Conditions: Breast Cancer - Female
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 80
Healthy volunteers: no

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.

Arms:
arm 1: 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). arm 2: 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).

Interventions: intervention 1: Melatonin intervention 2: Placebo
Intervention descriptions: intervention 1: 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). intervention 2: 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).

Protocol document:
Prot_SAP_001.pdf: 
Melatonin Supplementation for Cancer-Related Fatigue in Patients Receiving Radiotherapy: A 
Double Blind Placebo-Controlled Trial
MCC-12-08248
NCT02332928
12/10/2021


MCC Protocol #: MCC-12-08248 
1 
Version #:13 
Version Date: 12/10/2021 
Title: Melatonin supplementation for cancer-related fatigue in patients receiving 
radiotherapy: A double-blind placebo-controlled trial 
MCC Protocol #: MCC-12-08248 
Sponsor-Investigator: 
Alfredo Urdaneta, MD 
Version #: 13 
Version Date: 12/10/2021 


 
MCC Protocol #: MCC-12-08248 
2 
Version #:13 
 
 
Version Date: 12/10/2021 
PROTOCOL SUMMARY 
Title: 
Melatonin supplementation for cancer-related fatigue in patients 
receiving radiotherapy: A double-blind placebo-controlled trial 
Protocol Number: 
MCC-12-08248 
IND Sponsor: 
Alfredo Urdaneta, MD 
Sponsor-Investigator: 
Alfredo Urdaneta, MD 
Study Sites: 
 
Clinical Trial Phase: 
Phase 3 
Study Disease: 
Breast cancer 
Main Eligibility 
Criteria: 
Ambulatory outpatients with breast cancer to be treated with 
radiation therapy for curative intent; women ≥18 years of age; 
ECOG performance status <3. 
Primary Objectives: 
To determine whether the average increase in fatigue (as 
measured by the FACIT-Fatigue subscale) from baseline to 
completion of RT is different in those patients who received 
melatonin than in those who received placebo. 
Secondary Objectives: To determine whether the average increase in health-related 
quality of life (HRQOL) from baseline to completion of RT is greater 
in those patients who received melatonin than in those who 
received placebo. 
To determine whether the average increase in fatigue from 
baseline until (i) 2 weeks and (ii) 8 weeks after completion of RT is 
less in those patients who received melatonin than in those who 
received placebo. 
To determine whether the average increase in symptoms from 
baseline until completion of RT is less in those patients who 
received melatonin than in those who received placebo. 
To 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 
than in those who received placebo. 
To describe the level of agreement in reported fatigue scores when 
2 different survey instruments are used to measure fatigue. 
To determine whether patients receiving melatonin have fewer 
hospital admissions, emergency center visits, and medical days off 
work than patients receiving placebo. 


 
MCC Protocol #: MCC-12-08248 
3 
Version #:13 
 
 
Version Date: 12/10/2021 
 
Endpoints: 
The primary endpoint will use a comparison of FACIT-Fatigue 
subscale scores obtained at baseline and at the completion of RT. 
The secondary endpoints will use a comparison of FACIT-F scores 
obtained at baseline until (i) 2 weeks and (ii) 8 weeks after 
completion of RT. 
ESAS scores will be compared at baseline and at the completion of 
RT. 
A comparison of the PROMIS Fatigue-Short Form 8a scores 
obtained at baseline and at the completion of RT. 
A comparison of the scores obtained with the FACIT-Fatigue 
subscale and the PROMIS Fatigue-Short Form 8a at baseline and 
at the completion of RT. 
A patient survey and chart review will be used to determine the 
number of hospital admissions, emergency center visits, and 
medical days off of work. 
Study Design: 
Double-blind, placebo-controlled trial with participants randomized 
to melatonin or placebo. 
Study Agent/
Intervention 
Description: 
Melatonin (20 mg/day) or placebo, given orally at night, starting on 
the night before the first day of RT and continuing until 2 weeks 
beyond the completion of RT. 
Number of Patients: 
142 
Patient Participation 
Duration: 
Approximately 9-16 weeks (1-8 weeks of RT followed by 8 weeks 
of follow-up) 
Estimated Time to 
Complete Enrollment: 
2 years 
Statistical 
Methodology: 
A two-sided ANOVA F-test at a 4.5% level of significance for the 
primary objective will be used if the interim analysis allows the 
study to continue. Secondary analysis of each of the subscales 
and ESAS scale will be reported using an F-test at a 5% level of 
significance after necessary transformation needed for normality of 
the scores. 


 
MCC Protocol #: MCC-12-08248 
4 
Version #:13 
 
 
Version Date: 12/10/2021 
SCHEMA 
 
Breast 
cancer 
Randomize to melatonin or placebo 
RT (as clinically indicated) + 
melatonin (20 mg/day, orally at night, 
starting on the night before the first 
day of RT and continuing until 2 
weeks beyond the completion of RT) 
RT (as clinically indicated) + placebo 
(orally at night, starting on the night 
before the first day of RT and 
continuing until 2 weeks beyond the 
completion of RT) 
Evaluation at baseline, every 2 weeks (± 4 days) during 
melatonin/placebo treatment (for RT durations ≥ 3 weeks), at the 
completion of RT (± 4 days), 2 weeks post-RT (± 4 days), and 8 weeks 
post-RT (± 4 days) 
Evaluations include: FACIT-F, FACIT-Fatigue, PROMIS Fatigue Short 
Form 8a, and ESAS scales; correlative sampling for biomarkers 


 
MCC Protocol #: MCC-12-08248 
5 
Version #:13 
 
 
Version Date: 12/10/2021 
 
 
 
 
 
 
 
 
 
 
                                                            
 
 
 
 
 
 
 
 
 
 
 
 
 


 
MCC Protocol #: MCC-12-08248 
6 
Version #:13 
 
 
Version Date: 12/10/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
MCC Protocol #: MCC-12-08248 
7 
Version #:13 
 
 
Version Date: 12/10/2021 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
MCC Protocol #: MCC-12-08248 
8 
Version #:13 
 
 
Version Date: 12/10/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
MCC Protocol #: MCC-12-08248 
9 
Version #:13 
 
 
Version Date: 12/10/2021 
TABLE OF CONTENTS 
PROTOCOL SUMMARY ........................................................................................................... 2 
SCHEMA ................................................................................................................................... 4 
 
TABLE OF CONTENTS ............................................................................................................ 9 
LIST OF ABBREVIATIONS ......................................................................................................12 
1 
BACKGROUND .........................................................................................................13 
1.1 
CANCER AND FATIGUE ..................................................................................................13 
1.2 
MELATONIN ..................................................................................................................14 
1.3 
PROJECT SIGNIFICANCE ................................................................................................16 
2 
OBJECTIVES .............................................................................................................16 
2.1 
PRIMARY OBJECTIVE ....................................................................................................16 
2.2 
SECONDARY OBJECTIVES .............................................................................................16 
2.3 
EXPLORATORY OBJECTIVES ..........................................................................................17 
3 
STUDY DESIGN .........................................................................................................17 
3.1 
GENERAL DESCRIPTION ................................................................................................17 
3.2 
PRIMARY ENDPOINT ......................................................................................................17 
3.3 
SECONDARY ENDPOINTS ...............................................................................................18 
3.4 
EXPLORATORY ENDPOINTS ...........................................................................................18 
4 
PATIENT SELECTION ...............................................................................................18 
4.1 
INCLUSION CRITERIA .....................................................................................................18 
4.2 
EXCLUSION CRITERIA ...................................................................................................19 
5 
STUDY ENTRY AND WITHDRAWAL PROCEDURES ..............................................20 
5.1 
STUDY ENTRY PROCEDURES.........................................................................................20 
5.2 
STUDY WITHDRAWAL PROCEDURES ..............................................................................20 
6 
TREATMENT PLAN ...................................................................................................20 
6.1 
BASELINE TESTS AND PROCEDURES ..............................................................................20 
6.2 
INVESTIGATIONAL AGENT ADMINISTRATION ....................................................................21 
6.3 
ADDITIONAL TREATMENT MODALITIES ............................................................................21 
6.4 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ....................21 
6.5 
DURATION OF THERAPY ................................................................................................21 
6.6 
MONITORING PATIENT COMPLIANCE ..............................................................................21 
6.7 
FOLLOW-UP PERIOD .....................................................................................................21 
7 
DOSING DELAYS/DOSE MODIFICATIONS ..............................................................21 
7.1 
MELATONIN/PLACEBO TREATMENT ................................................................................21 
7.2 
RADIATION THERAPY ....................................................................................................22 
8 
ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS ..............22 
8.1 
DEFINITIONS .................................................................................................................22 
8.2 
KNOWN AES LIST .........................................................................................................24 
8.3 
TIME PERIOD AND GRADE OF AE CAPTURE ....................................................................25 


 
MCC Protocol #: MCC-12-08248 
10 
Version #:13 
 
 
Version Date: 12/10/2021 
8.4 
PROCEDURES FOR RECORDING AES, SAES, AND UPS ...................................................25 
8.5 
ROUTINE REPORTING PROCEDURES FOR AES ................................................................25 
8.6 
EXPEDITED REPORTING PROCEDURES FOR SAES AND UPS ...........................................26 
9 
PHARMACEUTICAL INFORMATION ........................................................................27 
9.1 
MELATONIN ..................................................................................................................27 
9.2 
PLACEBO .....................................................................................................................28 
10 
MEASUREMENT OF EFFECT ...................................................................................29 
10.1 
FATIGUE ASSESSMENT .................................................................................................29 
10.2 
SYMPTOM ASSESSMENT ...............................................................................................30 
10.3 
MISCELLANEOUS ASSESSMENTS ...................................................................................30 
11 
CORRELATIVE STUDIES .........................................................................................30 
11.1 
BACKGROUND ..............................................................................................................30 
11.2 
PARTICIPATION IN CORRELATIVE STUDIES ......................................................................31 
11.3 
TIME POINTS ................................................................................................................31 
11.4 
SAMPLE LABELING ........................................................................................................31 
11.5 
PROCEDURES, PROCESSING, AND STORAGE ..................................................................31 
11.6 
CLINICAL AND TRANSLATIONAL RESEARCH LABORATORY (CTRL)....................................32 
11.7 
SAMPLE ANALYSIS ........................................................................................................33 
12 
STUDY CALENDAR ..................................................................................................34 
13 
STATISTICAL CONSIDERATIONS ...........................................................................35 
13.1 
STUDY DESIGN AND ANALYSIS .......................................................................................35 
13.2 
PATIENT REPLACEMENT ................................................................................................35 
13.3 
SAMPLE SIZE/ACCRUAL RATES .....................................................................................35 
13.4 
STRATIFICATION FACTORS ............................................................................................36 
13.5 
ANALYSIS OF SECONDARY ENDPOINTS ..........................................................................36 
13.6 
INTERIM ANALYSIS ........................................................................................................36 
14 
DATA AND SAFETY MONITORING PLAN (DSMP) ..................................................36 
14.1 
STUDY TEAM ................................................................................................................36 
14.2 
MONITORING AND AUDITING ..........................................................................................37 
15 
REGULATORY COMPLIANCE AND ETHICS ...........................................................37 
15.1 
ETHICAL STANDARD ......................................................................................................37 
15.2 
REGULATORY COMPLIANCE ...........................................................................................37 
15.3 
INSTITUTIONAL REVIEW BOARD .....................................................................................37 
15.4 
INFORMED CONSENT PROCESS .....................................................................................38 
15.5 
PATIENT CONFIDENTIALITY AND ACCESS TO SOURCE DOCUMENTS/DATA ........................38 
16 
DATA HANDLING AND RECORD KEEPING ............................................................38 
16.1 
DATA MANAGEMENT RESPONSIBILITIES .........................................................................38 
16.2 
SOURCE DOCUMENTS ...................................................................................................39 
16.3 
CASE REPORT FORMS ..................................................................................................39 
16.4 
STUDY RECORD RETENTION .........................................................................................39 
17 
REFERENCES ...........................................................................................................40 
18 
APPENDIX 1. FACIT-F SCALE .................................................................................44 


 
MCC Protocol #: MCC-12-08248 
11 
Version #:13 
 
 
Version Date: 12/10/2021 
19 
APPENDIX 2. ESAS SCALE ......................................................................................43 
20 
APPENDIX 3. PROMIS FATIGUE-SHORT FORM 8A ...............................................45 
21 
APPENDIX 4. ECOG SCALE .....................................................................................47 
22 
APPENDIX 5. FOLLOW-UP QUESTIONNAIRE ........................................................48 
23 
APPENDIX 6. BLOODWORK FORM .........................................................................51 
24 
APPENDIX 7. DEMOGRAPHIC FORM ......................................................................53 
25 
APPENDIX 8. STUDY DIARY ....................................................................................56 
26 
APPENDIX 9. CONTRACEPTIVE USE AGREEMENT ..............................................58 
27 
APPENDIX 10. GENERAL INFORMATION ABOUT MELATONIN ............................60 
28 
APPENDIX 11. PATIENT RECRUITMENT FLYER ....................................................62 
 


 
MCC Protocol #: MCC-12-08248 
12 
Version #:13 
 
 
Version Date: 12/10/2021 
List of Abbreviations 
AE 
 
Adverse event 
ALT 
 
Alanine aminotransferase 
APBI  
Accelerated 
AST 
 
Aspartate aminotransferase 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTRL  
Clinical and Translational Research Laboratory 
DSMC  
Data and Safety Monitoring Committee 
DSMP  
Data and Safety Monitoring Plan 
ECOG  
Eastern Cooperative Oncology Group 
eCRF  
Electronic case report form 
ESAS  
Edmonton Symptom Assessment System 
FACIT  
Functional Assessment of Chronic Illness Therapy 
FDA 
 
Food and Drug Administration 
HPA 
 
Hypothalamic-pituitary-adrenal 
HRQOL 
Health-related quality of life 
LSM 
 
Lymphocyte Separation Medium 
OHRP  
Office for Human Research Protections 
PBMC  
Peripheral blood mononuclear cells 
QOL 
 
Quality of life 
RCT 
 
Randomized clinical trials 
RT 
 
Radiotherapy 
SAE 
 
Serious adverse event 
ULN 
 
Upper limit of normal 
UP 
 
Unanticipated problem 
 


 
MCC Protocol #: MCC-12-08248 
13 
Version #:13 
 
 
Version Date: 12/10/2021 
1 BACKGROUND 
1.1 Cancer and Fatigue 
Fatigue is the most common symptom in patients with cancer and has a multidimensional 
construct that includes physical, functional, psychological, and social elements. There are 
multiple contributing factors to fatigue including pro-inflammatory cytokines, hypothalamic-
pituitary-adrenal (HPA) dysfunction, cachexia, and psychosocial factors such as chronic 
stress and depression. Although supervised exercise improves fatigue in breast cancer 
patients, home-based interventions did not show the same benefit (1). Currently, there is 
no effective pharmacological therapy for cancer-related fatigue. Psychoeducational 
interventions to reduce fatigue during cancer therapy have also not been consistently 
effective (2). 
Fatigue is associated with radiotherapy (RT) for a number of different tumor types (3) and 
is reported to be present in almost 90% of patients. Patients with early-stage breast cancer 
receiving RT experience increased fatigue during treatment (4). Radiation-induced fatigue 
has also been studied in early-stage breast cancer patients receiving one of 3 different 
radiotherapies (standard whole breast RT [mean of 43 days on treatment]; accelerated 
partial breast irradiation [APBI; mean of 20.6 days on treatment]; or accelerated 
hypofractionated RT [mean of 20.8 days on treatment]) (5). In comparison to the fatigue 
scores obtained at the first treatment visit, fatigue scores for all 3 treatments were only 
slightly elevated at the midpoint of study treatment visit, were maximally elevated at the 
last study treatment visit, and were declining but still elevated relative to the midpoint 
scores. Although fatigue increased for patients on all 3 RT protocols, increased fatigue was 
more pronounced for the patients undergoing either standard whole breast RT or 
accelerated hypofractionated RT than it was for patients undergoing APBI. Heightened 
fatigue prior to treatment and an elevated level of IL-6 soluble receptor during therapy were 
found to be risk factors for increased fatigue during active radiation therapy (6). An 
increased pretreatment fatigue level has also been found to be a risk factor for persistent 
long-term fatigue following treatment completion (7). 
A multicenter study has used the Functional Assessment of Chronic Illness Therapy 
(FACIT) fatigue scales in patients receiving radiotherapy for head and neck cancer (8). The 
detrimental effects on quality of life (QOL) and functional status were significant, and opioid 
analgesia provided inadequate relief. This study and other reviews (9) suggested 
preventive rather than symptom palliation measures are needed to improve the QOL in 
patients receiving radiotherapy. The economic impact could be significant and is a 
suggested future research goal (10). 
RT has been identified as a cause of fatigue in patients with advanced cancer and also in 
those with localized disease being treated with curative intent. Attenuating the side effects 
of radiation with concurrent melatonin therapy at the start of RT may prevent exacerbation 
of fatigue and improve the QOL of cancer patients. Melatonin is an inexpensive, readily 
available, natural supplement that has been shown to be radioprotective in animal models 
and safe in humans. 


 
MCC Protocol #: MCC-12-08248 
14 
Version #:13 
 
 
Version Date: 12/10/2021 
1.2 Melatonin 
1.2.1 Preclinical Data 
Melatonin given to rats protects against irradiation induced oxidative (11) and 
chromosomal damage (12), and attenuates acute radiation enteritis (13). 
1.2.2 Clinical Data 
In humans, multiple studies have shown that melatonin supplementation in patients 
with cancer has clinical benefits such as decreasing the side effects of radiation and 
chemotherapy, improving symptoms, and prolonging survival (14). Systematic 
reviews and meta-analyses of melatonin therapy reported improvement in tumor 
remission, 1-year survival, and fewer radio- and chemotherapy-related side effects 
(15-17). Unfortunately, more recent independent randomized controlled trials have 
not been able to show that melatonin improves survival in patients with brain 
metastases receiving radiation (18) or improves appetite in patients with advanced 
GI or lung cancers (19).These recent randomized clinical trials (RCTs) may have 
failed to show benefit because patients with advanced cancer may be refractory to 
intervention with melatonin. A strategy of earlier intervention for the prevention of 
radiation-induced side effects would be more effective at reducing symptom burden 
and improving the QOL. 
1.2.3 Known and Potential Risks and Benefits 
Three systematic reviews have examined the benefits and side effects of melatonin 
as adjuvant therapy for patients with cancer (15-17). Pooled analysis showed 
benefit on survival (17), with numbers needed to treat ranging between 3 and 5. A 
subsequent systematic review of 10 randomized controlled trials and meta-analysis 
also found that melatonin consistently reduced the risk of death at 1 year across all 
doses and types of solid tumors (15). The meta-analysis concluded that melatonin 
had few side effects, was innocuous even at high doses, and appeared to have a 
high safety profile. Although the doses used in the studies were significantly higher 
(10-50 mg/d) than those used for other indications (0.5-5.0 mg/d), none of the 
studies found any serious side effects related to melatonin; on the contrary, 
“melatonin decreased some of the side effects resulting from chemotherapy and 
radiation therapy.” A meta-analysis (16) of randomized controlled trials (n=761) in 
patients with solid tumors found no severe adverse events (AEs) and “dramatically 
decreased radio-chemotherapy related side effects” including neurotoxicity and 
fatigue. 
We conducted a placebo-controlled trial of melatonin in patients with advanced 
cancer and found that the side effects seen with patients taking 20 mg melatonin 
were comparable to placebo (no statistically significant difference between the 
groups) (19). The toxicity of 10 mg of melatonin daily has been evaluated in a 
randomized double-blind placebo-controlled trial (20). The evaluations included 
polysomnography and a variety of laboratory tests (eg, complete blood count, 
urinalysis, sodium, potassium, calcium, total protein, albumin, glucose, lipid profile, 
blood urea nitrogen, creatinine, liver function tests, thyroid function tests, LH/FSH, 
and cortisol). In addition, volunteers were asked about possible side effects during 
the 28-day treatment period. Melatonin did not produce any toxicological alterations, 


 
MCC Protocol #: MCC-12-08248 
15 
Version #:13 
 
 
Version Date: 12/10/2021 
and the most frequent side effects were headache and somnolence. The placebo 
group reported a similar frequency of these side effects.  
Systematic reviews of melatonin for insomnia (21) or jet-lag lend further support for 
melatonin’s safety, although doses were lower than those used for adjuvant cancer 
therapy. The systematic review of melatonin for insomnia found no adverse effects, 
and the review concluded that melatonin was safe for short-term use (< 3 months). 
The Cochrane database analyzed trials of melatonin (22) for the treatment of jet-lag 
and concluded that the risks of side effects were low. Somnolence was avoided if 
melatonin was taken at the correct time before bed. 
Review of the Natural Standard's professional monograph of melatonin (23) shows 
fatigue at doses higher than 50 mg and suggests that caution should be exercised 
by those operating or driving heavy machinery. Excessive dosages may cause 
morning sedation or drowsiness. Less severe side effects reported by individuals 
taking melatonin include: abdominal cramps, confusion, depression, dizziness, 
anxiety, fatigue, headache, irritability, low blood pressure, nausea, and vomiting. 
Aspirin, beta blockers, and other NSAIDS may lead to decreased melatonin levels, 
and the bioavailability of oral melatonin is increased by the co-administration of 
fluvoxamine (due to the inhibition of the elimination of melatonin). Melatonin and 
progestin combinations can be additive in inhibiting ovarian function in women, and 
using melatonin with benzodiazepines, sedating antihistamines, sedating anti-
depressants and other sedating drugs may cause additive sedation and increase 
the incidence of adverse effects. Use of melatonin with corticosteroids may interfere 
with the efficacy of the corticosteroids and melatonin may decrease prothrombin 
time (PT). Use of melatonin with alcohol may lead to additive sedation. There are no 
known interactions with melatonin and food. Use of melatonin with valerian, 5-
hydroxytryptophan, or kava may lead to additive sedation. No apparent serious 
consequences have been reported in those taking up to 24 grams daily of melatonin 
for one month (23). 
Concerns regarding the safety of melatonin or the prospect of diminished efficacy of 
anti-tumor therapy are not supported by the literature. Our study (19) and others 
(14) have shown that 20-mg melatonin at night is safe, and further research is 
justified because “the preponderance of evidence supports a provisional conclusion 
that dietary antioxidants do not conflict with the use of radiotherapy in the treatment 
of a wide variety of cancers and may significantly mitigate the adverse effects of that 
treatment” (24). In addition, there are multiple experimental studies with cancer lines 
(25) and animal models suggesting that melatonin has an anti-tumor effect (26). 
Melatonin may also play a role in decreasing incidental cancer since night-shift work 
has been associated with an increased risk of breast (27) and endometrial cancer 
(28), possibly as a result of disruption of the circadian rhythm and diminished 
melatonin production from the pineal gland. 
1.2.4 Rationale for Using Melatonin for Fatigue 
The mechanisms of fatigue due to RT are multifactorial (29) and include 
inflammatory processes, a disruption of circadian rhythm, and mitochondrial 
dysfunction (30). Inflammatory biomarkers such as C-reactive protein are 
associated with increased fatigue during RT for localized breast and prostate cancer 


 
MCC Protocol #: MCC-12-08248 
16 
Version #:13 
 
 
Version Date: 12/10/2021 
(31). RT is also associated with decreased muscle endurance which could 
contribute to an increase in cancer-related fatigue. 
There is evidence that melatonin can modulate the mechanisms of RT-induced 
fatigue. Melatonin decreases the pro-inflammatory immune response, maintains 
circadian rhythm and sleep quality, and also prevents oxidative damage to 
mitochondria (32, 33). A meta-analysis of pooled data from 5 trials of patients 
receiving melatonin during concurrent chemoradiation, found a significantly 
decreased prevalence of fatigue compared to the control group. Although these 
trials were randomized, none were placebo-controlled and all were unblinded. 
Because of these methodological limitations, the efficacy of melatonin needs to be 
confirmed in a double-blind RCT. 
1.3 Project Significance 
This would be the first clinical trial using melatonin for prevention of fatigue and other 
symptoms associated with RT. This inter-programmatic project applies the expertise of 
Massey Cancer Center collaborators from the areas of Cancer Prevention and Control, 
Developmental Therapeutics, and Radiation Biology & Oncology. 
Recently, a National Cancer Institute Clinical Trials Planning Meeting made 
recommendations on how to implement high-priority research and clinical trials in cancer-
related fatigue, in order to advance the science and reduce symptom burden in this 
population. Because of the strong likelihood of a placebo effect in cancer-related fatigue, 
placebo-controlled trials were recommended in order to demonstrate efficacy (34). 
Because of the multidimensional construct of cancer-related fatigue, a future intervention 
trial may need to be combined with other supportive and behavioral components to 
produce an optimal result (35), eg, counseling improves the QOL and symptoms in head 
and neck patients undergoing radiotherapy (36). If our study shows melatonin is effective, 
future research should consider combination interventions (eg, physical activity, behavioral 
intervention) for additive or synergistic benefits. 
2 OBJECTIVES 
2.1 Primary Objective 
2.1.1 To determine whether the average increase in fatigue (as measured by the FACIT-
Fatigue subscale) from baseline to completion of RT is different in those patients 
who received melatonin than in those who received placebo. 
2.2 Secondary Objectives 
2.2.1 To determine whether the average increase in health-related quality of life (HRQOL) 
from baseline to completion of RT is greater in those patients who received 
melatonin than in those who received placebo. 
2.2.2 To 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. 


 
MCC Protocol #: MCC-12-08248 
17 
Version #:13 
 
 
Version Date: 12/10/2021 
2.2.3 To 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. 
2.2.4 To determine whether the average increase in symptoms from baseline until 
completion of RT is less in those patients who received melatonin than in those who 
received placebo. 
2.2.5 To 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 than in those who received placebo. 
2.2.6 To describe the level of agreement in reported fatigue scores when 2 different 
survey instruments are used to measure fatigue. 
2.2.7 To determine whether patients receiving melatonin have fewer hospital admissions, 
emergency center visits, and medical days off work than patients receiving placebo. 
 
 
 
 
 
 
3 STUDY DESIGN 
3.1 General Description 
This is a double-blind, placebo-controlled trial wherein patients with breast cancer will be 
randomized to receive either 20 mg oral melatonin or placebo the night before their first 
RT, nightly throughout their RT, and for an additional 2 weeks following the completion of 
their RT. After informed consent is obtained from eligible patients, they will then be 
electronically randomized on a 1:1 ratio to melatonin treatment or placebo. The patients 
will be stratified according to treatment duration (less than 3 weeks; equal to or greater 
than 3 weeks) and prior chemotherapy (yes/no). 
3.2 Primary Endpoint 
3.2.1 A comparison of FACIT-Fatigue subscale (corresponds to the “Additional Concerns” 
table of the FACIT-F scale; see Appendix 1) scores obtained at baseline and at the 
completion of RT.  


