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Cryoanalgesia to Treat Post-Amputation Phantom Limb Pain: A Department of Defense Funded Multicenter Study

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ClinicalTrials.gov Identifier: NCT03449667
Recruitment Status : Recruiting
First Posted : February 28, 2018
Last Update Posted : January 14, 2019
Sponsor:
Collaborators:
United States Department of Defense
Department of Outcomes Research, Cleveland Clinic
Information provided by (Responsible Party):
Brian M. Ilfeld, MD, MS, University of California, San Diego

Brief Summary:
When a limb is severed, pain perceived in the part of the body that no longer exists often develops and is called "phantom limb" pain. Unfortunately, phantom pain goes away in only 16% of afflicted individuals, and there is currently no reliable definitive treatment. The exact reason that phantom limb pain occurs is unclear, but when a nerve is cut-as happens with an amputation-changes occur in the brain and spinal cord that actually increase with worsening phantom pain. These abnormal changes may often be corrected by putting local anesthetic-called a "nerve block"-on the injured nerve, effectively keeping any "bad signals" from reaching the brain with a simultaneous resolution of the phantom limb pain. However, when the nerve block resolves after a few hours, the phantom pain returns. But, this demonstrates that the brain abnormalities-and phantom pain-that occur with an amputation are not necessarily fixed, and may be dependent upon the "bad" signals being sent from the injured nerve(s), suggesting that a very long peripheral nerve block-lasting many months rather than hours-may permanently reverse the abnormal changes in the brain, and provide definitive relief from phantom pain. A prolonged nerve block lasting a few months may be provided by freezing the nerve using a process called "cryoneurolysis". The ultimate objective of the proposed research study is to determine if cryoanalgesia is an effective treatment for intractable post-amputation phantom limb pain. The proposed research study will include subjects with an existing lower extremity amputation who experience intractable daily phantom limb pain. A single ultrasound-guided treatment of cryoneurolysis (or sham block-determined randomly like a flip of a coin) will be applied to the target nerve(s) involved with the phantom pain. Although not required, each subject may return four months later for the alternative treatment (if the first treatment is sham, then the second treatment would be cryoneurolysis) so that all participants have the option of receiving the active treatment. Subjects will be followed for a total of 12 months with data collected by telephone.

Condition or disease Intervention/treatment Phase
Post-Amputation Phantom Limb Pain Device: Cryoneurolysis Device: Sham Comparator Not Applicable

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Detailed Description:

Subjects will be asked to make no changes to their analgesic regimen for at least 1 month prior to the cryoneurolysis procedure and continuing for 4 months until the measurement of the primary end point-for the duration of the study, all patients will be allowed to continue their pre-intervention analgesics. All subjects will have a peripheral intravenous catheter inserted, standard noninvasive monitors applied, and oxygen administered via a facemask or nasal cannula. Midazolam and fentanyl (IV) will be titrated for patient comfort. The specific nerves targeted will be the sciatic and femoral (or their distal branches). The potential cryoneurolysis sites will be cleansed with chlorhexidine gluconate and isopropyl alcohol. The target nerves will be identified in a transverse cross-sectional (short axis) view using ultrasound. A Tuohy-tip needle will be inserted beneath the ultrasound transducer and directed until the needle tip is immediately adjacent to the target nerve. Local anesthetic (1-3 mL, lidocaine 2%) will be injected. This will be repeated for the femoral nerve. Within 20 minutes of the second injection, the subject's limb pain level will be evaluated on the 0-10 NRS and if higher than at baseline prior to injection, the subject will NOT continue with treatment and their participation in the study will terminate upon discharge.

Treatment group assignment (randomization). Remaining subjects will be allocated to one of two possible treatments:

  1. cryoneurolysis
  2. sham cryoneurolysis (placebo control)

Randomization will be computer-generated and stratified by enrolling institution in randomly chosen block sizes. Cryoneurolysis probes are available that either (1) pass nitrous oxide to the tip inducing freezing temperatures; or, (2) vent the nitrous oxide at the base of the probe so that no gas reaches the probe tip, resulting in no temperature change (PainBlocker, Epimed, Farmers Branch, Texas). Importantly, these probes are indistinguishable in appearance. Unmasking will not occur until statistical analysis is complete.

Intervention. The potential cryoneurolysis sites will be again cleansed with chlorhexidine gluconate and isopropyl alcohol. With the same ultrasound transducer used to previously administer local anesthetic, the target nerve will again be identified in a transverse cross-sectional (short axis) view at or distal to the deposition of local anesthetic. A cryoneurolysis device (PainBlocker, Epimed, Farmers Branch, Texas) will be inserted with the appropriate randomization-designated probe (either active or sham/placebo) and nitrous oxide. The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation (active or sham) separated by 1-minute defrost periods. The process will be repeated with the same treatment probe for the femoral nerve (e.g., both nerves will receive either active cryoneurolysis or sham/placebo, and not a mix of the two possible treatments).

Optional crossover treatment. Four to 6 months following the initial treatment, subjects may return for an optional repeated intervention procedure ("crossover") with the alternative treatment (either active cryoneurolysis or sham/placebo), again in a double-masked fashion using the same protocol as described for the initial intervention. The crossover treatment is not required for study participation, as the primary analyses will include a parallel study design for the initial intervention evaluated prior to any crossover treatment. This crossover will not affect the primary analyses, which will involve a parallel group study design and investigate the effects of cryoneurolysis within 4 months of the initial intervention.

Outcome measurements (endpoints). The primary end point will be the difference in average daily phantom pain intensity at baseline and 4 months following the initial intervention (measured with the NRS as part of the Brief Pain Inventory). The primary analyses will compare the two treatments (inter-subject comparisons) during the initial treatment period in which half of the subjects will receive active cryoneurolysis and the other half a sham/placebo treatment. Endpoints will be evaluated at baseline and post-treatment (Day 0), Days 1 and 7; and Months 1, 2, 3, 4, and 12. These same time points through Month 4 will be evaluated following the optional second (crossover) treatment.

Data collection. The questionnaires for all subjects-regardless of enrolling center-will be administered by telephone from the University of California San Diego by research coordinators specifically trained in these instruments' application, minimizing inter-rater discordance. Staff masked to treatment group assignment will perform all assessments.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 144 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: The primary endpoint at 4 months following the initial treatment will utilize a parallel group study design; however, an optional crossover is offered to subjects following this time point.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: All individuals will be masked to treatment with the exception of the anesthesiologist administering the procedure who will choose which probe to use: the functional or sham. Of note, this individual could not be masked to treatment since the cryoneurolysis ice ball is visualized on ultrasound; and, the practitioner would see a lack of ice ball formation for the sham probes.
Primary Purpose: Treatment
Official Title: Cryoanalgesia to Treat Post-Amputation Phantom Limb Pain: A Multicenter, Randomized, Double-Masked, Placebo-Controlled, Definitive Human Subjects Clinical Trial
Actual Study Start Date : March 23, 2018
Estimated Primary Completion Date : September 30, 2020
Estimated Study Completion Date : September 29, 2021

Arm Intervention/treatment
Active Comparator: Cryoneurolysis
Cryoneurolysis of the femoral and sciatic nerves (or their distal counterparts) in the residual limb: The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation separated by 1-minute defrost periods. For active probes, the nitrous oxide will be deployed to the tip where a drop in temperature to -70°C will result in cryoneurolysis.
Device: Cryoneurolysis
Cryoneurolysis of the femoral and sciatic nerves (or their distal counterparts) in the residual limb: The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation separated by 1-minute defrost periods. For active probes, the nitrous oxide will be deployed to the tip where a drop in temperature to -70°C will result in cryoneurolysis.
Other Name: Cryoanalgesia

Sham Comparator: Sham Comparator
Sham cryoneurolysis of the femoral and sciatic nerves (or their distal counterparts) in the residual limb: The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation separated by 1-minute defrost periods. However, for sham probes, the nitrous oxide is not deployed to the tip and therefore there is no drop in temperature resulting in cryoneurolysis.
Device: Sham Comparator
Sham cryoneurolysis of the femoral and sciatic nerves (or their distal counterparts) in the residual limb: The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation separated by 1-minute defrost periods. However, for sham probes, the nitrous oxide is not deployed to the tip and therefore there is no drop in temperature resulting in cryoneurolysis.
Other Name: placebo, control




Primary Outcome Measures :
  1. Average daily phantom pain intensity [ Time Frame: Baseline and 4 months later (difference between the two is the primary end point) ]
    The difference in average daily phantom pain intensity at baseline and 4 months following the initial intervention (measured with the NRS as part of the Brief Pain Inventory)


Secondary Outcome Measures :
  1. Average daily phantom pain intensity [ Time Frame: Endpoints will be evaluated at baseline and post-treatment (Day 0), Days 1 and 7; and Months 1, 2, 3, 4, and 12 [same for crossover subjects with the exception of the 12-month time point] ]
    The difference in average daily phantom pain intensity at baseline and various time points other than the primary at 4 months

  2. Brief Pain Inventory [ Time Frame: Endpoints will be evaluated at baseline and post-treatment (Day 0), Days 1 and 7; and Months 1, 2, 3, 4, and 12 [same for crossover subjects with the exception of the 12-month time point] ]
    The difference in the Brief Pain Inventory between baseline and various time points

  3. Residual limb pain (frequency and duration) [ Time Frame: Endpoints will be evaluated at baseline and post-treatment (Day 0), Days 1 and 7; and Months 1, 2, 3, 4, and 12 [same for crossover subjects with the exception of the 12-month time point] ]
    Pain that originates from a part of the injured limb that remains intact

  4. Patient Global Impression of Change [ Time Frame: Endpoints will be evaluated at baseline and post-treatment (Day 0), Days 1 and 7; and Months 1, 2, 3, 4, and 12 [same for crossover subjects with the exception of the 12-month time point] ]
    A 7-point scale of change from baseline at various time points

