Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Arimoclomol Prospective Study in Patients Diagnosed With NiemannPick Disease Type C

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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

Tracking Information
First Submitted Date  ICMJE November 12, 2015
First Posted Date  ICMJE November 23, 2015
Last Update Posted Date May 20, 2019
Actual Study Start Date  ICMJE June 14, 2016
Actual Primary Completion Date June 20, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 19, 2015)
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02612129 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 7, 2017)
  • 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]).
  • 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).
  • 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).
  • 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)
  • Change in the SARA score [ Time Frame: baseline (Visit 1) to 6 and 12 , 18, 24 and 36 months ]
    Change in the SARA score
  • 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
  • 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).
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: November 19, 2015)
  • Change in the Niemann Pick type C Clinical Database (NPC-cdb) score [ Time Frame: baseline (Visit 1) to 6 and 12 months ]
    Change in the Niemann Pick type C Clinical Database (NPC-cdb) score (modified "Stampfer Score" [Stampfer et al., 2013]).
  • Change in NPCCSS score [ Time Frame: baseline (Visit 1) to 6 months, 24 and 36 months ]
    Change in the NPC disease severity based on the NPCCSS scores (Yanjanin et al., 2010).
  • Change in NPCCSS score (individual domains) [ Time Frame: baseline (Visit 1) to 6 months, 12 months, 24 and 36 months ]
    Change in the individual domains of the NPC disease severity based on the NPCCSS scores (Yanjanin et al., 2010).
  • Change in Quality of Life (EQ5DY) [ Time Frame: baseline (Visit 1) to 6 and 12 , 24 and 36 months ]
    Change in Quality of Life (EQ5DY)
  • Change in the NPC disease progression rate [ Time Frame: baseline(visit 1) to 6 and 12 months ]
    Change in the NPC disease progression rate based on the NPCCSS scores
  • Changes in the size of the liver and spleen (assessed by ultrasound). [ Time Frame: baseline(visit 1) to 6 and 12 months ]
    Changes in the size of the liver and spleen (assessed by ultrasound).
  • Change in biomarkers [ Time Frame: baseline(visit 1) to 6 and 12 months, 24 and 36 months ]
    Analysis for biomarkers in biological material: NPC1 active protein; NPC1 protein function (cholesteryl esterification); Oxysterols; Un-esterified cholesterol and HSP70.
  • 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).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Arimoclomol Prospective Study in Patients Diagnosed With NiemannPick Disease Type C
Official Title  ICMJE Arimoclomol Prospective Doubleblind, Randomised, Placebo-controlled Study in Patients Diagnosed With NiemannPick Disease Type C
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.

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)]

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Niemann-Pick Disease, Type C
Intervention  ICMJE
  • Drug: arimoclomol
  • Drug: Placebo
Study Arms  ICMJE
  • Active Comparator: arimoclomol
    arimoclomol capsules for oral administration (3 times daily). Doses:150-600 mg/day (based on weight)
    Intervention: Drug: arimoclomol
  • Placebo Comparator: Placebo
    Matching placebo capsules
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 7, 2017)
50
Original Estimated Enrollment  ICMJE
 (submitted: November 19, 2015)
46
Estimated Study Completion Date  ICMJE October 2020
Actual Primary Completion Date June 20, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Denmark,   France,   Germany,   Italy,   Poland,   Spain,   Switzerland,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02612129
Other Study ID Numbers  ICMJE CT-ORZY-NPC-002
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Orphazyme
Study Sponsor  ICMJE Orphazyme
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Karl-Eugen Mengel Villa Metabolica, Mainz, Germany
PRS Account Orphazyme
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP