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A Pivotal Study of N-Acetyl-L-Leucine on Niemann-Pick Disease Type C

Primary Purpose

Niemann-Pick Disease, Type C

Status
Active
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
N-Acetyl-L-Leucine
Placebo
Sponsored by
IntraBio Inc
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Niemann-Pick Disease, Type C

Eligibility Criteria

4 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Written informed consent signed by the patient and/or their legal representative/ parent/ impartial witness
  2. Male or female aged ≥4 years with a confirmed genetic diagnosis of NPC 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 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:

    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 who 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 their last dose.
  7. 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.

  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 (authorized medicines for NPC [e.g. miglustat], 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 42 days 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:

  1. Patients who are unable to consistently Patients who have any known hypersensitivity or history of hypersensitivity to:

    1. Acetyl-Leucine (DL-, L-, D-) or derivatives.
    2. Excipients the IB1001 sachet (namely isomalt, hypromellose, and strawberry flavour).
    3. Excipients the placebo sachet (namely isomalt, hypromellose, strawberry flavour, citric acid, microcrystalline cellulose, lactose, denatonium benzoate).
  2. 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.
  3. Patients with a physical, cognitive, 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.
  4. Known or persistent use, misuse, or dependency of medication, drugs, or alcohol.
  5. Current or planned pregnancy or women who are breastfeeding.
  6. 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.
  7. 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.
  8. Patients unwilling and/or not able to undergo a 42 day period from any of the following prohibited medication prior to Visit 1 (Baseline 1) and remain without prohibited medication through Visit 6.

    1. N-Acetyl-DL-Leucine (e.g. Tanganil®);
    2. N-Acetyl-L-Leucine (prohibited if not provided as IMP in the IB1001-301 trial);
    3. Sulfasalazine;
    4. Rosuvastatin.

      -

Sites / Locations

  • Mayo Clinic
  • The Royal Melbourne Hospital
  • First Faculty of Medicine, Charles University Hospital Prague
  • University of Giessen
  • University of Hamburg
  • SphinCS - Institute of Clinical Science in Lysosomal Storage Disorders
  • Ludwig Maximilian University of Munich
  • University Hospital Münster
  • Amsterdam UMC
  • Comenius University in Bratislva
  • University Hospital Bern Inselspital
  • Great Ormond Street Hospital
  • Royal Free London NHS Foundation Trust
  • Royal Manchester Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

N-acetyl-L-leucine (IB1001)

Placebo comparator

Arm Description

Oral administration (granule in a sachet for suspension in water, orange juice, or almond milk). Patients ≥13 years old will receive a total daily dose of 4 g/day (administered as 3 doses per day); patients <13 will receive weight-tiered doses.

Oral administration (granule in a sachet for suspension in water, orange juice, or almond milk). Patients ≥13 years old will receive a total daily dose of 4 g/day (administered as 3 doses per day); patients <13 will receive weight-tiered doses.

Outcomes

Primary Outcome Measures

Scale for the Assessment and Rating of Ataxia (all jurisdictions except US)
Modified Scale for the Assessment and Rating of Ataxia (US only)

Secondary Outcome Measures

Spinocerebellar Ataxia Functional Index (SCAFI)
Modified Disability Rating Scale
Physician's / Caregiver's / Patient's Clinical Global Impressions (CGI)
EuroQuol- 5 Dimension (EQ-5D) Quality of Life Scale
Scale for the Assessment and Rating of Ataxia (US only)

Full Information

First Posted
December 6, 2021
Last Updated
September 11, 2023
Sponsor
IntraBio Inc
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1. Study Identification

Unique Protocol Identification Number
NCT05163288
Brief Title
A Pivotal Study of N-Acetyl-L-Leucine on Niemann-Pick Disease Type C
Official Title
Effects of N-Acetyl-L-Leucine on Niemann-Pick Disease Type C (NPC): A Phase III, Randomized, Placebo-controlled, Double-blind, Crossover Study
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
June 30, 2022 (Actual)
Primary Completion Date
June 12, 2023 (Actual)
Study Completion Date
November 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
IntraBio Inc