  5. Beck Depression Inventory [ Time Frame: At baseline, 4 months, 12 months (and 4 months following crossover for those subjects who choose to the crossover treatment) ]
    21-question questionnaire evaluating depression with 4-5 multiple choice responses

  6. Non-painful phantom sensations (frequency and duration) [ Time Frame: Endpoints will be evaluated at baseline and post-treatment (Day 0), Days 1 and 7; and Months 1, 2, 3, 4, and 12 [same for crossover subjects with the exception of the 12-month time point] ]
    Sensations that feel to emanate from the missing limb, but are not described as pain

  7. Phantom limb pain (frequency and duration) [ Time Frame: Endpoints will be evaluated at baseline and post-treatment (Day 0), Days 1 and 7; and Months 1, 2, 3, 4, and 12 [same for crossover subjects with the exception of the 12-month time point] ]
    Pain perceived to emanate from part of the injured limb that no longer exists

  8. Residual limb pain (NRS) [ Time Frame: Endpoints will be evaluated at baseline and post-treatment (Day 0), Days 1 and 7; and Months 1, 2, 3, 4, and 12 [same for crossover subjects with the exception of the 12-month time point] ]
    Pain that originates from a part of the injured limb that remains intact. Worst, least, average, and current pain levels will be recorded at each time point



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult patients of at least 18 years of age
  • with a lower limb traumatic or surgical amputation at least 12 weeks prior to enrollment distal to the hip (femoral head remaining)
  • who experience at least moderate phantom limb pain-defined as a 3 or higher on the Numeric Rating Scale (NRS; 0-10, 0= no pain; 10=worst imaginable pain)-at least daily for the previous 2 months.
  • accepting of a cryoneurolysis procedure
  • willing to avoid both changes to their analgesic regimen as well as elective surgical procedures from 1 month prior to and at least 4 months following the initial cryoneurolysis procedure.

Exclusion Criteria:

  • allergy to amide local anesthetics
  • pregnancy
  • incarceration
  • inability to communicate with the investigators
  • morbid obesity (body mass index > 40 kg/m2)
  • possessing any contraindication specific to cryoneurolysis such as a localized infection at the treatment site, cryoglobulinemia, cold urticaria and Reynaud's Syndrome.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03449667


Contacts
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Contact: Brian M Ilfeld, MD, MS (858) 822-0776 bilfeld@ucsd.edu
Contact: Rodney Gabriel, MD, MAS (858) 822-0776

Locations
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United States, California
Veterans Affairs Palo Alto Health Care System Not yet recruiting
Palo Alto, California, United States, 94304
Contact: Edward R Mariano, MD, MAS         
Principal Investigator: Edward R Mariano, MD, MAS         
University California San Diego Recruiting
San Diego, California, United States, 92103
Contact: Baharin Abdullah    858-534-1251    baabdullah@ucsd.edu   
Contact: Brian M Ilfeld, MD, MS    (858) 822-0776    phantompain@ucsd.edu   
Principal Investigator: Brian M Ilfeld, MD, MS         
Sub-Investigator: Rodney Gabriel, MD, MAS         
Naval Medical Center San Diego (NMCSD) Not yet recruiting
San Diego, California, United States, 92134
Contact: Carter Sigmon, MD         
Principal Investigator: Carter Sigmon, MD         
United States, Florida
University of Florida Not yet recruiting
Gainesville, Florida, United States, 32610
Contact: Cameron Smith, MD         
Principal Investigator: Cameron Smith, MD         
United States, Maryland
Walter Reed National Military Medical Center Not yet recruiting
Bethesda, Maryland, United States, 20889
Contact: Matthew Miller, MD         
Principal Investigator: Matthew Miller, MD         
United States, Ohio
Cleveland Clinic Not yet recruiting
Cleveland, Ohio, United States, 44195
Contact: Alparslan Turan, MD         
Principal Investigator: Alparslan Turan, MD         
Sponsors and Collaborators
University of California, San Diego
United States Department of Defense
Department of Outcomes Research, Cleveland Clinic
Investigators
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Principal Investigator: Brian M Ilfeld, MD, MS University California San Diego Department of Anesthesiology
Study Director: Rodney Gabriel, MD, MAS University California San Diego Department of Anesthesiology

Publications of Results:
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Responsible Party: Brian M. Ilfeld, MD, MS, Professor of Anesthesiology, In Residence, University of California, San Diego
ClinicalTrials.gov Identifier: NCT03449667     History of Changes
Other Study ID Numbers: CRYO for Phantom Pain (DoD)
W81XWH-17-2-0051 ( Other Grant/Funding Number: Peer Reviewed Medical Research Program (PRMRP) )
PR160263 ( Other Grant/Funding Number: Department of Defense Congressionally Directed Medical Research Programs )
First Posted: February 28, 2018    Key Record Dates
Last Update Posted: January 14, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Pending

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Pediatric Postmarket Surveillance of a Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Phantom Limb
Perceptual Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Pain, Postoperative
Postoperative Complications
Pathologic Processes
Signs and Symptoms
Pain
Nitrous Oxide
Anesthetics, Inhalation
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents