N-Acetyl-L-Leucine for Niemann-Pick Disease, Type C (NPC)

NCT03759639 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: IB1001-201
• Study Type: interventional
• Target: 33
• Locations: 5 countries
• Sites: 9

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 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.

Conditions

Niemann-Pick Disease, Type C

Outcome Measures

Primary Outcomes (1)

• Clinical Impression of Change in Severity (CI-CS) [Fields et al 2021]

  The Clinical Impression of Change in Severity assessment will instruct the blinded rater to consider: 'compared to the first video, how has the severity of their performance on the 9 Hole Peg Test of the Dominant Hand (9HPT-D) or 8 Meter Walk Test (8MWT) changed (improved or worsened) in 6-weeks as observed in the second video?' The Clinical Impression of Change in Severity is evaluated on a 7 point Likert scale (+3=significantly improved to -3= significantly worse).

  CI-CS comparing Baseline (Day 1) with IB1001 versus the end of 6-weeks treatment with IB1001 (Approximately Day 42) MINUS the CI-CS comparing the end of 6-weeks treatment with IB1001 (Approximately Day 42) versus the end of 6-weeks post-treatment washout

Secondary Outcomes (11)

• Key Secondary Endpoint: Individual Components of the CI-CS

  Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment);End of treatment with IB1001 to the end of post 6-week treatment washout

• Key Secondary Endpoint: Change in Severity Based on Average CI-S

  CI-CS comparing baseline period and end of treatment period minus the change in CI-S between end of treatment period and end of washout period.

• Key Secondary Endpoint: CI-CS Score Reclassified on a 3-Point Scale

  Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment);End of treatment with IB1001 to the end of post 6-week treatment washout

• Key Secondary Endpoint: CI-CS Score for the Non-Primary Anchor Test

  CI-CS of the non-primary anchor test was evaluated, comparing the CI-CS of Visit 4 versus Visit 2 and of Visit 6 versus Visit 4 as done for the primary anchor test.

• Spinocerebellar Ataxia Functional Index (SCAFI) [Schmitz-Hübsch et al, 2008]

  Baseline to end of treatment with IB1001 (Parent Study 6-weeks treatment); End of treatment with IB1001 to the end of post 6-week treatment washout

Study Arms (2)

Treatment with IB1001

EXPERIMENTAL

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)

Drug: IB1001

Post-Treatment Washout

NO INTERVENTION

After both the Parent Study 6-week treatment period, and Extension Phase one-year treatment period, patients will enter a 6-week post-treatment washout period.

Interventions

IB1001 DRUG

IB1001 (N-Acetyl-L-Leucine) is a modified amino-acid ester that is orally administered.

Also known as: N-Acetyl-L-Leucine

Treatment with IB1001

Eligibility Criteria

• Age: 6 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Individuals who meet all of the following criteria are eligible to participate in the study:
• Written informed consent signed by the patient and/or their legal representative/ parent
• 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.
• 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:
• intrauterine device (IUD);
• surgical sterilization of the partner (vasectomy for 6 months minimum);
• combined (estrogen or progestogen containing) hormonal contraception associated with the inhibition of ovulation (either oral, intravaginal, or transdermal);
• progestogen only hormonal contraception associated with the inhibition of ovulation (either oral, injectable, or implantable);
• intrauterine hormone releasing system (IUS);
• bilateral tubal occlusion.
• Females of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first dose:
• hysteroscopic sterilization;
• bilateral tubal ligation or bilateral salpingectomy;
• hysterectomy;
• bilateral oophorectomy;

You may not qualify if:

• Individuals who meet any of the following criteria are not eligible to participate in the study:
• Asymptomatic patients
• 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
• Patients who have any of the following:
• Chronic diarrhea;
• Unexplained visual loss;
• Malignancies;
• Insulin-dependent diabetes mellitus.
• Known history of hypersensitivity to the N-Acetyl-Leucine (DL-, L-, D-) or derivatives.
• History of known hypersensitivity to excipients of Ora-Blend® (namely sucrose, sorbitol, cellulose, carboxymethylcellulose, xanthan gum, carrageenan, dimethicone, methylparaben, and potassium sorbate).
• 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.
• 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.
• Known clinically-significant (at the discretion of the investigator) laboratories in hematology, coagulation, clinical chemistry, or urinalysis, including, but not limited to:
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>5x upper limit of normal (ULN);
• Total bilirubin \>1.5x ULN, unless Gilbert's syndrome is present in which case total bilirubin \>2x ULN.

Sponsors & Collaborators

• IntraBio Inc: lead

Study Sites (9)

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

University of Giessen

Giessen, 35389, Germany

Location

Ludwig Maximilian University of Munich

München, 80539, Germany

Location

Comenius University in Bratislva

Bratislava, 833 40, Slovakia

Location

Bellvitge University Hospital

Barcelona, 08907, Spain

Location

Salford Trust

Salford, Greater Manchester, M5 5AP, United Kingdom

Location

Great Ormond Street Hospital

London, WC1N 3JH, United Kingdom

Location

Royal Free London NHS Foundation Trust

London, United Kingdom

Location

Royal Manchester Children's Hospital

Manchester, M13 9WL, United Kingdom

Location

Related Publications (3)

• Bremova-Ertl T, Claassen J, Foltan T, Gascon-Bayarri J, Gissen P, Hahn A, Hassan A, Hennig A, Jones SA, Kolnikova M, Martakis K, Raethjen J, Ramaswami U, Sharma R, Schneider SA. Efficacy and safety of N-acetyl-L-leucine in Niemann-Pick disease type C. J Neurol. 2022 Mar;269(3):1651-1662. doi: 10.1007/s00415-021-10717-0. Epub 2021 Aug 13.

  PMID: 34387740 DERIVED

• Churchill GC, Strupp M, Factor C, Bremova-Ertl T, Factor M, Patterson MC, Platt FM, Galione A. Acetylation turns leucine into a drug by membrane transporter switching. Sci Rep. 2021 Aug 4;11(1):15812. doi: 10.1038/s41598-021-95255-5.

  PMID: 34349180 DERIVED

• Fields T, Patterson M, Bremova-Ertl T, Belcher G, Billington I, Churchill GC, Davis W, Evans W, Flint S, Galione A, Granzer U, Greenfield J, Karl R, Kay R, Lewi D, Mathieson T, Meyer T, Pangonis D, Platt FM, Tsang L, Verburg C, Factor M, Strupp M. A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia. Trials. 2021 Jan 22;22(1):84. doi: 10.1186/s13063-020-05009-3.

  PMID: 33482890 DERIVED

MeSH Terms

Conditions

Niemann-Pick Disease, Type C

Interventions

IB1001; acetylleucine

Condition Hierarchy (Ancestors)

Niemann-Pick Diseases; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Limitations and Caveats

This study was ongoing during the coronavirus disease 2019 (COVID-19) pandemic, and the conduct of this study was impacted by the COVID-19 pandemic.

Results Point of Contact

• Title: Taylor Fields, Chief Product Development Officer
• Organization: IntraBio Ltd

tfields@intrabio.com

+44 8081 641283

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: November 27, 2018
• First Posted: November 30, 2018
• Study Start: September 4, 2019
• Primary Completion: November 7, 2022
• Study Completion: November 7, 2022
• Last Updated: November 28, 2023
• Results First Posted: November 28, 2023

Record last verified: 2023-11

Locations

SL (1); US (1); ES (1); DE (2); GB (4)