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
A pivotal, randomized, double-blind, placebo controlled, multi-center therapeutic study for patients age 4 and older with a confirmed diagnosis of Niemann Pick disease type C (NPC). The objective of this study is to evaluate the safety, tolerability and efficacy of N-acetyl-L-leucine (IB1001) compared to standard of care.
Detailed Description
This is a multinational, randomized, placebo-controlled, double-blinded, cross-over Phase III study that will assess the safety and efficacy of N-Acetyl-L-Leucine (IB1001) versus Placebo for the treatment of Niemann-Pick type C disease (NPC). Patients will be assessed during three study periods: a baseline period (approximately 2-weeks), after which they will be randomized (1:1) to receive treatment with IB1001 or Placebo for approximately 12-weeks during the first intervention period ("Period I"). Following Period I, patients will crossover to receive the opposite treatment (IB1001 or Placebo) for approximately 12-weeks during a second intervention period ("Period II). Patients will be assessed twice during each study period. Patients who have participated in the study may be offered the opportunity to roll over into an Extension Phase, which is planned to allow patients to have further access to IB1001.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Niemann-Pick Disease, Type C

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Crossover Assignment
Model Description
Randomized, placebo-controlled, double-blind, crossover, multi-center, study with 1:1 randomization of IB1001 plus SOC for 12-weeks versus placebo plus SOC for 12-weeks, followed by open-label extension study.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation
Randomized
Enrollment
53 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
N-acetyl-L-leucine (IB1001)
Arm Type
Experimental
Arm Description
Oral administration (granule in a sachet for suspension in water, orange juice, or almond milk). Patients ≥13 years old will receive a total daily dose of 4 g/day (administered as 3 doses per day); patients <13 will receive weight-tiered doses.
Arm Title
Placebo comparator
Arm Type
Placebo Comparator
Arm Description
Oral administration (granule in a sachet for suspension in water, orange juice, or almond milk). Patients ≥13 years old will receive a total daily dose of 4 g/day (administered as 3 doses per day); patients <13 will receive weight-tiered doses.
Intervention Type
Drug
Intervention Name(s)
N-Acetyl-L-Leucine
Other Intervention Name(s)
IB1001
Intervention Description
N-Acetyl-L-Leucine is a modified amino-acid ester that is orally administered (granules for suspension in a sachet)
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Matching Placebo Sachet
Primary Outcome Measure Information:
Title
Scale for the Assessment and Rating of Ataxia (all jurisdictions except US)
Time Frame
End of Period I (week 12) vs. End of Period 2 (week 24)
Title
Modified Scale for the Assessment and Rating of Ataxia (US only)
Time Frame
End of Period I (week 12) vs. End of Period 2 (week 24)
Secondary Outcome Measure Information:
Title
Spinocerebellar Ataxia Functional Index (SCAFI)
Time Frame
End of Period I (week 12) vs. End of Period 2 (week 24)
Title
Modified Disability Rating Scale
Time Frame
End of Period I (week 12) vs. End of Period 2 (week 24)
Title
Physician's / Caregiver's / Patient's Clinical Global Impressions (CGI)
Time Frame
End of Period I (week 12) vs. End of Period 2 (week 24)
Title
EuroQuol- 5 Dimension (EQ-5D) Quality of Life Scale
Time Frame
End of Period I (week 12) vs. End of Period 2 (week 24)
Title
Scale for the Assessment and Rating of Ataxia (US only)
Time Frame
End of Period I (week 12) vs. End of Period 2 (week 24)
Other Pre-specified Outcome Measures:
Title
Niemann-Pick disease type C Clinical Severity Scale (NPC-CSS)
Time Frame
End of Period I (week 12) vs. End of Period 2 (week 24)
Title
5-Domain Niemann-Pick disease type C Clinical Severity Scale (NPC-CSS)
Time Frame
End of Period I (week 12) vs. End of Period 2 (week 24)
Title
Investigator's / Caregiver's / Patient's Clinical Global Impressions (CGI)
Time Frame
End of Period I (week 12) vs. End of Period 2 (week 24)
Title
Modified Scale for the Assessment and Rating of Ataxia (all jurisdictions except US)
Time Frame
