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CompletedNCT03759665Updated Mar 12, 2024Results posted

N-Acetyl-L-Leucine for GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease)

A Phase 2 interventional study of IB1001 in GM2 Gangliosidosis, Tay-Sachs Disease and Sandhoff Disease, sponsored by IntraBio Inc. Completed at 8 sites in 4 countries. Open to participants aged 6 Years and older. Per ClinicalTrials.gov, last updated 2024-03-12.

Sponsored by IntraBio Inc · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
30
Allocation
Non-randomized
Ages
6 Years and older
Sex
All
01

Study summary

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.

Read the detailed description

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.

02

Conditions studied

  • GM2 Gangliosidosis
  • Tay-Sachs Disease
  • Sandhoff Disease
03

Who can participate

Ages eligible
6 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility criteria

Parent Study Inclusion Criteria

Individuals who meet all of the following criteria are eligible to participate in the study:

  1. Written informed consent signed by the patient and/or their legal representative/ parent
  2. 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.

  3. 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:

    1. intrauterine device (IUD);
    2. surgical sterilization of the partner (vasectomy for 6 months minimum);
    3. combined (estrogen or progestogen containing) hormonal contraception associated with the inhibition of ovulation (either oral, intravaginal, or transdermal);
    4. progestogen-only hormonal contraception associated with the inhibition of ovulation (either oral, injectable, or implantable);
    5. intrauterine hormone-releasing system (IUS);
    6. bilateral tubal occlusion.

  4. Females of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first dose:

    1. hysteroscopic sterilization;
    2. bilateral tubal ligation or bilateral salpingectomy;
    3. hysterectomy;
    4. bilateral oophorectomy;

    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.

  5. 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.
  6. If male, the patient agrees not to donate sperm from the first dose until 90 days after dosing.

  7. 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.

  8. Weight ≥15 kg at screening.

  9. 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:

    1. The Investigator does not believe the medication/therapy will interfere with the study protocol/results
    2. Patients have been on a stable dose/duration and type of therapy for at least 6 weeks before Visit 1 (Baseline 1)
    3. Patients are willing to maintain a stable dose/do not change their therapy throughout the duration of the study.
  10. 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:

  1. Asymptomatic patients
  2. 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

  3. Patients who have any of the following:

    1. Chronic diarrhea;
    2. Unexplained visual loss;
    3. Malignancies;
    4. Insulin-dependent diabetes mellitus.
    5. Known history of hypersensitivity to the N-Acetyl-Leucine (DL-, L-, D-) or derivatives.
    6. History of known hypersensitivity to excipients of Ora-Blend® (namely sucrose, sorbitol, cellulose, carboxymethylcellulose, xanthan gum, carrageenan, dimethicone, methylparaben, and potassium sorbate).
  4. 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.
  5. 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.

  6. Known clinically-significant (at the discretion of the investigator) laboratories in hematology, coagulation, clinical chemistry, or urinalysis, including, but not limited to:

    1. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5x upper limit of normal (ULN);
    2. Total bilirubin >1.5x ULN, unless Gilbert's syndrome is present in which case total bilirubin >2x ULN.
  7. Known or persistent use, misuse, or dependency of medication, drugs, or alcohol.
  8. Current or planned pregnancy or women who are breastfeeding.
  9. 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.
  10. 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.

  11. 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.

    1. Aminopyridines (including sustained-release form);
    2. N-Acetyl-DL-Leucine (e.g. Tanganil®);
    3. N-Acetyl-L-Leucine (prohibited if not provided as IMP);
    4. Riluzole;
    5. Gabapentin;
    6. Varenicline;
    7. Chlorzoxazone;
    8. Sulfasalazine;
    9. Rosuvastatin.

Extension Phase Inclusion Criteria

  1. Completed Visit 6 of the IB1001-202 Parent Study
  2. The Principal Investigator determines further treatment with IB1001 to be in the patient's best interest
  3. Written informed consent signed by the patient and/or their legal representative/parent/ impartial witness for participation in the Extension Phase
  4. Patients are willing to continue to remain without the following prohibited medication from Visit 6 throughout the duration of the Extension Phase:

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.

04

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomized
Intervention model
Single group
Masking
Single (Outcomes assessor)
Enrollment
30 participants (actual)

Study arms

  • Experimental
    Treatment with IB1001

    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: * Patients aged 6-12 years weighing 15 to \<25 kg will take 2 g per day: 1 g in the morning and 1 g in the evening. * Patients aged 6-12 years weighing 25 to \<35 kg will take 3 g per day: 1 g in the morning, 1 g in the afternoon, and 1 g in the evening. * Patients aged 6-12 years weighing ≥35 kg will take 4 g per day: 2 g in the morning, 1g in the afternoon and 1 g in the evening (as per adults)

    Drug: IB1001

  • No intervention
    Post-Treatment Washout

    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.

Interventions

  • DrugIB1001

    IB1001 (N-Acetyl-L-Leucine) is a modified amino-acid ester that is orally administered.

