TITAN Trial: Reducing Phantom Limb Pain in People With Amputations (TITAN)

TITAN: a Randomised Controlled Trial Investigating the Effectiveness of Two Treatment Programs for Reducing Phantom Limb Pain Intensity and Its Interference With Function

The goal of this clinical trial is to investigate the effectiveness of two rehabilitation programs for individuals who have undergone amputations and are experiencing phantom limb pain. The main question it aims to answer is:

- In individuals who have undergone amputations and are experiencing phantom limb pain, what is the effectiveness of a progressive rehabilitation program compared to a treatment program consisting of transcutaneous electrical nerve stimulation and cranial electrical stimulation on reducing pain intensity and pain interference?

A total of 208 participants will be randomized into two groups: progressive rehabilitation program and stimulation devices. The progressive rehabilitation program includes pain science education, sensory training, and left/right judgements, imagined movements and mirror therapy. The treatment program for the group receiving the stimulation devices includes transcutaneous electrical nerve stimulation and cranial electrical stimulation. Both interventions will be delivered via eight, up to 1-hour telehealth sessions. Outcome measures will be assessed at baseline and weeks 12, 24 and 52.

Study Overview

• Status: Recruiting
• Conditions: Amputation; Phantom Limb Pain
• Intervention / Treatment: Other: Progressive rehabilitation program; Other: Stimulation devices

• Study Type: Interventional
• Enrollment (Estimated): 208
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: James H McAuley, PhD; Phone Number: +61293991266; Email: j.mcauley@neura.edu.au
• Study Contact Backup: Name: Rafael Z Pinto, PhD; Email: r.zambelli@neura.edu.au

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • Recruiting
      • Neuroscience Research Australia
      • Contact: James H McAuley, PhD; Phone Number: +61293991266; Email: j.mcauley@neura.edu.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Experiencing phantom limb pain for at least three months.
• Report at least one episode of phantom limb pain in the previous week.
• Report at least 4 points in pain intensity over the previous 7 days, assessed using the 11-point Numerical Pain Rating Scale.
• Be a resident in Australia for the intervention and follow-up period.
• Have access to the internet and smart device (e.g., mobile phone).
• Be proficient in English.

Exclusion Criteria:

• Bilateral amputation.
• Scheduled for major surgery during the study period.
• Pain in the intact limb.
• Vision impairment that would preclude successful participation.
• Auditory impairment that would preclude successful participation.
• Cognitive problems that would preclude effective participation in trial procedures (e.g., Alzheimer's, dementia).
• Previously diagnosed neurological disorders that affect the movement of the intact limb (e.g., stroke, Parkinson, Multiple Sclerosis).
• Completed Graded Motor Imagery in the order of left/right judgements, imagined movements, and mirror therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Progressive rehabilitation program; The progressive rehabilitation program is a multicomponent intervention, including pain science education, sensory training, implicit and explicit motor imagery, and mirror therapy.	Other: Progressive rehabilitation program; Twelve-week treatment program delivered via eight, up to 1-hour telehealth sessions. The first five sessions will be scheduled every week, and the final three sessions will be scheduled fortnightly. Participants will also be prescribed approximately 15-30 minutes of home activities daily. The treatment program includes pain science education, sensory training, implicit and explicit motor imagery, and mirror therapy. Participants will complete activities at a self-directed pace following a standard progression protocol. Participant adherence will be measured via session attendance and self-report therapy diaries.
Experimental: Stimulation devices; The treatment program includes Transcutaneous Electrical Nerve Stimulation and Cranial Electrical Stimulation. Participants will complete activities at a self-directed pace following a standard progression protocol.	Other: Stimulation devices; Twelve-week treatment program delivered via eight, up to 1-hour telehealth sessions. The first five sessions will be scheduled every week, and the final three sessions will be scheduled fortnightly. Participants will also be prescribed approximately 15-30 minutes of home activities daily. The treatment program includes transcutaneous electrical nerve stimulation and cranial electrical stimulation. Participants will complete activities at a self-directed pace following a standard progression protocol. Participant adherence will be measured via session attendance and self-report therapy diaries.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain intensity	Average pain intensity over the previous 7 days assessed using the 11-point Numerical Pain Rating Scale.	Week 12 post-randomisation
Pain interference	Average pain interference with function over the previous 7 days assessed using the 0-10 Pain Interference Scale of the Brief Pain Inventory.	Week 12 post-randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain intensity	Average pain intensity over the previous 7 days assessed using the 11-point Numerical Pain Rating Scale.	Weeks 24 and 52 post-randomisation
Pain interference	Average pain interference with function over the previous 7 days assessed using the 0-10 Pain Interference Scale of the Brief Pain Inventory.	Weeks 24 and 52 post-randomisation
Pain severity	Average pain intensity over the previous 7 days assessed using the 0-10 Pain Severity Scale of the Brief Pain Inventory.	Weeks 12, 24 and 52 post-randomisation
Sleep subscale of the Brief Pain Inventory's Pain Interference Scale	Sleep Quality assessed using the Sleep subscale of the Brief Pain Inventory's Pain Interference Scale. The participants will rate the interference of pain with sleep on a 0-10 scale where "0" represents "does not interfere" and "10" represents "completely interferes".	Weeks 12, 24 and 52 post-randomisation
PROMIS Self-Efficacy Manage Symptoms	Pain Self-efficacy assessed using PROMIS Self-Efficacy Manage Symptoms (Computer Adaptive Test) (28-item version; higher scores mean more self-efficacy).	Weeks 12, 24 and 52 post-randomisation
PROMIS Depression	Emotional distress and depression assessed using PROMIS Depression (Computer Adaptive Test) (28-item version; higher scores mean more depression).	Weeks 12, 24 and 52 post-randomisation
EuroQol 5-Dimension 5-Level (EQ-5D-5L)	Health-Related Quality of Life assessed using the EQ-5D-5L dimensions scale range, 1-5; higher scores indicate better quality of life) and health thermometer (range, 0-100; higher scores indicate better quality of life).	Weeks 12, 24 and 52 post-randomisation
Global Perceived Effect Scale	Perception of recovery assessed using the Global Perceived Effect scale (range from -5 to +5; higher scores mean greater improvement).	Weeks 12, 24 and 52 post-randomisation
Adverse events	Adverse events assessed via self-report.	From randomisation to week 12 post-randomisation
Adherence to treatment	Adherence to treatment assessed via session attendance and self-report (diary), including frequency per week and duration per day.	From randomisation to week 12 post-randomisation
Total health-care costs	Total health-care costs will be estimated as the trial intervention costs and outside trial health-care resource use attributable to phantom limb pain from the Medicare Benefits Scheme and Pharmaceutical Benefits Scheme. Quality-adjusted life-years (QALYs) from the EQ-5D-5L using the Australian utility weights will also be used in the trial-based cost-utility analysis.	Weeks 12, 24 and 52 post-randomisation
Treatment rationale credibility	Treatment rationale credibility assessed using the Credibility and Expectancy Questionnaire. The total score ranges from 0 to 48, with lower scores indicating lower credibility.	Week 1 post-randomisation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain Self-Efficacy Questionnaire (mediator)	Pain self efficacy measured using the Pain Self-Efficacy Questionnaire. The total score of this questionnaire ranges from 0 to 60, with higher scores indicating higher self-efficacy and functioning despite ongoing pain.	Weeks 6 and 10 post-randomisation
Concept of Pain Inventory (mediator)	Beliefs and knowledge of pain science assessed using the Concept of Pain Inventory. This is a 13-item questionnaire with scores ranging from 0 to 52 points, with higher scores reflecting greater alignment with contemporary pain science.	Weeks 6 and 10 post-randomisation
Pain Catastrophising Scale (mediator)	Pain catastrophising assessed using the Pain Catastrophising Scale. The total score ranges from 0 to 52, with higher scores indicating a higher level of catastrophising.	Weeks 6 and 10 post-randomisation
Phantom limb movement scale (mediator)	The ability to move the phantom limb assessed on an 11-point Numerical Rating Scale (0: No movement at all, 10: Complete range of movement as if the limb were still present).	Weeks 6 and 10 post-randomisation
Phantom limb body perception disturbance scale (mediator)	The phantom limb body perception disturbances assessed using 4 questions measuring ownership, awareness, attention and emotional feelings on an 11-point Numerical Rating Scale (range, 0-40; lower scores indicate more severe body perception disturbances). Adapted from the Bath Complex Regional Pain Syndrome body perception disturbance scale.	Weeks 6 and 10 post-randomisation

Collaborators and Investigators

• Sponsor: Neuroscience Research Australia
• Investigators: Principal Investigator: James H McAuley, PhD, Neuroscience Research Australia

Publications and helpful links

General Publications

• Limakatso K, Cashin AG, Williams S, Devonshire J, Parker R, McAuley JH. The Efficacy of Graded Motor Imagery and Its Components on Phantom Limb Pain and Disability: A Systematic Review and Meta-Analysis. Can J Pain. 2023 May 17;7(1):2188899. doi: 10.1080/24740527.2023.2188899. eCollection 2023.

Helpful Links

• Trial website

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2023
• Primary Completion (Estimated): December 18, 2026
• Study Completion (Estimated): December 18, 2027

Study Registration Dates

• First Submitted: November 26, 2023
• First Submitted That Met QC Criteria: December 7, 2023
• First Posted (Actual): December 12, 2023

Study Record Updates

• Last Update Posted (Actual): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 8, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Postoperative Complications; Pain; Neurologic Manifestations; Neurobehavioral Manifestations; Perceptual Disorders; Pain, Postoperative; Phantom Limb
• Other Study ID Numbers: U1111-1296-2782; X23-0202 & 2023/ETH00540 (Other Identifier: RPAH Ethics and Governance Office)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

De-identified individual participant data will be made to interested researchers only upon reasonable request and once the proposed research project has received separate ethics approval from a Human Research Ethics Committee.

Request to the data custodian, the Principal Investigator (j.mcauley@neura.edu.au).

• IPD Sharing Time Frame: Data will be made available after the publication of study reports. There is no end date for the availability of study data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No