Phase 3 Study to Evaluate Intravenous Trappsol(R) Cyclo(TM) in Pediatric and Adult Patients With Niemann-Pick Disease Type C1

Study Overview
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Brief Summary
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A prospective, randomized, double-blind, placebo controlled, multi-center therapeutic study for patients age 3 and older with confirmed diagnosis of Niemann Pick disease type C1 (NPC1). The objective of this study is to evaluate the safety, tolerability and efficacy of 2000 mg/kg dose of Trappsol Cyclo (hydroxypropyl betacyclodextrin) administered intravenously compared to standard of care. An open-label sub-study in countries following European Medicines Agency (EMA) guidance will enroll asymptomatic or symptomatic patients from infancy up to age 3 to evaluate safety in that population.

Detailed Description
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The TransportNPC study is a prospective, randomized, double-blind, placebo controlled therapeutic study for 93 patients age 3 and older with confirmed diagnosis of NPC1. The objective of this study is to evaluate the safety, tolerability and efficacy of 2000 mg/kg dose of Trappsol Cyclo (hydroxypropyl betacyclodextrin) administered intravenously by slow infusion every two weeks in addition to standard of care as compared to placebo and standard of care. Standard of care may include Miglustat or leucine products that are not currently under investigation as a therapeutic. Patients will be randomized to receive Trappsol Cyclo or placebo at a 2:1 ratio. The study duration is 96 weeks, with an unblinded interim analysis at 48 weeks. An open-label extension of up to 96 weeks follows the interventional study. Patients whose disease progression worsens by two levels in the Clinical Global Impression of Severity scale over 12 weeks, starting at week 36, may be moved to open label treatment. Efficacy will be measured at week 48 and week 96 by a composite score of major disease features. A sub-study will be conducted in countries following EMA guidance for up to 12 patients age 0 - 3 years who may be asymptomatic. Outcomes for the sub-study are safety, clinical and caregiver impression of disease.

Official Title
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Phase 3, Double-blind, Randomized, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Safety, Tolerability and Efficacy of 2000mg/kg of Trappsol®Cyclo™ (Hydroxypropyl-B-cyclodextrin) and Standard of Care Compared to Placebo and Standard of Care in Patients With Niemann-Pick Disease Type C1 (TransportNPC)

Conditions
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Niemann-Pick Disease, Type C1

Intervention / Treatment
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* Drug: Hydroxypropyl-beta-cyclodextrin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of NPC1 Annual Severity Increment Score between 0.5 and 2.0 using the 17-domain NPC Severity Scale Treated or Not Treated with Miglustat (patients must be on a stable dose for at least 3 months prior to the Screening Visit, or have discontinued Miglustat for at least 3 months prior to Screening Visit). Body weight greater than 4.5 kg and less than or equal to 125 kg Presenting at least 1 neurological symptom of the disease Written informed consent Willing and capable to participate in all aspects of trial design Ability to travel to the trial site at scheduled times Contraception requirements per protocol Caregiver consent as appropriate to participate in all protocol-specified assessments for duration of trial Inclusion criteria for Open Label Extension are 1) Received double-blind treatment for at least 48 weeks with CGI-S deterioration by at least 2 levels for 2 consecutive assessment visits 12 weeks apart, or 2) completion of double-blind treatment and completed all assessments through week 96, or 3) Discontinued early from double-blind treatment but completed all assessments through week 96 Inclusion criteria for patients age 0 to 3 years in open-label sub-study in countries following EMA guidance only: Confirmed diagnosis of NPC1; treated or not with Miglustat per main study; body weight greater than 4.5kg; patient may be asymptomatic; written assent for child to participate in safety assessments; caregiver consent to participate in caregiver assessments; ability to travel to the trial site for all scheduled visits. Exclusion Criteria: Recipient of a liver transplant within <12 months or planned liver transplantation Patients with active liver disease from any cause other than NPC1 Clinical evidence of acute liver disease including symptoms of jaundice or right upper quadrant pain or international normalized ratio > 1.8 Stage 3 chronic kidney disease or worse as indicated by an estimated glomerular filtration rate <60ml/min/1.73m2. Use of curcumin or fish oil within 12 weeks prior to enrollment Known or suspected allergy or intolerance to the study treatment In the opinion of the Investigator, the patient's clinical condition does not allow for the blood collection required as per protocol specific procedures. 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 Treatment with any other investigational drug during the study Pregnancy or breastfeeding Current participation in another trial 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) 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. Neurologically asymptomatic patients Inability to participate in the primary study assessment (4D-NPC-SS or 5D-NPC-SS) as determined by the Investigator Exclusion criteria for patients age 0 to 3 years in open-label sub-study in countries following EMA guidance only are similar to the main study with the addition of exclusion criterion of history of fetal hydrops or fetal ascites

Ages Eligible for Study
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Minimum Age: 3 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, placebo-controlled, multi-center, double-blind and parallel group study with 2:1 randomization of Trappsol Cyclo plus SOC versus placebo plus SOC over 96 weeks, followed by open-label extension study of 96 weeks
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>Intravenous administration of 2000 mg/kg hydroxypropyl betacyclodextrin (Trappsol Cyclo) (based on body weight) diluted with 0.5N saline over at least 6.5 hours every 2 weeks | Drug: Hydroxypropyl-beta-cyclodextrin<br>* Dose is 2000 mg/kg body weight provided every 2 weeks intravenously<br>* Other names: Trappsol Cyclo;|
| Placebo Comparator: Placebo comparator<br>Intravenous administration of 0.5N saline over at least 6.5 hours every 2 weeks | Drug: Placebo<br>* 0.5N saline provided every 2 weeks intravenously<br>* Other names: 0.5N saline;|
| Experimental: Open Label sub-study for Infants up to age 3<br>Up to 12 patients age 0 - 3 yrs in countries following EMA guidance may be enrolled in this open label sub-study. All patients will receive 2000 mg/kg hydroxypropyl betacyclodextrin (Trappsol Cyclo) diluted with 0.5N saline at the clinician's discretion over 6.5 hours every 2 weeks. Outcome measures are safety, clinician and caregiver impressions. | Drug: Hydroxypropyl-beta-cyclodextrin<br>* Dose is 2000 mg/kg body weight provided every 2 weeks intravenously<br>* Other names: Trappsol Cyclo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in 4-Domain NPC Severity Score (US only) | Ambulation, Fine Motor, Speech, Swallow | Interim Analysis at Week 48 | 
| Change from Baseline in 4-Domain NPC Severity Score (US only) | Ambulation, Fine Motor, Speech, Swallow | End of Study at Week 96 | 
| Change from Baseline in 5-Domain NPC Severity Score (ex-US) | Ambulation, Fine Motor, Speech, Swallow, Cognition | Interim Analysis at Week 48 | 
| Change from Baseline in 5-Domain NPC Severity Score (ex-US) | Ambulation, Fine Motor, Speech, Swallow, Cognition | End of Study at Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in ataxia as measured by Spinocerebellar ataxia functional index | SCAFI | Change from Baseline as measured every 12 weeks through week 96 and end of OLE week 192 | 
| Change in adaptive behavior as measured by Vineland Adaptive Behavior Scale II | Vineland Adaptive Behavior Scale II | Change from Baseline as measured every 12 weeks through week 96 and end of OLE week 192 | 
| Change in Swallow function evaluated by videofluoroscopy or fiberoptic endoscopy and measured by Penetration Aspiration Scale | PAS | Change from Baseline measured at Interim Analysis Week 48 | 
| Change in Swallow function evaluated by videofluoroscopy or fiberoptic endoscopy and measured by Penetration Aspiration Scale | PAS | Change from Baseline measured at End of Study Week 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NPC1, cyclodextrin, Niemann-Pick, Niemann-Pick Type C, NPC, Niemann Pick C, Niemann Pick Type C, Niemann Pick