Understanding the mechanism of the acute phase response following intravenous (IV) bisphosphonates and its prevention: a study of the effects of zoledronic acid and co-prescription with fluvastatin or placebo
| ISRCTN | ISRCTN37909269 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN37909269 |
| Secondary identifying numbers | CZOL446H GB09 |
- Submission date
- 04/04/2008
- Registration date
- 29/08/2008
- Last edited
- 05/04/2012
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Musculoskeletal Diseases
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English summary of protocol
Not provided at time of registration
Contact information
Prof David M Reid
Scientific
Scientific
Division of Applied Medicine
Medical School
University of Aberdeen
Foresterhill
Aberdeen
AB24 1FX
United Kingdom
| Phone | +44 1224 51154 |
|---|---|
| d.m.reid@abdn.ac.uk |
Study information
| Study design | Single-centre, randomised controlled trial. |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Not specified |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | |
| Study objectives | That co-treatment of patients receiving potent nitrogen containing bisphosphonates (N-BP), with a statin, would prevent the activation and increase in gamma,delta-T cells and therefore prevent the subsequent acute phase response that occurs after the infusion of the N-BP. |
| Ethics approval(s) | Grampian Local Research Ethics Committee. Date of approval: 24/03/2005 (ref: 05/S0801/39) |
| Health condition(s) or problem(s) studied | Osteopenia/ osteoporosis |
| Intervention | The participants will be randomly allocated to the following three arms: Arm 1: Oral fluvastatin (40 mg immediate release formulation) immediately prior to an intravenous (iv) infusion of zoledronic acid (5 mg) + an oral dose placebo fluvastatin on the 1st and 2nd day after the infusion. Arm 2: Single dose of matching placebo fluvastatin, immediately prior to an infusion of zoledronic acid (5 mg) and an oral dose placebo fluvastatin on the 1st and 2nd day after the infusion. Arm 3: Oral dose of fluvastatin (40 mg immediate release formulation) immediately prior to an iv infusion of zoledronic acid (5 mg) + an oral dose of fluvastatin on the 1st and 2nd day after the bisphosphonate infusion. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Specified |
| Drug / device / biological / vaccine name(s) | Bisphosphonates, zoledronic acid and fluvastatin. |
| Primary outcome measure | Serum C reactive protein (CRP) at 72 hours. |
| Secondary outcome measures | 1. Changes in cytokines (tumour necrosis factor-alpha [TNF-alpha], interleukin-6 [IL-6] and interferon gamma) at 24 hours 2. Changes in serum cholesterol at 48 hours 3. Alterations in temperature post infusion (at 24 hours) 4. Alterations in acute phase response as assessed by questionnaire at 72 hours |
| Overall study start date | 01/06/2005 |
| Completion date | 30/04/2008 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Female |
| Target number of participants | 60 |
| Key inclusion criteria | 1. Postmenopausal women over the age of 20 and more than 12 months after cessation of menses or with serum estradiol and/or follicle stimulating hormone (FSH) levels consistent with a post-menopausal state, but <= 10 years post menopause 2. Bisphosphonate naïve women with osteopenia as defined by the World Health Organization (WHO) (T-score <= 1.0 but >-2.5) or osteoporosis as defined by the WHO (T-score <-2.5) at the lumbar spine or total hip Bone Mineral Density (BMD) measurement sites 3. Women willing and able to give informed consent |
| Key exclusion criteria | 1. The patient has a history of hypersensitivity to any statin or previously exposed to fluvastatin 2. The patient has a history of any illness or has significant abnormalities on pre-study clinical or laboratory evaluation which, in the opinion of the investigator, might either pose an unacceptable risk to the patient from participation in this study or complicate the interpretation of study data 3. The patient is a current user of any illicit drugs or has a history of drug or alcohol abuse within the past five years 4. The patient has a history of or evidence for metabolic bone disease (other than postmenopausal bone loss) including but not limited to vitamin D deficiency, hypoparathyroidism, primary