Channeling Hope Trial 1: A Phase 1, Open-label, Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK) of Chronic Aprepitant Use in Individuals With Congenital Contractures of the Limbs and Face, Hypotonia, and Development Delay (CLIFAHDD)
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Number of Adverse events
研究概览
简要总结
There are no drug treatments for individuals with Congenital Contractures of the Limb and Face, Hypotonia, and Developmental Delay (CLIFAHDD), an ultra-rare and severe neurodevelopmental disease. The investigators have learned more about the cause of the disease and researched possible treatments based on both the cause of the disease and the way certain drugs work. The investigators are interested in understanding the safety of using aprepitant (a drug already approved by the United States Food & Drug Administration [FDA] to treat nausea and vomiting for kids and adults who are receiving chemotherapy) on people diagnosed with CLIFAHDD. The overall goal of this Phase 1 study is to study whether this drug is safe for daily use in individuals with CLIFAHDD and to find more information on how it impacts daily functioning and quality of life. The total study will take around 8 months total. This includes the 90 days before the drug starts and the 21 days after the drug ends.
详细描述
The sodium leak ion channel NALCN is responsible for a background sodium influx that contributes to the resting membrane potential and serves as a key regulator in neuronal and cell excitability. Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay (CLIFAHDD; OMIM 616266) is a debilitating and ultra-rare neurodevelopmental disease with early infancy onset caused by a de novo autosomal dominant mutation in NALCN, often associated with NALCN gain-of-function (GOF). CLIFAHDD is associated with global neurodevelopmental delay, hyperkinetic movement disorders (e.g., dystonia, chorea, ataxia), seizures, apnea, constipation, insomnia, and increased risk of early childhood mortality. There are currently no drug treatments for CLIFAHDD. A multidisciplinary drug repurposing pipeline identified aprepitant as a promising lead candidate with converging functional, in silico, in vitro, and in vivo preclinical data support.
The primary objective of this Phase 1 clinical trial is to determine the safety, tolerability and pharmacokinetics (PK) of chronic aprepitant use in individuals with CLIFAHDD. The hypothesis is that aprepitant will be safe, tolerable, and amendable to chronic use in patients with CLIFAHDD based on prior safety and PK data on aprepitant use in pediatric and adult populations, including off-label chronic use. The exploratory objectives are: (1) to identify potential pharmacodynamic biomarkers reflecting NALCN pathway modulation; (2) to assess preliminary signals of clinical efficacy and outcome measures for future trials.
The study is designed as a single-center, Phase 1, open-label, dose-escalation study designed to evaluate the safety, tolerability, and PK of chronically administered oral aprepitant in individuals with CLIFAHDD (n=3-5, with protocol-defined criteria allowing expansion to a max n=5).
Participants will undergo evaluations of disease severity and symptoms over a 90 day lead-in period. For the baseline visit and initiation of cycle 1, participants will travel to UTHSA for onsite clinical monitoring, collection of baseline clinical outcome assessments, and PK assessments. Following the initial dose, each participant's biological and pharmacokinetic response will be evaluated over a 72-hour period. PK sampling will include an 8-point plasma concentration-time profile followed by additional blood draws. After the initial PK assessment, participants will enter a structured dose escalation period, during which aprepitant will be increased in 1mg/kg every 4 weeks. PK analyses with an 8-point plasma concentration-time profile will be performed at the end of each 4-week cycle to establish steady state drug availability with chronic dosing. Safety evaluations, clinical outcome assessments, and pharmacodynamic biomarkers will be assessed at the end of each 4-week cycle. Safety data (rather than PK analyses) will be used to guide dose escalation and will be reviewed in real time by the study clinician and Principal Investigator, without a planned pause in study conduct. Escalation will continue until either a maximum tolerated dose (MTD) is established or the maximum FDA-approved dose is reached. At the maximum dose or end of Cycle 3, participants will undergo an 8-point plasma concentration-time profile to characterize dose-dependent PK changes and elimination. Participants will undergo details safety, clinical, and pharmacodynamic biomarker assessments. Remote safety monitoring will continue for 3 weeks
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Months 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of CLIFAHDD (confirmed by clinical and genetic report per best practices)
- •NALCN variant with predicted NALCN gain-of-function in established functional assays and/or computational assessments
- •Age >6 months at the time of initial consent/assent
- •Weight >6kg at the time of initial consent/assent
- •Ability of participant or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document.
