Arimoclomol Prospective Study in Participants Diagnosed With Niemann-Pick Disease Type C

NCT02612129 | Completed Phase 2 Results DMC

• 1 other identifier: CT-ORZY-NPC-002
• Study Type: interventional
• Target: 50
• Locations: 9 countries
• Sites: 14

Brief Summary

A prospective, randomized, double-blind, placebo controlled therapeutic study in participants with confirmed diagnosis of Niemann-Pick 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 participant's current prescribed best routine clinical care; participant's routine clinical 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 participants aged 6 to \<24 months at study enrolment.

Conditions

Niemann-Pick Disease, Type C

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in the Niemann-Pick Disease Type C (NPC) Disease Severity Assessed Based on the 5-domain NPCCSS Total Scores

  NPC disease severity was assessed based on the 5-domain NPC Clinical Severity Scale (NPCCSS). The 5-domain NPCCSS focuses on domains identified by participants, caregivers, and NPC experts as the most clinically relevant when assessing disease progression in NPC: Ambulation, fine motor skills, swallow, cognition, and speech. The scale is derived from the original 17-domain NPCCSS. Each domain is rated on a scale of 0-5 based on clinical assessments, observations, and interviews with participants/caregiver. The total score is a sum of the score of each of the 5 domains and ranges from 0-25, with a higher score indicating more severe clinical impairment.

  Baseline to Month 12

Secondary Outcomes (13)

• Percentage of Responders in Clinical Global Impression Scale of Improvement (CGI-I) - Defined as Percentage of Participants Where the CGI-I Score Remains Stable or Shows Improvement (This Outcome Measure Was Considered Co-primary by the FDA)

  Month 12

• Percentage of Responders in 5-domain NPCCSS - Defined as Participants Where the 5-domain NPCCSS Score Remains Stable or Improves as Compared to Baseline

  Baseline to Month 12

• Time to Worsening

  Baseline to Month 12

• Percentage of Participants With Worsening

  Months 6 and 12

• Change From Baseline in 17-domain NPCCSS Apart From Hearing Domains (i.e. Hearing and Auditory Brainstem Response)

  Baseline to 6 and 12 months

Study Arms (3)

Arimoclomol Single PK Dose

EXPERIMENTAL

Participants less than 12 years received a single oral dose of arimoclomol capsule, based on participant's body weight, on Day 1.

Drug: arimoclomol

Arimoclomol (12-month Double-blind Phase)

EXPERIMENTAL

Participants received arimoclomol capsules orally three times a day (TID) for 12 months. The dose was 31-124 mg arimoclomol base TID (equivalent to 50-200 mg arimoclomol citrate TID), based on participant's body weight.

Drug: arimoclomol

Placebo (12-month Double-blind Phase)

PLACEBO COMPARATOR

Participants received matching placebo capsules (with regard to weight, appearance, smell, flavor etc.) orally TID for 12 months.

Drug: Placebo

Interventions

arimoclomol DRUG

Arimoclomol (12-month Double-blind Phase); Arimoclomol Single PK Dose

Placebo DRUG

Placebo (12-month Double-blind Phase)

Eligibility Criteria

• Age: 2 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• EITHER NP-C participants who have entered the CT-ORZY-NPC-001 study and who have completed Visit 2 (EOS) of the CT-ORZY-NPC-001 study.
• NPC participants who did not enter or complete the CT-ORZY-NPC-001 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;
• 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 participants of child-bearing potential (post-menarchal) must use highly effective contraception during the study and until 1 week after the last dose of IMP.

You may not qualify if:

• 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 participant'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 participants who have not completed the CT-ORZY-NPC-001 study, fulfilling any of the criteria listed below:
• Participants 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 participants 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 participants;
• Severe manifestations of NP-C disease that would interfere with the participant's ability to comply with the requirements of this protocol;
• Treatment with any IMP within 4 weeks prior to the study enrolment.

Sponsors & Collaborators

• ZevraDenmark: lead

Study Sites (14)

UCSF Benioff Children's Hospital Oakland

Oakland, California, 94609, United States

Location

Mayo Clinic Children's Center

Rochester, Minnesota, 55905, United States

Location

University Hospital Copenhagen (Rigshospitalet)

Copenhagen, 2100, Denmark

Location

CHU de Montpellier

Montpellier, 34295 Montpellier Cedex 5, France

Location

Hôpital Trousseau

Paris, 75571 PARIS Cedex 12, France

Location

Villa Metabolica, Universitätsmedizin Mainz

Mainz, 55131, Germany

Location

Dr. von Haunersches Kinderspital der Universität München

Munich, 80337, Germany

Location

Ospedale Pediatrico Bambino Gesù

Rome, 00165, Italy

Location

Azienda Ospedaliero-Universitaria "Santa Maria della Misericordia" di Udin

Udine, 33100, Italy

Location

The Children´s Memorial Istitute Warsaw

Warsaw, 04-730, Poland

Location

Hospital Vall D'Hebron

Barcelona, 08035, Spain

Location

INSELSPITAL University Hospital Bern

Bern, CH-3010, Switzerland

Location

Birmingham Children's Hospital

Birmingham, B4 6NH, United Kingdom

Location

Great Ormond Street Hospital

London, WC1N 3JH, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 33579322 BACKGROUND

• 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.

  PMID: 34418116 RESULT

MeSH Terms

Conditions

Niemann-Pick Disease, Type C; Lysosomal Storage Diseases

Interventions

arimoclomol

Condition Hierarchy (Ancestors)

Niemann-Pick Diseases; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Results Point of Contact

• Title: Medical Affairs
• Organization: Zevra Denmark A/S

medicalaffairs@zevra.com

+1-888-289-5607

Study Officials

• Karl-Eugen Mengel

  SphinCS GmbH, Hochheim, Germany

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: November 12, 2015
• First Posted: November 23, 2015
• Study Start: June 14, 2016
• Primary Completion: June 25, 2018
• Study Completion: October 31, 2024
• Last Updated: November 29, 2024
• Results First Posted: June 9, 2023

Record last verified: 2024-11

Locations

IT (2); DE (2); CH (1); DK (1); GB (2); FR (2); PL (1); US (2); ES (1)