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Trial registered on ANZCTR


Registration number
ACTRN12621000141842
Ethics application status
Approved
Date submitted
26/10/2020
Date registered
11/02/2021
Date last updated
11/02/2021
Date data sharing statement initially provided
11/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
An Exploratory Randomised Controlled Open-Label Study of Methadone Rotation versus Other Opioid Rotation for the Treatment of Refractory Cancer Induced Bone Pain
Scientific title
An Exploratory Randomised Controlled Open-Label Study of Methadone Rotation versus Other Opioid Rotation for the Treatment of Refractory Cancer Induced Bone Pain
Secondary ID [1] 302624 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Refractory Cancer Induced Bone Pain 319521 0
Condition category
Condition code
Cancer 317473 317473 0 0
Any cancer
Anaesthesiology 317945 317945 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be admitted to hospital and rotated from usual opioid to racemic methadone, with the initial dose administered orally or subcutaneously, in the event when the oral route is not available. The methadone dose is not prespecified and will be determined by the patients baseline opioid dose and calculated according to the European Association for Palliative Care and the European Society for Medical Oncology opioid conversion guidelines. The total daily methadone dose will be administered in three or four divided doses for the first 48 hours, with the aim of achieving a twice to three times daily dosing after 5 days. This maintenance dosing scheduled will be ongoing for the duration of the study. Adherence to the intervention will be monitored daily through review of inpatient medication records
Intervention code [1] 318907 0
Treatment: Drugs
Comparator / control treatment
Participants will be admitted to be rotated from their baseline opioid to another opioid (i.e. morphine, hydromorphone or oxycodone). The opioid dose to be administered will be calculated based on their prior baseline opioid dose and using established opioid conversion guidelines. Opioid will be administered either orally or subcutaneously. Frequency of administration is dependent on the pharmacokinetics of the chosen opioid (twice daily for oral morphine and oxycodone and once daily for oral hydromorphone). Opioid rotation will be completed within 24 hours and the patient remains on the prescribed dose for the period of the study (2 weeks). Adherence is monitored through review of the medical records.
Control group
Active

Outcomes
Primary outcome [1] 325503 0
Changes in worst pain intensity at day 14. Pain intensity will be measured using a numerical rating score (0-10) where 0 is no pain and 10 is the worst pain imaginable. A significant response is classified as greater or equal to 30% pain reduction and substantial response as greater or equal to 50% pain reduction.
Timepoint [1] 325503 0
baseline and Day 14 post commencement of rotation
Primary outcome [2] 325950 0
Changes in average pain intensity at day 14. Pain intensity will be measured using a numerical rating score (0-10) where 0 is no pain and 10 is the worst pain imaginable. A significant response is classified as greater or equal to 30% pain reduction and substantial response as greater or equal to 50% pain reduction.
Timepoint [2] 325950 0
baseline and day 14 post commencement of rotation
Secondary outcome [1] 388214 0
Changes in breakthrough pain duration using Breakthrough Pain Assessment Tool
Timepoint [1] 388214 0
baseline, Day 7, Day 14 post commencement of rotation
Secondary outcome [2] 388215 0
Changes in breakthrough pain intensity using Breakthrough Pain Assessment Tool
Timepoint [2] 388215 0
baseline, Day 7, Day 14 post commencement of rotation
Secondary outcome [3] 388216 0
Changes in breakthrough pain frequency using Breakthrough Pain Assessment Tool
Timepoint [3] 388216 0
baseline, Day 7, Day 14 post commencement of rotation
Secondary outcome [4] 388217 0
Frequency of breakthrough analgesia administration based on electronic medical records (inpatient) or a patient medication diary (on discharge). At each time point, the 3-day average medication frequency will be calculated
Timepoint [4] 388217 0
Day 3, Day 5, Day 7, Day 10 and Day 14 post commencement of rotation
Secondary outcome [5] 388218 0
Treatment safety and tolerability. This will be assessed using composite Common Terminology Criteria for Adverse Events scores.
Timepoint [5] 388218 0
Day 3, Day 5, Day 7, Day 10 and Day 14 post commencement of rotation
Secondary outcome [6] 388219 0
Time taken to observe improvement will be calculated as difference between date of commencement of rotation and first date when there is observed greater than or equal to 30% pain reduction using the numerical rating scale (0-10) where 0 is no pain and 10 is worst pain imaginable.
Timepoint [6] 388219 0
Baseline, Day 3, Day 5, Day 7, Day 10 and Day 14 post commencement of rotation
Secondary outcome [7] 389636 0
Opioid escalation index (OEI). OEI is a surrogate marker of opioid responsiveness.
Timepoint [7] 389636 0
Day 14 post commencement of rotation
Secondary outcome [8] 389637 0
Proportion of responders (significant, >=30% reduction in pain score from baseline to day 14) as assessed using the numerical rating scale (0-10) where 0 is no pain and 10 is worst pain imaginable.
Timepoint [8] 389637 0
Day 14 post commencement of rotation
Secondary outcome [9] 389638 0
changes in Quality of Life as measured using the EuroQOL score from baseline
Timepoint [9] 389638 0
baseline, Day 7 and day 14 post commencement of rotation
Secondary outcome [10] 389639 0
changes in anxiety and depression score from baseline, assessed using Hospital Anxiety and Depression Scale
Timepoint [10] 389639 0
baseline, Day 7 and day 14 post commencement of rotation
Secondary outcome [11] 389640 0
Changes in total pain interferences score from baseline, assessed using the Brief Pain Inventory
Timepoint [11] 389640 0
baseline, Day 7 and day 14 post commencement of rotation
Secondary outcome [12] 389642 0
Changes in patient satisfaction with pain relief as assessed using the Brief Pain Inventory
Timepoint [12] 389642 0
baseline, Day 7 and day 14 post commencement of rotation
Secondary outcome [13] 391749 0
Proportion of responders (substantial >= 50% reduction in pain score from baseline to day 14) as assessed using the numerical rating scale (0-10) where 0 is no pain and 10 is worst pain imaginable.
Timepoint [13] 391749 0
Day 14 post commencement of rotation

Eligibility
Key inclusion criteria
• Age at least 18 years.
• Diagnosis of solid tumour or haematological cancer with a predicted prognosis of greater than 8 weeks.
• Diagnosis of CIBP confirmed through radiological investigations and meeting the core diagnostic criteria for CIBP as defined by The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks-American Pain Society (ACTTION-APS).
• On a strong baseline opioid pre-rotation (morphine, oxycodone or hydromorphone).
• Willing to be enrolled in a trial comparing methadone to another opioid rotation, where allocation is at random (1:1).
• greater than or equal to 4 of 10 worst pain from CIBP on 0 to 10 numeric rating scale (NRS) and/ or existing opioid results in opioid toxicity (CTCAE grade 2 or greater).
• Sufficiently proficient in English to be able to complete questionnaires and provide informed consent.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Received radiotherapy in the last 30 days.
• QTc >500msec.
• History of mental health condition or impaired cognition that would prevent completion of questionnaires.
• Too unwell to participate in the study as determined by the patient’s treating physician.

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)
The allocation will not be concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
All participants will be admitted to hospital to initiate study intervention (Methadone Rotation (MR) or Other Opioid Rotation (OOR)). Baseline information will be chelated prior to randomisation. Participants will be randomised to either MR or OOR in a 1:1 ratio using block randomisation with varied block sizes of 2, 4 and 6.

Pharmacy will be notified of participants in the study and a completed script of methadone or other opioid with study ID number will be provided to pharmacy. The participant ID, date of request, preparation and dispensing will be recorded in a log maintained by the site pharmacist for each randomisation. In view of safety, logistical and financial considerations, this study will be an open-label study with both participants and study investigator/ clinicians administering the intervention being aware of treatment allocation. Research staff completing the outcome assessments will be blinded to allocation.

Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Descriptive statistics will be used to summarise study cohort and results reported as mean (SD) or median (Q1-Q3) for continuous data, subject to the results of normality check and N (%) for categorical data. Between groups differences will be assessed using either Student T-test or Wilcoxon rank-sum test for continuous data or either Chi2 or Fisher’s exact test for categorical variables.
Mixed effect model will be used to assess the longitudinal differences in pain reduction, opioids escalation and quality of life measures between methadone and other opioids groups. Survival analysis will be used to compare time to event outcomes (i.e. time taken to observe pain improvement). Kaplan-Meyer survival curves will be constructed and either log-rank test or Cox proportional hazard model will be used. Spearman correlation will be used to examine any correlations between reduction in pain intensity and QOL score, HADS and other relevant continuous outcomes.
The analysis will be performed using Stata16 (StataCorp LS, College Station TX, USA) and p<0.05 will be considered statistically significant for all tests.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
15/02/2021
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 17897 0
Cabrini Hospital - Malvern - Malvern
Recruitment hospital [2] 17898 0
Cabrini Hospital - Prahran - Prahran East
Recruitment postcode(s) [1] 31755 0
3144 - Malvern
Recruitment postcode(s) [2] 31756 0
3181 - Prahran East

Funding & Sponsors
Funding source category [1] 307056 0
Charities/Societies/Foundations
Name [1] 307056 0
Cabrini Foundation Sambor Research Grant
Country [1] 307056 0
Australia
Primary sponsor type
Individual
Name
Dr Merlina Sulistio
Address
Cabrini Health
646 High Street,
Prahran VIC 3181
Country
Australia
Secondary sponsor category [1] 308046 0
Individual
Name [1] 308046 0
A/prof Natasha Michael
Address [1] 308046 0
Cabrini Health
646 High St
Prahran VIC 3181
Country [1] 308046 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307180 0
Monash Health
Ethics committee address [1] 307180 0
Ethics committee country [1] 307180 0
Australia
Date submitted for ethics approval [1] 307180 0
22/10/2020
Approval date [1] 307180 0
03/12/2020
Ethics approval number [1] 307180 0
RES-20-0000869C

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

Contacts
Principal investigator
Name 106306 0
A/Prof Natasha Michael
Address 106306 0
Cabrini Institute, Level 1
154 Wattletree Road,
Malvern, VIC 3141
Country 106306 0
Australia
Phone 106306 0
+61400966376
Fax 106306 0
Email 106306 0
nmichael@cabrini.com.au
Contact person for public queries
Name 106307 0
Natasha Michael
Address 106307 0
Cabrini Institute, Level 1
154 Wattletree Road,
Malvern, VIC 3141
Country 106307 0
Australia
Phone 106307 0
+61400966376
Fax 106307 0
Email 106307 0
nmichael@cabrini.com.au
Contact person for scientific queries
Name 106308 0
Natasha Michael
Address 106308 0
Cabrini Institute, Level 1
154 Wattletree Road,
Malvern, VIC 3141
Country 106308 0
Australia
Phone 106308 0
+61400966376
Fax 106308 0
Email 106308 0
nmichael@cabrini.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not part of the study protocol and consent will not be sought for this


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
EmbaseMethadone rotation versus other opioid rotation for refractory cancer induced bone pain: protocol of an exploratory randomised controlled open-label study.2023https://dx.doi.org/10.1186/s12904-023-01160-1
N.B. These documents automatically identified may not have been verified by the study sponsor.