| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Niemann-Pick Disease type C (NPC) |
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| E.1.1.1 | Medical condition in easily understood language |
| Niemann-Pick Disease type C (NPC) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10010331 |
| E.1.2 | Term | Congenital, familial and genetic disorders |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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.
For 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. |
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| E.2.2 | Secondary objectives of the trial |
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 patients with NPC, including patients aged ≥18 years in the United States and patients aged ≥13 years in Europe, and weight-tiered doses in patients 6 - 12 years of age in Europe
For the Extension Phase:
o 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
o 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 6 to 12 years of age, with NPC
o To characterize the pharmacokinetics (PK) of N-Acetyl-L-Leucine in patients with NPC
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 ≥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 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 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 dosing.
7. Patients must fall within:
a) A 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) (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:
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 6 weeks 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).
For the Extension Phase:
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
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| E.4 | Principal 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 completely negative result on a previous genetic test for NPC
3. Patients who have any of the following:
a) Chronic diarrhea;
b) Unexplained visual loss;
c) Malignancies;
d) Insulin-dependent diabetes mellitus.
e) Known history of hypersensitivity to the N-Acetyl-D-Leucine (DL-, L-, D-) or derivatives.
f) 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:
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 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.
a) Aminopyridines (including sustained-release form);
b) N-Acetyl-DL-Leucine (e.g. Tanganil®);
c) N-Acetyl-L-Leucine (prohibited if not provided as IMP);
d) Riluzole;
e) Gabapentin;
f) Varenicline;
g) Chlorzoxazone;
h) Sulfasalazine;
i) Rosuvastatin.
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| E.5 End points |
| E.5.1 | 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).
The comparison of the Visit 4 video with the Visit 2 video and the comparison of the Visit 6 video with the Visit 4 video will provide the scores that contribute to the primary endpoint. Each of these comparisons will score improvement on a 7-point Likert scale (+3=significantly improved to -3= significantly worse).
During the pre-treatment period, the treating physician will evaluate each patient’s clinical symptoms and select at Visit 1 either the 9HPT-D or 8MWT as the primary anchor around which the CI-CS assessment will be scored. A cognitive assessment should be performed at Visit 1 according to standard procedures of the clinical site to assist with the selection of the anchoring functional test appropriate for each patient from both a cognitive and a motor perspective.
The primary evaluation of the CI-CS will be performed by two independent raters whose assessments will be based on videos of the anchor test taken at each visit. These raters will be blinded to the treatment periods (baseline, treatment, or washout) to reduce detection and performance bias.
The primary endpoint is defined as the CI-CS comparing end of treatment with N-Acetyl-L-Leucine (Visit 4) with baseline (Visit 2) minus the CI-CS comparing the end of washout (Visit 6) with the end of treatment with N-Acetyl-L-Leucine (Visit 4).
The CI-CS assessment will instruct the blinded rater to consider: ‘compared to the first video, how has the severity of their performance on the 9HPT-D or 8MWT changed (improved or worsened) in 6-weeks as observed in the second video?’
It is expected that the blinded observers will reach agreement on the CI-CS scores by consensus. If consensus cannot be achieved, then the average score will be taken. All disagreements will be documented.
The statistical analysis of this endpoint will utilize a single sample t-test comparing the mean value of the primary endpoint with zero. This endpoint allows the effect N-Acetyl-L-Leucine to be measured both in terms of improvement during treatment followed by any deterioration once treatment is removed.
Summary statistics will in addition be calculated separately according to subgroups defined by the chosen anchor test
Extension phase primary endpoint:
The primary endpoint in this Extension Phase is success measured on the Clinical Impression of Change in Severity (CI-CS) from the Extension Phase baseline (Visit 7) to the end of treatment in the Extension Phase (Visit 9).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
CI-CS comparing Baseline (Day 1) with IB1001 verses 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) verses the end of 6-weeks post-treatment washout (Approximately day 84)
The primary endpoint in this Extension Phase is success measured on the Clinical Impression of Change in Severity (CI-CS) from the Extension Phase baseline (Visit 7) to the end of treatment in the Extension Phase (Visit 9). |
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| E.5.2 | Secondary end point(s) |
• Spinocerebellar Ataxia Functional Index (SCAFI)
• Scale for Assessment and Rating of Ataxia (SARA) score
• Quality of Life EQ-5D-5L for patients aged ≥18; EQ-5D-Y for patients aged <18 years (visual analogue scale; descriptive system)
• Modified Disability Rating Scale (mDRS)
• Treating Physician Clinical Global Impression of Severity (CGI-S) at every visit
• Treating Physician Clinical Global Impression of Change (CGI-C) comparing end of treatment (Visit 4) to baseline (Visit 2), and end of washout (Visit 6) to end of treatment (Visit 4)
• Caregiver Clinical Global Impression of Severity (CGI-S) at every visit
• Caregiver Clinical Global Impression of Change (CGI-C) comparing end of treatment (Visit 4) to baseline (Visit 2), and end of washout (Visit 6) to end of treatment (Visit 4)
• Patient Clinical Global Impression Scales Impression of Severity (CGI-S) at every visit if they are able
• Patient Clinical Global Impression of Change (CGI-C) comparing end of treatment (Visit 4) to baseline (Visit 2), and end of washout (Visit 6) to end of treatment (Visit 4) if they are able
For the extension phase:
Given the extended duration of treatment in the Extension Phase, the Niemann-Pick disease type C Clinical Severity Scale (NPC-CSS) will be introduced as an additional secondary endpoint, where the graduation of changes is expected to detect clinically relevant changes in functioning / benefit after one year of treatment |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline (Day 1) to end of treatment with IB1001 (Approximately Day 42); End of treatment with IB1001 (Approximately Day 42) to the end of post-treatment washout (Approximately Day 84)
For the extension phase:
Extension Phase Baseline (V7) to end of Extension Phase treatment with IB1001 ((V9; Approximately Day 365 of the extension phase treatment phase).
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Spain |
| Germany |
| Slovakia |
| United Kingdom |
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| E.8.7 | Trial 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
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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.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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