- •For children (<18y at time of consent/assent), informed assent (if developmentally appropriate) and parental informed consent to participate in the study
- •Willingness to comply with all study-related requirements, including Aprepitant regimen and travel to San Antonio, TX for specified visits
- •Has adequate organ functions as defined by the following laboratory parameters at baseline (laboratory parameters outside of these ranges that are deemed clinically insignificant should be discussed with the Independent Safety Monitor):
- •Absolute neutrophil count ≥1000 cells/uL;
- •hemoglobin ≥8.5 g/dL;
- •platelet count ≥100,000/mm3;
- •aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper limit of normal (ULN);
- •total bilirubin ≤ 1.5 x institutional ULN (exception: subjects with known Gilbert's syndrome and total bilirubin ≤2 x institutional ULN at screening or anytime during the prior 6 months are eligible);
- •adequate renal function defined as calculated creatinine clearance >60 mL/min using the Cockcroft Gault Method;
- •acceptable coagulation parameters including international normalized ratio (INR) <1.4 and partial thromboplastin time (PTT) ≤ 1.5 x institutional ULN;
- •serum albumin ≥3.0 g/dL
- •Women of child-bearing age participants must use highly effective forms of birth control defined as those with a failure rate of < 1% per year. Acceptable methods include: complete sexual abstinence (anticipated given severity of neurodevelopmental symptoms in CLIFAHDD), combined hormonal contraceptives, progestogen-only hormonal contraceptives, intrauterine devices (IUDs), intrauterine hormone-releasing systems (IUS), bilateral tubal occlusion, or vasectomized partner (provided the partner is the sole sexual partner).
排除标准
- •Known hypersensitivity to any component of the study treatment formulation(s)
- •Concomitant use of pimozide, terfenadine, astemizole, cisapride, flibanserin, lomitapide (contraindicated CYP3A4 substrate)
- •Concomitant use of strong (Clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) or moderate (amiodarone, erythromycin, fluconazole, miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, conivaptan, danazol, ketoconazole) CYP3A4 inhibitors and strong CYP3A4 inducers (apalutamide, carbamazepine, dexamethasone, enzalutamide, fosphenytoin, lumacaftor, midostaurin, mitotane, pentobarbital, phenobarbital, rifampin, phenytoin) or CYP3A4 substrates (Docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, vincristine, colchicine, axitinib). Participants on one of these medications but unable to discontinue for the trial and considered otherwise low risk should be discussed with the Independent Safety Monitor but may be considered for enrollment.
- •Concomitant use of high-risk cytochrome P450 family 2 subfamily C member 9 (CYP2C9) substrates (e.g., warfarin or phenytoin or tolbutamide)
- •Patients who are medically unstable or have been hospitalized for an acute medical condition in the 3 months prior to the first active drug visit
- •Patients who are acutely ill in the hospital or intensive care unit (ICU)
- •Any other history of clinically significant acute or chronic neurologic disease, respiratory disease, cardiovascular disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder, infectious disease, or any other medical or psychiatric condition that in the opinion of the investigator or study clinician will significantly increase the safety risk for the subject or confound the interpretation of the study data.
- •Currently receiving any other investigational agents or has received study treatment or used an investigational device within 30 days of the first dose of treatment
- •Caregivers unwilling to follow study procedures or follow protocol as outlined.
研究组 & 干预措施
Aprepitant treatment group
Participant enrolled in the study will be administered oral aprepitant to evaluate safety and tolerability
干预措施: Aprepitant Powder for Oral Suspension (Drug)
结局指标
主要结局
Number of Adverse events
时间窗: Baseline to 24 weeks
Adverse events will be assessed for relatedness to the study drug and assessed according to Common Terminology Criteria for Adverse Events (CTCAE) grade
Dose-limiting toxicity (DLT)
时间窗: Baseline to 24 weeks
Number of events that lead to specified worsening of patients neurologic or non-neurologic condition during the treatment period which may lead to study treatment interruption for more than 14 days
Maximum administered dose
时间窗: Baseline to 24 weeks
The highest dose at which no more than one instance of DLT is observed, or the maximum labeled dose
次要结局
- Area under the concentration-time curve (AUC)(Dose time to 72 hours)
研究者
Megan Iammarino
Assistant Professor
The University of Texas Health Science Center at San Antonio