End of Period I (week 12) vs. End of Period 2 (week 24)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 confirmed genetic diagnosis of NPC 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 abstinent 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: 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 who 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; 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 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. 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 NPC including those on the prohibited medication list. Non-prohibited medications/therapies (authorized medicines for NPC [e.g. miglustat], speech therapy, and physiotherapy) are permitted provided: The Investigator does not believe the medication/therapy will interfere with the study protocol/results Patients have been on a stable dose/duration and type of therapy for at least 42 days before Visit 1 (Baseline 1) 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). Exclusion Criteria: Patients who are unable to consistently Patients who have any known hypersensitivity or history of hypersensitivity to: Acetyl-Leucine (DL-, L-, D-) or derivatives. Excipients the IB1001 sachet (namely isomalt, hypromellose, and strawberry flavour). Excipients the placebo sachet (namely isomalt, hypromellose, strawberry flavour, 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, cognitive, 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 period from any of the following prohibited medication prior to Visit 1 (Baseline 1) and remain without prohibited medication through Visit 6. N-Acetyl-DL-Leucine (e.g. Tanganil®); N-Acetyl-L-Leucine (prohibited if not provided as IMP in the IB1001-301 trial); Sulfasalazine; Rosuvastatin. -
Facility Information:
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
The Royal Melbourne Hospital
City
Parkville
State/Province
Victoria
ZIP/Postal Code
3050
Country
Australia
Facility Name
First Faculty of Medicine, Charles University Hospital Prague
City
Praha
ZIP/Postal Code
128 08
Country
Czechia
Facility Name
University of Giessen
City
Gießen
ZIP/Postal Code
35389
Country
Germany
Facility Name
University of Hamburg
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Facility Name
SphinCS - Institute of Clinical Science in Lysosomal Storage Disorders
City
Hochheim
ZIP/Postal Code
65239
Country
Germany
Facility Name
Ludwig Maximilian University of Munich
City
München
ZIP/Postal Code
80539
Country
Germany
Facility Name
University Hospital Münster
City
Münster
ZIP/Postal Code
48149
Country
Germany
Facility Name
Amsterdam UMC
City
Amsterdam
ZIP/Postal Code
1105
Country
Netherlands
Facility Name
Comenius University in Bratislva
City
Bratislava
ZIP/Postal Code
833 40
Country
Slovakia
Facility Name
University Hospital Bern Inselspital
City
Bern
ZIP/Postal Code
3010
Country
Switzerland
Facility Name
Great Ormond Street Hospital
City
London
ZIP/Postal Code
WC1N 3JH
Country
United Kingdom
Facility Name
Royal Free London NHS Foundation Trust
City
London
Country
United Kingdom
Facility Name
Royal Manchester Children's Hospital
City
Manchester
ZIP/Postal Code
M13 9WL
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
The results of the study will be published within a reasonable timeframe of completion. Pseudonymised individual patient data may be available in these findings.
Citations:
PubMed Identifier
34387740
Citation
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.
Results Reference
result
PubMed Identifier
33738443
Citation
Kaya E, Smith DA, Smith C, Morris L, Bremova-Ertl T, Cortina-Borja M, Fineran P, Morten KJ, Poulton J, Boland B, Spencer J, Strupp M, Platt FM. Acetyl-leucine slows disease progression in lysosomal storage disorders. Brain Commun. 2020 Dec 20;3(1):fcaa148. doi: 10.1093/braincomms/fcaa148. eCollection 2021.
Results Reference
result
PubMed Identifier
30115089
Citation
Cortina-Borja M, Te Vruchte D, Mengel E, Amraoui Y, Imrie J, Jones SA, I Dali C, Fineran P, Kirkegaard T, Runz H, Lachmann R, Bremova-Ertl T, Strupp M, Platt FM. Annual severity increment score as a tool for stratifying patients with Niemann-Pick disease type C and for recruitment to clinical trials. Orphanet J Rare Dis. 2018 Aug 16;13(1):143. doi: 10.1186/s13023-018-0880-9.
Results Reference
result

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A Pivotal Study of N-Acetyl-L-Leucine on Niemann-Pick Disease Type C

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