A Phase 1/2 Open-label First-in-Human Dose-Escalating Safety and Efficacy Study Evaluating Subcutaneous Administration of PTH-IA in Adults and Children With Jansen s Metaphyseal Chondrodysplasia (JMC)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Period 1 - Adult: Evaluate the safety and tolerability of PTH-IA in adults with JMC (>= 18 years)
研究概览
简要总结
Jansen s Metaphyseal Chondrodysplasia (JMC) is a very rare disorder with only approximately 30 people known to have the disease worldwide. It is caused by parathyroid hormone 1 receptor (PTH1R) variants leading to constitutive activation of the receptor for parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP). PTH1R is predominantly expressed in the kidneys and bone and growth-plate chondrocytes. Individuals with JMC develop severe growth impairment resulting in significant short stature, scoliosis, frequent fractures, bone pain, mineral-ion abnormalities (typically hypercalcemia and hypercalciuria), hypertension, and chronic kidney disease due to nephrocalcinosis and nephrolithiasis. Children often undergo multiple surgeries for skeletal fractures and deformities; mobility is commonly impaired, usually requiring assistive devices for ambulation. Other complications may include premature closure of cranial sutures and cranial nerve compressions with the potential for vision and/or hearing loss [1-3]. Physical function impairment and the need for complication-related operations have profound deleterious effects on quality of life in individuals with JMC. There are currently no approved therapies for JMC, and novel therapies are critically needed to prevent irreversible disease complications and improve patient quality of life.
The inventors of the drug, parathyroid hormone inverse agonist (PTH-IA), have considerable expertise in both the basic and clinical aspects of PTH/PTHrP receptor molecular biology and pharmacology. They reported the first PTH1R JMC mutations (including the H223R mutation) over 20 years ago and identified certain PTH antagonist ligands that function as inverse agonists on the PTH1R JMC mutant receptors [2, 4]. These ligands suppress the mutant receptor s elevated basal rates of cAMP signalling, as assessed in cultured cells and animal models. In vivo studies confirm that inverse agonist ligands may be effective in treating JMC. This study involves the use of PTH-IA, a 30-amino acid PTH inverse agonist ligand with the amino acid sequence [Leu11,dTrp12,Trp23,Tyr36]-PTHrP(7-36)NH2. We hypothesize that PTH-IA will be a safe and effective treatment for individuals with JMC.
详细描述
Study Description:
This is a Phase 1/2 open-label, single-arm study to evaluate the safety of multiple ascending doses of PTH-IA administered subcutaneously twice a day in individuals with JMC conducted at the National Institutes of Health Clinical Center.
Objectives Primary Objectives
Period 1 - Adult
- Evaluate the safety and tolerability of PTH-IA in adults with JMC (>=18 years)
- Evaluate the pharmacokinetics (PK) of multiple ascending doses of PTH-IA in adults (>= 18 y/o) years old with JMC
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
- 3 Years 至 100 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA:
- •In order to be eligible to participate in this study, an individual must meet all of the following criteria:
- •Willingness of participant and/or guardian to sign a written informed consent form, which must be obtained prior to initiation of study procedures.
- •Period 1: Adults >=18 years of age
- •Period 2: Adults and children 3-17 years of age
- •Minimum body weight of 35 kg for participation in Period 1 and 18 kg for participation in Period
- •Have an activating germline mutation of PTHIR (H223R, I458K, I458R, T410P, or T410R)
- •Female participants of reproductive potential must agree to use one form of highly effective contraception. Highly effective contraception includes:
- •Total abstinence (when this is in line with the preferred and usual lifestyle of the participant). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post- ovulation methods) and withdrawal are not acceptable methods of contraception.
- •Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment.
- •Male sterilization (at least 6 months prior to screening). For female participants in the study, the vasectomized male partner should be the sole partner for that participant for the study duration.
- •Use of oral, injected, or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormonal vaginal ring or transdermal hormone contraception
- •Placement of an intrauterine device (IUD) or intrauterine system (IUS)
- •Barrier methods of contraception used correctly by the male partner: condom or occlusive cap (diaphragm or cervical/ vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
- •For males of reproductive potential: use of condoms or other methods described above to ensure effective contraception with partner.
- •Stated willingness to comply with all study procedures and availability for the duration of the study, including the ability and willingness to travel to the NIH Clinical Center.
排除标准
- •An individual who meets any of the following criteria will be excluded from participation in this study:
- •Pregnancy or lactation
- •25-hydroxyvitamin D <=20 ng/mL. Patients will be eligible for rescreening after a repletion period lasting up to 6 months.
- •Clinically significant renal disease with estimated glomerular filtration rate (eGFR) <=45 mL/ min/1.73 m
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times the upper limit of normal. If transaminitis is present, patients will be eligible for rescreening for a period of up to 6 months.
- •Hgb <12 gm/dL for women and girls >=16 years, <=13 gm/dL for men and boys >=16 years, and <=11.5 gm/dL in children <=15 years. If reduced hemoglobin levels are related to iron, B12, or folate deficiency, patients will be eligible for rescreening after a repletion period lasting up to 6 months.
- •Hypersensitivity or intolerance to any active substance or excipient of PTH-IA
- •History of surgical removal of all parathyroid glands.
- •Treatment with bisphosphonate use within 6 months of screening
- •Treatment with denosumab within 3 months of screening
- •Treatment with thiazides within 4 weeks of screening
- •Any other significant medical conditions that, in the opinion of the study team, may present a concern for participant safety or difficulty with data interpretation.
研究组 & 干预措施
Treatment with PTH-IA
All participants will receive PTH-IA for up to 90+/-7 days in Period 1, and 24 weeks +/- 7 days in Period 2.
干预措施: PTH-IA (Drug)
结局指标
主要结局
Period 1 - Adult: Evaluate the safety and tolerability of PTH-IA in adults with JMC (>= 18 years)
时间窗: 104 +/- 10 days
To assess dose-limiting toxicities (DLTs) and incidence, severity, seriousness, and causality of all treatment-emergent adverse events (TEAEs).
Period 1 - Adult: Evaluate the pharmacokinetics (PK) of multiple ascending doses of PTH-IA in adults (>= 18 y/o) years old with JMC
时间窗: 104 +/- 10 days
To determine PK parameters after multiple ascending doses of PTH-IA.
Period 2 - Adult and Pediatrics: Evaluate the safety and tolerability of PTH-IA in adults and children aged 3-17 years old with JMC.
时间窗: 28 weeks +/- 10 days
To assess dose-limiting toxicities (DLTs) and incidence, severity, seriousness, and causality of all treatment-emergent adverse events (TEAEs).
Period 2 - Adult and Pediatrics: Evaluate the pharmacokinetics (PK) of multiple ascending doses of PTH-IA in children aged 3-17 years old with JMC.
时间窗: 28 weeks +/- 10 days
To determine PK parameters after multiple ascending doses of PTH-IA.
Period 2 - Adult and Pediatrics: Evaluate the effect of PTH-IA on serum PTH levels in children and adults with JMC.
时间窗: 28 weeks +/- 10 days
To evaluate changes in serum PTH from baseline to the end of treatment.
次要结局
- Periods 1 and 2 - Identify the optimal dose range of PTH-IA.(Period 1: 104 +/- 10 days. Period 2: 28 weeks +/- 10 days.)
- Periods 1 and 2 - Evaluate potential measures of efficacy of PTH-IA in JMC.(Period 1: 104 +/- 10 days. Period 2: 28 weeks +/- 10 days.)