Arimoclomol Prospective Double-blind, Randomised, Placebo-controlled Study in Patients Diagnosed With Niemann-Pick Disease Type C
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 50
- 试验地点
- 14
- 主要终点
- Change From Baseline in the Niemann-Pick Disease Type C (NPC) Disease Severity Assessed Based on the 5-domain NPCCSS Total Scores
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 2 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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;
- •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.
排除标准
- •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.
研究组 & 干预措施
Arimoclomol Single PK Dose
Participants less than 12 years received a single oral dose of arimoclomol capsule, based on participant's body weight, on Day 1.
干预措施: arimoclomol (Drug)
Arimoclomol (12-month Double-blind Phase)
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.
干预措施: arimoclomol (Drug)
Placebo (12-month Double-blind Phase)
Participants received matching placebo capsules (with regard to weight, appearance, smell, flavor etc.) orally TID for 12 months.
干预措施: Placebo (Drug)
结局指标
主要结局
Change From Baseline in the Niemann-Pick Disease Type C (NPC) Disease Severity Assessed Based on the 5-domain NPCCSS Total Scores
时间窗: 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.
次要结局
- 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)
- Changes From Baseline in Each Individual Domain of the NPCCSS(Baseline to 6 and 12 months)
- Change From Baseline in the Scale for Assessment and Rating of Ataxia (SARA) Score(Baseline to 6 and 12 months)
- Change From Baseline in the Time Spent to Complete the Nine-Hole Peg Test (9HPT)(Baseline to 6 and 12 months)
- Percentage of Participants Within Each Severity Category of the Clinical Global Impression Scale of Severity (CGI-S)(Months 6 and 12)
- Percentage of Participants Within Each Category of the Clinical Global Impression Scale of Improvement (CGI-I)(Months 6 and 12)
- Change From Baseline in 5-domain NPCCSS Score(Baseline to 6 months)
- Change From Baseline in the NPC Clinical Database (NPC-CDB) Score (Modified "Stampfer Score")(Baseline to 6 and 12 months)
- Percentage of Participants With Change From Baseline in Quality of Life (EQ-5D-Y)(Baseline to 6 and 12 months)