Clinical Pharmacokinetics and Pharmacodynamics Study of Different Doses of Zoledronic Acid

Study Overview
=================
Brief Summary
-----------------
The recommended dosing regimen of zoledronic acid in Chinese osteoporosis patients is completely in accordance with the one of 5 mg per year abroad that based on the dosing regimen in Paget's disease. This dosing regimen lacks the actual supportive clinical data of Chinese patients. In addition, the overall incidence of acute phase response, the main adverse event after the first infusion, in Chinese patients is higher than that in Caucasian patients population. Moreover, the results of the similar drug clinical study in the Japanese patients shown that the purpose of effective treatment for osteoporosis could be achieved with half of the dosage in Caucasian population. Thus, it could be inferred from these that the dosing regimen of zoledronic acid might be inappropriate in Chinese osteoporosis patients. Therefore, the main purpose of this clinical trail is to compare the zoledronic acid pharmacokinetic and pharmacodynamic characteristic of different doses in Chinese postmenopausal subjects with low bone mass or osteoporosis and explore the best dosing regimen in Chinese patients.

Official Title
-----------------
The Pharmacokinetics and Pharmacodynamics Study of Intravenous Zoledronic Acid in Chinese Subjects With Low Bone Mass or Osteoporosis: a Randomized Placebo-controlled Trail

Conditions
-----------------
Postmenopausal Osteoporosis

Intervention / Treatment
-----------------
* Drug: Zoledronic Acid Injection
* Drug: Zoledronic Acid Injection
* Drug: Zoledronic Acid Injection
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Chinese postmenopausal women Aged between 60 and 70. Bone mineral density (BMD) values of less than 1 standard deviations (SD) below the normal adult mean. Willing to participate in this study. Exclusion Criteria: Hypersensitivity to zoledronic acid or other bisphosphonate or zoledronic acid formulation (excipients). Secondary osteoporosis. Receiving the following drugs that affect bone metabolism prior to randomization: (1) intravenous biphosphonates or denosumab. (2) oral biphosphonates, parathyroid hormone or its analogues, strontium, or fluoride within 12 months. (3) glucocorticoid, steroids, immunosuppressive agents, calcitonin, calcitriol or its analogues, thiazides diuretics, long-acting estrogen/progesterone, or statins within 3 months. 4. Combine other diseases affect bone metabolism: osteogenesis imperfecta, hyperthyroidism, malignant tumors, Paget's disease, rheumatoid arthritis, osteomalacia, osteopetrosis, ankylosing spondylitis, liver failure, or renal failure. 5. Hyperthyroidism or hypothyroidism during screening. 6. Treatment with any investigational drug within the past 3 months. 7. Creatinine clearance < 35 mL/min. 8. 25(OH)D level< 20 ng/mL. 9. Serum calcium level < 2.0 mmol/L (8 mg/dL), or >2.8 mmol/L (11.0 mg/dL). 10. Fever, severe infections, severe injuries, or major surgical operation within 30 days. 11. ECG corrected QT interval (QTc) > 480 ms. 12. Pending invasive dental procedure or in progress. 13. History of smoking within 6 months. 14. Diabetes with fasting blood glucose ≥ 7.0 mmol/L, or glycated hemoglobin (HbA1c) >6.3%. 15. History of drug or alcohol abuse. 16. History of stroke, cerebral ischemic stroke, or cerebral hemorrhage. 17. Any physiological or medical condition which, in the opinion of the investigator, would preclude the participant from this trail.

Ages Eligible for Study
-----------------
Minimum Age: 60 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: zoledronic acid 1mg<br>Add 20 mL of Zoledronic acid injection (100mL : 5mg) with 80 mL of normal saline to 100 mL. Infusion 20 minutes with constant speed. Administration only once. | Drug: Zoledronic Acid Injection<br>* Infusion 1mg zoledronic acid once.<br>* Other names: Yigu;|
| Experimental: zoledronic acid 2.5mg<br>Add 50 mL of Zoledronic acid injection (100mL : 5mg) with 50 mL of normal saline to 100 mL. Infusion 20 minutes with constant speed. Administration only once. | Drug: Zoledronic Acid Injection<br>* Infusion 2.5mg zoledronic acid once.<br>* Other names: Yigu;|
| Experimental: zoledronic acid 5mg<br>Infusion 100 mL of Zoledronic acid injection (100mL : 5mg) with constant speed in 20 minutes. Administration only once. | Drug: Zoledronic Acid Injection<br>* Infusion 5mg zoledronic acid once.<br>* Other names: Yigu;|
| Placebo Comparator: placebo<br>Infusion 100 mL of normal saline with constant speed in 20 minutes. Administration only once. | Drug: Placebo<br>* Infusion normal saline once.<br>* Other names: Yigu Placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of Zoledronic acid | Zoledronic acid concentration in plasma and urine. | Predose, 30 minutes, 2 hours, 24 hours, day 7, day 29, 3 months, 6 months, 12 months, 24 months, and 36 months post dose | 
| Maximum concentration of Zoledronic acid | The observed maximum concentration following administration (Cmax) in plasma after zoledronic acid infusion. | 0-36 months | 
| Time to reach maximum concentration of Zoledronic acid | The time to reach the maximum concentration after administration (Tmax) in plasma after zoledronic acid infusion. | 0-36 months | 
| AUC of Zoledronic acid | The area under the concentration-time curve (AUC) in plasma after zoledronic acid infusion. | 0-36 months | 
| terminal half-life of Zoledronic acid | The terminal half-life (t1/2) of zoledronic acid after administration. | 0-36 months | 
| apparent clearance of Zoledronic acid | The apparent clearance (CL/F) of zoledronic acid after administration. | 0-36 months | 
| apparent volume of distribution of Zoledronic acid | The apparent volume of distribution of zoledronic acid after administration. | 0-36 months | 
| Concentration of bone turnover markers | Concentration-time profile of procollagen type 1 N-propeptide (P1NP), bone-specific alkaline phosphatase (ALP), osteocalcin (OCN), C-telopeptide (CTx), and tartrate-resistant acid phosphatase 5b (TRACP-5b) with unit of ng/mL. | 0-36 months | 
| Concentration of 25(OH)D and FGF23 | Concentration determination of 25(OH)D and fibroblast growth factor 23 (FGF23) with unit of ng/mL | 0-36 months | 
| PTH concentration determination | Assessment of the profile of parathyroid hormone (PTH) | 0-36 months | 
| Serum sclerostin concentration determination | Concentration-time profile of sclerostin (SOST) after zoledronic acid infusion. | 0-36 months | 
| Pharmacodynamic of zoledronic acid | Assessment of lipid metabolism markers, such as low density lipoprotein (LDL), high density lipoprotein (HDL), total cholesterol, and triglycerides. | 0-36 months | 
| Pharmacodynamic of zoledronic acid | Assessment of fibroblast growth factor 19 (FGF19). | 0-36 months | 
| Pharmacodynamic of zoledronic acid | Assessment of total bile acid. | 0-36 months | 
| Pharmacodynamic of zoledronic acid | Assessment of bone mineral density at the lumbar spine, neck of femur, and total hip. | 0-36 months | 
| Change of immune indicator | Changes in white blood cells(WBC) | 0-36 months | 
| Change of immune indicator | Changes in C reaction protein (CRP) | 0-36 months | 
| Change of immune indicator | Changes in interferon-γ (IFN-γ) | 0-36 months | 
| Change of immune indicator | Changes in interleukin-6 (IL-6) | 0-36 months | 
| Change of immune indicator | Changes in γδT cells activation | 0-36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse event | The occurrence time and severity of fracture. The occurrence time and severity of acute phase response. The occurrence time and severity of other adverse event. | 0-36 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
zoledronic acid, pharmacokinetic, pharmacodynamic, Chinese osteoporosis