Breast Cancer
Conditions
Brief summary
Many women with breast cancer who are treated with aromatase inhibitor medications develop aches and pains during treatment, and some develop numbness and tingling in their hands and feet. Some examples of aromatase inhibitor medications include anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara). Frequently, pain medications do not work very well to relieve the pain. Duloxetine (Cymbalta) is a medication that was originally developed to treat depression. It has also been found to relieve pain that occurs in people with diabetes, fibromyalgia, arthritis, and other painful conditions. In this study we are testing to see if duloxetine will help treat the pain that can occur in women treated with aromatase inhibitors.
Detailed description
Aromatase inhibitor (AI) therapy is commonly used for treatment of postmenopausal women with hormone receptor-positive breast cancer. The most common toxicities are arthralgias and myalgias, which can be difficult to manage and necessitate discontinuation of therapy in up to 10% of patients. One potential interventional approach is with a pharmaceutical agent such as duloxetine, which has been shown to be effective for treatment of other types of chronic pain, including fibromyalgia and diabetic neuropathic pain. The primary objective of this pilot study is to determine the proportion of breast cancer patients with AI-associated musculoskeletal symptoms who experience a 30% reduction in average pain score from baseline to 8 weeks due to duloxetine treatment. Participants will be treated with duloxetine for 8 weeks. Questionnaires to evaluate pain, functional status, depression, menopausal symptoms, and sleep difficulties will be administered at baseline and after 2, 4, 6, and 8 weeks of therapy. In addition, 10 milliliters blood of will be drawn from the subjects at baseline for future pharmacogenetic evaluation. If the results of this pilot study suggest that the efficacy of duloxetine therapy is greater than that expected from placebo based on historical controls, then these data will be used to design future prospective, placebo-controlled, randomized trials of treatment with duloxetine in this patient population.
Interventions
DRUGDuloxetine
Patients will be treated with open-label duloxetine: * 30 mg daily x 7 days, then * 60 mg daily x 3 weeks, then * If a patient believes she has experienced a sufficient reduction in pain after 4 weeks of therapy, she will continue taking 60 mg daily for weeks 5-8 * If a patient does not believe she has experienced a sufficient reduction in pain after 4 weeks of therapy, she will have the option of increasing the dose to 60 mg twice daily for weeks 5-8. * After completion of 8 weeks of therapy, patients who wish to discontinue therapy will taper off the drug over 1 week (50% decrease for 4 days, then additional 50% decrease for 3 days). Patients may continue therapy off-study at the discretion of their treating physician.
Sponsors
Eli Lilly and Company
University of Michigan Rogel Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female; * Histologically proven stage 0-III invasive carcinoma of the breast that is ER and/or PR positive by immunohistochemical staining, who are receiving a standard dose of aromatase inhibitor (AI) therapy (letrozole 2.5mg once daily or exemestane 25mg once daily or anastrozole 1mg once daily). Women with oligometastatic disease may be included at the discretion of the principal investigator. Surgical resection, chemotherapy, and radiation therapy must have been completed at the time of study enrollment, with the exception of trastuzumab; * AI therapy has been ongoing for ≥ 2 weeks and treatment is expected to continue; * AI-associated musculoskeletal symptoms, defined as: * Grade 1 or higher musculoskeletal pain that developed or worsened (6 or 7 on CGICS) during AI therapy or * Grade 1 or higher sensory neuropathy that developed or worsened (6 or 7 on CGICS) during AI therapy; * Average pain of ≥4 on the 11-point Likert scale of question #5 of the Brief Pain Inventory; * ECOG performance status 0-2; * Willing and able to sign an informed consent document.
Exclusion criteria
* Known hypersensitivity to duloxetine or any of the inactive ingredients; * New musculoskeletal pain that is due specifically to fracture or traumatic injury; * Treatment with monoamine oxidase inhibitors (MAO-I) within 14 days of enrollment; * Concurrent treatment with phenothiazines (including thioridazine), propafenone, flecainide, triptans, MAO-Is, SSRIs, SNRIs, or tricyclic antidepressants; * Currently primary psychiatric diagnosis (schizophrenia, psychosis) or suicidal ideation, history of bipolar disorder, or seizure disorder; * Chronic liver disease, end stage renal disease, or creatinine clearance \< 30 mL/min as defined by the Cockroft-Gault equation; * Uncontrolled narrow-angle glaucoma or clinically significant coagulation disorder; * Pregnant or breast feeding; * History of alcohol or other substance abuse or dependence within the year prior to enrollment; * Serious or unstable medical condition that could likely lead to hospitalization during the course of the study or compromise study participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Who Experience 30% Reduction in Average Pain Score From Baseline to 8 Weeks Due to Duloxetine Therapy. | 8 weeks | Subjects were considered evaluable if they met all eligibility criteria and took at least one dose of duloxetine. Average pain was measured using Wisconsin Brief Pain Inventory Questionnaire.(BPI) The BPI is a 17-item patient self-rating scale that assessed sensory & reactive components of pain. The BPI uses 0 to 10 numeric rating scales for item rating.Since pain can be variable,the BPI asks patients to rate pain at completing questionnaire, and also at its worst, least, and average over the previous 24 hours. The primary endpoint is based on the 24-hour avg pain as reported on BPI. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Decrease in Average Pain With 8 Weeks of Duloxetine Therapy. (Sustained) | Baseline, 2, 4 , 6 and 8 weeks | A secondary measure is the percentage of patients treated with duloxetine who experience a sustained 30% reduction in average pain score from baseline to 8 weeks. Sustained 30% reduction is defined as at least 30% reduction in 24-hour average pain severity at the 8 week endpoint, with a 30% reduction from baseline at a visit at least 2 weeks prior to the last visit, and at least 20% reduction from baseline at every visit in between. |
Countries
United States
Participant flow
Recruitment details
Between December 2008 and May 2010 35 subjects enrolled and completed baseline questionnaires in the University of Michigan comprehensive cancer center's outpatient hematolgy / oncology clinic
Participants by arm
| Arm | Count |
|---|---|
| Duloxetine Participants took 30 mg oral capsules once a day for 7 days, then 60 mg per mouth once per day for 21 days. After 4 weeks if pain had decreased, subjects continued 60 mg. per mouth once per day for 4 weeks. If pain had not decreased, subjects took 60 mg twice per day per mouth for 4 weeks. 5 Questionnaires were administered at baseline and every 2 weeks for 8 weeks; medication was tapered at the end of study. | 35 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ineligible due to baseline average pain | 5 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Duloxetine |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants |
| Age Continuous | 56 years STANDARD_DEVIATION 0.9 |
| Region of Enrollment United States | 35 participants |
| Sex: Female, Male Female | 35 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 7 / 29 |
| serious Total, serious adverse events | 0 / 29 |
Outcome results
Primary
Percentage of Patients Who Experience 30% Reduction in Average Pain Score From Baseline to 8 Weeks Due to Duloxetine Therapy.
Subjects were considered evaluable if they met all eligibility criteria and took at least one dose of duloxetine. Average pain was measured using Wisconsin Brief Pain Inventory Questionnaire.(BPI) The BPI is a 17-item patient self-rating scale that assessed sensory & reactive components of pain. The BPI uses 0 to 10 numeric rating scales for item rating.Since pain can be variable,the BPI asks patients to rate pain at completing questionnaire, and also at its worst, least, and average over the previous 24 hours. The primary endpoint is based on the 24-hour avg pain as reported on BPI.
Time frame: 8 weeks
Population: Subjects were considered evaluable for the primary endpoint if they met all eligibility criteria and took at least one dose of duloxetine
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duloxetine | Percentage of Patients Who Experience 30% Reduction in Average Pain Score From Baseline to 8 Weeks Due to Duloxetine Therapy. | 72.4 percentage of participants |
Secondary
Decrease in Average Pain With 8 Weeks of Duloxetine Therapy. (Sustained)
A secondary measure is the percentage of patients treated with duloxetine who experience a sustained 30% reduction in average pain score from baseline to 8 weeks. Sustained 30% reduction is defined as at least 30% reduction in 24-hour average pain severity at the 8 week endpoint, with a 30% reduction from baseline at a visit at least 2 weeks prior to the last visit, and at least 20% reduction from baseline at every visit in between.
Time frame: Baseline, 2, 4 , 6 and 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Duloxetine | Decrease in Average Pain With 8 Weeks of Duloxetine Therapy. (Sustained) | 60.9 %of participants with 30% pain reduction |