 
MCC Protocol #: MCC-12-08248 
18 
Version #:13 
 
 
Version Date: 12/10/2021 
3.3 Secondary Endpoints 
3.3.1 A comparison of FACIT-F (Appendix 1) scores obtained at baseline and at the 
completion of RT. 
3.3.2 A comparison of FACIT-F (Appendix 1) and FACIT-Fatigue subscale (corresponds 
to the “Additional Concerns” table of the FACIT-F scale; see Appendix 1) scores 
obtained at baseline until 2 weeks after completion of RT. 
3.3.3 A comparison of FACIT-F (Appendix 1) and FACIT-Fatigue subscale (corresponds 
to the “Additional Concerns” table of the FACIT-F scale; see Appendix 1) scores 
obtained at baseline until 8 weeks after completion of RT. 
3.3.4 A comparison of Edmonton Symptom Assessment System (ESAS) (Appendix 2) 
scores obtained at baseline until completion of RT. 
3.3.5 A comparison of the PROMIS Fatigue-Short Form 8a (Appendix 3) scores obtained 
at baseline and at the completion of RT. 
3.3.6 A comparison of the scores obtained with the FACIT-Fatigue subscale and the 
PROMIS Fatigue-Short Form 8a at baseline and at the completion of RT. 
3.3.7 A patient survey and chart review will be conducted to determine the number of 
hospital admissions, emergency center visits, and medical days off of work. 
 
 
 
 
 
 
 
 
4 PATIENT SELECTION 
4.1 Inclusion Criteria 
A patient must meet all of the following inclusion criteria to be eligible to participate in the 
study. 
4.1.1 Ambulatory outpatients with breast (including ductal carcinoma in situ [DCIS]) 
cancer 


 
MCC Protocol #: MCC-12-08248 
19 
Version #:13 
 
 
Version Date: 12/10/2021 
4.1.2 Patients to be treated with RT for curative intent 
4.1.3 Women ≥ 18 years of age 
4.1.4 ECOG performance status <3 (Appendix 4) 
4.1.5 Hemoglobin ≥ 9 g/dL 
4.1.6 Either post-menopausal, surgically sterilized, or willing to use an acceptable method 
of birth control during study treatment and for 3 months afterwards 
4.1.7 Patients who are currently taking melatonin must discontinue melatonin for 5 days 
before enrolling in the study 
4.1.8 Ability to understand and the willingness to sign a written informed consent 
document 
4.2 Exclusion Criteria 
A patient who meets any of the following exclusion criteria is ineligible to participate in the 
study. 
4.2.1 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) 
Ca = SerumCa + 0.8 * (NormalAlbumin – PatientAlbumin) 
• 
decompensated congestive heart failure 
• 
chronic obstructive pulmonary disease requiring oxygen replacement 
4.2.2 Patients with a creatinine clearance <30 mL/min 
4.2.3 Aspartate aminotransferase (AST) > 3 X upper limit of normal (ULN) for the 
laboratory 
4.2.4 Alanine aminotransferase (ALT) > 3 X ULN for the laboratory 
4.2.5 Bilirubin > 1 X ULN for the laboratory 
4.2.6 Use of systemic steroids, or other pharmacological agents such as methylphenidate 
for cancer-related fatigue 
4.2.7 Current use of American ginseng, remelteon, or warfarin. 
4.2.8 Depression ≥ grade 2 (CTCAE v4.0) 


 
MCC Protocol #: MCC-12-08248 
20 
Version #:13 
 
 
Version Date: 12/10/2021 
5 STUDY ENTRY AND WITHDRAWAL PROCEDURES 
5.1 Study Entry Procedures 
5.1.1 Competition with Treatment Trials 
Priority will be given to treatment trials. A patient will not be approached for 
participation in this trial until it is determined that either co-enrollment is allowed or 
that the patient does not want to participate on a treatment trial. 
5.1.2 Required Pre-Registration Screening Tests and Procedures 
Refer to Section 12, STUDY CALENDAR, for the screening tests and procedures 
that are required prior to registration, and for the timing of these events relative to 
the start of treatment. 
5.1.3 Registration Process 
Patients who meet the eligibility requirements and sign the informed consent form 
will be registered on the study. Contact the study research nurse, 
 
 for registration: 
 
 
 
5.2 Study Withdrawal Procedures 
5.2.1 A patient may decide to withdraw from the study at any time. 
5.2.2 A patient may be removed from treatment for one of the following criteria: 
5.2.2.1 If in the opinion of the treating physician, it is in the best interest of the 
patient to do so. 
5.2.2.2 Sponsor-investigator’s decision to discontinue the study. 
5.2.3 The reason for withdrawal from the study and the date the patient was removed 
from the study must be documented in the case report form. 
6 TREATMENT PLAN 
6.1 Baseline Tests and Procedures 
After determination of eligibility, patients will complete a baseline assessment before 
treatment. Baseline tests are required as indicated in Section 12 (STUDY CALENDAR). 


 
MCC Protocol #: MCC-12-08248 
21 
Version #:13 
 
 
Version Date: 12/10/2021 
 
 
 
6.3 Additional Treatment Modalities 
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 APBI; (2) 3-4 weeks of an 
accelerated hypofractionation RT schedule; and (3) 6-8 weeks of a standard RT schedule.  
6.4 General Concomitant Medication and Supportive Care Guidelines 
No additional concomitant medication or supportive care guidelines are required for this 
study.  
6.5 Duration of Therapy 
Patients 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. 
6.6 Monitoring Patient Compliance 
Patients will be given a Study Diary (Appendix 8) to record their use of study medication. 
The research nurse reviews the diary with the participant and provides assistance with 
completing the diary if needed. 
6.7 Follow-Up Period 
Patients will be followed for 8 weeks (± 4 days) after completion of RT or until death, 
whichever occurs first. Patients removed from the study treatment for unacceptable AEs 
will be followed until resolution or stabilization of the AE. 
7 DOSING DELAYS/DOSE MODIFICATIONS 
7.1 Melatonin/Placebo Treatment 
7.1.1 A patient with a ≥ grade 3 AE that is possibly, probably, or definitely related to study 
drug will discontinue treatment with melatonin/placebo. 
7.1.2 A patient with a persistent (present over 2 consecutive follow-up intervals) grade 2 
AE that is possibly, probably, or definitely related to study drug will discontinue 
treatment with melatonin/placebo.  


 
MCC Protocol #: MCC-12-08248 
22 
Version #:13 
 
 
Version Date: 12/10/2021 
7.2 Radiation Therapy 
7.2.1 Dosing delays or dose modifications for RT are at the discretion of the treating 
physician. 
8 ADVERSE EVENTS: DEFINITIONS AND REPORTING 
REQUIREMENTS 
8.1 Definitions 
8.1.1 Adverse Event (AE) 
AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
8.1.2 Suspected Adverse Reaction (SAR) 
Any AE for which there is a reasonable possibility that the drug caused the AE. 
“Reasonable possibility” means that there is evidence to suggest a causal 
relationship between the drug and the AE. 
An AE with an attribution of possible, probable, or definite (see Section 8.1.8 below) 
is a SAR. 
8.1.3 Serious AE (SAE) or Serious SAR (SSAR) 
An AE or SAR is considered “serious” if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
• 
death, 
• 
a life-threatening AE (An AE or SAR is consider “life-threatening” if, in the view 
of either the investigator or sponsor, its occurrence places the patient or subject 
at immediate risk of death. It does not include an AE or SAR that, had it 
occurred in a more severe form, might have caused death.), 
• 
inpatient hospitalization or prolongation of existing hospitalization, 
• 
a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or 
• 
a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 


 
MCC Protocol #: MCC-12-08248 
23 
Version #:13 
 
 
Version Date: 12/10/2021 
8.1.4 Unexpected SAR 
A SAR is considered “unexpected” if 
• 
it is not listed in the investigator brochure or is not listed at the specificity or 
severity that has been observed; 
• 
or, if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan or elsewhere in 
the current application, as amended. 
• 
“Unexpected” as used in this definition, also refers to SARs that are mentioned 
in the investigator brochure as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
8.1.5 Unanticipated Problem (UP) 
Unanticipated problems include any incident, experience, or outcome that meets all 
of the following criteria: 
• 
unexpected (in terms of nature, severity, frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• 
related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
• 
suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
8.1.6 AE Description and Grade 
The descriptions and grading scales found in the revised Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. 
8.1.7 AE Expectedness 
AEs can be ‘Unexpected’ or ‘Expected’. 
Expected AEs are listed in Section 8.2 below. 
Unexpected AEs are those AEs occurring in one or more subjects participating in 
the research protocol, the nature, severity, or frequency of which is not consistent 
with either: 
• 
The known or foreseeable risk of AEs associated with the procedures involved 
in the research that are described in (a) the protocol-related document, such as 


 
MCC Protocol #: MCC-12-08248 
24 
Version #:13 
 
 
Version Date: 12/10/2021 
the IRB-approved research protocol, any applicable investigator brochure, and 
the current IRB-approved informed consent document, and other relevant 
sources of information, such as product labeling and package inserts; or 
• 
The expected natural progression of any underlying disease, disorder, or 
condition of the subject(s) experiencing the AE and the subject’s predisposing 
risk factor profile for the AE. 
8.1.8 AE Attribution 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unlikely – The AE is doubtfully related to the study treatment. 
• 
Unrelated – The AE is clearly NOT related to the study treatment. 
8.2 Known AEs List 
8.2.1 Melatonin 
Likely (10% or more of patients) 
• 
Sleepiness during the daytime 
• 
Headaches 
Less Likely (1-9% of patients) 
• 
Abdominal discomfort  
• 
Mild anxiety 
• 
Irritability 
• 
Confusion 
• 
Short-lasting depression 
• 
Dizziness 
8.2.2 Breast RT 
Likely (10% or more of patients) 
• 
Reddening of the skin during treatment and for several weeks following 
treatment 
• 
Tanning of the skin lasting months and may be permanent 
• 
Slightly smaller breast size or change in the way the breast looks 
• 
Tiredness and weakness during treatment and for several weeks following 
treatment 
• 
Swelling of breast 
• 
Peeling of the skin in the area treated with radiation 


 
MCC Protocol #: MCC-12-08248 
25 
Version #:13 
 
 
Version Date: 12/10/2021 
• 
Mild pain at the site of radiation treatment requiring over-the-counter pain 
relievers 
Less Likely (3-9% of patients) 
• 
Soreness or tightness in muscles of the chest wall under the treated breast 
• 
Severe pain at the site of radiation requiring prescription pain relievers 
Rare But Serious (less than 3% of patients) 
• 
Cough 
• 
Difficulty breathing 
• 
Inflammation of the heart muscle 
• 
Rib fracture 
• 
Slight increase in risk for heart disease for patients with cancer in the left breast 
• 
Risk of developing another cancer 
8.3 Time Period and Grade of AE Capture 
AEs will be followed from the beginning of study treatment through 30 days following the 
end of treatment. All AEs, regardless of attribution to study drug, will be captured. 
8.4 Procedures for Recording AEs, SAEs, and UPs 
Events will be recorded in OnCore. 
8.5 Routine Reporting Procedures for AEs 
Events will be recorded in OnCore within 30 days of occurrence for those events not 
requiring expedited reporting. 


 
MCC Protocol #: MCC-12-08248 
26 
Version #:13 
 
 
Version Date: 12/10/2021 
8.6 Expedited Reporting Procedures for SAEs and UPs 
Expedited Reporting Requirements (Events, Report Recipients, and Time Frames) 
SAEs 
UPs  
SARs 
Sponsor-Investigator1 
Alfredo Urdaneta, MD 
 
Sponsor-Investigator1 
Alfredo Urdaneta, MD 
.org 
FDA3 
 
DSMC1 
 
 
 
IRB2 
 
1 Report event within 2 business days of becoming aware of the occurrence. 
2 Each UP must be reported to the VCU IRB within 5 business days of becoming aware of 
the occurrence.  
3 The sponsor-investigator will report to the FDA any: 
• 
SARs that are both serious and unexpected within 15 days of determining that the 
information is reportable. 
• 
clinically important increase in the rate of SSARs within 15 days of determining that 
the information is reportable. 
• 
unexpected fatal or life-threatening SARs within 7 days of receipt of the information. 


 
MCC Protocol #: MCC-12-08248 
27 
Version #:13 
 
 
Version Date: 12/10/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
MCC Protocol #: MCC-12-08248 
28 
Version #:13 
 
 
Version Date: 12/10/2021 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
MCC Protocol #: MCC-12-08248 
29 
Version #:13 
 
 
Version Date: 12/10/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 MEASUREMENT OF EFFECT 
10.1 Fatigue Assessment 
Fatigue will be measured using the FACIT-F (Appendix 1) and the FACIT-Fatigue subscale  
(corresponds to the “Additional Concerns” table of the FACIT-F scale; see Appendix 1) 
QOL questionnaire (24). 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 


 
MCC Protocol #: MCC-12-08248 
30 
Version #:13 
 
 
Version Date: 12/10/2021 
less fatigue. According to the scoring manual, the negatively worded items on the FACIT-F 
are reverse-scored so that the higher scores indicate more positive health states (38). 
Fatigue will also be measured using the PROMIS Fatigue-Short Form 8a scale (Appendix 
3) (34, 39). 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. 
Refer to the study calendar (Section 12) for the fatigue assessment schedule.  
10.2 Symptom Assessment 
Symptoms will be assessed using the ESAS (Appendix 2) (40). 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 (41). The severity of each symptom is rated on a numerical scale of 
0–10 (0 = no symptom, 10 = worst possible severity). The ESAS is both valid and reliable 
in the assessment of the intensity of symptoms in cancer patients (42). 
Refer to the study calendar (Section 12) for the symptom assessment schedule.  
10.3 Miscellaneous Assessments 
10.3.1 ECOG Performance Status 
ECOG performance status (Appendix 4) is a simple rating of ability to function in 
usual activities. It has been widely used by clinicians to evaluate participants in drug 
clinical trials. It has been adapted (2) for patient self-report. 
Refer to the study calendar (Section 12) for the performance status assessment 
schedule.  
10.3.2 Medical History and Physical Exam 
Demographics including age, children at home, marital status, ethnicity, income, 
occupation. Tumor type, histology, and stage. Weight including weight loss within 
the previous 6 months (per history). Medications including opioids antiemetics, anti-
depressants, and anxiolytics. Hospital admissions, emergency center visits, and 
medical days off from work. 
Refer to the study calendar (Section 12) for the assessment schedule.  
11 CORRELATIVE STUDIES 
11.1 Background 
Biomarker Studies: Pro-inflammatory cytokines including IL-1 receptor antagonist (IL-
1RA) and IL-6 (31) will be measured to determine if their expression is correlated with 
fatigue.  


