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 |
Niemann-Pick Type C is a rare and inherited disease in which quantities of fatty substances accumulate in the brain and other organs. The brain, central nervous system, liver and spleen are affected |
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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 | 18.0 |
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 |
To characterize the individual patient disease progression profile (disease burden and progression) through the clinical, imaging, biological status, and quality of life prospectively recorded, together with the historic disease information collected from patient medical records. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety data of the disease-related therapy and
to record every adverse event (AE) linked to the disease. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Written informed consent (and assent if appropriate to local laws and regulations) prior to any study-related procedures
• Willing to participate in all aspects of trial design including serial blood sampling, skin biopsies and imaging (ultrasonography and magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS) collections
• Males and females aged from 2 years to 18 years and 11 months
• Patients of any ethnic background will be eligible for this study
• Diagnosis of Niemann-Pick disease type C (NP-C), NPC1/NPC2
• NP-C diagnosis genetically confirmed (deoxyribonucleic acid [DNA] sequence analysis);
• Presenting at least one neurological symptom of the disease (for example, but not limited to, hearing loss, vertical supranuclear gaze palsy, ataxia, dementia, dystonia, seizures dysarthria, or dysphagia)
• Treated or non-treated with miglustat; if the patient is under prescribed treatment with miglustat, it has to be under stable dose of the medication for ≥ 3 continuous months prior to inclusion in this study
• Patient weight ≥ 15th percentile of body mass index (BMI) for age according to the World Health Organisation (WHO) standards
• Ability to walk either independently or with assistance.
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E.4 | Principal exclusion criteria |
• No written informed consent obtained from the patient or their parent(s)/legal guardian(s) (and assent if appropriate to local laws and regulation) before any study related procedures
• Recipient of a liver transplant or planned liver transplantation
• Patients with uncontrolled severe epileptic seizures period (at least 3 consecutive severe epileptic seizures that required medication) within 2 months prior to the written consent. This includes patients with ongoing seizures that are not stable in frequency or type or duration over a 2 month period prior to enrollment, requiring change in dose of antiepileptic medication (other than adjustment for weight) over a 2 month period prior to enrollment, or requiring 3 or more antiepileptic medications to control seizures
• Neurologically asymptomatic patients
• Severe liver insufficiency (defined as hepatic laboratory parameters, aspartate transaminase [AST] and alanine transaminase [ALT] greater than three-times the upper limit of normal for age and gender
• Severe renal insufficiency, with serum creatinine level greater than 1.5 times the upper limit of normal
• Severe manifestations of NP-C disease that would interfere with the patient’s ability to comply with the requirements of this protocol
• In the opinion of the Investigator, the patient's clinical condition does not allow for the required blood collection and/or skin biopsies as per the protocol-specified procedures
• Treatment with any IMP within 4 weeks prior to the study enrolment, or during the study
• Current participation in another trial is not permitted unless it is a non-interventional study and the sole purpose of the trial is for long-term follow up/survival data (registry)
• Patients will be excluded if there is a confirmed risk linked to the MRI procedure [i.e.: implanted cardiac pacemaker or implantable cardioverter defibrillator, implanted neural pacemakers, cochlear implants, implanted metallic foreign bodies in the eye or CNS (such as a CNS aneurysmal clip), any form of implanted wire or metal device that may concentrate radio frequency fields and/or confirmed history of unexpected serious adverse reaction to sedation or anesthesia (if sedation is necessary)]
• Patients will be excluded if there is a confirmed risk linked to the skin punch biopsy procedure like severe thrombocytopaenia, at investigator’s discretion. |
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E.5 End points |
E.5.1 | Primary end point(s) |
STUDY ENDPOINTS
1. Clinical Status Endpoints
• NP-C clinical status scores [NP-C Clinical Severity Scale and NP-C “Stampfer” Score] to document the clinical progression of NP-C.
• Quality of life questionnaire applied to the patients (and/or the patients’ parent[s]/legal guardian[s])
2. Imaging Endpoints
• Changes in the central nervous system (CNS) structure and function (assessed by magnetic resonance imaging [MRI] and magnetic resonance spectroscopy [MRS])
• Changes in the size and/or characteristics of the liver and spleen (assessed by ultrasound)
3. Biomarker Endpoints
As there are no validated biomarkers in NP-C to evaluate disease progression burden and potential therapeutic response, the biomarkers (as listed in Table 14-1 of the protocol) will be explorative to confirm clinical observations and characterise the individual patient clinical status at every assessment time point. Absolute values in the listed biomarkers will be recorded and analysed.
4. Safety Endpoints
• Incidence of AEs (disease related and treatment related)
• Safety laboratory parameters, including haematology and clinical chemistry
• Changes in physical examination
• Changes in vital signs
• Clinical relevant changes in electrocardiograms (ECGs) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
All selected biological markers, clinical data and imaging will be evaluated at inclusion and after 26 weeks (± 2weeks) in order to define the biological/clinical status and progression pattern of the disease in each patient. |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Evaluate disease burden and progression profile |
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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 |
prospective-retrospective non-therapeutic interventional study |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
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 | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
prospective-retrospective non-therapeutic |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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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 | |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 11 |