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Trial registered on ANZCTR


Registration number
ACTRN12615000794505
Ethics application status
Approved
Date submitted
10/07/2015
Date registered
30/07/2015
Date last updated
5/08/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomized controlled trial to assess the effect of dexamethasone on the incidence of the acute phase response following treatment with zoledronic acid
Scientific title
In persons receiving treatment with zoledronic acid for fracture prevention or Paget's disease, does the administration of oral dexamethasone, compared to placebo, reduce the incidence of acute phase response?
Secondary ID [1] 287070 0
Nil
Universal Trial Number (UTN)
U1111-1171-5502
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Osteoporosis 295568 0
Paget's disease 295569 0
Metabolic bone disease 295570 0
Condition category
Condition code
Musculoskeletal 295837 295837 0 0
Osteoporosis
Musculoskeletal 295974 295974 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A single dose of dexamethasone 4mg will be given as an oral tablet at the same time that the zoledronic acid infusion is started.

Zoledronic acid is conventionally given as a dose of 5mg intravenously over 15 minutes. However, it may also be given as a dose of 2.5mg over 30-45 minutes in patients with mild renal impairment. The decision regarding dose and duration of zoledronic acid infusion will be made by the treating physician prior to study enrollment.

To facilitate data collection, participants will receive telephone calls from a study investigator one day, four days, and fifteen days following this intervention.
Intervention code [1] 292302 0
Treatment: Drugs
Comparator / control treatment
Placebo tablets containing microcrystalline cellulose will be given orally at the same time that the zoledronic acid infusion is started.

Zoledronic acid is conventionally given as a dose of 5mg intravenously over 15 minutes. However, it may also be given as a dose of 2.5mg over 30-45 minutes in patients with mild renal impairment. The decision regarding dose and duration of zoledronic acid infusion will be made by the treating physician prior to study enrollment.
Control group
Placebo

Outcomes
Primary outcome [1] 295527 0
Between-group difference in temperature change from baseline. Temperature will be assessed by the participant using a handheld oral thermometer.
Timepoint [1] 295527 0
The change in temperature from baseline over 3 days will be assessed.

Temperature measurements will occur at the following time-points: At baseline, 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] 315781 0
The between group difference in change in symptom score from baseline will be assessed.

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. This questionnaire is based on the Generic Assessment of Side Effects (GASE) scale, but has been modified for this study. Participants will assign each symptom a score of 0 (absent), 1 (mild), 2 (moderate) or 3 (severe). The scores assigned to each symptom will be added, to produce an overall symptom score of 0-12.

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.

Between-group change in overall symptom score (0-12) from baseline over 3 days, and also from baseline to 15 days will be assessed.
Timepoint [1] 315781 0
Overall symptom score will be assessed via questionnaire at the following time-points: Symptom score will be assessed at baseline. Following the intervention, overall symptom score will be assessed at bedtime on the evening of the intervention, and again before bed on the following 3 evenings (repeated 4 times in total). Participants will receive a phone call from a study investigator 15 days following the intervention, at which time they will be asked the questions on the questionnaire over the phone, so that an overall symptom score can be calculated.

Between-group difference in change in overall symptom score (0-12) 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 this analysis. Difference in change in overall symptom score from baseline to 15 days following the intervention will also be evaluated.
Secondary outcome [2] 315782 0
Between-group difference in the proportion of patients who have a significant increase in oral temperature (>1.0 degrees celsius). Temperature will be assessed by the participant using a handheld oral thermometer.
Timepoint [2] 315782 0
The change in temperature from baseline over 3 days will be assessed.

Temperature measurements will occur at the following time-points: At baseline, 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] 315783 0
Between-group difference in the proportion of patients reporting worsening severity of at least one symptom related to the acute phase response (defined as a change of 2 or more 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. This questionnaire is based on the Generic Assessment of Side Effects (GASE) scale, but has been modified for this study. Participants will assign each symptom a score of 0 (absent), 1 (mild), 2 (moderate) or 3 (severe).

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.

The proportion of participants who experience an increase in the severity of one or more symptoms at any time point during the follow-up period (defined as an increase of 2 or more severity units on the four-point scale from baseline, such as from 0 to 2 or from 1 to 3) will be compared between the groups.
Timepoint [3] 315783 0
Symptom scores will be assessed via questionnaire at the following time-points: Symptom scores will be assessed at baseline. Following the intervention, symptom score will be assessed at bedtime on the evening of the intervention, and again before bed on the following 3 evenings (repeated 4 times in total). Participants will receive a phone call from a study investigator 15 days following the intervention, at which time symptom scores will be determined.

The proportion of patients who experience an increase in the severity of one or more symptoms at any time point during the follow-up period will assessed after both 3 days of follow-up and again after 15 days of follow-up.
Secondary outcome [4] 315895 0
Between group difference in the proportion of patients requiring anti-inflammatory medication during the follow-up period.

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] 315895 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] 315896 0
Between-group difference in anti-inflammatory dosage during the follow-up period.

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] 315896 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 20 or older.
Prescribed zoledronic acid for the first time for fracture prevention or Paget's disease.
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 or uncontrolled hypertension (BP >160/90)
Treatment with glucocorticoids within the past week.
History of adverse reaction to glucocorticoids.
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. Treatment allocation will be predetermined using a balanced block design. Participants, study investigators, and the treating physicians and nurses will be blinded to treatment allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Blocks of varying sizes will be created and each row within the block will be assigned a random number (EXCEL 2013 rand() function). Blocks will be balanced for age, to ensure an equal number of participants 70 years or older in each group. Within each block, the rows will be sorted and those 50% of rows with the smallest numbers will be assigned placebo, and the remainder dexamethasone.
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 et al, Osteoporosis International 2012;23:503-512). A sample size of 40 (20 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%, allowing for 10% loss to follow-up (Pass 2002, WWW.NCSS.COM, Kaysville, Utah).

Change from baseline in mean temperature prior to infusion to morning, noon and night for three successive days will be modeled using a mixed effect model approach to repeated measures. The main effects of treatment allocation and time and their interaction will be modeled in the analysis of covariance (ANCOVA) which will include baseline mean temperature a covariate. Significant main or interaction effects will be further explored using the method of Tukey to preserve an overall pairwise error rate of 5%. In the unlikely event that change in temperature is not normally distributed, an appropriate normalizing transformation will be applied.

The analysis will be undertaken on an intention to treat basis with no data excluded from analysis and initially assuming an unstructured covariance. In secondary analysis, any missing temperatures will be imputed using standard imputation procedures (Proc Impute, SAS).

Should the distribution of change in symptom scores over time be normally distributed the same analysis method as will be used for change in temperature will be used, else repeated measures categorical modelling will be employed.

In sensitivity analysis, the potentially confounding effect of eGFR will be examined by repeating the primary analysis excluding those with impaired renal function (eGFR <60 mL/min/1.73m2). The influence of age will be explored by plotting the change in temperature at midday two days following the intervention (the anticipated maximum temperature based on the study by Wark et al, in Osteoporosis International 2012;23:503-512) by age for each treatment arm and comparing the slopes.

In secondary analysis, differences in the proportion of patients with a significant increase in oral temperature (i.e. a rise of > 1 degrees celsius) or a significant increase in symptom severity (i.e. an increase of 3 or more in the sum of symptom severities) will be assessed using Fisher’s exact test, and presented as relative risks. Differences in the proportion of patients who require anti-inflammatory medication will be assessed using Fisher’s exact test. Participants will also be classified into groups based on the dose of anti-inflammatory medication that they take over the 72 hours following the intervention (i.e. none, low dose, high dose), and differences in the proportion of patients in each dosage group will be compared between those who received dexamethasone and those who received placebo using the Chi-squared test.

These analyses will be performed on data from the first 3 days following the intervention. Two additional analyses will be performed, comparing firstly the proportion of people in each arm who have a significant increase in symptom severity reported at the phone call 15 days after the intervention and secondly the proportion in each arm who have a significant increase in symptom severity 15 days following intervention OR 0-3 days following intervention. The frequency of each symptom score 15 days following the intervention will be compared between treatment arms using the Chi-square test.

All tests will be two-tailed, and p <0.05 will be considered statistically significant.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
14/08/2015
Actual
17/09/2015
Date of last participant enrolment
Anticipated
Actual
27/07/2016
Date of last data collection
Anticipated
Actual
29/07/2016
Sample size
Target
40
Accrual to date
Final
40
Recruitment outside Australia
Country [1] 7029 0
New Zealand
State/province [1] 7029 0

Funding & Sponsors
Funding source category [1] 291631 0
University
Name [1] 291631 0
Doctoral Research Fund from the University of Auckland
Country [1] 291631 0
New Zealand
Primary sponsor type
University
Name
Bone & Joint Research Group, University of Auckland
Address
85 Park Road
Grafton, 1011
Auckland
Country
New Zealand
Secondary sponsor category [1] 290302 0
None
Name [1] 290302 0
Address [1] 290302 0
Country [1] 290302 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293161 0
Health and Disability Ethics Committee
Ethics committee address [1] 293161 0
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street
Wellington, 6011
Ethics committee country [1] 293161 0
New Zealand
Date submitted for ethics approval [1] 293161 0
10/07/2015
Approval date [1] 293161 0
26/08/2015
Ethics approval number [1] 293161 0

Summary
Brief summary
The aim of this study is to determine whether the daily temperature profile of patients receiving a zoledronic acid infusion is improved by the administration of oral dexamethasone at the time of infusion, compared to placebo. The study will also assess whether there is a decreased incidence and/or severity of symptoms of acute phase response (APR) with oral dexamethasone compared to placebo.

This is a prospective randomized-controlled trial of 40 individuals undergoing treatment with zoledronic acid for fracture prevention or Paget’s disease. Individuals meeting inclusion criteria will be randomly and equally allocated to receive either dexamethasone 4mg orally or a placebo tablet at the time of zoledronic acid infusion. Incidence and severity of the acute phase response, determined via assessment of symptoms and temperature, will be compared between groups.



At baseline, each participant will undergo oral temperature measurement and will complete a questionnaire relating to symptoms of APR. Daily assessments will continue for 3 days following the intervention. .Fifteen days after the intervention, participants will receive another phone call to inquire about ongoing symptoms.
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 521 521 0 0
/AnzctrAttachments/368914-Dexamethasone RCT - Protocol - draft 3.docx

Contacts
Principal investigator
Name 58714 0
Prof Ian Reid
Address 58714 0
Bone & Joint Research Group
Private Bag 92019
Auckland, 1142
Country 58714 0
New Zealand
Phone 58714 0
+64 9 373 7599
Fax 58714 0
Email 58714 0
[email protected]
Contact person for public queries
Name 58715 0
Emma Billington
Address 58715 0
Bone & Joint Research Group
Private Bag 92019
Auckland, 1142
Country 58715 0
New Zealand
Phone 58715 0
+64 9 923 4139
Fax 58715 0
Email 58715 0
[email protected]
Contact person for scientific queries
Name 58716 0
Emma Billington
Address 58716 0
Bone & Joint Research Group
Private Bag 92019
Auckland, 1142
Country 58716 0
New Zealand
Phone 58716 0
+64 9 923 4139
Fax 58716 0
Email 58716 0
[email protected]

No information has been provided regarding IPD availability


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 single-dose dexamethasone on acute phase response following zoledronic acid: a randomized controlled trial.2017https://dx.doi.org/10.1007/s00198-017-3960-0
N.B. These documents automatically identified may not have been verified by the study sponsor.