 
MCC Protocol #: MCC-12-08248 
31 
Version #:13 
 
 
Version Date: 12/10/2021 
Gene Polymorphism Studies: Other investigators have demonstrated that host factors 
such as cytokine gene polymorphisms may play an important role in the extent and 
duration of inflammatory processes in breast cancer patients (43) and the associated 
symptoms of fatigue. These included IL1B -511 C>T (rs16944), IL6 -174 G>C (rs1800795), 
and TNF -308 G>A (rs1800629) (37). Identifying patients with risk factors for fatigue and 
could facilitate earlier, more effective therapy. 
11.2 Participation in Correlative Studies 
Biomarker Studies: Participation in the biomarker studies is a study requirement. Any 
circumstance that prevents collection, submission or analysis of samples for correlative 
studies should be reviewed with the sponsor-investigator. 
Gene Polymorphism Studies: Participation in the gene polymorphism studies is 
optional. 
11.3 Time Points 
11.3.1 Biomarker Studies 
The biomarkers will be assessed at baseline, at 2-week (± 4 days) intervals during 
RT (for treatment durations equal to or greater than 3 weeks), at the completion of 
RT (± 4 days), at 2 weeks (± 4 days) after completion of RT, and at 8 weeks (± 4 
days) after completion of RT.  
11.3.2 Gene Polymorphism Studies 
Gene polymorphisms in IL1B, IL6, and TNF will be assessed in peripheral blood 
mononuclear cells (PBMCs) obtained at baseline.  
11.4 Sample Labeling 
Each sample should be labeled with the following information: 
• 
Study number 
• 
Patient identification number 
• 
“Plasma” (for plasma sample only) 
• 
Total cell number and “PBMC” (for PBMC sample only) 
• 
Date sample was drawn 
• 
Time point (eg, baseline, 2-week, 4-week) 
11.5 Procedures, Processing, and Storage 
11.5.1 Plasma Samples for Biomarker Studies 
Draw peripheral blood into one 6 mL EDTA or sodium heparin collection tube. 
Gently invert the collection tube 8 times immediately after collection. The sample 
must be processed within 30 hours of collection. Samples may be held at room 
temperature if they will be processed within 3 hours of collection; otherwise, the 
samples should be held in a refrigerator (~2°C to 8°C). If the sample cannot be 
centrifuged at the site where it is drawn, the sample should be transported to the 


 
MCC Protocol #: MCC-12-08248 
32 
Version #:13 
 
 
Version Date: 12/10/2021 
MCC Clinical and Translational Research Laboratory (CTRL; see Section 11.6) such 
that the samples can be processed within 30 hours of collection and such that the 
proscribed temperatures are maintained (transport on wet or “blue” ice should be 
used when refrigerated temperatures need to be maintained). 
To process, the sample should be centrifuged (1,300 x g, 10 min, 4°C). The plasma 
should then be separated from the cellular elements by transferring 0.5 mL aliquots 
of plasma (taking care not to disrupt the cell pellet) into 2 mL polypropylene 
cryogenic tubes (a sufficient number of tubes should be used to preserve the entire 
plasma sample). 
The plasma samples should be flash frozen in liquid nitrogen (if available) and 
stored at -20°C for short-term storage (≤ 1 week) and at -70°C to -90°C for long-
term storage. The cell pellets should be discarded. 
11.5.2 PBMC Samples for Gene Polymorphism Studies 
For patients who consent to the optional gene polymorphism studies, draw 
peripheral blood into one 10 mL EDTA or sodium heparin collection tube. Gently 
invert the collection tube 8 times immediately after collection. The sample must be 
processed within 30 hours of collection. Samples may be held at room temperature 
if they will be processed within 3 hours of collection; otherwise, the samples should 
be held in a refrigerator (~2°C to 8°C). If the sample cannot be centrifuged at the 
site where it is drawn, the sample should be transported to the CTRL (see Section 
11.6) such that the samples can be processed within 30 hours of collection and 
such that the proscribed temperatures are maintained (transport on wet or “blue” ice 
should be used when refrigerated temperatures need to be maintained). 
The sample should be processed to isolate PBMCs by using a density gradient 
separation media such as Ficoll-Hypaque or Lymphocyte Separation Medium 
(LSM). The processing should be performed by dedicated research personnel 
according to the manufacturer-specified protocol. The obtained PBMCs should be 
washed 3 times with phosphate buffered saline and the cell concentration 
determined. The cell suspension should be centrifuged (250 x g, 10 min at room 
temperature) in a 1.5 mL microfuge tube, after which the supernatant should be 
removed without disturbing the cell pellet. 
11.5.3 The cell pellet should then be flash frozen with liquid nitrogen and stored at -20°C 
for short-term storage (≤ 1 week) and at -70°C to -90°C for long-term storage. 
11.6 Clinical and Translational Research Laboratory (CTRL) 
All samples will be processed by the Massey Cancer Center CTRL, the CTRL should be 
notified at least 1 day in advance. 
CTRL Contact Information (For specimen collection, processing, storage, and 
transportation questions): 
 


 
MCC Protocol #: MCC-12-08248 
33 
Version #:13 
 
 
Version Date: 12/10/2021 
 
 
 
 
 
11.7 Sample Analysis 
Samples will be stored by the CTRL and evaluated for biomarkers such as C-reactive 
protein, pro-inflammatory cytokines including IL-1 receptor antagonist, IL-6 (31), plasma 
citrulline and gene polymorphisms. 


 
MCC Protocol #: MCC-12-08248 
34 
Version #:13 
 
 
Version Date: 12/10/2021 
12 STUDY CALENDAR 
Item 
Eligibility1 
Baseline 
(Prior to 
start of 
RT) 
Every 2 
weeks (± 4 
days) 
through RT 
(for RT 
durations ≥ 
3 weeks) 
and at the 
completion 
of RT(± 4 
days)2 
2 weeks (± 4 
days) post-
RT 
8 weeks (± 4 
days) post-
RT 
History & 
physical exam3 
x 
x 
x 
x 
x 
ESAS scale 
 
x 
x 
x 
x 
ECOG scale 
 
x 
x 
x 
x 
PROMIS scale 
 
x 
x 
x 
x 
Hemoglobin 
x 
 
 
 
 
Creatinine 
x 
 
 
 
 
TSH 
x4 
 
 
 
 
Ca 
x5 
 
 
 
 
CBC 
x 
 
 
 
 
Albumin 
x5 
 
 
 
 
Bilirubin, ALT, 
AST 
x 
 
 
 
 
AE assessment 
 
x 
x 
x 
x 
FACIT-F, 
FACIT-Fatigue 
 
x 
x 
x 
x 
Blood collection 
for biomarker 
studies 
(plasma) 
 
x6 
X6 
X6 
X6 
Optional blood 
collection for 
gene 
polymorphism 
studies 
(PBMCs) 
 
x7 
 
 
 
1Required within 28 days preceding the beginning of therapy. 
2Patients who have both a 2-week follow-up visit and an end-of-RT visit within a 5-day 
window will have an end-of-RT visit only. 
3May be performed by a mid-level provider. 
4Only required if hypothyroidism is suspected. 


 
MCC Protocol #: MCC-12-08248 
35 
Version #:13 
 
 
Version Date: 12/10/2021 
5Only required if hypercalcemia is suspected. 
6Draw peripheral blood into one EDTA or sodium heparin collection tube (1 x 6 mL). 
7For patients who consent to the optional gene polymorphism studies, draw peripheral blood 
into one EDTA or sodium heparin collection tube (1 x 10 mL). 
 
13 STATISTICAL CONSIDERATIONS 
13.1 Study Design and Analysis 
This is a double-blind, placebo-controlled trial randomizing participants to 20 mg oral 
melatonin at night throughout the course of their RT plus an additional 2 weeks. Eligible 
patients will be electronically randomized on a 1:1 ratio within each stratum to melatonin 
treatment or placebo. Investigational pharmacists will dispense either melatonin or placebo 
capsules according to a computer-generated random assignment list. The allocation 
scheme would keep the allocation ratio approximately equal across all of the strata. 
Stratification is done according to treatment duration (less than 3 weeks; equal to or 
greater than 3 weeks) and prior chemotherapy (yes/no).Treatment allocation will be 
concealed from patients, investigators, and study coordinators enrolling the participants. 
The statistical collaborator will be unblinded and provide the randomization list to the 
pharmacy. Interim results needed for Data and Safety Monitoring Committee (DSMC) 
review will be provided by the research nurse in a blinded manner; however, the 
statistician can unblind groups to the DSMC if there is a concern. The primary investigators 
and other collaborators would remain blinded. 
The primary hypothesis of no change in fatigue will be tested using the ANOVA F-test after 
adjusting for duration of RT (binary) and prior chemotherapy. Stratified randomization will 
be used to keep the groups balanced; however, statistical model will also be adjusting for 
them. The final hypothesis test level will be adjusted using O’Brien Fleming spending 
function for type I error. Details of interim analysis are provided in Section 13.6. 
13.2 Patient Replacement 
Patients (on either the melatonin treatment or placebo arm of the study) who are not 
evaluable for the primary endpoint because they drop out or are removed from the study 
prior to completing the FACIT-Fatigue subscale at the completion (± 4 days) of RT will be 
replaced. 
13.3 Sample Size/Accrual Rates 
The primary endpoint of the study is the change in FACIT-F score for patients receiving 
melatonin and the same for patients receiving placebo. In a prior study of a 
pharmacological intervention for cancer-related fatigue (44), the expected mean and SD of 
the overall change in FACIT-F score in the placebo group was 13 and SD was 14.78. We 
assume the same SD for the melatonin subgroup and a clinically meaningful difference is 
deemed to be a half SD difference which is approximately 7 units. Based on these findings 
and using a two-sided t-test at 5% level of significance, we would need 71 patients in each 
of the placebo and melatonin groups for 80% power. Our target cohort size is, therefore, 
142 patients. 


 
MCC Protocol #: MCC-12-08248 
36 
Version #:13 
 
 
Version Date: 12/10/2021 
Compliance is expected to be very high, and the drop-out rate is expected to be minimal. 
As a result, no adjustment of the sample size is done to accommodate drop outs or lack of 
compliance; however, the patients dropping out before the completion of the post 
treatment questionnaire will be replaced.  
13.4 Stratification Factors 
The patients will be stratified according to duration of radiation treatment (less than 3 
weeks; equal to or greater than 3 weeks) and prior chemotherapy (yes/no). Analysis of the 
primary hypothesis will be adjusted for the stratification factors. However, the sample size 
computation used only the data available from one strata as there is little knowledge about 
the effect size in each individual strata. Target power is kept at 80% to protect against 
possible lack of separation in some strata, keeping the target sample size in a feasible 
range.  
13.5 Analysis of Secondary Endpoints 
Secondary analysis of each of the subscales and ESAS scale for each strata will be 
reported using a 2 sample t-test with necessary adjustment needed for normality of the 
scores. Cohorts will be tested for homogeneity at baseline with respect to each of the 
scales. Other secondary outcomes will be summarized in the overall cohort, as well as in 
each subgroup of patients. Exploratory analysis will be done to identify the patient 
subgroup with relatively high effect and low effect. 
13.6 Interim Analysis 
 An interim analysis will be performed once one-half of the target patient sample size is 
accrued and evaluable. The unified family method with rho=0.3 (45) will be used as the 
spending function to determine the rejection boundary, which is a modified version of the 
O’Brien Fleming method. As computed by SAS proc Seqdesign, 36 evaluable patients in 
each arm will be needed to perform this analysis and a standardized absolute z value of 
2.49 will be needed to reject the null hypothesis at the interim stage. To maintain a 5% 
level of significance, the final analysis will be done at the 0.037 level, which is equivalent to 
using an absolute z score of 2.02 for rejecting the null hypothesis. The sponsor-
investigator will remain blinded to the interim analysis, although it will be made available to 
the DSMC. 
14 DATA AND SAFETY MONITORING PLAN (DSMP) 
The DSMP for this study will consist of the following 3 elements: 
14.1 Study Team 
The study team minimally consists of the sponsor-investigator, the research nurse, the 
clinical research associate, and the study biostatistician. While patients are on treatment, 
the sponsor-investigator, the research nurse, and the clinical research associate will meet 
at least monthly, and will meet at least quarterly with the study biostatistician, to review 
study status This review will include, but not be limited to, reportable AEs and UPs, and an 
update of the ongoing study summary that describes study progress in terms of the study 
schema. The appropriateness of further patient enrollment and the specific intervention for 


 
MCC Protocol #: MCC-12-08248 
37 
Version #:13 
 
 
Version Date: 12/10/2021 
a next patient enrollment are addressed. All meetings including attendance are 
documented.  
14.2 Monitoring and Auditing 
14.2.1 MCC Compliance Office 
Compliance specialists in the MCC Compliance Office will provide ongoing 
monitoring and auditing for this trial.  
14.2.2 Data and Safety Monitoring Committee 
The study will be reviewed by the MCC Data and Safety Monitoring Committee 
(DSMC) initially according to the risk level specified by the MCC Protocol Review 
and Monitoring Committee (PRMC) and then according to a schedule based on 
study status and quality indicators. The DSMC reviews reports of the sponsor-
investigator/study team and the MCC Compliance Office focusing on data integrity 
and patient safety. 
15 REGULATORY COMPLIANCE AND ETHICS 
15.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research (US National Commission for the Protection of Human Subjects of Biomedical 
and Behavioral Research, April 18, 1979). 
15.2 Regulatory Compliance 
This study will be conducted in compliance with: 
• 
The protocol 
• 
Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards); 21 CFR 312 
(IND Application); and 45 CFR 46 Subparts A (Common Rule), B (Pregnant Women, 
Human Fetuses and Neonates), C (Prisoners), and D (Children) 
15.3 Institutional Review Board 
Each participating institution must provide for the review and approval of this protocol and 
the associated informed consent documents and recruitment material by an appropriate 
IRB registered with the Office for Human Research Protections (OHRP). Any amendments 
to the protocol or consent materials must also be approved. In the United States and in 
other countries, only institutions holding a current US Federalwide Assurance issued by 
OHRP may participate. 


 
MCC Protocol #: MCC-12-08248 
38 
Version #:13 
 
 
Version Date: 12/10/2021 
15.4 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Extensive discussion of risks and possible benefits of this therapy will be provided to the 
patients and their families. Consent forms describing in detail the study interventions/
products, study procedures, and risks are given to the patient and written documentation of 
informed consent is required prior to starting intervention/administering study product. 
Consent forms will be IRB-approved and the patient will be asked to read and review the 
document. Upon reviewing the document, the investigator or research nurse will explain 
the research study to the subject and answer any questions that may arise. The subject 
will sign the informed consent document prior to any procedures being done specifically for 
the study. The patients should have the opportunity to discuss the study with their 
surrogates or think about it prior to agreeing to participate. The patients may withdraw 
consent at any time throughout the course of the trial. A copy of the informed consent 
document will be given to the subjects for their records. The rights and welfare of the 
patients will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this study. 
15.5 Patient Confidentiality and Access to Source Documents/Data 
Patient confidentiality is strictly held in trust by the participating investigators and their staff. 
This confidentiality includes the clinical information relating to participating patients, as well 
as any genetic or biological testing. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor-investigator. 
The sponsor-investigator will allow access to all source data and documents for the 
purposes of monitoring, audits, IRB review, and regulatory inspections.  
The study monitor or other authorized representatives of the sponsor-investigator may 
inspect all documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
patients in this study. The clinical study site will permit access to such records. 
16 DATA HANDLING AND RECORD KEEPING 
16.1 Data Management Responsibilities 
The sponsor-investigator is responsible for: (i) the overall conduct of the investigation; (ii) 
ongoing review of trial data including all safety reports; and (iii) apprising participating sites 
of any UPs. 
The responsible investigator at each site is responsible for: (i) the data management at his 
or her site; and (ii) reporting SAEs and UPs as required in Section 8. 


 
MCC Protocol #: MCC-12-08248 
39 
Version #:13 
 
 
Version Date: 12/10/2021 
Any laboratory conducting correlative studies must maintain the laboratory records and 
documentation (laboratory notebooks, laboratory protocols, print-outs, recordings, 
photographs, etc.). 
16.2 Source Documents 
Source documents for clinical information (patient history, diagnosis, clinical and diagnostic 
test reports, etc.) are maintained in the patient’s clinical file. Source documents for the 
correlative studies are maintained in the laboratory conducting the study. 
16.3 Case Report Forms 
MCC OnCore data management will provide standard electronic case report forms 
(eCRFs) and create study-specific eCRFs to capture all the information required by the 
protocol. The eCRFs will be approved by the study team to ensure the most effective data 
acquisition. All information on eCRFs will be traceable to the source documents which are 
generally maintained in the patient’s file. All eCRFs should be completed and available for 
collection within a timely manner, preferably no more than 14 days after the patient’s visit. 
16.4 Study Record Retention 
As applicable, study records will be maintained a minimum of 5 years beyond: (i) the 
publication of any abstract or manuscript reporting the results of the protocol; (2) the 
submission of any sponsored research final report; or (iii) submission of a final report to 
clinicaltrials.gov. 


 
MCC Protocol #: MCC-12-08248 
40 
Version #:13 
 
 
Version Date: 12/10/2021 
17 REFERENCES 
1. 
Dodd MJ, Cho MH, Miaskowski C, Painter PL, Paul SM, Cooper BA, Duda J, Krasnoff J, 
Bank KA. A Randomized Controlled Trial of Home-Based Exercise for Cancer-Related 
Fatigue in Women During and after Chemotherapy with or without Radiation Therapy. 
Cancer Nurs. 2010; 33(4):245-257. PMID: 20467301. 
2. 
Barsevick A, Beck SL, Dudley WN, Wong B, Berger AM, Whitmer K, Newhall T, Brown 
S, Stewart K. Efficacy of an Intervention for Fatigue and Sleep Disturbance During 
Cancer Chemotherapy. J Pain Symptom Manage. 2010; 40(2):200-216. PMID: 
20705231. 
3. 
Spratt DE, Sakae M, Riaz N, Lok BH, Essandoh S, Hsu M, Zhang Z, Schupak K, Setton 
J, Lee NY. Time Course and Predictors for Cancer-Related Fatigue in a Series of 
Oropharyngeal Cancer Patients Treated with Chemoradiation Therapy. Oncologist. 
2012; 17(4):569-576. PMID: 22398160. 
4. 
Donovan KA, Jacobsen PB, Andrykowski MA, Winters EM, Balducci L, Malik U, Kenady 
D, McGrath P. Course of Fatigue in Women Receiving Chemotherapy and/or 
Radiotherapy for Early Stage Breast Cancer. J Pain Symptom Manage. 2004; 28(4):373-
380. PMID: 15471655. 
5. 
Taunk NK, Haffty BG, Chen S, Khan AJ, Nelson C, Pierce D, Goyal S. Comparison of 
Radiation-Induced Fatigue across 3 Different Radiotherapeutic Methods for Early Stage 
Breast Cancer. Cancer. 2011; 117(18):4116-4124. PMID: 21365631. 
6. 
Courtier N, Gambling T, Enright S, Barrett-Lee P, Abraham J, Mason MD. Psychological 
and Immunological Characteristics of Fatigued Women Undergoing Radiotherapy for 
Early-Stage Breast Cancer. Support Care Cancer. 2013; 21(1):173-181. PMID: 
22644262. 
7. 
Geinitz H, Zimmermann FB, Thamm R, Keller M, Busch R, Molls M. Fatigue in Patients 
with Adjuvant Radiation Therapy for Breast Cancer: Long-Term Follow-Up. J Cancer 
Res Clin Oncol. 2004; 130(6):327-333. PMID: 15007642. 
8. 
Epstein JB, Robertson M, Emerton S, Phillips N, Stevenson-Moore P. Quality of Life and 
Oral Function in Patients Treated with Radiation Therapy for Head and Neck Cancer. 
Head Neck. 2001; 23(5):389-398. PMID: 11295813. 
9. 
Citrin D, Cotrim AP, Hyodo F, Baum BJ, Krishna MC, Mitchell JB. Radioprotectors and 
Mitigators of Radiation-Induced Normal Tissue Injury. Oncologist. 2010; 15(4):360-371. 
PMID: 20413641. 
10. 
Peterman A, Cella D, Glandon G, Dobrez D, Yount S. Mucositis in Head and Neck 
Cancer: Economic and Quality-of-Life Outcomes. J Natl Cancer Inst Monogr. 2001; 
29(29):45-51. PMID: 11694566. 
11. 
Shirazi A, Mihandoost E, Mohseni M, Ghazi-Khansari M, Rabie Mahdavi S. Radio-
Protective Effects of Melatonin against Irradiation-Induced Oxidative Damage in Rat 
Peripheral Blood. Phys Med. 2013; 29(1):65-74. PMID: 22177584. 


 
MCC Protocol #: MCC-12-08248 
41 
Version #:13 
 
 
Version Date: 12/10/2021 
12. 
Assayed ME, Abd El-Aty AM. Protection of Rat Chromosomes by Melatonin against 
Gamma Radiation-Induced Damage. Mutat Res. 2009; 677(1-2):14-20. PMID: 
19465147. 
13. 
Hussein MR, Abu-Dief EE, Kamel E, Abou El-Ghait AT, Abdulwahed SR, Ahmad MH. 
Melatonin and Roentgen Irradiation-Induced Acute Radiation Enteritis in Albino Rats: An 
Animal Model. Cell Biol Int. 2008; 32(11):1353-1361. PMID: 18762261. 
14. 
Lissoni P. Is There a Role for Melatonin in Supportive Care? Support Care Cancer. 
2002; 10(2):110-116. PMID: 11862501. 
15. 
Seely D, Wu P, Fritz H, Kennedy DA, Tsui T, Seely AJ, Mills E. Melatonin as Adjuvant 
Cancer Care with and without Chemotherapy: A Systematic Review and Meta-Analysis 
of Randomized Trials. Integr Cancer Ther. 2012; 11(4):293-303. PMID: 22019490. 
16. 
Wang YM, Jin BZ, Ai F, Duan CH, Lu YZ, Dong TF, Fu QL. The Efficacy and Safety of 
Melatonin in Concurrent Chemotherapy or Radiotherapy for Solid Tumors: A Meta-
Analysis of Randomized Controlled Trials. Cancer Chemother Pharmacol. 2012; 
69(5):1213-1220. PMID: 22271210. 
17. 
Mills E, Wu P, Seely D, Guyatt G. Melatonin in the Treatment of Cancer: A Systematic 
Review of Randomized Controlled Trials and Meta-Analysis. J Pineal Res. 2005; 
39(4):360-366. PMID: 16207291. 
18. 
Berk L, Berkey B, Rich T, Hrushesky W, Blask D, Gallagher M, Kudrimoti M, McGarry 
RC, Suh J, Mehta M. Randomized Phase II Trial of High-Dose Melatonin and Radiation 
Therapy for Rpa Class 2 Patients with Brain Metastases (Rtog 0119). Int J Radiat Oncol 
Biol Phys. 2007; 68(3):852-857. PMID: 17418968. 
19. 
Del Fabbro E, Dev R, Hui D, Palmer L, Bruera E. Effects of Melatonin on Appetite and 
Other Symptoms in Patients with Advanced Cancer and Cachexia: A Double-Blind 
Placebo-Controlled Trial. J Clin Oncol. 2013; 31(10):1271-1276. PMID: 23439759. 
20. 
Seabra ML, Bignotto M, Pinto LR, Jr., Tufik S. Randomized, Double-Blind Clinical Trial, 
Controlled with Placebo, of the Toxicology of Chronic Melatonin Treatment. J Pineal 
Res. 2000; 29(4):193-200. PMID: 11068941. 
21. 
Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Baker G, 
Klassen TP, Vohra S. The Efficacy and Safety of Exogenous Melatonin for Primary 
Sleep Disorders. A Meta-Analysis. J Gen Intern Med. 2005; 20(12):1151-1158. PMID: 
16423108. 
22. 
Herxheimer A, Petrie KJ. Melatonin for the Prevention and Treatment of Jet Lag. 
Cochrane Database Syst Rev. 2002; Epub ahead of print, DOI: 
10.1002/14651858.CD001520(2):CD001520. PMID: 12076414. 
23. 
Melatonin: Natural Standard Professional Mongraph. Last accessed: 1/27/2015. 
Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-
herbs-supplements/m/melatonin/professional.aspx. 


 
MCC Protocol #: MCC-12-08248 
42 
Version #:13 
 
 
Version Date: 12/10/2021 
24. 
Moss RW. Do Antioxidants Interfere with Radiation Therapy for Cancer? Integr Cancer 
Ther. 2007; 6(3):281-292. PMID: 17761641. 
25. 
Casado-Zapico S, Rodriguez-Blanco J, Garcia-Santos G, Martin V, Sanchez-Sanchez 
AM, Antolin I, Rodriguez C. Synergistic Antitumor Effect of Melatonin with Several 
Chemotherapeutic Drugs on Human Ewing Sarcoma Cancer Cells: Potentiation of the 
Extrinsic Apoptotic Pathway. J Pineal Res. 2010; 48(1):72-80. PMID: 20025643. 
26. 
Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP. Therapeutic 
Actions of Melatonin in Cancer: Possible Mechanisms. Integr Cancer Ther. 2008; 
7(3):189-203. PMID: 18815150. 
27. 
Schernhammer ES, Laden F, Speizer FE, Willett WC, Hunter DJ, Kawachi I, Colditz GA. 
Rotating Night Shifts and Risk of Breast Cancer in Women Participating in the Nurses' 
Health Study. J Natl Cancer Inst. 2001; 93(20):1563-1568. PMID: 11604480. 
28. 
Viswanathan AN, Hankinson SE, Schernhammer ES. Night Shift Work and the Risk of 
Endometrial Cancer. Cancer Res. 2007; 67(21):10618-10622. PMID: 17975006. 
29. 
Purcell A, Fleming J, Bennett S, McGuane K, Burmeister B, Haines T. A 
Multidimensional Examination of Correlates of Fatigue During Radiotherapy. Cancer. 
2010; 116(2):529-537. PMID: 19921735. 
30. 
Xu H, Crawford D, Hutchinson KR, Youtz DJ, Lucchesi PA, Velten M, McCarthy DO, 
Wold LE. Myocardial Dysfunction in an Animal Model of Cancer Cachexia. Life Sci. 
2011; 88(9-10):406-410. PMID: 21167183. 
31. 
Bower JE, Ganz PA, Tao ML, Hu W, Belin TR, Sepah S, Cole S, Aziz N. Inflammatory 
Biomarkers and Fatigue During Radiation Therapy for Breast and Prostate Cancer. Clin 
Cancer Res. 2009; 15(17):5534-5540. PMID: 19706826. 
32. 
Luchetti F, Canonico B, Curci R, Battistelli M, Mannello F, Papa S, Tarzia G, Falcieri E. 
Melatonin Prevents Apoptosis Induced by Uv-B Treatment in U937 Cell Line. J Pineal 
Res. 2006; 40(2):158-167. PMID: 16441553. 
33. 
Wang WZ, Fang XH, Stephenson LL, Zhang X, Khiabani KT, Zamboni WA. Melatonin 
Attenuates I/R-Induced Mitochondrial Dysfunction in Skeletal Muscle. J Surg Res. 2011; 
171(1):108-113. PMID: 20421117. 
34. 
Barsevick AM, Irwin MR, Hinds P, Miller A, Berger A, Jacobsen P, Ancoli-Israel S, 
Reeve BB, Mustian K, O'Mara A, Lai JS, Fisch M, Cella D, National Cancer Institute 
Clinical Trials Planning M. Recommendations for High-Priority Research on Cancer-
Related Fatigue in Children and Adults. J Natl Cancer Inst. 2013; 105(19):1432-1440. 
PMID: 24047960. 
35. 
Benton B, Norton C, Lindsay JO, Dolan S, Andreyev HJ. Can Nurses Manage 
Gastrointestinal Symptoms Arising from Pelvic Radiation Disease? Clin Oncol (R Coll 
Radiol). 2011; 23(8):538-551. PMID: 21530194. 


 
MCC Protocol #: MCC-12-08248 
43 
Version #:13 
 
 
Version Date: 12/10/2021 
36. 
Ravasco P, Monteiro-Grillo I, Marques Vidal P, Camilo ME. Impact of Nutrition on 
Outcome: A Prospective Randomized Controlled Trial in Patients with Head and Neck 
Cancer Undergoing Radiotherapy. Head Neck. 2005; 27(8):659-668. PMID: 15920748. 
37. 
Bower JE, Ganz PA, Irwin MR, Castellon S, Arevalo J, Cole SW. Cytokine Genetic 
Variations and Fatigue among Patients with Breast Cancer. J Clin Oncol. 2013; 
31(13):1656-1661. PMID: 23530106. 
38. 
Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, Silberman M, Yellen SB, 
Winicour P, Brannon J, et al. The Functional Assessment of Cancer Therapy Scale: 
Development and Validation of the General Measure. J Clin Oncol. 1993; 11(3):570-579. 
PMID: 8445433. 
39. 
Promis: Dynamic Tools to Measure Health Outcomes from the Patient Perspective. Last 
accessed: June 19, 2014. Available from: 
http://www.nihpromis.org/measures/availableinstruments. 
40. 
Zeng L, Koo K, Zhang L, Jon F, Dennis K, Holden L, Nguyen J, Tsao M, Barnes E, 
Danjoux C, Sahgal A, Chow E. Fatigue in Advanced Cancer Patients Attending an 
Outpatient Palliative Radiotherapy Clinic as Screened by the Edmonton Symptom 
Assessment System. Support Care Cancer. 2012; 20(5):1037-1042. PMID: 21538097. 
41. 
Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. The Edmonton Symptom 
Assessment System (Esas): A Simple Method for the Assessment of Palliative Care 
Patients. J Palliat Care. 1991; 7(2):6-9. PMID: 1714502. 
42. 
Chang VT, Hwang SS, Feuerman M. Validation of the Edmonton Symptom Assessment 
Scale. Cancer. 2000; 88(9):2164-2171. PMID: 10813730. 
43. 
Collado-Hidalgo A, Bower JE, Ganz PA, Irwin MR, Cole SW. Cytokine Gene 
Polymorphisms and Fatigue in Breast Cancer Survivors: Early Findings. Brain Behav 
Immun. 2008; 22(8):1197-1200. PMID: 18617366. 
44. 
Bruera E, El Osta B, Valero V, Driver LC, Pei BL, Shen L, Poulter VA, Palmer JL. 
Donepezil for Cancer Fatigue: A Double-Blind, Randomized, Placebo-Controlled Trial. J 
Clin Oncol. 2007; 25(23):3475-3481. PMID: 17687152. 
45. 
Kittelson JM, Emerson SS. A Unifying Family of Group Sequential Test Designs. 
Biometrics. 1999; 55(3):874-882. PMID: 11315020. 
46. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. 
Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982; 5(6):649-655. PMID: 7165009. 
 


 
MCC Protocol #: MCC-12-08248 
44 
Version #:13 
 
 
Version Date: 12/10/2021 
18 APPENDIX 1. FACIT-F SCALE 
The FACIT-F scale is given on the following 3 pages. 
 


FACIT-F (Version 4) 
English (Universal) 
 
16 November 2007 
Copyright 1987, 1997 
 
Page 1 of 3 
 
Patient’s Initials: _______________ 
Date: _______________ 
 
Study ID #: _______________ 
Time Point: _______________ 
 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GP1 
I have a lack of energy
 ..........................................................................................  
0 
1 
2 
3 
4 
GP2 
I have nausea
 ..........................................................................................  
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family
 ..........................................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain
 ..........................................................................................  
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment
 ..........................................................................................  
0 
1 
2 
3 
4 
GP6 
I feel ill
 ..........................................................................................  
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GS1 
I feel close to my friends
 ..........................................................................................  
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family
 ..........................................................................................  
0 
1 
2 
3 
4 
GS3 
I get support from my friends
 ..........................................................................................  
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness
 ..........................................................................................  
0 
1 
2 
3 
4 


FACIT-F (Version 4) 
English (Universal) 
 
16 November 2007 
Copyright 1987, 1997 
 
Page 2 of 3 
 
 
 
GS5 
I am satisfied with family communication about my 
illness
 ..........................................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support)
 ..........................................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box         and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life
0 
1 
2 
3 
4 


FACIT-F (Version 4) 
English (Universal) 
 
16 November 2007 
Copyright 1987, 1997 
 
Page 3 of 3 
 
Patient’s Initials: _______________ 
 
Study ID #: _______________ 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GE1 
I feel sad
 ..........................................................................................  
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness
 ..........................................................................................  
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness
 ..........................................................................................  
0 
1 
2 
3 
4 
GE4 
I feel nervous
 ..........................................................................................  
0 
1 
2 
3 
4 
GE5 
I worry about dying
 ..........................................................................................  
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home)
 ..........................................................................................  
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling
 ..........................................................................................  
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life
 ..........................................................................................  
0 
1 
2 
3 
4 
GF4 
I have accepted my illness
 ..........................................................................................  
0 
1 
2 
3 
4 
GF5 
I am sleeping well
 ..........................................................................................  
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun
 ..........................................................................................  
0 
1 
2 
3 
4 


FACIT-F (Version 4) 
English (Universal) 
 
16 November 2007 
Copyright 1987, 1997 
 
Page 4 of 3 
 
GF7 
I am content with the quality of my life right now
0 
1 
2 
3 
4 
 
 
 


FACIT-F (Version 4) 
English (Universal) 
 
16 November 2007 
Copyright 1987, 1997 
 
Page 5 of 3 
 
Patient’s Initials: _______________ 
 
Study ID #: _______________ 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
HI7 
I feel fatigued
 ..........................................................................................  
0 
1 
2 
3 
4 
HI12 
I feel weak all over
 ..........................................................................................  
0 
1 
2 
3 
4 
An1 
I feel listless (“washed out”)
 ..........................................................................................  
0 
1 
2 
3 
4 
An2 
I feel tired
 ..........................................................................................  
0 
1 
2 
3 
4 
An3 
I have trouble starting things because I am tired
 ..........................................................................................  
0 
1 
2 
3 
4 
An4 
I have trouble finishing things because I am tired
 ..........................................................................................  
0 
1 
2 
3 
4 
An5 
I have energy
 ..........................................................................................  
0 
1 
2 
3 
4 
An7 
I am able to do my usual activities
 ..........................................................................................  
0 
1 
2 
3 
4 
An8 
I need to sleep during the day
 ..........................................................................................  
0 
1 
2 
3 
4 
An12 
I am too tired to eat
 ..........................................................................................  
0 
1 
2 
3 
4 
An14 
I need help doing my usual activities
 ..........................................................................................  
0 
1 
2 
3 
4 
An15 
I am frustrated by being too tired to do the things I want 
to do
 ..........................................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
An16 
I have to limit my social activity because I am tired
0 
1 
2 
3 
4 
 
 


FACIT-F (Version 4) 
English (Universal) 
 
16 November 2007 
Copyright 1987, 1997 
 
Page 6 of 3 
 
 
 


 
MCC Protocol #: MCC-12-08248 
43 
Version #: 12 
 
 
Version Date: 06/04/2019 
19 APPENDIX 2. ESAS SCALE 
The ESAS scale is provided on the following page. The “Other problem,” listed as the last 
optional item on the scale, will be sleep. Best sleep=0; worst possible sleep=10. 
 


 
 
 
Patient’s Initials: _______________ 
 
Study ID #: _______________ 
 
Date: _______________ 
 
Time Point: _______________ 
 
Initials 
Best sleep 
Worst possible sleep 


 
MCC Protocol #: MCC-12-08248 
45 
Version #: 12 
 
 
Version Date: 06/04/2019 
20 APPENDIX 3. PROMIS FATIGUE-SHORT FORM 8A 
The PROMIS Fatigue-Short Form 8a is provided on the following page.  
 


 
 
Patient’s Initials: _______________ 
Date: _______________ 
 
Study ID #: _______________ 
Time Point: _______________ 
 


 
MCC Protocol #: MCC-12-08248 
47 
Version #: 12 
 
 
Version Date: 06/04/2019 
21 APPENDIX 4. ECOG SCALE 
ECOG Performance Status Scale (46) 
Grade 
Criteria 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
5 
Dead 
 


 
MCC Protocol #: MCC-12-08248 
48 
Version #: 12 
 
 
Version Date: 06/04/2019 
22 APPENDIX 5. FOLLOW-UP QUESTIONNAIRE 
The Follow-Up Questionnaire is given on the following page. 
 


 
 
 
V.2,8/06/13 
 
 
 
 
MCC-12-08248:  Melatonin supplementation for cancer-related fatigue in patients 
receiving radiotherapy:  A double – blind placebo-controlled trial. 
 
 
Patient Initials (L,F, M)__          _______  Patient ID_            __________  Date__________ 
 
 
 
 
 
 
 
 
 
 
 
 
Timepoint_____ 
 
Follow-up Questionnaire 
 
 
Weight (assess at all visits):    
  
 
 
 
______ (kg/ lbs)   
 
 
Height :   
 
 
 
 
 
 
 
_______ (cm/in) 
 
 
BMI:                      
 
 
 
 
 
 
_______ 
 
 
ECOG performance status (assess at all visits):    
 
_______ 
 
 
 
Has the patient had any hospital admissions since the last contact? ____  
If yes, how many?_____ 
Reason for Admission: _______________________________________ 
Hospital: ____________________________________________ Date(s):   ______ 
Hospital: ____________________________________________  Date(s):  ______ 
(Note:  **Obtain a release of information if appropriate**) 
  
 
Has the patient had any emergency department (ED) visits since the last contact?  _____  
If yes, how many? ______ 
Reason for ED visit: _______________________________________________ 
Hospital: ____________________________________________   Date(s): _____ 
Hospital: ____________________________________________   Date(s): _____ 
 (Note:  **Obtain a release of information if appropriate**) 
  
  
 
Has the patient had any medical days off from work since the last contact? 
 _____ If yes, how many?  ______ 
Reason for missed days: ________________________________  Date(s): ________ 
Reason for missed days: ________________________________  Date(s): ________ 
Reason for missed days: ________________________________  Date(s): ________ 
 
 
 
 
 


 
 
 
V.2,8/06/13 
 
 
 
 
Review and Update Medication list : 
(please list all opiods, benzodiazepines, prescription sleeping aids, steroids and central nervous 
system stimulants 
 
____________________  
 
____________________ 
 
____________________ 
 
____________________ 
 
____________________ 
 
____________________ 
 
 
 
Laboratory Studies:                                                Date Obtained: _______________________  
 
______ 
WBC 
 
______ 
RBC 
 
______ 
Hemoglobin 
 
______ 
HCT 
 
______ 
PLT 
 
______ 
Creatinine (baseline only) 
 
**Note reason if not obtained: _____________________________________________________ 
 
Compliance Assessment: 
 
Patient has taken _________ mLs this cycle.  
She/he has missed ___________ mLs, as indicated on diary. 
 
