N-Acetyl-L-Leucine for Niemann-Pick Disease, Type C (NPC)
Condition: Niemann-Pick Disease, Type C
MeSH terms: Pick Disease of the Brain; Aphasia, Primary Progressive; Frontotemporal Dementia; Niemann-Pick Diseases; Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type C
Intervention: IB1001
Intervention description: IB1001 (N-Acetyl-L-Leucine) is a modified amino-acid ester that is orally administered.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Intervention model description: In both the Parent Study and Extension Phase, patients will be assessed during three study phases: a baseline period (with or without a study run-in), a treatment period, and a washout period.
Patients who complete the Parent Study have the opportunity to, at the discretion of their Principal Investigator (PI), continue treatment with N-Acetyl-L-Leucine (IB1001) in an Extension Study, provided they fulfill the inclusion/exclusion criteria.
Masking: Single (Outcomes Assessor)
Masking description: The primary evaluation of the Clinical Impression of Change in Severity (CI-CS; Primary Endpoint) will be performed by two independent neurologists whose assessments are based on videos of patient's performance on either the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or the 8 Meter Walk Test (8MWT) taken at each visit.
Enrollment: 33.0
Sex: All
Minimum age: 6 Years
Healthy volunteers: No

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
      Niemann-Pick type C disease (NPC).

      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) for the
      symptomatic treatment of NPC.

      The Extension Phase evaluates the long-term safety and efficacy of IB1001 for the
      neuroprotective, disease-modifying treatment of NPC.
    

Eligibility criteria:

        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 NPC at the time of signing informed consent. Patients must have
             clinical features of NPC and a positive genetic test for mutations in both copies of
             NPC1 or in both copies of NPC2.

          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, 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)
             (Scale for Spinocerebellar Ataxia Functional Index [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 NPC, including those on the prohibited medication list. Non-prohibited
             medications/therapies (e.g. miglustat, 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).

        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 NPC and a positive biomarker screen and/or filipin
             test, but a negative result on a previous genetic test for NPC

          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 IB1001-201 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:

               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.