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Trial registered on ANZCTR


Registration number
ACTRN12620000656932
Ethics application status
Approved
Date submitted
21/04/2020
Date registered
5/06/2020
Date last updated
26/05/2024
Date data sharing statement initially provided
5/06/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Duloxetine and Pregabalin for Neuropathic Cancer Pain
Scientific title
A Phase III, international, multi-centre, double-blind, dose increment, parallel-arm, randomised controlled trial of duloxetine versus pregabalin over 14 days for cancer-related neuropathic pain.
Secondary ID [1] 301051 0
040/18
Universal Trial Number (UTN)
Trial acronym
Linked study record
The Japanese parallel study is registered via the following link:

https://jrct.niph.go.jp/en-latest-detail/jRCTs051190097

Health condition
Health condition(s) or problem(s) studied:
Neuropathic Cancer Pain 317101 0
Cancer 317102 0
Condition category
Condition code
Anaesthesiology 315266 315266 0 0
Pain management
Cancer 315836 315836 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Duloxetine 30mg/day orally for 7 days, then increase to 60mg/day for 7 days, then downward titrate to 30mg/day for 7 days.
Total duration of treatment is up to 21 days, titrate up to maximal dose to primary endpoint at day 14. Option to be unblinded at Day 14 or taper down dose and cease the study medication. Participants who opt to be unblinded can continue on duloxetine in open-label form, obtained by usual access method and supervised by their usual treating clinician.
Adherence will be monitored by review of daily dosing record completed by participant (at each contact), and reconciliation of returns.
Intervention code [1] 317354 0
Treatment: Drugs
Comparator / control treatment
Pregabalin 50mg/day orally for 3 days, 150mg/day for 4 days, then 300mg/day for 7 days, then downward titration to 150mg/day for 4 days, and 50mg/day for 3 days.
Total duration of treatment is up to 21 days, titrate up to maximal dose to primary endpoint at day 14, Option to be unblinded at Day 14 or taper down dose and cease the study medication. Participants who opt to be unblinded can continue on pregabalin in open-label form, obtained by usual access method and supervised by their usual treating clinician.
Adherence will be monitored by review of daily dosing record completed by participant (at each contact), and reconciliation of returns.
Control group
Active

Outcomes
Primary outcome [1] 323507 0
Primary outcome is a clinically meaningful difference in the worst pain intensity (BPI item 3) (score = 2 out of 10) between groups (pregabalin vs duloxetine).
Timepoint [1] 323507 0
Day 14
Secondary outcome [1] 382093 0
The average pain intensity (BPI items 5)
Timepoint [1] 382093 0
Day 14
Secondary outcome [2] 382095 0
The short-form McGill Pain Questionnaire 2 (SF-MPQ-2 scores)
Timepoint [2] 382095 0
Day 14
Secondary outcome [3] 382096 0
European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C15-PAL
Timepoint [3] 382096 0
Day 14
Secondary outcome [4] 382097 0
The Hospital Anxiety and Depression Scale (HADS)
Timepoint [4] 382097 0
Day 14
Secondary outcome [5] 382098 0
Daily opioid dose using a participant completed daily diary of dosing and medications.
Timepoint [5] 382098 0
Daily to day 21
Secondary outcome [6] 382099 0
Toxicity assessment (NCI CTCAE; Nausea, Light-headedness, Sleepiness, Oedema/PRO-AE)
Timepoint [6] 382099 0
Day 14 and 21
Secondary outcome [7] 382100 0
Percentage of participants with a reduction (BPI-I items 3) decrease from the baseline
Timepoint [7] 382100 0
Days 3, 7 and 21.
Secondary outcome [8] 382101 0
Health service utilization- including planned and unplanned contact, investigations, hospitalisations. Recorded via participant report of health service use.
Timepoint [8] 382101 0
Day 14 and 21
Secondary outcome [9] 433629 0
Percentage of participants who were commenced on pregabalin between referral and baseline with a reduction (BPI-I items 3) from baseline
Timepoint [9] 433629 0
Secondary outcome [10] 433630 0
Percentage of participants who were commenced on pregabalin between referral and baseline with a reduction (BPI-I items 3) from baseline
Timepoint [10] 433630 0
Day 3, Day 7, Day 14

