Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer

Study Overview
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Brief Summary
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RATIONALE: Duloxetine may lessen peripheral neuropathy caused by chemotherapy. It is not yet known whether duloxetine is more effective than a placebo in treating peripheral neuropathy caused by chemotherapy. PURPOSE: This randomized phase III trial is studying duloxetine to see how well it works compared with a placebo in treating peripheral neuropathy caused by chemotherapy in patients with cancer.

Detailed Description
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OBJECTIVES: Primary Determine the efficacy of duloxetine hydrochloride in cancer patients with painful chemotherapy-induced (taxane or platinum agent) peripheral neuropathy. Secondary Determine the influence of this drug on peripheral neuropathy-related functional status and quality of life of these patients. Describe the differences in duloxetine hydrochloride efficacy when used to treat pain caused by chemotherapy-induced peripheral neuropathy based on the neurotoxic drug and class. OUTLINE: This is a randomized, double-blind, placebo-controlled, crossover study. Patients are stratified according to prior neurotoxic agent (paclitaxel vs oxaliplatin vs other taxane agents without paclitaxel vs platinum agents [cisplatin] without oxaliplatin) and high risk for developing painful chemotherapy-induced peripheral neuropathy (no vs yes). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral duloxetine hydrochloride once or twice daily in weeks 1-6. After a 1-week rest period, patients cross over to receive an oral placebo once or twice daily in weeks 8-13. Arm II: Patients receive an oral placebo once or twice daily in weeks 1-6. After a 1-week rest period, patients cross over to receive oral duloxetine hydrochloride once or twice daily in weeks 8-13. Patients complete pain and quality of life questionnaires, including the BPI-SF once weekly and FACT/GOG-NTX and EORTC QLQ-C30 questionnaires, in weeks 1, 6, 8, and 13. After completion of study treatment, patients are followed for 2 weeks.

Official Title
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A Phase III Double Blind Trial of Oral Duloxetine for Treatment of Pain Associated With Chemotherapy-Induced Peripheral Neuropathy

Conditions
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Neurotoxicity, Pain, Peripheral Neuropathy, Unspecified Adult Solid Tumor, Protocol Specific

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: Diagnosis of cancer CNS malignancy allowed with the exception of leptomeningeal carcinomatosis Must have painful sensory chemotherapy-induced peripheral neuropathy (CIPN) resulting from prior treatment with single-agent taxane or platinum agents (paclitaxel, docetaxel, nab-paclitaxel, oxaliplatin, cisplatin) (may not have received drugs from both classes) CIPN > grade 1 as measured by NCI-CTCAE v 4.0 Average neuropathic pain score ≥ 4 Patients with the following illnesses known to cause peripheral neuropathy are eligible, provided they have no evidence of neuropathy from these illnesses: Diabetes mellitus Peripheral vascular disease HIV infection Significant degenerative or familial neurologic disorder known to cause peripheral neuropathy No clinical or subclinical neuropathy from nerve compression injuries (i.e., carpal tunnel syndrome, brachial plexopathy, spinal stenosis, or spinal nerve root compression) PATIENT CHARACTERISTICS: AST ≤ 3 times upper limit of normal Total bilirubin ≤ normal Creatinine clearance > 30 mL/min Not pregnant or nursing Able to take oral or enteral medication No history of seizure disorder No diagnosis of ethanol addiction or dependence within the past 10 years No history of narrow-angle glaucoma None of the following: History of suicidal thoughts Symptoms of or history of schizophrenia, bipolar disease, or a major depression Serious eating disorder such as bulimia or anorexia where electrolyte imbalance is likely PRIOR CONCURRENT THERAPY: At least 3 months since prior and no concurrent taxane or platinum agent At least 14 days since prior and no concurrent monoamine oxidase inhibitors or other antidepressants No other prior or concurrent neurotoxic drugs (e.g., vincristine, vinblastine, cytarabine, thalidomide, bortezomib, carboplatin, or procarbazine) No concurrent anticonvulsants No concurrent B or E vitamin supplementation in doses greater than the recommended daily allowance (RDA) Centrum (standard formula) and One-A-Day essential formula which contain 100% RDA for vitamins B6, E, and B12 allowed Other multivitamins allowed provided they contain no more than 100% RDA of B vitamins and vitamin E No concurrent treatment (pharmacologic) for depression

Ages Eligible for Study
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Minimum Age: 25 Years

Sexes Eligible for Study
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All

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: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I/Group A (Duloxetine then Placebo)<br>Patients receive oral duloxetine hydrochloride once or twice daily in weeks 1-6. After a 1-week rest period, patients cross over to receive an oral placebo once or twice daily in weeks 8-13. | Drug: duloxetine hydrochloride<br>* Given orally<br>Other: placebo<br>* Given orally<br>|
| Experimental: Arm II/Group B (Placebo then Duloxetine)<br>Patients receive an oral placebo once or twice daily in weeks 1-6. After a 1-week rest period, patients cross over to receive oral duloxetine hydrochloride once or twice daily in weeks 8-13. | Drug: duloxetine hydrochloride<br>* Given orally<br>Other: placebo<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Average Pain From Week 1 to Week 5, as Measured by the BPI-SF Average Pain Severity Item | Change in average pain from Week 1 to Week 5, measured on day 1 of Weeks 1 and 6 by the Brief Pain Inventory Short Form (BPI-SF) was calculated as value at Day 1 of Week 1 minus value at Day 1 of Week 6 to yield positive improvement values. The BPI-SF contains 4 items assessing average, worst, least, and intermediate pain severity in the last 24 hours. Pain severity items are scored using an 11-point numeric rating scale (0, no pain; 10, pain as bad as you can imagine). Average pain severity was chosen as the primary outcome based on recommendations from the Initiative on Methods, Measurements, and Pain Assessment in Clinical Trials (IMMPACT). Patients completed the BPI-SF when thinking only about pain from peripheral neuropathy. The Cronbach's alpha reliability for the BPI ranges between 0.77 and 0.91. The comparison of interest was the difference between the 2 treatment groups in pain change during the initial treatment period. | Day 1 of Week 1 to Day 1 of Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pain-related Functional Interference Score From Week 1 to Week 5, as Measured by the BPI-SF Interference Score | Change in pain-related functional interference score during the initial treatment period (Week 1 to Week 5), as measured by the BPI-SF interference score: Using an accepted method for accessing the influence of pain on function, 7 BPI-SF items were used to quantify the degree to which pain interfered with daily activities or function (0, does not interfere; 10 completely interferes). The 7 items were summed to obtain a total interference score, which ranged from 0 to 70, with lower scores meaning less interference. The mean change in pain-related functional interference score during the initial treatment period are reported below for each treatment arm and was calculated as value at Day 1 of Week 1 minus value at Day 1 of Week 6 to yield positive improvement values. | Day 1 of Week 1 to Day 1 to Week 6 | 
| Change in the Total Score of the FACT/COG-NTX From Week 1 to Week 5 | Patient-reported QOL was assessed using the Functional Assessment of Cancer Treatment, Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) subscale on day 1 of weeks 1, 6, 8, and 13. The instrument contains 11 questions, assessing numbness, tingling, and discomfort in the hands or feet; difficulty hearing; tinnitus; joint pain or muscle cramps; weakness; or trouble walking, buttoning buttons, or feeling small shapes when placed in the hand. Items are scored from 0 to 4 (o, not at all; 4, very much) and summed (total score range, 0-44, with higher scores indicating a worse outcome). A 2- to 3-point change is defined as a clinically meaningful improvement in QOL per published recommendations specific to similar measures. The Mean Change During Initial Treatment Period in the FACT/GOG-Ntx total score are reported for each treatment arm and was calculated as value at Day 1 of Week 1 minus value at Day 1 of Week 6 to yield positive improvement values. | Day 1 of Week 1 to Day 1 of Week 6 | 
| Change in Average Pain From Week 8 to Week 12, as Measured by the BPI-SF Average Pain Severity Item | Change in average pain from Week 8 to Week 12, measured on day 1 of Weeks 8 and 13 by the Brief Pain Inventory Short Form (BPI-SF) was calculated as value at Day 1 of Week 8 minus value at Day 1 of Week 13 to yield positive improvement values. The BPI-SF contains 4 items assessing average, worst, least, and intermediate pain severity in the last 24 hours. Pain severity items are scored using an 11-point numeric rating scale (0, no pain; 10, pain as bad as you can imagine). Average pain severity was chosen as the primary outcome based on recommendations from the Initiative on Methods, Measurements, and Pain Assessment in Clinical Trials (IMMPACT). Patients completed the BPI-SF when thinking only about pain from peripheral neuropathy. The Cronbach's alpha reliability for the BPI ranges between 0.77 and 0.91. The comparison of interest was the difference between the 2 treatment groups in pain change during the crossover treatment period. | Day 1 of Week 8 to Day 1 of Week 13 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pain, unspecified adult solid tumor, protocol specific, neurotoxicity, peripheral neuropathy