Not provided
Not provided
Not provided
Not provided
Not provided
Determined priority was to recruit directly to the pivotal Phase III double-blind, placebo-controlled, randomised study (NCT07221292).
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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 Ataxia-Telangiectasia (A-T).
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) for the symptomatic treatment of A-T.
The Extension Phase evaluates the long-term safety and efficacy of IB1001 for the neuroprotective, disease-modifying treatment of A-T.
The primary purpose of the study is to evaluate the safety and efficacy of N-Acetyl-L-Leucine (IB1001) in the treatment of A-T investigating the efficacy in terms of improving symptoms, functioning, and quality of life against the defined endpoints in patients with A-T.
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 this study.
For each individual patient, the study lasts for approximately 3.5 - 4 months during which there are 6 study 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 the treatment period. For each individual patient, the Extension Phase lasts for approximately 25.5 months, during which there are 6 visits to the study site.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment with IB1001 | Experimental | 6-weeks 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:
After the 6-week treatment period, patients will enter a 6-week post-treatment washout period. |
|
| Post-Treatment Washout | No Intervention | After the 6-week 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. |
|
| 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 the CI-CS comparing the end of 6-weeks treatment with IB1001 (Approximately Day 42) versus the end of 6-weeks post-treatment washout |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
Not provided
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 with a confirmed diagnosis of A-T 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 A-T, 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).
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 A-T, but a completely negative result on a previous genetic test for A-T.
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.
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California - Los Angeles | Los Angeles | California | 90095 | United States | ||
| University of Giessen |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40739200 | Derived | Hendrickx N, Mentre F, Hamdan A, Karlsson MO, Hooker AC, Traschutz A, Gagnon C, Schule R, Synofzik M, Comets E; ARCA Study Group, EVIDENCE-RND consortium. Comparing randomized trial designs to estimate treatment effect in rare diseases with longitudinal models: a simulation study showcased by Autosomal Recessive Cerebellar Ataxias using the SARA score. BMC Med Res Methodol. 2025 Jul 30;25(1):179. doi: 10.1186/s12874-025-02626-x. | |
| 34620022 |
Not provided
Not provided
All patients began treatment with N-Acetyl-L-Leucine (IB1001) in this open-label study schema. In the parent study, the post-treatment washout period followed the IB treatment period.
After the parent study, patients could enter an extension phase.
Not provided
Not provided
| 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 |
|
| ||||||||||||||||||
| Post-Treatment Washout |
| |||||||||||||||||||
| Extension Phase |
|
Not provided
Not provided
| 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 |
|
| 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 the CI-CS comparing the end of 6-weeks treatment with IB1001 (Approximately Day 42) versus the end of 6-weeks post-treatment washout |
For the parent study (treatment with IB1001 and Post-treatment washout): from signing of the informed consent form through to End of Study (Day 84, scheduled at 42 days post last IB1001dose); For the extension phase: from signing of the extension phase informed consent form through to End of Study for the extension phase (Day 767).
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).
All patients were naïve, so a separate arm for non-naive participants who needed a 6-weeks washout prior to starting treatment, could not be evaluated separately.
Not provided
| 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 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastrointestinal lymphoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 22.0 | Non-systematic Assessment | severe, not related |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain upper | Gastrointestinal disorders | 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. Additionally, it was determined by the Sponsor that a Phase III, double-blind, randomized, placebo- controlled study for A-T should be conducted to support the marketing application with IB1001 for A-T (NCT NCT06673056). Accordingly, the IB1001-203 clinical study was terminated prior to reaching the target recruitment, to prioritize the pivotal Phase III trial.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Taylor Fields, Chief Product Development Officer | Intrabio Ltd | +44 8081 | 641283 | tfields@intrabio.com |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 5, 2023 | Jan 20, 2026 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jun 18, 2024 | Jan 20, 2026 | SAP_001.pdf |
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D001260 | Ataxia Telangiectasia |
| ID | Term |
|---|---|
| D020754 | Spinocerebellar Ataxias |
| D002524 | Cerebellar Ataxia |
| D002526 | Cerebellar Diseases |
| D001927 | Brain Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C579324 | IB1001 |
| C088117 | acetylleucine |
Not provided
Not provided
Not provided
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.
Not provided
Not provided
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.
| (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]) |
| Secondary Efficacy Endpoint: Individual Components of 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)). | 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. |
| Secondary Efficacy 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 |
| Secondary Efficacy 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. |
| Secondary Efficacy Endpoint: Change in the 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 (Day 1) to end of treatment with IB1001 (Approximately Day 42); End of treatment with IB1001 (Approximately Day 42) to the end of post-treatment washout (Approximately Day 84) |
| Secondary Efficacy Endpoint: 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. | Baseline (Day 1) to end of treatment with IB1001 (Approximately Day 42); End of treatment with IB1001 (Approximately Day 42) to the end of post-treatment washout (Approximately Day 84) |
| Secondary Efficacy Endpoint: EuroQuol- 5 Dimension (EQ-5D) Quality of Life Scale | 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 100 indicating best health. | Baseline (Day 1) to end of treatment with IB1001 (Approximately Day 42); End of treatment with IB1001 (Approximately Day 42) to the end of post-treatment washout (Approximately Day 84) |
| Secondary Efficacy Endpoint: Clinical Global Impression of Severity (Treating Physician, Caregiver, Patient) | The Clinical Global Impression of Severity(CGI-S) evaluates the question "Considering your total (clinical) experience with this particular population, how ill is the patient (how ill are you) at this time?" based on answers from the treating physician, the caregiver, or the patients (if able). This was rated on the following seven-point scale: 1=normal, not at all ill; 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill the patient has been/I have ever been. | Visits of Parent study: Visit 1 (Day -14), Visit 2 (Day 1), Visit 3 (Day 28), Visit 4 (Day 42), Visit 5 (Day 70), and Visit 6 (Day 84). |
| Secondary Efficacy Endpoint: Clinical Global Impression of Change (Treating Physician, Caregiver, Patient) | 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 (Day 1) to end of treatment with IB1001 (Approximately Day 42); End of treatment with IB1001 (Approximately Day 42) to the end of post-treatment washout (Approximately Day 84) |
| Giessen |
| Germany |
| Hospital Universitario La Paz | Madrid | Spain | Spain |
| Royal Papworth Hospital NHS Foundation Trust | Cambridge | Cambridgeshire | CB2 0AY | United Kingdom |
| Derived |
| Brueggemann A, Bicvic A, Goeldlin M, Kalla R, Kerkeni H, Mantokoudis G, Abegg M, Kolnikova M, Mohaupt M, Bremova-Ertl T. Effects of Acetyl-DL-Leucine on Ataxia and Downbeat-Nystagmus in Six Patients With Ataxia Telangiectasia. J Child Neurol. 2022 Jan;37(1):20-27. doi: 10.1177/08830738211028394. Epub 2021 Oct 7. |
| 34349180 | Derived | 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 |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
|
|
|
| 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]) |
|
|
|
| Secondary | Secondary Efficacy Endpoint: Individual Components of 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). | 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. |
|
|
|
| Secondary | Secondary Efficacy 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). | 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 | 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 |
|
|
|
| Secondary | Secondary Efficacy 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). | 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. |
|
|
|
| Secondary | Secondary Efficacy Endpoint: Change in the 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)). | 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 | Baseline (Day 1) to end of treatment with IB1001 (Approximately Day 42); End of treatment with IB1001 (Approximately Day 42) to the end of post-treatment washout (Approximately Day 84) |
|
|
|
| Secondary | Secondary Efficacy Endpoint: 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). | Posted | Mean | Standard Deviation | Score on a scale | Baseline (Day 1) to end of treatment with IB1001 (Approximately Day 42); End of treatment with IB1001 (Approximately Day 42) to the end of post-treatment washout (Approximately Day 84) |
|
|
|
| Secondary | Secondary Efficacy Endpoint: EuroQuol- 5 Dimension (EQ-5D) Quality of Life Scale | 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 100 indicating best health. | 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 | Baseline (Day 1) to end of treatment with IB1001 (Approximately Day 42); End of treatment with IB1001 (Approximately Day 42) to the end of post-treatment washout (Approximately Day 84) |
|
|
|
| Secondary | Secondary Efficacy Endpoint: Clinical Global Impression of Severity (Treating Physician, Caregiver, Patient) | The Clinical Global Impression of Severity(CGI-S) evaluates the question "Considering your total (clinical) experience with this particular population, how ill is the patient (how ill are you) at this time?" based on answers from the treating physician, the caregiver, or the patients (if able). This was rated on the following seven-point scale: 1=normal, not at all ill; 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill the patient has been/I have ever been. | 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 | Visits of Parent study: Visit 1 (Day -14), Visit 2 (Day 1), Visit 3 (Day 28), Visit 4 (Day 42), Visit 5 (Day 70), and Visit 6 (Day 84). |