Eligibility
Key inclusion criteria
Inpatients and outpatients with diagnoses of cancer and neuropathic pain (probable or definite neuropathic pain by IASP criteria).
Age 18 years or more.
Able to complete study assessments and comply with the study procedures.
Ability to provide informed written consent.
Pain related to cancer with a worst pain score of 4 or greater on BPI item 3 (worst pain intensity) score within 24 hours of baseline.
Neuropathic Pain on LANSS or s-LANSS of 12 or greater within 7 days of study commencement.
Taking stable regular analgesics and any type of regular adjuvant analgesic except pregabalin and gabapentin within 48 hours before commencing on the study. Methadone dose must be stable for 72 hours before commencing on the study.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Chemotherapy-Induced Peripheral Neuropathy (CIPN) (glove and stocking) as the primary pain. CIPN is allowed as an additional pain if the patient has another source of neuropathic pain.
Spinal cord compression within 4 weeks of baseline. Spinal cord compression which is untreatable or treated at least 4 weeks prior and is on a stable dose of steroids is allowed.
Contraindication for duloxetine or pregabalin.
Taking duloxetine for any reason within 2 weeks of baseline.
Taking pregabalin greater than 50 mg/day for any reason (25 mg per day if the participant has an eGFR 30-50 mL/min/1.73m2) or taking gabapentin greater than 300mg/day for any reason (150mg per day if the participant has an eGFR 30-50 mL/min/1.73m2).
Taking moclobemide or fluvoxamine or venlafaxine for any reason.
Taking reversible monoamine oxidase inhibitors (MAOIs)
Participants who have participated in a clinical trial involving a new chemical entity within four weeks prior to study entry.
Patients with clinically significant cognitive impairment (clinician defined) causing unreliable completion of study procedures.
Patients who have a current or recent history of abuse of alcohol, or recent history of substance misuse..
Patients who are pregnant, breastfeeding or may possibly be pregnant.
Other patients who are determined to be inappropriate for participation in the study by the clinical investigator.
Starting a new chemotherapy regimen within 14 days of baseline .
Patients with renal failure defined as eGFR less than 30ml/min/1.73m2 calculated according to the CKD-EPI formula. For those with a Body Mass Index (BMI)=18, the PI is to individually assess the circumstances of the participant and use an alternative approach to calculate renal function and confirm the absence of renal failure.
Bilirubin greater than twice the upper limit of normal at baseline.

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)
All medicine packs will be prepared by the manufacturer according to the randomisation schedule. Blinded medicine packs, identifiable only by a unique kit-code will be supplied for dispensing to participants. Treatment allocation will not be disclosed to study staff, treating clinicians or investigators while the participant is still on the trial.
Participants may be unblinded after all three of the below criteria are met:
1. After the day 14 visit. Participants who withdraw must still wait until day 14 to be unblinded.
2. After cessation of study medication, including any tapering doses if the participant is tapering.
3. After all assessments have been completed up to and including day 14.
The participant and their treating clinician will be informed of the allocation. All further management will be under the supervision of the treating clinician.

Unblinding outside of the aforementioned conditions will only be in cases of extreme emergency. Such situations only include where knowledge of the treatment allocation will have consequences for clinical decision making in consultation with the Lead Chief Investigator.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The VIEDoc randomisation tool will be used to facilitate randomisation. Treatment for each participant will be allocated in a 1:1 ratio. Randomisation will be done with minimization method, with 7 allocation factors; Country (Australia or Japan), Body weight (greater than or equal to 80kg or less than 80kg), Dose of Opioid (greater than or equal to 90mg oral morphine equivalent dose, 60-90mg, greater than 0 to 60mg, 0mg), Gabapentinoid use in last 24h (none or greater than 0mg), NRS score (greater than or equal to 7, less than or equal to 6 ), HADS score (greater than or equal to 11, less than or equal to 10), and sites.
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
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Primary efficacy outcome is to determine if there is a clinically meaningful difference in the treatment outcomes of participants treated with duloxetine vs pregabalin.
Analysis will use an estimand based approach:
• Population: Participants with neuropathic pain who met the inclusion/exclusion criteria
• Endpoint: Worst pain intensity (BPI item 3) at Day 14
• Treatment condition: While on treatment
• Intercurrent events: Increase in background opioid dose; change in other analgesia or chemotherapy; death; dropout from study; discontinuation of study medication; reduction in dosage of study medication.
• Population level summary: Change in worst pain intensity (BPI item 3) from baseline to Day 14 (by treatment arm) including 95% confidence intervals. Point estimates and 95% Confidence Intervals (CIs) for the difference between the two-group means will be calculated.
Between groups comparisons will be analysed using an analysis of covariance model for the change in worst pain intensity BPI item 3 score from baseline to Day 14 with treatment group, baseline BPI item 3 worst pain intensity score and OME (> 60 mg and = 60 mg) included as independent variables.
A supplementary analysis using a composite strategy will be conducted.
Further details will be included in a separate Statistical Analysis Plan.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/07/2022
Actual
29/11/2022
Date of last participant enrolment
Anticipated
31/03/2025
Actual
Date of last data collection
Anticipated
28/04/2025
Actual
Sample size
Target
84
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 16483 0
Liverpool Hospital - Liverpool
Recruitment hospital [2] 16484 0
Mater Adult Hospital - South Brisbane
Recruitment hospital [3] 16485 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [4] 19888 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [5] 19889 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [6] 19890 0
Calvary Health Care Sydney Ltd - Kogarah
Recruitment hospital [7] 19891 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [8] 19892 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [9] 22662 0
Concord Repatriation Hospital - Concord
Recruitment hospital [10] 26580 0
Mater Mother's Hospital - South Brisbane
Recruitment hospital [11] 26581 0
Mater Private Hospital Brisbane - South Brisbane
Recruitment hospital [12] 26582 0
Mater Private Hospital Redland - Cleveland
Recruitment hospital [13] 26583 0
Mater Private Hospital Springfield - Springfield Central
Recruitment postcode(s) [1] 30033 0
2170 - Liverpool
Recruitment postcode(s) [2] 30034 0
4101 - South Brisbane
Recruitment postcode(s) [3] 30035 0
3050 - Parkville
Recruitment postcode(s) [4] 34589 0
2010 - Darlinghurst
Recruitment postcode(s) [5] 34590 0
3065 - Fitzroy
Recruitment postcode(s) [6] 34591 0
2217 - Kogarah
Recruitment postcode(s) [7] 34592 0
3084 - Heidelberg
Recruitment postcode(s) [8] 34593 0
3000 - Melbourne
Recruitment postcode(s) [9] 37939 0
2139 - Concord
Recruitment postcode(s) [10] 42624 0
4101 - South Brisbane
Recruitment postcode(s) [11] 42625 0
4163 - Cleveland
Recruitment postcode(s) [12] 42626 0
4300 - Springfield Central

Funding & Sponsors
Funding source category [1] 305493 0
Government body
Name [1] 305493 0
NHMRC
Country [1] 305493 0
Australia
Primary sponsor type
University
Name
University of Technology Sydney
Address
15 Broadway
Ultimo NSW 2007
Country
Australia
Secondary sponsor category [1] 305891 0
None
Name [1] 305891 0
Address [1] 305891 0
Country [1] 305891 0
Other collaborator category [1] 281290 0
Other Collaborative groups
Name [1] 281290 0
Japanese Organisation for Research and Treatment of Cancer
Address [1] 281290 0
3 Chome-4-1 Kowakae, Higashiosaka, Osaka 577-8502, Japan
Country [1] 281290 0
Japan

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305805 0
South Western Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 305805 0
Ethics committee country [1] 305805 0
Australia
Date submitted for ethics approval [1] 305805 0
01/05/2020
Approval date [1] 305805 0
19/06/2020
Ethics approval number [1] 305805 0
2019/ETH12548
Ethics committee name [2] 308930 0
Mater Misericordiae LTD Human Research Ethics Committee
Ethics committee address [2] 308930 0
Ethics committee country [2] 308930 0
Australia
Date submitted for ethics approval [2] 308930 0
23/10/2020
Approval date [2] 308930 0
03/12/2020
Ethics approval number [2] 308930 0
69605
Ethics committee name [3] 308931 0
UTS Human Research Ethics Committee
Ethics committee address [3] 308931 0
Ethics committee country [3] 308931 0
Australia
Date submitted for ethics approval [3] 308931 0
08/07/2020
Approval date [3] 308931 0
13/08/2020
Ethics approval number [3] 308931 0
ETH20-5152

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

Contacts
Principal investigator
Name 101658 0
Dr Jessica Lee
Address 101658 0
Department of Palliative Care, Level 2, Building 75, Concord Hospital, Hospital Road, Concord, NSW 2139
Country 101658 0
Australia
Phone 101658 0
+61 2 9767 6799
Fax 101658 0
Email 101658 0
jessica.lee1@health.nsw.gov.au
Contact person for public queries
Name 101659 0
Jessica Lee
Address 101659 0
Department of Palliative Care, Level 2, Building 75, Concord Hospital, Hospital Road, Concord, NSW 2139
Country 101659 0
Australia
Phone 101659 0
+61 2 9767 6799
Fax 101659 0
Email 101659 0
jessica.lee1@health.nsw.gov.au
Contact person for scientific queries
Name 101660 0
Jessica Lee
Address 101660 0
Department of Palliative Care, Level 2, Building 75, Concord Hospital, Hospital Road, Concord, NSW 2139
Country 101660 0
Australia
Phone 101660 0
+61 2 9767 6799
Fax 101660 0
Email 101660 0
jessica.lee1@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data that underlie the results reported in the primary publication, after de-identification (text, tables, figures and appendices). Medicare and all other administrative data will not be available.
When will data be available (start and end dates)?
Data is available from the date of publication, for a period of 15 years.
Available to whom?
Other researchers who have specifically applied to the Principal Investigator and whose projects have appropriate Human Research Ethics committee approval. To be decided on a case by case basis by the Principal Investigator.
Available for what types of analyses?
Data will be available for analysis to achieve the aims in the approved proposal.
How or where can data be obtained?
Anyone who wishes to access the data should submit a proposal to itcc@uts.edu.au for approval. Data requestors will need to sign a data access agreement. After that, the Data Center will transfer the data and other documents to data requestors.


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
No additional documents have been identified.