Melatonin Supplementation for Cancer-related Fatigue in Patients Receiving Radiotherapy

Study Overview
=================
Brief Summary
-----------------
This is a double-blind, placebo-controlled trial wherein subjects with breast cancer will be randomized to receive either 20 mg oral melatonin or placebo the night before their first radiotherapy (RT), nightly throughout their RT, and for an additional 2 weeks following the completion of their RT. After informed consent is obtained from eligible subjects, they will then be electronically randomized on a 1:1 ratio to melatonin treatment or placebo. The subjects will be stratified according to treatment duration (less than 3 weeks; equal to or greater than 3 weeks) and prior chemotherapy.

Detailed Description
-----------------
Subjects will be randomized to receive either melatonin or placebo. Subjects will receive 20-mg oral melatonin or placebo the night before their first RT treatment, each night throughout the course of RT treatment, and for 2 weeks following the completion of RT. Patients with localized breast cancer will receive standard-of-care RT as determined by the treating physician. The RT regimens include: (1) 1 week of accelerated (APBI); (2) 3-4 weeks of an accelerated hypofractionation RT schedule; and (3) 6-8 weeks of a standard RT schedule. No additional concomitant medication or supportive care guidelines are required for this study. Subjects will receive daily melatonin or placebo beginning the night before their course of RT and for an additional 2-week period that extends beyond the conclusion of their RT. Subjects will be given a Study Diary to record their use of study medication. Patients will be followed for 60 days after removal from the study treatment or until death, whichever occurs first. Patients removed from the study treatment for unacceptable adverse events (AEs) will be followed until resolution or stabilization of the adverse event.

Official Title
-----------------
Melatonin Supplementation for Cancer-related Fatigue in Patients Receiving Radiotherapy: A Double Blind Placebo-Controlled Trial

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

Intervention / Treatment
-----------------
* Drug: Melatonin
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Ambulatory outpatients with breast (including ductal carcinoma in situ [DCIS]) cancer. Patients to be treated with RT for curative intent. Women ≥18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status <3 (Appendix 4). Hemoglobin ≥ 9 g/dL Either post-menopausal, surgically sterilized, or willing to use an acceptable method of birth control during study treatment and for 3 months afterwards. Subjects who are currently taking melatonin must discontinue melatonin for 5 days before enrolling in the study. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria Fatigue brought on by conditions other than cancer such as (the indicated tests are required only if that mechanism of fatigue is suspected): uncontrolled hypothyroidism (TSH >10 IU) hypercalcemia (calcium >11 mg/dL) Calcium (Ca) = Serum Calcium (SerumCa) + 0.8 * (NormalAlbumin - PatientAlbumin) decompensated congestive heart failure chronic obstructive pulmonary disease requiring oxygen replacement Patients with a creatinine clearance <30 mL/min Aspartate aminotransferase (AST) > 3X upper limit of normal (ULN) Alanine aminotransferase (ALT) > 3X ULN Bilirubin > 1X ULN Use of systemic steroids, or other pharmacological agents such as methylphenidate for cancer-related fatigue Current use of American ginseng, remelteon, or warfarin. Depression ≥ grade 2 (CTCAE v4.0)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

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

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

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

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 20 mg Melatonin<br>RT (as clinically indicated) + melatonin (Subjects will receive 20-mg oral melatonin the night before their first RT treatment, each night throughout the course of RT treatment, and for 2 weeks following the completion of RT). | Drug: Melatonin<br>* Melatonin + RT (as clinically indicated) (Subjects will receive 20-mg oral melatonin or placebo the night before their first RT treatment, each night throughout the course of RT treatment, and for 2 weeks following the completion of RT).<br>|
| Placebo Comparator: Placebo<br>RT (as clinically indicated) + placebo (Subjects will receive 20-mg oral placebo the night before their first RT treatment, each night throughout the course of RT treatment, and for 2 weeks following the completion of RT). | Drug: Placebo<br>* Placebo + RT (as clinically indicated) (Subjects will receive 20-mg oral melatonin or placebo the night before their first RT treatment, each night throughout the course of RT treatment, and for 2 weeks following the completion of RT).<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of FACIT-Fatigue Subscale | Determine if the average increase in fatigue (as measured by the Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue subscale) from baseline to completion of RT is different in those patients who received melatonin than in those who received placebo. The FACIT-F is a well-validated QOL instrument widely used for the assessment of cancer-related fatigue in clinical trials. It consists of 27 general QOL questions divided into 4 domains (physical, social, emotional, and functional), plus a 13-item fatigue sub-score. The patient rates the intensity of fatigue and its related symptoms on a scale of 0-4. The total score ranges between 0 and 52, with higher scores denoting less fatigue. | Baseline,( Day 1), 2 weeks post radiation therapy completion (variable, approximately 58 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of Functional Assessment of Chronic Illness Therapy (FACIT-F) Scores in Fatigue From Baseline Until 2 Weeks After Completion of RT in Those Patients Who Received Melatonin Compared to Those Who Received Placebo. | Determine whether the average increase in fatigue from baseline until 2 weeks after completion of RT is less in those patients who received melatonin than in those who received placebo. The FACIT-F is a well-validated QOL instrument widely used for the assessment of cancer-related fatigue in clinical trials. It consists of 27 general QOL questions divided into 4 domains (physical, social, emotional, and functional), plus a 13-item fatigue sub-score. The patient rates the intensity of fatigue and its related symptoms on a scale of 0-4. The total score ranges between 0 and 52, with higher scores denoting less fatigue. | Baseline,( Day 1), 2 weeks post radiation therapy completion (variable, approximately 58 weeks) | 
| Comparison in Functional Assessment of Chronic Illness Therapy (FACIT) in Fatigue From Baseline Until 8 Weeks After Completion of RT in Those Patients Who Received Melatonin Compared to Those Who Received Placebo. | Determine whether the average increase in fatigue from baseline until 8 weeks after completion of RT is less in those patients who received melatonin than in those who received placebo. The FACIT-F is a well-validated QOL instrument widely used for the assessment of cancer-related fatigue in clinical trials. It consists of 27 general QOL questions divided into 4 domains (physical, social, emotional, and functional), plus a 13-item fatigue sub-score. The patient rates the intensity of fatigue and its related symptoms on a scale of 0-4. The total score ranges between 0 and 52, with higher scores denoting less fatigue. | Baseline (Day 1) and 8 weeks post RT (variable, approximately 64 weeks) | 
| Comparison of Edmonton Symptom Assessment System (ESAS) Scores Obtained at Baseline Until Completion of RT. | Average increase in symptoms from baseline until completion of RT for those patients who received melatonin compared to those who received placebo. The ESAS assesses 10 symptoms experienced by cancer patients during the previous 24 hours: pain, fatigue, nausea, depression, anxiety, drowsiness, dyspnea, anorexia, sleep disturbance, and feelings of well-being. The severity of each symptom is rated on a numerical scale of 0-10 (0 = no symptom, 10 = worst possible severity). | Baseline,( Day 1), 2 weeks post radiation therapy completion (variable, approximately 58 weeks) | 
| Comparison of the Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue-Short Form 8a Scores Obtained at Baseline and at the Completion of RT. | Determine whether the average increase in fatigue (as measured by the PROMIS Fatigue-Short Form 8a) from baseline to completion of RT is less in those patients who received melatonin compared to those who received placebo. The higher score, the worse fatigue. The PROMIS Fatigue-Short Form 8a scale consists of 8 general questions regarding fatigue. The patient rates the intensity of fatigue and related symptoms on a scale of 1-5. The total score can range between 8 and 40, with higher scores denoting more fatigue. | Baseline,( Day 1), 2 weeks post radiation therapy completion (variable, approximately 58 weeks) | 
| Determine the Level of Agreement in Reported Fatigue Scores When 2 Different Survey Instruments Are Used to Measure Fatigue. | Compare the scores obtained with the FACIT-Fatigue subscale and the PROMIS Fatigue-Short Form at completion of RT. The FACIT-F is a well-validated QOL instrument widely used for the assessment of cancer-related fatigue in clinical trials. It consists of 27 general QOL questions divided into 4 domains (physical, social, emotional, and functional), plus a 13-item fatigue sub-score. The patient rates the intensity of fatigue and its related symptoms on a scale of 0-4. The total score ranges between 0 and 52, with higher scores denoting less fatigue. The PROMIS Fatigue-Short Form 8a scale. It consists of 8 general questions regarding fatigue. The patient rates the intensity of fatigue and related symptoms on a scale of 1-5. The total score can range between 8 and 40, with higher scores denoting more fatigue. | Baseline,( Day 1), 2 weeks post radiation therapy completion (variable, approximately 58 weeks) | 
| Compare the Number of Hospital Admissions, Emergency Center Visits, and Medical Days Off Work Between Patients Receiving Melatonin Compared to Placebo. | Determine whether patients receiving melatonin have fewer hospital admissions, emergency center visits, and medical days off work than patients receiving placebo | Baseline (day 1) to 8 weeks post RT (variable, approximately 64 weeks) |