A Phase I/II study to evaluate Trappsol Cyclo (hydroxypropyl-ß-cyclodextrin) in patients with Niemann-Pick disease type C (NPC-1) to assess what the drug does to the body, and what the body does to the drug, and the side effects and benefits experienced by patients

• Register: EUCTR
• Last refreshed on: 2 March 2022
• Main ID: EUCTR2015-005761-23-SE
• Date of registration: 09/09/2016
• Prospective Registration: Yes
• Primary sponsor: Cyclo Therapeutics, Inc.
• Public title: A Phase I/II study to evaluate Trappsol Cyclo (hydroxypropyl-ß-cyclodextrin) in patients with Niemann-Pick disease type C (NPC-1) to assess what the drug does to the body, and what the body does to the drug, and the side effects and benefits experienced by patients
• Scientific title: A Phase I/II study to evaluate the safety and pharmacokinetics of intravenous Trappsol Cyclo (HP-ß-CD) in patients with Niemann-Pick disease type C (NPC-1) and the pharmacodynamic effects of treatment upon markers of cholesterol metabolism and clinical outcomes
• Date of first enrolment: 19/01/2017
• Target sample size: 11
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-005761-23
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: yes; Open: Single blind: yes; Double blind: Parallel group: Cross over: Other: yes; Other trial design description: Pharmacist is unblinded to dose.; If controlled, specify comparator, Other Medicinial Product: Placebo: Other:
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Italy, Sweden, United Kingdom

Contacts

• Name: CSO & SVPMA
• Affiliation: Cyclo Therapeutics, Inc.

• Name: CSO & SVPMA
• Affiliation: Cyclo Therapeutics, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Confirmed diagnosis of NPC-1 defined as one of the following:
a) Two NPC-1 mutations on genotyping
b) One NPC-1 mutation and positive filipin staining (current or prior)
c) Vertical supranuclear gaze palsy [VSNGP] plus either = one NPC-1 mutation or positive filipin staining and no NPC-2 mutations
2. NIH NPC Severity Score <30 and with no more than 4 individual domains with a score = 3.
3. Age range: 2 years upwards
a) Inclusion of the first six patients will be restricted to individuals aged = 5 years. In the event that three patients aged >18 (i.e. adults) are recruited before the total recruitment has reached n=6, no more adults will be randomised to treatment until the first cohort of 6 patients is complete. Once the first six are recruited and randomised, study entry will be open to all ages =2 years as per the protocol.
4. Negative pregnancy test for females of child bearing potential
5. Written, informed consent
Are the trial subjects under 18? yes
Number of subjects for this age range: 6
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 5
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. The presence of NPC-2 mutations on genotyping
2. Previous receipt of cyclodextrin therapy
3. Lanksy score < 50 if aged =16 or Karnofsky score < 40 if aged > 16.
4. Inability to comply with the proposed protocol assessments
5. Concurrent treatment with any type of cholesterol lowering agents such as statins, fibrates, ezetimibe
6. Concurrent medical conditions representing a contraindication to any of the study medications
7. Stage 3 chronic kidney disease (CKD) or worse as indicated by an eGFR < 60 mL/min/1.73 m2. In patients aged = 18 years, eGFR is calculated according to the Schwartz equation (ref: Schwartz GJ & Work DF) and in patients aged > 18 years eGFR is calculated using the MDRD equation.
8. Clinical evidence of acute liver disease including symptoms of jaundice or right upper quadrant pain or international normalised ratio (INR) >1. 8
9. Involvement in another interventional clinical trial within the previous 6 months from screening
10. Weight >100 kg
11. Females of childbearing potential who are not willing to use a method of highly effective contraception (hormonal contraception, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, or true abstinence) during the study and the follow-up period. True abstinence can only be in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration
of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception.
12. Females who are breastfeeding.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Niemann-Pick disease type C
MedDRA version: 20.0 Level: PT Classification code 10029403 Term: Niemann-Pick disease System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Intervention(s)

Product Name: Trappsol Cyclo
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: hydroxypropyl-beta-cyclodextrin
CAS Number: 128446-35-5
Current Sponsor code: Trappsol Cyclo
Other descriptive name: hydroxypropyl-beta-cyclodextrin
Concentration unit: % (W/V) percent weight/volume
Concentration type: equal
Concentration number: 25-

