Intercostobrachial Nerve Sparing to Reduce Post-Surgical Pain (INSPIRE)

June 24, 2020 updated by: McMaster University

Intercostobrachial Nerve Sparing in Breast Cancer Surgery to Reduce Persistent Post-surgical Pain - an International Randomized Controlled Trial

Sacrifice of the intercostobrachial nerve (ICBN) during surgery is associated with development of persistent post-surgical pain (PPSP), which affects up to 60% of breast cancer surgery patients. A large, definitive trial is needed to establish whether nerve preservation techniques are effective in reducing post-surgical pain after breast cancer surgery. If the effect of ICBN preservation is consistent with observational studies, the absolute reduction of rates of persistent pain would be considerable.The primary objective is to determine the effect of ICBN preservation, versus usual care, on the prevalence and intensity of PPSP at one year after breast cancer surgery involving axillary lymph node dissection (ALND). Within the larger INSPIRE pilot, we will also be conducting a biomarker sub-study. The objectives of the biomarker sub-study are: 1) to determine the association between pro-inflammatory cytokine levels and the presence and intensity of persistent pain at 3 weeks, and 3 months post-surgery, and) 2) to determine the effect of study intervention on the change in cytokine levels (pre-operative to post-operative) in participants who consent to participate in the sub-study.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

A 2016 systematic review that included 30 observational studies (n= 19,813 patients) found high quality evidence that axillary lymph node dissection (ALND) is associated with a 21% absolute risk increase of PPSP (95% CI = 13% to 29%). In many cases of breast cancer, surgery involves axillary approaches; however, preliminary evidence suggests that preservation of the intercostobrachial nerves (ICBN) may reduce the incidence of PPSP after axillary clearance. A 2014 systematic review found 3 small, single-center randomized controlled trials (RCTs), that enrolled a total of 309 patients, and explored the effect of ICBN preservation versus sacrifice during breast cancer surgery. This review found that division of the ICBN was associated with higher risk of sensory deficits, and that nerve preservation techniques increased the median operating time by 5 minutes. Due to limitations of existing evidence, clinical practice guidelines currently provide no recommendations on whether the ICBN should be preserved during axillary lymph node dissection.A large, definitive trial is needed to establish whether nerve preservation techniques are effective in reducing PPSP after breast cancer surgery involving ALND. If all the apparent effect of axillary dissection is associated with lack of ICBN preservation, the absolute reduction of rates of PPSP would be considerable. Furthermore, nerve sparing requires no specialized equipment, suggesting that scalability will be highly feasible.

In addition, there is substantial evidence that neuro-inflammation as a result of neural damage leads to peripheral and central changes that can be described as peripheral and central sensitization, leading to PPSP. As such, we will be conducting a biomarker sub-study as part of the pilot program. Identification of biomarkers to correlate with the development of neuropathic pain may facilitate identification of individuals at risk for development of PPSP at an early stage. The INSPIRE trial provides an important opportunity to compare patients before and after nerve injury to further explore the association of persistent pain with cytokine biomarkers. The findings will improve our mechanistic understanding of PPSP.

Study Type

Interventional

Enrollment (Anticipated)

50

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Hamilton, Ontario, Canada, L8V 1C3
        • Recruiting
        • Juravinski Hospital
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Pilot Study

Inclusion Criteria:

  1. Females aged 18 years and older.
  2. Known or suspected invasive breast cancer.
  3. Planned ALND (not sentinel lymph node biopsy) either alone or with planned mastectomy or breast conserving surgery.
  4. The ICBN is preservable (as confirmed in the OR)
  5. Cognitive ability and language skills required to complete the outcome measures.
  6. Provision of informed consent.

Exclusion Criteria:

  1. The patient has chronic pain or a chronic pain syndrome for which they have received daily medication (i.e. opioid, anti-convulsant, anti-spasmodic, anti-depressant, anti-inflammatory) or routine pain intervention (i.e. nerve blocks) during the past 3 months.

    Note: Chronic pain refers to known chronic pain disorder (i.e. post-herpetic neuralgia, complex regional pain syndrome, fibromyalgia, diabetic neuropathy, post-stroke pain, etc.). The diagnosis for a 'chronic pain syndrome' is outlined by the use of pain medications and interventions. The pain medication must be used by the patient to treat pain. For a pain intervention to be considered routine, it must be given in its prescribed frequency during the past three months (e.g. a patient that has been prescribed to receive a nerve block once a month, received three nerve blocks in the past three months).

  2. The patient has a prior history of completing ALND on the ipsilateral side.
  3. Detectable metastatic disease at the time of initial diagnosis.
  4. Planned bilateral ALND.
  5. History of shoulder trauma or pathology on the same side as their breast cancer.
  6. Preservation of the ICBN is not possible, in the judgement of the attending surgeon (as confirmed in the OR).
  7. Anticipated problems with the patient being available for follow-up.
  8. Incarceration.
  9. The patient is or may be enrolled in a competing trial.
  10. Other reason to exclude the patient, as specified.

