Clinical Trial Results:
Effects of N-Acetyl-L-Leucine on GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease): A multinational, multicenter, open-label, rater-blinded Phase II study.
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Summary
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EudraCT number |
2018-004406-25 |
Trial protocol |
DE ES GB |
Global end of trial date |
09 Jan 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Dec 2023
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First version publication date |
22 Dec 2023
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Other versions |
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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 |
IB1001-202
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03759665 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
IntraBio Ltd.
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Sponsor organisation address |
Begbroke Science Park, Begbroke Hill; Woodstock Road, Begbroke, United Kingdom, OX5 1PF
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Public contact |
Taylor Fields, IntraBio Ltd, +44 7426956368, tfields@intrabio.com
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Scientific contact |
Taylor Fields, IntraBio Ltd, +44 7426956368, tfields@intrabio.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 |
09 Nov 2023
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
09 Jan 2023
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Global end of trial reached? |
Yes
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Global end of trial date |
09 Jan 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 |
The primary objective is to evaluate the efficacy of N-Acetyl-L-Leucine based on blinded raters’ clinical impression of change in severity (CI-CS) in the treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease).
For the Extension Phase:
The primary objective is to evaluate the efficacy of N-Acetyl-L-Leucine based on blinded raters' Clinical Impression of Change in Severity (CICS) in the long-term treatment of GM2.
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Protection of trial subjects |
The study was performed in accordance with the requirements of the Declaration of Helsinki, ICH-GCP, Directive 2001/20/EC, and by the Food and Drug Administration (FDA) CFR as well as the requirements of national drug and data protection laws and other applicable regulatory requirements. Informed consent was obtained from each patient or their legal representative in writing prior to any study-related procedures.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
07 Jun 2019
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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 |
Spain: 1
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
Germany: 18
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Country: Number of subjects enrolled |
United States: 10
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Worldwide total number of subjects |
30
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EEA total number of subjects |
19
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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) |
8
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Adolescents (12-17 years) |
2
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Adults (18-64 years) |
20
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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 |
The study was performed from 07-June-2019 (first informed consent) to 09-January-2023 (extension phase completion date). Subjects were recruited at sites in Germany, Spain, the United Kingdom, and the United States. | ||||||||||||||
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Pre-assignment
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Screening details |
At the initial screening visit, patients were classified as either “naïve” or “non-naïve” depending on their use of prohibited medications within the past 42 days. | ||||||||||||||
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Period 1
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Period 1 title |
Treatment with IB1001
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
Blinding implementation details |
As the study only had one treatment arm, blinding of treatment was not applicable. However, the primary CI-CS and secondary CI-S assessments were performed by centralized, independent blinded
raters based on videos of each patient performing a designated primary anchor test - the 9HPT-D or 8MWT.
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Arms
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Arm title
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Total Treatment with IB1001 | ||||||||||||||
Arm description |
All subjects in the parent study ; 6-weeks treatment with IB1001 administered orally. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
N-Acetyl-L-Leucine
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Investigational medicinal product code |
IB1001
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Other name |
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Pharmaceutical forms |
Oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
IB1001 was administered orally. Patients aged ≥13 years old received 4 g/day, patients aged 6-12 years weighing ≥35 kg received 4 g/day, patients aged 6-12 years weighing 25 to <35 kg received 3 g/day, patients aged 6-12 years weighing 15 to <25 kg received 2 g/day.
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Period 2
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Period 2 title |
Post-Treatment Washout
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Is this the baseline period? |
No | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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Total Post-Treatment Washout | ||||||||||||||
Arm description |
After the 6-week treatment period, patients entered a 6-week post-treatment washout period. | ||||||||||||||
Arm type |
No intervention | ||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
Treatment with IB1001
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Safety Analysis Set (SAF)
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The Safety Analysis Set (SAF) consisted of all patients who received at least 1 dose of study drug (IB1001).
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Subject analysis set title |
mITT
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The modified Intention-to-Treat (mITT) analysis set consisted of all patients in the SAF with a video recording at either Visit 1 or Visit 2 (or both) and 1 video recording at either Visit 3 or Visit 4 (or both).
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End points reporting groups
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Reporting group title |
Total Treatment with IB1001
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Reporting group description |
All subjects in the parent study ; 6-weeks treatment with IB1001 administered orally. | ||
Reporting group title |
Total Post-Treatment Washout
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Reporting group description |
After the 6-week treatment period, patients entered a 6-week post-treatment washout period. | ||
Subject analysis set title |
Safety Analysis Set (SAF)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The Safety Analysis Set (SAF) consisted of all patients who received at least 1 dose of study drug (IB1001).
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Subject analysis set title |
mITT
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The modified Intention-to-Treat (mITT) analysis set consisted of all patients in the SAF with a video recording at either Visit 1 or Visit 2 (or both) and 1 video recording at either Visit 3 or Visit 4 (or both).
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End point title |
Clinical Impression of Change in Severity (CI-CS) [1] | ||||||||
End point description |
The primary efficacy endpoint was based on the blinded raters’ CI-CS of patient's change in performance over 6 weeks on either the 9-Hole Peg Test of the Dominant Hand (9HPT-D) or the 8-Meter Walk Test (8MWT). The primary endpoint was defined as the CI-CS comparing the end of treatment (Visit 4) with baseline (Visit 2) minus the CI-CS comparing the end of washout (Visit 6) with the end of treatment (Visit 4).
A one-sided Wilcoxon signed-rank test was performed to investigate statistical significance of the primary efficacy endpoint as compared to a value of 0 for the mITT population. The (pseudo-) median of the difference in CI-CS using the Hodges-Lehmann estimator was 0.75 (90% CI: 0.00, 1.50). The CI-CS primary endpoint of the study reached statistical significance with p-value: 0.044. In addition, a one-sided t-test was performed to support the statistical significance. The p-value was 0.039.
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End point type |
Primary
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End point timeframe |
Primary endpoint for the parent study; CI-CS comparing the End of treatment (Visit 4) with baseline (Visit 2) minus the CI-CS comparing the end of washout (Visit 6) with the end of treatment (Visit 4).
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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 was a single-arm study. Thus, inferential statistics comparing two groups were not done. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Key secondary endpoint: Individual Components of CI-CS | ||||||||||||
End point description |
The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video?
The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse).
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End point type |
Secondary
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End point timeframe |
Treatment with IB1001: comparing the End of treatment (Visit 4) with baseline (Visit 2); Post-treatment washout: comparing the end of washout (Visit 6) with the end of treatment (Visit 4)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Key secondary endpoint: Change in Severity Based on Average CI-S | ||||||||
End point description |
The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video? The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3=significantly worse).
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End point type |
Secondary
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End point timeframe |
CI-CS comparing baseline period and end of treatment period minus the change in CI-S between end of treatment period and end of washout period.
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| No statistical analyses for this end point | |||||||||
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End point title |
Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale | ||||||||||||||||||
End point description |
The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D)or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video? The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3=significantly worse).
CI-CS scores <0 were reclassified as worsened (-1), CI-CS scores 0 remained classified as not changed (0), and CI-CS scores >0 were reclassified as improved (+1).
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End point type |
Secondary
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End point timeframe |
Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout.
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Key Secondary Endpoint: CI-CS Score for the Non-Primary Anchor Test | ||||||||||||
End point description |
The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video? The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse).
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End point type |
Secondary
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End point timeframe |
CI-CS of the non-primary anchor test was evaluated, comparing the CI-CS of Visit 4 versus Visit 2 and of Visit 6 versus Visit 4 as done for the primary anchor test.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Spinocerebellar Ataxia Functional Index (SCAFI) [Schmitz-Hübsch et al, 2008] | ||||||||||||
End point description |
Spinocerebellar Ataxia Functional Index (SCAFI) is composed of 8 MeterWalk Test, 9-Hole Peg Test of Dominant and Non-Dominant Hand (9HPT-D/9HPT-ND) (the 3 tests are timed assessments; each is done twice andvalues are averaged; the 8MWT and 9HPT-D and 9HPT-ND values are converted from times to rates, and the results expressed as a composite Z-score of each test relative to baseline) and the PATA rate (counted number how often a patient can repeat the syllables "PATA" within 10 seconds), a measure of speech performance. The scores of these 3 were transformed to Z-scores (=individual's average of both trials to perform the respective task -mean of study population at baseline) / SD of study population at baseline). A Z-score of 0 equates to the population mean at baseline. For all 3, higher Z-scores (above mean) mean better performance. The SCAFI total score was calculated as the arithmetic mean of the non-missing Z-scores for the 3. A higher total score means better performance.
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End point type |
Secondary
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End point timeframe |
Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment);End of treatment with IB1001 to the end of post 6-week treatment washout
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Scale for Assessment and Rating of Ataxia (SARA) Score [Schmitz- Hübsch etal, 2006; Subramony, 2007] | ||||||||||||
End point description |
The Scale for Assessment and Rating of Ataxia has 8 items that are related to gait, stance, sitting, speech, finger-chase test, nose-finger test, fast alternating movements, and heel-shin test. The range is 0-40 points, with a lower score representing neurological improvement and a higher score representing neurological worsening.
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End point type |
Secondary
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End point timeframe |
Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout
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| No statistical analyses for this end point | |||||||||||||
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End point title |
EuroQuol- 5 Dimension (EQ-5D) Quality of Life Scale Visual Analogue Scale | ||||||||||||
End point description |
For posting, health-related quality of life based on the EQ-5D visual analogue scale (VAS) was presented as a secondary endpoint. EQ-5D visual analogue scale (VAS) is a 0 to 100 scale where patients are asked to indicate their overall health, with a score of 0 indicating worst health and a score of 100 indicating best health.
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End point type |
Secondary
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End point timeframe |
Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Modified Disability Rating Scale (mDRS) [Iturriaga et al. 2006] | ||||||||||||
End point description |
Overall neurological status based on six domains (ambulation, manipulation, language, swallowing, seizures and ocular movements). The Modified Disability Rating Scale ranges from 0-24, where 0 is the best neurological status and 24 is the worst.
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End point type |
Secondary
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End point timeframe |
Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Investigator's Clinical Global Impressions of Change (CGI-C) | ||||||||||||
End point description |
The Clinical Global Impression of Change assessed by the investigator is evaluated on a 7 point Likert scale ranging from 1='very much improved' to 7='very much worse'
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End point type |
Secondary
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End point timeframe |
Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Parent/Caregiver's Clinical Global Impression of Change (CGI-C) | ||||||||||||
End point description |
The Clinical Global Impression of Change assessed by the parent/caregiver is evaluated on a 7 point Likert scale ranging from 1='very much improved' to 7='very much worse'.
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End point type |
Secondary
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End point timeframe |
Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Patient's Clinical Global Impressions (CGI) if Able | ||||||||||||
End point description |
The Clinical Global Impression of Change assessed by the patient (if able) is evaluated on a 7 point Likert scale ranging from 1='very much improved' to 7='very much worse'.
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End point type |
Secondary
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End point timeframe |
Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout
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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 |
All AEs occurring during the clinical study were to be documented, commencing with the signing of the ICF through the End of Study (EOS) Visit (scheduled at 42 days post last IB1001 dose).
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Adverse event reporting additional description |
A treatment emergent adverse event (TEAE) was defined as an AE that appeared during or after study treatment and was absent before, or an AE which was present before treatment and worsened while on treatment.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.0
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Reporting groups
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Reporting group title |
Total Treatment with IB1001
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Reporting group description |
The Safety Analysis Set (SAF) consisted of all patients who received at least one 1 dose of study drug (IB1001). Participants in the Total Treatment with IB1001 period received 6-weeks treatment with IB1001 administered orally. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Post-treatment washout
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Reporting group description |
The Safety Analysis Set (SAF) consisted of all patients who received at least one 1 dose of study drug (IB1001). After the Parent Study 6-week treatment period, patients entered a 6-week post-treatment washout period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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27 Sep 2019 |
The reason for this amendment was feedback from United States FDA following the IND review period and European National Regulatory Agencies (including Germany, Spain, Slovakia, and United Kingdom) during the review of Clinical Trial Applications and for general protocol updates regarding updates and/or corrections to the study procedures
Key changes were:
• Visit 1 for “naïve” patients reclassified as “non-naïve” was not to be confirmed as Visit 0; patients instead returned for a repeat Visit 1 after study run-in;
• Addition of a secondary endpoint examining CI-CS for the non-primary anchor test to further directly supplement the analysis of the primary endpoint;
• If consensus could not be achieved between 2 blinded raters on the CI-CS assessment, a third rater was used to agree with 1 of the 2 raters so that a final rating could be determined to improve the process for allowing a final CI CS rating for analysis to be selected;
• Detailing of adjudication process for secondary CI-S assessment to improve process for allowing a final CI-S rating for analysis to be selected;
• Addition of study protocol for the Extension Phase in Appendix 6 to provide procedures and design of the Extension Phase protocol.
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16 Jan 2020 |
The reason for this amendment was inclusion of the new IB1001 sachet formulation manufactured for clinical use in the Extension Phase of the IB1001-202 study.
Key changes were:
• Addition that written informed consent could be obtained by an impartial witness to clarify that it was permissible for an impartial witness to sign the ICF on behalf of an adult patient who was mentally able to consent, physically unable to, and provided verbal consent to participate in the study;
• Updating informed consent procedures for identifying adults lacking capacity to consent and legal representatives to ensure correct informed consent was obtained from each eligible participant;
• Addition of new IMP dosage form for clinical use in the Extension Phase.
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23 Oct 2020 |
The reason for this amendment was inclusion of the impact of COVID-19 pandemic on the IB1001 202 study and inclusion of an additional 1-year treatment period in the Extension Phase.
Key changes were:
• Modifications to original study schema and study conduct (including, but not limited to, study duration, patient withdrawal, dose scheduling, remote assessments, vital signs, ECGs, safety laboratory measurements, monitoring, reconsent, DSMB involvement [DSMB reviewed the Sponsor guidances related to changes to the protocol due to COVID-19]) to reflect the impact of COVID-19 on the IB1001-202 study;
• Addition of 1-year treatment period (Visit 11, Visit 12) in the Extension Phase;
• Addition of ITT population and updated definition of mITT population;
• Addition of key subgroups;
• Addition of sensitivity measurement of secondary endpoint CI-CS on a 3-point scale, caregiver and patient CGI-C measures and EQ-5D-VAS to be evaluated descriptively to reflect procedures defined in the SAP;
• Updating procedures for analyzing the mITT population, including LOCF approach and sensitivity analysis.
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30 Nov 2022 |
The reason for this amendment was to align the Extension Phase analysis plan with the Pivotal IB1001-201 clinical trial Extension Phase design.
Key changes were:
• mDRS instated as primary endpoint for the Extension Phase.
• All other efficacy endpoints in the Extension Phase were to be considered exploratory and evaluated descriptively.
• The CI-CS endpoint may be assessed in the future to support the validation of the assessment.
(The amendment was dated 30-Nov-2022 and approved by the regulatory authority on 27-Jan-2023). |
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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. | |||
| This study was ongoing during the COVID-19 pandemic, and the conduct of this study was impacted by the COVID-19 pandemic. | |||
