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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Niemann-Pick Disease, Type C1
• Intervention / Treatment: Drug: Hydroxypropyl-beta-cyclodextrin; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 94
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Hospital de Alta Complejidad en Red "El Cruce"
  • Córdoba, Argentina
    • Hospital de Niños de la Santísima Trinidad
• Australia
  • Adelaide, Australia
    • Metabolic Clinical Trials Unit
  • Victoria
    • Parkville, Victoria, Australia
      • Royal Melbourne Hospital
    • Parkville, Victoria, Australia
      • Melbourne Children's Trials Centre Murdoch Children's Research Institute
• Brazil
  • Porto Alegre, Brazil
    • Hospital de Clinicas de Porto Alegre
  • São Paulo, Brazil
    • Universidade de São Paulo
  • São Paulo, Brazil
    • University of Campinas
• Germany
  • Hochheim, Germany
    • SphinCS GmbH
  • Münster, Germany
    • University Münster
• Israel
  • Afula, Israel
    • Emek Medical Center-Department of Pediatrics
  • Be'er Sheva, Israel
    • Soroka Medical Center
• Italy
  • Catania, Italy
    • University of Catania
  • Milan, Italy
    • Istituto Neurologico Carlo Besta
  • Padova, Italy
    • University Hospital of Padova
  • Udine, Italy
    • Centro di Coordinamento Regionale Malattie Rare
• Poland
  • Kraków, Poland
    • Szpital Uniwersytecki w Krakowie
  • Warsaw, Poland
    • MediPark
• Saudi Arabia
  • Riyadh, Saudi Arabia
    • King Faisal Specialist Hospital and Research Centre
• Spain
  • Barcelona, Spain
    • Hospital Universitari de Bellvitge
  • Barcelona, Spain
    • Hospital Sant Joan de Déu - Neurology Department
  • Madrid, Spain
    • Hospital Universitario 12 de Octubre
• Taiwan
  • Taipei, Taiwan
    • National Taiwan University Hospital
• Turkey
  • Ankara, Turkey
    • Gazi University Faculty of Medicine
  • İzmir, Turkey
    • Ege University Medical School, Department of Inborn Errors of Metabolism
• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Children's Hospital NHS Foundation Trust · Department of Inherited Metabolic Disorders Service
  • London, United Kingdom
    • University College London
  • Salford, United Kingdom
    • Salford Royal Foundation NHS Trust
• United States
  • California
    • Oakland, California, United States, 94609
      • UCSF Benioff Children's Hospital Oakland
  • Florida
    • Jacksonville, Florida, United States, 32207
      • University of Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • UPMC Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University Utah
  • Virginia
    • Fairfax, Virginia, United States, 22030
      • Lysosomal and Rare Disorders Research & Treatment Center, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental; 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; Dose is 2000 mg/kg body weight provided every 2 weeks intravenously; Other Names: Trappsol Cyclo
Placebo Comparator: Placebo comparator; Intravenous administration of 0.5N saline over at least 6.5 hours every 2 weeks	Drug: Placebo; 0.5N saline provided every 2 weeks intravenously; Other Names: 0.5N saline
Experimental: Open Label sub-study for Infants up to age 3; 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; Dose is 2000 mg/kg body weight provided every 2 weeks intravenously; Other Names: Trappsol Cyclo

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in speaking ability compared to Baseline as measured by voice recordings collected in SpeechVitals mobile device application	Measurement of speech features including articulatory precision, speaking and pause rates	Baseline and every two weeks through week 192
Change in speaking ability compared to Pre-Infusion as measured by voice recordings collected in SpeechVitals mobile device application	Measurement of speech features including articulatory precision, speaking and pause rates within 24 hours post-infusion	Every two weeks through week 192
Change in Scores of Clinical Global Impression of Severity and of Change compared to Baseline	Clinical Global Impression of Severity and of Change	Baseline, weeks 2, 4, 12, 24, 36, 48, 60, 72, 84, 96, 100, 120, 144, 168, 192
Change in Scores of Caregiver Global Impression of Severity and of Change scales	Caregiver Global Impression of Severity and of Change	Baseline, weeks 2, 4, 12, 24, 36, 48, 60, 72, 84, 96, 100, 120, 144, 168, 192
Caregiver Global Impression of Change at 24 hours post infusion	Caregiver Global Impression of Change at 24 hours post infusion	Baseline and every 2 weeks through week 192
Change from Baseline in Respiratory function measured by Forced Expiratory Volume in 1 second	FEV1	Baseline, weeks 2, 4, 12, 24, 36, 48, 60, 72, 84, 96, 100, 192
Change from Baseline in Liver function as measured by liver enzyme assessments	Liver function measured by liver enzyme assessments including alanine and aspartate aminotransferases	Baseline, weeks 2, 4, 12, 24, 36, 48, 60, 72, 84, 96, 100, 120, 144, 168, 192
Safety assessments to include incidence of Adverse Events and Serious Adverse Events	Incidence of AEs, SAEs, incidence of abnormal laboratory test results, abnormal ECGs, abnormal physical exams, abnormal vital signs and abnormal hearing assessments assessments	Regular assessments per protocol through week 192

Collaborators and Investigators

• Sponsor: Cyclo Therapeutics, Inc.
• Investigators: Study Director: Karen Mullen, MD, Cyclo Therapeutics, Inc.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2021
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: April 15, 2021
• First Submitted That Met QC Criteria: April 22, 2021
• First Posted (Actual): April 27, 2021

Study Record Updates

• Last Update Posted (Estimated): June 4, 2024
• Last Update Submitted That Met QC Criteria: June 3, 2024
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: NPC; NPC1; Niemann-Pick Type C; Niemann-Pick; cyclodextrin; Niemann Pick Type C; Niemann Pick; Niemann Pick C
• Additional Relevant MeSH Terms: Mental Disorders; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Lymphatic Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Genetic Diseases, Inborn; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Dementia; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Language Disorders; Communication Disorders; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Speech Disorders; Frontotemporal Lobar Degeneration; Aphasia; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain; Niemann-Pick Diseases; Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type C; Molecular Mechanisms of Pharmacological Action; Sequestering Agents; Betadex
• Other Study ID Numbers: CTD-TCNPC-301

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No