A randomized, double-blind, placebo-controlled Phase I clinical study to evaluate the safety, tolerability and pharmacokinetics of ZYPH0907, a novel PTH-1r agonist , following oral administration in volunteers
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 96
- 试验地点
- 1
- 主要终点
- Safety and tolerability
研究概览
简要总结
Osteoporosis is a major health problem, particularly for elderly women. It is characterised by diminished bone mass, decreased bone mineral density (BMD), bone strength and associated with an increased risk of bone fracture. Osteoporosis occurs when the rate of the bone resorption is greater than the rate of bone formation. At present, there is no safe and effective orally bioavailable therapy available for the treatment of osteoporosis. Clinically used anti-osteoporosis agents such as Estrogen, Raloxifene, Calcitonin and Bisphosphonate derivatives, only prevent bone resorption and do not contribute towards bone formation. xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /
The native human Parathyroid Hormone (PTH) is an 84 amino acids polypeptide. It regulates calcium homeostasis in the human body through its direct action on bone and kidneys. Administration of PTH via parenteral route efficiently increases bone mineral density (BMD), bone strength and reduces the incidence of new osteoporotic fractures in osteoporotic patients. PTH exerts all these effects primarily through its interaction with a cell surface PTH receptor (mainly PTH-1r; a GPCR). PTH binds to the PTH-1r with affinity in the nM range. The primary intracellular effector enzyme activated by the PTH receptor in response to PTH peptide is adenylyl cyclase (AC) and cyclic adenosine monophosphate (cAMP), which regulates the downstream cellular processes involved in bone remolding. Since PTH regulates blood calcium and the phosphate levels and exhibit potent anabolic (bone-forming) effects, the parathyroid hormone and its derivatives represent potential therapeutic agent for the treatment of osteoporosis. Currently, truncated PTH derivative (34 amino acid PTH peptide), under the brand name Forteo/ teriparatide acetate (Eli Lilly), has been approved for the treatment of osteoporosis. Administration of Forteo via parenteral route efficiently increases bone mineral density (BMD), bone strength and reduces the incidence of new osteoporotic fractures in osteoporotic patients.
Unfortunately, due to the large molecular weight, Forteo cannot be administered via oral route. Also, long term tolerability of Forteo is limit due to increased risk of hypercalcemia and osteosarcoma. Thus, under clinical set-up, interim and cautious use of Forteo is recommended for the treatment of osteoporosis. Therefore, Zydus Research Centre of Cadila Healthcare Ltd developed a novel and orally bioavailable peptidomimetic based PTH-1r agonist (ZYPH0907) for the safe and effective treatment of osteoporosis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Random Number Table
- 盲法
- Participant and Investigator Blinded
入排标准
- 年龄范围
- 30.00 Year(s) 至 55.00 Year(s)（—）
- 性别
- All
入选标准
- •1.Healthy Male or female between 30 and 55 years of age 2.A female subject is eligible to participate if she is of non-childbearing potential 3.Male subjects must agree to use one of the contraception methods 4.BMI within the range
- •29.9 kg per m2 5.Capable of giving written informed consent, which includes compliance with protocol 6.QTcB or QTcF less than 450msec. In case of post menopausal women, 1.Postmenopausal women diagnosed as osteoporosis with T score between ranges of -1 to -4 at any one of the two sites measured (lumbar spine and femoral neck). 2.Subjects who are in the opinion of the investigator, likely to comply with the protocol and the investigator’s instructions during the study period. 3.Subjects giving informed consent for participation in the study.
- •Subjects who are taking low-dose aspirin for cardiovascular prophylaxis (81mg or less) are eligible to participate in the study, but the aspirin must be discontinued from Screening to the Follow-up visit.
排除标准
- •1.Presence or history of hypersensitivity to any of the active or inactive ingredients of ZYPH0907 formulation 2.History of nephrolithiasis/ urolithiasis in the past 1 year.
- •3.Abnormal liver function test (ALT/AST more than or equal to 2.5 times UNL) or kidney function test (serum creatinine more than or equal to 2.0 mg/dl and calculated GFR value).
- •4.Abnormal laboratory values of parathyroid hormone (PTH), Serum Calcium (Ca),and Alkaline phosphatase (ALP).
- •5.History of hyperuricemia/gout.
- •6.History of diseases causing malabsorption in the last one year.
- •7.Subjects with abnormal ECG findings.
- •8.The subject has a positive pre-study drug/alcohol screen 9.Positive urinary cotinine levels or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
- •10.History of regular alcohol consumption within 6 months of the study 11.History of sensitivity to heparin or heparin-induced thrombocytopenia 12.Unable or unwilling to abstain from caffeine-or xanthine-containing products for 24 hours prior to dosing until the final post-dose assessment at each treatment level.
- •13.History or presence of significant drug abuse 14.Use of alcohol for 24 hours prior to dosing until final post-dose assessment at each treatment level.
- •15.A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening 16.A positive test for HIV antibody 17.Pregnant females as determined by positive urine hCG test at screening or prior to dosing 18.Lactating females 19.Has anemia defined by hemoglobin concentration 11.0g/dL for males or less than 10.0g/dL for females.
- •20.Abnormal vital signs 21.History of any gastrointestinal or hepatic conditions that could impact absorption of the investigational compound.
- •22.Family history of torsade de pointes or other ventricular arrhythmias.
- •23.Family history of unexplained sudden death.
- •24.Subjects who have asthma or a history of asthma 25.Exposure to more than four new chemical entities within 12 months prior to the first dosing day 26.Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days or 14 days if the drug is a potential enzyme inducer or 5 half-lives prior to the first dose of study medication, unless in the opinion of the Investigator and CHL Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
- •27.Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period 28.Unwillingness or inability to follow the procedures outlined in the protocol.
- •29.As a result of the medical interview, physical examination, or screening investigations, the investigator considers the subject unfit for the study.
- •30.Subject is either an immediate family member of a participating investigator, study coordinator, employee of an investigator; or is a member of the staff conducting the study.
结局指标
主要结局
Safety and tolerability
时间窗: Safety and tolerability | Plans I,II and III[upto | Day 8] | Plan IV [ upto Day 21 ]
次要结局
- Pharmacodynamics and pharmacokinetics(PK: 1.Blood •Plans I, II, III: [Time frame: pre dose to 72 hrs post Dose on Day 8])