S1202: Duloxetine Hydrochloride for Muscle/Joint Pain in Early-Stage Breast Cancer Receiving Hormone Therapy

Study Overview
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Brief Summary
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RATIONALE: Duloxetine hydrochloride may lessen muscle, bone, and joint pain caused by hormone therapy. It is not yet known whether duloxetine hydrochloride is more effective than a placebo in treating patients with muscle, bone, and joint pain caused by hormone therapy. PURPOSE: This randomized phase III trial studies how well duloxetine hydrochloride works compared to a placebo in treating muscle, bone, and joint pain in patients with early-stage breast cancer receiving hormone therapy.

Detailed Description
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OBJECTIVES: Primary To assess whether daily duloxetine hydrochloride (duloxetine) decreases average joint pain in women with aromatase inhibitor-associated musculoskeletal syndrome (AIMSS), as measured at 12 weeks by the modified Brief Pain Inventory Short Form (BPI-SF). Secondary To assess whether daily duloxetine decreases worst joint pain in women with AIMSS, as measured at 12 weeks by the modified BPI-SF. To assess whether daily duloxetine decreases pain interference in women with AIMSS, as measured at 12 weeks by the modified BPI-SF. To investigate whether daily duloxetine improves functioning, pain, and stiffness in the knees/hips according to the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scale. (Exploratory) To investigate whether daily duloxetine improves function, pain, and stiffness in the hands according to the Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH). (Exploratory) To investigate whether daily duloxetine improves functional quality of life as measured by the Functional Assessment of Cancer Therapy-Endocrine Scale (FACT-ES). (Exploratory) To investigate whether daily duloxetine improves the proportion of patients reporting changes for the better versus worst as measured by the Global Rating of Change Scale. (Exploratory) To investigate whether daily duloxetine decreases analgesic use. To investigate whether daily duloxetine increases adherence to, and reduces the discontinuation rate for, aromatase inhibitor (AI) therapy. (Exploratory) To assess whether patients receiving duloxetine as compared to placebo have improved depression as measured by the Patient Health Questionnaire (PHQ-9) at Weeks 6 and 12. (Exploratory) To explore the relationship between inherited variants in genes responsible for duloxetine metabolism and activity (COMT, HTR3A, SLC6A2, SLC6A4, CYP1A2, CYP2D6) and aromatase (CYP19A1) and change in pain with 12 weeks of treatment. (Exploratory) To explore the impact of treatment on serum inflammatory cytokine levels with 12 weeks of treatment at baseline and 12 weeks. (Exploratory) To bank blood samples for future correlative analyses. (Exploratory) OUTLINE: This is a multicenter study. Patients are stratified according to baseline pain score (4-6 vs 7-10), and prior taxane use (yes vs no). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive duloxetine hydrochloride orally (PO) once daily (QD) on days 1-7, twice daily (BID) on days 8-84, and then QD on days 85-91. Arm II: Patients receive placebo PO QD on days 1-7, BID on days 8-84, and then QD on days 85-91. Patients complete the modified Brief Pain Inventory Short Form (BPI-SF) questionnaire at baseline and periodically during study treatment. Patients may also complete the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scale, the Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH), the Functional Assessment of Cancer Therapy-Endocrine Scale (FACT-ES), Global Rating of Change Scale, and the patient Health Questionnaire (PHQ-9). Patients undergo blood sample collection at baseline and periodically during treatment for correlative studies, including biomarker and genetic studies. After completion of study treatment, patients are followed up for 168 days.

Official Title
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A Randomized Placebo-Controlled Phase III Study of Duloxetine for Treatment of Aromatase Inhibitor-Associated Musculoskeletal Symptoms in Women With Early Stage Breast Cancer

Conditions
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Breast Cancer, Musculoskeletal Complications, Pain

Intervention / Treatment
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* Drug: duloxetine hydrochloride
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Patients must be women with histologically confirmed estrogen receptor (ER)- and/or progesterone receptor (PgR)-positive invasive carcinoma of the breast with no evidence of metastatic disease (M0) Patients must have completed mastectomy or breast-sparing surgery and must have recovered from all side effects of the surgery Patients must have aromatase inhibitor (AI)-associated musculoskeletal symptoms that began or increased after starting AI therapy; new musculoskeletal pain must not be due specifically to fracture or traumatic injury Patients must have completed the S1202 Brief Pain Inventory-Short Form (BPI-SF) within 7 days prior to registration; patients must have an average pain of at least 4 on the BPI-SF PATIENT CHARACTERISTICS: Patients must be post-menopausal, as defined by at least one of the following: At least 12 months since the last menstrual period Prior bilateral oophorectomy Previous hysterectomy with one or both ovaries left in place (or previous hysterectomy in which documentation of bilateral oophorectomy is unavailable) AND follicle-stimulating hormone (FSH) values consistent with the institutional normal values for the post menopausal state; if patient is under the age of 55, FSH levels must be obtained within 28 days prior to registration OR Have been on LHRH agonist therapy for at least 3 months and estradiol levels drawn within 28 days prior to registration are consistent with the institutional normal values for post-menopausal state. Patients must have Zubrod performance status of 0-2 Patients must have no known allergy or hypersensitivity to duloxetine or any of the inactive ingredients in the matching placebo Patients must not have any contraindicated concurrent illnesses listed on the duloxetine package insert including: Current primary psychiatric diagnosis (schizophrenia, psychosis) or suicidal ideation, history of bipolar disorder, or seizure disorder History of alcohol or other substance abuse or dependence within 365 days prior to registration Chronic liver disease End-stage renal disease Uncontrolled narrow-angle glaucoma Clinically significant coagulation disorder Creatinine clearance > 30 mL/min Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both within 3 x upper limit of normal Total bilirubin within the upper limit of normal Patients must be able to complete study questionnaires in English or Spanish Patients must not have concurrent medical/arthritic disease that could confound or interfere with evaluation of pain or efficacy including: inflammatory arthritis (rheumatoid arthritis, systemic lupus, spondyloarthropathy, psoriatic arthritis, polymyalgia rheumatica), or cancer involving the bone Patients must be willing to submit blood samples for correlative studies; baseline samples must be obtained prior to beginning protocol treatment PRIOR CONCURRENT THERAPY: See Disease Characteristics If patients were treated with chemotherapy and/or radiation therapy, these treatments must be completed at least 28 days prior to study registration Concurrent bisphosphonate and trastuzumab therapies are allowed Patients should have recovered from all Grade 2 or higher side effects of chemotherapy and/or radiation therapy with the exception of alopecia and peripheral neuropathy Patients must currently be taking one of the following aromatase inhibitor (AI) doses for at least 21 days, but no longer than 12 months, prior to registration and plans to continue for at least an additional 180 days after registration Anastrozole (Arimidex®) 1 mg daily Letrozole (Femara®) 2.5 mg daily Exemestane (Aromasin®) 25 mg daily Patients must not be taking any contraindicated medications listed on the duloxetine package insert including the following: treatment with phenothiazines, propafenone, flecainide, or linezolid; treatment with monoamine oxidase (MAO)-inhibitor within 14 days prior to registration; or current use of anticoagulation medication (e.g., heparin, warfarin) Patients must not require selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephirine reuptake inhibitors (SNRIs), or tricyclic antidepressants during study participation; patients must have been able to taper and discontinue treatment with these medications at least 7 days prior to registration; patients must not have taken duloxetine or milnacipran within 90 days prior to registration Patients who are receiving treatment with narcotics, tramadol, gabapentin, and/or pregabalin must have been taking a stable dose for at least 30 days prior to registration

Ages Eligible for Study
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Maximum Age: 120 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive duloxetine hydrochloride orally (PO) once daily (QD) on days 1-7, twice daily (BID) on days 8-84, and then QD on days 85-91. | Drug: duloxetine hydrochloride<br>* Given PO<br>* Other names: NSC-744012;|
| Placebo Comparator: Arm II<br>Patients receive placebo PO QD on days 1-7, BID on days 8-84, and then QD on days 85-91. | Other: placebo<br>* Given PO<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Joint Pain According to BPI-SF | Average joint pain according to the Brief Pain Inventory - Short Form (BPI-SF) average pain score (item #4). This item has a scale of 0 to 10 with 0 indicating No pain and 10 indicating Pain as bad as you can imagine. | Weeks 2, 6, 12, and 24; Week 12 reported | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Worst Joint Pain According to the BPI-SF | Worst joint pain according to the BPI-SF worst pain score (item #2). This item has a scale of 0 to 10 with 0 indicating No pain and 10 indicating Pain as bad as you can imagine. | Weeks 2, 6, 12, and 24; Week 12 reported | 
| Pain Interference According to the BPI-SF | Pain interference according to the BPI-SF: this item has a scale of 0 to 10 with 0 indicating Does not interfere and 10 indicating Completely interferes. | Weeks 2, 6, 12, and 24; Week 12 reported | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer, stage IA breast cancer, stage IB breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, pain, musculoskeletal complications