Clinical Trial Results:
A phase II, randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety, efficacy, and pharmacodynamics of 52 weeks of treatment with basmisanil in participants aged 2 to 14 years old with Dup15q syndrome followed by a 2-year optional open-label extension
Summary
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EudraCT number |
2021-003791-13 |
Trial protocol |
IT ES PT PL NL |
Global end of trial date |
04 Mar 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Sep 2024
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First version publication date |
20 Sep 2024
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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 |
BP42992
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT05307679 | ||
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) |
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 |
30 May 2024
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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 |
04 Mar 2024
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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 |
To evaluate the effects of 52 weeks of treatment with basmisanil on core symptom domains of Dup15q syndrome (language and social skills) and daily functioning
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Protection of trial subjects |
All participants were required to sign an Informed Consent Form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 May 2022
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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: 1
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Country: Number of subjects enrolled |
United States: 3
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Country: Number of subjects enrolled |
Spain: 3
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Worldwide total number of subjects |
7
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EEA total number of subjects |
3
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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) |
7
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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 |
- | |||||||||||||||
Pre-assignment
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Screening details |
Aged 6-14 years with documented maternal duplication (3 copies) or triplication (4 copies) of the chromosome 15q11.2-q13.1 region including the Prader-Willi/Angelman critical region defined as [BP2-BP3] segment, and a Dup15q syndrome Clinician Global Impression of Severity scale (Dup15q CGI S)overall severity score >/= 4 (at least moderately ill). | |||||||||||||||
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 |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator | |||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||
Arm description |
Part 1: Participants received oral placebo twice (BID) on the first day of treatment, then three times daily (TID) to Day 365. | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Granules
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Routes of administration |
Oral use
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Dosage and administration details |
Participants received oral placebo BID on Day 1, then TID on Days 2-365.
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Arm title
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Basmisanil | |||||||||||||||
Arm description |
Part 1: Participants received oral basmisanil BID on the first day of treatment, then TID to Day 365. Part 2: Participants who completed Part 1 were to receive oral basmisanil for approximately 2 years. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Basmisanil
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Investigational medicinal product code |
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Other name |
RO5186582
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Pharmaceutical forms |
Granules
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Routes of administration |
Oral use
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Dosage and administration details |
Part 1: Participants received oral basmisanil BID on Day 1, then TID on Days 2-365. Part 2: Participants were to receive oral basmisanil for up to 2 years.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Part 1: Participants received oral placebo twice (BID) on the first day of treatment, then three times daily (TID) to Day 365. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Basmisanil
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Reporting group description |
Part 1: Participants received oral basmisanil BID on the first day of treatment, then TID to Day 365. Part 2: Participants who completed Part 1 were to receive oral basmisanil for approximately 2 years. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Part 1: Participants received oral placebo twice (BID) on the first day of treatment, then three times daily (TID) to Day 365. | ||
Reporting group title |
Basmisanil
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Reporting group description |
Part 1: Participants received oral basmisanil BID on the first day of treatment, then TID to Day 365. Part 2: Participants who completed Part 1 were to receive oral basmisanil for approximately 2 years. |
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End point title |
Vineland-3 adaptive behavior composite scores [1] | |||||||||||||||
End point description |
The Vineland-3 is an instrument that measures communication, daily living skills, socialization, and motor skills. Items are either scored as 2 = Usually,
1 = Sometimes, 0 = Never; or scored as 2 = Yes, 0 = No in the case of items that require a binary response. Lower scores indicate lower adaptive behavior abilities.
Only baseline data have been reported. The low n for remaining timepoints (Day 183, Day 365) leads to an unacceptable risk of participant re-identification.
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End point type |
Primary
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End point timeframe |
Baseline, Day 183, Day 365
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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 formal statistical analyses were performed due to the low number of trial participants. |
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No statistical analyses for this end point |
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End point title |
Vineland-3 gross and fine motor subdomains scores | ||||||||||||||||||
End point description |
The Vineland-3 is an instrument that measures communication, daily living skills, socialization, and motor skills. Items are either scored as 2 = Usually,
1 = Sometimes, 0 = Never; or scored as 2 = Yes, 0 = No in the case of items that require a binary response. Lower scores indicate lower adaptive behavior abilities.
Only baseline data have been reported. The low n for remaining timepoints (Day 183, Day 365) leads to an unacceptable risk of participant re-identification.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 183, Day 365
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Notes [2] - Data not reported for participants older than 9 years; normative data only available for ages 0-9y |
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No statistical analyses for this end point |
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End point title |
Vineland 3 expressive and receptive communication subdomains | ||||||||||||||||||
End point description |
The Vineland-3 is an instrument that measures communication, daily living skills, socialization, and motor skills. Items are either scored as 2 = Usually,
1 = Sometimes, 0 = Never; or scored as 2 = Yes, 0 = No in the case of items that require a binary response. Lower scores indicate lower adaptive behavior abilities.
Only baseline data have been reported. The low n for remaining timepoints (Day 183, Day 365) leads to an unacceptable risk of participant re-identification.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 183, Day 365
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No statistical analyses for this end point |
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End point title |
Vineland-3 play and leisure time and interpersonal relationships subdomains | ||||||||||||||||||
End point description |
The Vineland-3 is an instrument that measures communication, daily living skills, socialization, and motor skills. Items are either scored as 2 = Usually,
1 = Sometimes, 0 = Never; or scored as 2 = Yes, 0 = No in the case of items that require a binary response. Lower scores indicate lower adaptive behavior abilities. V-scale scores are presented.
Only baseline data have been reported. The low n for remaining timepoints (Day 183, Day 365) leads to an unacceptable risk of participant re-identification.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 183, Day 365
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No statistical analyses for this end point |
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End point title |
Mullen Scales of Early Learning (MSEL) gross and fine motor domains | ||||||||||||||||||
End point description |
The MSEL are designed for a certified rater to provide an assessment of cognitive ability and motor development of typically developing children from birth through age 68 months. It was administered to all participants in this study irrespective of their chronological age. The instrument consists of 124 items across five scales measuring Gross Motor, Visual Reception, Fine Motor, Expressive Language, and Receptive Language. The scoring for each item ranges from 0 to 5 points, with lower scores indicating lower developmental abilities.
Only baseline data have been reported. The low n for remaining timepoints leads to an unacceptable risk of participant re-identification.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 183, Day 365
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No statistical analyses for this end point |
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End point title |
MSEL visual reception domain scores | |||||||||||||||
End point description |
The MSEL are designed for a certified rater to provide an assessment of cognitive ability and motor development of typically developing children from birth through age 68 months. It was administered to all participants in this study irrespective of their chronological age. The instrument consists of 124 items across five scales measuring Gross Motor, Visual Reception, Fine Motor, Expressive Language, and Receptive Language. The scoring for each item ranges from 0 to 5 points, with lower scores indicating lower developmental abilities.
Only baseline data have been reported. The low n for remaining timepoints leads to an unacceptable risk of participant re-identification.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 183, Day 365
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No statistical analyses for this end point |
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End point title |
MSEL expressive and receptive language subdomains | ||||||||||||||||||
End point description |
The MSEL are designed for a certified rater to provide an assessment of cognitive ability and motor development of typically developing children from birth through age 68 months. It was administered to all participants in this study irrespective of their chronological age. The instrument consists of 124 items across five scales measuring Gross Motor, Visual Reception, Fine Motor, Expressive Language, and Receptive Language. The scoring for each item ranges from 0 to 5 points, with lower scores indicating lower developmental abilities.
Only baseline data have been reported. The low n for remaining timepoints leads to an unacceptable risk of participant re-identification.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 183, Day 365
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No statistical analyses for this end point |
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End point title |
Dup15q syndrome Clinician Global Impression of Severity (CGI-S) scale scores | ||||||||||||||||||
End point description |
The Dup15q CGI-S is a 10-domain clinician-rated measure on a 6-point scale that measures global severity of illness at a given point in time. The ten domains are seizures, expressive communication difficulties, fine motor skills difficulties, gross motor skills difficulties, cognitive/intellectual impairment, impairment in activities of daily living/self-care, socialization, maladaptive behavior, sleep difficulties, and overall severity. Response options are:
1 = none
2 = very mild
3 = mild
4 = moderate
5 = severe
6 = very severe.
Only baseline and Day 28 data have been reported. The low n for remaining timepoints leads to an unacceptable risk of participant re-identification.
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End point type |
Secondary
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End point timeframe |
Baseline - Day 365
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No statistical analyses for this end point |
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End point title |
Dup15q syndrome Clinician Global Impression of Change scale (CGI-C) scores | |||||||||||||||
End point description |
The Dup15q CGI-C is a 10-domain clinician-rated measure on a 7-point scale that assesses the clinician’s impression of change in illness compared with baseline. The ten domains are seizures, expressive communication difficulties, fine motor skills difficulties, gross motor skills difficulties, cognitive/intellectual impairment, impairment in activities of daily living/self-care, socialization, maladaptive behavior, sleep difficulties, and overall severity. Response options are:
1 = very much improved
2 = much improved
3 = minimally improved
4 = no change
5 = minimally worse
6 = much worse
7= very much worse
Only Day 28 data have been reported. The low n for remaining timepoints leads to an unacceptable risk of participant re-identification.
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End point type |
Secondary
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End point timeframe |
Day 28 - Day 365
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No statistical analyses for this end point |
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End point title |
Aberrant Behavior Checklist - Second Edition - Community Version (ABC-2-C) domain scores - Irritability | ||||||||||||||||||
End point description |
The ABC-2 is an updated, empirically derived, validated 58-item caregiver-completed rating scale that measures the severity of a range of maladaptive behaviors commonly observed in children, adolescents, and adults with intellectual and developmental disabilities. The Community version of the scale (ABC-2-C) will be used. It is designed for use in individuals who are not residing in institutional settings. The checklist assesses symptoms across five domains: irritability,
social withdrawal, stereotypic behavior, hyperactive/noncompliance, and inappropriate speech. Items are scored on a 4-point scale from 0 (never) to 3 (severe problem). Subscale scores and a total score can be calculated with higher scores indicating greater severity.
Only baseline and Day 28 data have been reported. The low n for remaining timepoints leads to an unacceptable risk of participant re-identification.
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End point type |
Secondary
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End point timeframe |
Baseline - Day 365
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No statistical analyses for this end point |
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End point title |
ABC-2-C domain scores - Social Withdrawal | ||||||||||||||||||
End point description |
The ABC-2 is an updated, empirically derived, validated 58-item caregiver-completed rating scale that measures the severity of a range of maladaptive behaviors commonly observed in children, adolescents, and adults with intellectual and developmental disabilities. The Community version of the scale (ABC-2-C) will be used. It is designed for use in individuals who are not residing in institutional settings. The checklist assesses symptoms across five domains: irritability,
social withdrawal, stereotypic behavior, hyperactive/noncompliance, and inappropriate speech. Items are scored on a 4-point scale from 0 (never) to 3 (severe problem). Subscale scores and a total score can be calculated with higher scores indicating greater severity.
Only baseline and Day 28 data have been reported. The low n for remaining timepoints leads to an unacceptable risk of participant re-identification.
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End point type |
Secondary
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End point timeframe |
Baseline - Day 365
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No statistical analyses for this end point |
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End point title |
ABC-2-C domain scores - Stereotypic Behavior | ||||||||||||||||||
End point description |
The ABC-2 is an updated, empirically derived, validated 58-item caregiver-completed rating scale that measures the severity of a range of maladaptive behaviors commonly observed in children, adolescents, and adults with intellectual and developmental disabilities. The Community version of the scale (ABC-2-C) will be used. It is designed for use in individuals who are not residing in institutional settings. The checklist assesses symptoms across five domains: irritability,
social withdrawal, stereotypic behavior, hyperactive/noncompliance, and inappropriate speech. Items are scored on a 4-point scale from 0 (never) to 3 (severe problem). Subscale scores and a total score can be calculated with higher scores indicating greater severity.
Only baseline and Day 28 data have been reported. The low n for remaining timepoints leads to an unacceptable risk of participant re-identification.
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End point type |
Secondary
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End point timeframe |
Baseline - Day 365
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No statistical analyses for this end point |
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End point title |
ABC-2-C domain scores - Hyperactivity/Non-Compliance | ||||||||||||||||||
End point description |
The ABC-2 is an updated, empirically derived, validated 58-item caregiver-completed rating scale that measures the severity of a range of maladaptive behaviors commonly observed in children, adolescents, and adults with intellectual and developmental disabilities. The Community version of the scale (ABC-2-C) will be used. It is designed for use in individuals who are not residing in institutional settings. The checklist assesses symptoms across five domains: irritability,
social withdrawal, stereotypic behavior, hyperactive/noncompliance, and inappropriate speech. Items are scored on a 4-point scale from 0 (never) to 3 (severe problem). Subscale scores and a total score can be calculated with higher scores indicating greater severity.
Only baseline and Day 28 data have been reported. The low n for remaining timepoints leads to an unacceptable risk of participant re-identification.
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End point type |
Secondary
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End point timeframe |
Baseline - Day 365
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No statistical analyses for this end point |
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End point title |
ABC-2-C domain scores - Inappropriate Speech | ||||||||||||||||||
End point description |
The ABC-2 is an updated, empirically derived, validated 58-item caregiver-completed rating scale that measures the severity of a range of maladaptive behaviors commonly observed in children, adolescents, and adults with intellectual and developmental disabilities. The Community version of the scale (ABC-2-C) will be used. It is designed for use in individuals who are not residing in institutional settings. The checklist assesses symptoms across five domains: irritability,
social withdrawal, stereotypic behavior, hyperactive/noncompliance, and inappropriate speech. Items are scored on a 4-point scale from 0 (never) to 3 (severe problem). Subscale scores and a total score can be calculated with higher scores indicating greater severity.
Only baseline and Day 28 data have been reported. The low n for remaining timepoints leads to an unacceptable risk of participant re-identification.
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End point type |
Secondary
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End point timeframe |
Baseline - Day 365
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No statistical analyses for this end point |
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End point title |
Plasma concentration of basmisanil [3] | ||||||||||||||||||||||||||||||||||
End point description |
Data for certain timepoints (Day 1 Hour 7, Day 1 Hour 8, Day 14 Hour -1, Day 183 Hour 0) has been excluded due to an unacceptable risk of patient re-identification.
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End point type |
Secondary
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End point timeframe |
Day 1 - Day 365
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Notes [3] - 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 was specific to the basmisanil arm as the placebo arm did not receive basmisanil. |
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No statistical analyses for this end point |
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End point title |
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | ||||||||||||
End point description |
An adverse event is any untoward medical occurrence in a participant 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.
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End point type |
Secondary
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End point timeframe |
Up to 52 weeks
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No statistical analyses for this end point |
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End point title |
Plasma concentration of the basmisanil metabolite M1 [4] | ||||||||||||||||||||||||||||||||||
End point description |
Data for certain timepoints (Day 1 Hour 7, Day 1 Hour 8, Day 14 Hour -1, Day 183 Hour 0) has been excluded due to an unacceptable risk of patient re-identification.
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End point type |
Secondary
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End point timeframe |
Day 1 - Day 365
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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 was specific to the basmisanil arm as the placebo arm did not receive basmisanil. |
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No statistical analyses for this end point |
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End point title |
Quantitative EEG (qEEG) beta-band power | ||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline, Day 14
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No statistical analyses for this end point |
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Adverse events information [1]
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Timeframe for reporting adverse events |
Baseline - Day 365
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Adverse event reporting additional description |
All subjects were affected by non-serious adverse events (NSAEs). One subject was affected by serious adverse events (SAEs). There were no deaths. The exact NSAEs and SAEs are not reported due to the risk of patient re-identification.
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Assessment type |
Systematic | |||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||
Dictionary version |
27.0
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Reporting groups
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Reporting group title |
Basmisanil
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Reporting group description |
Part 1: Participants received oral basmisanil BID on the first day of treatment, then TID to Day 365. Part 2: Participants who completed Part 1 were to receive oral basmisanil for approximately 2 years. | |||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Part 1: Participants received oral placebo twice (BID) on the first day of treatment, then three times daily (TID) to Day 365. | |||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||
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Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: All participants reported at least one AE. The exact nature of the AEs has not been disclosed due to the high risk of patient re-identification due to the low number of participants. |
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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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25 Jan 2022 |
Changes to the schedule of activities, including additional assessments; updates to inclusion and exclusion criteria. |
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25 Jul 2023 |
Addition of optional open-label extension of two years; modification of age criteria; changes to study assessments. |
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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. | |||
Data for certain timepoints with only 1 analyzed participant is not reported due to an unacceptable risk of participant re-identification. |