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 | 19.0 |
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 evaluate therapeutic response to arimoclomol versus placebo, both in addition best available standard of care, at 12 months. |
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E.2.2 | Secondary objectives of the trial |
•To evaluate the therapeutic response to arimoclomol through clinical, biological and imaging assessments at 6 and 12 months;
•To evaluate the long term therapeutic response (clinical and biological assessments) at 18 and 24 months and hereafter annually until study end;
•To evaluate the safety of arimoclomol.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In order to be eligible for inclusion into this study, each patient must fulfil all of the following inclusion criteria at enrolment of the study.
•EITHER
NPC patients who have entered the CT ORZY NPC 001 study when aged from 2 years to 18 years and 11 months; and who have completed Visit 2 (EOS) of the CT ORZY NPC 001 study.
OR
NPC patients who did not enter or complete the CT ORZY NPC 001 study but are fulfilling all of criteria listed below:
oDiagnosis of NPC1 or NPC2;
oNPC diagnosis confirmed by:
-Genetically confirmed (deoxyribonucleic acid [DNA] sequence analysis) by mutations in both alleles of NPC1 or NPC2,
OR
-Mutation in only one allele of NPC1 or NPC2 plus either positive filipin staining or elevated cholestane triol/oxysterols (>2 x upper limit of normal).
oMales and females aged from 2 years to 18 years and 11 months;
oTreated or not treated with miglustat;
oIf a patient is under prescribed treatment with miglustat, it has to be under stable dose of the medication for at least 6 continuous months prior to inclusion in the CT ORZY NPC 002 study;
oIf a patient has been discontinued from prescribed treatment with miglustat, they must have been discontinued for at least 3 continuous months prior to inclusion in the CT-ORZY-NPC-002 study;
oBody mass index (BMI) Z score ≥ -2 SD (standard deviation) for age, according to the World Health Organisation (WHO) standards;
oPresenting 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);
oAbility to walk either independently or with assistance.
•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 blood sampling (PK, blood biomarkers and safety labs), skin biopsies and imaging (ultrasonography of the liver and spleen);
•Ability to travel to the corresponding clinical trial site at the scheduled visit times for evaluation and follow-up;
•All sexually active female patients of child-bearing potential (post-menarchal) must use highly effective contraception during the study and until 1 week after the last dose of IMP.
Highly effective birth control methods include: Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable); intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; and vasectomised partner.
All sexually active male patients with female partners of child-bearing potential (post-menarchal) must use a condom with or without spermicide in addition to the birth control used by their partners during the study and until 3 months after the last dose of IMP.
Sexual abstinence is considered a highly effective birth control method only if it is defined as refraining from heterosexual intercourse during the study and for 1 week after the last dose of IMP (for female patients of child-bearing potential) and for 3 months after the last dose of IMP (for male patients with female partners of child-bearing potential). The reliability of sexual abstinence needs to be evaluated by the Investigator in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.
•Ability to comply with the protocol-specified procedures/evaluations and scheduled visits.
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E.4 | Principal exclusion criteria |
Each of the following criteria will be taken as reason for exclusion from participation in the trial:
•Recipient of a liver transplant or planned liver transplantation;
•Severe liver insufficiency (defined as hepatic laboratory parameters, AST and/or ALT greater than three-times the upper limit of normal for age and gender (central laboratory assessment);
•Renal insufficiency, with serum creatinine level greater than 1.5 times the upper limit of normal (central laboratory assessment);
•Known or suspected allergy or intolerance to the IMP (arimoclomol or constituents);
•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 investigational drug during the study or in the 4 weeks prior to entering the study.
This includes treatment with any investigational drug during the study in an attempt to treat NP-C;
•Pregnancy or breastfeeding;
•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);
•For patients who have not completed the CT ORZY NPC 001 study, fulfilling any of the criteria listed below:
oPatients 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 enrolment, requiring change in dose of antiepileptic medication (other than adjustment for weight) over a 2 month period prior to enrolment, or requiring 3 or more antiepileptic medications to control seizures;
oNeurologically asymptomatic patients;
oSevere manifestations of NP-C disease that would interfere with the patient’s ability to comply with the requirements of this protocol;
oTreatment with any IMP within 4 weeks prior to the study enrolment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
•Change in the NPC disease severity based on the NPCCSS scores (Yanjanin et al., 2010) from baseline (Visit 1) to 12 months. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
•Change in NPCCSS at 6 months (placebo versus arimoclomol), 18 and 24 months and annually thereafter;
•Changes in each individual domain of the NPCCSS (Yanjanin et al., 2010) at 6 and 12 months (placebo versus arimoclomol), 18 and 24 months and annually thereafter;
•Change in the Niemann Pick type C Clinical Database (NPC-cdb) score (modified "Stampfer Score" [Stampfer et al., 2013]) at 6 and 12 months placebo versus arimoclomol), 18 and 24 months and annually thereafter;
•Change in Quality of Life (EQ 5D Y) at 6 and 12 months (placebo versus arimoclomol), 18 and 24 months and annually thereafter;
•Change in the SARA score at 6 and 12 months (placebo versus arimoclomol), 18 and 24 months and annually thereafter;
•Change in the 9HPT time at 6 and 12 months (placebo versus arimoclomol), 18 and 24 months and annually thereafter.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints will be at 6 months, 12 months, 18 Months and 24 months
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 15 |
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 |
Denmark |
France |
Germany |
Italy |
Poland |
Spain |
Switzerland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 36 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 36 |
E.8.9.2 | In all countries concerned by the trial days | 0 |