Trial Review

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Trial registered on ANZCTR


Registration number
Help: Registration number
ACTRN12626001192370
Ethics application status
Help: Ethics application status
Approved
Date submitted
Help: Date submitted
17/05/2026
Date registered
Help: Date registered
24/09/2026
Date last updated
Help: Date last updated
24/09/2026
Date data sharing statement initially provided
Help: Data sharing statement date
24/09/2026
Type of registration
Help: Type of registration
Prospectively registered

Titles & IDs
Public title
Botulinum type A neurotoxin (Btx-A) for residual limb pain after major lower limb amputation
Scientific title
RELIEF: REsidual Limb pain after major lower limb amputation: an evaluation of Btx-A Injection Efficacy and saFety
Additional trial identifiers [1] 317313 0
Nil.
Universal Trial Number (UTN)
U1111-1327-1009
Trial acronym
RELIEF
Related trial records

Health condition
Health condition(s) studied:
Residual limb pain after major lower limb amputation 341956 0
Condition category
Condition code
Anaesthesiology 338031 338031 0 0
Pain management
Physical Medicine / Rehabilitation 338032 338032 0 0
Other physical medicine / rehabilitation
Neurological 338438 338438 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of the intervention or exposure
Treatment as usual plus three sessions of Botulinum type A neurotoxin (Btx-A) injections, administered by a study physician over a 4 week period, each spaced two weeks apart (week 0, week 2, week 4). Btx-A will be reconstituted with 0.9% normal saline at a concentration of 60 units/ml. An injection dosage of 120 units of Btx-A (Dysport) will be delivered subcutaneously to the residual limb in the first session. Identical procedures will be followed in the 2nd and 3rd administrations, but the dose of Btx-A delivered will be increased to 180, then 300 units respectively. Treatment adherence, including number of injection sessions completed and the number of injections per session, will be recorded. Total study duration will be 16 weeks. Treatment as usual will be carefully documented for each participant and may include regular pharmacological (e.g. anticonvulsants) or non-pharmacological (e.g. mirror therapy) interventions. During the 16-week trial period, participants will be asked not to start any new pain treatments or change their pain medication dose without first consulting with the study team.
Intervention code [1] 334091 0
Treatment: Drugs
Description of the comparator or control
Treatment as usual plus three sessions of placebo (0.9% normal saline) injections subcutaneously to the residual limb spaced two weeks apart. Treatment adherence, including the number of injection sessions completed and the number of injections per session, will be recorded.
Control group
Placebo

Outcomes
Primary outcome [1] 345439 0
Proportion of responders (%), defined as greater than or equal to 50% improvement in residual limb pain
Timepoint [1] 345439 0
From week 0 (baseline) to week 7 (primary endpoint) and from week 0 (baseline) to week 16.
Secondary outcome [1] 461664 0
Proportion of responders, defined as greater than or equal to 30% improvement in residual limb pain
Timepoint [1] 461664 0
From week 0 (baseline) to week 7 and from week 0 (baseline) to week 16.
Secondary outcome [2] 461665 0
Proportion of responders, defined as greater than or equal to a 50% improvement in phantom limb pain
Timepoint [2] 461665 0
From week 0 (baseline) to week 7 and from week 0 (baseline) to week 16.
Secondary outcome [3] 461666 0
Proportion of responders, defined as greater than or equal to a 30% improvement in phantom limb pain
Timepoint [3] 461666 0
From week 0 (baseline) to week 7 and from week 0 to week 16.
Secondary outcome [4] 461667 0
Worst pain intensity - residual limb pain
Timepoint [4] 461667 0
Week 0 (baseline), week 7 and week 16
Secondary outcome [5] 461668 0
Worst pain intensity - phantom limb pain
Timepoint [5] 461668 0
Week 0 (baseline), week 7, week 16
Secondary outcome [6] 461669 0
Pain interference - Residual limb pain
Timepoint [6] 461669 0
Week 0 (baseline), week 7 and week 16.
Secondary outcome [7] 461670 0
Pain interference - Phantom limb pain
Timepoint [7] 461670 0
Week 0 (baseline), week 7 and week 16
Secondary outcome [8] 461671 0
Condition-Specific Quality of Life
Timepoint [8] 461671 0
Week 0 (baseline), week 7 and week 16
Secondary outcome [9] 461672 0
Psychological distress
Timepoint [9] 461672 0
Week 0 (baseline), week 7 and week 16
Secondary outcome [10] 461673 0
Health Related Suffering / Burden
Timepoint [10] 461673 0
Week 0 (baseline), week 7, week 16.
Secondary outcome [11] 461674 0
Sleep Quality
Timepoint [11] 461674 0
Week 0 (baseline), week 7, week 16
Secondary outcome [12] 461675 0
Health Related Quality of Life
Timepoint [12] 461675 0
Week 0 (baseline), week 7 and week 16
Secondary outcome [13] 461677 0
Prosthesis Wear
Timepoint [13] 461677 0
Week 0 (baseline, week 7 and week 16
Secondary outcome [14] 461678 0
Perceived Treatment Effect
Timepoint [14] 461678 0
Week 7, Week 16
Secondary outcome [15] 461679 0
Adverse Events - Injection Related Pain
Timepoint [15] 461679 0
Week 0, Week 2, Week 4
Secondary outcome [16] 461680 0
Treatment Emergent Adverse Events
Timepoint [16] 461680 0
From week 0 (baseline) to week 16

Eligibility
Key inclusion criteria
Males and females 18 years of age or older who have had an above knee or below knee lower limb amputation, who are otherwise medically stable, have had ongoing residual limb pain for 3 months or more and who report average residual limb pain in the last week of greater than or equal to 4/10 on a scale of 0 = “no pain” and 10 = “pain as bad as you can imagine” that is interfering with their prosthetic use, activities of daily living, sleep or mood at the time of initial screening
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Healthy volunteers
No
Key exclusion criteria
Pregnancy or planning pregnancy; Have not yet attended an initial appointment with Peke Waihanga (NZ Artificial Limb Service); History of botox injection; History of botulism, allergy or hypersensitivity to botulinum toxin; Disorders of the neuromuscular junction (e.g. myasthenia); Current use of pain neuromodulation therapies (e.g., spinal cord stimulation); Active infection at the injection site; Major psychiatric disorders with active psychosis or Current addiction or treatment under community alcohol and drugs services.

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)
sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified by sex and the presence of allodynia on an initial screening questionnaire and randomised in a 2:1 ratio to the intervention or control groups using a computer-generated randomisation schedule with permuted blocks of variable size.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint/s
Statistical methods / analysis
To observe a between-group difference in the primary outcome with 80% power and a two-sided alpha of p<0.05, an estimated sample size of 36 participants (24 intervention, 12 control) is required, based on an expected responder proportion of 18% in the control group [34] and (estimated) 65% in the intervention group. To account for up to a 25% dropout rate [21], the recruitment target will be 48 participants (32 intervention, 16 control). However, due to a lack of similar, prior research to estimate the responder proportion in the intervention group (i.e. multiple Btx-A administrations in a RLP population, specifically), an adaptive design will be employed, with the required sample size re-estimated after 24 (50%) participants have completed follow-up, based on the observed responder proportions in each group.

Study results will first undergo descriptive level statistical analyses. All data will be analysed by both intention-to-treat and per-protocol (all participants who completed the intervention as planned). The primary outcome (proportion of responders) will be compared between groups using stratified multivariable logistic regression and mixed models, with treatment group as the independent variable and covariates of stratification factors (allodynia, sex), and other potential confounders. The difference in secondary outcomes at week 7 and 16 follow up points will be analysed with linear or general linear mixed effects models, controlling for baseline scores, stratification factors and other potential confounders. For secondary outcomes, a sequential Holm-Bonferroni correction for multiple comparisons will be utilised. We will report the number of participants with missing scores for each outcome and any imputations will be carried out consistent with the approaches laid out in Gelman and Hill [37]. We will report our imputation methods (if any), and we will perform a sensitivity analysis, examining effects on the outcomes reported, using the approach recommended by White et al [38]. With respect to participant safety, discontinuation rates, serious adverse events and treatment emergent adverse events will be reported and, where appropriate, compared between groups using independent t-tests, mann-whitney u, chi-square or fisher’s exact tests. While underpowered for formal statistical analysis, safety and efficacy outcomes will also be reported by sex, given established sex differences in both pain mechanisms and response to other treatments [28]. With respect to participant safety, pain on injection, discontinuation rates, serious adverse events and treatment emergent adverse events will be reported and, where appropriate, compared between groups using independent t-tests, mann-whitney u, chi-square or fisher’s exact tests. All tests will be two sided, with statistical significance set at < 0.05.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/10/2026
Actual
Date of last participant enrolment
Anticipated
1/11/2027
Actual
Date of last data collection
Anticipated
31/03/2028
Actual
Sample size
Target
48
Accrual to date
Final
Recruitment outside Australia
Country [1] 28108 0
New Zealand
State/province [1] 28108 0

Funding & Sponsors
Funding source category [1] 321881 0
Charities/Societies/Foundations
Name [1] 321881 0
Auckland Medical Research Foundation
Country [1] 321881 0
New Zealand
Primary sponsor type
University
Name
Auckland University of Technology
Address
Country
New Zealand
Secondary sponsor category [1] 324741 0
None
Name [1] 324741 0
Address [1] 324741 0
Country [1] 324741 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 320420 0
Northern B Health and Disability Ethics Committee 
Ethics committee address [1] 320420 0
Ethics committee country [1] 320420 0
New Zealand
Date submitted for ethics approval [1] 320420 0
16/04/2026
Approval date [1] 320420 0
25/05/2026
Ethics approval number [1] 320420 0

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

Contacts
Principal investigator
Name 150426 0
Prof David Rice
Address 150426 0
Auckland University of Technology, 90 Akoranga Drive, Northcote, 0626, Auckland
Country 150426 0
New Zealand
Phone 150426 0
+64 09 921 9999
Fax 150426 0
Email 150426 0
[email protected]
Contact person for public queries
Name 150427 0
David Rice
Address 150427 0
Auckland University of Technology, 90 Akoranga Drive, Northcote, 0626, Auckland
Country 150427 0
New Zealand
Phone 150427 0
+64 09 921 9999
Fax 150427 0
Email 150427 0
[email protected]
Contact person for scientific queries
Name 150428 0
David Rice
Address 150428 0
Auckland University of Technology, 90 Akoranga Drive, Northcote, 0626, Auckland
Country 150428 0
New Zealand
Phone 150428 0
+64 09 921 9999
Fax 150428 0
Email 150428 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• Researchers
Conditions for requesting access:
• Yes, conditions apply:
• Requires review on a case-by-case basis by the trial custodian, sponsor or data sharing committee
• Requires a data sharing agreement between data requester and trial custodian or sponsor
What individual participant data might be shared?
• All de-identified individual participant data
What types of analyses could be done with individual participant data?
• Any type of analysis (i.e. no restrictions on data re-use)
When can requests for individual participant data be made (start and end dates)?
From:
After publication of main results
To:
Not yet decided
Where can requests to access individual participant data be made, or data be obtained directly?
• Email of trial custodian, sponsor or committee: [email protected]

Are there extra considerations when requesting access to individual participant data?
No


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.