Comments:  
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
__________________________________________________________________________ 
 
Completed by: ______________________________________  Date: ____________________ 
 
 
 
 


 
MCC Protocol #: MCC-12-08248 
51 
Version #: 12 
 
 
Version Date: 06/04/2019 
23 APPENDIX 6. BLOODWORK FORM 
The Bloodwork Form is provided on the following page.  
 


 
V.2,8/06/13 
MCC-12-08248:  Melatonin supplementation for cancer-related fatigue in 
patients receiving radiotherapy:  A double – blind placebo-controlled trial. 
 
 
Patient Initials (L,F, M)__          _______  Patient ID_            __________  
Date__________ 
 
 
 
 
 
 
 
 
 
 
 
 
Timepoint_____ 
 
 
Bloodwork 
 
 
 
______ 
WBC 
 
 
______ 
RBC 
 
 
______ 
Hemoglobin 
 
 
______ 
HCT 
 
 
______ 
PLT 
 
 
______ 
Creatinine(baseline only) 


 
MCC Protocol #: MCC-12-08248 
53 
Version #: 12 
 
 
Version Date: 06/04/2019 
24 APPENDIX 7. DEMOGRAPHIC FORM 
The Demographic Form is provided on the following page.  
 


Demographic Form 
Page: 1 of 2 
Patient Initials (Last, first, middle):    
Gender: ______M      _____F   _____Unknown    
Date of Birth: ____/___/_______  Age:_______  
Zip Code: _______ 
Marital  Status: 
_____Single, Never Married 
_____ Married; Living with significant other 
_____  Divorced or Separated                               
Children: 
_____Yes.  Ages: 
_________________________ 
_____No    
   
Date Informed Consent Signed: 
_________/   _________/  __________ / 
Date HIPPA Form Signed: 
_________/  ___________/ ___________/  
Race:  
____White 
____ Black or African-American 
____Native Hawaiian or other Pacific Islander 
____ Asian 
____ American Indian or Alaska Native 
____Not reported (patient refused) 
____Unknown (patient unsure)     
Ethnicity: 
____Not Hispanic or Latino 
____Hispanic or Latino 
____Not reported (patient refused) 
____ Unknown (Patient unsure)    
Method of Payment: 
____Private Insurance 
____Medicare 
____Medicare and Private Insurance 
____Medicaid    
____Military or Veterans Sponsored 
____ Self pay (no insurance) 
____ Other 
____Unknown 
Household Income: 
____<$20,000 
____$20,001 - $40,000 
____$40,001 - $60,000 
____$60,001 - $80,000 
____$80,001 and above 
Employment Status: 
____Retired 
____Unemployed 
____Employed (list occupation on next line) 
___________________________________ 
 


Demographic Form 
Page: 2 of 2 
Medical History    
Date of Diagnosis: 
_________/__________/ _______/     
Pathology: 
 
Stage:  T____ N____ M____ 
Weight prior to cancer diagnosis:                                 
Weight on enrollment into study: 
   
  
 


 
MCC Protocol #: MCC-12-08248 
56 
Version #: 12 
 
 
Version Date: 06/04/2017 
25 APPENDIX 8. STUDY DIARY 
The Study Diary is provided on the following page.  


 
 
 
 
 
 
 
 
 
BRING THIS DIARY AND STUDY MEDICATION BOTTLE(S) ON EACH CLINIC VISIT, OR AS DIRECTED BY RESEARCH NURSE. 
 
Patient’s Initials:___________    MR#:____________    Visit:_________    Study Number:____________ 
Day 
Pre 
Rad 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Education of study meds by: 
                                                 . 
date:                                   . 
 
Date  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
***Melatonin/ 
Placebo*** 
take 10 ml suspension orally at night 
 
 
 
Missed  
 
 
 
 
Missed  
 
 
 
 
Missed 
 
 
 
 
Missed  
 
 
 
 
Missed 
 
 
 
 
Missed  
 
 
 
 
Missed  
 
 
 
 
Missed 
 
 
 
 
Missed  
 
 
 
 
Missed  
 
 
 
 
Missed  
 
 
 
 
Missed 
 
 
 
 
Missed  
 
 
 
 
Missed  
 
 
 
 
Missed  
 
Comments/ Please List 
Reasons for Missing 
Study Drug 
 
SIDE EFFECTS  
 
 
Sleepiness during the daytime 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dizziness 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Headaches 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Abdominal discomfort 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild Anxiety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Irritability 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confusion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Short-lasting depression 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other side effects experienced: 
 
 
 
 
 
 
Patient has taken _____________ml this cycle.  She/he has missed _________ml, as indicated on diary. 
 
This diary & suspension dosing log was reviewed with pt by the Research Nurse / CRA   _______________________   DATE  __________________ 


 
MCC Protocol #: MCC-12-08248 
58 
Version #: 12 
 
 
Version Date: 06/04/2017 
 
26 APPENDIX 9. CONTRACEPTIVE USE AGREEMENT 
The Contraceptive Use Agreement is provided on the following page.  
 


 
 
MCC-12-08248 Agreement to Use Adequate 
Contraception 
 
Patient’s Initials: 
Study Number: 
Date: 
 
Because of the effects of radiation and melatonin that are known/unknown to the 
developing fetus, I am required to agree to use adequate contraception prior to study 
entry, for the duration of study participation, and 3 months after completion.  For the 
purpose of this study, adequate contraception is defined as any of the following 
methods: Either post-menopausal, surgically sterilized or willing to use an acceptable 
method of birth control (all hormone-based contraceptives are deemed to be 
unacceptable forms of birth control with respect to meeting inclusion criteria).  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. 
 
I agree to the above and have been given a copy of this document for my records. 
 
□ The above statement does not apply due to patient’s menopausal status. 
 
 
_________________________________               _________________________ 
Patient’s Initials                                                        Date 
 
 
_________________________________               _________________________ 
Research Nurse                                                       Date 
 
 


 
MCC Protocol #: MCC-12-08248 
60 
Version #: 12 
 
 
Version Date: 06/04/2017 
 
27 APPENDIX 10. GENERAL INFORMATION ABOUT MELATONIN 
A general information sheet to be provided to study patients is shown on the following page. 
 


 
 
General Information About Your Study Medication 
This bottle contains your study medication, which is melatonin or a placebo.  
Please begin taking a 10 mL dose of your study drug at night on ____________ and 
continue taking it every night (including weekends and holidays) while you are 
receiving radiation treatment and continue to take it for two weeks after your 
radiation treatment has ended.  
Please remember to shake the bottle before you dispense each dose. The 10-mL 
dose has been marked on the medication cups provided for your use. 
Please use the form in the folder that you have been given to record each dose you 
take or any doses you miss. Also record any side effects that you notice. Your study 
nurse will be contacting you to check on you the week following your first dose.  
If anything changes in your radiation plan, if you stop radiation, or if your radiation 
treatment is shortened or lengthened, please call your research nurse or ask your 
radiation nurse to call your research nurse. Unless you are having unacceptable 
side effects, which is very unlikely, please do not stop taking your melatonin without 
first speaking with your research nurse. 
A brief word about measuring your dose. Your medication cups are marked at 
the 10 mL point. This is the line we would like you to use when measuring your 
dose. It is best to place the cup on a flat surface and pour the liquid into the cup. 
Please be mindful that the best way to view the line is to look at eye level on the 
side of the cup while the cup is resting on a flat surface. 
Thank you for participating in this important clinical trial! 
Please feel free to contact your study nurse if you have concerns, questions, 
or side effects that you wish to discuss. 
                                                   
 
                                                      
    
                          
 


 
MCC Protocol #: MCC-12-08248 
62 
Version #: 12 
 
 
Version Date: 06/04/2017 
28 APPENDIX 11. PATIENT RECRUITMENT FLYER 
The Patient Recruitment Flyer is provided on the following pages.  
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
                              
  
                             
 
                    
 
 
 
 
 
 
                                
 
 
                               
 
                               
 
                                
 
 
 
 
  



ICF_000.pdf: 
MCC-12-08248
NCT02332928
4/01/2020


MCC Protocol #: MCC-12-08248
Page 1 of 12
Version Date: 03/19/2020
RESEARCH PARTICIPANT INFORMED CONSENT 
TITLE:
Melatonin supplementation for cancer-related fatigue in patients receiving 
radiotherapy: A double-blind placebo-controlled trial
PROTOCOL #:
MCC-12-08248
VCU IRB #:
HM20003275
SPONSOR/
INVESTIGATOR:
Egidio Del Fabbro, MD
OVERVIEW AND KEY INFORMATION 
Taking part in this study is your choice
You can choose to take part or you can choose not to take part in this study. You also can 
change your mind at any time. Whatever choice you make, you will not lose access to your 
medical care or give up any legal rights or benefits.
Why is this study being done?
Fatigue, or a sense of exhaustion, is commonly experienced by patients with cancer. When 
patients with breast cancer are treated with radiation therapy they often experience increased 
levels of fatigue. The purpose of this research study is to test the effectiveness of melatonin in 
lessening the fatigue that frequently occurs in patients receiving radiation therapy. 
You are being asked to participate in this study because you have been diagnosed with breast 
cancer and because you may meet the study entry requirements.
 Up to 142 individuals will participate in this study.
What will happen if I decide to take part in this study?
You will be randomly assigned (like the flip of a coin) to receive either melatonin or placebo. The 
melatonin and placebo treatments will involve taking a liquid syrup orally each night, beginning 
the night before radiation therapy begins and ending 2 weeks after the radiation therapy is 
completed.
We will ask you to keep a diary and write down when you take your study drugs. 
We will ask to collect a blood sample for research purposes prior to beginning treatment, during 
treatment, and after your radiation treatment.
We will give you surveys to fill out with questions about how you’re feeling prior to beginning 
treatment, during treatment, and after your radiation treatment.
We will also collect other information about you and your cancer treatment from your medical 
records.
Approved by the VCU IRB on 4/1/2020


MCC Protocol #: MCC-12-08248
Page 2 of 12
Version Date: 03/19/2020
How long will I be in this study?
Your participation in this study will last up to 16 weeks.
What are my other choices if I do not take part in this study?
If you decide not to enter this study, there may be other treatments for fatigue available. The 
study doctor will discuss these with you. You do not have to participate in this study to be 
treated for breast cancer.
What are the risks and benefits of taking part in this study?
There are both risks and benefits to taking part in this study. It is important for you to think 
carefully about these as you make your decision. 
Risks
We want to make sure you know about a few key risks right now. We give you more information 
in the Risks and Discomforts section.
If you choose to take part in this study, there is a chance that you could have side effects from 
the melatonin. 
Some of the most common side effects that the study doctors know about are:
•
Sleepiness during the daytime, especially if combined with a sedative
•
Headaches
Benefits
There is no guarantee that you will receive any medical benefits from being in this study. If you 
are receiving melatonin, and if melatonin can relieve the symptoms of fatigue, you may feel less 
tired during this study. If you are receiving the placebo, you may also feel less tired during the 
study. While you may not receive any direct benefit from receiving the study drug, the 
information from this research study may lead to a better treatment in the future for the fatigue 
associated with cancer and radiation therapy.
Approved by the VCU IRB on 4/1/2020


MCC Protocol #: MCC-12-08248
Page 3 of 12
Version Date: 03/19/2020
DETAILED RESEARCH CONSENT
Now that you have a general overview of the study, we want to provide the details about what 
your participation involves. Please read, or have someone read to you, the rest of this 
document. If there is anything you don’t understand, be sure to ask the study staff.
DESCRIPTION OF THE STUDY 
Melatonin is sold over-the-counter in the United States as a dietary supplement. Because 
melatonin is not regulated as a drug, the FDA does not require the manufacturer to demonstrate 
its safety or effectiveness. Nonetheless, this study is designed to test the effectiveness of 
melatonin in lessening the symptoms of fatigue that are associated with cancer and radiation 
therapy.
In this study, melatonin will be compared to a placebo (a look-alike inactive substance) for its 
ability to make patients with breast cancer feel less tired while undergoing treatment with 
radiation therapy. As determined by their treating physician, patients will receive one of three 
types of standard-of-care radiation therapy. The 3 types of radiation therapy include the 
following therapies:

1 week of accelerated partial breast irradiation (5 consecutive days of treatment)

3-4 weeks of an accelerated hypofractionated radiation therapy schedule (5 consecutive 
days of treatment per week)

6-8 weeks of a standard radiation therapy schedule (5 consecutive days of treatment per 
week)
One-half of the patients will be treated with melatonin and one-half of the patients will be treated 
with placebo. The dose of melatonin used in this study will be at least four times higher than is 
typically used as an over-the-counter dietary supplement. The melatonin and placebo 
treatments will involve taking a liquid syrup orally each night, beginning the night before 
radiation therapy begins and ending 2 weeks after the conclusion of radiation therapy.
Prior to beginning treatment, during treatment, and for approximately 8 weeks following 
treatment, patients will complete 2 surveys that will measure their fatigue and 1 survey that will 
measure their symptoms. The surveys should take less than 20 minutes to complete. A small 
amount of blood (about 1 teaspoon) will also be taken to measure how melatonin affects the 
levels of different biological molecules. This part of the study will not use your samples to 
sequence all or part of your DNA. If you choose to take part in the optional studies described in 
the Additional Studies Section, a small amount of blood (about 1 teaspoon) will also be taken.
Blood samples will continue to be used until they are used up. The individual results of the 
research using your samples will not be provided to you. The samples are collected only for the 
research study. There will be no benefit to you. 
The study doctor will tell you about new information or changes in the study that may affect your 
health or your willingness to continue participation. 
Approved by the VCU IRB on 4/1/2020


MCC Protocol #: MCC-12-08248
Page 4 of 12
Version Date: 03/19/2020
PROCEDURES
If you decide to be in this research study, you will be asked to sign this consent form after you 
have had all your questions answered. You will also be asked to sign a separate HIPAA 
authorization form that gives the research team permission to use your private health 
information for the purposes of this research study. This information will be used to determine if 
patients receiving melatonin, in comparison to patients receiving placebo, have fewer hospital 
admissions, emergency center visits, and medical days off work.
At your first study visit, your medical history will be taken and a physical exam will be performed. 
This exam will include measurements of your weight and vital signs (pulse, blood pressure and 
temperature). A blood sample will be collected for routine lab tests. Approximately 2 to 3 
tablespoons of blood will be collected. This information will be used to make sure that you 
qualify to participate on the study. You must begin the study within 28 days of your examination 
and any of the lab tests that are done. 
If you qualify for the study, you will be randomly assigned (like the flip of a coin) to receive either 
melatonin or placebo. You have an equal chance of being assigned to either one of these 
groups.
Neither you nor the study doctor will know if you are receiving melatonin or placebo. This 
information is available to the study doctor if needed in an emergency. This is called double 
blinding, and it is done so that a fair evaluation of results may be made. 
You will have a physical exam and a blood sample will be collected (about 1 teaspoon) to 
measure if and how different cells and molecules change when you take the study drug. You will 
be asked a series of questions using the ESAS numerical scale, FACIT-F scale, and PROMIS 
scale. This examination and the tests will be repeated at the conclusion of your radiation 
therapy, and they will be repeated at 2 weeks and 8 weeks following your last radiation 
treatment. If your radiation therapy lasts for 3 weeks or longer, this examination and the tests 
will be repeated approximately every 2 weeks while you remain on radiation therapy. 
The melatonin is suspended in liquid syrup that has a citrus-berry flavoring. The placebo is the 
same liquid syrup, but does not contain melatonin. Both the melatonin and placebo are light 
sensitive and you should store them in the light-resistant amber bottle in which you receive 
them. Each product should be stored at room temperature and shaken well before use.
You will begin taking your study drug (melatonin or placebo) by mouth starting the night before 
you begin radiation therapy. You should use the measuring cup provided to you to measure 10 
mL for each dose that you take. You will keep a study diary to record the time each dose is 
taken and any side effects you are having. You should continue taking the study drug every 
night while you are receiving radiation therapy and for an additional 2 weeks after your radiation 
therapy has ended.
At each visit, you should bring all of your remaining study drug supply to the research clinic. At 
each visit, you should also bring your study diary.
Approved by the VCU IRB on 4/1/2020


MCC Protocol #: MCC-12-08248
Page 5 of 12
Version Date: 03/19/2020
RISKS AND DISCOMFORTS
Possible side effects associated with the use of melatonin include:
Likely (10% or more of patients)

Sleepiness during the daytime, especially if combined with a sedative

Headaches
Less Likely (1-9% of patients)

Abdominal discomfort

Mild anxiety

Irritability

Confusion

Short-lasting depression

Dizziness
Any drug may cause allergic reactions; these may be serious, even life-threatening.
Possible side effects associated with treating breast cancer with radiation therapy:
Likely (10% or more of patients)

Reddening of the skin during treatment and for several weeks following treatment

Tanning of the skin lasting months and may be permanent

Slightly smaller breast size or change in the way the breast looks

Tiredness and weakness during treatment and for several weeks following treatment

Swelling of breast

Peeling of the skin in the area treated with radiation

Mild pain at the site of radiation treatment requiring over-the-counter pain relievers
Less Likely (3-9% of patients)

Soreness or tightness in muscles of the chest wall under the treated breast

Severe pain at the site of radiation requiring prescription pain relievers
Rare But Serious (less than 3% of patients)

Cough

Difficulty breathing

Inflammation of the heart muscle

Rib fracture

Slight increase in risk for heart disease for patients with cancer in the left breast

Risk of developing another cancer
Approved by the VCU IRB on 4/1/2020


MCC Protocol #: MCC-12-08248
Page 6 of 12
Version Date: 03/19/2020
Reproductive risks:
As the study procedures might injure an unborn child, pregnant women may not participate. 
Women who might become pregnant should use a medically accepted form of birth control such 
as total abstinence, an IUD, diaphragm, or condoms plus a spermicide. Because of a possible 
interaction with melatonin, hormonal forms of birth control should not be used. Methods of birth 
control other than total abstinence are not 100% effective, and should a woman become 
pregnant there is a risk of injury to an unborn child. You will be asked to sign an agreement that 
confirms that you will use an adequate form of birth control during your participation on the 
study and for 3 months following completion of the study.
Risks associated with blood draws:
The collection of your blood may cause pain, swelling, bruising, irritation or redness at the 
needle site. You may feel faint during or after a blood draw. It is also possible to get an infection 
at the site of the needle puncture, but this is extremely rare.
Risks of completing surveys:
Some of the questions about physical, emotional, or social difficulties may be upsetting to you. 
You may skip any questions that you do not wish to answer.
Risks associated with breach of confidentiality:
Although it is unlikely, it is possible that your private health information could be discovered by 
someone who is unauthorized to have access to it. See the forthcoming “Confidentiality” section 
for more information on safeguards in place to prevent a breach in confidentiality.
COSTS
You will not be charged for the study drug, the two-month follow-up, and blood tests that are 
performed only for this study (extra blood draws). You and/or your health plan/insurance 
company will need to pay for the radiation therapy, physical exams, and associated lab tests 
that are part of your regular cancer treatment. Check with your health plan or insurance 
company to find out what they will pay for. Taking part in this study may or may not cost your 
insurance company more than the cost of getting regular cancer treatment.
The study will not pay for medical treatment.
Approved by the VCU IRB on 4/1/2020


MCC Protocol #: MCC-12-08248
Page 7 of 12
Version Date: 03/19/2020
CONFIDENTIALITY
Your research information and your personal identifying information will be kept private through 
the use of password-protected electronic files, locked research areas, and study identification 
numbers. Blood samples obtained for research purposes will be stored with the same 
safeguards.
In the future, identifiers might be removed from the information and samples you provide in this 
study, and after that removal, the information and samples could be used for other research 
studies by this study team or another researcher without asking you for additional consent.
Every effort will be made to ensure that the personal information in your medical record will be 
kept private. However, we cannot guarantee total privacy. Your personal information may be 
given out if required by law. If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used. 
Organizations that may look at and/or copy your medical records for research, quality 
assurance, and data analysis include:

The National Cancer Institute (NCI) and other government agencies like the Food and Drug 
Administration (FDA) involved in keeping research safe for people.

Virginia Commonwealth University and its Institutional Review Board (VCU IRB).
There are no plans to share any money or profits with you if the use of your sample(s) results in 
inventions or discoveries that have commercial value. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This website will not include information that can identify you. At most, the website 
will include a summary of the results. You can search this website at any time.
Approved by the VCU IRB on 4/1/2020


MCC Protocol #: MCC-12-08248
Page 8 of 12
Version Date: 03/19/2020
COMPENSATION FOR INJURY or ILLNESS 
If you are injured by, or become ill, from participating in this study, please contact your study 
doctor immediately. Medical treatment is available at the Virginia Commonwealth University 
Health System (VCU Health System). Your study doctor will arrange for short-term emergency 
care at the VCU Health System or for a referral if it is needed.
Fees for such treatment may be billed to you or to appropriate third party insurance. Your health 
insurance company may or may not pay for treatment of injuries or illness as a result of your 
participation in this study.
To help avoid research-related injury or illness, it is very important to follow all study directions.
VOLUNTARY PARTICIPATION AND WITHDRAWAL
Your participation in this study is voluntary. You may decide to not participate in this study. Your 
decision not to take part will involve no penalty or loss of benefits to which you are otherwise 
entitled. If you do participate, you may freely withdraw from the study at any time. 
Your participation in this study may be stopped at any time by the study doctor or the sponsor 
without your consent. The reasons might include:

the study doctor thinks it necessary for your health or safety;

you have not followed study instructions;

the sponsor has stopped the study; or

administrative reasons require your withdrawal.
Approved by the VCU IRB on 4/1/2020


MCC Protocol #: MCC-12-08248
Page 9 of 12
Version Date: 03/19/2020
QUESTIONS
In the future, you may have questions about your study participation. You may also have 
questions about a possible research-related injury. If you have any questions, complaints, or 
concerns about your participation in this research, contact:
Principal Investigator:
Responsible Research Nurse:
Egidio Del Fabbro, MD
Gwendolyn Parker, MS, FNP-C
Department of Internal Medicine
Massey Cancer Center
Virginia Commonwealth University
Virginia Commonwealth University
1101 E. Marshall Street
401 College Street
Box 980230
Box 980037
Richmond, VA 23298
Richmond, VA 23298
Phone: 804-628-0617
Phone: 804-828-5090
Email: egidio.delfabbro@vcuhealth.org
Email: ggparker@vcu.edu
The principal investigator and the responsible research nurse named above are the best people 
to call for questions about your participation in this study.
If you have general questions about your rights as a participant in this or any other research, 
you may contact:
Office of Research
Virginia Commonwealth University
800 East Leigh Street, Suite 3000
Box 980568
Richmond, VA 23298
Telephone: (804) 827-2157
Contact this number for general questions, concerns, or complaints about research. You may 
also call this number if you cannot reach the research team or if you wish to talk to someone 
else. General information about participation in research studies can also be found at 
http://www.research.vcu.edu/irb/volunteers.htm
Do not sign this consent form unless you have had a chance to ask questions and have 
received satisfactory answers to all of your questions.
Approved by the VCU IRB on 4/1/2020


MCC Protocol #: MCC-12-08248
Page 10 of 12
Version Date: 03/19/2020
ADDITIONAL STUDIES SECTION
This section is about optional studies you can choose to take part in 
This part of the consent form is about optional studies that you can choose to take part in. You 
will not get health benefits from any of these studies. The researchers leading this optional 
study hope the results will help other people with cancer in the future.
You will not be billed for these optional studies. You can still take part in the main study even if 
you say “no” to any or all of these studies. If you sign up for but cannot complete any of the 
studies for any reason, you can still take part in the main study.
Initial your choice of “yes” or “no” at the end of this section.
Background information: 
This study might use your samples to sequence part of your DNA. Deoxyribonucleic acid (DNA) 
is the “blueprint” or “recipe” that gives the body’s cells instructions on how to do their jobs. 
Scientists can use a test called whole genome sequencing to determine the order of all or part 
of the molecules that make up your DNA, like reading all the letters in a book. Sequencing is 
usually done to look for changes in the molecules of DNA that may cause health problems. 
The optional studies involve genes, a form of DNA. Genes carry information about features that 
are found in you and in people who are related to you. Researchers are interested in the way 
that genes affect how your body responds to treatment.
We will study your DNA sequences, or genes, that code for three proteins called IL-1B, IL-6, 
and TNF. The genes that code for IL-1B, IL-6, and TNF sometimes differ slightly among 
different individuals and these differences might be important in causing the fatigue that 
sometimes occurs with radiation therapy. By studying your IL-1B, IL-6, and TNF genes we hope 
to determine if there is such an association. 
What is involved: If you agree to take part, the study doctor for the main study would like to 
collect 1 additional blood sample (about 1 teaspoon) before your study treatment begins for the 
optional laboratory study. 
Future contact concerning genetic testing results: 
Sometimes samples are used for genetic research (about diseases that are passed on in 
families). Even if your samples are used for this kind of research, the results will not be given to 
you or your doctor. These reports will not be put in your health record. The research will not 
have an effect on your care.
Approved by the VCU IRB on 4/1/2020


MCC Protocol #: MCC-12-08248
Page 11 of 12
Version Date: 03/19/2020
Withdrawal of genetic testing consent:
If you decide now that your specimens can be kept for genetic testing and later change your 
mind, just contact us and let us know that you do not want us to use your specimens. The 
specimens that remain will no longer be used for research. You may contact the investigator 
and/or responsible research nurse at the number listed on this form.
Confidentiality: 
The results of genetic research on your specimens will not be put in your health record. 
While this study has safeguards in place to protect your confidential genetic information and to 
make it extremely unlikely that your identity would be connected with any special studies that 
are performed on your tissue, it is possible that this information could be discovered by 
someone who is unauthorized to have access to it.
Your specimens will be used only for research and will not be sold. The research done with your 
specimens may help to develop new products in the future.
Samples for the Optional Laboratory Studies:
My blood samples may be stored and used for the research described above about fatigue in 
cancer patients.
YES
NO
initial
initial
Future contact concerning further research: 
I agree to allow my study doctor or someone approved by my study doctor, to contact me 
regarding future research involving my participation in this or related research.
YES
NO
initial
initial
Approved by the VCU IRB on 4/1/2020


MCC Protocol #: MCC-12-08248
Page 12 of 12
Version Date: 03/19/2020
My Signature Agreeing to Take Part in the Main Study
I have been provided with an opportunity to read this consent form carefully. All of the questions 
that I wish to raise concerning this study have been answered.
By signing this consent form, I have not waived any of the legal rights or benefits, to which I 
otherwise would be entitled. My signature indicates that I freely consent to participate in this 
research study. I will receive a copy of the consent form once I have agreed to participate.
________________________________________________
Participant Name, printed
________________________________________________ 
________________
Participant Signature 
Date
________________________________________________
Name of Person Conducting Informed Consent Discussion
________________________________________________ 
________________
Signature of Person Conducting Informed Consent
Date
Discussion
________________________________________________ 
________________
Investigator Signature (if different from above) 
Date 
Approved by the VCU IRB on 4/1/2020