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

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)

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.

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.

Inclusion Criteria:

1. Confirmed diagnosis of NPC1
2. Annual Severity Increment Score between 0.5 and 2.0 using the 17-domain NPC Severity Scale
3. 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).
4. Body weight greater than 4.5 kg and less than or equal to 125 kg
5. Presenting at least 1 neurological symptom of the disease
6. Written informed consent
7. Willing and capable to participate in all aspects of trial design
8. Ability to travel to the trial site at scheduled times
9. Contraception requirements per protocol
10. Caregiver consent as appropriate to participate in all protocol-specified assessments for duration of trial
11. 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
12. 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:

1. Recipient of a liver transplant within <12 months or planned liver transplantation
2. Patients with active liver disease from any cause other than NPC1
3. Clinical evidence of acute liver disease including 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 <60ml/min/1.73m2.
5. Use of curcumin or fish oil within 12 weeks prior to enrollment
6. Known or suspected allergy or intolerance to the study treatment
7. In the opinion of the Investigator, the patient's clinical condition does not allow for the blood collection required as per protocol specific procedures.
8. 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
9. Treatment with any other investigational drug during the study
10. Pregnancy or breastfeeding
11. 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)
12. 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.
13. Neurologically asymptomatic patients
14. Inability to participate in the primary study assessment (4D-NPC-SS or 5D-NPC-SS) as determined by the Investigator
15. 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