|
|
|
| Secondary | Secondary Efficacy Endpoint: Clinical Global Impression of Change (Treating Physician, Caregiver, Patient) | 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)). | 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 | Baseline (Day 1) to end of treatment with IB1001 (Approximately Day 42); End of treatment with IB1001 (Approximately Day 42) to the end of post-treatment washout (Approximately Day 84) |
|
|
|
| 0 |
| 17 |
| 1 |
| 17 |
| 9 |
| 17 |
| EG001 | Post-treatment Washout | After the Parent Study 6-week treatment period, patients entered a 6-week post-treatment washout period. | 0 | 17 | 0 | 17 | 2 | 17 |
| EG002 | Extension Phase | Patients who completed the Parent Study were to be offered the opportunity to participate in the Extension Phase if the investigator determined it was in their best interest. Patients received treatment with IB1001 for two one-year treatment periods, separated by a 6-week washout. All patients received the study drug during the treatment periods. Patients who completed Visit 6 of the parent study and continued into the Extension Phase were assessed approximately 6 times over a 116-week period. | 1 | 13 | 2 | 13 | 11 | 13 |
|
| Infection | Infections and infestations | MedDRA 22.0 | Non-systematic Assessment | severe, not related |
|
| Mastitis | Infections and infestations | MedDRA 22.0 | Non-systematic Assessment | severe, not related |
|
| Seroma | Injury, poisoning and procedural complications | MedDRA 22.0 | Non-systematic Assessment | severe, not related |
|
| Intraductal proliferative breast lesion | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 22.0 | Non-systematic Assessment | moderate, not related |
|
| Erythema | Skin and subcutaneous tissue disorders | MedDRA 22.0 | Non-systematic Assessment | severe, not related |
|
| Peritoneal mesothelioma malignant | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 22.0 | Non-systematic Assessment | severe, not related |
|
| Nasopharyngitis | Infections and infestations | MedDRA 22.0 | Non-systematic Assessment |
|
| Oral herpes | Infections and infestations | MedDRA 22.0 | Non-systematic Assessment |
|
| Respiratory tract infection | Infections and infestations | MedDRA 22.0 | Non-systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 22.0 | Non-systematic Assessment |
|
| Chorea | Nervous system disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Gastrointestinal lymphoma | Blood and lymphatic system disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Fatigue | General disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Hypertransaminasaemia | Hepatobiliary disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Pollakiuria | Renal and urinary disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Menstruation irregular | Reproductive system and breast disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Hyperhydrosis | Skin and subcutaneous tissue disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Bronchitis | Infections and infestations | MedDRA 22.0 | Non-systematic Assessment |
|
| Candida infection | Infections and infestations | MedDRA 22.0 | Non-systematic Assessment |
|
| Corona virus infection | Infections and infestations | MedDRA 22.0 | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | MedDRA 22.0 | Non-systematic Assessment |
|
| Hand fracture | Injury, poisoning and procedural complications | MedDRA 22.0 | Non-systematic Assessment |
|
| Speech disorder | Nervous system disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Tremor | Nervous system disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| B-lymphocyte count abnormal | Investigations | MedDRA 22.0 | Non-systematic Assessment |
|
| T-lymphocyte count abnormal | Investigations | MedDRA 22.0 | Non-systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Gait disturbance | General disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Type 2 diabetes mellitus | Metabolism and nutrition disorders | MedDRA 22.0 | Non-systematic Assessment |
|
| Micturition urgency | Renal and urinary disorders | MedDRA 22.0 | Non-systematic Assessment |
|
Not provided
Not provided
| D002493 |
| Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D020752 | Neurocutaneous Syndromes |
| D001259 | Ataxia |
| D020820 | Dyskinesias |
| D009461 | Neurologic Manifestations |
| D013684 | Telangiectasis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D000081207 | Primary Immunodeficiency Diseases |
| D049914 | DNA Repair-Deficiency Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| Post-treatment washout |
|
| Title | Measurements |
|---|---|
|
| Treating physician: Visit 4 |
|
| Treating physician: Visit 5 |
|
| Treating physician: Visit 6 |
|
| Caregiver: Visit 1 |
|
| Caregiver: Visit 2 |
|
| Caregiver: Visit 3 |
|
| Caregiver: Visit 4 |
|
| Caregiver: Visit 5 |
|
| Caregiver: Visit 6 |
|
| Patient: Visit 1 |
|
| Patient: Visit 2 |
|
| Patient: Visit 3 |
|
| Patient: Visit 4 |
|
| Patient: Visit 5 |
|
| Patient: Visit 6 |
|
|
| Caregiver: Post-treatment washout |
|
| Patient: Treatment with IB1001 |
|
| Patient: Post-treatment washout |
|