Clinical Pharmacokinetics and Pharmacodynamics Study of Different Doses of Zoledronic Acid

Postmenopausal Osteoporosis Clinical Trial

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04719650
• Other study ID #: M2020427
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: October 2021
• Est. completion date: November 2024

Study information

• Verified date: January 2021
• Source: Peking University Third Hospital
• Contact: Qi Liu, Ph. D.
• Phone: +8615501060136
• Email: liuqicpu[@]hotmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 64
• Est. completion date: November 2024
• Est. primary completion date: October 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 60 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Osteoporosis
• Osteoporosis, Postmenopausal
• Postmenopausal Osteoporosis

Intervention

Drug:
• Zoledronic Acid Injection
Infusion 1mg zoledronic acid once.
• Zoledronic Acid Injection
Infusion 2.5mg zoledronic acid once.
• Zoledronic Acid Injection
Infusion 5mg zoledronic acid once.
• Placebo
Infusion normal saline once.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Peking University Third Hospital

References & Publications (3)

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. Erratum in: Osteoporos Int. 2015 Jul;26(7):2045-7. — View 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. — View 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. Epub 2003 Apr 10. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Maximum concentration of Zoledronic acid	The observed maximum concentration following administration (Cmax) in plasma after zoledronic acid infusion.	0-36 months
Primary	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
Primary	AUC of Zoledronic acid	The area under the concentration-time curve (AUC) in plasma after zoledronic acid infusion.	0-36 months
Primary	terminal half-life of Zoledronic acid	The terminal half-life (t1/2) of zoledronic acid after administration.	0-36 months
Primary	apparent clearance of Zoledronic acid	The apparent clearance (CL/F) of zoledronic acid after administration.	0-36 months
Primary	apparent volume of distribution of Zoledronic acid	The apparent volume of distribution of zoledronic acid after administration.	0-36 months
Primary	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
Primary	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
Primary	PTH concentration determination	Assessment of the profile of parathyroid hormone (PTH)	0-36 months
Primary	Serum sclerostin concentration determination	Concentration-time profile of sclerostin (SOST) after zoledronic acid infusion.	0-36 months
Primary	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
Primary	Pharmacodynamic of zoledronic acid	Assessment of fibroblast growth factor 19 (FGF19).	0-36 months
Primary	Pharmacodynamic of zoledronic acid	Assessment of total bile acid.	0-36 months
Primary	Pharmacodynamic of zoledronic acid	Assessment of bone mineral density at the lumbar spine, neck of femur, and total hip.	0-36 months
Primary	Change of immune indicator	Changes in white blood cells(WBC)	0-36 months
Primary	Change of immune indicator	Changes in C reaction protein (CRP)	0-36 months
Primary	Change of immune indicator	Changes in interferon-? (IFN-?)	0-36 months
Primary	Change of immune indicator	Changes in interleukin-6 (IL-6)	0-36 months
Primary	Change of immune indicator	Changes in ?dT cells activation	0-36 months
Secondary	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