Naltrexone RCT for Treatment-Emergent Fatigue in Patients Receiving Radiation Therapy for Breast Cancer

Study Overview
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Brief Summary
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Naltrexone is a drug which blocks some effects of chemicals called beta-endorphins that are made in the body. Beta-endorphins can be made in response to stress, injury, and also pleasurable activities. In previous studies, it has been shown that levels of beta-endorphins in the blood go up during radiation therapy, and that this increase is linked to fatigue. This suggests that naltrexone may help to reduce fatigue in people who are getting radiation therapy In this research study, the investigators are looking to see whether naltrexone works better than a placebo in reducing fatigue during radiation therapy.

Detailed Description
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This trial has two phases (a monitoring and an intervention phase). Monitoring Phase: Prior to starting radiotherapy for non-metastatic breast cancer, participants will be approached and consented for the monitoring phase of the study, which involves longitudinal monitoring of fatigue in order to establish whether a patient develops fatigue after starting radiation. The level of pre-radiotherapy fatigue will be obtained during the final two weeks before radiotherapy is started. All participants will undergo weekly monitoring of fatigue via a brief self-report questionnaire. The monitoring period will continue up until one month after the conclusion of radiotherapy. Those whose fatigue symptoms increase above the pre-specified threshold at any point during the monitoring period will be approached about enrollment into the intervention phase of the study. Intervention Phase: This is a randomized, double-blind, parallel-arm 5-week clinical trial which will be used to determine the effect of naltrexone on fatigue emerging during radiation therapy for non-metastatic breast cancer.

Official Title
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Naltrexone Randomized Controlled Trial for Treatment-Emergent Fatigue in Patients Receiving Radiation Therapy for Breast Cancer

Conditions
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Invasive Breast Cancer (Stage I-III), Ductal Carcinoma in Situ, Lobular Carcinoma in Situ, Lobular Carcinoma, Fatigue Related to Cancer Treatment

Intervention / Treatment
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* Drug: Naltrexone
* Drug: Sugar Pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Eligibility Criteria for Monitoring Phase Age ≥ 18 Diagnosis of: invasive breast cancer (stage I-III), ductal carcinoma in situ, lobular carcinoma in situ, lobular carcinoma Plan to receive radiation therapy Eligibility Criteria for Randomization Phase Participants may have had prior breast surgery and/or chemotherapy. Age ≥18 years. --Because no dosing or adverse event data are currently available on the use of naltrexone in cancer patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials. Participants must have acceptable pre-treatment laboratory values as defined below: total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal creatinine within normal institutional limits OR creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal. If child-bearing potential, willingness to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Ability to understand and the willingness to sign a written informed consent document Receiving radiation therapy of any type at DFCI, BWH, or MGH (including but not limited to partial breast irradiation, two-field, three-field, and four-field plans) FACIT-F subscale score >=10 pre-radiation therapy and decrease in FACIT-F of 10 points or more as compared to pre-radiotherapy baseline Exclusion Criteria: Exclusion Criteria for Monitoring Phase Suicidal ideation, as determined via PHQ-9 Non-English speaking Exclusion Criteria for Randomization Phase Participants with major depressive disorder and/or suicidal ideation as determined by PHQ-9. Participants who are receiving any other investigational agents that might interact with study medication or influence the measurement of study outcomes. Participants with known metastatic disease should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. History of allergic reactions attributed to compounds of similar chemical or biologic composition to naltrexone. Participants who have used opioid-containing medications (including cough/cold medications containing codeine and/or antidiarrheals containing loperamide) in the past 2 weeks, or who are expected to require opioid-containing medications within the duration of the treatment period. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women are excluded from this study because naltrexone is category C agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with naltrexone, breastfeeding should be discontinued if the mother is treated with naltrexone. Participants using other contraindicated medications (thioridazine, yohimbine)

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Naltrexone<br>The treatment schedule includes a daily dose of naltrexone for 5 weeks. Treatment will be initiated at 25 mg/day during the first week to improve tolerability. The dose will be escalated to 50 mg/day after one week barring significant early improvement in fatigue or adverse events precluding dose escalation, and participants will continue to take 50 mg/day (or 25 mg/day if dose is not escalated) for 4 weeks to complete a 5-week treatment period. | Drug: Naltrexone<br> <br> * Other names: ReVia®;|
| Placebo Comparator: Sugar Pill<br>The treatment schedule includes a daily dose of equivalent placebo for 5 weeks. Treatment will be initiated at 25 mg/day during the first week to improve tolerability. The dose will be escalated to 50 mg/day after one week barring significant early improvement in fatigue or adverse events precluding dose escalation, and participants will continue to take 50 mg/day (or 25 mg/day if dose is not escalated) for 4 weeks to complete a 5-week treatment period. | Drug: Sugar Pill<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FACIT-fatigue Subscale Score From Randomization to End of Study | Functional Assessment of Chronic Illness Therapy-Fatigue Subscale (FACIT-fatigue subscale): This 13-item self-report scale measuring fatigue and functional impairment as a result of fatigue has been validated in cancer patients (Cella et al. Cancer 2002;94:528-38) The scale is reverse-scored and the range is 0 (maximum fatigue) - 52 (minimum fatigue). According to ICD10 criteria, a score <= 34 indicates significant cancer related fatigue. A change of 10 points has been shown to constitute a clinically meaningful difference on this subscale. | Evaluated at baseline, weekly monitoring visits from start of radiation therapy and meets fatigue eligibility threshold | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Invasive Breast Cancer (Stage I-III), Ductal Carcinoma in Situ, Lobular Carcinoma in Situ, Lobular Carcinoma, Fatigue Related to Cancer Treatment