Niemann-Pick Disease, Type CPhase 2/3NCT02612129
Arimoclomol Prospective Study in Participants Diagnosed With Niemann-Pick Disease Type C
A Phase 2/3 study testing arimoclomol in people with Niemann-Pick Disease, Type C, run by ZevraDenmark at 14 sites in 9 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 2 to 18 years
- Conditions the study is for
- Niemann-Pick Disease, Type C
- What is being tested?
- arimoclomol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 50 participants
- Where
- 14 sitesin 9 countries
- Study dates
- 14 Jun 2016to 31 Oct 2024
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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.
- OR
- 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
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- 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 participant 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;
- o If a participant 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 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.
- 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 participants 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 participants of child-bearing potential) and for 3 months after the last dose of IMP (for male participants 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 participant.
- •Ability to comply with the protocol-specified procedures/evaluations and scheduled visits.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
14 sites in 9 countries.
14 sites in 9 countries
United States2 sites
UCSF Benioff Children's Hospital Oakland
Oakland, California, 94609
Mayo Clinic Children's Center
Rochester, Minnesota, 55905
France2 sites
CHU de Montpellier
Montpellier, 34295 Montpellier Cedex 5
Hôpital Trousseau
Paris, 75571 PARIS Cedex 12
Germany2 sites
Villa Metabolica, Universitätsmedizin Mainz
Mainz, 55131
Dr. von Haunersches Kinderspital der Universität München
Munich, 80337
Italy2 sites
Ospedale Pediatrico Bambino Gesù
Rome, 00165
Azienda Ospedaliero-Universitaria "Santa Maria della Misericordia" di Udin
Udine, 33100
United Kingdom2 sites
Birmingham Children's Hospital
Birmingham, B4 6NH
Great Ormond Street Hospital
London, WC1N 3JH
Denmark1 site
University Hospital Copenhagen (Rigshospitalet)
Copenhagen, 2100
About this study
Official title: Arimoclomol Prospective Double-blind, Randomised, Placebo-controlled Study in Patients Diagnosed With Niemann-Pick Disease Type C
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.
Read the detailed description
A prospective, randomized, double-blind, placebo controlled therapeutic study in participants with confirmed diagnosis of Niemann-Pick disease type C (NPC).
Participants must either 1) have completed Visit 2 (end of study [EOS]) of the CT-ORZY-NPC-001 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 participant's current prescribed best routine clinical care; participant's routine clinical care may, or may not, include miglustat.
Randomization:
Participants will be randomized to receive placebo or arimoclomol (with an allocation ratio of 1:2).
Pharmacokinetic evaluation (age below 12):
To confirm the selected dose, participants less than 12 years of age will undergo an arimoclomol single-dose pharmacokinetic (PK) evaluation before randomization and the start of continuous (multiple dosing) treatment.
Early Escape Clause:
In participants 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 participant can be treated with arimoclomol (as per blinded phase study schedule) and be followed up according to the study schedule 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 participants will be offered to continue into the extension phase of the study where every participant will receive arimoclomol and be followed up and attend site visits every 6 months until 60 months after randomization. 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 participants 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 participant's current prescribed best routine clinical care; participant's routine clinical 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 participants are planned to be enrolled. All participants will be treated with arimoclomol.
Main 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 participants above 18 months
- Treated or not treated with miglustat;
- If a participant 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 participant 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 participant to participate in all aspects of the trial design
Main 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
- Participants with known causes of active liver disease or prolonged icterus or malformation of organs other than NPC
- Participant was born before 37 weeks of gestation
- Participant weight <5 kg at study enrollment
- Participant is diagnosed with severe intra-uterine growth restriction
- Participant has severe neurological symptoms
- Participant 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 participant's weight in kg.
Randomization: Open Label
Pharmacokinetic: To confirm the selected dose, participants will undergo an arimoclomol single-dose pharmacokinetic (PK) evaluation before the start of continuous treatment.
Visit schedule time frame: Screening (V1); enrollment Week 1 (V2 baseline), Weeks 2 (V3), continuing visits at months 1 (V4), 3 (V5), 6 (V6), 9 (V7), 12 (V8), 15 (V8a), 18 (V9), 24 (V10), 30 (V11) and 36 (V12).
Primary objective: Safety and tolerability
Main Endpoint measures:
Safety data: Adverse events (AEs); Vital signs; Hematology; Clinical chemistry
Clinical status data: Clinical signs and symptoms captured through physical examination; Change from baseline in patient weight and height; Change in Bayley III score: Developmental delay scoring
Imaging data: Changes from baseline in the size of the liver and spleen assessed by ultrasound
- Conditions
- Niemann-Pick Disease, Type C
- Being tested
- arimoclomol, Placebo
- Keywords
- NPC1, Niemann-Pick Type C, Niemann-Pick, arimoclomol, lysosomal storage disorder, lysosomal storage disease, NPC2, NP-C
- Medical subject headings
- Niemann-Pick Disease, Type C, Lysosomal Storage Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
arimoclomolDrug
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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)
The CGI-I is a 7-point scale that rates total improvement of participant's condition. The clinician rates the participants from 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much worse, or 7=Very much worse. Scores thus range from 1-7 with lower scores indicating greater improvement. Responders were the participants with a score of 1 or 2 at Month 12.
Measured: 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
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. Stable was defined as a participant's total score for the 5 domains being the same at month 12 as at baseline. Improvement was defined as a participant's total score at month 12 being lower than at baseline.
Measured: Baseline to Month 12
Time to Worsening
Time to worsening was defined as the time until the participant reached the predefined minimal clinically important difference (MCID) of 2 points compared to baseline 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. The values reported per group are the 25th percentile Kaplan-Meier estimates and 95% confidence interval.
Measured: Baseline to Month 12
Percentage of Participants With Worsening
Worsening was defined as participants that have reached the predefined MCID of 2 points on their 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.
Measured: Months 6 and 12
Change From Baseline in 17-domain NPCCSS Apart From Hearing Domains (i.e. Hearing and Auditory Brainstem Response)
The NPC Clinical Severity Scale (NPCCSS) is a disease-specific, clinician-reported outcome measure developed to characterize and quantify NPC disease progression. The 17-domain NPCCSS includes clinical signs and symptoms in nine major and eight minor domains, which are rated on scales of 0-5 (for the major domains) or 0-2 (for the minor domains). The total score is the sum of the score of each of the 17 domains and ranges from 0 to 61, with a high score indicating a more severe clinical impairment.
Measured: Baseline to 6 and 12 months
Change From Baseline in 5-domain NPCCSS Score
The 5-domain NPC Clinical Severity Scale (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.
Measured: Baseline to 6 months
Changes From Baseline in Each Individual Domain of the NPCCSS
The NPC Clinical Severity Scale (NPCCSS) is a disease-specific, clinician-reported outcome measure developed to characterize and quantify disease progression. The 17-domain NPCCSS includes clinical signs and symptoms in nine major (ambulation, cognition, eye movement, fine motor, hearing, memory, seizures, speech, swallowing,) and eight minor (auditory brainstem response, behavior, gelastic cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, respiratory problems) domains, which are rated on scales of 0-5 (for the major domains) or 0-2 (for the minor domains). A higher score indicates a more severe clinical impairment.
Measured: Baseline to 6 and 12 months
Change From Baseline in the NPC Clinical Database (NPC-CDB) Score (Modified "Stampfer Score")
The NPC Clinical Database (NPC-cdb) score aims to reflect the current clinical status of the participant. The NPC-cdb score represents both historical symptoms and a current status. The test consists of ten areas: visceral signs, development, motor function, ocular-motor abnormalities, seizures/cataplexy/narcolepsy, cognitive abilities and memory, behavioral and psychiatric abnormalities, speech, hearing, and abilities in daily life. The current status score is a severity-weighted sum of 72 symptoms considered as disease-relevant at the time of assessment. Each symptom contributes with a score between 1 and 5, the maximum score is 125. An increase in score reflects a reduction in the participant's abilities.
Measured: Baseline to 6 and 12 months
Percentage of Participants With Change From Baseline in Quality of Life (EQ-5D-Y)
The EQ-5D-Y descriptive system includes 5 descriptive items: Mobility, self-care, doing usual activities, having pain or discomfort, and feeling anxiety or depressed. Each dimension has 3 levels: No problems, some problems, and a lot of problems. The change in the 5 individual items of the EQ-5D-Y per participant was explored by using the pareto principle at 6 and 12 months to show the number (%) of participants who felt:
- Better (better on at least one dimension and no worse in any other dimension),
- Worse (worse in at least one dimension, and no better in any other dimension)
Measured: Baseline to 6 and 12 months
Change From Baseline in the Scale for Assessment and Rating of Ataxia (SARA) Score
The SARA included eight items reflecting neurologic manifestations of cerebellar ataxia. The test provides a direct and simple description of motor function in a participant. The test consists of 8 test items: gait, stance, sitting, speech disturbance, finger chase, nose-finger test, fast alternating hand movements, and heel-shin slide. The total score of the 8 items ranges from 0 (normal cerebellar function) to 40 (not able to perform any of the test items).
Measured: Baseline to 6 and 12 months
Change From Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT)
The 9HPT test is a direct and simple measurement of fine motor coordination function, eye/hand coordination, and the ability to follow a simple direction. The 9HPT is a timed test in which nine pegs are inserted and removed from nine holes in the pegboard. Both hands are tested starting with the dominant hand. The time spent in completing the 9 HPT using each hand was recorded.
Measured: Baseline to 6 and 12 months
Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S)
The CGI-S is a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment. A rating of 1 is considered normal, or with the least severe symptoms, a rating of 7 is extremely ill, or the worst symptoms. Scores thus range from 1-7 with lower scores indicating less severe disease.
Measured: Months 6 and 12
Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I)
The CGI-I is a 7-point scale that rates total improvement of participant's condition. The clinician rates the participants from 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much worse, or 7=Very much worse. Scores thus range from 1-7 with lower scores indicating greater improvement.
Measured: Months 6 and 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Nov 2015 (estimated)
- Study start14 Jun 2016
- Primary completion25 Jun 2018
- Study completion31 Oct 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Niemann-Pick Disease, Type CStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 50 participants (actual)
Sponsor and investigators
- Lead sponsor
- ZevraDenmark
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Karl-Eugen Mengel, Principal investigator, SphinCS GmbH, Hochheim, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02612129
- Sponsor's protocol ID
- CT-ORZY-NPC-002
- Status last verified
- Nov 2024
- First submitted
- 12 Nov 2015
- Last updated
- 29 Nov 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Expanded access
- Available
Publications
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.
PubMed 33579322Mengel 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.
PubMed 34418116
Study at a glance
From the registry record, last updated by the sponsor on 29 Nov 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Arimoclomol Prospective Double-blind, Randomised, Placebo-controlled Study in Patients Diagnosed With Niemann-Pick Disease Type C
- ClinicalTrials.gov ID
- NCT02612129
- Acronym / sponsor ID
- CT-ORZY-NPC-002
- Conditions
- Niemann-Pick Disease, Type C
- Keywords
- NPC1, Niemann-Pick Type C, Niemann-Pick, arimoclomol, lysosomal storage disorder, lysosomal storage disease, NPC2, NP-C
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 50 participants (actual)
- Lead sponsor
- ZevraDenmarkIndustry (pharma, biotech, devices)
- Study start
- 14 Jun 2016 (actual)
- Primary completion
- 25 Jun 2018 (actual)
- Study completion
- 31 Oct 2024 (actual)
- First posted
- 23 Nov 2015 (estimated)
- Results
- Posted 9 Jun 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
A prospective, randomized, double-blind, placebo controlled therapeutic study in participants with confirmed diagnosis of Niemann-Pick disease type C (NPC).
Participants must either 1) have completed Visit 2 (end of study [EOS]) of the CT-ORZY-NPC-001 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 participant's current prescribed best routine clinical care; participant's routine clinical care may, or may not, include miglustat.
Randomization:
Participants will be randomized to receive placebo or arimoclomol (with an allocation ratio of 1:2).
Pharmacokinetic evaluation (age below 12):
To confirm the selected dose, participants less than 12 years of age will undergo an arimoclomol single-dose pharmacokinetic (PK) evaluation before randomization and the start of continuous (multiple dosing) treatment.
Early Escape Clause:
In participants 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 participant can be treated with arimoclomol (as per blinded phase study schedule) and be followed up according to the study schedule 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 participants will be offered to continue into the extension phase of the study where every participant will receive arimoclomol and be followed up and attend site visits every 6 months until 60 months after randomization. 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 participants 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 participant's current prescribed best routine clinical care; participant's routine clinical 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 participants are planned to be enrolled. All participants will be treated with arimoclomol.
Main 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 participants above 18 months
- Treated or not treated with miglustat;
- If a participant 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 participant 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 participant to participate in all aspects of the trial design
Main 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
- Participants with known causes of active liver disease or prolonged icterus or malformation of organs other than NPC
- Participant was born before 37 weeks of gestation
- Participant weight <5 kg at study enrollment
- Participant is diagnosed with severe intra-uterine growth restriction
- Participant has severe neurological symptoms
- Participant 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 participant's weight in kg.
Randomization: Open Label
Pharmacokinetic: To confirm the selected dose, participants will undergo an arimoclomol single-dose pharmacokinetic (PK) evaluation before the start of continuous treatment.
Visit schedule time frame: Screening (V1); enrollment Week 1 (V2 baseline), Weeks 2 (V3), continuing visits at months 1 (V4), 3 (V5), 6 (V6), 9 (V7), 12 (V8), 15 (V8a), 18 (V9), 24 (V10), 30 (V11) and 36 (V12).
Primary objective: Safety and tolerability
Main Endpoint measures:
Safety data: Adverse events (AEs); Vital signs; Hematology; Clinical chemistry
Clinical status data: Clinical signs and symptoms captured through physical examination; Change from baseline in patient weight and height; Change in Bayley III score: Developmental delay scoring
Imaging data: Changes from baseline in the size of the liver and spleen assessed by ultrasound
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Arimoclomol Single PK Dose | Experimental | Drug: arimoclomolParticipants less than 12 years received a single oral dose of arimoclomol capsule, based on participant's body weight, on Day 1. |
| Arimoclomol (12-month Double-blind Phase) | Experimental | Drug: arimoclomolParticipants 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. |
| Placebo (12-month Double-blind Phase) | Placebo comparator | Drug: PlaceboParticipants received matching placebo capsules (with regard to weight, appearance, smell, flavor etc.) orally TID for 12 months. |
Who may qualify
- Ages
- 2 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (22 listed)
- 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.
- OR
- 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;
- Genetically confirmed (deoxyribonucleic acid [DNA] sequence analysis) by mutations in both alleles of NPC1 or NPC2, OR
Key exclusion criteria (14 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| arimoclomol | Drug | Arimoclomol (12-month Double-blind Phase), Arimoclomol Single PK Dose |
| Placebo | Drug | Placebo (12-month Double-blind Phase) |
Primary outcome
Change From Baseline in the Niemann-Pick Disease Type C (NPC) Disease Severity Assessed Based on the 5-domain NPCCSS Total Scores
Time frame: Baseline to Month 12
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.
13 secondary outcomes
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)
Time frame: 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
Time frame: Baseline to Month 12
Time to Worsening
Time frame: Baseline to Month 12
Percentage of Participants With Worsening
Time frame: Months 6 and 12
Change From Baseline in 17-domain NPCCSS Apart From Hearing Domains (i.e. Hearing and Auditory Brainstem Response)
Time frame: Baseline to 6 and 12 months
Change From Baseline in 5-domain NPCCSS Score
Time frame: Baseline to 6 months
Changes From Baseline in Each Individual Domain of the NPCCSS
Time frame: Baseline to 6 and 12 months
Change From Baseline in the NPC Clinical Database (NPC-CDB) Score (Modified "Stampfer Score")
Time frame: Baseline to 6 and 12 months
Percentage of Participants With Change From Baseline in Quality of Life (EQ-5D-Y)
Time frame: Baseline to 6 and 12 months
Change From Baseline in the Scale for Assessment and Rating of Ataxia (SARA) Score
Time frame: Baseline to 6 and 12 months
Change From Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT)
Time frame: Baseline to 6 and 12 months
Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S)
Time frame: Months 6 and 12
Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I)
Time frame: Months 6 and 12
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Nov 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 33579322Patterson 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.
- Results publication: PubMed 34418116Mengel 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Karl-Eugen Mengel principal investigator
SphinCS GmbH, Hochheim, Germany
14 sites in 9 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing arimoclomol in people with Niemann-Pick Disease, Type C, run by ZevraDenmark at 14 sites in 9 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 22 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 14 sites in United States, France, Germany, Italy, United Kingdom and 4 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Jun 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change From Baseline in the Niemann-Pick Disease Type C (NPC) Disease Severity Assessed Based on the 5-domain NPCCSS Total Scores (time frame: Baseline to Month 12). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02612129, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Nov 2024; AzTrials last refreshed its copy on 7 Nov 2026.