To demonstrate that N-Acetyl-L-Leucine is effective in improving symptoms, functioning, and quality of life in patients with Niemann-Pick Type C disease (NPC). MedDRA version: 20.0 Level: PT Classification code 10029403 Term: Niemann-Pick disease System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Product Name: N-Acetyl-L-Leucine
Product Code: IB1001
Pharmaceutical Form: Powder for oral suspension
INN or Proposed INN: SUB195712
CAS Number: 1188-21-2
Current Sponsor code: IB1001-201
Other descri
Sponsors
IntraBio Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion Criteria: 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 NPC at the time of signing informed consent. Confirmed diagnosis includes [Patterson et al. 2017]: a) Clinical features and positive biomarker screen and/or filipin test without genetic tests results (has not been performed) b) Clinical features and positive genetic test c) Clinical features and positive biomarker screen and/or filipin test but only one NPC mutation identified on genetic test d) Clinical features with positive biomarker screen and/or filipin test and positive genetic test 3. Females of childbearing potential, defined as a premenopausal female capable of becoming pregnant, will be included if they are either sexually inactive (sexually abstinent22 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 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 NPC, including those on the prohibited medication list. Non-prohibited medications/therapies (e.g. miglustat, concomitant speech therapy, and physiotherapy)
Exclusion criteria
Exclusion criteria: A patient will not be included in this study if one or more of the following criteria apply: 1. Asymptomatic patients 2. Patient has clinical features of NPC and a positive biomarker screen and/or filipin test, but a completely negative result on a previous genetic test for NPC 3. Patients who have any of the following: g) Chronic diarrhea; h) Unexplained visual loss; i) Malignancies; j) Insulin-dependent diabetes mellitus. k) Known history of hypersensitivity to Acetyl-Leucine (DL-, L-, D-) or derivatives. l) 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 haematology, 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. j) Aminopyridines (including sustained-release form); k) N-Acetyl-DL-Leucine (e.g. Tanganil®); l) N-Acetyl-L-Leucine (prohibited if not provided as IMP); m) Riluzole; n) Gabapentin; o) Varenicline; p) Chlorzoxazone; q) Sulfasalazine; r) Rosuvastatin.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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 NPC. In 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 NPC;Secondary Objective: - To assess the clinical efficacy of N-Acetyl-L-Leucine on symptoms of ataxia, functioning, and quality of life for patients with NPC; - To evaluate the safety and tolerability of N-Acetyl-L-Leucine at 4 g/day in adults and children with NPC, 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. In the Extension Phase: oTo assess the clinical efficacy of long-term treatment with N-Acetyl-L-Leucine on symptoms, functioning, and quality of life for patients with NPC oTo 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 NPC oTo characterize the pharmacokinetics (PK) of N-Acetyl-L-Leucine in patients with NPC Additional secondary endpoints will investigate other measures of symptoms and quality of life. Descriptive statistics will be provided for these measur;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-Leuci | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 • Niemann-Pick Disease Type C Clinical Severity Scale (NPC-CSS) • 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 baselin | — |
Countries
Germany, Slovakia, Spain, United Kingdom, United States
Contacts
Public ContactSenior CRA
Rachel Kneafsey
Outcome results
None listed