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Trial registered on ANZCTR


Registration number
ACTRN12621000415808
Ethics application status
Approved
Date submitted
3/02/2021
Date registered
15/04/2021
Date last updated
21/04/2023
Date data sharing statement initially provided
15/04/2021
Date results provided
21/10/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomized study investigating whether taking a steroid medication (dexamethasone) for three days reduces the risk of an acute phase response reaction
Scientific title
A randomized controlled trial to assess the effect of a three day course of dexamethasone on the incidence of the acute phase response following treatment with zoledronic acid
Secondary ID [1] 303336 0
Nil known
Universal Trial Number (UTN)
U1111-1262-1658
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
osteoporosis
 320584 0
Paget's disease 321065 0
Condition category
Condition code
Musculoskeletal 318443 318443 0 0
Osteoporosis
Musculoskeletal 318872 318872 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomized to receive either 3 days of dexamethasone tablets or 3 days of placebo tablets. The group randomized to receive the intervention will receive dexamethasone 4 mg orally administered 1-4 hours prior to the zoledronate infusion and then once daily in the morning for two further days. The method of administration will be an oral tablet.


Intervention code [1] 319646 0
Treatment: Drugs
Comparator / control treatment
The control group will receive a placebo tablet orally administered 1-4 hours prior to the zoledronate infusion and then once daily in the morning for two further days. This will be a glucose tablet.
Control group
Placebo

Outcomes
Primary outcome [1] 326407 0
Between-group difference in temperature change from baseline will be compared. Temperature will be measured by participants using a digital thermometer. Participants will have temperature recorded at baseline and then three times per day (before breakfast, mid-afternoon and bedtime) for three days after the infusion.
Timepoint [1] 326407 0
The change in temperature from baseline over the 72 hours following zoledronic acid infusion will be assessed. The primary outcome will be the difference in temperature between the groups in the first 72 hours (primary timepoint the first 72 hours after the zoledronic acid infusion).

Temperature measurements will occur at the following time-points: At baseline, the temperature will be measured 3 times, each reading taken 1 minute apart. These results will be averaged. Following the intervention, a single temperature measurement will be taken at bedtime on the evening of the intervention. Single temperature measurements will be taken 3 times a day for the 3 days following the intervention, at the following times: first thing in the morning (before breakfast), mid-afternoon, and bedtime.

Between-group difference in temperature change from baseline to bedtime three days after the intervention will be assessed using repeated measures analysis of covariance. All time-points will be included in analysis.
Secondary outcome [1] 391358 0
Between-group difference in change in symptom score from baseline will be compared. Symptom score will be calculated by summing the severity scores for four acute phase response-related symptoms - headache, nausea, muscle or joint pain and feverishness, and could range from 0-12. This is a composite endpoint.

Timepoint [1] 391358 0
Participants will complete a questionnaire regarding symptoms of acute phase response at baseline and will repeat the questionnaire on four consecutive evenings, beginning on the evening of the study intervention. Participants will also receive a phone call from a study investigator 15 days following the zoledronate infusion where they will be asked if they have any symptoms since completing the last symptom questionnaire. The questionnaire used is from a similar study done previously which investigated the efficacy of a single dose of dexamethasone on acute phase response (Billington et al., 2007).
Reference: Billington E, Horne A, Gamble G et al. Effect of single-dose dexamethasone on acute phase response following zoledronic acid : a randomized controlled trial. Osteoporos Int. 2017.Jun;28(6):1867-1874..
Secondary outcome [2] 391375 0
Proportion of patients in each group who have a significant increase in oral temperature following intervention, defined as an increase of at least 1 degree Celsius (to a temperature above 37.5 degrees Celsius) from baseline.
Timepoint [2] 391375 0
Temperature measurements will occur at the following time-points: At baseline, the temperature will be measured 3 times, each reading taken 1 minute apart. These results will be averaged. Following the intervention, a single temperature measurement will be taken at bedtime on the evening of the intervention. Single temperature measurements will be taken 3 times a day for the 3 days following the intervention, at the following times: first thing in the morning (before breakfast), mid-afternoon, and bedtime.

Between-group difference in the proportion of participants with a significant increase in oral temperature at any of the time points following intervention will be compared.
Secondary outcome [3] 391376 0
The difference in proportion of patients in each group reporting worsening severity of at least one acute phase response-related symptom (a change of greater than or equal to 2 severity units on the four-point scale). At baseline, participants will complete a questionnaire relating to four common symptoms of the acute phase response (headache, nausea, muscle or joint symptoms, feverishness) that they may have experienced within the preceding 24 hours. . Participants will assign each symptom a score of 0 (absent), 1 (mild), 2 (moderate) or 3 (severe).

Timepoint [3] 391376 0
Following the intervention, participants will complete this same questionnaire before bed on the evening of the intervention. The questionnaire will be completed again before bed on the following 3 evenings. Fifteen days after the intervention, participants will receive a phone call from a study investigator, where they will be asked the questions on the symptom questionnaire over the phone.
Secondary outcome [4] 391381 0
The difference in proportion of patients receiving an anti-inflammatory medication. At the time of intervention, participants will be provided a form on which to document the use of anti-inflammatory medications. They will be asked to complete this form before bed on the evening of the intervention, and again on the following 3 evenings (4 times total). Each time they complete this form, participants will list the name of the medication taken, the time the medication was taken, and the dose that was taken.
Timepoint [4] 391381 0
Participants will document the use of anti-inflammatory medications on the evening of the intervention, and again for 3 consecutive evenings. Any use of anti-inflammatory medication within 3 days of the invention will be included in analysis.
Secondary outcome [5] 391384 0
Difference in anti-inflammatory dosage between groups will be analysed.

