Arimoclomol Prospective Study in Patients Diagnosed With NiemannPick Disease Type C

• ClinicalTrials.gov Identifier: NCT02612129
• Recruitment Status: Active, not recruiting
• First Posted: November 23, 2015
• Last Update Posted: April 19, 2021
• Sponsor: ZevraDenmark
• Information provided by (Responsible Party): ZevraDenmark

Study Description

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

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 3-5 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, with a cap of maximum 3 patients above 18 months

• Treated or not treated with miglustat;

  • 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]

   o Haematology

   o 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 Design

• 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 25, 2018
• Estimated Study Completion Date: May 8, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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

Outcome Measures

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 and 18 months and every 6 months thereafter until End of Extension Phase at 60 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 and 18 months and every 6 months thereafter until End of Extension Phase at 60 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 and 18 months and every 6 months thereafter until End of Extension Phase at 60 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 18 months and every 6 months thereafter until End of Extension Phase at 60 months ]
   Change in Quality of Life (EQ5DY)
5. Change in the SARA score [ Time Frame: Baseline (Visit 1) - to 6 and 18 months and every 6 months thereafter until End of Extension Phase at 60 months ]
   Change in the SARA score
6. Change in the 9HPT (9 Hole Peg Test) [ Time Frame: Baseline (Visit 1) - to 6 and 18 months and every 6 months thereafter until End of Extension Phase at 60 months ]
   Change in the 9HPT
7. Adverse events (AEs); [ Time Frame: Baseline (Visit 1) - 60 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 18 months and every 6 months thereafter until End of Extension Phase at 60 months ]
   Change in CGI-S and CGI-I Score

Eligibility Criteria

• 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.

Contacts and Locations

Locations

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, Universitätsmedizin 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

ZevraDenmark

Investigators

• Principal Investigator: Karl-Eugen Mengel; SphinCS GmbH, Hochheim, Germany

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Mengel E, Patterson MC, Da Riol RM, Del Toro M, Deodato F, Gautschi M, Grunewald S, Gronborg S, Harmatz P, Heron B, Maier EM, Roubertie A, Santra S, Tylki-Szymanska A, Day S, Andreasen AK, Geist MA, Havnsoe Torp Petersen N, Ingemann L, Hansen T, Blaettler T, Kirkegaard T, I Dali C. Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a double-blind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment. J Inherit Metab Dis. 2021 Nov;44(6):1463-1480. doi: 10.1002/jimd.12428. Epub 2021 Sep 7.

Patterson MC, Lloyd-Price L, Guldberg C, Doll H, Burbridge C, Chladek M, iDali C, Mengel E, Symonds T. Validation of the 5-domain Niemann-Pick type C Clinical Severity Scale. Orphanet J Rare Dis. 2021 Feb 12;16(1):79. doi: 10.1186/s13023-021-01719-2.

• Responsible Party: ZevraDenmark
• ClinicalTrials.gov Identifier: NCT02612129
• Other Study ID Numbers: CT-ORZY-NPC-002
• First Posted: November 23, 2015
• Last Update Posted: April 19, 2021
• Last Verified: April 2021

Keywords provided by ZevraDenmark:

NPC1; Niemann-Pick Type C; Niemann-Pick; arimoclomol; lysosomal storage disorder; lysosomal storage disease; NPC2; NP-C

Additional relevant MeSH terms:

Pick Disease of the Brain; Niemann-Pick Diseases; Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type C; Disease; Pathologic Processes; 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