A Randomized, Double-Blind, Multiple Ascending Oral Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PCO371 in Patients With Hypoparathyroidism
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 11
- 主要终点
- Treatment-emergent adverse events
研究概览
简要总结
This is a multi-center, placebo-controlled, randomized, double-blind, multiple-ascending dose study in patients with hypoparathyroidism.
The total duration of study medication treatment will be 13 weeks and includes a Fixed-Dose Treatment period and a Dose Titration Treatment period. The Fixed-Dose Treatment period consists of multiple daily dosing at a fixed dose level. Once patients have completed the Fixed-Dose Treatment period, patients will enter the Dose Titration Treatment period where PCO371 (or placebo), oral calcium and oral active vitamin D can each be titrated according to the patient's albumin-corrected serum calcium level.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able and willing to provide written informed consent, to use the device for PRO and electronic diary and to comply with the requirements of the protocol.
- •Adult males or females ≥18 years of age
- •History of hypoparathyroidism for more than 1-year post initial diagnosis
- •PTH level is inappropriately low
- •Dose of thyroid replacement therapy must have been stable for ≥3 months prior to first dose if receiving thyroid replacement therapy
- •Receiving treatment with active vitamin D therapy (calcitriol ≥0.25 μg/day or alfacalcidol ≥0.5 μg/day)
- •Receiving Oral calcium treatment (≥1000 mg/day)
- •No significant changes in the diet from 4 weeks prior to Screening and for the duration of the study.
- •Fasting albumin-corrected serum calcium concentration between 8.0 and 9.0 mg/dL at 2 consecutive visits during the Run-In period, and no more than 25% change in daily doses of oral Ca and active vitamin D between the 2 consecutive visits during the Run-In period.
- •On Day 1, fasting albumin-corrected serum calcium level between 7.5 and 9.0 mg/dL
- •Serum magnesium level ≥ lower limit of normal and ≤ 1.2 x laboratory upper limit of normal
- •Serum 25[OH] vitamin D level within the laboratory normal range
- •Estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2
- •Women of childbearing potential must have a negative highly sensitive urine or serum pregnancy test result
- •For women of childbearing potential: agreement to use a highly effective contraceptive method during the treatment period and for 28 days after the last dose of study drug. Hormonal contraceptive methods must be supplemented by a barrier method (preferably male condom) and agreement to refrain from egg donation during the treatment period and for 28 days after the last dose of study drug.
- •For men: agreement to remain abstinent or use contraceptive measures. Men must refrain from donating sperm during this same period.
- •Ability to comply with the study protocol, in the investigator's judgment.
- •For Canadian sites only: Ferritin, as assessed by the local laboratory at screening, must be ≥ the lower limit of normal (LLN).
排除标准
- •Pregnant or breastfeeding or intending to become pregnant during the study or within 28 days after the last dose of PCO371
- •Known or suspected history of hypoparathyroidism resulting from an activating mutation in the Ca-sensing receptor gene or impaired responsiveness to PTH (pseudohypoparathyroidism)
- •Clinically significant hypomagnesemia. Adequately treated hypomagnesemia is permitted
- •Any disease that might affect calcium metabolism or calcium-phosphate homeostasis other than hypoparathyroidism
- •History of a major bone fracture within 3 months prior to Screening
- •Any history of clinically significant bleeding disorder or clinically significant abnormal clotting times
- •History of thyroid cancer unless documented to be disease free for ≥1 year
- •History of any other cancer in the past 3 years from Screening with the exception of thyroid cancer , completely removed nonmelanoma skin cancer, basal cell skin carcinoma, and cancer in situ of the cervix
- •Dependence on monthly or more frequent parenteral calcium infusions to maintain calcium homeostasis
- •Disease processes that may adversely affect gastrointestinal absorption
- •Use of oral bisphosphonates within 6 months of Screening and/or intravenous bisphosphonate preparations within 12 months of Screening. Any use of zoledronic acid prior to Screening.
- •Use of other drugs known to influence calcium and bone metabolism such as calcitonin, fluoride tablets or cinacalcet hydrochloride within 4 weeks prior to Screening.
- •Patients who have taken inducers of CYP3A4, Pgp,or BCRP within 1 month before IMP administration or taken inhibitors of CYP3A4, P-gp, or BCRP within 2 weeks before IMP administration (or either 6 times the t1/2 of the drugs mentioned above, whichever is longer).
- •Use of loop or thiazide diuretics within 14 days prior to first dose of IMP
- •Use of anti-coagulants, anti-platelet medications, and aspirin within 2 weeks (or within 6 times the t1/2 of the drug mentioned above, whichever is longer) prior to IMP administration
- •Use of proton pump inhibitors or H2 blockers within 48 hours prior to the first dose of IMP and antacids within 4 hours prior to the first dose of IMP.
- •History of radiotherapy to the skeleton within 5 years
- •Presence of open epiphyses at the distal radius and ulna as well as carpals, metacarpals, phalanges, and pelvis
- •ALT, AST, or ALP > 2.5 × ULN at Screening
- •Patients with documented active HBV, active HCV infection or any other known active virus infection considered to be clinically relevant by the investigator.
- •Evidence of active alcohol, drug, or other substance abuse or addiction
- •History of a seizure that is unrelated to hypocalcemia within 6 months prior to Screening
- •Insulin dependent diabetes mellitus or poorly controlled Type II diabetes mellitus (defined as hemoglobin A1c [HbA1c] >8%)
- •Chronic/severe cardiac disease
- •Active gout or history of active gout within 6 months prior to first dose of study medication
- •History of clinically significant cognitive deficit that would, at the discretion of the investigator, interfere with a patient's ability to participate in the trial.
- •Any disease or condition that, in the opinion of the investigator, has a high probability of precluding the patient from completing the study or where the patient could not or would not appropriately comply with study requirements
- •Participation in any clinical trials or has taken any IMP (including placebo) either within 2 months or 5 times the t1/2 of the IMP, whichever is longer, prior to first dose of IMP for this study
- •Previous treatment with PTH-like drugs, including PTH(1-84), PTH(1-34) or other Nterminal fragments or analogs of PTH or PTH-related proteins within 2 months or 5 times the t1/2 of the treatment (whichever is longer) prior to Screening.
- •Patients with hypersensitivity to PCO371 or to any component of this drug product
研究组 & 干预措施
PCO371 Low Dose and Low administration frequency
PCO371 low dose and low administration frequency by oral administration for the first period ( Fixed-Dose treatment period). PCO371 will be titrated in the following period (Dose Titration Treatment period).
干预措施: PCO371 (Drug)
PCO371 High Dose and Low administration frequency
PCO371 high dose and low administration frequency by oral administration for the first period ( Fixed-Dose treatment period). PCO371 will be titrated in the following period (Dose Titration Treatment period).
干预措施: PCO371 (Drug)
PCO371 High Dose and High administration frequency
PCO371 high dose and high administration frequency by oral administration for the first period ( Fixed-Dose treatment period). PCO371 will be titrated in the following period (Dose Titration Treatment period).
干预措施: PCO371 (Drug)
Placebo
Placebo by oral administration.
干预措施: Placebo (Drug)
结局指标
主要结局
Treatment-emergent adverse events
时间窗: 13 weeks
Treatment-emergent adverse events (TEAEs) will be assessed including the number and rate of TEAEs.
Clinically significant change in the safety parameters; body weight
时间窗: 13 weeks
Abnormal change in body weight.
Clinically significant change in the safety parameters; physical examination findings
时间窗: 13 weeks
Abnormal change in physical examination findings.
Clinically significant change in the safety parameters; laboratory test value
时间窗: 13 weeks
Abnormal change in laboratory test value including hematology, biochemistry, coagulation, urinalysis.
Clinically significant change in the safety parameters; electrocardiogram results
时间窗: 13 weeks
Abnormal change in electrocardiogram results including PQ (PR), RR, QRS, QT, pulse, QTcB, QTcF and ECG abnormalities.
Selected adverse events
时间窗: 13 weeks
Hypercalcemia and hypocalcemia will be assessed including the number and rate of these.
Clinically significant change in the safety parameters; vital signs
时间窗: 13 weeks
Abnormal change in vital signs.
次要结局
- Pharmacodynamic data in serum or plasma(13 weeks)
- Pharmacodynamic data; nephrogenous cAMP concentration(13 weeks)
- Pharmacodynamic data; bone turnover markers in serum or plasma(13 weeks)
- Pharmacokinetic data of PCO371; Plasma concentrations of PCO371(13 weeks)
- Pharmacokinetic data of PCO371; AUC0-last(13 weeks)
- Pharmacokinetic data of PCO371; Cmax of PCO371(13 weeks)
- Pharmacokinetic data of PCO371; Tmax of PCO371(13 weeks)
- Pharmacokinetic data of PCO371; T1/2 of PCO371(13 weeks)
- Pharmacodynamic data in urine(13 weeks)