orally once daily. In the case of breastfeeding, the subject should be fed prior to dosing, winded, and risdiplam administered. In subjects able to swallow, risdiplam is administered with a syringe inserted between baby's gum and cheek. Thereafter, water (approx. 10–20 mL) should be administered with a baby’s bottle to prevent prolonged contact of study drug with buccal mucosa. Similarly, the peribuccal- area of the SMA infant is washed with water in case of drug drooling or spitting. Subjects unable to swallow the study medication and who have a naso-gastric or gastrostomy tube in situ should receive the study medication by bolus via the tube. This should be followed by a bolus flush of water through the tube.
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Baseline characteristics reporting groups
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Reporting group title |
Exploratory Part 1 - Cohort 1
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Reporting group description |
Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 1 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 1 was targeting an exposure of mean AUC0-24h,ss 700 ng*h/mL. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Exploratory Part 1 - Cohort 2
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Reporting group description |
Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 2 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 2 was targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Confirmatory Part 2 - Risdiplam
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Reporting group description |
Subjects received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the subject’s age. All subjects had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 5 mg when the subject reached 20 kg body weight. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Exploratory Part 1 - Cohort 1
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Reporting group description |
Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 1 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 1 was targeting an exposure of mean AUC0-24h,ss 700 ng*h/mL. | ||
Reporting group title |
Exploratory Part 1 - Cohort 2
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Reporting group description |
Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 2 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 2 was targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL. | ||
Reporting group title |
Confirmatory Part 2 - Risdiplam
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Reporting group description |
Subjects received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the subject’s age. All subjects had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 5 mg when the subject reached 20 kg body weight. | ||
Subject analysis set title |
Part 1: Intent-to-Treat (ITT)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The intent-to-treat (ITT) population was defined as all subjects enrolled in Part 1 of the study, regardless of whether they received treatment or not.
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Subject analysis set title |
Part 1: Safety Population
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subjects in Part 1 who received at least one dose of study medication (risdiplam) were included in the safety population.
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Subject analysis set title |
Part 2: ITT
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The intent-to-treat (ITT) population for Part 2 was defined as all subjects enrolled in Part 2 of the study, regardless of whether they received treatment or not. The ITT population was the primary analysis population for all efficacy analyses.
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Subject analysis set title |
Part 2: Safety Population
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subjects in Part 2 who received at least one dose of study medication (risdiplam) were included in the safety population.
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Subject analysis set title |
Exploratory Part 1 - Risdiplam
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Infants aged between 28 days (1 month) of life and 210 days (7 months) received at least one dose of risdiplam orally or by bolus via naso-gastric or gastrostomy tube, and had available data at the time of the data snapshot for selecting the Part 2 dose.
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Subject analysis set title |
Part 2: Pharmacokinetic Analysis Set
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
All participants with at least one time point with a risdiplam concentration measurement were included in the PK analysis data set.
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End point title |
Part 2: Percentage of Infants who are Sitting Without Support for at least 5 Seconds as Assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler development Third Edition (BSID-III) at Month 12 [1] [2] | ||||||||
End point description |
The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children and consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22 is not considered achieved if the infant sits alone for less than 5 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The result was compared to a performance criterion of 5% derived from natural history data (p<0.0001). The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study.
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End point type |
Primary
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End point timeframe |
Month 12
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This primary endpoint only reports data for one arm in Part 2 of the study. No statistical analysis was performed. [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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No statistical analyses for this end point |
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End point title |
Part 1: Selected Part 2 Dose of Risdiplam [3] | ||||||||
End point description |
All safety, tolerability, PK and PD data available up to the database snapshot on 6 February 2018 were included in the Internal Monitoring Committee (IMC) review. The IMC was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng*h/mL (adjusted for free-fraction, if required); 3. Resulted in an SMN protein increase that was expected to be clinically relevant. The analysis population included all participants in Part 1 who received at least one dose of risdiplam and had available data at the time of the data snapshot for selecting the Part 2 dose.
