| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
To demonstrate that N-Acetyl-L-Leucine is effective in improving
symptoms, functioning, and quality of life in patients GM2 Gangliosidosis (Tay-Sachs and Sandhoff Disease). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Tay–Sachs disease (α-mutations) and Sandhoff disease (β-mutations) are neurovisceral autosomal-recessive inherited metabolic, lysosomal storage disorder (LSD). |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10043147 |
| E.1.2 | Term | Tay-Sachs disease |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10081314 |
| E.1.2 | Term | Sandhoff disease |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective is to evaluate the efficacy of N-Acetyl-L-Leucine based on blinded raters’ clinical impression of change in severity (CI-CS) in the treatment of Tay-Sachs and Sandhoff Disease (GM2 Gangliosidosis).
For the Extension Phase:
The primary objective is to evaluate the efficacy of N-Acetyl-L-Leucine based on blinded raters’ Clinical Impression of Change in Severity (CI-CS) in the long-term treatment of GM2 Gangliosidosis |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the clinical efficacy of N-Acetyl-L-Leucine on symptoms of ataxia,
functioning, and quality of life for patients with Tay-Sachs and Sandhoff Disease (GM2 Gangliosidosis);
- To evaluate the safety and tolerability of N-Acetyl-L-Leucine at 4 g/day in adults and children with Tay-Sachs and Sandhoff Disease (GM2 Gangliosidosis), including patients aged ≥18 years in the United States and patients aged ≥13 years in Europe, and weight-tiered doses in children 6 to 12 years of age in Europe
For the Extension Phase:
o To assess the clinical efficacy of long-term treatment with N-Acetyl-L-Leucine on symptoms, functioning, and quality of life for patients with GM2 Gangliosidosis
o To evaluate the long-term safety and tolerability of N-Acetyl-L-Leucine at 4 g/day in patients aged ≥13 years, and weight-tiered doses in patients 6 to 12 years of age, with GM2 Gangliosidosis
o To characterize the pharmacokinetics (PK) of N-Acetyl-L-Leucine in patients with GM2 Gangliosidosis
The explora |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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/impartial witness
2. Male or female aged ≥6 years in Europe OR ≥18 years in the United States with a
confirmed diagnosis of GM2 Gangliosidosis at the time of signing informed
consent. Confirmed diagnosis, i.e., clinical features and positive genetic test GM2-
gangliosidosis caused by β-hexosaminidase deficiency resulting from mutations in the
HEXA or HEXB genes
3. Females of childbearing potential, defined as a premenopausal female capable of
becoming pregnant, will be included if they are either sexually inactive (sexually
abstinent4 for 14 days prior to the first dose and confirm to continue 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:
a) intrauterine device (IUD);
b) surgical sterilization of the partner (vasectomy for 6 months minimum);
c) combined (estrogen or progestogen containing) hormonal contraception associated
with the inhibition of ovulation (either oral, intravaginal, or transdermal);
d) progestogen only hormonal contraception associated with the inhibition of
ovulation (either oral, injectable, or implantable);
e) intrauterine hormone releasing system (IUS);
f) 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:
a) hysteroscopic sterilization;
b) bilateral tubal ligation or bilateral salpingectomy;
c) hysterectomy;
d) 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, patient agrees not to donate sperm from the first dose until 90 days after theirlast dose.
7. Patients must fall within:
a) A SARA score of 5 ≤ X ≤ 33 points (out of 40)
AND
b) Either:
i. Within the 2-7 range (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. Nonprohibited medications/therapies (e.g. concomitant speech therapy, and physiotherapy) are permitted provided:
a) The Investigator does not believe the medication/therapy will interfere with the
study protocol/results
b) Patients have been on a stable dose/duration and type of therapy for at least 42 days before Visit 1 (Baseline 1)
c) 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).
For the Extension Phase:
1. Completed Visit 6 of the IB1001-202 Parent Study
2. The Principal Investigator determines further treatment with IB1001 to be in 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 the Extension Phase:
a) Aminopyridines (including sustained-release form);
b) N-Acetyl-DL-Leucine (e.g. Tanganil®);
c) N-Acetyl-L-Leucine (prohibited if not provided as investigational medicinal product [IMP]);
d) Riluzole;
e) Gabapentin;
f) Varenicline;
g) Chlorzoxazone;
h) Sulfasalazine;
i) Rosuvastatin.
|
|
| E.4 | Principal 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 GM2 Gangliosidosis, but a completely negative result on a previous genetic test for GM2 Gangliosidosis
3. Patients who have any of the following:
a) Chronic diarrhea;
b) Unexplained visual loss;
c) Malignancies;
d) Insulin-dependent diabetes mellitus.
e) Known history of hypersensitivity to the Acetyl-Leucine (DL-, L-, D-) or
derivatives.
f) 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:
a. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5x
upper limit of normal (ULN);
b. 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 42 day washout period from any of the following prohibited medication prior to Visit 1 (Baseline 1) and remain without prohibited medication through Visit 6.
a) 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint for the study is based on blinded raters’ Clinical Impression of Change in Severity (CI-CS) comparing videos showing the patient’s change in performance over 6 weeks on a pre-defined anchor clinical symptom scale: either the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or the 8 Meter Walk Test (8MWT).
For the Extension Phase:
The primary endpoint is defined as success on the Clinical Impression of Change in Severity (CI-CS) comparing videos of the primary anchor test at (i) the end of the Extension Phase treatment with N-Acetyl-L-Leucine (Visit 9) versus (ii) the Extension Phase baseline (Visit 7). Success is defined as a CI-CS value of 0 (no change) or better (≥1, some improvement at least).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The comparison of the Visit 4 video with the Visit 2 video and the comparison of the Visit 6 video with the Visit 4 video will provide the scores that contribute to the primary endpoint.
Each of these comparisons will score change on a 7-point Likert scale (+3=significantly
improved to -3= significantly worse). |
|
| E.5.2 | Secondary end point(s) |
• The individual components of the primary endpoint, that is the CI-CS from Visit 2 to Visit 4 and the CI-CS from Visit 4 to Visit 6.
• Differences in the blinded rater’s Clinical Impression of Severity (CI-S) values from baseline to end of treatment and from end of treatment to end of washout. The two CI-S values at each of these periods (Visit 1 and Visit 2 for baseline, Visit 3 and Visit 4 for end of treatment and Visit 5 and Visit 6 for end of washout) will be averaged.
• Sensitivity measurement of change in performance on either the 9HPT-D or the 8MWT
on a 3-point scale. Using the CI-CS outcome for the pre-specified anchor test based on the data for Visits 2 and Visit 4, any patient given a score of -1, -2, or -3 on the CI-CS will be classified as worsened (-1). Any patient classified as 0 on the CI-CS will be classified no change (0). Any patient given a score of +1, +2, +3 on the CI-CS will be classified as improved (+1). A similar classification will use the CI-CS comparing the end of treatment with N-Acetyl-L-Leucine with end of washout based on the data for Visits 4 and Visit 6 and the difference between these scores calculated.
For the Extension Phase:
"Additional secondary endpoints will investigate other measures of symptoms and quality of life. Descriptive statistics will be provided for these measures at each visit and also changes from Extension Phase baseline (Visit 7) to the end of Extension Phase treatment with N-Acetyl-L-Leucine (Visit 9) for the following measures:
• Spinocerebellar Ataxia Functional Index (SCAFI) score
• Scale for Assessment and Rating of Ataxia (SARA) score
• Modified Disability Rating Scale (mDRS)
• Quality of Life EQ-5D-5L for patients aged ≥18; EQ-5D-Y for patients aged <18 years
• Treating Physician Clinical Global Impression of Severity (CGI-S)
• Treating Physician Clinical Global Impression of Change (CGI-C) comparing end of treatment (Visit 9) to Extension Phase baseline (Visit 7)
• Caregiver Clinical Global Impression of Severity (CGI-S)
• Caregiver Clinical Global Impression of Change (CGI-C) comparing end of treatment (Visit 9) to Extension Phase baseline (Visit 7)
• Patient Clinical Global Impression Scales Impression of Severity (CGI-S) if they are able
• Patient Clinical Global Impression of Change (CGI-C) comparing end of treatment (Visit 9) to Extension Phase baseline (Visit 7) if they are able
• Annual Severity Increment Score (ASIS)"
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Germany |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
LVLS
A patient is considered to have completed the Extension Phase if he/she has completed all routine visits of the Extension Phase including the last visit (Visit 10).
The end of the study (Parent Study + Extension Phase) is defined as the date of the last visit of the last patient in Study IB1001-202 globally. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 17 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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