E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Niemann Pick Disease Type C1 |
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E.1.1.1 | Medical condition in easily understood language |
Rare inherited lysosomal lipidosis resulting in a progressive and fatal neurological deterioration |
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E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029403 |
E.1.2 | Term | Niemann-Pick disease |
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 |
This study has dual primary objectives, such that the primary objective is to evaluate the effectiveness of Trappsol Cyclo and standard of care (SOC) compared to placebo and SOC as measured by an improvement in the 4-domain (4D-NPC-SS) or 5-domain (5D-NPC-SS) Niemann-Pick disease Type C Severity Scale: •The 4D-NPC-SS will be utilized as the primary objective for the US. •The 5D-NPC-SS will be utilized as an exploratory objective for the US. •The 5D-NPC-SS will be utilized as the primary objective for the EU and RoW. •The 4D-NPC-SS will be utilized as an exploratory objective for the EU and RoW.
All randomized patients, regardless of country, will be assessed by both the 4D-NPC-SS and the 5D-NPC-SS assessment tools per the Schedule of Assessments (SoA).
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E.2.2 | Secondary objectives of the trial |
•To determine the ability of Trappsol Cyclo and SOC compared to placebo and SOC to improve ataxia as assessed by the Spinocerebellar Ataxia Functional Index (SCAFI) •To evaluate the effectiveness of Trappsol Cyclo and SOC compared to placebo and SOC as assessed by the Vineland Adaptive Behavior Scale 2nd edition (Vineland 2) composite raw score, including the optional Motor Skills domain •To evaluate the effectiveness of Trappsol Cyclo and SOC compared to placebo and SOC with regards to the patient’s ability to swallow as assessed by the Penetration Aspiration Scale (PAS)
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sub-study for Patients Newborn to <3 Years of Age. This sub-study will only be conducted in the EU and RoW; this sub-study will not be conducted in the US. This substudy will enroll patients from newborn to <3 years of age in an exploratory module to evaluate the safety of Trappsol Cyclo in these patients, and to obtain descriptive data regarding global severity and improvement in response to Trappsol Cyclo from both Investigator and patient perspective (CGI-S, CGI-C, CaGI-S, CaGI-C, and CaGI C24). These patients will not be randomized, rather, these patients will all receive open-label Trappsol Cyclo and SOC. These patients will not contribute to the efficacy or safety data sets addressing the principal hypotheses of the study. These patients are eligible for 192 weeks of treatment with Trappsol Cyclo. |
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E.3 | Principal inclusion criteria |
1. Patients ≥3 years of age at Screening. 2. Diagnosis of NPC1 confirmed by: a. Genetically confirmed (deoxyribonucleic acid sequence analysis) by mutations in both alleles of NPC1 OR b. Mutation in only 1 allele of NPC1 and either positive filipin staining in skin or vertical supranuclear gaze palsy (VSGP). 3. Patients with an ASIS between 0.5 to 2.0 (inclusive) at Screening using the 17 Domain Niemann-Pick Type C Severity Scale (17D-NPC-SS) composite score. For patients who remain incontinent due to inability to train to become continent, the relative contribution to the 17-D-NPC-CSS composite score can be adjusted per the Investigator's judgment as not applicable, following conferring with the Medical Monitor. A not applicable score will be scored as a "0" for this domain. 4.Treated or not treated with miglustat. a. If a patient is receiving treatment with miglustat, the dose must have been stable for at least 3 continuous months prior to the first Screening Visit. b. If a patient has been discontinued from prescribed treatment with miglustat, she/he must have been discontinued for at least 3 continuous months prior to the first Screening Visit. 5. Body weight >4.5 kg to ≤125 kg 6. Presenting at least 1 neurological symptom of the disease (including, but not limited to, hearing loss, VSGP, ataxia, dementia, dystonia, history of seizures, cataplexy, dysarthria, or dysphagia) 7. Willing and capable to participate in all aspects of study design, including blood sampling (efficacy, PK, blood biomarkers, and safety laboratory tests). Adequate compliance with the assessments to obtain complete data can become a discussion between the Investigator and the medical monitor prior to randomization at the Baseline Visit the Medical Monitor prior to randomization at the Baseline Visit. 8.Patients who have previously been treated with hydroxypropyl-β- cyclodextrin (HPβCD) are eligible for participation in the study if their last intrathecal administration was 3 months or longer ago or if their last IV administration was 6 months or longer ago. No more than approximately 10% of the total number of randomized patients can previously have been exposed to HPβCD. 9. Ability to travel to the corresponding clinical study site at the scheduled visit times for evaluation and follow-up 10. Contraception requirements: a. All sexually active WOCBP (post menarche) must use highly effective contraception during the study and until 3 months after the last dose of study treatment b. Highly effective birth control methods include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal); progestogen only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable); intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; or vasectomized partner c. All sexually active male patients with WOCBP partners (post menarche) must use a condom with or without spermicide in addition to the birth control used by their partners during the study and until 3 months after the last dose of study treatment d. Sexual abstinence is considered a highly effective birth control method only if it is defined as refraining from heterosexual intercourse during the study and for 3 months after the last dose of study treatment for WOCBP and for male patients with WOCBP partners. The reliability of sexual abstinence needs to be evaluated by the Investigator in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient 11. The patient or legally authorized representative has read and signed the informed consent (or assent, as applicable) form prior to any study-related procedures 12. The legally authorized representative (if applicable) agrees for the patient to participate in all aspects of the study 13. The patient’s caregiver (as applicable) agrees to participate in all of the protocol-specified assessment scales, questionnaires, and interviews for the duration of the trial
Criteria to Switch to Open label Trappsol Cyclo Treatment Prior to Week 96 1. Received double-blind treatment for ≥36 weeks, AND 2. CGI-S Overall Disease deterioration of ≥2 levels from Baseline at 2 consecutive assessment visits 12 weeks apart per SoA Note that based on these criteria the earliest timepoint that a patient may be switched to open-label Trappsol Cyclo due to deterioration is following completion of Week 48 assessments. Trappsol Cyclo will be administered at subsequent visits. Switching should be confirmed with the Medical Monitor.
