Evaluation of N-Acetyl-L-Leucine Efficacy in Ataxia-Telangiectasia: A Phase III Randomized, Placebo-Controlled, Double-Blind, Crossover Study

Trial ID: 2024-517706-29-00
Protocol: IB1001-303
Sponsor: Intrabio Limited

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Diseases & Conditions

Ataxia telangiectasia

Objectives

The primary objective of this study is to evaluate the **efficacy** of N-Acetyl-L-Leucine in the chronic treatment of **Ataxia Telangiectasia** (A-T) using the Scale for the Assessment and Rating of Ataxia (SARA). This is clinically relevant as it aims to determine the potential of N-Acetyl-L-Leucine to improve motor function and reduce ataxia symptoms in patients with A-T, a rare and progressive neurodegenerative disorder.

Secondary objectives include:

Assessing the clinical efficacy of N-Acetyl-L-Leucine on symptoms, functioning, and quality of life for patients with A-T.
Evaluating the safety and tolerability of N-Acetyl-L-Leucine in weight-tiered doses in A-T patients.

Participants

The clinical trial involves a total of **25 participants** diagnosed with **Ataxia Telangiectasia**. The study population includes both male and female subjects, aged 4 years and older, with a genetically confirmed diagnosis of the condition. Participants were selected based on their ability to provide informed consent and their willingness to comply with study requirements. The trial includes individuals who are capable of maintaining a stable medication regimen for the symptoms of Ataxia Telangiectasia, provided these do not interfere with the study protocol. Participants must have a **Scale for the Assessment and Rating of Ataxia (SARA)** score between 7 and 34 points and meet specific criteria related to gait and hand dexterity tests. The study population is considered vulnerable, and the trial ensures that all participants meet the necessary health and safety standards to partake in the research. Lifestyle factors such as diet and physical activity are not specified, but participants are required to disclose existing medications and therapies. The trial does not specify any particular lifestyle modifications for participants beyond maintaining stable therapy regimens.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **N-Acetyl-L-Leucine** in the treatment of **Ataxia Telangiectasia**. This is a Phase III, randomized, placebo-controlled, double-blind, crossover study. The trial aims to assess the primary endpoint using the Scale for the Assessment and Rating of Ataxia (SARA) and includes secondary endpoints such as the Spinocerebellar Ataxia Functional Index (SCAFI), International Cooperative Rating Scale (ICARS), and Quality of Life assessments (EQ-5D-5L for adults and EQ-5D-Y for children). The study is expected to commence recruitment on February 3, 2025, and conclude by June 30, 2028.

Participants will be involved in the study for a maximum treatment period of 12 weeks, with a maximum daily dose of 4 grams of the investigational product administered as an oral suspension. The trial includes several key visits: an initial screening visit to confirm eligibility, baseline visits to establish initial measurements, periodic follow-up visits to monitor progress and safety, and an end-of-study visit to assess final outcomes. Participants must meet specific inclusion criteria, such as a genetically confirmed diagnosis of Ataxia Telangiectasia, a SARA score within a defined range, and a minimum weight of 15 kg. Exclusion criteria are not specified in the provided data.

Participants may be withdrawn from the study if they fail to comply with the study protocol, experience adverse effects that necessitate discontinuation, or choose to withdraw consent. The study is conducted under strict ethical guidelines, requiring informed consent from participants or their legal representatives. The trial's design ensures that neither the participants nor the investigators know which treatment the participants receive, maintaining the integrity of the double-blind methodology. The study's crossover design allows each participant to receive both the investigational product and the placebo at different times, providing a comprehensive assessment of the treatment's efficacy.

Treatment

The clinical trial involves the administration of **N-Acetyl-L-Leucine**, an experimental medication formulated as an **oral suspension**. The active substance in this formulation is **L-Acetylleucine**, a chemical compound. The medication is administered orally, with a maximum daily dose of 4 grams. The treatment period is set for a maximum of 12 weeks. The pharmaceutical product is identified by the sponsor product code IB1001 and is manufactured by Intrabio Limited. The trial aims to evaluate the efficacy of N-Acetyl-L-Leucine in the treatment of Ataxia-Telangiectasia, with the primary objective being assessed using the Scale for the Assessment and Rating of Ataxia (SARA).

In addition to the experimental treatment, the study includes a **placebo** control group. The placebo is presented as granules for suspension, although specific details regarding its pharmaceutical form, active substance, and route of administration are not provided. The placebo serves as a comparator to assess the efficacy of the experimental treatment in a double-blind, randomized, crossover study design. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy

The efficacy of N-Acetyl-L-Leucine in the treatment of **Ataxia-Telangiectasia (A-T)** will be assessed using several parameters. The primary endpoint is the Scale for the Assessment and Rating of Ataxia (SARA), which will be used to evaluate the chronic treatment effects. Secondary endpoints include the Spinocerebellar Ataxia Functional Index (SCAFI), the International Cooperative Rating Scale (ICARS), and the Quality of Life assessments using EQ-5D-5L for patients aged 18 and older, and EQ-5D-Y for those under 18. Additionally, the Investigator’s, Caregiver’s, and Patient’s Clinical Global Impression of Improvement (CGI-I) will be compared from the end of period I (Visit 4) to baseline (Visit 2).

The trial is designed as a Phase III, randomized, placebo-controlled, double-blind, crossover study. Efficacy assessments will be conducted at specified timepoints throughout the study, with the primary objective being to determine the impact of the treatment on the SARA score. The study will ensure that all measurements are collected and analyzed using validated scales and instruments to maintain the integrity and reliability of the data. The trial is expected to conclude by June 2028, with recruitment starting in February 2025.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written informed consent signed by the patient and/or their legal representative / parent/ impartial witness
Male or female aged ≥4 years with a genetically 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 abstinent5 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.
Females of non-childbearing potential who have undergone one of the following sterilization procedures at least 6 months prior to the first dose: a) hysteroscopic sterilization; b) 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.
Non-vasectomized male patient agrees to use a condom with spermicide 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, patient agrees not to donate sperm from the first dose until 90 days after their last dose.
Patients must fall within: a) A SARA score of 7 ≤ X ≤ 34 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.
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, 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.
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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Exclusion Criteria

Patients who have any known hypersensitivity or history of hypersensitivity to: a. Acetyl-Leucine (DL-, L-, D-) or derivatives. b. Excipients the IB1001 sachet (namely isomalt, hypromellose, and strawberry flavor). c. Excipients the placebo sachet (namely isomalt, hypromellose, strawberry flavor, citric acid, microcrystalline cellulose, lactose, denatonium benzoate).
Simultaneous participation in another clinical study or participation in any clinical study involving administration of an investigational medicinal product (IMP; ‘study drug’) for at least 42 days prior to Visit 1. At the discretion of the investigator, Medical Monitor, and Sponsor, the washout period for specific IMPs may be longer based on the pharmacological activity and pharmacokinetics of the drug.
Patients with a physical or psychiatric condition which, at the investigator’s discretion and in consultation with the Medical Monitor and Sponsor (as applicable), may put the patient at risk, may confound the study results, or may interfere with the patient’s participation in the clinical study, i.e. reliably perform study assessments.
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 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) N-Acetyl-DL-Leucine (e.g. Tanganil); b) N-Acetyl-L-Leucine (prohibited if not provided as IMP in the IB1001-303 trial); c) Sulfasalazine; d) Rosuvastatin.