E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Niemann-Pick disease type C |
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E.1.1.1 | Medical condition in easily understood language |
A rare, genetically inherited and neurologically progressive disease in which fatty substances accumulate in the brain and other major organs |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029403 |
E.1.2 | Term | Niemann-Pick disease |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Stage 1 • To compare the plasma pharmacokinetics of hydroxypropyl-β-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
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E.2.2 | Secondary objectives of the trial |
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-β-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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Stage 1 • Plasma concentrations of HP-β-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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
See Section E.5.1 In addition, interim analysis will be performed |
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E.5.2 | 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-β-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) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
See Section E.5.2 In addition, interim analysis will be performed |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Trappsol Cyclo has previously been administered in a compassionate use/named patient programme. |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Pharmacist is unblinded to dose. |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |