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Arimoclomol Prospective Study in Patients Diagnosed With NiemannPick Disease Type C

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ClinicalTrials.gov Identifier: NCT02612129
Recruitment Status : Active, not recruiting
First Posted : November 23, 2015
Last Update Posted : May 20, 2019
Sponsor:
Information provided by (Responsible Party):
Orphazyme

Brief Summary:

A prospective, randomised, double-blind, placebo controlled therapeutic study in patients with confirmed diagnosis of NiemannPick disease type C (NPC).

The purpose of this study is to assess the efficacy and safety of arimoclomol (compared to placebo) when it is administered as an add-on therapy to the patient's current prescribed best standard of care; patient's standard of care may, or may not, include miglustat.

The CT-ORZY-NPC-002 study has been expanded to include an open label paediatric sub-study including patients aged 6 to <24 months at study enrolment.


Condition or disease Intervention/treatment Phase
Niemann-Pick Disease, Type C Drug: arimoclomol Drug: Placebo Phase 2 Phase 3

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Detailed Description:

A prospective, randomised, double-blind, placebo controlled therapeutic study in patients with confirmed diagnosis of NiemannPick disease type C (NPC).

Patients must either 1) have completed Visit 2 (end of study [EOS]) of the CTORZYNPC001 study or 2) meet the eligibility criteria of this study including a requirement of stable treatment with miglustat for 6 months (if on miglustat therapy) prior to enrolment into the study.

Aim:

The purpose of this study is to assess the efficacy and safety of arimoclomol (compared to placebo) when it is administered as an add-on therapy to the patient's current prescribed best standard of care; patient's standard of care may, or may not, include miglustat.

Randomisation:

Patients will be randomised to receive placebo or arimoclomol (with an allocation ratio of 1:2).

Pharmacokinetic evaluation(age below 12):

To confirm the selected dose, patients less than 12 years of age will undergo an arimoclomol single-dose pharmacokinetic (PK) evaluation before randomisation and the start of continuous (multiple dosing) treatment.

Early Escape Clause:

In patients whose disease progression is too severe and/or too fast, the "early escape clause" will allow the Investigator to apply the escape route which implies that the patient can be treated with arimoclomol (as per blinded phase study schedule) and be followed up on an annual basis until arimoclomol has received EU MA or until the analysis of data from the controlled, 12 month blinded phase study period does not support the efficacy and/or safety of arimoclomol.

Study duration:

The duration of the blinded phase study period will be 12 months.

Following this, all patients will be offered to continue into the extension phase of the study where every patient will receive arimoclomol and be followed up and attend site visits at 18 months and 24 months (after randomisation) and then on an annual basis thereafter.The extension phase runs until arimoclomol has received Regulatory Approval or until the analysis of data from the controlled, blinded phase 12 month study period does not support the efficacy and/or safety of arimoclomol.

The CT-ORZY-NPC-002 protocol has been updated to include a paediatric sub-study including new and naïve patients aged 6 to <24 months at study enrolment.

Aim:

The purpose of the paediatric sub-study, is to assess the safety and tolerability of 36 months of open-label arimoclomol when administered as an add-on therapy to the patient's current prescribed best standard of care; patient's standard of care may, or may not, include miglustat.

The Paediatric sub-study will run at the open sites participating in the main study. A total of 2-5 patients are planned to be enrolled. All patients will be treated with arimoclomol.

Inclusion criteria:

  • Diagnosis of NPC1 or NPC2;
  • NPC 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).
  • Males and females aged 6 to <24 months
  • If a patient is on prescribed treatment with miglustat, the dose must have been stable for at least 1 month prior to inclusion in the paediatric sub-study
  • If a patient has been discontinued from prescribed treatment with miglustat, they must have been discontinued for at least 1 month prior to inclusion in the paediatric sub-study
  • The Legal Authorised Representative (LAR) has read and signed the Informed Consent Form (ICF) prior to any study-related procedures
  • The LAR agrees for the patient to participate in all aspects of the trial design

Exclusion Criteria:

  • Recipient of a liver transplant or a planned liver transplant
  • The Aspartate Transaminase (AST) and/or Alanine Transaminase (ALT) >3 x Upper Limit of Normal (ULN) for age and gender
  • Renal insufficiency with serum creatinine level >1.5 x ULN
  • Patients with known causes of active liver disease or prolonged icterus or malformation of organs other than NPC
  • Patient was born before 37 weeks gestation
  • Patient weight <5 kg at study enrollment
  • Patient is diagnosed with severe intra-uterine growth restriction
  • Patient has severe neurological symptoms
  • Patient has received or plans to receive a bone marrow transplant

Arms and Intervention:

1 arm open label treatment with arimoclomol capsules 100 mg (dispersed in water) for oral administration (3 times daily). Doses: The dose in mL is based on the patient's weight in kg.

Randomization:

Open Label

Pharmacokinetic:

To confirm the selected dose, patients will undergo an arimoclomol single-dose pharmacokinetic (PK) evaluation before the start of continuous treatment.

Outcome measures:

Primary/Safety Outcome Measures

Collection of safety data:

  • Adverse events (AEs)
  • Vital signs

[Time Frame: Screening (V1), to week 1(V2 baseline), weeks 2, 4, 12, 24, 36, 48, 72, 96, 120 and 144 after baseline]

  • Haematology
  • Clinical chemistry

[Time Frame: Screening (V1), to weeks 2, 4, 12, 24, 36, 48, 72, 96, 120 and 144 after baseline - V2]

Secondary Outcome Measures

  • Clinical signs and symptoms captured through physical examination,
  • Change from baseline in patient weight measured in kg

[Time Frame: Screening (Visit 1) to Baseline V2- 1 week after V1, 1, 3, 6, 9, 12, 15, 18, 24, 30 and 36 months after baseline]

• Change from baseline in patient height measured in meter

[Time Frame: Screening (Visit 1) to Baseline V2- 1 week after V1, 3, 6, 12 , 18, 24, 30 and 36 months after baseline]

  • Change in Developmental delay scoring, using the Bayley III score
  • Changes from baseline in the size of the liver and spleen assed by ultrasound

[Time Frame: Baseline, months 6,12, and 18 (Visit 2, 6, 8, 9)]


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Arimoclomol Prospective Doubleblind, Randomised, Placebo-controlled Study in Patients Diagnosed With NiemannPick Disease Type C
Actual Study Start Date : June 14, 2016
Actual Primary Completion Date : June 20, 2018
Estimated Study Completion Date : October 2020


Arm Intervention/treatment
Active Comparator: arimoclomol
arimoclomol capsules for oral administration (3 times daily). Doses:150-600 mg/day (based on weight)
Drug: arimoclomol
Placebo Comparator: Placebo
Matching placebo capsules
Drug: Placebo



Primary Outcome Measures :
  1. Change in NPC disease severity score [ Time Frame: baseline (Visit 1) to 12 months ]
    Change in the NPC disease severity based on the NPCCSS scores (Yanjanin et al., 2010).


Secondary Outcome Measures :
  1. Change in the Niemann Pick type C Clinical Database (NPC-cdb) score [ Time Frame: baseline (Visit 1) to 6 months, 12, 18, 24 and 36 months ]
    Change in the Niemann Pick type C Clinical Database (NPC-cdb) score (modified "Stampfer Score" [Stampfer et al., 2013]).

  2. Change in NPCCSS score [ Time Frame: baseline (Visit 1) to 6 months, 18, 24 and 36 months ]
    Change in the NPC disease severity based on the NPCCSS scores (Yanjanin et al., 2010).

  3. Change in NPCCSS score (individual domains) [ Time Frame: baseline (Visit 1) to 6 months, 12, 18, 24 and 36 months ]
    Change in the individual domains of the NPC disease severity based on the NPCCSS scores (Yanjanin et al., 2010).

  4. Change in Quality of Life (EQ5DY) [ Time Frame: baseline (Visit 1) to 6 and 12 , 18, 24 and 36 months ]
    Change in Quality of Life (EQ5DY)

  5. Change in the SARA score [ Time Frame: baseline (Visit 1) to 6 and 12 , 18, 24 and 36 months ]
    Change in the SARA score

  6. Change in the 9HPT (9 Hole Peg Test) [ Time Frame: baseline (Visit 1) to 6 and 12 , 18, 24 and 36 months ]
    Change in the 9HPT

  7. Adverse events (AEs); [ Time Frame: Baseline (Visit 1) - 36 months ]
    Collection of safety data: Adverse events (AEs); Haematology; Clinical chemistry; Physical examination; Vital signs; Electrocardiogram (ECG).

  8. Change in CGI-S and CGI-I Score (Clinical Global Impression-Severity/Improvement) [ Time Frame: Baseline (Visit 1) - to 6 and 12 , 18, 24 and 36 months ]
    Change in CGI-S and CGI-I Score



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   2 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

EITHER NP-C patients who have entered the CTORZYNPC001 study and who have completed Visit 2 (EOS) of the CTORZYNPC001 study.

OR

NPC patients who did not enter or complete the CTORZYNPC001 study but are fulfilling all of criteria listed below:

◦Diagnosis of NPC1 or NPC2;

NPC 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).

    • Males and females aged from 2 years to 18 years and 11 months;
    • Treated or not treated with miglustat;
    • If 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 CTORZYNPC002 study;

      o If 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;

    • Body mass index (BMI) Z score ≥ -2 SD (standard deviation) for age, according to the World Health Organisation (WHO) standards;
    • 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.

      • 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.

Exclusion Criteria:

  • 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 CTORZYNPC001 study, fulfilling any of the criteria listed below:

    • 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 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;
    • Neurologically asymptomatic patients;
    • Severe manifestations of NP-C disease that would interfere with the patient's ability to comply with the requirements of this protocol;
    • Treatment with any IMP within 4 weeks prior to the study enrolment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02612129


Locations
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United States, California
UCSF Benioff Children's Hospital Oakland
Oakland, California, United States, 94609
United States, Minnesota
Mayo Clinic Children's Center
Rochester, Minnesota, United States, 55905
Denmark
University Hospital Copenhagen (Rigshospitalet)
Copenhagen, Denmark, 2100
France
CHU de Montpellier
Montpellier, France, 34295 Montpellier Cedex 5
Hôpital Trousseau
Paris, France, 75571 PARIS Cedex 12
Germany
Villa Metabolica Mainz
Mainz, Germany, 55131
Dr. von Haunersches Kinderspital der Universität München
Munich, Germany, 80337
Italy
Ospedale Pediatrico Bambino Gesù
Rome, Italy, 00165
Azienda Ospedaliero-Universitaria "Santa Maria della Misericordia" di Udin
Udine, Italy, 33100
Poland
The Children´s Memorial Istitute Warsaw
Warsaw, Poland, 04-730
Spain
Hospital Vall D'Hebron
Barcelona, Spain, 08035
Switzerland
INSELSPITAL University Hospital Bern
Bern, Switzerland, CH-3010
United Kingdom
Birmingham Children's Hospital
Birmingham, United Kingdom, B4 6NH
Great Ormond Street Hospital
London, United Kingdom, WC1N 3JH
Sponsors and Collaborators
Orphazyme
Investigators
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Principal Investigator: Karl-Eugen Mengel Villa Metabolica, Mainz, Germany

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Responsible Party: Orphazyme
ClinicalTrials.gov Identifier: NCT02612129     History of Changes
Other Study ID Numbers: CT-ORZY-NPC-002
First Posted: November 23, 2015    Key Record Dates
Last Update Posted: May 20, 2019
Last Verified: May 2019
Keywords provided by Orphazyme:
NPC1
Niemann-Pick Type C
Niemann-Pick
arimoclomol
lysosomal storage disorder
lysosomal storage disease
NPC2
NP-C
Additional relevant MeSH terms:
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Pick Disease of the Brain
Niemann-Pick Diseases
Niemann-Pick Disease, Type A
Niemann-Pick Disease, Type C
Frontotemporal Dementia
Frontotemporal Lobar Degeneration
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Metabolic Diseases
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Histiocytosis, Non-Langerhans-Cell
Histiocytosis
Lymphatic Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Lipid Metabolism Disorders