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

Brief Title

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

Official Title

Effects of N-Acetyl-L-Leucine on GM2 Gangliosdisosis (Tay-Sachs and Sandhoff Disease): A Multinational, Multicenter, Open-label, Rater-blinded Phase II Study

Brief 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.
    

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Clinical Impression of Change in Severity (CI-CS)

Secondary Outcome

 Spinocerebellar Ataxia Functional Index (SCAFI)

Condition

GM2 Gangliosidosis

Intervention

IB1001

Study Arms / Comparison Groups

 Treatment with IB1001
Description:  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)

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

39

Start Date

June 7, 2019

Completion Date

December 1, 2022

Primary Completion Date

June 1, 2022

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 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.
      

Gender

All

Ages

6 Years - N/A

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

Germany

Location Countries

Germany

Administrative Informations


NCT ID

NCT03759665

Organization ID

IB1001-202


Responsible Party

Sponsor

Study Sponsor

IntraBio Inc


Study Sponsor

, , 


Verification Date

May 2021