Primary Outcome(s)

Main Objective: Stage 1
• To compare the plasma pharmacokinetics of hydroxypropyl-ß-cyclodextrin following 3 different single doses of intravenous Trappsol Cyclo in patients with NPC-1

Stage 2
• To evaluate the efficacy and tolerability of 3 different doses of Trappsol Cyclo in the management of clinical manifestations of NPC-1

Timepoint(s) of evaluation of this end point: See Section E.5.1
In addition, interim analysis will be performed

Primary end point(s): Stage 1
• Plasma concentrations of HP-ß-CD during and following infusion to evaluate Tmax, Cmax, volume of distribution and elimination half-life (at 0, 2, 4, 6 and 8 hours after the start of infusion and 30 minutes, 1, 2, 4, 8 and 12 hours after the end of the infusion)

Stage 2
• Change from baseline in global impression of disease severity at 48 weeks
• The proportion of patients at 48 weeks with a reduction from baseline of at least one point in two or more domains of the NIH NPC severity scale

Secondary Objective: Stage 1
• To investigate the effect of 3 different doses of intravenous Trappsol Cyclo in patients upon serum and lymphocytic markers of cholesterol metabolism in patients with NPC-1
• To evaluate hydroxypropyl-ß-cyclodextrin concentrations in cerebrospinal fluid following intravenous administration of Trappsol Cyclo in patients with NPC-1

Stage 2
• To investigate the effect of 3 different doses of intravenous Trappsol Cyclo upon serum and lymphocytic markers of cholesterol metabolism in patients with NPC-1
• To evaluate the impact of treatment upon measures of neurological function including ataxia, cognitive impairment, fine motor skills and saccadic eye movements in patients with NPC-1
• To evaluate the impact of treatment upon behavioural aspects of NPC-1 disease

Secondary Outcome(s)

Secondary end point(s): Stage 1
• Change from baseline in serum cholesterol precursors (lanosterol, lathosterol, desmosterol) and cholesterol metabolites/bile acid precursors (4b-, 24S-, 25-, 27- hydroxycholesterol) (days 2, 3, 5, 8, and 15 post-dose in Stage 1)
• Change from baseline in markers of lipid trafficking in peripheral blood mononuclear cells (PBMCs) (at day 15 post-dose in Stage 1)
• CSF concentrations of HP-ß-CD at 4, 8 and 12 hours following the start of the intravenous administration. In paediatric patients the number of
samples may be reduced at the discretion of the Investigator to one post dose sample taken approximately within 1 hour after the end of the
infusion. (Stage 1)
• AEs, laboratory abnormalities, time to withdrawal due to AE (every visit)

Stage 2
• Change from baseline in serum cholesterol precursors (lanosterol, lathosterol, desmosterol) and cholesterol metabolites/bile acid precursors (4b-, 24S-, 25-, 27- hydroxycholesterol) (4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 weeks)
• Change from baseline in markers of lipid trafficking in peripheral blood mononuclear cells (PBMCs) (12, 24, 36 and 48 weeks)
• Change from baseline in NIH NPC severity scale at 12, 24, 36 and 48 weeks
• Change from baseline in individual NIH NPC scale domains at 12, 24, 36 and 48 weeks
• Change from baseline in neurologic symptoms at 12, 24, 36 and 48 weeks
- ataxia (using the Scale for the assessment and rating of ataxia [SARA] scale)
- cognitive impairment (using the Mini-Mental State Evaluation score [MMSE])
- saccadic eye movements
- fine motor skills (using the bead threading test)
• Change from baseline in hepatic, splenic and renal morphology (abdominal ultrasound) at 24 and 48 weeks
• Change from baseline in quality of life using the PedsQL (Pediatric Quality of Life Inventory) at 12, 24, 36 and 48 weeks
• AEs, laboratory abnormalities, time to withdrawal due to AE (every visit)
• Auditory acuity assessment (weeks 12, 24, 36, 48 and follow-up)

Timepoint(s) of evaluation of this end point: See Section E.5.2
In addition, interim analysis will be performed

Secondary ID(s)

CTD-TCNPC-201

2015-005761-23-GB

Source(s) of Monetary Support

Cyclo Therapeutics, Inc.

Ethics review

Status: Approved
Approval date: 19/01/2017
Contact: