Study to Assess Effect of 8 Wks of Duloxetine Therapy on Breast Cancer Patients With Aromatase-Inhibitor Associated Pain

Study Overview
=================
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.

Official Title
-----------------
UMCC 2008.62: Prospective Pilot Study Evaluating the Use of Duloxetine for Treatment of Aromatase Inhibitor-associated Musculoskeletal Symptoms in Breast Cancer Patients

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Duloxetine


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 21 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Duloxetine<br> | Drug: Duloxetine<br>* 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.<br>* Other names: Cymbalta;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, 2, 4 , 6 and 8 weeks |