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    EudraCT Number:2021-005356-10
    Sponsor's Protocol Code Number:IB1001-301
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-12-29
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2021-005356-10
    A.3Full title of the trial
    Effects of N-Acetyl-L-Leucine on Niemann-Pick disease type C (NPC): A Phase III, randomized, placebo-controlled, double-blind, crossover study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A pivotal study of N-Acetyl-L-Leucine on Niemann-Pick disease type C
    A.4.1Sponsor's protocol code numberIB1001-301
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/043/2022
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorIntraBio Ltd
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportIntraBio Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIntraBio Ltd
    B.5.2Functional name of contact pointTaylor Fields
    B.5.3 Address:
    B.5.3.1Street AddressBerkeley street 17, Flat 1
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeW1J 8EA
    B.5.3.4CountryUnited Kingdom
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/17/1848
    D.3 Description of the IMP
    D.3.1Product nameN-acetyl-L-leucine
    D.3.2Product code IB1001
    D.3.4Pharmaceutical form Granules for oral suspension in sachet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNN-Acetyl-L-Leucine
    D.3.9.3Other descriptive name2(S)-(ACETYLAMINO)-4-METHYLPENTANOIC ACID
    D.3.9.4EV Substance CodeSUB195712
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboGranules for oral solution in sachet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Niemann-Pick Disease type C (NPC)
    E.1.1.1Medical condition in easily understood language
    Niemann-Pick Disease type C (NPC)
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to evaluate the efficacy of N-acetyl-L-leucine based on the Scale for the Assessment and Rating of Ataxia (SARA) for the chronic treatment of NPC.

    For the extension phase, the primary objective is to evaluate the efficacy of N-Acetyl-L-Leucine based on the 5-domain Niemann-pick disease type c clinical severity scale (NPC-CSS)
    E.2.2Secondary objectives of the trial
    -- To assess the clinical efficacy of N-Acetyl-L-Leucine on symptoms, 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 NPC patients aged ≥13 years, and weight-tiered doses in NPC patients aged 4 to 12 years of age

    In the extension phase, the secondary objectives are to:
    -- To assess the clinical efficacy of long-term treatment with N-Acetyl-L-Leucine on symptoms, functioning, and quality of life for patients with NPC
    -- To 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 4 to 12 years of age, with NPC
    -- To characterize the pharmacokinetics (PK) of N-Acetyl-L-Leucine in patients with NPC
    E.2.3Trial contains a sub-study No
    E.3Principal 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/ 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:
    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 who have undergone one of the following sterilization procedures at least 6 months prior to the first dose:
    a) hysteroscopic sterilization;
    b) 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 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)
    b) Either:
    i. Within the 2-7 range (0-8 range) of the Gait subtest of the SARA scale
    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:
    a) The Investigator does not believe the medication/therapy will interfere with the study protocol/results
    b) Patients have been on a stable dose/duration and type of therapy for at least 42 days before Visit 1 (Baseline 1)
    c) 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).
    E.4Principal exclusion criteria
    Individuals who meet any of the following criteria are not eligible to participate in the study:
    1. Patients who have any known hypersensitivity or history of hypersensitivity to:
    a. Acetyl-Leucine (DL-, L-, D-) or derivatives.
    b. Excipients the IB1001 sachet (namely isomalt, Hypromellose, and Strawberry Flavour).
    c. Excipients the placebo sachet (namely isomalt, Hypromellose, Strawberry Flavour, Citric acide, 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 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 washout period from any of the following prohibited medication prior to Visit 1 (Baseline 1) and remain without prohibited medication through Visit 6.
    a) N-Acetyl-DL-Leucine (e.g. Tanganil®);
    b) N-Acetyl-L-Leucine (prohibited if not provided as IMP in the IB1001-301 trial);
    c) Sulfasalazine;
    d) Rosuvastatin.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the Scale for the Assessment and Rating of Ataxia (SARA) [Schmitz-Hübsch et al, 2006; Subramony, 2007] is an eight-item clinical rating scale (range 0–40, where 0 is the best neurological status and 40 the worst). It is a reliable and valid clinical scale with a high internal consistency that measures the severity of symptoms and ataxia and increases with ataxia disease stage.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint is based on the analysis of covariance comparing the mean SARA at the end of Period I (Visit 4) minus the mean SARA at the end of Period II (Visit 6 with the Baseline SARA (Visit 2) as a covariate.
    E.5.2Secondary end point(s)
    • Spinocerebellar Ataxia Functional Index (SCAFI)
    • Quality of Life EQ-5D-5L for patients aged ≥18; EQ-5D-Y for patients aged <18 years
    • Modified Disability Rating Scale (mDRS)
    • Physician’s, Caregiver’s, and Patient’s (if able) Clinical Global Impression of Improvement (CGI-I) comparing end of period I (Visit 4) to baseline (Visit 2), and end of period II (Visit 6) to end of period I (Visit 4)
    E.5.2.1Timepoint(s) of evaluation of this end point
    The change from Visit 4 (end of period I) to Visit 6 (end of period II).
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    A patient is considered to have completed the study if he/she has completed all phases of the study including the last visit.
    The end of the study (Parent Study + Extension Phase) is defined as the date of the last visit of the last patient in the study globally.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 20
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F. of subjects for this age range: 10
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 3
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F. of subjects incapable of giving consent
    Signed consent required by patient and/or their legal representative/ parent / Impaired witness
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 22
    F.4.2.2In the whole clinical trial 53
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients who have participated in the study will be offered the opportunity to participate in the rollover, open-label extension phase if the safety and tolerability during the parent study are considered to be acceptable by the Investigator for each specific patient, and the Investigator determines further treatment with IB1001 to be in the patient's interest.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-03-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-02-25
    P. End of Trial
    P.End of Trial StatusOngoing
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