Clinical trial NCT04719481: Pravastatin Reduces Acute Phase Response of Zoledronic Acid
Official title: The Reduction Effect of Oral Pravastatin on Acute Phase Response of Intravenous Zoledronic Acid: a Real-world Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Postmenopausal Osteoporosis
Keywords: acute phase response
zoledronic acid
pravastatin
Lead sponsor: Peking University Third Hospital
Sponsor class: OTHER
First posted: 2021-01-22
Enrollment: 110
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of acute phase response
timeFrame: 0-72 hours
Secondary outcomes:
measure: Occurrence time of fever
timeFrame: 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.
measure: Severity of fever
timeFrame: 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.
measure: Occurrence time of pain
timeFrame: 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.
measure: Severity of pain
timeFrame: 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.
measure: Frequency of acetaminophen usage after zoledronic acid infusion
timeFrame: within 72 hours after zoledronic acid infusion
measure: Amount of acetaminophen usage after zoledronic acid infusion
timeFrame: within 72 hours after zoledronic acid infusion
measure: White blood cells
timeFrame: baseline and 48 hours after infusion
measure: C reaction protein
timeFrame: baseline and 48 hours after infusion
measure: interferon-γ expression
timeFrame: baseline and 48 hours after infusion
measure: interleukin-6 expression
timeFrame: baseline and 48 hours after infusion
measure: γδT cells activation
timeFrame: baseline and 48 hours after infusion
measure: Adverse event occurrence
timeFrame: 0-10 days
Other outcomes:
Locations:
Study officials:
affiliation: Peking University Third Hospital
name: Chunli Song, M.D.; Ph. D.
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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. doi: 10.1111/j.1365-2249.2005.02665.x.
citation: Sireci G, Espinosa E, Di Sano C, Dieli F, Fournie JJ, Salerno A. Differential activation of human gammadelta cells by nonpeptide phosphoantigens. Eur J Immunol. 2001 May;31(5):1628-35. doi: 10.1002/1521-4141(200105)31:53.0.CO;2-T.
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 Vgamma9Vdelta2-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.
citation: Liu Q, Han G, Li R, Fan D, Du G, Zhang M, Tao L, Li H, Liu D, Song C. Reduction effect of oral pravastatin on the acute phase response to intravenous zoledronic acid: protocol for a real-world prospective, placebo-controlled trial. BMJ Open. 2022 Jul 13;12(7):e060703. doi: 10.1136/bmjopen-2021-060703.