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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03421522
Recruitment Status : Recruiting
First Posted : February 5, 2018
Last Update Posted : June 26, 2020
Sponsor:
Collaborator:
Hamilton Health Sciences Corporation
Information provided by (Responsible Party):
McMaster University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Post-surgical Pain Pain, Chronic Intercostal Pain Breast Cancer Other: ICBN preservation surgery Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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
Masking: Single (Participant)
Masking Description: Eligible participants will be randomized to one of two treatment groups: 1) ICBN preservation, or 2) usual surgical technique (ICBN sacrifice). Due to the nature of the intervention, it will not be feasible to blind the treating surgeons or the study personnel. The patients, data analysts, and those interpreting the study results will be blinded to treatment allocation.To ensure concealed allocation, eligible patients will be randomized using the randomization function within the REDCap Cloud electronic data capture system. Treatment allocation will be stratified by clinical site to account for systematic differences in surgeons and peri-operative care. To avoid crossover between treatment allocation, randomization will take place in the operating room after the surgeon has confirmed that the participant is a candidate for ICBN preservation.
Primary Purpose: Prevention
Official Title: Intercostobrachial Nerve Sparing in Breast Cancer Surgery to Reduce Persistent Post-surgical Pain - an International Randomized Controlled Trial
Actual Study Start Date : October 15, 2019
Estimated Primary Completion Date : December 1, 2020
Estimated Study Completion Date : December 1, 2020

Resource links provided by the National Library of Medicine


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.



Primary Outcome Measures :
  1. 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.

  2. 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.


  3. 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

  4. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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)


  3. 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)


  4. 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).


  5. Return to Work [ Time Frame: 12 months ]
    We will document when participants, who were employed before their surgery, return to work.

  6. 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.

  7. 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.


  8. 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.

  9. Return to household activities [ Time Frame: 12 months ]
    We will document when participants return to their normal household activities.

  10. Return to leisure activities [ Time Frame: 12 months ]
    We will document when participants return to their normal leisure activities.

  11. 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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

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.


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): NCT03421522


Contacts
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Contact: Toni Tidy 905-525-9140 ext 21737 tonitidy@mcmaster.ca
Contact: Gina Del Fabbro delfabbg@mcmaster.ca

Locations
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Canada, Ontario
Juravinski Hospital Recruiting
Hamilton, Ontario, Canada, L8V 1C3
Contact: Susan Reid, MD    905-521-2100 ext 73188    reid@mcmaster.ca   
Sponsors and Collaborators
McMaster University
Hamilton Health Sciences Corporation
Investigators
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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
Additional Information:
Publications:

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Responsible Party: McMaster University
ClinicalTrials.gov Identifier: NCT03421522    
Other Study ID Numbers: INSPIRE-001
First Posted: February 5, 2018    Key Record Dates
Last Update Posted: June 26, 2020
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by McMaster University:
PPSP
ICBN
Additional relevant MeSH terms:
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Breast Neoplasms
Chronic Pain
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Pain
Neurologic Manifestations
Signs and Symptoms