hyperparathyroidism, recent hyperthyroidism (suppressed thyroid stimulating hormone [TSH] within the six months prior to entry into the study), Paget's disease of bone, osteomalacia or renal osteodystrophy 5. The patient has any other disease potentially associated with increased bone turnover including, but not exclusive to, rheumatoid arthritis, Crohn's disease, severe renal impairment or severe hepatic disease 6. The patient has a history of cancer except for the following: 6.1. Superficial basal or squamous cell carcinoma of the skin which has been completely resected 6.2. Stage I breast cancer (lesion <= 3 cm with no nodal or local invasion) which has been completely treated more than one year ago with no evidence of recurrence 6.3. Other malignancies completely treated without recurrence or treatment in the last 5 years 7. Baseline renal insufficiency defined as either baseline creatinine of >177 mmol/l and/or calculated creatinine clearance of < 40ml/min 8. Serum 25-OH vitamin D level <15 ng/ml 9. Serum calcium <2 mmol/L and >2.75 mmol/L 10. Serum alkaline phosphatase >1.5x Upper Limit of Normal (ULN) and/or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 x ULN 11. The patient is receiving or has received treatment prior to randomisation which might influence bone turnover, including: 11.1. Any treatment with parathyroid hormone during the year prior to randomisation 11.2. Within the last 6 months: oestrogen, oestrogen analogues (e.g., raloxifene, tamoxifen), tibolone or anabolic steroids. Oestrogen taken >3 months ago for <= 1 week is acceptable. Topical (vaginal) oestrogen cream (<= 2 g) used up to two times weekly is acceptable 11.3. Thyroid hormone, unless on a stable dose for at least six weeks before randomisation with serum TSH within the normal range; patients found at screening to have mild hypothyroidism (as indicated by an elevation in TSH to no more than 15 µIU/ml) are eligible to enter the study provided they receive careful thyroid replacement therapy, if needed, and TSH levels are monitored three months later and as appropriate during the study 11.4. Glucocorticoid treatment for more than one month with >7.5 mg of oral prednisone (or the equivalent) per day within six months prior to randomisation; high-dose, intravenously within 6 months prior to randomisation; patients who have received therapeutic glucocorticoids in the past must be considered highly unlikely to require retreatment (with >7.5 mg of oral prednisone daily or the equivalent for more than one month or <= 500 mg of methylprednisolone pulse at any time) during the course of the study 12. Treatment with an immunosuppressant (e.g., cyclosporine, azathioprine) within the previous year 13. The patient is receiving or is expected to receive during the course of the study any medication (other than study medication) that might alter bone or calcium metabolism, including vitamin D in excess of 5000 IU per day, calcitonin, phenytoin, heparin, or lithium 14. HIV patients 15. No History of uveitis, iritis or conjunctivitis 16. No history of retinopathy or nephropathy especially in the presence of uncontrollable insulin dependent diabetes mellitus HB1AC >10%. 17. Any patient with severe dental problems or current dental infections, or with recent or pending surgery within 3 months of dosing |
| Date of first enrolment | 01/06/2005 |
| Date of final enrolment | 30/04/2008 |
Locations
Countries of recruitment
- Scotland
- United Kingdom
Study participating centre
Division of Applied Medicine
Aberdeen
AB24 1FX
United Kingdom
AB24 1FX
United Kingdom
Sponsor information
University of Aberdeen (UK)
University/education
University/education
c/o Mr Fred Stevenson-Robb
Research & Innovation
Regent Walk
Aberdeen
AB24 1FX
Scotland
United Kingdom
| f.stevenson-robb@abdn.ac.uk | |
| Website | http://www.abdn.ac.uk |
"ROR" |
https://ror.org/016476m91 |
Funders
Funder type
Industry
Novartis Pharmaceuticals (Switzerland)
No information available
Results and Publications
| Intention to publish date | |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not provided at time of registration |
| Publication and dissemination plan | Not provided at time of registration |
| IPD sharing plan |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 01/07/2011 | Yes | No |