Biomarker Sub-Study Eligibility:

All eligible patients who consent to participate in the INSPIRE trial will be asked to participate in the biomarker sub-study. Participants who decline to participate in the biomarker sub-study will still be enrolled into the INSPIRE trial. During the pilot phase of the INSPIRE trial, we will confirm our ability to obtain and analyze blood samples from ≥ 90% of INSPIRE participants.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: PREVENTION
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: SINGLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Intervention - ICBN preservation
For participants randomized to the ICBN preserving technique, surgeons will perform axillary dissection in which the second ICBN, just inferior to the axillary vein, will be preserved.
Other: ICBN preservation surgery

For participants randomized to the ICBN preserving technique, surgeons will perform axillary dissection in which the second ICBN, just inferior to the axillary vein, will be preserved. Surgeons will be asked to indicate whether the ICBN nerve was fully preserved, partially preserved, or sacrificed.

All study participants will receive anesthetic management at the discretion of the attending physician, which will be documented.
NO_INTERVENTION: Control - Usual Care
For participants allocated to the usual surgical care arm, attending surgeons will perform a standard Level 1 and 2 axillary node dissection (sacrifice of the ICBN), either alone or with mastectomy or breast conserving surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Persistent post-surgical pain (PPSP)
Time Frame: 12 months

Post-surgery as defined by the World Health Organization (WHO).

The WHO's definition requires 4 criteria for the diagnosis of PPSP:

  1. Pain that began after surgery or a tissue trauma is experienced;
  2. The pain is in an area of preceding surgery or tissue trauma,
  3. The pain has persisted for at least three months after surgery, and
  4. The pain is not better explained by an infection, malignancy, a pre-existing pain condition or any other alternative cause.
12 months
Moderate-to-severe PPSP
Time Frame: 12 months

We will establish the severity of PPSP with an item from the Brief Pain Inventory Short Form (BPI-SF), which asks patients to report their 'average' pain intensity rating in the past 24 hrs, on a scale of 0 (no pain) to 10 (maximum pain).

As per the BPI-SF scoring system, we will define moderate-to-severe pain as scores of ≥4 out of 10.
12 months
Biomarker Sub-Study: Cytokine Levels and PPSP
Time Frame: 3 weeks, 3 months
We will determine the correlation between pro-inflammatory cytokine levels and the presence and intensity of persistent pain at 3 weeks, and 3 months post-surgery
3 weeks, 3 months
Biomarker Sub-Study: Cytokine Levels Pre and Post-Op
Time Frame: 3 weeks
We will determine the effect of the study intervention on the change in cytokine levels (pre-operative to post-operative) in participants who consent to participate in the sub-study.
3 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Operative Time
Time Frame: 12 months
Operative time will be measured from the time of the first incision until the time of closure of the incision.
12 months
General physical functioning
Time Frame: 12 months

Short Form-36 Health Assessment Survey (SF-36) Physical Component Summary score.

The range of possible scores goes from 0 (worst possible physical functioning) to 100 (best possible physical functioning)
12 months
General Mental functioning
Time Frame: 12 months

Short Form-36 Health Assessment Survey (SF-36) Mental Component Summary score.

The range of possible scores goes from 0 (worst possible mental functioning) to 100 (best possible mental functioning)
12 months
Upper limb-specific physical functioning
Time Frame: 12 months

The Quick-Disability Arm Shoulder Hand Survey (Quick-DASH).

An 11-item scale that measures physical function in people with any or multiple musculoskeletal disorders of the upper limb.

The range of scores goes from 0 (worst possible functioning) to 100 (best possible functioning).
12 months
Return to Work
Time Frame: 12 months
We will document when participants, who were employed before their surgery, return to work.
12 months
Adverse Events
Time Frame: 12 months
All adverse events will be documented on the study specific case report forms. An independent medical monitor will also review each adverse event to determine its relatedness to the surgical treatment.
12 months
Pain Interference
Time Frame: 12 months

Item PAININ18 of the PROMIS will be used to determine the proportion of patients who report somewhat-to-very much pain interference over 12 months post-surgery.

This item is scored from 0 (not at all) to 4 (very much), and we will use a cut-off value of 2 (somewhat) or higher to define an event.
12 months
Use of Prescription Opioids
Time Frame: 12 months
We will capture the proportion of patients who are prescribed an opioid at 3, 6, 9 and 12-months post-surgery, including the type and dose.
12 months
Return to household activities
Time Frame: 12 months
We will document when participants return to their normal household activities.
12 months
Return to leisure activities
Time Frame: 12 months
We will document when participants return to their normal leisure activities.
12 months
Return to pre-surgical functioning
Time Frame: 12 months
We will document when participants achieve 80% of their pre-surgery function, as measured on a percentage scale of 0% (no function) to 100% (full pre-surgical function).
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

McMaster University

Collaborators

Hamilton Health Sciences Corporation

Investigators

  • Principal Investigator: Susan Dr Reid, Hamilton Health Sciences - Juravinski Hospital
  • Principal Investigator: Jason Busse, McMaster Michael DeGroote Centre for National Pain Research and Care
  • Principal Investigator: Sheila Sprague, Mcmaster

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

October 15, 2019

Primary Completion (ANTICIPATED)

December 1, 2020

Study Completion (ANTICIPATED)

December 1, 2020

Study Registration Dates

First Submitted

January 18, 2018

First Submitted That Met QC Criteria

January 29, 2018

First Posted (ACTUAL)

February 5, 2018

Study Record Updates

Last Update Posted (ACTUAL)

June 26, 2020

Last Update Submitted That Met QC Criteria

June 24, 2020

Last Verified

December 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • INSPIRE-001

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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