A Prospective Non-therapeutic Study in Patients Diagnosed With Niemann-Pick Disease Type C

Primary outcomes

• NP-C clinical disease severity [at week 0 and week 24-28]: Change in NP-C Clinical Severity scale
• Quality of life questionnaire (EQ-5D-Y) [at week 0 and week 24-28]: Change in the Quality of life
• Ultrasonographic evaluation of liver and spleen [at week 0 and week 24-28]: Changes in the size and/or characteristics of the liver and spleen (assessed by ultrasound).
• Oxysterol [at week 0 and week 24-28]: Change in Oxysterol concentrations
• NPC clinical symptoms [at week 0 and week 24-28]: Change in NPC clinical symptoms
• NPC protein [at week 0 and week 24-28]: Change in NPC protein concentrations

Secondary outcomes

• Safety Parameters [at week 0 and week 24-28]: Adverse events (AEs) (disease related and treatment related), haematology, clinical chemistry, physical examination, vital signs and electrocardiogram (ECG).

Sex: All, ages: 2 Years to 18 Years

Inclusion Criteria:

* Written informed consent (and assent if appropriate to local laws and regulations) prior to any study-related procedures;
* Males and females aged from 2 years to 18 years and 11 months;
* Patients of any ethnic background will be eligible for this study;
* Patient weight ≥15th percentile of body mass index (BMI) for age according to the World Health Organisation (WHO) standards;
* Diagnosis of Niemann Pick disease Type C (NP-C), either NPC1 or NPC2;
* NP-C diagnosis genetically confirmed (deoxyribonucleic acid \[DNA\] sequence analysis);
* Both NPC1 and NPC2 patients are eligible;
* 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);
* Ability to walk either independently or with assistance;
* Ability to travel to the corresponding clinical trial site repeatedly (every 6 months) for evaluation and follow-up;
* Treated or non-treated with miglustat;
* If a 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 the study;
* Sexually active patients must be willing and able to use an adequate method of contraception throughout the study, for example: diaphragm + spermicide; intrauterine contraceptive device; oral contraceptives; implant; injection of a progestogen medication;
* Ability to comply with the protocol-specified procedures/evaluations and scheduled visits;
* Willing to participate in all aspects of trial design including serial blood sampling, skin biopsies and imaging (ultrasonography) collections.

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 enrollment;
* Treatment with any IMP during the study in an attempt to treat NP-C;
* 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 to be performed in the subsequent therapeutic interventional study \[i.e.: implanted cardiac pacemaker or implantable cardioverter defibrillator, implanted neural pacemakers, cochlear implants, implanted metallic foreign bodies in the eye or CNS (such as a CNS aneurysmal clip), any form of implanted wire or metal device that may concentrate radio frequency fields and/or confirmed history of unexpected serious adverse reaction to sedation or anesthesia (if sedation is necessary)\];
* Patients will be excluded if there is a confirmed risk linked to the skin punch biopsy procedure like severe thrombocytopaenia, at investigator's discretion.

• Results publication: Mengel E, Bembi B, Del Toro M, Deodato F, Gautschi M, Grunewald S, Gronborg S, Heron B, Maier EM, Roubertie A, Santra S, Tylki-Szymanska A, Day S, Symonds T, Hudgens S, Patterson MC, Guldberg C, Ingemann L, Petersen NHT, Kirkegaard T, I Dali C. Clinical disease progression and biomarkers in Niemann-Pick disease type C: a prospective cohort study. Orphanet J Rare Dis. 2020 Nov 23;15(1):328. doi: 10.1186/s13023-020-01616-0. PMID 33228797

• Karl-Eugen Mengel, Principal investigator, Villa Metabolica, Mainz, Germany

NIH grants: 2014