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

• ClinicalTrials.gov Identifier: NCT04860960
• Recruitment Status: Recruiting
• First Posted: April 27, 2021
• Last Update Posted: April 25, 2023
• Sponsor: Cyclo Therapeutics, Inc.
• Information provided by (Responsible Party): Cyclo Therapeutics, Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Niemann-Pick Disease, Type C1	Drug: Hydroxypropyl-beta-cyclodextrin; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 93 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• 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
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: July 20, 2021
• Estimated Primary Completion Date: December 2023
• Estimated Study Completion Date: December 2025

Arms and Interventions

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 Name: 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 Name: 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 Name: Trappsol Cyclo

Outcome Measures

Primary Outcome Measures :

1. Change from Baseline in 4-Domain NPC Severity Score (US only) [ Time Frame: Interim Analysis at Week 48 ]
   Ambulation, Fine Motor, Speech, Swallow
2. Change from Baseline in 4-Domain NPC Severity Score (US only) [ Time Frame: End of Study at Week 96 ]
   Ambulation, Fine Motor, Speech, Swallow
3. Change from Baseline in 5-Domain NPC Severity Score (ex-US) [ Time Frame: Interim Analysis at Week 48 ]
   Ambulation, Fine Motor, Speech, Swallow, Cognition
4. Change from Baseline in 5-Domain NPC Severity Score (ex-US) [ Time Frame: End of Study at Week 96 ]
   Ambulation, Fine Motor, Speech, Swallow, Cognition

Secondary Outcome Measures :

1. Change in ataxia as measured by Spinocerebellar ataxia functional index [ Time Frame: Change from Baseline as measured every 12 weeks through week 96 and end of OLE week 192 ]
   SCAFI
2. Change in adaptive behavior as measured by Vineland Adaptive Behavior Scale II [ Time Frame: Change from Baseline as measured every 12 weeks through week 96 and end of OLE week 192 ]
   Vineland Adaptive Behavior Scale II
3. Change in Swallow function evaluated by videofluoroscopy or fiberoptic endoscopy and measured by Penetration Aspiration Scale [ Time Frame: Change from Baseline measured at Interim Analysis Week 48 ]
   PAS
4. Change in Swallow function evaluated by videofluoroscopy or fiberoptic endoscopy and measured by Penetration Aspiration Scale [ Time Frame: Change from Baseline measured at End of Study Week 96 ]
   PAS

Other Outcome Measures:

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

Eligibility Criteria

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

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

Contacts and Locations

Contacts

Contact: Lori M Gorski; 13864188060; Lori.Gorski@cyclodex.com

Locations

United States, California

UCSF Benioff Children's Hospital Oakland; Recruiting

Oakland, California, United States, 94609

Contact: Investigator

United States, Ohio

Cincinnati Children's Hospital Medical Center; Recruiting

Cincinnati, Ohio, United States, 45229

Contact: Investigator

United States, Pennsylvania

UPMC Children's Hospital; Recruiting

Pittsburgh, Pennsylvania, United States, 15224

Contact: Investigator

United States, Virginia

Lysosomal and Rare Disorders Research & Treatment Center, Inc.; Recruiting

Fairfax, Virginia, United States, 22030

Contact: Investigator

Australia, Victoria

Melbourne Children's Trials Centre Murdoch Children's Research Institute; Recruiting

Parkville, Victoria, Australia

Contact: Investigator

Royal Melbourne Hospital; Recruiting

Parkville, Victoria, Australia

Australia

Metabolic Clinical Trials Unit; Recruiting

Adelaide, Australia

Contact: Investigator

Germany

SphinCS GmbH; Recruiting

Hochheim, Germany

Contact: Investigator

Israel

Emek Medical Center-Department of Pediatrics; Recruiting

Afula, Israel

Contact: Investigator

Soroka Medical Center; Recruiting

Be'er Sheva, Israel

Contact: Investigator

Poland

Szpital Uniwersytecki w Krakowie; Recruiting

Kraków, Poland

Contact: Investigator

Spain

Hospital Sant Joan de Déu - Neurology Department; Recruiting

Barcelona, Spain

Contact: Investigator

Hospital Universitari de Bellvitge; Recruiting

Barcelona, Spain

Contact: Investigator

Turkey

Gazi University Faculty of Medicine; Recruiting

Ankara, Turkey

Contact: Investigator

Sponsors and Collaborators

Cyclo Therapeutics, Inc.

Investigators

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Cyclo Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT04860960
• Other Study ID Numbers: CTD-TCNPC-301
• First Posted: April 27, 2021
• Last Update Posted: April 25, 2023
• Last Verified: January 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Cyclo Therapeutics, Inc.:

NPC1; cyclodextrin

Additional relevant MeSH terms:

Pick Disease of the Brain; Niemann-Pick Diseases; Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type C; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Speech Disorders; Language Disorders; Communication Disorders; Neurodegenerative Diseases; Metabolic Diseases; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Lymphatic Diseases; Genetic Diseases, Inborn; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Aphasia, Primary Progressive; Frontotemporal Dementia; Frontotemporal Lobar Degeneration; Dementia; Aphasia; Neurobehavioral Manifestations; Neurologic Manifestations; TDP-43 Proteinopathies; Proteostasis Deficiencies