Trial Review

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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT05009394




Registration number
NCT05009394
Ethics application status
Date submitted
12/07/2021
Date registered
17/08/2021
Date last updated
29/09/2023

Titles & IDs
Public title
Surgical Treatments for Postamputation Pain
Scientific title
Surgical Treatments for Postamputation Pain
Secondary ID [1] 0 0
2021-02346
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Residual Limb Pain 0 0
Amputation Neuroma 0 0
Phantom Limb Pain 0 0
Pain, Neuropathic 0 0
Pain, Nerve 0 0
Condition category
Condition code
Neurological 0 0 0 0
Other neurological disorders
Mental Health 0 0 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Surgery - Targeted Muscle Reinnervation (TMR)
Treatment: Surgery - Regenerative Peripheral Nerve Interface (RPNI)
Treatment: Surgery - Standard neuroma treatment, neuroma excision, and muscle burying

Active Comparator: Targeted Muscle Reinnervation (TMR) - The surgical procedure comprises three steps: preparation of the donor nerve, identification of a motor branch to the targeted muscle, and nerve coaptation. To prepare the donor nerve, the surgeon will identify the nerve with a painful neuroma and resect the neuroma up to healthy fascicles. Next, the surgeon will identify a motor branch to a nearby target muscle and will confirm muscle contraction using a hand-held nerve stimulator. The motor branch to the target muscle will be transected as close as possible to its entry point without tension. In the final step, the previous nerve stump from which the neuroma was resected will be transferred and coapted to the newly severed motor branch that innervates the target muscle and secured by 2-3 non-resorbable monofilament sutures. The surgery time is approximately 2-3 hours and it takes place in the hospital.

Active Comparator: Regenerative Peripheral Nerve Interface (RPNI) - The RPNI procedure involves construction of a residual peripheral nerve split into several nerve fascicles and implanted into free skeletal muscle grafts. First, the surgeon identifies the nerve with a painful neuroma and resect the neuroma up to healthy fascicles. Then, a longitudinal intraneural dissection will be performed exposing its fascicles. Next, autologous muscle grafts will be harvested from a healthy donor site, and the dissected nerve stumps will be placed parallel to the muscle fibers. The nerve stump will be secured to the muscle graft, thereafter the graft will be wrapped around the nerve stump and anchored in the folded graft, thus creating an RPNI. This will be repeated for each fascicle obtained from splitting the transected nerve. Lastly, the RPNIs will be placed in a protected area. The surgery time is approximately 2-3 hours and it takes place in the hospital.

Active Comparator: Standard neuroma treatment, neuroma excision, and muscle burying - The standard neuroma treatment, also called neuroma transposition, includes excision of the terminal neuroma and burying the nerve into an adjacent deep muscle.The standard neuroma treatment entails the excision of the terminal neuroma and then implanting the nerve into an adjacent muscle. Firstly, the surgeon will identify the nerve with a painful neuroma and thereafter resect the neuroma up to healthy fascicles. Next, the surgeon will identify a nearby muscle which is not involved in joint motion and has limited output opportunities for the nerve. The nerve will then be channeled at least 1 cm inside the muscle without applying any tension to it and secured by 1-2 non-resorbable monofilament sutures. The identified nerve with the painful neuroma will not be treated with any additional therapy than the resection (e.g., diathermy, pharmacotherapy, crushing, etc.). The surgery time is approximately 1-2 hours and it takes place in the hospital.


Treatment: Surgery: Targeted Muscle Reinnervation (TMR)
Surgical procedure used to rewire injured proximal nerves to motor nerves directly innervating an otherwise redundant target muscle.

Treatment: Surgery: Regenerative Peripheral Nerve Interface (RPNI)
Surgical procedure where the the nerve is split into fascicles and wrapped in free muscle grafts.

Treatment: Surgery: Standard neuroma treatment, neuroma excision, and muscle burying
Surgical procedure where the neuroma is excised and the nerve stump is buried in an adjacent deep muscle.
Intervention code [1] 0 0
Treatment: Surgery
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Residual limb pain intensity
Timepoint [1] 0 0
Baseline to 12-month post-surgery
Secondary outcome [1] 0 0
Neuroma pain intensity
Timepoint [1] 0 0
Baseline to 12-month post-surgery
Secondary outcome [2] 0 0
Phantom limb pain intensity
Timepoint [2] 0 0
Baseline to12-month post-surgery

Eligibility
Key inclusion criteria
- The participant must have a major limb amputation.

- The participant is = 18 years old at the time of consent.

- The participant must be in generally good health to undergo a surgical intervention,
as per the clinical investigator's opinion.

- Time since the last amputation must be over a year at the time of consent.

- The participant must have an average residual limb pain score equal or greater than 4
on the Numerical Rating Scale (NRS, 0-10) after the baseline period.

- If the participant has been prescribed pharmacological treatments for pain, there must
be no variations in dosage (steady consumption) for at least 1 month before the
screening visit.

- If the participant has been prescribed non-pharmacological treatments for pain, such
as spinal cord stimulation, transcutaneous electrical nerve stimulation, and mirror
therapy, the treatment must have ended at least 1 month before the screening visit.

- The participant must have a stable prosthetic fitting for at least a month before the
screening visit.

- The participant has a sufficient understanding of the language in which the
assessments will be conducted, as per the clinical investigator's opinion.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Neurological or other conditions that affect nerve regeneration for the nerve to be
treated.

- Active infection in the residual limb.

- Prior RPNI or TMR surgery of the nerve to be treated (with painful neuroma) to address
postamputation pain.

- Mental disorders (e.g., schizophrenia, paranoia, psychosis, etc.), reluctance, or
language difficulties that result in difficulty understanding the meaning of study
participation.

- Ongoing participation in a clinical study that the clinical investigator deems
detrimental to participation in this study.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
Not Applicable
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
20/06/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/06/2028
Actual
Sample size
Target
110
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Dandenong Hospital, Monash Health - Melbourne
Recruitment postcode(s) [1] 0 0
- Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Illinois
Country [2] 0 0
United States of America
State/province [2] 0 0
Massachusetts
Country [3] 0 0
United States of America
State/province [3] 0 0
Michigan
Country [4] 0 0
Canada
State/province [4] 0 0
Alberta
Country [5] 0 0
Chile
State/province [5] 0 0
Santiago
Country [6] 0 0
Italy
State/province [6] 0 0
Emilia-Romagna
Country [7] 0 0
Sweden
State/province [7] 0 0
Västra Götaland
Country [8] 0 0
United Kingdom
State/province [8] 0 0
Edinburgh

Funding & Sponsors
Primary sponsor type
Other
Name
Center for Bionics and Pain Research
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Vastra Gotaland Region
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Göteborg University
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Chalmers University of Technology
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
Istituto Ortopedico Rizzoli
Address [4] 0 0
Country [4] 0 0
Other collaborator category [5] 0 0
Other
Name [5] 0 0
Hospital del Trabajador de Santiago
Address [5] 0 0
Country [5] 0 0
Other collaborator category [6] 0 0
Other
Name [6] 0 0
NHS Lothian
Address [6] 0 0
Country [6] 0 0
Other collaborator category [7] 0 0
Other
Name [7] 0 0
NHS Greater Clyde and Glasgow
Address [7] 0 0
Country [7] 0 0
Other collaborator category [8] 0 0
Other
Name [8] 0 0
NHS Grampian
Address [8] 0 0
Country [8] 0 0
Other collaborator category [9] 0 0
Other
Name [9] 0 0
Northwestern Memorial Hospital
Address [9] 0 0
Country [9] 0 0
Other collaborator category [10] 0 0
Other
Name [10] 0 0
University of Michigan
Address [10] 0 0
Country [10] 0 0
Other collaborator category [11] 0 0
Other
Name [11] 0 0
Massachusetts General Hospital
Address [11] 0 0
Country [11] 0 0
Other collaborator category [12] 0 0
Other
Name [12] 0 0
Dandenong Hospital
Address [12] 0 0
Country [12] 0 0
Other collaborator category [13] 0 0
Other
Name [13] 0 0
The Bionics Institute of Australia
Address [13] 0 0
Country [13] 0 0
Other collaborator category [14] 0 0
Other
Name [14] 0 0
University of Alberta
Address [14] 0 0
Country [14] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This is a double-blind randomised controlled trial (RCT) which compares the effectiveness of
three surgical techniques for alleviating residual limb pain (RLP), neuroma pain and phantom
limb pain (PLP). The three surgical treatments are Targeted Muscles Reinnervation (TMR),
Regenerative Peripheral Nerve Interface (RPNI), and an active control (neuroma excision and
muscle burying). Patients will be follow-up for 4 years.
Trial website
https://clinicaltrials.gov/ct2/show/NCT05009394
Trial related presentations / publications
Dumanian GA, Potter BK, Mioton LM, Ko JH, Cheesborough JE, Souza JM, Ertl WJ, Tintle SM, Nanos GP, Valerio IL, Kuiken TA, Apkarian AV, Porter K, Jordan SW. Targeted Muscle Reinnervation Treats Neuroma and Phantom Pain in Major Limb Amputees: A Randomized Clinical Trial. Ann Surg. 2019 Aug;270(2):238-246. doi: 10.1097/SLA.0000000000003088.
Souza JM, Cheesborough JE, Ko JH, Cho MS, Kuiken TA, Dumanian GA. Targeted muscle reinnervation: a novel approach to postamputation neuroma pain. Clin Orthop Relat Res. 2014 Oct;472(10):2984-90. doi: 10.1007/s11999-014-3528-7.
Woo SL, Kung TA, Brown DL, Leonard JA, Kelly BM, Cederna PS. Regenerative Peripheral Nerve Interfaces for the Treatment of Postamputation Neuroma Pain: A Pilot Study. Plast Reconstr Surg Glob Open. 2016 Dec 27;4(12):e1038. doi: 10.1097/GOX.0000000000001038. eCollection 2016 Dec.
Pettersen E, Sassu P, Reinholdt C, Dahm P, Rolfson O, Bjorkman A, Innocenti M, Pedrini FA, Breyer JM, Roche A, Hart A, Harrington L, Ladak A, Power H, Hebert J, Ortiz-Catalan M. Surgical treatments for postamputation pain: study protocol for an international, double-blind, randomised controlled trial. Trials. 2023 May 2;24(1):304. doi: 10.1186/s13063-023-07286-0. Erratum In: Trials. 2023 Oct 9;24(1):654.
Chang BL, Mondshine J, Attinger CE, Kleiber GM. Targeted Muscle Reinnervation Improves Pain and Ambulation Outcomes in Highly Comorbid Amputees. Plast Reconstr Surg. 2021 Aug 1;148(2):376-386. doi: 10.1097/PRS.0000000000008153.
Bjorklund KA, Alexander J, Tulchin-Francis K, Yanes NS, Singh S, Valerio I, Klingele K, Scharschmidt T. Targeted Muscle Reinnervation for Limb Amputation to Avoid Neuroma and Phantom Limb Pain in Patients Treated at a Pediatric Hospital. Plast Reconstr Surg Glob Open. 2023 Apr 13;11(4):e4944. doi: 10.1097/GOX.0000000000004944. eCollection 2023 Apr.
Kubiak CA, Kemp SWP, Cederna PS, Kung TA. Prophylactic Regenerative Peripheral Nerve Interfaces to Prevent Postamputation Pain. Plast Reconstr Surg. 2019 Sep;144(3):421e-430e. doi: 10.1097/PRS.0000000000005922.
Valerio IL, Dumanian GA, Jordan SW, Mioton LM, Bowen JB, West JM, Porter K, Ko JH, Souza JM, Potter BK. Preemptive Treatment of Phantom and Residual Limb Pain with Targeted Muscle Reinnervation at the Time of Major Limb Amputation. J Am Coll Surg. 2019 Mar;228(3):217-226. doi: 10.1016/j.jamcollsurg.2018.12.015. Epub 2019 Jan 8.
Public notes

Contacts
Principal investigator
Name 0 0
Max Ortiz Catalan, PhD
Address 0 0
Center for Bionics and Pain Research
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Emily Pettersen, MSc
Address 0 0
Country 0 0
Phone 0 0
+46764026503
Fax 0 0
Email 0 0
emily.pettersen@vgregion.se
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT05009394