Clinical trial NCT01912612: Mechanistic Study of Duloxetine in Breast Cancer Patients With Chronic Pain
Official title: A Study to Identify Predictors of Response to Duloxetine in Breast Cancer Patients With Chronic Pain
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pain
Keywords: Breast cancer
Pain sensitivity
Lead sponsor: University of Michigan Rogel Cancer Center
Sponsor class: OTHER
Collaborators: name: American Cancer Society, Inc.
First posted: 2013-07-31
Enrollment: 82
Sex: FEMALE
Minimum age (years): 25
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: Trial was initially a randomized cross-over design. Soon after study initiation the trial design was amended because of poor accrual, and instead was a single arm open label trial in which all patients with pain were treated with study drug. Since so few patients had been enrolled at the time of study redesign, the only data analyzed were from the single treatment arm portion of the trial, and the non-intervention (baseline only) comparator.
Primary purpose: TREATMENT

Brief summary: Early stage breast cancer is typically treated with surgery, chemotherapy, radiation therapy, and/or endocrine therapy. Following treatment, 25-60% of breast cancer survivors have reported chronic pain, which can be difficult to manage. Duloxetine is a serotonin norepinephrine reuptake inhibitor that is FDA approved for treatment of depression, anxiety, fibromyalgia, diabetic neuropathic pain, knee arthritis, and low back pain.

Pilot data suggest that duloxetine is effective in management of endocrine therapy-associated musculoskeletal pain, and a randomized placebo controlled trial of duloxetine has demonstrated efficacy for treatment of chemotherapy-induced neuropathic pain. In this mechanistic study of duloxetine, we will investigate the change in pain sensitivity with treatment in order to evaluate both why duloxetine is effective for management of pain for some patients, as well as predictors of who is likely to benefit from duloxetine. A total of 84 women with early stage breast cancer who have chronic pain following treatment, as well as 48 women who are pain free, will be enrolled. All subjects will undergo assessment of pain sensitivity and complete questionnaires. Subjects with pain will be treated with duloxetine for a total of 7 weeks, with pain sensitivity assessments before treatment and after 4 weeks of full-dose treatment.

Detailed description: Early stage breast cancer is typically treated with surgery, chemotherapy, radiation therapy, and/or endocrine therapy. Following treatment, 25-60% of breast cancer survivors have reported chronic pain, which can be difficult to manage. Duloxetine is a serotonin norepinephrine reuptake inhibitor that is FDA approved for treatment of depression, anxiety, fibromyalgia, diabetic neuropathic pain, knee arthritis, and low back pain.

Data from a randomized, placebo-controlled clinical trial of duloxetine demonstrated that it is effective in management of both aromatase inhibitor-associated musculoskeletal pain and chemotherapy-induced neuropathic pain. In this mechanistic study, we investigated the change in pain sensitivity with treatment in order to evaluate both why duloxetine is effective for management of pain for some patients, as well as predictors of who is likely to benefit from duloxetine. The original protocol was designed as a randomized, placebo-controlled cross-over trial, with planned enrollment of a total of 84 women with early stage breast cancer who have chronic pain following treatment, as well as 48 women who are pain free. However because of challenges with logistics of the protocol and pain testing, the trial was redesigned after only 7 patients with pain were enrolled. The new design was a single arm trial, and all patients with pain were treated with duloxetine (no placebo); there was still a non-treatment comparator arm of patients without pain. Patients were enrolled first at the University of Michigan and then the University of Utah. A total of 39 patients with pain and 43 controls without pain were enrolled before the trial closed to enrollment. All subjects underwent assessment of pain sensitivity and completed questionnaires. Subjects with pain were treated with duloxetine for a total of 7 weeks, with pain sensitivity assessments before treatment and after 4 weeks of full-dose treatment. The data from the control patients (who did not receive any study medication) are being compared to those from the patients with pain to understand more about the differences between patients who do and do not experience treatment-related pain, and to interpret the post-intervention patient-reported and pain assessment results.

Eligibility criteria: Inclusion Criteria:

1. Female patients at least 25 years of age
2. Diagnosis of stage 0-III breast cancer within 12 years prior to enrollment. All indicated surgery, chemotherapy, and/or radiation therapy must have been completed at least 12 weeks prior to enrollment. Concomitant endocrine therapy and targeted therapies such as palbociclib, pertuzumab, and trastuzumab are permitted.
3. Pain that developed or worsened since breast cancer diagnosis and is not due to identifiable traumatic event or fracture
4. Patient-reported worst pain score between 5 and 10 (inclusive) on a 0-10 scale (assessed verbally)
5. Female patients must be at least 1 year postmenopausal or surgically sterile; or must agree to use a medically acceptable form of contraception
6. Willing to withdraw from selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA) prior to treatment initiation
7. Patients who are currently taking non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, naproxen, meloxicam, gabapentin, pregabalin) and/or opioid pain medications must remain on a stable dosage throughout the duration of the study
8. Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.

Exclusion Criteria:

1. Prior use of duloxetine or milnacipran.
2. Prior or current use of venlafaxine specifically for treatment of pain (prior or current use for treatment of other indications, such as hot flashes, is permitted, although cases currently taking venlafaxine must discontinue use prior to study treatment initiation)
3. Patients must not be taking any contraindicated medications listed on the duloxetine package insert including the following: phenothiazines, propafenone, flecainide, linezolid, or anticoagulation medication (e.g., heparin, warfarin, or direct oral anticoagulants); treatment with monoamine oxidase inhibitor within 14 days prior to registration.
4. Thumbnail abnormalities on either hand (such as due to chemotherapy or trauma, or artificial nails) that are likely to alter pain perception during testing
5. Peripheral sensory neuropathy at the thumbs bilaterally that interferes with function and/or activities of daily living
6. Significant risk of suicide based on the Investigator's judgment
7. History or behavior that would, in the Investigator's judgment, prohibit compliance for the duration of the study.
8. History of alcohol or other substance abuse or dependence within the year prior to registration
9. Known chronic liver disease, end stage renal disease, or creatinine clearance \<30 mL/min as defined by Cockcroft-Gault equation
10. Uncontrolled narrow-angle glaucoma.
11. Clinically significant coagulation disorder
12. History of seizure disorder
13. Pregnant or breast-feeding. Urine pregnancy test will be assessed at the baseline visit in women of child-bearing potential with chronic pain.
14. Unable to take oral medications or any medical condition that would interfere with the absorption of study medication capsules.
15. Currently taking SSRI, serotonin-norepinephrine reuptake inhibitor (SNRI), or TCA regimen (including Wellbutrin) for treatment of major depressive disorder or generalized anxiety disorder (without approval and involvement of the patient's treating psychiatrist to taper cases off these medications prior to study treatment).

Controls are patients without chronic pain who otherwise meet the following eligibility criteria (inclusion #1, 2, 8, exclusion #1, 2, 4, 5, worst pain score 0-1, and not currently on medication for pain)

Primary outcomes:
measure: Change in Patient-reported Worst Pain Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
Secondary outcomes:
measure: Change in Patient-reported Average Pain Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in Pain Interference Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in Number of Sites of Pain Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in Fibromyalgia Symptom Severity Score Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in PainDETECT Score Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in Neuropathy Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in Fatigue Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in Sleep Disturbance Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in Physical Function Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in Anxiety Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in Depression Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in Cognitive Difficulties - Language Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in Cognitive Difficulties - Visual-Perceptual Ability Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in Cognitive Difficulties - Verbal Memory Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in Cognitive Difficulties - Visual-Spatial Memory Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in Cognitive Difficulties - Attention/Concentration Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in Objectively Assessed Pain Sensitivity Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
measure: Change in Objectively Assessed Conditioned Pain Modulation Between Baseline and 5 Weeks of Treatment With Duloxetine
timeFrame: 5 weeks
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan Rogel Cancer Center
state: Michigan
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
Study officials:
affiliation: University of Michigan
name: Lynn Henry, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: