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This is a multinational, multicenter, open-label, rater-blinded prospective Phase II study which will assess the safety and efficacy of N-Acetyl-L-Leucine (IB1001) for the treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease).
There are two phases to this study: the Parent Study, and the Extension Phase.
The Parent Study evaluates the safety and efficacy of N-Acetyl-L-Leucine (IB1001) in the symptomatic treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease).
The Extension Phase evaluates the long-term safety and efficacy of IB1001 for the neuroprotective, disease-modifying treatment of GM2 Gangliosidosis. The Extension Phase was considered exploratory.
In the Parent Study, Patients will be assessed during three study phases: a baseline period, a 6-week treatment period, and a 6-week post-treatment washout period. If within 6 weeks prior to the initial screening visit, a patient has received any of the prohibited medications defined in the eligibility criteria (irrespective of the preceding treatment duration) a wash-out study-run-in of 6 weeks is required prior to the first baseline assessment. All patients will receive the study drug during the treatment period. For each individual patient, the Parent Study lasts for approximately 3.5 - 4 months during which there are 6 visits to the study site.
This Extension Phase allows patients who have completed the Parent Study to, at the discretion of the Principal Investigator (PI), continue treatment with N-Acetyl-L-Leucine (IB1001). Patients will receive treatment with IB1001 for two one-year treatment periods, separated by a 6-week washout. All patients will receive the study drug during these two one-year treatment periods. For each individual patient, the Extension Phase lasts for approximately 25.5 months, during which there are 6 visits to the study site.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment with IB1001 | Experimental | Parent Study: 6-weeks treatment with IB1001 administered orally. Extension Phase: 1-year treatment with IB1001 administered orally. Patients ≥13 years old will receive a total daily dose of 4 g/day (administered as 3 doses per day). Patients 6-12 years old will receive weight-tiered doses:
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| Post-Treatment Washout | No Intervention | After the Parent Study 6-week treatment period, and Extension Phase one-year treatment period, patients will enter a 6-week post-treatment washout period. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| IB1001 | Drug | IB1001 (N-Acetyl-L-Leucine) is a modified amino-acid ester that is orally administered. |
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| Measure | Description | Time Frame |
|---|---|---|
| Clinical Impression of Change in Severity (CI-CS) [Fields et al 2021] | 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). Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). Then, the mean change obtained in the post-treatment period was subtracted from the mean change obtained for the treatment with IB1001 period, with a positive value indicating an improvement in the treatment period compared to the post-treatment washout period. | (CI-CS comparing Baseline [Day 1] with IB1001 versus the end of 6-weeks treatment with IB1001 [approximately Day 42]) MINUS (CI-CS comparing the end of 6-weeks treatment with IB1001 [approximately Day 42] versus end of 6-weeks post-treatment washout); |
| Measure | Description | Time Frame |
|---|---|---|
| Key Secondary Endpoint: Individual Components of the CI-CS | 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). Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). |
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Parent Study Inclusion Criteria
Individuals who meet all of the following criteria are eligible to participate in the study:
Written informed consent signed by the patient and/or their legal representative/ parent
Male or female aged ≥6 years in Europe OR ≥18 years in the United States with a confirmed diagnosis of GM2 Gangliosidosis ( i.e., clinical features and positive genetic test GM2-gangliosidosis caused by β-hexosaminidase deficiency resulting from mutations in the HEXA or HEXB genes) at the time of signing informed consent.
Females of childbearing potential, defined as a premenopausal female capable of becoming pregnant, will be included if they are either sexually inactive (sexually abstinent for 14 days prior to the first dose continuing through 28 days after the last dose) or using one of the following highly effective contraceptives (i.e. results in <1% failure rate when used consistently and correctly) 14 days prior to the first dose continuing through 28 days after the last dose:
Females of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first dose:
OR
be postmenopausal with amenorrhea for at least 1 year prior to the first dose and follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status. FSH analysis for postmenopausal women will be done at screening. FSH levels should be in the postmenopausal range as determined by the central laboratory.
Non-vasectomized male patient agrees to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days beyond the last dose of study medication and the female partner agrees to comply with inclusion criteria 3 or 4. For a vasectomized male who has had his vasectomy 6 months or more prior to study start, it is required that they use a condom during sexual intercourse. A male who has been vasectomized less than 6 months prior to study start must follow the same restrictions as a non-vasectomized male.
If male, the patient agrees not to donate sperm from the first dose until 90 days after dosing.
Patients must fall within:
a) A Scale for the Assessment and Rating of Ataxia (SARA) score of 5 ≤ X ≤ 33 points (out of 40) AND i. Within the 2-7 range (out of 0-8 range) of the Gait subtest of the SARA scale OR ii. Be able to perform the 9 Hole Peg Test with Dominant Hand (9HPT-D) (SCAFI subtest) in 20 ≤ X ≤150 seconds.
Weight ≥15 kg at screening.
Patients are willing to disclose their existing medications/therapies for (the symptoms) of GM2 Gangliosidosis, including those on the prohibited medication list. Non-prohibited medications/therapies (e.g. concomitant speech therapy, and physiotherapy) are permitted provided:
An understanding of the implications of study participation, provided in the written patient information and informed consent by patients or their legal representative/parent, and demonstrates a willingness to comply with instructions and attend required study visits (for children this criterion will also be assessed in parents or appointed guardians).
Parent Study Exclusion Criteria
Individuals who meet any of the following criteria are not eligible to participate in the study:
Asymptomatic patients
Patient has clinical features of Tay-Sachs or Sandhoff disease, but a completely negative result on a previous genetic test for GM2 Gangliosidosis caused by β-hexosaminidase deficiency resulting from mutations in the HEXA or HEXB genes
Patients who have any of the following:
Simultaneous participation in another clinical study or participation in any clinical study involving administration of an investigational medicinal product (IMP; 'study drug') within 6 weeks prior to Visit 1.
Patients with a physical or psychiatric condition which, at the investigator's discretion, may put the patient at risk, may confound the study results, or may interfere with the patient's participation in the clinical study.
Known clinically-significant (at the discretion of the investigator) laboratories in hematology, coagulation, clinical chemistry, or urinalysis, including, but not limited to:
Known or persistent use, misuse, or dependency of medication, drugs, or alcohol.
Current or planned pregnancy or women who are breastfeeding.
Patients with severe vision or hearing impairment (that is not corrected by glasses or hearing aids) that, at the investigator's discretion, interferes with their ability to perform study assessments.
Patients who have been diagnosed with arthritis or other musculoskeletal disorders affecting joints, muscles, ligaments, and/or nerves that by themselves affects patient's mobility and, at the investigator's discretion, interferes with their ability to perform study assessments.
Patients unwilling and/or not able to undergo a 6-week washout period from any of the following prohibited medication prior to Visit 1 (Baseline 1) and remain without prohibited medication through Visit 6.
Extension Phase Inclusion Criteria
Aminopyridines (including sustained-release form); b) N-Acetyl-DL-Leucine (e.g. Tanganil®); c) N-Acetyl-L-Leucine (prohibited if not provided as IMP); d) Riluzole; e) Gabapentin; f) Varenicline; g) Chlorzoxazone; h) Sulfasalazine; i) Rosuvastatin.
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California - Los Angeles | Los Angeles | California | 90095 | United States | ||
| Mayo Clinic |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36456200 | Derived | Martakis K, Claassen J, Gascon-Bayari J, Goldschagg N, Hahn A, Hassan A, Hennig A, Jones S, Kay R, Lau H, Perlman S, Sharma R, Schneider S, Bremova-Ertl T. Efficacy and Safety of N-Acetyl-l-Leucine in Children and Adults With GM2 Gangliosidoses. Neurology. 2023 Mar 7;100(10):e1072-e1083. doi: 10.1212/WNL.0000000000201660. Epub 2022 Dec 1. | |
| 34349180 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Parent Study | 6-weeks treatment with IB1001 administered orally. Patients ≥13 years old received a total daily dose of 4 g/day (administered as 3 doses per day). Patients 6-12 years old received weight-tiered doses:
IB1001: IB1001 (N-Acetyl-L-Leucine) is a modified amino-acid ester that is orally administered. After the 6-week treatment period, patients entered a 6-week post-treatment washout period. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment With IB1001 |
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| Post-Treatment Washout |
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| ID | Title | Description |
|---|---|---|
| BG000 | Parent Study | All patients were first dosed with IB1001.Therefore, the baseline characteristics of patients dosed in the first IB1001treatment period in the parent study constitute the baseline characteristics for the entire study. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Clinical Impression of Change in Severity (CI-CS) [Fields et al 2021] | 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). Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). Then, the mean change obtained in the post-treatment period was subtracted from the mean change obtained for the treatment with IB1001 period, with a positive value indicating an improvement in the treatment period compared to the post-treatment washout period. | Modified Intention to Treat (mITT) Analysis Set is defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). | Posted | Mean | Standard Deviation | score on a scale | (CI-CS comparing Baseline [Day 1] with IB1001 versus the end of 6-weeks treatment with IB1001 [approximately Day 42]) MINUS (CI-CS comparing the end of 6-weeks treatment with IB1001 [approximately Day 42] versus end of 6-weeks post-treatment washout); |
From signing of the informed consent form through to End of Study (Day 84, scheduled at 42 days post last IB1001dose).
Adverse events (AEs) / serious adverse events (SAEs) consistent with the definition from ClinicalTrial.Gov. AEs/SAEs were collected in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use - Good Clinical Practice (ICH-CGP).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Treatment With IB1001 | Parent Study: 6-weeks treatment with IB1001 administered orally. Patients ≥13 years old in Europe and ≥18 years old in the United States received a total daily dose of 4 g/day (administered as 3 doses per day). Patients 6-12 years old received weight-tiered doses:
IB1001: IB1001 (N-Acetyl-L-Leucine) is a modified amino-acid ester that is orally administered. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fall | Injury, poisoning and procedural complications | MedDRA 22.0 | Non-systematic Assessment | The patient experienced a fracture of lumbar vertebrae due to a fall. The patient had recurrent falls in the medical history, as a symptom of Tay-Sachs disease and the investigator considered the event not related to study medication. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fall | Injury, poisoning and procedural complications | MedDRA 22.0 | Non-systematic Assessment |
This study was ongoing during the COVID-19 pandemic, and the conduct of this study was impacted by the COVID-19 pandemic.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Taylor Fields, Chief Product Development Officer | IntraBio Ltd. | +44 8081 | 641283 | tfields@intrabio.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Nov 30, 2022 | Dec 7, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Mar 8, 2023 | Jan 4, 2024 | SAP_002.pdf |
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| ID | Term |
|---|---|
| D020143 | Gangliosidoses, GM2 |
| D013661 | Tay-Sachs Disease |
| D012497 | Sandhoff Disease |
| ID | Term |
|---|---|
| D005733 | Gangliosidoses |
| D013106 | Sphingolipidoses |
| D020140 | Lysosomal Storage Diseases, Nervous System |
| D020739 | Brain Diseases, Metabolic, Inborn |
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| ID | Term |
|---|---|
| C579324 | IB1001 |
| C088117 | acetylleucine |
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In both the Parent Study and Extension Phase, patients will be assessed during three study phases: a baseline period (with or without a study run-in), a treatment period, and a washout period.
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The primary evaluation of the Clinical Impression of Change in Severity (CI-CS; Primary Endpoint) will be performed by two independent neurologists whose assessments are based on videos of patient's performance on either the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or the 8 Meter Walk Test (8MWT) taken at each visit.
| 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. |
| Key Secondary Endpoint: Change in Severity Based on Average CI-S | The Change in Severity assessment will instruct the blinded rater to consider the severity of the patient at each visit. The Clinical Impression of Severity (CI-S)-assessment ranged from +3 ="normal not ill at all" to -3="among the most extremely ill patients ". Change values were calculated for each period, i.e. treatment with IB1001 (change between the baseline period (average for Visit 1 and Visit 2) and end of treatment period (average for Visit 3 and Visit 4)) and post-treatment washout (between end of treatment period (average for Visit 3 and Visit 4) and end of washout period (average for Visit 5 and Visit 6). Then, the mean change in the post-treatment period was subtracted from the mean change in the treatment with IB1001 period. | (CI-S comparing baseline period [average for Visit 1 and 2] and end of treatment period [average for Visit 3 and 4]) minus (change in CI-S between end of treatment period [average for Visit 3 and 4] and end of washout period [average for Visit 5 and 6]). |
| Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale | 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). When comparing Visit 4 versus Visit 2 and Visit 6 versus Visit 4, 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). | 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 |
| Key Secondary Endpoint: CI-CS Score for the Non-Primary Anchor Test | 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). Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). | CI-CS of the non-primary anchor test was evaluated, comparing the CI-CS of Visit 4 (end of treatment) versus Visit 2 (baseline) and of Visit 6 (end of washout) versus Visit 4 (end of treatment) as done for the primary anchor test. |
| Spinocerebellar Ataxia Functional Index (SCAFI) [Schmitz-Hübsch et al, 2008] | Spinocerebellar Ataxia Functional Index (SCAFI) is composed of 8 Meter Walk 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 and values 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. | Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). |
| Scale for Assessment and Rating of Ataxia (SARA) Score [Schmitz-Hübsch Etal, 2006; Subramony, 2007] | 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. Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). | Baseline to end of treatment with IB1001 (Parent Study Day 42); End of treatment with IB1001 to the end of post treatment washout |
| EuroQuol- 5 Dimension (EQ-5D) Quality of Life Scale: Visual Analogue Scale (VAS) | For posting, health-related quality of life based on the EQ-5D visual analogue scale (VAS) was presented as a secondary endpoint. EQ-5D VAS is a 0-100 scale where patients are asked to indicate their overall health, with a score of 0 indicating worst health and a score of 100indicating best health. | Baseline to end of treatment with IB1001 (Parent Study 6-week treatment): observed VAS values at visit 4; End of treatment with IB1001 to the end of post treatment washout: observed VAS values at visit 6. |
| Modified Disability Rating Scale (mDRS) [Iturriaga et al. 2006] | Overall neurological status based on six domains (ambulation, manipulation,language, swallowing, seizures and ocular movements). The Modified Disability Rating Scale (mDRS) ranges from 0-24, where 0 is the best neurological status and 24 is the worst. Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)) | Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout. |
| Investigator's Clinical Global Impressions of Change (CGI-c) | 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' Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). | Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout. |
| Parent/Caregiver's Clinical Global Impression of Change (CGI-C) | 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'. Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). | Baseline to end of treatment with IB1001 (Parent Study 6-week treatment); End of treatment with IB1001 to the end of post treatment washout |
| Patient's Clinical Global Impressions (CGI) if Able | 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'. Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). | Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout. |
| Rochester |
| Minnesota |
| 55905 |
| United States |
| NYU Langone School of Medicine | New York | New York | 10017 | United States |
| University of Giessen | Giessen | 35389 | Germany |
| Ludwig Maximilian University of Munich | München | 80539 | Germany |
| Bellvitge University Hospital | Barcelona | 08907 | Spain |
| Salford Trust | Salford | Greater Manchester | M5 5AP | United Kingdom |
| Royal Manchester Children's Hospital | Manchester | M13 9WL | United Kingdom |
| Churchill GC, Strupp M, Factor C, Bremova-Ertl T, Factor M, Patterson MC, Platt FM, Galione A. Acetylation turns leucine into a drug by membrane transporter switching. Sci Rep. 2021 Aug 4;11(1):15812. doi: 10.1038/s41598-021-95255-5. |
| 33482890 | Derived | Fields T, Patterson M, Bremova-Ertl T, Belcher G, Billington I, Churchill GC, Davis W, Evans W, Flint S, Galione A, Granzer U, Greenfield J, Karl R, Kay R, Lewi D, Mathieson T, Meyer T, Pangonis D, Platt FM, Tsang L, Verburg C, Factor M, Strupp M. A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia. Trials. 2021 Jan 22;22(1):84. doi: 10.1186/s13063-020-05009-3. |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Tay-Sachs vs. Sandhoff Patients | Number | participants |
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| Secondary | Key Secondary Endpoint: Individual Components of the CI-CS | 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). Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). | Modified Intention to Treat (mITT) Analysis Set is defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 29 participants had values for the CI-CS analysis in the Treatment with IB1001 period and 27 participants in the Post-Treatment washout period. | Posted | Mean | Standard Deviation | score on a scale | 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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| Secondary | Key Secondary Endpoint: Change in Severity Based on Average CI-S | The Change in Severity assessment will instruct the blinded rater to consider the severity of the patient at each visit. The Clinical Impression of Severity (CI-S)-assessment ranged from +3 ="normal not ill at all" to -3="among the most extremely ill patients ". Change values were calculated for each period, i.e. treatment with IB1001 (change between the baseline period (average for Visit 1 and Visit 2) and end of treatment period (average for Visit 3 and Visit 4)) and post-treatment washout (between end of treatment period (average for Visit 3 and Visit 4) and end of washout period (average for Visit 5 and Visit 6). Then, the mean change in the post-treatment period was subtracted from the mean change in the treatment with IB1001 period. | Modified Intention to Treat (mITT) Analysis Set is defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). | Posted | Mean | Standard Deviation | score on a scale | (CI-S comparing baseline period [average for Visit 1 and 2] and end of treatment period [average for Visit 3 and 4]) minus (change in CI-S between end of treatment period [average for Visit 3 and 4] and end of washout period [average for Visit 5 and 6]). |
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| Secondary | Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale | 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). When comparing Visit 4 versus Visit 2 and Visit 6 versus Visit 4, 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). | The Modified Intention to Treat (mITT) analysis set was defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 29 participants had values for the CI-CS analysis in the Treatment with IB1001 period and 27 participants in the Post-Treatment washout period. | Posted | Count of Participants | Participants | 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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| Secondary | Key Secondary Endpoint: CI-CS Score for the Non-Primary Anchor Test | 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). Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). | Modified Intention to Treat (mITT) Analysis Set is defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 22 participants had values for the CI-CS Score for the Non-Primary Anchor Test analysis in the Treatment with IB1001 period and 20 participants in the Post-Treatment washout period | Posted | Mean | Standard Deviation | score on a scale | CI-CS of the non-primary anchor test was evaluated, comparing the CI-CS of Visit 4 (end of treatment) versus Visit 2 (baseline) and of Visit 6 (end of washout) versus Visit 4 (end of treatment) as done for the primary anchor test. |
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| Secondary | Spinocerebellar Ataxia Functional Index (SCAFI) [Schmitz-Hübsch et al, 2008] | Spinocerebellar Ataxia Functional Index (SCAFI) is composed of 8 Meter Walk 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 and values 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. | Modified Intention to Treat (mITT) Analysis Set is defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 26 participants had values for the SCAFI Total score analysis in the Treatment with IB1001 period and 25 participants in the Post-Treatment washout period | Posted | Mean | Standard Deviation | Z-scores | Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). |
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| Secondary | Scale for Assessment and Rating of Ataxia (SARA) Score [Schmitz-Hübsch Etal, 2006; Subramony, 2007] | 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. Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). | The Modified Intention to Treat (mITT) analysis set was defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 28 participants had values for the SARA analysis in the Treatment with IB1001 period and 27 participants in the Post-Treatment washout period. | Posted | Mean | Standard Deviation | score on a scale | Baseline to end of treatment with IB1001 (Parent Study Day 42); End of treatment with IB1001 to the end of post treatment washout |
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| Secondary | EuroQuol- 5 Dimension (EQ-5D) Quality of Life Scale: Visual Analogue Scale (VAS) | For posting, health-related quality of life based on the EQ-5D visual analogue scale (VAS) was presented as a secondary endpoint. EQ-5D VAS is a 0-100 scale where patients are asked to indicate their overall health, with a score of 0 indicating worst health and a score of 100indicating best health. | The Modified Intention to Treat (mITT) analysis set was defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 28 participants had values for the EQ-5D VAS analysis in the Treatment with IB1001 period and 27 participants in the Post-Treatment washout period. | Posted | Mean | Standard Deviation | score on a scale | Baseline to end of treatment with IB1001 (Parent Study 6-week treatment): observed VAS values at visit 4; End of treatment with IB1001 to the end of post treatment washout: observed VAS values at visit 6. |
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| Secondary | Modified Disability Rating Scale (mDRS) [Iturriaga et al. 2006] | Overall neurological status based on six domains (ambulation, manipulation,language, swallowing, seizures and ocular movements). The Modified Disability Rating Scale (mDRS) ranges from 0-24, where 0 is the best neurological status and 24 is the worst. Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)) | The Modified Intention to Treat (mITT) analysis set was defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 28 participants had values for the mDRS analysis in the Treatment with IB1001 period and 27 participants in the Post-Treatment washout period | Posted | Mean | Standard Deviation | score on a scale | Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout. |
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| Secondary | Investigator's Clinical Global Impressions of Change (CGI-c) | 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' Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). | The Modified Intention to Treat (mITT) analysis set was defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 28 participants had values for theInvestigator's CGI-C analysis in the Treatment with IB1001 period and 27 participants in the Post-Treatment washout period. | Posted | Mean | Standard Deviation | score on a scale | Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout. |
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| Secondary | Parent/Caregiver's Clinical Global Impression of Change (CGI-C) | 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'. Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). | The Modified Intention to Treat (mITT) analysis set was defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 26 participants had values for the Parent/Caregiver's CGI-C analysis in the Treatment with IB1001 period and 25 participants in the Post-Treatment washout period. | Posted | Mean | Standard Deviation | score on a scale | Baseline to end of treatment with IB1001 (Parent Study 6-week treatment); End of treatment with IB1001 to the end of post treatment washout |
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| Secondary | Patient's Clinical Global Impressions (CGI) if Able | 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'. Change values were calculated for each period, i.e. treatment with IB1001 (comparing the end of treatment (Visit 4) with baseline (Visit 2)) and post-treatment washout (comparing the end of washout (Visit 6) with the end of treatment (Visit 4)). | The Modified Intention to Treat (mITT) analysis set was defined as all patients who receive at least one dose of the study drug and with one video recording during the baseline period (Visit 1 or 2, or both) and treatment period (Visit 3 or Visit 4, or both). The overall mITT comprised 29 participants. Of these, 28 participants had values for the Patient's CGI if Able analysis in the Treatment with IB1001 period and 27 participants in the Post-Treatment washout period. | Posted | Mean | Standard Deviation | score on a scale | Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout. |
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| 0 |
| 30 |
| 2 |
| 30 |
| 17 |
| 30 |
| EG001 | Post-Treatment Washout | After the Parent Study 6-week treatment period, patients entered a 6-week post-treatment washout period. | 0 | 30 | 0 | 30 | 15 | 30 |
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| Lumbar vertebral fracture | Injury, poisoning and procedural complications | MedDRA 22.0 | Non-systematic Assessment | The patient experienced a fracture of lumbar vertebrae due to a fall. The patient had recurrent falls in the medical history, as a symptom of Tay-Sachs disease and the investigator considered the event not related to study medication. |
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| Psychotic disorder | Psychiatric disorders | MedDRA 22.0 | Non-systematic Assessment | The patient suffered from concomitant bipolar disorder which deteriorated. The investigator judged the event not related to study medication. |
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| Bipolar disorder | Psychiatric disorders | MedDRA 22.0 | Non-systematic Assessment | The patient suffered from concomitant bipolar disorder which deteriorated. The investigator judged the event not related to study medication. |
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| Contusion | Injury, poisoning and procedural complications | MedDRA 22.0 | Non-systematic Assessment |
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| Tremor | Nervous system disorders | MedDRA 22.0 | Non-systematic Assessment |
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| Balance disorder | Nervous system disorders | MedDRA 22.0 | Non-systematic Assessment |
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| Seizure | Nervous system disorders | MedDRA 22.0 | Non-systematic Assessment |
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| Fatigue | General disorders | MedDRA 22.0 | Non-systematic Assessment |
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| Incontinence | Renal and urinary disorders | MedDRA 22.0 | Non-systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Non-systematic Assessment |
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| Respiratory tract infection | Infections and infestations | MedDRA 22.0 | Non-systematic Assessment |
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Not provided
Not provided
| D001928 | Brain Diseases, Metabolic |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008064 | Lipidoses |
| D008052 | Lipid Metabolism, Inborn Errors |
| D016464 | Lysosomal Storage Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D052439 | Lipid Metabolism Disorders |
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| +1 (Improved) |
|
| Post-treatment washout |
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|
|
|
| 0.212 |
| Hodges-Lehmann Estimator |
| -0.0291 |
| 2-Sided |
| 90 |
| -0.0863 |
| 0.0262 |
| Superiority |
|
| 0.001 |
| Hodges-Lehmann Estimator |
| 1.25 |
| 2-Sided |
| 90 |
| 0.50 |
| 2.00 |
| Superiority |
|
|
| <0.001 |
| Hodges-Lehmann Estimator |
| 0.042 |
| 2-Sided |
| 90 |
| 0.021 |
| 0.063 |
| Superiority |
|
| <0.001 |
| Hodges-Lehmann Estimator |
| 5.0 |
| 2-Sided |
| 90 |
| 4.5 |
| 5.0 |
| Superiority |
|
|