Clinical trial NCT04719650: Clinical Pharmacokinetics and Pharmacodynamics Study of Different Doses of Zoledronic Acid
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Postmenopausal Osteoporosis
Keywords: zoledronic acid
pharmacokinetic
pharmacodynamic
Chinese osteoporosis
Lead sponsor: Peking University Third Hospital
Sponsor class: OTHER
First posted: 2021-01-22
Enrollment: 64
Sex: FEMALE
Minimum age (years): 60
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

1. Chinese postmenopausal women
2. Aged between 60 and 70.
3. Bone mineral density (BMD) values of less than 1 standard deviations (SD) below the normal adult mean.
4. Willing to participate in this study.

Exclusion Criteria:

1. Hypersensitivity to zoledronic acid or other bisphosphonate or zoledronic acid formulation (excipients).
2. Secondary osteoporosis.
3. 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.

Primary outcomes:
measure: Concentration of Zoledronic acid
timeFrame: Predose, 30 minutes, 2 hours, 24 hours, day 7, day 29, 3 months, 6 months, 12 months, 24 months, and 36 months post dose
measure: Maximum concentration of Zoledronic acid
timeFrame: 0-36 months
measure: Time to reach maximum concentration of Zoledronic acid
timeFrame: 0-36 months
measure: AUC of Zoledronic acid
timeFrame: 0-36 months
measure: terminal half-life of Zoledronic acid
timeFrame: 0-36 months
measure: apparent clearance of Zoledronic acid
timeFrame: 0-36 months
measure: apparent volume of distribution of Zoledronic acid
timeFrame: 0-36 months
measure: Concentration of bone turnover markers
timeFrame: 0-36 months
measure: Concentration of 25(OH)D and FGF23
timeFrame: 0-36 months
measure: PTH concentration determination
timeFrame: 0-36 months
measure: Serum sclerostin concentration determination
timeFrame: 0-36 months
measure: Pharmacodynamic of zoledronic acid
timeFrame: 0-36 months
measure: Pharmacodynamic of zoledronic acid
timeFrame: 0-36 months
measure: Pharmacodynamic of zoledronic acid
timeFrame: 0-36 months
measure: Pharmacodynamic of zoledronic acid
timeFrame: 0-36 months
measure: Change of immune indicator
timeFrame: 0-36 months
measure: Change of immune indicator
timeFrame: 0-36 months
measure: Change of immune indicator
timeFrame: 0-36 months
measure: Change of immune indicator
timeFrame: 0-36 months
measure: Change of immune indicator
timeFrame: 0-36 months
Secondary outcomes:
measure: Incidence of adverse event
timeFrame: 0-36 months
Other outcomes:
Locations:
Study officials:
affiliation: Peking University Third Hospital
name: Chunli Song, M.D.; Ph. D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R; National Osteoporosis Foundation. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014 Oct;25(10):2359-81. doi: 10.1007/s00198-014-2794-2. Epub 2014 Aug 15.
citation: Shiraki M, Fukunaga M, Kushida K, Kishimoto H, Taketani Y, Minaguchi H, Inoue T, Morita R, Morii H, Yamamoto K, Ohashi Y, Orimo H. A double-blind dose-ranging study of risedronate in Japanese patients with osteoporosis (a study by the Risedronate Late Phase II Research Group). Osteoporos Int. 2003 May;14(3):225-34. doi: 10.1007/s00198-002-1369-9. Epub 2003 Apr 10.
citation: Ding Y, Zeng JC, Yin F, Zhang CL, Zhang Y, Li SX, Liu X, Zhang C, Xue QY, Lin H, Pei FX. Multicenter Study on Observation of Acute-phase Responses After Infusion of Zoledronic Acid 5 mg in Chinese Women with Postmenopausal Osteoporosis. Orthop Surg. 2017 Aug;9(3):284-289. doi: 10.1111/os.12338.