Clinical Trial Results:
Multicenter, Open-Label, Single-Arm Study to Evaluate Long-Term Safety, Tolerability, and Effectiveness of 10 mg/kg BID Olesoxime in Patients With Spinal Muscular Atrophy
Summary
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EudraCT number |
2015-001589-25 |
Trial protocol |
GB IT DE BE NL FR PL |
Global end of trial date |
18 Dec 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Jun 2019
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First version publication date |
22 Jun 2019
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Other versions |
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 |
BN29854
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02628743 | ||
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, CH-4070
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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) |
No
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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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 May 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
18 Dec 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
18 Dec 2018
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The main objective of this open-label, single arm study is to further characterize the safety, tolerability and effectiveness profile of olesoxime in Spinal Muscular Atrophy (SMA).
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Protection of trial subjects |
All study subjects were required to read and sign an Informed Consent Form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
20 Jan 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
United Kingdom: 14
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Country: Number of subjects enrolled |
Belgium: 14
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Country: Number of subjects enrolled |
France: 28
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Country: Number of subjects enrolled |
Germany: 10
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Country: Number of subjects enrolled |
Italy: 39
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Country: Number of subjects enrolled |
Netherlands: 6
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Country: Number of subjects enrolled |
Poland: 20
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Worldwide total number of subjects |
131
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EEA total number of subjects |
131
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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) |
0
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Children (2-11 years) |
56
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Adolescents (12-17 years) |
36
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Adults (18-64 years) |
39
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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 |
- | ||||||||||||||||
Pre-assignment
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Screening details |
A total of 131 patients were screened and enrolled into the study. | ||||||||||||||||
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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Arm title
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Olesoxime | ||||||||||||||||
Arm description |
Participants received a dose of 10 mg/kg suspension once a day (QD) orally or via a naso-gastric or gastronomy tube. Participants who consented to dose increase received 10 milligrams per kilogram (mg/kg) suspension twice a day (BID) either orally or via a naso-gastric or gastrostomy tube. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
Olesoxime
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for oral suspension
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Routes of administration |
Nasogastric use , Oral use, Gastroenteral use
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Dosage and administration details |
Participant will receive 10 milligrams per kilogram (mg/kg) suspension once a day orally or via a naso-gastric or gastronomy tube. Participants who had consented to the dose increase also received 10 mg/kg suspension twice a day (BID).
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Baseline characteristics reporting groups
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Reporting group title |
Olesoxime
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Reporting group description |
Participants received a dose of 10 mg/kg suspension once a day (QD) orally or via a naso-gastric or gastronomy tube. Participants who consented to dose increase received 10 milligrams per kilogram (mg/kg) suspension twice a day (BID) either orally or via a naso-gastric or gastrostomy tube. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Olesoxime
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Reporting group description |
Participants received a dose of 10 mg/kg suspension once a day (QD) orally or via a naso-gastric or gastronomy tube. Participants who consented to dose increase received 10 milligrams per kilogram (mg/kg) suspension twice a day (BID) either orally or via a naso-gastric or gastrostomy tube. |
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End point title |
Percentage of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) [1] | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Baseline up to approximately 3 years
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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: No statistical analyses were defined for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Motor Function Measure (MFM) Dimension 1 (D1) + Dimension 2 (D2) Score | ||||||||||||||||||||
End point description |
The MFM scale evaluated motor function in three dimensions. D1 evaluates functions related to standing and transfer, D2 evaluates axial and proximal function in supine and sitting position on mat and chair and D3 evaluates distal motor function. The scoring of each task uses a 4-point Likert scale based on the participant’s maximal abilities without assistance: 0, cannot initiate the task or maintain the starting position; 1, performs the task partially; 2, performs the task incompletely or imperfectly (with compensatory/uncontrolled movements or slowness); and 3, performs the task fully and “normally”. The score is expressed as a percentage of the maximum possible score. The lower the total score, the more severe the impairment.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104 and 130
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No statistical analyses for this end point |
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End point title |
Change From Baseline in MFM Total Score (D1+ D2 + Dimension 3 [D3]) Score | ||||||||||||||||||||
End point description |
The MFM scale evaluated motor function in three dimensions. D1 evaluates functions related to standing and transfer, D2 evaluates axial and proximal function in supine and sitting position on mat and chair and D3 evaluates distal motor function. The scoring of each task uses a 4-point Likert scale based on the participant’s maximal abilities without assistance: 0, cannot initiate the task or maintain the starting position; 1, performs the task partially; 2, performs the task incompletely or imperfectly (with compensatory/uncontrolled movements or slowness); and 3, performs the task fully and “normally”. The score is expressed as a percentage of the maximum possible score. The lower the total score, the more severe the impairment.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104 and 130
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No statistical analyses for this end point |
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End point title |
Plasma Concentrations of Olesoxime | ||||||||||||||||||||||||||||
End point description |
Values are reported separately for QD and BID doses. Dose increase occurred after Week 104.
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End point type |
Secondary
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End point timeframe |
Pre-dose (Hour 0) at Weeks 1, 13, 26, 39, 52, 78, 104 and 130
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Pediatric Quality of Life Questionnaire (PedsQL) Generic Core Scale Version 4.0 Score | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The PedsQL Generic Core Scale includes 23 items using self-report and/or parent report (ages 5+). The instrument covers physical, emotional, social and school functioning. Scale items are linearly transformed to a 0–100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, and 4 = 0) so that higher scores indicate better health related quality of life.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104 and 130
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Caregiver PedsQL Generic Core Scales Version 4.0 Score | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The PedsQL Generic Core Scale includes 23 items. The instrument covers physical, emotional, social and school functioning. Scale items are linearly transformed to a 0–100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, and 4 = 0) so that higher scores indicate better health related quality of life. Questionnaire was completed by the caregiver.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104 and 130
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No statistical analyses for this end point |
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End point title |
Change from Baseline in PedsQL Neuromuscular Module Version 3.0 Scale Score | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The PedsQL Neuromuscular Module (Version 3.0) includes 25 items using self-report (ages 5 - 18) and/or parent report (ages 5 -18). The instrument covers problems related to neuromuscular disease, communication and family resources. Scale items are linearly transformed to a 0–100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, and 4 = 0) so that higher scores indicate better health related quality of life.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104 and 130
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Caregiver PedsQL Neuromuscular Module Version 3.0 Scale Score | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The PedsQL Neuromuscular Module (Version 3.0) includes 25 items using self-report (ages 5 - 18) and/or parent report (ages 5 -18). The instrument covers problems related to neuromuscular disease, communication and family resources. Scale items are linearly transformed to a 0–100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, and 4 = 0) so that higher scores indicate better health related quality of life. Questionnaire was completed by the caregiver.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104 and 130
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No statistical analyses for this end point |
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End point title |
Change from Baseline in EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire Index Score - Total Score | ||||||||||||||||||||
End point description |
The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. Overall scores range from 0 to 1, with low scores representing a higher level of dysfunction.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104, 130; thereafter every 26 weeks up to 5 years
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Caregiver Proxy EQ-5D-5L Questionnaire Index Score - Total Score | ||||||||||||||||||||
End point description |
The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. Overall scores range from 0 to 1, with low scores representing a higher level of dysfunction. The questionnaire was completed by the caregiver.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104, 130; thereafter every 26 weeks up to 5 years
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No statistical analyses for this end point |
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End point title |
Change from Baseline in EQ-5D-5L Visual Analogue Scale (EQ-5D-5L VAS) Score | ||||||||||||||||||||
End point description |
The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. The VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104, 130; thereafter every 26 weeks up to 5 years
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Caregiver Proxy EQ-5D-5L VAS Score | ||||||||||||||||||||
End point description |
The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. The VAS is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. Questionnaire was completed by the caregiver.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104, 130; thereafter every 26 weeks up to 5 years
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No statistical analyses for this end point |
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End point title |
Number of Subjects Employed Assessed Using the Work Productivity and Activity Impairment Questionnaire: Caregiver (WPAI:CG) Questionnaire | ||||||||||||||||||
End point description |
The WPAI:CG consists of four questions about the effects of Spinal Muscular Atrophy (SMA) on the following: employment status, hours missed due to patient caregiving, hours missed due to other reasons, hours actually worked and two questions that measure the degree to which patient caregiving affected productivity and regular daily activities.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104 and 130
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Hours Actually Worked and Work Hours Missed Assessed Using WPAI:CG Questionnaire | ||||||||||||||||||||||||||||||||||||||||||||
End point description |
The WPAI:CG consists of four questions about the effects of SMA on the following: employment status, hours missed due to patient caregiving (HMC), hours missed due to other reasons (HMO), hours actually worked (HAW) and two questions that measure the degree to which patient caregiving affected productivity and regular daily activities.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104 and 130
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Work Time Missed, Impairment While Working, Overall Work Impairment and Activity Impairment Assessed Using WPAI:CG Questionnaire Score | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The WPAI:CG consists of four questions about the effects of Spinal Muscular Atrophy (SMA) on the following: employment status, hours missed due to patient caregiving, hours missed due to other reasons, hours actually worked and two questions that measure the degree to which patient caregiving affected productivity and regular daily activities. WPAI:CG outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity. The outcomes are presented for Percent work time missed (WTM), Percent impairment (IMP), Percent overall work impairment (OWI) and Percent activity impairment (AIM).
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104 and 130
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Degree Patient Caregiving Affected Productivity and Activities Using WPAI:CG Questionnaire | ||||||||||||||||||||||||||||||||
End point description |
The WPAI:CG consists of four questions about the effects of Spinal Muscular Atrophy (SMA) on the following: employment status, hours missed due to patient caregiving, hours missed due to other reasons, hours actually worked and two questions that measure the degree to which patient caregiving affected productivity and regular daily activities. WPAI:CG outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104 and 130
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Short-Form 36 (SF-36) Physical Composite Scores (PCS) and Mental Composite Scores (MCS): Caregiver | ||||||||||||||||||||||||||||||||
End point description |
The SF-36 was used to assess health-related quality of life at baseline and at on-treatment visits. The SF-36 consisted of 36 questions covering 8 domains (physical functioning, role-functioning physical, bodily pain, general health, vitality, social functioning, role-functioning emotional and mental health), with each domain scoring on a scale 0-100 (a score of 0 = maximum disability and a score of 100 = no disability). The 8 domains are further summarized to 2 distinct higher-ordered clusters: the physical and mental composite t-scores (PCS and MCS). The range for all 8 domains as well as for the composite norm-based t-scores is from 0 to 100 with 100 as best possible health status and 0 as worst health status. Reported here are the Physical Composite Scores (PCS) and Mental Composite Scores (MCS).
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104 and 130
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No statistical analyses for this end point |
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End point title |
Change from Baseline in SF-36 Domain Scores: Caregiver | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The SF-36 was used to assess health-related quality of life at baseline and at on-treatment visits. The SF-36 consisted of 36 questions covering 8 domains (physical functioning, role-functioning physical, bodily pain, general health, vitality, social functioning, role-functioning emotional and mental health), with each domain scoring on a scale 0-100 (a score of 0 = maximum disability and a score of 100 = no disability). The range for all 8 norm-based domains was from 0 to 100 with 100 as best possible health status and 0 as worst health status.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104 and 130
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Revised Utility Index Score (SF-6D_R2): Caregiver | ||||||||||||||||||||
End point description |
The SF-6D focuses on seven of the eight health domains covered by the SF-36: physical functioning, role participation (combined role-physical and role-emotional), social functioning, bodily pain, mental health, and vitality. SF-6D Health Utility Index (HUI) Score = 0 (worst measured health state) to 1 (best measured health state).
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End point type |
Secondary
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End point timeframe |
Baseline (Week 1), Weeks 26, 52, 78, 104 and 130
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No statistical analyses for this end point |
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End point title |
SMA Independence Scale (SMAIS) Score: Patient and Caregiver | ||||||||||||||||
End point description |
The SMAIS was developed specifically for SMA in order to assess function-related independence. The SMAIS contains 29 items, assessing the amount of assistance required from another individual to perform daily activities, such as eating or transferring to/from a wheelchair. Each item is scored on a zero to four scale (with an additional option to indicate that an item is non-applicable). Item scores are summed to create the total score. Lower scores indicate greater dependence on another individual.
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End point type |
Secondary
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End point timeframe |
Week 104 and Week 130
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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 |
Baseline up to approximately 3 years
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Adverse event reporting additional description |
Safety population included all patients who received at least one dose of study medication.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
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Reporting groups
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Reporting group title |
Olesoxime
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Reporting group description |
Participants received a dose of 10 mg/kg suspension once a day (QD) orally or via a naso-gastric or gastronomy tube. Participants who consented to dose increase received 10 milligrams per kilogram (mg/kg) suspension twice a day (BID) either orally or via a naso-gastric or gastrostomy tube. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 | |||
Date |
Amendment |
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09 Sep 2015 |
Clarity regarding contraception use, as well as withdrawal in case of pregnancy have been included in the protocol. |
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19 Aug 2016 |
The Hammersmith Functional Motor Scale (HFMS) scale was removed to decrease patient and site burden, the use of anticoagulants as prohibited medications was removed to align with the Investigator’s Brochure and added new information regarding pharmacokinetic characteristics of the study drug. |
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14 Nov 2017 |
Olesoxime dose increased from 10 mg/kg once daily (QD) to 10 mg/kg twice daily (BID) and a newly developed scale assessing function-related independence has been introduced as a patient-reported outcome measure: the SMA Independence Scale (SMAIS). |
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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 |