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End point type |
Primary
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End point timeframe |
Minimum of 2 weeks at steady state exposure
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Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This primary endpoint reports the selected dose for Part 2. No statistical analysis was performed. |
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No statistical analyses for this end point |
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End point title |
Part 2: Percentage of Infants who Achieve a Score of 40 or Higher in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) at Month 12 [4] | ||||||||
End point description |
The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The result was compared to a performance criterion of 17% derived from natural history data (p<0.0001). The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
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End point type |
Secondary
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End point timeframe |
Month 12
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Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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No statistical analyses for this end point |
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End point title |
Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in their CHOP-INTEND Score from Baseline at Month 8 and 12 [5] | ||||||||||||
End point description |
The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The result was compared to a performance criterion of 17% derived from natural history data (p<0.0001). Statistical analysis was only performed for Month 12 data. The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
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End point type |
Secondary
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End point timeframe |
At Month 8 and Month 12 (Up to the CCOD of 14 November 2019)
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Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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No statistical analyses for this end point |
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End point title |
Part 2: Percentage of Infants who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8 [6] | ||||||||||||||||||||||||||||||||
End point description |
The HINE was designed to evaluate infants between 2 months and 24 months of age. It is a simple and standardized instrument that includes 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of the HINE (HINE-2) was assessed. The HINE-2 evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. This measure represents subset numbers at Month 8 for head control, ability to kick and rolling milestones only. The ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
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End point type |
Secondary
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End point timeframe |
Month 8
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Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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No statistical analyses for this end point |
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End point title |
Part 2: Percentage of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) at Months 8, 12 and 24 [7] | ||||||||||||||
End point description |
The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
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End point type |
Secondary
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End point timeframe |
Month 8, Month 12, Month 24
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Notes [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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No statistical analyses for this end point |
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End point title |
Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24 [8] | ||||||||||||||
End point description |
The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). In this study the gross motor scale was assessed in a modified way compared with the standard administration. A total raw score was calculated by summing the item scores to give a maximum possible score of 72. The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
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End point type |
Secondary
|
||||||||||||||
End point timeframe |
Baseline, Month 12, Month 24
|
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Notes [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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Notes [9] - Only subjects for whom data were collected are included in the analysis at each time point. |
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No statistical analyses for this end point |
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End point title |
Part 2: Percentage of Infants who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 [10] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The HINE was designed to evaluate infants between 2 months and 24 months of age. It is a simple and standardized instrument that includes 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of the HINE (HINE-2) was assessed. The HINE-2 evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. The ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
|
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Month 12
|
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Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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No statistical analyses for this end point |
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End point title |
Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 [11] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The HINE was designed to evaluate infants between 2 months and 24 months of age. It is a simple and standardized instrument that includes 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of the HINE (HINE-2) was assessed. The HINE-2 evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. The ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
|
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Month 24
|
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Notes [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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No statistical analyses for this end point |
|
|||||||||||||
End point title |
Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Months 12 and 24 [12] | ||||||||||||
End point description |
The HINE-2 evaluates 8 developmental milestones scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. For the responder definition, an improvement in a motor milestone is defined as at least a 2-point increase in ability to kick (or maximal score) or a 1-point increase in head control, rolling, sitting, crawling, standing, or walking. Worsening is defined as a 2-point decrease in ability to kick (or lowest score) or a 1-point decrease in head control, rolling, sitting, crawling, standing, or walking. Voluntary grasp is excluded. An infant is a responder if more motor milestones show improvement than show worsening. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. Result at Month 12 was compared to a performance criterion of 12% derived from natural history data (p<0.0001). ITT population: all infants enrolled in Part 2 of the study.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Month 12, Month 24
|
||||||||||||
Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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|
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No statistical analyses for this end point |
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End point title |
Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 [13] | ||||||||||||||||||||||||||||||||
End point description |
The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). This measure included 6 milestones: Item 9 ‘Controls head while upright for 15 seconds’, Item 14 ‘Rolls from side to back’, Item 22 ‘Sits without support for 5 seconds’, Item 30 ‘Crawls on stomach’, Item 40 ‘Stands alone’ and Item 42 ‘Walks alone’. M12 indicates Month 12 and M24 indicates Month 24. Reported here is the percentage of participants for whom the reported item was the highest item achieved out of these six items by Months 12 and 24. ITT population is defined as all infants enrolled in Part 2 of the study.
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
Month 12, Month 24
|
||||||||||||||||||||||||||||||||
Notes [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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No statistical analyses for this end point |
|
|||||||||
End point title |
Part 2: Percentage of Infants Who Are Standing Alone as Assessed by Item 40 of the BSID-III Gross Motor Scale at Month 24 [14] | ||||||||
End point description |
The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Reported here is the percentage of participants who achieved item 40 ‘Stands alone’ at Month 24. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The result was compared to a performance criterion of 5% derived from natural history data (p=1.0000). ITT population is defined as all infants enrolled in Part 2 of the study.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Month 24
|
||||||||
Notes [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 30 Seconds as Assessed by Item 26 of the BSID-III Gross Motor Scale at Month 24 [15] | ||||||||
End point description |
The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 26 is not considered achieved if the infant sits alone for less than 30 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The result was compared to a performance criterion of 5% derived from natural history data (p<0.0001). ITT population is defined as all infants enrolled in Part 2 of the study.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Month 24
|
||||||||
Notes [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 5 Seconds as Assessed by Item 22 of the BSID-III Gross Motor Scale at Month 24 [16] | ||||||||
End point description |
The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22 is not considered achieved if the infant sits alone for less than 5 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The result was compared to a performance criterion of 5% derived from natural history data (p<0.0001). ITT population is defined as all infants enrolled in Part 2 of the study.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Month 24
|
||||||||
Notes [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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|
|||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Part 2: Percentage of Infants Who Are Alive Without Permanent Ventilation at Months 12 and 24 [17] | ||||||||||||
End point description |
Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation. The result was compared to a performance criterion of 42% derived from natural history data (p<0.0001). Statistical analysis was only performed for Month 12 data. ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Month 12, Month 24
|
||||||||||||
Notes [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Part 2: Percentage of Infants Who Are Alive at Months 12 and 24 [18] | ||||||||||||
End point description |
Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation. The result was compared to a performance criterion of 60% derived from natural history data (p=0.0005). Statistical analysis was only performed for Month 12 data. ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Month 12, Month 24
|
||||||||||||
Notes [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Part 2: Time to Permanent Ventilation [19] | ||||||||
End point description |
Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley. ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not. The median time to permanent ventilation was not estimable as few subjects had an event. 9999=not estimable
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 24 months
|
||||||||
Notes [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
|||||||||
|
|||||||||
Notes [20] - The median time to permanent ventilation was not estimable as few subjects had an event. |
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Part 2: Time to Death or Permanent Ventilation [21] | ||||||||
End point description |
Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley. ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not. The median time to death or permanent ventilation was not estimable as few subjects had an event. 9999=not estimable
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 24 months
|
||||||||
Notes [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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|
|||||||||
Notes [22] - The median time to death or permanent ventilation was not estimable as few subjects had an event. |
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No statistical analyses for this end point |
|
|||||||||
End point title |
Part 2: Percentage of Infants Who Are Walking Alone as Assessed by Item 42 of the BSID-III Gross Motor Scale at Month 24 [23] | ||||||||
End point description |
The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Reported here is the percentage of participants who achieved item 42 ‘Walks alone’ at Month
24. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The result was compared to a performance criterion of 5% derived from natural history data (p=1.0000). ITT population is defined as all infants enrolled in Part 2 of the study.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Month 24
|
||||||||
Notes [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Part 2: Time to Death [24] | ||||||||
End point description |
The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley. ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not. The median time to death was not estimable as few subjects had an event. 9999=not estimable
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to 24 months
|
||||||||
Notes [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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|
|||||||||
Notes [25] - The median time to death was not estimable as few subjects had an event. |
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No statistical analyses for this end point |
|
|||||||||||||
End point title |
Part 2: Percentage of Infants Able to Feed Orally at Months 12 and 24 [26] | ||||||||||||
End point description |
Able to feed orally includes subjects fed orally and subjects fed via a combination of oral and tube feeding. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Month 12, Month 24
|
||||||||||||
Notes [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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|
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No statistical analyses for this end point |
|
|||||||||||||
End point title |
Part 2: Percentage of Infants not Requiring Respiratory Support (Invasive or Non-Invasive) at Months 12 and 24 [27] | ||||||||||||
End point description |
90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Month 12, Month 24
|
||||||||||||
Notes [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Part 2: Percentage of Infants who Achieve a Reduction of At Least 30 Degrees in Phase Angle From Baseline, as Measured by Respiratory Plethysmography (RP) at Month 12 [28] | ||||||||
End point description |
RP measures the degree of synchrony between abdominal and thoracic cage-driven breathing. The weakness of intercostal muscles leads to asynchrony of the thorax with the diaphragm, resulting in inefficient and paradoxical breathing patterns. The degree of synchrony between the movement of the chest wall and abdomen during the respiratory cycle can be expressed as the phase angle between the two compartments and measured by placing two RP bands around the thorax and abdomen. In paradoxical breathing, the phase angle is reversed compared with the normal ventilation cycle. A phase angle of 0° indicates perfect in-phase movement, while a value of 180° indicates completely out-of-phase movement between the two compartments. In this measure, 8 or more valid breaths were required to determine the phase angle at each visit. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. ITT population is defined as all infants enrolled in Part 2 of the study.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Month 12
|
||||||||
Notes [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Months 12 and 24 [29] | ||||||||||||
End point description |
Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation. The result was compared to a performance criterion of 89% derived from natural history data (p=0.2595). Statistical analysis was only performed for Month 12 data. ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Month 12, Month 24
|
||||||||||||
Notes [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Part 2: Anthropometric Examination of Weight Measured in Kilograms [30] | ||||||||||||
End point description |
Anthropometric examination included weight, height, head circumference and chest circumference. All infants who received at least one dose of study medication (risdiplam) were included in the safety population. Only participants for whom data were collected are included in the analysis.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Month 12, Month 24
|
||||||||||||
Notes [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
|||||||||||||
|
|||||||||||||
Notes [31] - Only subjects for whom data were collected are included in the analysis at each time point. |
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Part 2: Number of Subjects With AEs and SAEs Leading to Treatment Modification/Interruption [32] | ||||||||||||
End point description |
An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. All infants who received at least one dose of study medication (risdiplam) were included in the safety population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From first dose up to 30 days after last dose of risdiplam (up to 60 months)
|
||||||||||||
Notes [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Part 2: Number of Subjects With AEs and SAEs Leading to Treatment Discontinuation [33] | ||||||||||||
End point description |
An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. All infants who received at least one dose of study medication (risdiplam) were included in the safety population.
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End point type |
Secondary
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End point timeframe |
From first dose up to 30 days after last dose of risdiplam (up to 60 months)
|
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Notes [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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No statistical analyses for this end point |
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End point title |
Part 1 and Part 2: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | ||||||||||||||||||||||||
End point description |
An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Adverse events reported during the safety follow-up period are excluded from this interim analysis. All infants who received at least one dose of study medication (risdiplam) were included in the safety population.
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End point type |
Secondary
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End point timeframe |
From first dose up to 30 days after last dose of risdiplam (up to 60 months)
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No statistical analyses for this end point |
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End point title |
Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeter [34] | ||||||||||||||||||||
End point description |
Anthropometric examination included weight, height, head circumference and chest circumference. All infants who received at least one dose of study medication (risdiplam) were included in the safety population. Only participants for whom data were collected are included in the analysis.
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End point type |
Secondary
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End point timeframe |
Month 12, Month 24
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Notes [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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Notes [35] - Only subjects for whom data were collected are included in the analysis at each time point. |
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No statistical analyses for this end point |
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End point title |
Part 2: Maximum Plasma Concentration (Cmax) of Risdiplam at Year 5 [36] | ||||||||
End point description |
Reported here is the maximum observed concentration throughout the observation period. All participants with at least one time point with a risdiplam concentration measurement were included in the pharmacokinetic (PK) analysis data
set.
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End point type |
Secondary
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End point timeframe |
Day 1: predose, 2, 4, 6, 24 hours; Days 14, 119, 245, 364, 427, 490, 609, 728: predose; Days 28, 56, 182, 301, 546, 672: predose, 2, 4, 6 hour
|
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Notes [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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No statistical analyses for this end point |
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End point title |
Part 2: Area Under the Curve (AUC) from 0 to 24 Hours of Risdiplam at Year 5 Visit [37] | ||||||||
End point description |
All participants with at least one time point with a risdiplam concentration measurement were included in the PK analysis data set. Only participants for whom data were collected are included in the analysis.
|
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End point type |
Secondary
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End point timeframe |
Year 5 visit: pre-dose
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Notes [37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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No statistical analyses for this end point |
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End point title |
Part 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5 [38] | ||||||||
End point description |
All participants with at least one time point with a risdiplam concentration measurement were included in the PK analysis data set. Only participants for whom data were collected are included in the analysis.
|
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End point type |
Secondary
|
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End point timeframe |
The last predose sample collected from each participant who had at least 1400 days of risdiplam treatment duration.
|
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Notes [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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No statistical analyses for this end point |
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End point title |
Part 2: Median Fold Change from Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood [39] | ||||||||||||||||||||||||||
End point description |
All participants with at least one time point with a protein measurement were included in the pharmacodynamic (PD) analysis data set. Only participants for whom data were collected are included in the analysis.
|
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End point type |
Secondary
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End point timeframe |
Days 1, 28, 119, 245, 364, 609, 728, 819 and 1820
|
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Notes [39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint is only reporting data for Part 2 of the study. Therefore, only the Part 2 arm is included. |
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No statistical analyses for this end point |
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Adverse events information
|
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Timeframe for reporting adverse events |
From first dose up to 30 days after last dose of risdiplam (up to 60 months)
|
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Adverse event reporting additional description |
All infants who received at least one dose of risdiplam were included in the safety population.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.1
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Reporting groups
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Reporting group title |
Exploratory Part 1 - Cohort 1
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Reporting group description |
Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 1 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 1 was targeting an exposure of mean AUC0-24h,ss 700 ng*h/mL. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Confirmatory Part 2 - Risdiplam
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Reporting group description |
Subjects received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the subject’s age. All subjects had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 5 mg when subject reached 20 kg body weight. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Exploratory Part 1 - Cohort 2
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Reporting group description |
Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 2 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 2 was targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
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Amendment |
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10 Feb 2017 |
The protocol was updated to clarify the nature of the decisions to be taken by the IMC and the meeting schedule of the IMC; Exclusion criterion #3 was updated to reflect the fact that some subjects may have taken the recently approved drug, Spinraza™, as part of medical care, rather than
only in a study; Exclusion criterion #22 was updated to clarify the term ‘use’ (in relation to prohibited
medication use within 90 days prior to enrollment) as administration for at least 8 weeks within 90 days of beginning the study; Details on dilution factors for drug preparation were removed from the protocol as they are provided in the pharmacy manual (referenced in the protocol); The protocol was updated to clarify that subjects could be breastfed and winded if needed, followed by study drug administration. |
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22 May 2017 |
A new, optimized formulation was introduced. Subjects participating in the Part 1 extension of the study continued to use the Part 1 clinical formulation until they switched to the Part 2 clinical formulation upon availability of the new formulation. Subjects in Part 2 of the study receive the Part 2 formulation throughout their participation in the study; In Part 2, compound muscle action potential (CMAP) acquired from below the elbow stimulation was included following suggestions from different therapeutic area experts. This technical change was expected to give better wave forms in smaller infants, as the size of the hand may be too small for consistent placement of electrodes on the hand and wrist, and ultimately more consistent results. |
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06 Apr 2018 |
The Part 2 dose was incorporated into the protocol based on the Part 1 data, as reviewed by the internal monitoring committee (IMC) and the independent data monitoring committee (iDMC) in February 2018. In addition, the protocol was updated to allow all subjects in Part 1 to receive the dose selected for Part 2, including the first enrolled subject who per protocol thus far remained at the low target exposure of AUC 700 ng*h/mL; Following experience gained in Part 1, some ophthalmology assessments were modified to decrease unnecessary burden to subjects while optimizing quality of the main assessment (OCT); An option to enroll subjects in a specifically extended China enrollment phase after the global enrollment phase at China Food and Drug Administration (CFDA)-recognized sites, was added to ensure approximately 10 subjects are included in the China subpopulation; The definition of permanent ventilation was changed to >/= 16 hours of non-invasive ventilation per day or intubation for > 21 consecutive days in the absence of, or following the resolution of, an acute reversible event or tracheostomy. This definition better reflects the clinical situation in which an acute but reversible event could necessitate the use of non-invasive ventilation for several hours a day after which the subjects could be weaned, thus not truly meeting the original definition; An independent Permanent Ventilation Adjudication Committee was added to review all pertinent data for subjects who may have met the definition of permanent ventilation. This committee has been added to address the change in the definition of permanent ventilation described above and to provide greater transparency if a patient met this endpoint; |
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06 Apr 2018 |
Pharmacokinetic (PK) monitoring and dose adjustments as required were added to ensure subjects are within the targeted exposure and are in compliance with the exposure cap; The secondary objective to investigate muscle electrophysiology, as assessed by
CMAP was changed to an exploratory objective as it is less well defined with regards to clinical meaningfulness than the multiple motor assessments already being performed; An efficacy outcome measure of ability to swallow and feed orally was added because these data are an important clinical outcome for subjects with SMA Type 1, who in the natural history of the disease lose the ability to swallow; In the context of the independent safety surveillance provided by the iDMC once Part 2 was initiated, AEs of skin or subcutaneous reaction, pharyngeal/laryngeal or mucosal reaction; and clinically relevant retinal abnormalities on OCT/fundus photography were removed from the list of non-serious AEs of special interest (AESI). |
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27 Jan 2019 |
Results from in vitro studies characterizing the inhibition of CYP3A4 by risdiplam were added. This inhibition has the potential to increase the concentration of concomitant medications predominantly metabolized by the CYP3A4 enzyme; The permitted therapy section was updated to state that concomitant medications that are CYP3A4 substrates are permitted if required; however, as per usual clinical practice, potential toxicities should be monitored carefully, in particular for
medications with a narrow therapeutic window. If possible, a different concomitant medication should be chosen; The Clinical Domain Level Global Impression assessment was added to collect
information on the respiratory function and swallowing ability of subjects which will be compared with their abilities at baseline, with untreated patients with Type 1 SMA, and with typically developing infants. Exploring the effect of treatment with risdiplam on respiratory function and the ability to swallow, as assessed by the clinical domain level items, was added as an exploratory efficacy objective; Evaluation of the change from baseline in weight and height at 12 and 24 months
was added as an exploratory efficacy objective; Text was added to clarify that the dose of risdiplam administered may be higher than the dose levels explicitly listed in the protocol in order to maintain the exposure level over time in an individual growing subject. |
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18 May 2020 |
Protocol was released but is not effective. |
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17 Jun 2020 |
Given the absence of any risdiplam-induced ophthalmological findings to date in 471 subjects exposed to risdiplam for up to 3 years, the frequency of ophthalmology assessments has been reduced to every 6 months and colour fundus photography will no longer be performed; The length of the open-label extension phase has been defined as 3 years for each subject to allow for a longer safety follow-up period. Continued access to risdiplam will be provided until the end of study, provided that risdiplam is not commercially available in the subject's country. The length of the study has been modified and will not exceed 5 years after the last subject is enrolled in the study; Cautionary language on the concomitant use of CYP3A4 substrates has been removed, based on the recent results of the clinical drug-drug interaction Study BP41361 and subsequent physiologically-based pharmacokinetic modelling for extrapolation to children and infants. The study showed that coadministration with risdiplam led to only a small increase in exposure of the sensitive CYP3A
substrate midazolam, which is not considered to be clinically relevant; |
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17 Jun 2020 |
The safety monitoring period has been modified to extend from screening through the open-label extension, the study completion/early withdrawal visit, and follow-up (phone call). Language related to the study completion/early withdrawal visit and follow-up has been clarified to ensure that all assessments are performed at the last visit for each subject, and that the follow-up should occur 30 days after that visit; Safety monitoring and stopping rules for adverse events affecting the skin, mouth, pharynx, and larynx have been removed to align with current data on potential risks updated in the Risdiplam Investigator's Brochure, Version 7; The adverse event reporting period has been reduced to 30 days after the study completion/early withdrawal visit (i.e., at least 30 days after the last dose of study
drug), to reflect that adverse events are not expected beyond this reporting period; the elimination half-life of risdiplam will not exceed 30 days. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |