Clinical trial NCT01700959
Conditions: Cancer Malignancies
Keywords: Melatonin Neurocognitive impairment Sleep disturbance Childhood cancer survivors
Sponsor: St. Jude Children's Research Hospital
Start date: 2013-02-06; Completion date: 2017-04-19
Enrollment: 911 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary objective:

1. To examine the efficacy of melatonin treatment on neurocognitive functioning in adult survivors of childhood cancer.

Secondary objectives:

1. To evaluate the efficacy of melatonin treatment on delayed sleep onset latency in long-term childhood cancer survivors.
2. To investigate whether improvement in sleep onset latency due to melatonin treatment is associated with neurocognitive improvement in long-term childhood cancer survivors.

This study is a randomized double-blind placebo controlled trial of time release melatonin for adult survivors of childhood cancer who demonstrate impaired neurocognitive functioning and/or difficulty falling asleep.

Detailed description:
All participants undergo a general neurocognitive evaluation at baseline and 6-month follow-up, focused on assessment of intelligence, academic skills, attention, processing speed, memory and executive functions.

Sleep parameters using self-report and actigraphy will be assessed at three time points during the study: Baseline, 3-months, and 6-months.

Participants will be divided into 3 mutually exclusive groups:

* Cohort 1: Participant has neurocognitive impairment defined as performance on at least one measure of attention, memory, and/or executive functioning at or below the 10th percentile, AND is absent of delayed sleep onset latency defined as an inability to fall asleep within 30 minutes less than once a week during the past month.
* Cohort 2: Participant has neurocognitive impairment defined as performance on at least one measure of attention, memory, and/or executive functioning at or below the 10th percentile, AND has delayed sleep onset latency defined as self-report of an inability to fall asleep within 30 minutes at least once a week during the past month.
* Cohort 3: Participant is absent of neurocognitive impairment defined as performance \>10th percentile on all six measures of attention, memory, and executive functioning, AND has delayed sleep onset latency defined as self-report of an inability to fall asleep within 30 minutes \> once a week during the past month.

Within each group, participants will be randomly assigned to take either 3 mgs of time release melatonin or placebo 1-2 hours before bedtime each night for 6 months.

Psychosocial measures of health-related quality of life and psychological distress will be completed at baseline and following 6 months of melatonin/placebo treatment.

Biological samples for serum melatonin levels will be collected at baseline and at the 6 month follow-up evaluation.

Arms: arm 1: Participants receive 3 mgs of time-release melatonin 1-2 hours prior to bedtime. arm 2: Participants receive a placebo identical to the time-release melatonin and are instructed to take it 1-2 hours prior to bedtime.
Interventions: intervention 1: melatonin intervention 2: placebo
Intervention descriptions: intervention 1: Melatonin 3mg time release will be given. Participants will be instructed to take one 3mg time released tablet by mouth approximately 1-2 hours before initiating sleep onset, preferably at the same time each night. intervention 2: Placebo tablets to match the melatonin will be comprised of inert substances.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Revision 4.3, dated: 09-20-16 
 
 
 
  IRB Approval date: 10-11-16 
Protocol document date: 09-20-16 
 
NCT01700959 - MIND 
St. Jude 
MIND 
Initial version, dated:  May 23, 2012 (resubmitted to CT-SCR 08-06-2012), (IRB Approved: 09-
27-12) 
Activation Date: 
Amendment 1.0, dated: October 22, 2012 (IRB Approved: 12-20-12) 
Activation Date: January 24, 2013 
Amendment 2.0, dated: March 1, 2013 (IRB Approved: 05-28-13)     
Activation Date: June 4, 2013 
Revision 2.1, dated: September 9, 2013 (IRB Approved: 10-29-13) 
Amendment 3.0, dated: June 16, 2014 (IRB Approved: 09-18-14) 
Activation Date: September 18, 2014 
Amendment 4.0, dated: January 26, 2015 (IRB Approved: 03-10-15) 
Activation Date: March 11, 2015 
Revision 4.1, dated: October 27, 2015 (IRB Approved: 12-2-15) 
Revision 4.2, dated: March 16, 2016 (IRB Approved: 03-29-16) 
Revision 4.3, dated: September 20, 2016 (IRB Approved:10-11-16) 
Activation date: October 17, 2016 
 
 
 
 
MELATONIN INTERVENTION FOR NEUROCOGNITIVE DEFICITS IN THE  
 
ST. JUDE LIFETIME COHORT 
 
 
 
 
 
 
Principal Investigator 
Tara Brinkman, PhD 
Epidemiology and Cancer Control 
 
 
 
 
 
 
 
 
 
St. Jude Children's Research Hospital 
 
262 Danny Thomas Place 
 
Memphis, Tennessee  38105-3678 
 
Telephone:  (901) 595-3300 


 
 
Revision 4.3, dated: 09-20-16 
 
 
 
  IRB Approval date: 10-11-16 
Protocol document date: 09-20-16 
 
 
Protocol Summary 
 
Protocol MNEMONIC and Title: MIND - Melatonin Intervention for Neurocognitive 
Deficits in the St. Jude Lifetime Cohort 
Principal Investigator: Tara Brinkman, Ph.D. 
IND Holder: N/A 
Brief Overview: This study is a randomized double-blind placebo controlled trial of 
time release melatonin for adult survivors of childhood cancer who demonstrate 
impaired neurocognitive functioning and/or delayed sleep onset latency. The sample 
will be stratified to generate three mutually exclusive cohorts. Cohort 1: 
neurocognitive impairment without delayed sleep onset latency; Cohort 2: 
neurocognitive impairment with delayed sleep onset latency; Cohort 3: delayed sleep 
onset without neurocognitive impairment. Within each group, participants will be 
randomly allocated to either melatonin or placebo for a 6-month trial. Participants will 
take 3mg of time release melatonin or placebo orally each night prior to initiating sleep 
onset. Baseline and follow-up evaluations will be completed to determine the effects 
of melatonin on specific neurocognitive processes and sleep parameters. 
Intervention: Survivors who previously underwent neurocognitive evaluation as part 
of the SJLIFE study, as well as survivors who are eligible for future neurocognitive 
evaluation through SJLIFE will be recruited. Initial eligibility will be determined via 
review of previous neurocognitive assessment data and telephone screening. Interested 
survivors meeting the pre-screen criteria will complete standardized sleep measures at 
their baseline visit. Baseline neurocognitive assessments will occur as part of the 
SJLIFE study.  Neurocognitive assessments will be administered again at 6 months. 
Subjective and objective sleep measures including actigraphy will be assessed at 
baseline, 3 months, and 6 months. Correlative psychosocial measures of health-related 
quality of life and psychological distress will be completed at baseline as part of the 
SJLIFE study and following 6 months on treatment. Serum melatonin will be collected 
at baseline and 6 month follow-up.   
Brief Outline of Treatment Plan: Participants will take a fixed 3 mg oral dose of time 
release melatonin or placebo once per day 1-2 hours before initiating sleep onset for a 
6 month period. Participants will be called biweekly throughout the intervention to 
monitor treatment adherence, side effects, and adverse events. 


 
Revision 4.3, dated: 09-20-16 
 
 
 
  IRB Approval date: 10-11-16 
Protocol document date: 09-20-16 
 
Protocol MNEMONIC and Title: MIND - Melatonin Intervention for Neurocognitive 
Deficits in the St. Jude Lifetime Cohort 
Primary Objective: 
To examine the efficacy of melatonin treatment on neurocognitive functioning in 
adult survivors of childhood cancer. 
Responsible Investigator: Tara Brinkman and Kevin Krull 
Secondary Objectives: 
To evaluate the efficacy of melatonin treatment on delayed sleep onset latency in 
long-term childhood cancer survivors. 
To investigate whether improvement in sleep onset latency due to melatonin 
treatment is associated with neurocognitive improvement in long-term childhood cancer 
survivors. 
Responsible Investigators: Belinda Mandrell and Tara Brinkman  
Exploratory Objective: 
To explore the association between endogenous melatonin levels and improvement in 
sleep onset latency. 
To explore the association between sleep quality and health-related quality of life and 
distress.  
Responsible Investigators: Kevin Krull and Tara Brinkman  
Estimated date for completion of data collection: December 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Revision 4.3, dated: 09-20-16 
 
 
 
  IRB Approval date: 10-11-16 
Protocol document date: 09-20-16 
 
Protocol MNEMONIC and Title: MIND - Melatonin Intervention for Neurocognitive 
Deficits in the St. Jude Lifetime Cohort 
Hypotheses/Estimates:  
 Hypothesis 1: Long-term survivors of childhood cancer with documented 
baseline neurocognitive deficits (Cohorts 1 and 2) in attention, memory, and/or 
executive functioning, randomized to the melatonin treatment arm, will 
demonstrate improved neurocognitive performance following six months of 
treatment compared to those randomized to placebo. 
 
 Hypothesis 2: Long-term survivors of childhood cancer with delayed sleep 
onset latency at baseline (Cohorts 2 and 3), randomized to the melatonin 
treatment arm, will demonstrate improved sleep onset latency following 6 
months of treatment compared to the placebo groups. 
 
 Hypothesis 3: Improvement in sleep onset latency with melatonin treatment 
will result in improved neurocognitive performance in long-term childhood 
cancer survivors who have both comorbid sleep onset latency and 
neurocognitive deficits at baseline (Cohort 2). 
 
 Exploratory Hypothesis 1: Improvement in sleep onset latency following 
melatonin treatment will be independent of baseline endogenous melatonin 
levels. 
 
 Exploratory Hypothesis 2: Improved sleep quality will be associated with 
decreased psychological distress and enhanced quality of life. 
 
 
 
 
 
 
Criteria for Evaluation:  
Three domains of neurocognition will be examined as primary study outcomes 1) 
attention, 2) memory, and 3) executive functioning.  Sleep parameters to be assessed 
include objective and subjective measures.  Correlative psychosocial measures of health-
related quality of life and psychological distress will be evaluated. Treatment adherence 
and side effects will be monitored. 
Study Design: Prospective randomized, double-blind, placebo-controlled study 


 
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Protocol MNEMONIC and Title: MIND - Melatonin Intervention for Neurocognitive 
Deficits in the St. Jude Lifetime Cohort 
Study Population: 
Inclusion Criteria: 
1) Previously treated at SJCRH and a participant in St Jude Life.  
2) Is 10 or more years from diagnosis 
3) FSIQ score > 79 
4) > 18 years of age 
5) Able to speak and understand the English language 
6) Cohort 1 participant: 
a. Has neurocognitive impairment defined as performance on at least one measure 
of attention, memory, and/or executive functioning < 10th percentile. 
b. Is absent of delayed sleep onset latency defined as an inability to fall asleep 
within 30 minutes < once a week during the past month. 
Cohort 2 participant: 
a. Has neurocognitive impairment defined as performance on at least one measure 
of attention, memory, and/or executive functioning < 10th percentile. 
b. Has delayed sleep onset latency defined as self-report of an inability to fall 
asleep within 30 minutes > once a week during the past month. 
Cohort 3 participant: 
a. Is absent of neurocognitive impairment defined as performance >10th percentile 
on all six measures of attention, memory, and executive functioning. 
b. Has delayed sleep onset latency defined as self-report of an inability to fall 
asleep within 30 minutes > once a week during the past month. 
 
Study Population: 
Exclusion Criteria: 
1) Known allergy to melatonin or any ingredients of the study product or placebo 
2)  Currently taking Melatonin 
3)  Known sleep apnea 
4)  Known medically treated sleep disorder (e.g. restless leg syndrome) 
5)  Known diabetes mellitus – insulin treated 
6)  Uncontrolled seizure disorder in the past 12 months 
7)  Reported current illicit drug or alcohol abuse or dependence 
8)  Reported current major psychiatric illness (i.e. schizophrenia, bipolar disorder) 
9)  Current treatment with:  
a. Benzodiazepines or other CNS depressants 
b. Fluvoxamine 
c. Anticoagulants (e.g. Coumadin) 
d. Immunosuppressant or corticosteroids 
e. Nifedipine 
10)  Employed in a position that requires night work (i.e. 10pm to 6am) 
11)  Females who are pregnant or lactating/nursing 
12)  History of neurologic event unrelated to cancer or its treatment 
13)  Sensory impairment (vision, hearing) that prohibits completion of neurocognitive  
examination 


 
Revision 4.3, dated: 09-20-16 
 
 
 
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Protocol document date: 09-20-16 
 
Protocol MNEMONIC and Title: MIND - Melatonin Intervention for Neurocognitive 
Deficits in the St. Jude Lifetime Cohort 
Sample Size: Targeted enrollment 987 and expected evaluable 395 research participants 
 
Cohort 1 = 131 
 
Cohort 2 = 131 
 
Cohort 3 = 133 
Randomization:  
Participants in each cohort will be randomized 1:1 to receive time release melatonin 3 mg 
or placebo daily for 6 months. 
Data Analyses: 
Primary Aim: The primary aim of this study is to determine the difference between 
changes in neurocognitive functioning from baseline to the 6 month follow-up in adult 
survivors of childhood cancer who are randomized to receive melatonin compared to 
those randomized to receive placebo. We hypothesize that survivors randomized to the 
melatonin group will have a greater improvement in neurocognitive functioning than 
those randomized to the placebo group. We have identified six neurocognitive domains in 
which the marginal impairment rate is >15% in the SJLIFE cohort. Normalized Z-scores 
(M=0, SD=1) are available for each domain and survivors who score at or below the 10th 
percentile will be classified as impaired on that specific domain. The lowest test-retest 
correlation coefficient for the neurocognitive measures has been observed to be 0.60. 
Then, assuming the difference in the Z-scores to be normally distributed but assuming 
(conservatively) the variance to be 1, we need outcome data for 131 survivors between 
the melatonin and placebo arms in Cohorts 1 and Group 2 to detect an improvement of 
.66 units (in standardized scale, considered to be clinically meaningful) with 80% power 
with type I error control =0.05/6=0.0083 to adjust for multiplicity of 6 tests for each 
subscale. The analysis for Aim 1 will be completed using a two-sample t-test.  Assuming 
an attrition and loss to follow up of 25%, we plan to enroll 987 survivors (Cohort 1=328; 
Cohort 2=328; Cohort 3=331). 


 
Revision 4.3, dated: 09-20-16 
 
 
 
  IRB Approval date: 10-11-16 
Protocol document date: 09-20-16 
 
Protocol MNEMONIC and Title: MIND - Melatonin Intervention for Neurocognitive 
Deficits in the St. Jude Lifetime Cohort 
Secondary Aim 1: The primary interest of secondary aim one is to assess the efficacy of 
melatonin on delayed sleep onset latency in adult survivors of childhood cancer, which 
will be evaluated in Cohorts 2 and 3. We hypothesize that survivors randomized to the 
melatonin treatment arm will evidence a greater reduction in sleep onset latency 
compared to survivors randomized to placebo. The CCSS cohort mean and SD for sleep 
onset latency among participants with delayed sleep onset latency (i.e. SOL > 30 
minutes) is 46.2 and 27.7 minutes, respectively. The test-retest correlation for sleep onset 
latency from the PSQI has been observed to be in the range of 0.70. Following the 
justification set forth in the Primary Aim, and assuming the SD to be 27.7, we will need 
outcome data for 131 survivors in Cohort 2 and 133 in Cohort 3 between the melatonin 
and placebo arms for these Cohorts to see an improvement of 15 minutes in sleep onset 
latency with 80% power with type I error control =0.05. The analysis for Aim 2 will be 
completed using a two-sample t-test. 
Secondary Aim 2: The aim of this objective is to investigate the association between 
sleep onset latency and specific neurocognitive processes [Cohort 2]. We hypothesize 
that decreased sleep onset latency following 6 months of melatonin treatment will be 
associated with improved neurocognitive performance. We will need outcome data for 
131 survivors in Cohort 2 [66 randomized to melatonin, 65 randomized to placebo] so 
that we will have 80% power to detect a correlation of at least 0.25 between reduced 
sleep onset latency and improved neurocognitive performance with type 1 error control 
=0.05. 
Exploratory Aims: To explore the association between endogenous melatonin levels and 
improvement in sleep onset latency. To explore the association between sleep quality and 
psychological distress and health related quality of life. 
Primary Anticipated Completion Date:  December 31, 2016 
Anticipated Study Completion Date:  December 31, 2017 
Timeframe for Primary Outcome Measure:  Approximately 6 months 
Data Management: Data will be managed by the Neuropsychology Research Team and 
the Clinical and Survey Research Center in the Department of Epidemiology and Cancer 
Control and the Department of Nursing Research. Statistical analysis will be provided by 
the Biostatistics Department at St. Jude Children’s Research Hospital. 
Human Subjects:  
The risks to the subjects will be related to the side effects of melatonin which may 
include drowsiness, headache, additional sedation if taken with other sedating drugs, an 
allergic reaction, confusion, and rarely seizures, and tachycardia. Adverse events are rare, 
occurring at similar frequency to those with placebo in published research in adults with 
primary insomnia. Participants will be informed of these side effects during the informed 
consent discussion. Adverse events will be monitored and reported and treated 
accordingly. 


 
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Table of Contents 
 
Protocol Summary 
 
1.0     OBJECTIVES ..................................................................................................1 
1.1   Primary Objective....................................................................................1 
1.2   Secondary Objectives ..............................................................................1 
1.3   Exploratory Objectives ............................................................................2 
2.0     BACKGROUND AND RATIONALE ............................................................2 
2.1   Background .............................................................................................2 
2.2   Rationale ..................................................................................................4 
2.3   Preliminary Studies .................................................................................8 
3.0     RESEARCH PARTICIPANT ELIGIBILITY CRITERIA 
          AND STUDY ENROLLMENT ......................................................................9 
3.1   Inclusion Criteria .....................................................................................9 
3.2   Exclusion Criteria ....................................................................................10 
3.3   Research Participant Recruitment ...........................................................11 
3.4   Procedures for Identifying Research Participants ...................................13 
3.5   Enrollment on Study ................................................................................13 
3.6   Procedures for Randomizing Research Participants ...............................13 
4.0     STUDY PROCEDURES .................................................................................15 
4.1   Neurocognitive Functioning Measures ...................................................15 
4.2   Sleep Measures ........................................................................................17 
4.3   Correlative Psychosocial Measures .........................................................19 
4.4   Serum Melatonin .....................................................................................19 
4.5   Intervention .............................................................................................20 
4.6   Dose Modifications .................................................................................23 
4.7   Concomitant Therapy ..............................................................................23 
5.0     DRUG INFORMATION .................................................................................24 
6.0     REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS ................25 
6.1   Pre-Screening Evaluations for Eligibility................................................25 
6.2   Evaluations during Therapy ....................................................................26 
6.3   End of Study Evaluations ........................................................................27 
6.4   Long-Term Follow-up Evaluations .........................................................28 
7.0     EVALUATION CRITERIA ............................................................................28 
7.1   Response Criteria ....................................................................................28 
7.2   Toxicity Evaluation Criteria  ...................................................................28 
7.3   Acceptable Percentage of Missed Doses for Research and  
Standard of Care Drugs............................................................................29 
8.0     OFF THERAPY AND OFF STUDY CRITERIA ...........................................29 
8.1  Off Study Criteria .....................................................................................29 
9.0    SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS .........29 
9.1   Reporting Serious Adverse Experiences and Death ................................29 
9.2   Recording Adverse Events and Serious Adverse Events ........................30 
10.0    DATA COLLECTION, STUDY MONITORING,  
 
AND CONFIDENTIALITY ...........................................................................30 
10.1  Data Collection .......................................................................................30 
10.2  Study Monitoring....................................................................................31 
10.3  Confidentiality ........................................................................................32 


 
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11.0    STATISTICAL CONSIDERATIONS............................................................32 
11.1  Anticipated Completion Dates ...............................................................35 
11.2  Summary of Primary and Secondary Objectives ....................................36 
12.0    OBTAINING INFORMED CONSENT .........................................................37 
13.0    REFERENCES ...............................................................................................38 
 
Appendices 
Appendix I:  Schedule of Evaluations 
Appendix II:  Research Tests 
Appendix III:  Sleep Measures 
Appendix IV:  Neurocognitive Functioning Measures 
Appendix V:  Correlative Psychosocial Measures 
 


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1.0 
OBJECTIVES 
 
Over 80% of children diagnosed with a pediatric malignancy become long-term 
survivors. Many of these survivors received neurotoxic cancer treatments that may 
interfere with the development of specific neurocognitive abilities, deficits that are lasting 
and appear to be progressive over time. Furthermore, survivors are at increased risk for 
sleep problems and fatigue that may exacerbate neurocognitive impairment.  Few 
interventions have been offered to remediate neurocognitive deficits in adult survivors of 
childhood cancer and even less attention has been directed at improving sleep difficulties. 
Melatonin is an endogenously produced hormone with known sleep-promoting effects 
and recent evidence demonstrates that melatonin can improve neurocognitive functioning 
in adults at-risk for cognitive decline. As such, treatment with exogenous melatonin may 
provide an ideal method by which to intervene on these two distinct, yet interrelated late 
effects of childhood cancer, neurocognitive and sleep dysfunction. 
 
This application proposes a randomized double-blind placebo controlled trial of time 
release melatonin for long-term adult survivors of childhood cancer who demonstrate 
impaired neurocognitive functioning and/or delayed sleep onset latency. The sample will 
be stratified to generate three mutually exclusive groups [Cohort 1: neurocognitive 
impairment without delayed sleep onset latency; Cohort 2: neurocognitive impairment 
with delayed sleep onset latency; Cohort 3: delayed sleep onset without neurocognitive 
impairment]. Within each cohort, participants will be randomly allocated to either 
melatonin or placebo treatment for a 6 month trial. Baseline and follow-up evaluations 
will be completed to determine the efficacy of melatonin treatment on specific 
neurocognitive processes and sleep parameters. 
 
1.1 
Primary Objective 
 
1.1.1 To examine the efficacy of melatonin treatment on neurocognitive 
 
functioning in adult survivors of childhood cancer. 
 
 
 
Hypothesis 1 
 
Long-term survivors of childhood cancer with documented 
baseline neurocognitive deficits (Cohorts 1 and 2) in attention, 
memory, and/or executive functioning, randomized to the 
melatonin 
treatment 
arm, 
will 
demonstrate 
improved 
neurocognitive performance following six months of treatment 
compared to those randomized to placebo. 
 
1.2 
Secondary Objectives 
 
 
1.2.1 
To evaluate the efficacy of melatonin treatment on delayed sleep 
 
onset latency in long-term childhood cancer survivors. 
 
 
 
 
Hypothesis 2 
 


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Long-term survivors of childhood cancer with delayed sleep onset 
latency at baseline (Cohorts 2 and 3), randomized to the melatonin 
treatment arm, will demonstrate improved sleep onset latency 
following six (6) months of treatment compared to the placebo 
groups. 
 
1.2.2 To investigate whether improvement in sleep onset latency due to 
melatonin 
treatment 
is 
associated 
with 
neurocognitive 
improvement in long-term childhood cancer survivors.  
 
 
 
 
 
Hypothesis 3  
 
 
 
 
Improvement in sleep onset latency with melatonin treatment will 
result in improved neurocognitive performance in long-term 
childhood cancer survivors who have both comorbid delayed sleep 
onset latency and neurocognitive deficits at baseline (Cohort 2). 
 
1.3 
Exploratory Objectives 
 
 
1.3.1 To explore the association between endogenous melatonin levels 
and improvement in sleep onset latency. 
 
Exploratory Hypothesis 1 
 
Improvement in sleep onset latency following melatonin treatment 
will be independent of baseline endogenous melatonin levels.  
 
1.3.2 To explore the association between sleep quality and health-related 
 
quality of life and psychological distress. 
 
Exploratory Hypothesis 2 
 
Improved sleep quality will be associated with decreased 
psychological distress and enhanced quality of life. 
 
 
2.0  
BACKGROUND AND RATIONALE 
 
 
2.1 
Background 
 
Neurocognitive impairment is one of the most common late effects 
experienced by long-term survivors of childhood cancer. Prevalence 
estimates indicate that 20% to 80% of long-term survivors experience 
neurocognitive dysfunction, varying due to sample characteristics, 
cognitive processes studied, measures employed, and definition of 
impairment utilized.1-4 Treatment with cranial radiation therapy is a well-
established risk factor for neurocognitive late effects,1,5 although 


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antimetabolite chemotherapy (i.e. methotrexate) and corticosteroids also 
have been implicated.6-8 Neurocognitive impairment demonstrated by 
survivors includes deficits in attention,9,10 memory,5,10 processing speed,11 
and executive function.12 These deficits often increase with time after 
treatment exposure5 and have the potential to impact multiple areas of 
adult functioning including educational attainment,2 employment,2 health 
behaviors,13 quality of life14 and social functioning.2,15 Given the potential 
pervasive impact of neurocognitive impairment on daily life, interventions 
directed at mitigating neurocognitive dysfunction are imperative. 
 
Survivors of childhood cancer are also frequently reported to experience 
fatigue and sleep disturbance. For example, survivors of childhood 
leukemia report significant fatigue many years after completion of 
treatment,16,17 and survivors of Hodgkin lymphoma (HL) report more 
fatigue than their siblings and population-based controls.18-20 Sleep 
disturbance and fatigue are also found to disrupt neurocognitive function, 
specifically in the domains of processing speed, attention and memory.21,22 
Among adults diagnosed with chronic fatigue, slowed processing speed, 
impaired working memory, and poor memory and learning of new 
information has been reported.23,24 The presence of significant fatigue has 
been associated with poor neuropsychological functioning in adults with 
acute medical conditions.25-28 Importantly, differential sensitivity of poor 
sleep quality and fatigue on neurocognitive functions within cohorts at risk 
for neurologic impairment may exist. Sleep is essential for neural recovery 
following brain injury29 and sleep deprivation among individuals with 
traumatic brain injury exacerbates the degree of neurocognitive 
impairment.30 Thus, the impact of fatigue and sleep loss on neurocognitive 
performance may be more salient in survivors who are at risk for brain 
injury following neurotoxic cancer therapy (i.e. cranial radiation, 
antimetabolite chemotherapy). 
 
Little is known of the association between sleep problems and 
neurocognitive outcomes among survivors of childhood cancer. A recent 
report from the Childhood Cancer Survivor Study indicated that 49.5% of 
all survivors demonstrated significant problems with fatigue, vitality, 
daytime sleepiness, or sleep quality.31 Poor sleep quality and fatigue were 
independently associated with a 3 to 4 fold increased prevalence of 
impaired attention and processing speed, as well as problems with 
working memory and memory retrieval. These findings suggest that 
neurocognitive functions in adult survivors of childhood cancer are 
particularly vulnerable to the effects of fatigue and sleep problems. 
  
While significant effort has been directed at characterizing neurocognitive 
impairment in long-term survivors of childhood cancer, limited research 
has focused on interventions to ameliorate these well-established late 
effects. In fact, few systematic efforts have targeted remediation of 
neurocognitive deficits following cancer treatment, and such endeavors 
have been restricted to children and adolescents fewer than 10 years from 


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their initial diagnosis. Nonpharmacological interventions, such as 
cognitive training/remediation programs have yielded small, short-term 
improvements on select neurocognitive processes; however, such 
programs are extremely time-intensive, costly, and suffer from high 
dropout rates. Additionally, there are no published reports of interventions 
for sleep or fatigue problems in adult survivors of childhood cancer, 
despite the documented adverse effects of such problems on 
neurocognitive processes and other functional outcomes. There is a clear 
need to test interventions with the potential to impact the interrelated 
processes of neurocognitive functioning and sleep, and for approaches that 
are feasible, of low burden to the participant and have a strong potential 
for efficacy.  
 
This study proposes a highly disseminable intervention for  improving 
neurocognitive function and sleep difficulties in adult survivors of 
childhood cancer. Melatonin (N-acetyl-5-methoxytryptamine) is the 
primary hormone released nocturnally by the pineal gland with 
demonstrated safety and efficacy in animal models and clinical trials. Its 
powerful anti-oxidant and anti-inflammatory properties have been 
implicated in enhanced neurocognitive functions and melatonin has well 
known effects on sleep. Melatonin has not yet been studied in adult 
survivors of childhood cancer. Investigating the effectiveness of melatonin 
is important as it will provide a safe, non-intensive intervention approach 
with the strong potential to improve neurocognitive and sleep dysfunction 
in an at-risk population. 
2.2 
Rationale 
 
Research on childhood cancer survivors has reached a critical juncture 
where a shift from characterization of late effects to remediation of these 
deficits is necessary. Toward this aim, this study proposes the novel use of 
melatonin to intervene on two distinct, yet highly interrelated late effects 
of childhood cancer. This extends the traditional conceptualization of 
melatonin as a hormone that promotes sleep onset to one with the additive 
benefit of enhancing neurocognition. 
 
2.2.1 Melatonin and neurocognition: Cognitive dysfunction is one of 
the most common late effects following treatment with CNS directed 
therapies for childhood cancer. While the pathogenesis of radiation-
induced cognitive decline is not well understood, recent evidence suggests 
that disruption of hippocampal neurogenesis may be involved.32 
Additionally, oxidative stress has been identified as a potential biological 
mechanism for CNS injury and predictor of neurocognitive dysfunction in 
survivors of childhood leukemia.33,34 Importantly, Manda et al35 reported 
that treatment with melatonin protected against cranial irradiation induced 
inhibition of hippocampal neurogenesis by reducing oxidative stress in 
mice. Specifically, melatonin was found to reduce neuronal damage by 
scavenging free radicals and activating antioxidative enzymes36 and 


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mounting evidence from animal models indicates that melatonin enhances 
neurocognitive function through its strong anti-inflammatory and anti-
oxidant properties. Taken together, these lines of research provide a 
framework for understanding the potential mechanisms by which 
melatonin may address the delayed neurocognitive effects of cranial 
radiation therapy in childhood cancer survivors.  
 
Patterns of neurocognitive impairment in adult survivors of childhood 
cancer may reflect premature aging,37 thus normal aging may provide a 
model for understanding the potential effects of melatonin on cognition. 
As endogenous melatonin production decreases with age, it is suggested 
that antioxidant defenses are reduced, leading to neuronal death and the 
behavioral correlates of aging (i.e., memory decline).38  Although clinical 
trials in humans have begun to explore this hypothesis, much of the 
supporting evidence is founded in animal research. For example, Esteban 
and colleagues38 determined that aged rats chronically treated with 
melatonin performed better on working memory and motor coordination 
tasks compared to untreated aged rats. This functional improvement was 
attributed to the direct impact of melatonin on the synthesis and uptake of 
serotonin, dopamine and norepinephrine, neurotransmitters implicated in a 
myriad of cognitive functions. 
 
Given the association of decreasing melatonin secretion with aging, 
increasing melatonin levels through exogenous administration has been 
identified as a possible preventative treatment for the cognitive decline 
seen in advanced aging, as well as Alzheimer’s disease (AD) and other 
disorders associated with progressive cognitive impairment.39 Importantly, 
children who experience traumatic brain injury are at increased risk for 
early onset of dementia.40,41 One possible mechanism is the over-
expression of amyloid precursor protein which may result in the formation 
of neuritic plaques, a pathognomonic finding of AD.40 Similar to traumatic 
brain injury, children who received neurotoxic cancer treatments have 
sustained diffuse CNS injury, and therefore may be vulnerable to similar 
cognitive decline and dementia. 
 
Animal models of several diseases lend further support to the 
neuroprotective characteristic of melatonin, especially in age related 
neurodegenerative disorders where oxidative burden is a major culprit. 
Familial AD is a specific animal model that has been used to elucidate the 
antioxidant properties of melatonin and its impact on functional outcomes. 
The AD animal model is particularly important as melatonin levels 
measured in cerebrospinal fluid have been found to be reduced in pre-
clinical AD human cohorts. This implicates low melatonin levels as a 
potential risk factor for AD and supports the relationship between 
melatonin and cognition. Olcese and colleagues42 reported that chronic 
melatonin treatment protected AD mice from expected cognitive decline. 
In fact, AD mice treated with melatonin were cognitively indistinguishable 
from normal mice. The protection against cognitive decline was attributed 


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to three mechanisms including: 1) reduced presence of human protein B-
amyloid in the brain, 2) decreased inflammatory cytokines within the 
brain, and 3) reduced oxidative stress within the brain. 
 
Beneficial effects of exogenous melatonin on neurocognition have also 
been reported in open-label studies of human adults with and without 
neurodegenerative disease. Specifically, melatonin has been proposed as a 
potential therapeutic agent for mild cognitive impairment (MCI).43 In 
patients with MCI, treatment with 3-9mg of melatonin for 9-24 months 
was associated with improved performance on measures of attention, 
verbal learning, executive functioning, and mental status.43,44 Similarly, 
6mg of melatonin treatment over 10 days was associated with improved 
verbal memory in elderly patients with MCI.39 Melatonin treatment also 
has been reported to attenuate progression of cognitive decline in AD.45 
Cognitive enhancement has been reported in healthy older adults as 
melatonin treatment has been associated with improved verbal recall 
following interference.46 While these studies provide important 
preliminary data on the potential benefit of melatonin on specific 
neurocognitive processes, there is a need for larger, randomized controlled 
trials. Furthermore, while growing evidence indicates that melatonin may 
enhance aspects of cognitive function in elderly and early dementia 
patients, additional studies are needed to examine the potential impact of 
melatonin on cognition in other populations who may be at risk for 
cognitive impairment. Childhood cancer survivors who received 
neurotoxic treatments are at heightened risk for long-term cognitive 
dysfunction and thus comprise a population for whom interventions 
targeted toward ameliorating cognitive deficits is warranted. 
 
2.2.2 Melatonin and sleep: Melatonin also has demonstrated efficacy in 
stimulating sleep onset in animals and humans. Nonhuman primates are 
considered an ideal model, as the suprachiasmatic nucleus (SCN) exerts 
similar regulatory properties on the circadian system in humans and 
monkeys.47 Zhdanova et al48 evaluated the effects of melatonin on several 
sleep properties in three macaque species using actigraphy. Across 
species, melatonin significantly reduced sleep onset latency, resulting in 
extended total sleep time.48 Sleep offset time was not altered, suggesting 
that although melatonin promoted sleep, it did not cause a circadian phase 
shift.47 Such findings provide additional evidence of the sleep promoting 
effect of melatonin and support the use of sleep onset latency as an 
outcome variable.  
 
Exogenous melatonin also has been demonstrated to promote sleep onset 
latency in healthy adult humans,49 as well as adults with insomnia 
combined with dementia,50 and mild cognitive impairment.43 A meta-
analysis on the efficacy of exogenous melatonin for primary insomnia 
reported reduced sleep onset latency of -7.2 minutes (95% CI -12.0 to -
2.4).51 Efficacy has further been demonstrated in individuals with 
intellectual disabilities and autism spectrum disorder.52 Recent meta-


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analyses of the effects of exogenous melatonin on sleep parameters 
reported decreased sleep latency of 23 and 34 minutes in individuals with 
delayed sleep phase disorder53 and intellectual disabilities,54 respectively. 
In a large randomized double blind placebo controlled trial, Wade and 
colleagues demonstrated significantly reduced sleep onset latency in adults 
18-80 years of age over a six month trial, with a treatment effect of -6.8 
minutes (95% CI -10.9 to -2.6).55 Furthermore, their data demonstrated 
that treatment efficacy was independent of endogenous melatonin levels 
with no signs of tolerance or reduction in benefit during the 6-month 
treatment period. 
 
2.2.3 A safe intervention: Importantly, animal and human studies have 
shown melatonin toxicity to be remarkably low with no serious negative 
side effects even at high doses. In a randomized, double-blind placebo 
controlled trial, Seabra et al56 investigated the toxicology of 10mg of 
melatonin administered to healthy adults for 28 days. The most common 
side effects included somnolence and headache, with intensity of 
symptoms most often reported as light or moderate. No difference in 
frequency or intensity of side effects was observed between melatonin and 
placebo. Similarly, in the largest double-blind randomized placebo 
controlled trial of sustained release melatonin, Wade et al55 reported no 
difference in the type or frequency of adverse events  between melatonin 
and placebo treatment groups during a 6 month trial with sample size of 
722. Twelve percent of patients treated with 2mg of sustained release 
melatonin reported a drug related adverse event compared to 17% of 
patients treated with placebo.55 Two recent meta-analyses of melatonin 
treatment reported the most common adverse events were headache, 
dizziness, nausea, and drowsiness, with no significant difference between 
melatonin and placebo.51,57 The safety and efficacy of 4 to 6mg of 
sustained release melatonin over a treatment period of 6 to 72 months was 
demonstrated in children with neurodevelopmental disorders.58 
 
Most recently, Lemoine et al59 reported results from a 6-12 month open-
label study of the efficacy, safety, and withdrawal of 2mg prolonged 
release melatonin in 244 adults, ages 20-80, who previously participated in 
a double-blind placebo-controlled trial (i.e. Wade et al55). The efficacy of 
prolonged release melatonin was maintained during the open-label period 
and no differences were reported in safety parameters between patients 
who were treated for 6 compared to 12 months. Additionally, few rebound 
and withdrawal symptoms were reported following discontinuation of 
melatonin treatment. 
 
2.2.4 Novel contributions of the current proposal: There are nearly 
300,000 survivors of childhood cancer in the United States, many of 
whom received neurotoxic treatment that interfered with the development 
of neurocognitive abilities. Moreover, these treatment effects appear to be 
progressive over time, thus increasing risk for early cognitive decline 
among adult survivors of childhood cancer. Neurocognitive difficulties 


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appear to be exacerbated in the context of poor sleep and fatigue, with 
increased vulnerability observed in childhood cancer survivors. There are 
few interventions for neurocognitive deficits and those available are 
limited by problems of feasibility (i.e. high dropout rates, limited 
disseminability), resource requirements (i.e. time intensive, supervision, 
cost), and questionable efficacy. This protocol is innovative as it proposes 
an intervention that is cost-effective, safe, and of low burden to the cancer 
survivor. The intervention is portable and uses a single treatment modality 
to target two distinct, highly prevalent late effects in childhood cancer 
survivors, neurocognitive and sleep dysfunction. 
 
2.3 
PRELIMINARY STUDIES 
 
Data from ongoing and completed studies by SJCRH researchers further 
elucidate the association between sleep, fatigue and neurocognitive 
impairment in adult survivors of childhood cancer. These data underscore 
the need for interventions that have the potential to ameliorate both 
neurocognitive and sleep dysfunction in adult survivors of childhood 
cancer. 
 
2.3.1 Sleep, Fatigue and Neurocognition: Research efforts led by Dr. 
Krull using the Childhood Cancer Survivor Study (CCSS) cohort provide 
strong evidence for the associations between sleep quality, fatigue and 
neurocognitive impairment. Participants included 1,426 adult survivors of 
childhood cancer who were treated before 18 years of age and survived >5 
years from their original diagnosis. Among those with fatigue, 53% 
reported impaired attention and processing speed compared to 15% of 
those without fatigue. Similarly, 40% of survivors with poor sleep quality 
had impaired attention and processing speed compared to 16% of those 
without poor sleep. Multivariable logistic regression models controlling 
for sex, age, cranial radiation therapy, psychological distress, and 
household income revealed increased risk for impaired attention and 
processing speed for survivors with reduced vitality (RR=1.75, 95% CI, 
1.33-2.30), fatigue (RR=1.34, 95% CI, 1.13-1.59), daytime sleepiness 
(RR=1.68, 95% CI, 1.55-1.83), and poor sleep quality (RR=1.23; 95% CI, 
1.01-1.49). Reduced vitality (RR=2.01, 95% CI, 1.42-2.86), daytime 
sleepiness (RR=2.05, 95% CI, 1.63-2.58), and poor sleep quality 
(RR=1.45, 95% CI, 1.19-1.76) significantly predicted impaired memory. 
Importantly, the risk for neurocognitive impairment associated with 
fatigue and sleep disturbance was roughly equivalent to that seen with 
high-dose cranial radiation. 
2.3.2 Actigraphy and Neurocognition: Drs. Mandrell and Krull 
recently completed a pilot study examining sleep parameters in relation to 
specific neurocognitive processes in 35 adult survivors of Hodgkin’s 
disease using the St. Jude Lifetime Cohort (SJLIFE) at SJCRH. 
Participants were on average 15 years old at the time of their cancer 
diagnosis (range, 5 to 18 years) and 42 years of age at the time of study 
completion (range, 34 to 55 years). Survivors completed the Epworth 


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Sleepiness Scale, Pittsburgh Sleep Quality Index and five days of 
actigraphy. Seventeen (49%) participants reported impaired daytime 
sleepiness while 21 (60%) reported poor sleep quality. Actigraphy data are 
presented in Table A.  
 
Table A:  Sleep parameters in childhood cancer survivors 
 
 
Mean 
Range 
Sleep onset latency (mins) 
44 
0-133 
Wake after sleep onset (mins) 
66 
0-168 
Sleep efficiency (%) 
82 
10-100 
Wake episodes (number) 
10 
n/a 
 
Increased daytime sleepiness was associated with reduced short-term 
memory (p=0.017), learning (p=0.017), and aspects of executive 
functioning including shifting attention (p=0.026) and emotional control 
(p=0.021). Poorer sleep quality was associated with reduced working 
memory (p=0.024) and fatigue (p=0.005). Longer sleep onset latency was 
associated with reduced long-term memory (p=0.02) and organizational 
difficulties (p=0.01). Greater number of minutes awake after sleep onset 
was associated with decreased learning (p=0.02) and reduced working 
memory (p=0.02). Lastly, total number of minutes slept and greater sleep 
efficiency were positively associated with better rates of learning new 
information (p=0.005; p=0.017, respectively). These data demonstrate the 
associations between performance-based neurocognitive measures and 
objectively measured sleep parameters. 
 
3.0  
RESEARCH PARTICIPANT ELIGIBILITY CRITERIA AND STUDY  
ENROLLMENT  
 
According to institutional and NIH policy, the study will accession 
research participants regardless of gender and ethnic background.  
Institutional experience confirms broad representation in this regard. 
 
3.1 
Inclusion Criteria 
 
3.1.1 A St Jude Life participant who was previously treated at SJCRH. 
 
3.1.2 Participant is 10 or more years from diagnosis. 
 
3.1.3. Participant is > 18 years of age. 
 
3.1.4 Participant is able to speak and understand the English language. 
 
3.1.5 Participant has a FSIQ score >79. 
 
 
3.1.6 Cohort 1 participant: 


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a. Has neurocognitive impairment defined as performance on at 
least one measure of attention, memory, and/or executive 
functioning <10th percentile. 
 
 
b. Is absent of delayed sleep onset latency defined as an inability to 
fall asleep within 30 minutes < once a week during the past month. 
 
 
Cohort 2 participant: 
 
 
a. Has neurocognitive impairment defined as performance on at 
least one measure of attention, memory, and/ or executive 
functioning <10th percentile. 
 
 
b. Has delayed sleep onset latency defined as self-report of an 
inability to fall asleep within 30 minutes > once a week during the 
past month. 
 
  
Cohort 3 participant: 
 
 
a. Is absent of neurocognitive impairment defined as performance 
>10th percentile on all six measures of attention, memory, and 
executive functioning. 
 
 
b. Has delayed sleep onset latency defined as self-report of an 
inability to fall asleep within 30 minutes > once a week during the 
past month. 
 
3.1.7  Female participant of childbearing age must not be pregnant 
(confirmed by serum or urine pregnancy test within 1 week of 
eligibility) or lactating. 
  
 
 
3.1.8 Female research participant of childbearing age and male research  
 
 
 
participant of child fathering potential must agree to use safe  
 
 
 
contraceptive methods. 
 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Participant has a known allergy to melatonin or any ingredients of 
the study product or placebo  
  
3.2.2 Participant currently is taking Melatonin 
 
3.2.2 Participant has known sleep apnea or medically treated sleep 
disorder (e.g. restless leg syndrome) 
 


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3.2.3 Participant has known diabetes mellitus – insulin treated 
 
3.2.3 Participant has uncontrolled seizure disorder in past 12 months 
 
3.2.4 Participant has current reported illicit drug or alcohol abuse or 
dependence 
 
3.2.5 Participant has current major psychiatric illness (i.e. schizophrenia, 
bipolar disorder) 
 
3.2.6 Participant is currently receiving treatment with benzodiazepines 
or other CNS depressants  
 
3.2.7 Participant is currently receiving treatment with fluvoxamine  
 
3.2.8 Participant is currently receiving treatment with anticoagulants 
(e.g. Coumadin)  
 
3.2.9 Participant is currently receiving treatment with 
immunosuppressants or corticosteroids   
 
3.2.10 Participant is currently receiving treatment with Nifedipine 
(Procardia XL®) 
 
3.2.11  Participant is employed in a position that requires night work (i.e. 
10pm to 6am) 
 
3.2.12  Female participants who are pregnant or lactating/nursing 
 
3.2.13  Participant has a history of neurologic event (i.e. traumatic brain 
injury) unrelated to cancer or its treatment 
 
3.2.14  Participant has a sensory impairment (vision, hearing) that 
prohibits completion of neurocognitive examination 
 
 
 
 
 
3.3 
Research Participant Recruitment 
 
Recruitment:  The study sample will be recruited from participants in the 
St. Jude Lifetime Cohort (SJLIFE) at SJCRH. This established survivor 
cohort includes all individuals diagnosed and treated at SJCRH during 
childhood who are now 10 or more years from diagnosis and are 18 years 
of age or older. Cohort participants receive risk-based medical follow-up 
care during their SJLIFE evaluation. Complete medical and treatment 
records for all survivors are available for review. Survivors undergo a 
neurocognitive evaluation as a part of the established SJLIFE parent 


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protocol. We will recruit survivors who previously underwent 
neurocognitive evaluation as a part of the parent protocol, as well as 
survivors who are eligible for future neurocognitive evaluation through 
SJLIFE. 
 
As of June 6, 2012, 4,287 patients treated at SJCRH are eligible for 
participation in SJLIFE and 2,809 have agreed to return to the SJCRH 
campus for a SJLIFE evaluation. We propose to recruit 342 patients from 
the available sample, 232 with documented neurocognitive impairment 
and 110 without neurocognitive impairment. Between December 2007 and 
June 2011 we completed neurocognitive evaluations for 1,183 SJLIFE 
participants. Of these, 986 have a measured IQ >79 (83%). Sixty percent 
of patients with IQ >79 had observed impairment in >1 of the six 
neurocognitive domains required for inclusion in the current study. Based 
on sleep data obtained from the Childhood Cancer Survivor Study Cohort, 
we estimate that approximately 30% of survivors will have delayed sleep 
onset latency (SOL) >30 minutes once per week or more frequently. 
Figure 1 provides a schematic representation of expected study 
participants eligible for recruitment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Flow diagram of expected study participants eligible for recruitment 
SLIFE Eligible 
N=4,287 
Agreed to Campus Visit 
N=2,809 
Expected Study Eligible 
N=2,331 
>1 Impairment 
N=1,410 
No Impairment 
N=921 
SOL < 30mins 
N=987 
SOL > 30mins 
N=423 
SOL > 30mins 
N=276 
SOL < 30mins 
N=645 
70% 
60.5% 
70% 
39.5% 
30% 
30% 
IQ < 79 (17%) 
Cohort 1 
Cohort 2 
Cohort 3 


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3.4 
Procedures for Identifying Research Participants 
 
Potentially eligible study participants will be mailed a letter to introduce 
the study and inform him or her of their potential eligibility. The letter will 
state that a study team member will be contacting them in approximately 
two weeks to discuss the study, answer questions they may have, and ask 
if they are interested in participating. A toll-free number is in place to 
receive calls from participants if they wish to call sooner to discuss the 
study or if they would like to decline participation. A study-specific pre-
screening form will be included with the mailing for their review.  This 
form will ask two questions about his or her sleep habits and questions 
relevant to the exclusion criteria in Section 3.2. 
 
Approximately two weeks after the letter has been mailed a study team 
member will contact each potentially eligible participant to discuss the 
study, answer questions, and see if they are interested in participating.  If 
interested, preliminary eligibility will be reviewed by use of the pre-
screening form. If the potential participant meets the prescreening criteria, 
he or she will be scheduled to complete a SJLIFE campus visit. Prior to 
arriving on campus, all SJLIFE participants are mailed a packet of health 
status questionnaires, including measures of health-related quality of life 
and psychological distress, to complete and return prior to their campus 
visit. Participants who do not return the measures by mail will have the 
opportunity to complete the measures during their SJLIFE campus visit. 
 
3.5 
Enrollment on Study 
 
A member of the study team will confirm potential participant eligibility 
as defined in Section 3.1-3.2, complete and sign the ‘Participant Eligibility 
Checklist’.  The study team will enter the Eligibility Checklist information 
into the Patient Protocol Manager (PPM) system. Initial eligibility will be 
reviewed, and a research participant-specific consent form will be 
generated. The complete signed Eligibility Checklist and consent/assent 
form(s) must be faxed or sent electronically to the CPDMO to complete 
the enrollment process. 
 
 
The CPDMO is staffed 7:30 am-5:00 pm CST, Monday through Friday. A 
staff member is available at (901) 413-8591 for enrollment during the 
weekend. 
 
3.6 
Procedures for Randomizing Research Participants 
 
Once participants have completed baseline neurocognitive and sleep 
evaluations, they will be stratified into three cohorts. For stratification 
purposes the following definitions will apply: 
 
1) Neurocognitive impairment will be defined as performance on at least 
one measure of attention, memory, and/or executive functioning <10th 


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percentile.  Performance will be measured using the following tests: Trail 
Making Test Part B, Digit Span Forward and Backward, Controlled Oral 
Word Association Test, California Verbal Learning Test-II (long delay 
free recall), and Conners’ Continuous Performance Test-II (variability 
index). 
 
2) Absence of neurocognitive impairment will be defined as 
performance >10th percentile on all six measures of attention, memory, 
and executive functioning. 
 
3) Delayed sleep onset latency will be defined as self-report of inability 
to fall asleep within 30 minutes > once a week during the past month. 
 
4) Absence of delayed sleep onset latency will be defined as inability to 
fall asleep within 30 minutes < once a week during the past month. 
 
Each of the cohorts is described below: 
 
Cohort 1: 
 
a.  Has neurocognitive impairment defined as performance on at least one 
measure of attention, memory, and/or executive functioning <10th 
percentile. 
b. Is absent of delayed sleep onset latency defined as an inability to fall 
asleep within 30 minutes < once a week during the past month. 
 
Cohort 2: 
 
a.  Has neurocognitive impairment defined as performance on at least one 
measure of attention, memory, and/ or executive functioning <10th 
percentile. 
b.  Has delayed sleep onset latency defined as self-report of an inability to 
fall asleep within 30 minutes > once a week during the past month. 
 
Cohort 3: 
 
a. Is absent of neurocognitive impairment defined as performance >10th 
percentile on all six measures of attention, memory, and executive 
functioning. 
 
b. Has delayed sleep onset latency defined as self-report of an inability to 
fall asleep within 30 minutes > once a week during the past month. 
 
Upon completion of baseline neurocognitive and sleep evaluations, if it is 
determined that the participant does not have neurocognitive impairment 
and no delayed sleep onset latency, he or she will not be randomized and 
will be taken off study. 
 


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            Randomization & Blinding: This is a double-blind study in which 
neither the participant nor investigator will know the treatment 
assignment.  Upon determination of cohort assignment, the participants in 
each cohort assignment will be randomized 1:1 to receive time release 
melatonin 3 mg or placebo daily for 6 months. The randomization to 
melatonin/placebo arms will be done using a program written in C++. This 
program resides in the Department of Biostatistics and has been routinely 
used for randomization since 1992. Access to the program will be 
provided to a member of the Pharmaceutical Services department for 
randomization. The system stores all required data for randomization into 
a secure Access database. Once a participant is randomized all related data 
are frozen in the database and cannot be changed. Blinding of group 
assignment will be maintained until the study is complete or in the case of 
an adverse event for which removal of the blind is necessary to allow for 
appropriate patient care. 
 
4.0 
Study Procedures 
 
4.1 
Neurocognitive Functioning Measures 
 
During their visit to SJCRH all participants in the St. Jude Lifetime Cohort  
undergo a general neurocognitive evaluation focused on assessment of 
intelligence, academic skills, attention, processing speed, memory and 
executive functions (Table B). This battery, which requires 120 minutes 
for completion, will be administered at baseline and following 6 months of 
melatonin/placebo treatment. For this study, three domains of 
neurocognition will be examined as primary study outcomes 1) attention, 
2) memory, and 3) executive functioning. Observed rates of impairment in 
each of these domains is >15% for current SJLIFE participants. 
Importantly, these neurocognitive processes constitute common areas of 
impairment in long-term childhood cancer survivors, are known to be 
vulnerable to the effects of poor sleep and fatigue, and have been shown to 
be amenable to treatment with exogenous melatonin. To control for 
practice effects, alternate tests forms will be used, as available, at the 6-
month follow-up evaluation. All test scores will be converted to Z-score 
distributions (M=0, SD=1). All neurocognitive tests will be administered 
by trained psychological examiners under the direct supervision of Dr. 
Brinkman, Dr. Krull, or Dr. Kimberg. 
 
 
 
 
 
 


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4.1.1 Attention  
 
Digit Span Forward: Digit Span Forward (DSF), from the Digit Span 
subtest on the WAIS-IV, is a measure of focused attention and short-term 
memory span. The examiner reads aloud numbers and the participant is 
required to repeat the numbers in the same order. The number of digits 
recalled in the longest span is converted to a standard score using age-
based norms. Considered a process score on the WAIS-IV DSF is found to 
have acceptable reliability and validity parameters. 
 
Conners’ Continuous Performance Test- II, Version 5- Variability: The 
Conners’ Continuous Performance Test- II, Version 5 (CPT-II), is a 
computerized attention task that assesses several components of attention. 
The Variability index is a measure of sustained attention, specifically the 
extent to which hit reaction time changes over the course of the task. The 
CPT-II is widely accepted as a measure of attention and demonstrates 
good psychometric properties. 
 
4.1.2 Memory 
 
Digit Span Backward: Digit Span Backward (DSB), from the Digit Span 
subtest on the WAIS-IV, is a measure of working memory. The examiner 
reads aloud numbers and the participant is required to repeat the numbers 
backwards. The number of digits recalled in the longest span is converted 
Table B. Neurocognitive Measures 
Variable 
Test Descriptor 
 
Neurocognitive Process 
Intelligence 
 
 
 
Wechsler Abbreviated Intelligence Scale – 
Full Scale IQ 
Global cognitive functioning 
Academics 
 
 
 
 
Woodcock – Johnson – Letter/Word 
Identification Test 
Basic reading skills 
 
Woodcock – Johnson – Calculation Test 
Basic math skills 
Attention 
 
 
 
Trail Making Test: Part A 
Focused attention 
 
Conners’ Continuous Performance Test 
Sustained attention, consistency of attention 
 
Digit Span Test – Forward Span 
Attention span 
Memory 
 
 
 
California Verbal Learning Test  
Short and long term memory for new information 
 
Visual Selective Reminding Test 
Short and long term visual memory 
Processing Speed 
 
 
 
Grooved Pegboard Dominant Hand Score 
Speed of visual-motor processing using the dominant 
hand 
 
Coding Test from the Wechsler Scale 
Speed of copying number-symbol associations 
 
Symbol Search Test from the Wechsler 
Scale 
Speed of visually scanning symbol patterns 
Executive Function  
 
 
Trail Making Test: Part B 
Cognitive Flexibility 
 
Verbal Fluency test 
Cognitive Fluency 
 
Digit Span Test – Backward Span 
Working Memory 
 
Behavior Rating Inventory of Executive 
Function 
Self-report of executive functioning problems 


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to a standard score using age-based norms. Considered a process score on 
the WAIS-IV DSB is found to have acceptable reliability and validity 
parameters. 
 
California Verbal Learning Test-Second Edition- Long Delay Free Recall: 
The California Verbal Learning Test- Second Edition (CVLT-II) is a 
measure of verbal memory during which examinees are read a list of 
words and asked to recall them across five trials.  Long Delay Free Recall 
is administered after a 20 minute delay and participants are asked to recall 
the list of words.  An alternate form of the CVLT-II has been developed to 
reduce practice effects and will be utilized in the second study visit. The 
CVLT-II is found to have acceptable psychometric properties.  
 
4.1.3 Executive Function 
 
Trails B: This is a timed task that requires a participant to shift his/her 
attention adaptively and flexibly.  Specifically, participants are asked to 
draw a line from a number to a letter in ascending order as quickly as 
possible. Considered a measure of cognitive flexibility, Trails B is found 
to have adequate psychometric properties.  
 
Controlled Oral Word Association (COWA): This is a task of verbal 
fluency. Participants are given a letter and must say as many words that 
start with that letter within 60 seconds. There are two versions of the test, 
one using the letters FAS and the other using CFL, to control for practice 
effects.  
4.2 
Sleep Measures 
 
Sleep parameters will be assessed at three time points during the study: 
Baseline, 3-months, and 6-months. The Baseline assessment will occur 
prior to initiation of the melatonin intervention. The two follow-up 
assessments will occur while participants are actively enrolled on the 
intervention trial. Each assessment will include the objective and 
subjective measures as outlined below. 
 
4.2.1 Actigraphy  
 
Sleep-pattern measures of each participant will be measured with 
Actigraphy to be worn over 5 consecutive days at three specified intervals 
[Baseline, 3 months, 6 months]. Actigraphy provides objective assessment 
of wrist movement that infers wakefulness and sleep. Functionally, the 
actigraph provides sleep-pattern measures including: sleep onset latency 
(SOL), wake after sleep onset (WASO), and total sleep time (TST). 
Movement triggering the actigraph is relatively high during wakefulness 
and decreases to near-zero values during sleep. The actigraphy will collect 
data in the zero crossing mode, where the transducer signal is compared 
with a fixed sensitivity threshold. The number of times the signal voltage 


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crosses the reference voltage is accumulated in temporary memory storage 
until the user-defined epoch length has transpired.  
[Acceleration Index—the acceleration index (AI) is calculated by the 
formula: AI=2p-1] 
Where p is the proportion of the interval required for 50% of the total 
activity in the interval to be completed.  For example, for a 1-hour 
interval, if the activity total for the interval was 1000 and 800 counts 
occurred in the first 20 minutes of the interval, p would be 20/60 or .33. 
Doubling p and subtracting 1 scales the index form -1 to +1.  Thus, 
negative values represent slowing during the interval, 0 represents uniform 
distribution of activity during the interval, and positive values represent 
acceleration during the interval. 
 
Analysis of actigraphic records reveals sleep-wake patterns that correlate 
closely with patterns obtained via polysomnographic recordings and 
behavioral observations.60-67 Furthermore, actigraphy is a reliable method 
for assessing sleep-wake patterns and monitoring of treatment response 
among insomnia patients.67 The American Academy of Sleep Medicine 
practice parameters state that actigraphy is an accurate estimate of sleep 
patterns in normal healthy adults and there is evidence to support the use 
of actigraphy to describe sleep patterns among those with insomnia and as 
a study outcome measure.68 Actigraphy is able to sensitively capture 
change in sleep-wake patterns before and after behavioral or medical 
interventions, and actigraphic data from either wrist is highly similar. 
 
4.2.2 Daily Sleep Diary 
 
The daily sleep diary is a 15 item self-report measure that assesses 
participant sleep patterns during the previous night. The items measure 
sleep parameters such as onset latency, efficiency, duration, and quality.69 
The sleep diary will be completed for five consecutive days to correspond 
with 5 days of actigraphy data collection. Sleep logs are widely employed 
in research and are more accurate than a single, global, and retrospective 
estimate of sleep parameters.70  
 
4.2.3 Pittsburgh Sleep Quality Index (PSQI) 
 
The PSQI assesses sleep quality over the previous month and is comprised 
of 19 items that are scored on a 4-point Likert scale (0 = not at all during 
the past month to 3 = three or more times a week). Seven equally weighted 
components are measured by the PSQI, including subjective sleep quality, 
sleep onset latency, sleep duration, habitual efficiency, sleep disturbance, 
and daytime dysfunction. Component scores can be evaluated individually 
or summed to provide an overall score from 0 to 21. Higher scores 
indicate poorer quality of sleep. The overall reliability coefficient 
(Cronbach alpha) is 0.83 and test-retest reliability has a Pearson 
correlation of 0.85. 
 


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4.2.4 Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-Fatigue)  
The FACIT-Fatigue is a measure of physical and functional consequences 
associated with fatigue. The 13 items comprising this measure are scored 
on a reverse 4-point Likert scale (4 = not at all to 0 = very much). Scores 
range from 0 to 52 with lower scores indicating more fatigue. The FACIT-
Fatigue has been validated in cancer patients and has good test-retest 
reliability (r=0.90) and internal consistency (alpha’s=0.93-0.95). 
 
4.2.5 Epworth Sleepiness Scale (ESS)  
The ESS measures daytime sleepiness and likelihood of falling asleep 
during routine daily situations. The ESS is comprised of 8 items which are 
scored on a 4-point Likert scale (0=would never doze to 3=high chance of 
dozing). Scores range from 0 to 24, with higher scores indicating 
increased daytime sleepiness. Cronbach alpha is 0.88 and test-retest 
correlation is r = 0.82. 
 
4.3 
Correlative Psychosocial Measures  
Psychosocial measures of health-related quality of life and psychological 
distress will be completed at baseline as part of the SJLIFE protocol and 
following 6 months of melatonin/placebo treatment. Previous studies have 
demonstrated an association between melatonin treatment and depressive 
symptoms and quality of life has been identified as an important 
functional outcome of clinical trials. 
 
4.3.1 Medical Outcomes Survey 36-Item Short Form Health Survey 
(SF-36)  
Health-related quality of life (HRQOL) will be measured with the SF-36, a 
widely used generic health profile which provides subscale scores for 8 
domains of HRQOL: general health, role physical, physical function, 
bodily pain, vitality, mental health, social function, and role emotional. 
The SF-36 provides age and sex-specific norms to generate T scores with 
a mean of 50 and standard deviation of 10. The internal consistency, 
validity, and test-retest reliability are excellent.71  
 
4.3.2  Brief Symptom Inventory-18 (BSI-18).  
Psychological distress will measured by the BSI-18.72 Sex-specific scores 
from the BSI-18 will calculated based on standardized normative values 
(M=50, SD=10) and scores falling ≥ 90th percentile will classified as 
demonstrating a clinical level of acute emotional distress. Subscales are 
provided for anxiety, depression, and somatization as well as an overall 
global severity index. This measure has previously been validated in adult 
survivors of childhood cancer. 
 
4.4 
Serum Melatonin 
 


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Biological samples will be collected at baseline and at the 6 month follow-
up evaluation. A total of 12mL of blood will be drawn from every 
participant at each time point according to standard procedures. These 
samples will be collected in combination with labs collected for routine 
clinical reasons when possible. Blood will be collected into three, 4mL red 
top tubes. Samples will be taken to the TTU Shared Resources Laboratory 
where within 30 minutes of collection, the samples will be processed 
according to Standard Operating Procedures.  The serum will be removed 
and aliquoted to 1.2 mL cryovials which hold 0.5mL of serum. The vials 
will be labeled with the participant’s assigned study number. Of note, it is 
necessary to collect 12mL of blood per participant since melatonin levels 
have not been previously established in this unique participant population. 
Therefore, it is possible that samples will need to be processed multiple 
times to accurately characterize the levels The cryovials will be stored at -
70 to -80 degrees Celsius in a freezer located in the TTU Shared 
Resources Laboratory.  Samples will be stored until they are ready for 
testing, at which point samples will be sent to an outside testing service 
via standardized shipping procedures.   
 
Serum melatonin will be analyzed via quantitative radioimmunoassay. 
Recent data indicate strong correlations between serum and plasma levels 
as well as urine and serum levels, suggesting that serum is a useful 
specimen for the quantification of melatonin levels. Daytime adult levels 
range from 3.4 to 53.9pg/mL while nighttime levels range from 7.1 to 
89.5pg/mL. Importantly, a five-fold difference in melatonin levels has 
been reported with serum collected in the morning hours compared to that 
collected in the afternoon. Therefore, all blood samples will be drawn in 
the morning.73Participants may choose to participate in the Melatonin 
blood sample at the baseline and 6 month visits as part of the consent 
process.  
 
4.5 
Intervention 
 
 
 
 
Melatonin  
To our knowledge, there are no studies reporting on the use of exogenous 
melatonin in adult survivors of childhood cancer. Studies have reported 
low nocturnal salivary74 and 24-hour plasma75 levels of endogenous 
melatonin in childhood survivors of craniopharyngioma. Increased 
daytime sleepiness was associated with decreased nocturnal melatonin 
levels in these survivors and supplementation with 6mg of exogenous 
melatonin resulted in improved daytime sleepiness.74 
 
Data are lacking on the pharmacokinetics and pharmacodynamics of 
melatonin in cancer survivors, although among adults individual variation 
is apparent. The ability to synthesize melatonin varies among individuals 
with low secretors (18 to 40pg/mL) and high secretors (54 to 75pg/mL) 
distinguished.76 Immediate release exogenous melatonin has rapid 
absorption, with peak levels occurring 20-30 minutes after administration, 


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though estimates of its half-life in serum range from 30 to 60 minutes.76 
Approximately 90% of the supplement is cleared by hepatic first-pass 
metabolism and involves oxidation by CYP1A2 and CYP2C19.77 When 
formulated with absorption retarding binders, melatonin availability 
mimics that of normal nocturnal secretion.78,79 Sustained release melatonin 
circumvents the fast clearance of the hormone and essentially mimics 
physiological patterns of endogenous secretion of the hormone. Sustained 
release products are have been demonstrated to maintain, high, near 
physiological, plasmas levels for 5 to 7 hours.80 
 
The optimal dosing of melatonin is unclear. Clinically, melatonin has two 
primary uses including soporific (3mg) which is sleep inducing and phase 
shifting which may be achieved with a lower dose (0.5mg)81 That is, lower 
doses are commonly used for shift phasing purposes while higher doses 
are found most effective in promoting sleep onset. The most common dose 
used in studies for free running sleep disorder was 3 mg and the duration 
of treatment ranged from 1 month to 6 years.82 Pharmacological doses of 
melatonin range from 0.1-10mg and doses greater than 0.5mg produce 
endogenous levels greater than those observed physiologically. At the high 
end of the dosage range melatonin levels can be thousands of times higher 
than normal. 3mg of melatonin may produce peak levels that are 10 times 
physiological concentrations.83 Attenburrow et al84 demonstrated that 1mg 
but not 0.3mg improved sleep in middle-aged adults, suggesting a 
supraphysiological threshold is necessary for sleep-promoting effects. 
 
The active melatonin product will be purchased in its marketed form from 
Natrol®, a reputable manufacturer in the United States.  For the current 
study Natrol® 3mg time release melatonin will be utilized. Additional 
ingredients included in the Natrol®  3 mg time release melatonin tablets 
includes Vitamin B6 (from pyridoxine hydrochloride), cellulose, dibasic 
calcium phosphate, hypromellose, silica,  stearic acid, magnesium stearate, 
methylcellulose and glycerin.  Melatonin is considered a nutraceutical and 
is not FDA approved for prevention, diagnosis or treatment of disease. 
 
 UPM Pharmaceuticals, Inc. will develop and manufacture placebo tablets 
matching the melatonin product to achieve similar shape, weight and color 
of the Natrol® brand melatonin tablet. UPM Pharmaceuticals will test the 
potency, content uniformity, and timed release dissolution of the 
melatonin in its marketed form. Both active melatonin and placebo will be 
shipped to St. Jude Pharmaceutical Services, and these bulk shipments will 
be repackaged into appropriate containers for dispensing to patients, with 
appropriate labeling. All study drugs will be stored and processed by 
Pharmaceutical Services at SJCRH. Both melatonin and placebo will be 
labeled in a manner that will assure blinding of the study. 
Melatonin/placebo will be dispensed in 1 bottle, containing 60 tablets. 
Medication will be sent via FedEx (2 day delivery) or other commercial 
courier at 2-month intervals. Dr. Greene (co-Investigator) has extensive 


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experience with randomized clinical drug trials and will manage the 
processing and blinded distribution of melatonin/placebo to participants.   
 
Participants will be instructed to take one 3mg tablet of time release 
melatonin or placebo each night during the 6-month trial. Consistent with 
procedures described by Wade et al55 participants will be instructed to take 
one tablet of melatonin/placebo orally, 1-2 hours before initiating sleep 
onset, preferably at the same time each night. 
 
4.5.1 Adherence  
 
  
Medication Event Monitoring Systems 
Electronic monitors are often considered the “gold standard”, with 
respect to adherence measurement.85 Medication event monitoring 
systems (MEMS), a type of electronic monitor, registers the date 
and time when a medication vial cap is opened,86 thus, providing 
real-time monitoring and documentation of medication adherence. 
Despite this, MEMS caps are a proxy for adherence measurement, 
as there is no confirmation that a participant actually takes the 
medication after opening the pill bottle. Therefore, it is 
recommended that electronic monitoring be used in conjunction 
with other adherence measures. 
  
Pill Count 
Pills counts have been widely used to assess adherence to 
medication regimens. Pill counts compare the amount of 
medication remaining in a container with the amount that would be 
left if all prescribed medication was consumed. A study staff 
member will contact each participant by telephone or electronic 
mail. He or she will be asked to self-report the number of 
melatonin/placebo pills remaining in their medication container.  
The self-reported pill counts will be obtained approximately every 
30 days while on the study. Adherence for study drug will be 
documented through the use of a telephone log. 
 
Problem Solving 
Participants who do not demonstrate at least 80% adherence to the 
prescribed intervention, as measured by monthly pill counts, will 
be contacted via telephone to participate in a problem-solving 
exercise. Dr. Kimberg will monitor participant adherence 
throughout the interventions trial and will contact participants who 
demonstrate poor adherence behaviors to problem-solve potential 
barriers to adherence, as well as identify and discuss possible 
solutions (see problem solving phone script). 
4.5.2 Side Effect Monitoring 
 
 
Side Effect Profile 


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Reports of adverse events will be monitored. The research 
participant will be contacted at the end of the first week on study 
drug then biweekly for the duration of the study.  Adverse event 
information will be collected throughout the study by participant 
reporting and direct questioning using the patient report of 
incidence of side effects (PRISE), frequency and intensity of side 
effect rating (FISER), and global rating of side effects burden 
(GRSEB). The PRISE form assesses the presence of side effects 
for a variety of biological systems. For each of the nine 
organ/function systems (gastrointestinal, nervous system, heart, 
eyes/ears, skin, genital/urinary, sleep, sexual functioning, and 
other), the participant indicates the presence of a side effect, and if 
present, the tolerability of the side effect (tolerable or distressing). 
The FISER and GRSEB assess three domains of medication side 
effect impact: frequency, intensity, and burden. Each domain is 
rated on a 7-point Likert scale (i.e. Frequency, ranging from no 
side effects to present all the time; Intensity, ranging from no side 
effects to intolerable; and Burden, ranging from no impairment to 
unable to function due to side effects). Reliability and validity have 
been reported. 
 
4.6 
Dose Modifications 
 
There will be no dose modifications for melatonin or placebo. Treatment 
will be discontinued if a participant reports an adverse event that is not 
tolerable which the investigator deems related to the study drug.  The 
participant will end treatment on the study and arrangements will be made 
for the return of unused melatonin/placebo. 
 
4.7 
Concomitant Therapy 
 
Females may take oral contraceptives. If at any time during the six months 
of study treatment with melatonin/placebo, the participant must start the 
use of any of the medications listed in the exclusion criteria for medical 
conditions not present at the time of enrollment, he/she will be taken off-
treatment.  These medications include: 1) benzodiazepines or other CNS 
depressants; 2) fluvoxamine; 3) anticoagulants 4) immuno-suppressants or 
corticosteroids and 5) Nifedipine (Procardia XL) 
 


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5.0 
DRUG INFORMATION  
 
Melatonin  
Source and Pharmacology: Melatonin (N-Acetyl-5-Methoxytryptamine) is a 
neurohormone produced in the pineal gland that is involved in the promotion of 
sleep. It is naturally released during the dark hours of the normal day-night cycle. 
It is also thought to play a role in regulating the secretion of growth hormones and 
gonadotropic hormones. Melatonin may also possess some antioxidant properties.  
Melatonin undergoes significant first-pass metabolism (up to 60%) with an oral 
dosage form, and is metabolized into two inactive metabolites: 6-
hydroxymelatonin and N-acetyl serotonin. Clearance is severely reduced in 
patients with hepatic insufficiency. Melatonin is mostly excreted in the urine as 
the inactive metabolite 6-hydroxymelatonin. Adults experience approximately a 
37% decline in melatonin production between the ages of 20 and 70 years. 
In vitro data suggests that melatonin may inhibit the CYP1A2 isoenzyme and may 
affect the disposition of CYP2C9. Use with caution in individuals taking 
medications influenced by these enzyme systems. Melatonin may interact with 
calcium channel blockers leading to an increase in blood pressure. Possible 
immune-stimulating effects of melatonin may interfere with immunosuppressant 
therapy. 
Formulation and Stability: Melatonin 3 mg time release tablets will be used. 
The tablets are to be stored at controlled room temperature and are stable 
according to manufacturer’s labeling.  
 
Supplier:   Commercially available from various manufacturers. For the current 
study Natrol® 3mg time release melatonin will be utilized.  Additional ingredients 
included in the Natrol®  3 mg time release melatonin tablets includes Vitamin B6 
(from pyridoxine hydrochloride), cellulose, dibasic calcium phosphate, 
hypromellose, silica,  stearic acid, magnesium stearate, methylcellulose and 
glycerin.  Melatonin is considered a nutraceutical and is not FDA approved for 
prevention, diagnosis or treatment of disease. 
 
Toxicity: Drug toxicities with melatonin are rare. Serious side effects have not 
been reported but long term studies have not been performed. The most common 
side effects of using melatonin are drowsiness and confusion, especially if used 
with other CNS sedating drugs. Other toxicities that have been associated with 
melatonin are headache, hypersensitivity, tachycardia, hypothermia, and increased 
seizure activity. Melatonin may reduce glucose tolerance and insulin sensitivity. 
Use with caution in individuals with a history of bleeding disorders, hemostatic 
disorders and in individuals taking anticoagulant medications (warfarin, aspirin, 
NSAIDs or antiplatelet agents) or antidiabetic agents or insulin. Avoid use in 
women who are pregnant or may become pregnant. 
 


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Dosage and Route of Administration:  Participants will be instructed to take one 
3mg time released tablet of melatonin or placebo by mouth approximately 1-2 
hours before initiating sleep onset, preferably at the same time each night. 
 
Placebo  
Placebo tablets to match the melatonin will be comprised of inert substances. 
Placebo will be developed and manufactured by UPM Pharmaceuticals, Inc. Jim 
Knight, Director of Quality Assurance at the St. Jude GMP Facility, has reviewed 
the proposed placebo development methods to assure that Good Manufacturing 
Processes are used. 
 
6.0  
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS 
 
6.1 
Pre-Screening Evaluations for Eligibility 
 
Pre-screening will occur to determine eligibility prior to scheduling 
participants for their campus visit. If the participant appears eligible based 
upon telephone screening, a SJLIFE study visit will be scheduled.  The 
remaining evaluations for study eligibility will occur prior to randomization 
on the study.  All of the evaluations have been described in detail in section 
4 above. 
 
Baseline Measures: Baseline evaluation for all participants will include a 
medical evaluation, neurocognitive assessment, and collection of biological 
samples. Because evaluations performed, as detailed in the Children’s 
Oncology Group “Long-Term Follow-Up Guidelines for Survivors of 
Childhood, Adolescent, and Young Adult Cancers,” are standard care in the 
SJLIFE clinic, no additional monetary funds will be required for the 
baseline medical or neurocognitive evaluation in the proposed study cohort. 
Medical evaluations are based on primary cancer diagnosis, age at 
diagnosis, and therapeutic interventions and are limited to screening and 
diagnostic evaluations to characterize cancer-related health complications. 
Complete treatment records, including all information from all medical 
follow-up, will be available to study investigators. Dr. Hudson is the 
Director of the SJLIFE clinic and carefully reviews and approves each 
abstracted treatment summary and medical history. The existing data give 
us the ability to carefully evaluate whether patients in our study are similar 
to or differ from nonparticipants. Table D summarizes the pre-screening 
evaluations and baseline measures. 
 
 
 
 
 


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Table D: Pre-screen and Baseline Measures 
Evaluations –  
must be obtained prior to 
randomization 
Prescreen 
Baseline Visit 
Inclusion/Exclusion criteria 
questions 
X1 
 
Sleep-related questions  
 
X 
Informed consent 
 
X 
HIPAA 
 
X 
Standardized Sleep Measures 
 
X 
Melatonin  
 
X3 
Correlative Psychosocial 
Measures 
 
X2 
PRISE (side effect 
monitoring) 
 
X 
Neurocognitive Assessment 
Measures 
 
X2 
Pregnancy Test** 
 
X2 
History and Physical Exam 
 
X2 
** The St. Jude IRB requires that a female patient of childbearing potential must have a negative 
pregnancy test as a condition of clinical research eligibility. 
1Mailed with introductory letter. 
2Completed as part of SJLIFE protocol  
3Optional 
 
6.2 
Evaluations During Therapy 
 
After completion of the campus visit, participants will complete a five (5) 
day home-based sleep assessment to include actigraphy and a daily sleep 
diary.  Participants will be contacted after the first week +7 days of taking 
the study drug and biweekly +7 days thereafter to monitor for side effects 
and adverse events. Monthly +10 days, research participants will be asked 
to conduct a pill count and report the number of pills remaining in their 
medication vial as a measure of treatment adherence. Three (3) months + 1 
week into the intervention trial, participants will complete objective and 
subjective sleep measures at home, including five days of actigraphy, a 
daily sleep diary, and standardized sleep measures. These data will allow 
for the examination of short-term effects of melatonin on sleep parameters. 
Table E summarizes the evaluations to be completed during therapy. 
 
 
 
 
 
 
 
 
 


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Table E: Evaluations During Therapy 
Evaluation 
7-10 days 
after 
baseline 
visit 
Monthly      
(+10 days) 
3 months    
(+1 week)  
6 months     
(+ 4weeks)  
 
Actigraphy 
X1 
 
X1 
X1 
 
Daily Sleep Diary 
X1 
 
X1 
X1 
 
Standardized Sleep 
Measures 
 
 
X1 
X1 
 
Side effect 
monitoring  
X2 
X2 
 
 
 
Study drug 
adherence (Pill 
Count) 
 
X3 
 
 
 
Correlative 
Psychosocial 
Measures 
 
 
 
X1 
 
Interim History and 
Visit with a Medical 
Provider 
 
 
 
X 
 
Neurocognitive 
Assessment 
Measures 
 
 
 
X 
 
Melatonin 
 
 
 
X4 
1Completed at home.  
2Initially after the first week +7 days of taking study drug, then biweekly +7 days for the duration on study. 
3Obtained every 30 days +10 for duration on study. 
4Optional 
 
 
6.3 
End of Study Evaluations 
 
An interval of approximately six (6) months will occur between completion of baseline 
and follow-up measures. Participants will be scheduled for a return visit to SJCRH within 
6 months +4 weeks to complete a follow-up evaluation. One to two weeks prior to their 
scheduled follow-up visit, participants will complete objective and subjective sleep 
measures at home, including five days of actigraphy, daily sleep diary, and standardized 
sleep measures. Participants will also complete measures of health-related quality of life 
and psychological distress prior to returning to SJCRH. During their campus visit 
participants will have a visit with a medical provider, provide an interim history, undergo 
a neurocognitive evaluation, and have biological samples collected. If a participant is 
unable to return to St. Jude to complete their 6 month visit, a standardized neurocognitive 
questionnaire, which is also administered at baseline, along with the objective and 
subjective sleep measures will be mailed to them to complete at home and return. The 
follow-up assessment will be scheduled to occur while participants are actively taking 
melatonin/placebo. However, treatment with melatonin/placebo will not be extended by 
more than two weeks.6.4 
Long-Term Follow-up Evaluations 
 
The study is approximately six (6) months in duration. No long-term 


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follow-up evaluations will be performed. 
 
7.0  
EVALUATION CRITERIA 
 
7.1 
Response Criteria 
 
Three domains of neurocognitive functioning will be evaluated as primary 
study outcomes 1) attention, 2) memory, and 3) executive functioning. 
These will be examined at the 6 month interval.  The secondary outcomes 
will be evaluated by subjective and objective sleep parameters assessed at 
the 3 month and 6 month time periods. 
 
Response in the neurocognitive functioning domains of attention, memory, 
and executive functioning will be documented as either 1) Improvement; 
2) No change; or 3) Worsened.  The same responses will be used for sleep 
onset latency.  Correlative psychosocial measures of health-related quality 
of life and psychological distress will be examined at 6 months of 
melatonin/placebo treatment.   
 
7.2 
Toxicity Evaluation Criteria 
 
Adverse events will be monitored and graded according to the Common 
Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). A 
copy of the current version of the CTCAE version 4.0 can be 
downloaded from the CTEP home page (http://ctep.info.nih.gov) or from 
the St. Jude home page. 
 
7.3 
Acceptable Percentage of Missed Doses for Research and Standard of 
Care Drugs 
 
Participant adherence to melatonin/placebo treatment will be monitored 
following the first week of therapy and monthly thereafter during the six 
month trial. Participants who reported <80% adherence will be contacted 
by telephone to problem-solve potential barriers to adherence and 
brainstorm solutions to improve adherence. A standardized problem-
solving model will be utilized for this process. The participant will select 
one solution that he/she is willing to try over the next month and this 
solution will be operationalized. Participants will not be removed from the 
study trial due to poor adherence. 
 


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8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND  
OFF-STUDY CRITERIA 
 
8.1      Off-study Criteria 
 
8.1.1 
Death 
8.1.2 
Lost to follow-up 
8.1.3 
Request of the research participant 
8.1.4 
Development of unacceptable toxicity during treatment 
8.1.5 
Discretion of the Study PI, such as the following:  
 
The researcher decides that continuing in the study would be 
harmful  
 
A treatment/medication is needed that is not allowed on this 
study 
 
New information is learned that a better treatment is available 
 
The study is not in the participant’s best interest 
 
8.1.6 
Participant develops a subsequent malignant neoplasm while on 
study  
 
8.1.7     Participant develops a serious and/or life threatening medical 
 
             condition while on study 
8.1.8 
Study evaluations are complete 
8.1.9 
Participant does not have neurocognitive impairment and no 
delayed sleep onset latency at baseline 
 
9.0 
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS 
 
9.1 
Reporting Adverse Experiences and Deaths  
 
Principal investigators are responsible for promptly reporting to the IRB 
any adverse events that are unanticipated, serious, and that may represent 
potential harm or increased risk to research participants. When an 
unanticipated death occurs, the PI should report it to the Director of the 
Office of Human Subjects’ Protection immediately, by phone: (901) 595-
4359, Cell: (901) 336-2894, fax: (901) 595-4361, or e-mail: hsp-
1@stjude.org). 
 
A reportable event entry into TRACKS should follow within 48 hours. 
Serious, unanticipated, and related or possibly related events must be 
reported within 10 working days. 
 
The principal investigator is responsible for reviewing the aggregate 
toxicity reports and reporting to the IRB if the frequency or severity of 
serious toxicities exceed those expected as defined in the protocol or based 
on clinical experience or the published literature. Any proposed changes in 
the consent form or research procedures resulting from the report are to be 
prepared by the study team and submitted with the report to the IRB for 
approval.  
 


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The following definitions apply: 
 
A serious event refers to any event in which the outcome is fatal or life-
threatening, 
results 
in 
permanent 
disability, 
causes 
inpatient 
hospitalization or prolongs existing inpatient hospitalization, or is a 
congenital anomaly, cancer, or overdose. 
 
An unanticipated adverse event refers to those not identified in their 
nature, severity, or frequency in the current risk documents (e.g., 
investigator’s brochure), or consistent with the investigational plan. 
 
The following are considered reportable: Any injuries, serious event or 
other unanticipated adverse events involving risk to participants or others 
which occur at a frequency above that considered acceptable by the 
investigators and the IRB. (FDA) As described in 4.3 above, the OHSP 
Director or designee performs the initial review of unanticipated problems 
or serious adverse event reports. Internal reports of events that are 
unanticipated, serious, and related or possibly related to study 
interventions or procedures are then forwarded to the IRB Chair or 
designee and if necessary, referred to the full IRB. Based on the frequency 
and seriousness of adverse events, the IRB Chair or Committee may deem 
it necessary to suspend or terminate a research study or studies. 
 
All anticipated Grade III or IV adverse events will be reported to the IRB 
in the continuing review report and/or summary. The DSMB will monitor 
accrual and toxicities every six months. 
 
9.2 
Recording Adverse Events and Serious Adverse Events 
 
All serious adverse events will be recorded in the source, database and/or 
case report form.  Adverse events unrelated to the trial will not be 
recorded unless they are grade III or above (CTCAEv4).  Adverse events 
that are related to the trial will be captured in the source document, 
database and/or case report form.  Adverse events related to the trial will 
be collected until the time of the participant’s six month follow-up visit. 
 
10.0 
DATA COLLECTION, STUDY MONITORING, & CONFIDENTIALITY 
 
10.1 
Data Collection  
 
Data for this study will be managed by the Neuropsychology Research 
Team and the Clinical and Survey Research Center in the Department of 
Epidemiology and Cancer Control. Data collected at baseline and follow-
up assessments will be entered by optical scanning. The optical scanning 
program has the capacity for designer specific error checks, flagged at the 
time the questionnaires are scanned. After data are scanned, they are 
processed and converted into a SAS (Cary, NC) format where a second 
error check is completed. Data from neurocognitive tests are double-


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entered into a separate secure Access database and compared for accuracy. 
Data from biological specimens will be transmitted to the survey research 
center with a secure file transport protocol, double-entered and compared 
for accuracy. All data mismatches will be reviewed by two members of 
the survey center staff and compared to the original documents (when 
applicable) for resolution. Actigraphy and MEMS cap data will be 
downloaded using software provided by the product manufacturers and 
processed with published coding algorithms.  
 
10.2 
Study Monitoring 
 
Source document verification of eligibility for all SJCRH cases will be 
performed within two weeks of completion of enrollment. This will 
include verification of appropriate documentation of consent. Monitoring 
of timeliness of serious adverse event reporting will be done as events are 
reported in TRACKS.  
 
Monitoring of this protocol is considered to be in the “moderate” risk 
category.  The Monitoring Plan is outlined in a separate document from 
this protocol, but has been submitted for review and approval by the 
Clinical Trials Scientific Review Committee and the Institutional Review 
Board (IRB). 
 
The study team will hold monthly meetings and review case histories or 
quality summaries on participants. Source document verification of 
eligibility and informed consent for 100% of St. Jude participants will be 
performed by the Eligibility Coordinators within 10 working days of 
completion of enrollment. The Clinical Research Monitor will perform 
monitoring of applicable essential regulatory documentation.  Also, 
reviewing for the timeliness of serious adverse event reporting (type, 
grade, attribution, duration, timeliness and appropriateness) for selected 
study participants semi-annually and track accrual continuously.  The 
monitor will verify those data points relating to the primary study 
objective for a certain number of study enrollees as specified in the 
Moderate Risk monitoring plan checklist for this study.  Protocol 
compliance monitoring will include participant status, safety assessments, 
eligibility, the informed consent process, participant protocol status, off-
study, and off-therapy criteria.  The Monitor will generate a formal report 
which is shared with the Principal Investigator (PI), study team and the 
Internal Monitoring Committee (IMC). 
 
The DSMB will monitor the study every 6 months. 
 
Monitoring may be conducted more frequently if deemed necessary by the 
CPDMO or the IMC.  Continuing reviews by the IRB and CT-SRC will 
occur at least annually.  In addition, SAE reports in TRACKS (Total 
Research and Knowledge System) are reviewed in a timely manner by the 
IRB/ OHSP. 


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10.3 
Confidentiality 
 
All study information will be stored in locked research files and password 
protected databases.  Any information learned from this study in which the 
subject might be identified will be confidential and disclosed only with the 
subject’s permission.  Publications will present the results in such a way as 
to make it impossible to identify individuals.  Upon agreeing to 
participate, the consent form and Health Insurance Portability and 
Accountability ACT (HIPAA) compliance form will be signed by the 
participant and the principal investigator or designee. 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
The primary focus of this study is to evaluate the efficacy of melatonin on 
neurocognitive functioning in long term survivors of childhood cancer. Currently, 
there are 2,331 survivors potentially eligible for this study and 1,410 (61% have 
been identified as expected to have least one area of neurocognitive impairment. 
Further, it is estimated that among all the eligible survivors roughly 30% will 
have delayed sleep (sleep onset latency ≥ 30 minutes). Thus, the eligible survivors 
can be classified into three distinct cohorts (I) Those who are neurocognitively 
impaired but don’t have delayed sleep 987 (II) Those who are neurocognitively 
impaired and have delayed sleep 423, i.e. 30% of 1,410, and (III) Those who 
don’t have neurocognitive impairment but have delayed sleep problems (this 
would be roughly 30% (276) of those who are not neurocognitively impaired. 
Targeted enrollment for the study is 987 survivors and expected evaluable is 395. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. Three group stratification with parallel allocation to melatonin/placebo 
 
Primary Objective:  Examine the efficacy of melatonin treatment on 
neurocognitive functioning in adult survivors of childhood cancer. 
 Hypothesis 1: Long-term survivors of childhood cancer with documented 
baseline neurocognitive deficits (Cohorts 1 and 2), in  attention, memory, 


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and/or executive functioning, randomized to the melatonin treatment arm, 
will demonstrate improved neurocognitive performance following six  
months of treatment compared to those randomized to placebo.   
 
The primary objective of this study is to demonstrate that treatment with 
melatonin will be associated with improvement in neurocognitive performance. 
This will be evaluated in Cohorts 1 and 2 independently. The study will be 
conducted by randomizing survivors to melatonin or placebo within each of the 
two Cohorts.  
 
For those who are in Cohorts 1 and 2 baseline neurocognitive evaluation along 
with other evaluations will be obtained prior to randomization to melatonin or 
placebo arm. After randomization, sleep data will be collected using actigraphy in 
week one when the survivors are in their homes. The intervention will be 
delivered for a period of six months with regular phone calls for monitoring. Then 
one week before the six month visit sleep data using actigraphy will be collected. 
The neurocognitive data will be collected at the 6 month return visit (post-
treatment). 
 
There are 10 subscales on which a survivor could be impaired and, out of 10 such 
subscales, we have identified six in which the marginal impairment rates were 
seen to be greater than 15%. There are normalized Z-scores available for each 
subscale and a survivor that falls below the 10% (≤ -1.3) is classified as impaired 
on that subscale . It is possible that a survivor could be impaired on more than one 
subscale but we will assess improvement in each subscale independently. Thus, 
we will have the Z-score corresponding to each of the subscales within at baseline 
and at follow-up visit. For simplicity, consider the first subscale. We don’t expect 
to see any change in the Z-scores for the placebo arm but we do expect to see an 
improvement in the melatonin arm. Let 
1
1m
Z
 and 
1
2m
Z
 denote the Z-scores at 
baseline and follow-up time points for the first subscale on melatonin arm and let 
1
1p
Z  and 
1
2 p
Z
 denote the Z-scores at baseline and follow-up time points for the first 
subscale in the placebo arm. Let 
1
1
1
2
1
DM
m
m
Z
Z
Z


and
1
1
1
2
1
DP
p
p
Z
Z
Z


 denote the 
difference between the two time points in the two arms. Then our interest is in 
testing the null hypothesis H0:
1
1
DM
DP
Z
Z



vs H1: 
1
1
DM
DP
Z
Z



i.e. the mean of the 
difference scores for the first subscale would be same for the two arms vs. they 
will be different. The lowest test-retest correlation coefficient for the 
neurocognitive measures has been observed to be 0.60. Then, assuming the 
difference in the Z-scores to be normally distributed but assuming 
(conservatively) the variance to be 1, we will need to randomize 131 survivors 
between the melatonin and placebo arm to detect an improvement of 0.66 units (in 
standardized scale, considered to be clinically meaningful) with 80% power with 
type I error control =0.05/6=0.0083 to adjust for multiplicity of 6 tests for each 
subscale. However, the sample size required to evaluate the secondary objective 
in cohorts 2 and 3 is 131 and 133, respectively, per cohort. Thus, we plan to enroll 
131 research participants from Cohorts 1 and 2 and 133 research participants from 
Cohort 3. 
 


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In addition to analyzing the differences for each subscale we will also analyze the 
data in an alternative manner as follows. For each subscale an improvement will 
be defined if the difference in the Z-score (follow-up time point – baseline) is 
greater than 0.6 units (≥0.6). Let us assume that the probability of observing an 
improvement in a subscale in an individual in the placebo group is about 5% and 
then the total of 6 subscales (assuming them to be independent with the same 
probability of improvement) will follow a Binomial distribution B(6, 0.05) with a 
mean of 0.3 and SD of 0.54. If we assume that the probability of improvement to 
be higher say about 12% in the melatonin group then the total score in that group 
will follow a Binomial distribution B(6, 0.12) with a mean of 0.72 and SD of 
0.80. Then, we will use two-sample Behrens-Fisher t-statistic to compare the two 
means. With a sample size of between 65 and 67 in each group we will have 
roughly 90% power to detect a difference of 0.42 units with type I error control 
α=0.05. 
 
Secondary Objective:  Evaluate the efficacy of melatonin treatment on delayed 
sleep onset latency in long-term childhood cancer survivors.  
 Hypothesis 2: Long-term survivors of childhood cancer with delayed sleep 
onset latency at baseline (Cohorts 2 and 3), randomized to the melatonin 
treatment arm, will demonstrate improved sleep onset latency following 
six months of treatment compared to the placebo groups.  
 
The primary interest of Objective 2 is to assess the efficacy of melatonin on 
delayed sleep onset latency in adult survivors of childhood cancer, which will be 
evaluated in Cohorts 2 and 3. We hypothesize that survivors randomized to the 
melatonin treatment arm will evidence a greater improvement in sleep onset 
latency compared to survivors randomized to placebo. The CCSS cohort mean 
and SD for sleep onset latency among participants with delayed sleep onset 
latency (i.e. SOL > 30minutes) is 46.2 and 27.7 minutes, respectively. The test-
retest correlation for sleep onset latency from the PSQI has been observed to be in 
the range of 0.70. Following the justification set forth in Aim 1, and assuming the 
SD to be 27.7, we will need to randomize 131 and 133 survivors between the 
melatonin and placebo arms in Cohort 2 and Cohort 3, respectively, to see an 
improvement of 15 minutes in sleep onset latency with 80% power with type I 
error control =0.05. The analysis for Aim 2 will be completed using a two-
sample t-test. 
 
Secondary Objective: Investigate whether improvement in sleep onset latency 
due to melatonin treatment is associated with neurocognitive improvement in 
long-term childhood cancer survivors. 
 Hypothesis 3: Improvement in sleep onset latency with melatonin 
treatment will result in improved neurocognitive performance in long-term 
childhood cancer survivors who have both comorbid sleep onset latency 
and neurocognitive deficits at baseline (Cohort 2). 
 
The secondary interest of Objective 2 is to investigate the association between 


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sleep onset latency and specific neurocognitive processes in survivors with 
comorbid sleep and neurocognitive dysfunction [Cohort 2]. We hypothesize that 
decreased sleep onset latency following 6 months of melatonin treatment will be 
associated with improved neurocognitive performance. With a sample size of 131 
in Cohort 2 [66 randomized to melatonin, 65 randomized to placebo] we will have 
80% power to detect a correlation of at least 0.25 between reduced sleep onset 
latency and improved neurocognitive performance with type 1 error control 
=0.05. 
 
Exploratory Objective: Explore the association between endogenous melatonin 
levels and improvement in sleep onset latency. 
 
 Exploratory Hypothesis 1: Improvement in sleep onset latency following 
melatonin treatment will be independent of baseline endogenous 
melatonin levels. 
 
Linear regression model and/or logistic regression model will be used to evaluate 
the association between serum melatonin and improvement in sleep. 
 
Exploratory Objective: Explore the association between sleep quality and 
health-related quality of life and distress. 
 
 Exploratory Hypothesis 3: Improved sleep quality will be associated with 
decreased psychological distress and enhanced quality of life. 
Once again regression approaches, as discussed above, will be utilized to evaluate 
the association between sleep quality and health-related quality of life and 
psychological distress.  
 
11.1  Anticipated Completion Dates 
 
Anticipated Primary Completion Date: December 2016 
Anticipated Study Completion Date: December 2017 
 


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11.2  Summary of Primary and Secondary Objectives  
 
 
 
Primary and Secondary Summary of Objectives 
 
Objective 
# 
Objective 
Type 
Analysis 
# 
Resp 
Party 
Stat 
Safety 
Analysis 
Measure 
Analysis Title 
Data 
Collection 
Time Frame 
# of Participants 
1.1 
P 
1 
TB 
KS 
N 
Patient 
Neurocognition 
Compare neurocognitive function by 
treatment group 
Baseline 
6 month 
232 
 
2.1 
S 
1 
TB 
KS 
N 
Patient 
Sleep onset latency 
Compare sleep onset latency by  
treatment group 
Baseline 
3 month 
6 month 
226 
2.2 
S 
1 
TB 
KS 
N 
Patient 
Neurocognition 
and  
Sleep onset latency 
Evaluate impact of sleep on  
neurocognitive function 
Baseline 
6 month 
131 
3.1 
E 
1 
TB 
KS 
N 
Patient 
Melatonin  
 
Evaluate endogenous melatonin levels 
Baseline 
6 month 
395 
3.2 
E 
1 
TB 
KS 
N 
Patient 
Melatonin,  
Neurocognition  
Sleep onset latency 
Evaluate association between endogenous melatonin and 
sleep 
 
Baseline 
6 month 
395 


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12.0  OBTAINING INFORMED CONSENT 
 
Potentially eligible study participants will be mailed a letter to introduce the study 
and inform him or her of their potential eligibility. The letter will state that a study 
team member will be contacting them in approximately two weeks to discuss the 
study, answer questions they may have, and see if they are interested in 
participating. The letter will include a toll free number that participants can call 
sooner to discuss the study or if they would like to decline participation. A study-
specific pre-screening form will be included with the mailing for their review.   
This form will ask two questions about his or her sleep habits and questions 
relevant to the exclusion criteria for the study.  Approximately two weeks after 
the letter is mailed, a research team member will contact each eligible participant 
to discuss the study, ask if they have any questions and to see if they are 
interested in participating. The formal informed consent will take place at SJCRH 
when the participant comes in for their SJLIFE and screening measures visit. A 
research team member will explain the research study; the measures involved in 
the study, and review the potential risks and benefits. The participant will have 
time to read the consent and have all questions answered by the study team 
member. Upon agreeing to participate, the consent form and a Health Insurance 
Portability and Accountability ACT (HIPAA) compliance form will be signed by 
the research participant and the principal investigator or designee.   


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13.0 
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52. 
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Behav Sleep 2:148-61, 2004 
 
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de Souza L, Benedito-Silva, A.A., Pires, M.L., Poyares, D., Tufik, S., 
Cali, H.M.: Further validation of actigraphy for sleep studies. Sleep 26:81-5, 2003 
 
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Edinger JD, Means, M.K., Stechuchak, K.M., Olsen, M.K.  : A pilot study 
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Gagnadoux F, Nguyen, X.L., Rakotonanahary, D, Vidal, S., Fleyry, B.: 
Wrist-actigraphic estimation of sleep time under nCPAP tratment in sleep apnoea 
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64. 
Lichstein KL, Stone, K.C., Donaldson, J., et al.: Actigraphy validation 
with insomnia. Sleep 29:232-9, 2006 
 
65. 
Lotjonen J, Korhonen, I., Hirvonen, K., Eskelinen, S., Myllymaki, M., 
Partinen, M.: Automatic sleep-wake and nap analysis with a new wrist worn online 
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66. 
Singer C, Tractenberg, R.E., Kaye, J., et al: A multicenter, placebo-
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67. 
Vallieres A, Morin, C.M.: Actigraphy in the assessment of insomnia sleep. 
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68. 
Morgenthaler T, Alessi C, Friedman L, et al: Practice parameters for the 
use of actigraphy in the assessment of sleep and sleep disorders: an update for 2007. 
Sleep 30:519-29, 2007 
 
69. 
Manber R, Bootzin RR, Acebo C, et al: The effects of regularizing sleep-
wake schedules on daytime sleepiness. Sleep 19:432-41, 1996 


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Sateia MJ, Doghramji K, Hauri PJ, et al: Evaluation of chronic insomnia. 
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72. 
Derogatis L: Brief Symptom Inventory (BSI): Administration, scoring, 
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Hsing AW, Meyer TE, Niwa S, et al: Measuring serum melatonin in 
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Muller HL, Handwerker G, Gebhardt U, et al: Melatonin treatment in 
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Lipton J, Megerian JT, Kothare SV, et al: Melatonin deficiency and 
disrupted circadian rhythms in pediatric survivors of craniopharyngioma. Neurology 
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Vijayalaxmi, Thomas CR, Jr., Reiter RJ, et al: Melatonin: from basic 
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78. 
Hughes RJ, Sack RL, Lewy AJ: The role of melatonin and circadian phase 
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Singer C, Tractenberg RE, Kaye J, et al: A multicenter, placebo-controlled 
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Lewy AJ, Sack RL: Exogenous melatonin's phase-shifting effects on the 
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Sack RL, Auckley D, Auger RR, et al: Circadian rhythm sleep disorders: 
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83. 
Sack RL, Hughes RJ, Edgar DM, et al: Sleep-promoting effects of 
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Sleep 20:908-15, 1997 
 
84. 
Attenburrow ME, Cowen PJ, Sharpley AL: Low dose melatonin improves 
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Quittner AL, Modi AC, Lemanek KL, et al: Evidence-based assessment of 
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Shi L, Liu J, Koleva Y, et al: Concordance of adherence measurement 
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APPENDICES 
 
Appendix I:   Schedule of Evaluations 
 
Eligibility 
Baseline 
On-Study 
End 
Evaluation 
Pre-
Screen 
 Study 
Entry 
Within 
7–10 
days of 
baseline 
visit 
 
Monthly  
(+10 
days) 
3 
months  
(+ 1 
week) 
6 
months  
(+ 28 
days) 
Inclusion/Exclusion 
criteria questions 
X1 
  
 
 
 
 
Sleep-related 
questions 
 
       X 
 
 
 
 
Informed consent 
 
 
X 
 
 
 
 
HIPAA 
 
 
X 
 
 
 
 
Standardized Sleep 
Measures 
 
 
X 
 
 
X3 
X3 
Neurocognitive 
Assessment 
Measures 
 
 
X2 
 
 
 
X 
Correlative 
Psychosocial 
Measures 
 
 
X2 
 
 
 
X3 
Pregnancy test 
 
 
X2 
 
 
 
 
History and 
Medical Provider 
visit 
 
 
X2 
 
 
 
X 
Actigraphy 
 
  
X3 
 
X3 
X3 
Daily Sleep Diary 
 
  
X3 
 
X3 
X3 
Side effect 
monitoring 
 
      X 
X4 
 
 
 
Study drug 
adherence (Pill 
Count) 
 
  
 
X 
 
 
1Mailed with introductory letter 
2Completed as part of SJLIFE protocol 
3Actigraph and sleep measures mailed to participant’s home for completion. Standardized sleep measures 
completed at home at 3 months and 6 months. Correlative psychosocial measures completed at home at 6 
months.  
4Initially completed after 7-10 days on study medication; then bi-weekly for remainder of study. 
 
 
 
 
 
 
 
 


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APPENDIX II: RESEARCH TESTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Baseline measures completed as part of SJLIFE Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Test 
Time Point 
 
Standardized Sleep Measures 
Baseline 
3 month 
6 month 
Required 
Neurocognitive Assessment Measures1 Baseline 
6 month 
Required 
Correlative Psychosocial Measures1 
Baseline  
6 month 
Required 
Actigraphy 
Baseline  
90 day  
6 month 
Required 
Daily Sleep Diary 
Baseline  
90 day  
6 month 
Required 
Melatonin – blood 
Baseline 
6 month 
Required 


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Appendix III:  Sleep Measures  
[NOTE:  This appendix contains copyrighted material and has been redacted.] 
 
PITTSBURGH SLEEP QUALITY INDEX 
 
INSTRUCTIONS: The following questions relate to your usual sleep habits during the 
past month only. Your answers should indicate the most accurate reply for the majority of 
days and nights in the past month. Please answer all questions. 
 
1. During the past month, what time have you usually gone to bed at night? 
 
BED TIME ___________ 
 
2. During the past month, how long (in minutes) has it usually taken you to fall asleep each night? 
 
NUMBER OF MINUTES ___________ 
 
3. During the past month, what time have you usually gotten up in the morning? 
 
GETTING UP TIME ___________ 
 
4. During the past month, how many hours of actual sleep did you get at night? (This may be 
different than the number of hours you spent in bed.) 
 
HOURS OF SLEEP PER NIGHT ___________ 
 
For each of the remaining questions, check the one best response. Please answer all questions. 
 
5. During the past month, how often have you had trouble sleeping because you . . . 
 
a) Cannot get to sleep within 30 minutes 
 
 
Not during the 
Less than 
Once or twice 
Three or more 
 
past month_____ 
once a week_____ 
a week_____ 
times a week_____ 
 
b) Wake up in the middle of the night or early morning 
 
 
Not during the 
Less than 
Once or twice 
Three or more 
 
past month_____ 
once a week_____ 
a week_____ 
times a week_____ 
 
c) Have to get up to use the bathroom 
 
 
Not during the 
Less than  
Once or twice  
Three or more 
 
past month_____ 
once a week_____ 
a week_____ 
times a week_____ 
 
d) Cannot breathe comfortably 
 
 
Not during the  
Less than 
Once or twice 
Three or more 
 
past month_____ 
once a week_____ 
a week_____ 
times a week_____ 
 


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e) Cough or snore loudly 
 
 
Not during the 
Less than 
Once or twice 
Three or more 
 
past month_____ 
once a week_____ 
a week_____ 
times a week_____ 
 
f) Feel too cold 
 
 
Not during the  
Less than  
Once or twice  
Three or more 
 
past month_____  
once a week_____  
a week_____  
times a week_____ 
 
g) Feel too hot 
 
 
Not during the  
Less than  
Once or twice  
Three or more 
 
past month_____  
once a week_____  
a week_____  
times a week_____ 
 
h) Had bad dreams 
 
 
Not during the  
Less than  
Once or twice  
Three or more 
 
past month_____  
once a week_____  
a week_____  
times a week_____ 
 
i) Have pain 
 
 
Not during the  
Less than  
Once or twice  
Three or more 
 
past month_____ once a week_____  
a week_____  
times a week_____ 
 
j) Other reason(s), please describe_________________________________________________ 
___________________________________________________________________________ 
 
5. How often during the past month have you had trouble sleeping because of this? 
 
 
Not during the  
Less than  
Once or twice  
Three or more 
 
past month_____  
once a week_____  
a week_____  
times a week_____ 
 
6. During the past month, how would you rate your sleep quality overall? 
 
 
Very good ___________ 
 
Fairly good ___________ 
 
Fairly bad ___________ 
 
Very bad ___________ 
 
7. During the past month, how often have you taken medicine (prescribed or "over the counter") 
to help you sleep? 
 
 
Not during the  
Less than  
Once or twice  
Three or more 
 
past month_____  
once a week_____  
a week_____  
times a week_____ 
 
8. During the past month, how often have you had trouble staying awake while driving, eating 
meals, or engaging in social activity? 
 


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Not during the  
Less than  
Once or twice  
Three or more 
 
past month_____  
once a week_____  
a week_____  
times a week_____ 
 
9. During the past month, how much of a problem has it been for you to keep up enough 
enthusiasm to get things done? 
 
 
No problem at all __________ 
 
Only a very slight problem __________ 
 
Somewhat of a problem __________ 
 
A very big problem __________ 
 
10. Do you have a bed partner or roommate? 
 
 
No bed partner or room mate __________ 
 
Partner/roommate in other room __________ 
 
Partner in same room, but not same bed __________ 
 
Partner in same bed __________ 
 
If you have a roommate or bed partner, ask him/her how often in the past month you have had... 
 
a) Loud snoring 
 
 
Not during the  
Less than  
Once or twice  
Three or more 
 
past month_____  
once a week_____  
a week_____  
times a week_____ 
 
b) Long pauses between breaths while asleep 
 
 
Not during the  
Less than  
Once or twice  
Three or more 
 
past month_____  
once a week_____  
a week_____  
times a week_____ 
 
c) Legs twitching or jerking while you sleep 
 
 
Not during the  
Less than  
Once or twice  
Three or more 
 
past month_____  
once a week_____  
a week_____  
times a week_____ 
 
d) Episodes of disorientation or confusion during sleep 
 
 
Not during the  
Less than  
Once or twice  
Three or more 
 
past month_____  
once a week_____  
a week_____  
times a week_____ 
 
e) Other restlessness while you sleep; please describe__________________________________ 
 
___________________________________________________________________________ 
 
 
Not during the  
Less than  
Once or twice  
Three or more 
 
past month_____  
once a week_____  
a week_____  
times a week_____ 
 
 
 
 
 
© 1989, University of Pittsburgh. All rights reserved. Developed by Buysse, D.J., Reynolds, C.F., Monk, T.H., Berman, S.R., and 


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Kupfer, D.J. of the University of Pittsburgh using National Institute of Mental Health Funding. 
 
Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ: Psychiatry Research, 28:193-213, 1989. 
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) 
 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
ADDITIONAL CONCERNS 
Not 
A little Some- 
Quite 
Very 
 
 
at all 
bit 
what 
a bit 
much 
 
1.   I feel fatigued .............................................................. 0 
1 
2 
3 
4 
 
2.   I feel weak all over....................................................... 0 
1 
2 
3 
4 
 
3.   I feel listless (“washed out”) ....................................... 0 
1 
2 
3 
4 
 
4.   I feel tired .................................................................... 0 
1 
2 
3 
4 
 
5.   I have trouble starting things because I am tired….... 0 
1 
2 
3 
4 
 
6.   I have trouble finishing things because I am tired ..... 0 
1 
2 
3 
4 
 
7.   I have energy ............................................................... 0 
1 
2 
3 
4 
 
8.   I am able to do my usual activities............................... 0 
1 
2 
3 
4 
 
9.   I need to sleep during the day ...................................... 0 
1 
2 
3 
4 
 
10. I am too tired to eat .......................................................0 
1 
2 
3 
4 
 
11. I need help doing my usual activities............................ 0 
1 
2 
3 
4 
 
12. I am frustrated by being too tired to do the things I  
   want to do......................................................................0 
1 
2 
3 
4 
 
13. I have to limit my social activity because I am tired.... 0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 


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THE EPWORTH SLEEPINESS SCALE 
 
How likely are you to doze off or fall asleep in the following situation, in contrast to 
feeling just tired?  This refers to your usual way of life in recent times.  Even if you have 
not done some of these things recently try to work out how they would have affected you.   
Use the following scale to choose the most appropriate number for each situation: 
 
 
0 = would never doze 
 
1 = slight chance of dozing 
 
2 = moderate chance of dozing 
 
3 = high chance of dozing 
 
SITUATION  
 
CHANCE OF DOZING 
 
Sitting and reading 
0 
1 
2 
3 
 
Watching television 
0 
1 
2 
3 
 
Sitting inactive in a public place (e.g. theatre, meeting) 
0 
1 
2 
3 
 
 
As a passenger in a car for an hour without a break 
0 
1 
2 
3 
 
 
Lying down to rest in the afternoon when circumstances permit 0 
1 
2 
3 
 
Sitting and talking to someone 
0 
1 
2 
3 
 
Sitting quietly after a lunch without alcohol 
0 
1 
2 
3 
 
In a car, while stopped for a few minutes in traffic 
0 
1 
2 
3 
 
 
TOTAL SCORE = __________ 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix IV - Neurocognitive Functioning Measures 
[NOTE:  This appendix contains copyrighted material and has been redacted.] 
 
Digit Span Forward and Backward 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conners’ Continuous Performance Test- II, Version 5 
 
This is computerized test. No sample available. 
 
 
 
 
 
 


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California Verbal Learning Test-Second Edition- Standard Form 
 
 
 


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California Verbal Learning Test-Second Edition- Alternate Form 
 
 
 
 
 


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Trails B (page 1) 
 
 
 


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Trails B (page 2) 
 
 
 


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Controlled Oral Word Association (COWA) 
 
 
 
 


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Controlled Oral Word Association (COWA) - Alternate 
 
 
 
 


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Appendix V – Correlative Psychosocial Measures 
[NOTE:  This appendix contains copyrighted material and has been redacted.] 
 
Medical Outcomes Survey 36-Item Short Form Health Survey (SF-36) 
 
 
 
 
 


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Brief Symptom Inventory-18 (BSI-18)