    Also known as: N-Acetyl-L-Leucine

05

What researchers measure

Primary outcomes

  1. 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.

    Time frame: (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);

Secondary outcomes

  1. 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)).

    Time frame: 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.

  2. 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.

    Time frame: (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]).

  3. 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).

    Time frame: 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

  4. 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)).

    Time frame: 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.

  5. 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.

    Time frame: 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)).

  6. 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)).

    Time frame: Baseline to end of treatment with IB1001 (Parent Study Day 42); End of treatment with IB1001 to the end of post treatment washout

  7. 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.

    Time frame: 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.

  8. 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))

    Time frame: Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout.

  9. 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)).

    Time frame: Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout.

  10. 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)).

    Time frame: Baseline to end of treatment with IB1001 (Parent Study 6-week treatment); End of treatment with IB1001 to the end of post treatment washout

  11. 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)).

    Time frame: Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout.

06

Results

Posted Mar 12, 2024
Limitations and caveats
This study was ongoing during the COVID-19 pandemic, and the conduct of this study was impacted by the COVID-19 pandemic.

Participant flow

Treatment With IB1001
Participant flow — Treatment With IB1001
MilestoneParent Study
Started30
Completed27
Not completed3
Post-Treatment Washout
Participant flow — Post-Treatment Washout
MilestoneParent Study
Started27
Completed27
Not completed0

Outcome measures

PrimaryClinical 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.

Time frame:
(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);
Reported as:
Mean · score on a scale
Clinical Impression of Change in Severity (CI-CS) [Fields et al 2021]
score on a scaleParent Study
Clinical Impression of Change in Severity (CI-CS) [Fields et al 2021]0.71 ± 2.09
Statistical analysis
  • Parent Study · 1-sided Wilcoxon signed-rank test · p = 0.044 · Hodges-lehmann estimator: 0.75 · 90% CI 0.00 to 1.50
SecondaryKey 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)).

Time frame:
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.
Reported as:
Mean · score on a scale
Key Secondary Endpoint: Individual Components of the CI-CS
score on a scaleParent Study
Treatment with IB10010.34 ± 1.59
Post-TreatmentWashout-0.36 ± 1.33
SecondaryKey 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.

Time frame:
(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]).
Reported as:
Mean · score on a scale
Key Secondary Endpoint: Change in Severity Based on Average CI-S
score on a scaleParent Study
Key Secondary Endpoint: Change in Severity Based on Average CI-S0.09 ± 0.71
Statistical analysis
  • Parent Study · 1-sided Wilcoxon signed-rank test · p = 0.206 · Hodges-lehmann estimator: 0.13 · 90% CI -0.13 to 0.25
SecondaryKey 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).

Time frame:
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
Reported as:
Count of participants · Participants
Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale
ParticipantsParent Study
Treatment with IB1001 — -1 (Worsened)12
Treatment with IB1001 — 0 (No observable change)1
Treatment with IB1001 — +1 (Improved)16
Post-treatment washout — -1 (Worsened)16
Post-treatment washout — 0 (No observable change)3
Post-treatment washout — +1 (Improved)8
SecondaryKey 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)).

Time frame:
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.
Reported as:
Mean · score on a scale
Key Secondary Endpoint: CI-CS Score for the Non-Primary Anchor Test
score on a scaleParent Study
Treatment with IB1001-0.30 ± 1.33
Post-treatment washout0.23 ± 1.43
SecondarySpinocerebellar 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.

Time frame:
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)).
Reported as:
Mean · Z-scores
Spinocerebellar Ataxia Functional Index (SCAFI) [Schmitz-Hübsch et al, 2008]
Z-scoresParent Study
Treatment with IB10010.0163 ± 0.2749
Post-treatment washout-0.0080 ± 0.2420
Statistical analysis
  • Parent Study · 1-sided Wilcoxon signed-rank test · p = 0.210 · Hodges-lehmann estimator: 0.0327 · 90% CI -0.0327 to 0.1040
  • Parent Study · 1-sided Wilcoxon signed-rank test · p = 0.212 · Hodges-lehmann estimator: -0.0291 · 90% CI -0.0863 to 0.0262
SecondaryScale 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)).

Time frame:
Baseline to end of treatment with IB1001 (Parent Study Day 42); End of treatment with IB1001 to the end of post treatment washout
Reported as:
Mean · score on a scale
Scale for Assessment and Rating of Ataxia (SARA) Score [Schmitz-Hübsch Etal, 2006; Subramony, 2007]
score on a scaleParent Study
Treatment with IB1001-1.41 ± 1.67
Post-treatment washout1.43 ± 2.08
Statistical analysis
  • Parent Study · 1-sided Wilcoxon signed-rank test · p = <0.001 · Hodges-lehmann estimator: -1.25 · 90% CI -1.75 to -0.75
  • Parent Study · 1-sided Wilcoxon signed-rank test · p = 0.001 · Hodges-lehmann estimator: 1.25 · 90% CI 0.50 to 2.00
SecondaryEuroQuol- 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.

Time frame:
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.
Reported as:
Mean · score on a scale
EuroQuol- 5 Dimension (EQ-5D) Quality of Life Scale: Visual Analogue Scale (VAS)
score on a scaleParent Study
Treatment with IB100171.3 ± 23.2
Post-Treatment Washout71.1 ± 21.2
SecondaryModified 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))

Time frame:
Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout.
Reported as:
Mean · score on a scale
Modified Disability Rating Scale (mDRS) [Iturriaga et al. 2006]
score on a scaleParent Study
Treatment with IB1001-0.030 ± 0.075
Post-Treatment Washout0.042 ± 0.058
Statistical analysis
  • Parent Study · 1-sided Wilcoxon signed-rank test · p = 0.020 · Hodges-lehmann estimator: -0.031 · 90% CI -0.063 to 0.000
  • Parent Study · 1-sided Wilcoxon signed-rank test · p = <0.001 · Hodges-lehmann estimator: 0.042 · 90% CI 0.021 to 0.063
SecondaryInvestigator'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)).

Time frame:
Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout.
Reported as:
Mean · score on a scale
Investigator's Clinical Global Impressions of Change (CGI-c)
score on a scaleParent Study
Treatment with IB10013.2 ± 1.0
Post-Treatment Washout4.9 ± 0.8
Statistical analysis
  • Parent Study · 1-sided Wilcoxon signed-rank test · p = <0.001 · Hodges-lehmann estimator: 3.0 · 90% CI 3.0 to 3.5
  • Parent Study · 1-sided Wilcoxon signed-rank test · p = <0.001 · Hodges-lehmann estimator: 5.0 · 90% CI 4.5 to 5.0
SecondaryParent/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)).

Time frame:
Baseline to end of treatment with IB1001 (Parent Study 6-week treatment); End of treatment with IB1001 to the end of post treatment washout
Reported as:
Mean · score on a scale
Parent/Caregiver's Clinical Global Impression of Change (CGI-C)
score on a scaleParent Study
Treatment With IB10013.2 ± 1.2
Post-Treatment Washout4.8 ± 1.0
SecondaryPatient'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)).

Time frame:
Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post treatment washout.
Reported as:
Mean · score on a scale
Patient's Clinical Global Impressions (CGI) if Able
score on a scaleParent Study
Treatment With IB10013.0 ± 1.1
Post-Treatment Washout4.6 ± 1.2

Adverse events

Collected over From signing of the informed consent form through to End of Study (Day 84, scheduled at 42 days post last IB1001dose).. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Treatment With IB10010/30 (0%)2/30 (6.7%)17/30 (56.7%)
Post-Treatment Washout0/30 (0%)0/30 (0%)15/30 (50%)
Most frequent serious events
Most frequent serious events
EventTreatment With IB1001Post-Treatment Washout
FallInjury, poisoning and procedural complications1/300/30
Lumbar vertebral fractureInjury, poisoning and procedural complications1/300/30
Psychotic disorderPsychiatric disorders1/300/30
Bipolar disorderPsychiatric disorders1/300/30
Most frequent other events
Most frequent other events
EventTreatment With IB1001Post-Treatment Washout
FallInjury, poisoning and procedural complications7/306/30
TremorNervous system disorders4/301/30
ContusionInjury, poisoning and procedural complications0/303/30
Balance disorderNervous system disorders2/301/30
SeizureNervous system disorders0/302/30
FatigueGeneral disorders2/300/30
IncontinenceRenal and urinary disorders0/302/30
ArthralgiaMusculoskeletal and connective tissue disorders2/300/30
Respiratory tract infectionInfections and infestations2/300/30

Baseline characteristics

Age, Continuous
Age, Continuous(years)Parent Study
Mean27 ± 15.2
Sex: Female, Male
Sex: Female, Male(Participants)Parent Study
Female19
Male11
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Parent Study
Hispanic or Latino0
Not Hispanic or Latino22
Unknown or Not Reported8
Region of Enrollment
Region of Enrollment(participants)Parent Study
United States10
United Kingdom1
Germany18
Spain1
Tay-Sachs vs. Sandhoff Patients
Tay-Sachs vs. Sandhoff Patients(participants)Parent Study
Tay-Sachs27
Sandhoff3
07

Study locations

8 sites
  • University of California - Los Angeles
    Los Angeles, California 90095, United States
  • Mayo Clinic
    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
08

References and documents

Publications

  • 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. PubMed 34349180 ↗
  • 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. PubMed 33482890 ↗

Study documents

  • Study protocol · Nov 30, 2022
  • Statistical analysis plan · Mar 8, 2023

Documents are hosted by the registry — open the source record to download them.

09

Registry details

Key details

Study ID
NCT03759665
Lead sponsor
IntraBio Inc
Responsible party
Sponsor
First posted
Nov 30, 2018
Start date
Jun 7, 2019
Primary completion
Jan 9, 2023
Completion
Jan 9, 2023
Results posted
Mar 12, 2024
Last update
Mar 12, 2024

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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