| 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 with Ataxia-Telangiectasia (A-T) |
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| E.1.1.1 | Medical condition in easily understood language |
| Ataxia Telangiectasia is a rare inherited disorder that affects the nervous system, immune system, and other body systems. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| 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 Ataxia-Telangiectasia.
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| 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 Ataxia-Telangiectasia;
- To evaluate the safety and tolerability of N-Acetyl-L-Leucine up to 4 g/day in patients Ataxia-Telangiectasia, including patients aged ≥18 years in the United States and patients aged ≥13 years in Europe, and weight-tiered doses in patients 6 to 12 years of age in Europe. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A patient can be included in this study if the following criteria are met:
1. Written informed consent signed by the patient or their legal representative/ parent
2. Male or female aged ≥6 years in Europe OR ≥18 years in the United States with a confirmed genetic diagnosis of A-T 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 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 their last 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 A-T, including those on the prohibited medication list. Non-prohibited 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 6 weeks 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).
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| E.4 | Principal exclusion criteria |
1. Asymptomatic patients
2. Patient has clinical features of A-T, but a completely negative result on a previous genetic test
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-D-Leucine (DL-, L-, D-) or derivatives.
f) History of known hypersensitivity to excipients of Ora-Blend® (namely sucrose, sorbitol, cellulose, carboxymethylcellulose, xanthan gum, carrageenan, dimethiconne, 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) >3x 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 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.
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.
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| 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).
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| 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).
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| 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.
• An evaluation of the CI-CS for the test (9HPT-D or 8MWT) that was not selected as the primary anchor test will also be undertaken. This will enable the separate analysis of CI-CS for both the 9HPT-D and the 8MWT. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
There will also be an investigation of the intra-rater correlation in relation to Videos from Visits 1 and 2, Visits 3 and 4, and Visits 5 and 6 to help investigate the stability of the outcome evaluation and the disease itself. Pearson rank correlation coefficients will be calculated for each of these pairings for each of the two raters.
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| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| 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 |
| United Kingdom |
| United States |
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| 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
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| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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