At the time of intervention, participants will be provided a form on which to document the use of anti-inflammatory medications. They will be asked to complete this form before bed on the evening of the intervention, and again on the following 3 evenings (4 times total). Each time they complete this form, participants will list the name of the medication taken, the time the medication was taken, and the dose that was taken.

For each participant, the total dose of anti-inflammatory medication taken in the 3 days following the intervention will be determined, and participants will be grouped based on whether they required no anti-inflammatories, a low dose of anti-inflammatories, or a high dose of anti-inflammatories.
Timepoint [5] 391384 0
Participants will document the use of anti-inflammatory medications on the evening of the intervention, and again for 3 consecutive evenings. All anti-inflammatory medication taken during this time will be included in analysis.

Eligibility
Key inclusion criteria
-Females or males aged greater than or equal to 20 years
-Prescribed zoledronic acid for the first time
Minimum age
20 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-Prior treatment with zoledronic acid
-History of fever, infection, or influenza-like illness within the past week
-Diabetes mellitus
-Uncontrolled hypertension (blood pressure over 160/90)
-Treatment with glucocorticoids within the past week
-History of adverse reaction to glucocorticoids in the past
-Major systemic illness, including malignancy

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Consenting study participants will be assigned a sequential study number. Each number corresponds to sequentially numbered treatment packs, prepared and numbered by study personnel not involved in patient management or endpoint assessment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Treatment allocation will be predetermined using a balanced block design.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
In a previous study, a mean temperature increase of approximately 0.85 degrees Celsius within 34 hours was observed following zoledronic acid infusion, compared to a mean temperature increase of 0.20 degrees Celsius in individuals receiving placebo. Mean difference in temperature change between the groups was 0.65 degrees Celsius [Wark, J.D., et al., Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg. Osteoporos Int, 2012. 23(2): p. 503-12.). A sample size of 60 (30 participants per group) will provide >80% power to detect a temperature difference of at least 0.65 degrees Celsius between treatment groups, at a significance threshold of 5% [Machin, D., et al., Sample Size Tables for Clinical Studies, 2nd Edition. 1997, Malden, MA: Blackwell Science., Zar, J., Biostatistical Analysis (Second Edition). 1984, Englewood Cliffs, New Jersey: Prentice-Hall..) Pass 2018, WWW.NCSS.COM, Kaysville, Utah).

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
30/04/2021
Actual
24/05/2021
Date of last participant enrolment
Anticipated
3/11/2022
Actual
5/09/2022
Date of last data collection
Anticipated
17/11/2022
Actual
20/09/2022
Sample size
Target
60
Accrual to date
Final
60
Recruitment outside Australia
Country [1] 23428 0
New Zealand
State/province [1] 23428 0
Auckland

Funding & Sponsors
Funding source category [1] 307754 0
Charities/Societies/Foundations
Name [1] 307754 0
Health Research Council of New Zealand
Country [1] 307754 0
New Zealand
Primary sponsor type
University
Name
Bone & Joint Research Group, University of Auckland
Address
22-30 Park Avenue,
Grafton,
Auckland 1023
Country
New Zealand
Secondary sponsor category [1] 308455 0
None
Name [1] 308455 0
Address [1] 308455 0
Country [1] 308455 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307775 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 307775 0
Ethics committee country [1] 307775 0
New Zealand
Date submitted for ethics approval [1] 307775 0
02/12/2020
Approval date [1] 307775 0
01/02/2021
Ethics approval number [1] 307775 0
20/CEN/276

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 108454 0
Dr Rachel Murdoch
Address 108454 0
Bone and Joint Research Group,
Faculty of Medical and Health Sciences,
University of Auckland,
Building 507, Lower Ground Level
22-30 Park Avenue
Grafton
Auckland 1023
Country 108454 0
New Zealand
Phone 108454 0
+64 9 923 9787
Fax 108454 0
Email 108454 0
rachel.murdoch@auckland.ac.nz
Contact person for public queries
Name 108455 0
Anne Horne
Address 108455 0
Bone and Joint Research Group,
Faculty of Medical and Health Sciences,
University of Auckland,
Building 507, Lower Ground Level
22-30 Park Avenue
Grafton
Auckland 1023
Country 108455 0
New Zealand
Phone 108455 0
+64 9 923 9787
Fax 108455 0
Email 108455 0
a.horne@auckland.ac.nz
Contact person for scientific queries
Name 108456 0
Anne Horne
Address 108456 0
Bone and Joint Research Group,
Faculty of Medical and Health Sciences,
University of Auckland,
Building 507, Lower Ground Level
22-30 Park Avenue
Grafton
Auckland 1023
Country 108456 0
New Zealand
Phone 108456 0
+64 9 923 9787
Fax 108456 0
Email 108456 0
a.horne@auckland.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No plans to share individual participant data.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseEffect of a Three-Day Course of Dexamethasone on Acute Phase Response Following Treatment With Zoledronate: A Randomized Controlled Trial.2023https://dx.doi.org/10.1002/jbmr.4802
N.B. These documents automatically identified may not have been verified by the study sponsor.