Clinical trial NCT04860960: Phase 3 Study to Evaluate Intravenous Trappsol(R) Cyclo(TM) in Pediatric and Adult Patients With Niemann-Pick Disease Type C1
Official title: 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Niemann-Pick Disease, Type C1
Keywords: NPC1
cyclodextrin
Niemann-Pick
Niemann-Pick Type C
NPC
Niemann Pick C
Niemann Pick Type C
Niemann Pick
Lead sponsor: Cyclo Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2021-04-27
Enrollment: 94
Sex: ALL
Minimum age (years): 3
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change from Baseline in 4-Domain NPC Severity Score (US only)
timeFrame: Interim Analysis at Week 48
measure: Change from Baseline in 4-Domain NPC Severity Score (US only)
timeFrame: End of Study at Week 96
measure: Change from Baseline in 5-Domain NPC Severity Score (ex-US)
timeFrame: Interim Analysis at Week 48
measure: Change from Baseline in 5-Domain NPC Severity Score (ex-US)
timeFrame: End of Study at Week 96
Secondary outcomes:
measure: Change in ataxia as measured by Spinocerebellar ataxia functional index
timeFrame: Change from Baseline as measured every 12 weeks through week 96 and end of OLE week 192
measure: Change in adaptive behavior as measured by Vineland Adaptive Behavior Scale II
timeFrame: Change from Baseline as measured every 12 weeks through week 96 and end of OLE week 192
measure: Change in Swallow function evaluated by videofluoroscopy or fiberoptic endoscopy and measured by Penetration Aspiration Scale
timeFrame: Change from Baseline measured at Interim Analysis Week 48
measure: Change in Swallow function evaluated by videofluoroscopy or fiberoptic endoscopy and measured by Penetration Aspiration Scale
timeFrame: Change from Baseline measured at End of Study Week 96
Other outcomes:
measure: Change in speaking ability compared to Baseline as measured by voice recordings collected in SpeechVitals mobile device application
timeFrame: Baseline and every two weeks through week 192
measure: Change in speaking ability compared to Pre-Infusion as measured by voice recordings collected in SpeechVitals mobile device application
timeFrame: Every two weeks through week 192
measure: Change in Scores of Clinical Global Impression of Severity and of Change compared to Baseline
timeFrame: Baseline, weeks 2, 4, 12, 24, 36, 48, 60, 72, 84, 96, 100, 120, 144, 168, 192
measure: Change in Scores of Caregiver Global Impression of Severity and of Change scales
timeFrame: Baseline, weeks 2, 4, 12, 24, 36, 48, 60, 72, 84, 96, 100, 120, 144, 168, 192
measure: Caregiver Global Impression of Change at 24 hours post infusion
timeFrame: Baseline and every 2 weeks through week 192
measure: Change from Baseline in Respiratory function measured by Forced Expiratory Volume in 1 second
timeFrame: Baseline, weeks 2, 4, 12, 24, 36, 48, 60, 72, 84, 96, 100, 192
measure: Change from Baseline in Liver function as measured by liver enzyme assessments
timeFrame: Baseline, weeks 2, 4, 12, 24, 36, 48, 60, 72, 84, 96, 100, 120, 144, 168, 192
measure: Safety assessments to include incidence of Adverse Events and Serious Adverse Events
timeFrame: Regular assessments per protocol through week 192
Locations:
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital Oakland
state: California
city: Jacksonville
country: United States
facility: University of Florida
state: Florida
city: Atlanta
country: United States
facility: Emory
state: Georgia
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University Utah
state: Utah
city: Fairfax
country: United States
facility: Lysosomal and Rare Disorders Research & Treatment Center, Inc.
state: Virginia
city: Buenos Aires
country: Argentina
facility: Hospital de Alta Complejidad en Red "El Cruce"
city: Córdoba
country: Argentina
facility: Hospital de Niños de la Santísima Trinidad
city: Parkville
country: Australia
facility: Melbourne Children's Trials Centre Murdoch Children's Research Institute
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Adelaide
country: Australia
facility: Metabolic Clinical Trials Unit
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
city: São Paulo
country: Brazil
facility: Universidade de São Paulo
city: São Paulo
country: Brazil
facility: University of Campinas
city: Hochheim
country: Germany
facility: SphinCS GmbH
city: Münster
country: Germany
facility: University Munster
city: Afula
country: Israel
facility: Emek Medical Center-Department of Pediatrics
city: Be'er Sheva
country: Israel
facility: Soroka Medical Center
city: Catania
country: Italy
facility: University of Catania
city: Milan
country: Italy
facility: Istituto Neurologico Carlo Besta
city: Padova
country: Italy
facility: University Hospital of Padova
city: Udine
country: Italy
facility: Centro di Coordinamento Regionale Malattie Rare
city: Kraków
country: Poland
facility: Szpital Uniwersytecki w Krakowie
city: Warsaw
country: Poland
facility: MediPark
city: Riyadh
country: Saudi Arabia
facility: King Faisal Specialist Hospital and Research Centre
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Déu - Neurology Department
city: Barcelona
country: Spain
facility: Hospital Universitari de Bellvitge
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Ankara
country: Turkey
facility: Gazi University Faculty of Medicine
city: İzmir
country: Turkey
facility: Ege University Medical School, Department of Inborn Errors of Metabolism
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital NHS Foundation Trust · Department of Inherited Metabolic Disorders Service
city: London
country: United Kingdom
facility: University College London
city: Salford
country: United Kingdom
facility: Salford Royal Foundation NHS Trust
Study officials:
affiliation: Cyclo Therapeutics, Inc.
name: Karen Mullen, MD
role: STUDY_DIRECTOR
References:
citation: Hastings C, Liu B, Hurst B, Cox GF, Hrynkow S. Intravenous 2-hydroxypropyl-beta-cyclodextrin (Trappsol(R) Cyclo) demonstrates biological activity and impacts cholesterol metabolism in the central nervous system and peripheral tissues in adult subjects with Niemann-Pick Disease Type C1: Results of a phase 1 trial. Mol Genet Metab. 2022 Dec;137(4):309-319. doi: 10.1016/j.ymgme.2022.10.004. Epub 2022 Oct 17.