Criteria to Participate in the Open-label Extension 1. Completed double-blind treatment through Week 92 and completed Week 96 assessments, OR 2. Discontinued early from double-blind treatment for reasons other than safety but completed all assessments through Week 96 |
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E.4 | Principal exclusion criteria |
1. Recipient of a liver transplant within <12 months or planned liver transplantation. Patients who have received a successful transplant over 12 months or longer ago can be screened. 2. Patients with active liver disease from any cause other than NPC1 or prolonged icterus or malformation of organs other than NPC1 3. Clinical evidence of acute liver disease including associated symptoms of jaundice or right upper quadrant pain or international normalized ratio >1.8 4. Stage 3 chronic kidney disease or worse as indicated by an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. In patients aged ≤18 years, eGFR is calculated according to the Schwartz equation (Schwartz and Work, 2009), and in patients aged >18 years eGFR is calculated using the Modification of Diet in Renal Disease equation 5. Use of curcumin or fish oil supplements within 12 weeks prior to enrollment 6. Known or suspected allergy or intolerance to the study treatment 7. Treatment with any investigational drug during the 3 months prior to entering the study. If the investigational drug has a short half-life (<8 hours) and would be expected to be cleared from the body within 1 month, then the wash-out period is 1 month. Treatment with any form of leucine, whether as an investigational drug or other formulation is not allowed. Please consult with the Medical Monitor on a case-by-case basis. 8. Treatment with any other investigational drug during the study 9. Pregnancy or breastfeeding 10. Current participation in another study is not permitted unless it is a noninterventional study and the sole purpose of the trial is for long term follow up describing clinical features or survival data (registry) 11. Patients with uncontrolled, severe epileptic seizure periods (at least 3 consecutive severe epileptic seizures that required medication) within 2 months prior to completion of informed consent (or assent, as applicable). This includes patients with ongoing seizures that are not stable in frequency or type or duration over a 2-month period prior to enrollment, requiring change in dose of antiepileptic medication (other than adjustment for weight) over a 2-month period prior to enrollment, or requiring 3 or more antiepileptic medications to control seizures over a 2-month period prior to enrollment 12. Neurologically asymptomatic patients 13. Inability to participate in the primary study assessment (4D-NPC-SS and 5D-NPC-SS) as determined by the Investigator. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoints as measured in study patients, regardless of region and country, but submitted as primary to the EU and RoW are: • Interim Analysis: Mean change in the 5D NPC SS composite score (Ambulation, Fine Motor, Speech, Swallow, and Cognition) from Baseline (Week 0) to 48 weeks •Final Analysis: Mean change in the 5D NPC SS composite score (Ambulation, Fine Motor, Speech, Swallow, and Cognition) from Baseline (Week 0) to 96 weeks
The primary endpoints as measured in all study patients, regardless of country, but submitted as primary to US are: • Interim Analysis: Mean change in the 4D-NPC-SS (Ambulation, Fine Motor, Speech, and Swallow) composite score from Baseline (Week 0) to 48 weeks • Final Analysis: Mean change in the 4D-NPC-SS (Ambulation, Fine Motor, Speech, and Swallow) composite score from Baseline (Week 0) to 96 weeks |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Mean change from Baseline in the SCAFI at 48 and 96 weeks • Mean change from Baseline in the Vineland 2 composite raw score, including the optional Motor Skills domain, at 48 and 96 weeks • Mean change from Baseline in the patient’s ability to swallow as assessed by the PAS, at 48 and 96 weeks (at select sites)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.3 | Therapy | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Eligible patients may enter an Open-label extension upon completion of blinded treatment period |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 12 |
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 |
Argentina |
Ukraine |
Taiwan |
Australia |
Brazil |
Israel |
Saudi Arabia |
United Kingdom |
United States |
Germany |
Italy |
Poland |
Spain |
Türkiye |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 3 |