Niemann-Pick Disease, Type C1
Conditions
Keywords
NPC1, cyclodextrin, Niemann-Pick, Niemann-Pick Type C, NPC, Niemann Pick C, Niemann Pick Type C, Niemann Pick
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.
Interventions
Dose is 2000 mg/kg body weight provided every 2 weeks intravenously
DRUGPlacebo
0.5N saline provided every 2 weeks intravenously
Sponsors
Cyclo Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
Eligibility
Sex/Gender
ALL
Age
3 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from Baseline in 4-Domain NPC Severity Score (US only) | Interim Analysis at Week 48 | Ambulation, Fine Motor, Speech, Swallow |
| Change from Baseline in 5-Domain NPC Severity Score (ex-US) | Interim Analysis at Week 48 | Ambulation, Fine Motor, Speech, Swallow, Cognition |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in ataxia as measured by Spinocerebellar ataxia functional index | Change from Baseline as measured every 12 weeks through week 96 and end of OLE week 192 | SCAFI |
| Change in adaptive behavior as measured by Vineland Adaptive Behavior Scale II | Change from Baseline as measured every 12 weeks through week 96 and end of OLE week 192 | Vineland Adaptive Behavior Scale II |
| Change in Swallow function evaluated by videofluoroscopy or fiberoptic endoscopy and measured by Penetration Aspiration Scale | Change from Baseline measured at Interim Analysis Week 48 | PAS |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change from Baseline in Respiratory function measured by Forced Expiratory Volume in 1 second | Baseline, weeks 2, 4, 12, 24, 36, 48, 60, 72, 84, 96, 100, 192 | FEV1 |
| Change in speaking ability compared to Baseline as measured by voice recordings collected in SpeechVitals mobile device application | Baseline and every two weeks through week 192 | Measurement of speech features including articulatory precision, speaking and pause rates |
| Safety assessments to include incidence of Adverse Events and Serious Adverse Events | 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 |
| Change from Baseline in Liver function as measured by liver enzyme assessments | 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 |
| Change in speaking ability compared to Pre-Infusion as measured by voice recordings collected in SpeechVitals mobile device application | Every two weeks through week 192 | Measurement of speech features including articulatory precision, speaking and pause rates within 24 hours post-infusion |
| Change in Scores of Clinical Global Impression of Severity and of Change compared to Baseline | 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 |
| Change in Scores of Caregiver Global Impression of Severity and of Change scales | 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 |
| Caregiver Global Impression of Change at 24 hours post infusion | Baseline and every 2 weeks through week 192 | Caregiver Global Impression of Change at 24 hours post infusion |
Countries
Argentina, Australia, Brazil, Germany, Israel, Italy, Poland, Saudi Arabia, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Outcome results
None listed