Pravastatin Reduces Acute Phase Response of Zoledronic Acid

Postmenopausal Osteoporosis Clinical Trial

Official title:

The Reduction Effect of Oral Pravastatin on Acute Phase Response of Intravenous Zoledronic Acid: a Real-world Study

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04719481
• Other study ID #: M2020180
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: November 2021
• Est. completion date: April 2022

Study information

• Verified date: June 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

Acute phase response (APR) is one of the most common adverse events in osteoporosis with zoledronic acid treatment. It's reported that this reaction is related to the blockade of the mevalonate pathway, leading to isopentenyl pyrophosphate (IPP) accumulation. And the latter can active γδT cells in the circulation, resulting in inflammatory cytokine release. Statins can inhibit the conversion of HMG-CoA to mevalonate that may reduce the accumulation of IPP. Therefore, it is possible that statins can be taken in advance to reduce APR caused by zoledronic acid infusion.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 110
• Est. completion date: April 2022
• Est. primary completion date: November 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: N/A and older

Eligibility

Inclusion Criteria:

1. Chinese Han ethnic postmenopausal women.

2. Bone mineral density values of less than 2.5 standard deviations (SD) below the normal adult mean.

3. Willing to participate in this study.

Exclusion Criteria:

1. Prior treatment with biphosphonates (oral or intravenous).

2. Fever and/or any viral or bacterial infections within 30 days prior to randomization.

3. Patients with evidence of any cancer or with a history of cancer.

4. Contraindication to zoledronic acid:

Known hypersensitivity to zoledronic acid or other bisphosphonate or zoledronic acid formulation (excipients); Serum calcium level < 2.13 mmol/L (8.5 mg/dL), free serum calcium level <0.95 mmol/L (3.8 mg/dL) or untreated hypocalcemia; Childbearing or child-breastfeeding women; Creatinine clearance < 35 mL/min;

Restrictions:

Patients currently receiving aminoglycoside, diuretics or thalidomide.

5. Contraindication to pravastatin:

Known hypersensitivity to pravastatin or other excipients in pravastatin sodium formulation.

Restrictions:

Patients with severe liver insufficiency, history of severe liver insufficiency, active liver disease or continuously elevated transaminase; Patients with severe renal insufficiency or history of severe renal insufficiency; Patients currently receiving fibrates (e.g., bezafibrate), immunosuppressive drug (e.g., cyclosporine) or niacin.

6. Any physiological or medical condition which, in the opinion of the investigator, would preclude the participant from this trail.

Related Conditions & MeSH terms

• Acute-Phase Reaction
• Osteoporosis
• Osteoporosis, Postmenopausal
• Postmenopausal Osteoporosis

Intervention

Drug:
• Pravastatin Sodium 80 MG
daily oral administration of 80mg
• Placebo
daily oral administration

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Peking University Third Hospital

References & Publications (4)

Hewitt RE, Lissina A, Green AE, Slay ES, Price DA, Sewell AK. The bisphosphonate acute phase response: rapid and copious production of proinflammatory cytokines by peripheral blood gd T cells in response to aminobisphosphonates is inhibited by statins. Clin Exp Immunol. 2005 Jan;139(1):101-11. — View Citation

Schneiders FL, Huijts CM, Reijm M, Bontkes HJ, Verheul HMW, de Gruijl TD, van der Vliet HJ. The effects of systemic treatment with aminobisphosphonates and statins on circulating V?9Vd2-T cells in patients with advanced cancer. Immunobiology. 2018 Feb;223(2):171-177. doi: 10.1016/j.imbio.2017.10.029. Epub 2017 Oct 16. — View Citation

Sieber P, Lardelli P, Kraenzlin CA, Kraenzlin ME, Meier C. Intravenous bisphosphonates for postmenopausal osteoporosis: safety profiles of zoledronic acid and ibandronate in clinical practice. Clin Drug Investig. 2013 Feb;33(2):117-22. doi: 10.1007/s40261-012-0041-1. — View Citation

Sireci G, Espinosa E, Di Sano C, Dieli F, Fournié JJ, Salerno A. Differential activation of human gammadelta cells by nonpeptide phosphoantigens. Eur J Immunol. 2001 May;31(5):1628-35. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of acute phase response	Effect of oral pravastatin on the incidence of acute phase response within 72 hours after zoledronic acid infusion	0-72 hours
Secondary	Occurrence time of fever	Effect of oral pravastatin on the occurrence time of fever after zoledronic acid infusion	from 8:00 a.m. to 8:00 p.m. with interval of 4 hours in Day -2 and Day -1, from 9:00 a.m. to 9:00 p.m. with interval of 3 hours in Day 0, 1, 2, 3. It should be recorded when fever occurs in other time.
Secondary	Severity of fever	Effect of oral pravastatin on the severity of fever (body temperature) after zoledronic acid infusion.	from 8:00 a.m. to 8:00 p.m. with interval of 4 hours in Day -2 and Day -1, from 9:00 a.m. to 9:00 p.m. with interval of 3 hours in Day 0, 1, 2, 3. It should be recorded when fever occurs in other time.
Secondary	Occurrence time of pain	Effect of oral pravastatin on the occurrence time of pain after zoledronic acid infusion	from 8:00 a.m. to 8:00 p.m. with interval of 4 hours in Day -2 and Day -1, from 9:00 a.m. to 9:00 p.m. with interval of 3 hours in Day 0, 1, 2, 3. It should be recorded when pain occurs in other time.
Secondary	Severity of pain	Effect of oral pravastatin on the severity of pain (visual analogue scale, VAS) after zoledronic acid infusion	from 8:00 a.m. to 8:00 p.m. with interval of 4 hours in Day -2 and Day -1, from 9:00 a.m. to 9:00 p.m. with interval of 3 hours in Day 0, 1, 2, 3. It should be recorded when pain occurs in other time.
Secondary	Frequency of acetaminophen usage after zoledronic acid infusion	To compare the frequency of acetaminophen within 72 hours after zoledronic acid infusion between pravastatin arm and placebo arm.	within 72 hours after zoledronic acid infusion
Secondary	Amount of acetaminophen usage after zoledronic acid infusion	To compare the amount of acetaminophen within 72 hours after zoledronic acid infusion between pravastatin arm and placebo arm.	within 72 hours after zoledronic acid infusion
Secondary	White blood cells	To compare the changes in white blood cells (WBC) count within 48 hours after zoledronic acid infusion between pravastatin arm and placebo arm.	baseline and 48 hours after infusion
Secondary	C reaction protein	To compare the changes in C reaction protein (CRP) within 48 hours after zoledronic acid infusion between pravastatin arm and placebo arm.	baseline and 48 hours after infusion
Secondary	interferon-? expression	To compare the changes in interferon-? (IFN-?) within 48 hours after zoledronic acid infusion between pravastatin arm and placebo arm.	baseline and 48 hours after infusion
Secondary	interleukin-6 expression	To compare the changes in interleukin-6 (IL-6) within 48 hours after zoledronic acid infusion between pravastatin arm and placebo arm.	baseline and 48 hours after infusion
Secondary	?dT cells activation	To compare the changes in count of ?dT cells activation within 48 hours after zoledronic acid infusion pravastatin arm and placebo arm.	baseline and 48 hours after infusion
Secondary	Adverse event occurrence	The occurrence of adverse event within 10 days after zoledronic acid infusion	0-10 days