Multimodal Therapy for the Treatment of Sleep Disturbance in Patients With Cancer
Phase: PHASE2
Conditions: Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm, Sleep Disorder
Sponsor: M.D. Anderson Cancer Center

MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2012-0120 
Protocol Title 
Multimodal Therapy For The Treatment Of Sleep Disturbance In 
Patients With Cancer 
Protocol Phase 
II 
Protocol Version 
15 
Version Date 
07/07/2020 
Protocol PI 
Sriram Yennu, MD, MS 
Department 
Palliative Care and Rehabilitation Medicine 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
115546 

2012-0120 
Rev. June 27, 2016 
1 
 
Structured Abstract 
 
Primary objective:  
Aim 1. To obtain preliminary estimates of the effects of CBT and various treatments[light therapy, 
melatonin, Methylphenidate] and combinations of treatments in MMT in reducing sleep disturbance in 
patients with cancer, as measured by change in PSQI scores taken at baseline and on Day 15. 
 
Secondary objectives:  
Aim 2. To explore the effect of MMT on Insomnia Severity Index, cancer related symptoms [fatigue 
(FACIT-F subscale, ESAS), anxiety ,depression anxiety (Hospital Anxiety Depression Scale [HADS], 
ESAS), quality of life(FACT-G, ESAS), and physical activity/sleep efficacy (Actigraphy), before and after 
treatment with various SD treatment combinations of MMT;   
Aim 3. To determine the safety of MMT (type, frequency, and severity of the adverse events). 
 
The primary outcome variable for this study is the change in PSQI score. 
 
Sleep Disturbance (SD) occurs in 24%–95% of patients with cancer [1-3]. In recent study at supportive 
care center at UT MDACC, 75% (330/440) were diagnosed to have moderate to severe sleep 
disturbance (4). Patients who experience SD can also experience significant distress due to decline in 
cognitive function, an inability to engage in work or recreational activities, loss of hedonic capacity, 
lower quality of life, and adverse alterations to immune and neuroendocrine functions [2,5-7]. Even so, 
SD is frequently underdiagnosed and undertreated in clinical oncology practice [2,3, 5].  Although SD is 
common and distressing in patients with advanced cancer, there are limited treatment options in 
patients with advanced cancer. One reason for the lack of effective treatments is that few controlled 
studies targeting SD; hence, further studies are needed [2,9].  
 
The proposed study would determine the effect of various combinations of light therapy, melatonin, and 
methylphenidate with cognitive behavioral therapy (that is, multimodal therapy, or MMT) for the 
treatment for SD; if effective, these low-cost, low-risk; easily accessible interventions would potentially 
benefit many other cancer patients. The factorial design utilized in this study will test not only the 
preliminary outcomes and adherence of each individual treatment (light therapy [2,10-14], 
melatonin[15-18], methylphenidate (MP) [19-22] and cognitive behavioral therapy (CBT) [3,23-27], but 
also their combinations which we hypothesize will produce a larger reduction in SD. Thus, data 
collected from this novel randomized factorial design will enable us to assess the three treatments used 
in this study without the need for a second, larger study, but if one or more treatment combinations do 
appear effective, a larger study will be designed using estimates of intersubject variability and treatment 
efficacies estimated from the present design. 
 
Innovation. We consider this study innovative because we will obtain important data about preliminary 
outcomes and patients’ adherence to MMT in a randomized controlled trial including all the proposed 
interventions in patients with SD. The factorial design is highly innovative for assessing treatments for 
SD because it allows us to study the effects three safe, readily available and low-cost interventions and 
their combinations simultaneously with CBT in one clinical study in comparison to other traditional 
designs which would require multiple individual clinical trials requiring a longer time to complete and be 
very costly, rendering them to be a less feasible option. This study is novel because not only will the 
data collected from this randomized factorial design be used to assess the main effects CBT and the 
three treatments for SD, but also the factorial design will allow us to assess the synergies between the 
treatments. This study is also novel because we will use this innovative design performed in a very 
controlled setting in a well defined population.  

2012-0120 
Rev. June 27, 2016 
2 
 
Factorial designs are the standard experimental design used when it is possible to give treatment 
combinations [28,29]. This is the advantage of factorial designs and why they are used so 
predominantly in industrial experiments. As Fisher [28] showed, experimental designs that test only two 
treatment groups at a time are highly inefficient. A factorial design allows the effect of several factors 
and interactions between them to be determined by using the same number of patients that would be 
necessary to estimate a single treatment. The only reason that factorial designs are not commonly used 
in oncology trials is that toxicity due to combined treatments is generally an overriding concern in 
administering cytotoxic agents to cancer patients. Based on prior clinical trials, the study interventions 
(cognitive behavioral therapy [3,23-27], light therapy,melatonin and methylphenidate [2,10-22]) are not 
expected to result in toxic effects in patients, either alone or in combination. Factorial design would be 
ideal to test multidimensional symptom interventions or their combinations necessary to treat the 
multifactorial nature of SD. And lastly assessment of SD requires the use of continuous scales unlike 
physician reported outcomes for cancer trials, analyses of which require sophisticated analyses. 
 
In this study, we will assess 3 treatments (light therapy, melatonin, and methylphenidate) and their 
placebos treatments with CBT in 8 replications of a complete factorial design.  A total of 32 patients will 
receive each primary treatment and 32 will not. Within each group of 32, the allocation of the other 
treatment combinations will be balanced so that the additive effects of the other treatments cancel out; 
this means that we will be able to make comparisons between each of the 3 main treatments with the 
same level of accuracy as if we had performed 3 trials, each with 64 patients. In other words, the 
variance of the estimate of the main treatment effects is the same as if the trial had been performed 
with 64 patients, 32 receiving treatment and 32 receiving placebo. For the three second-order 
interactions, comparisons will have the same error variance that would have been estimated with 16 
patients assigned to the two-drug combination and 48 to placebo. The variance of the estimate of the 
effect of the 3-drug combination will be similar to the variance that would be estimated if 8 of 64 
patients were receiving the three drug combination and 56 were receiving the placebo. The objective of 
the proposed project is to explore the effects of MMT on SD and safety in patients with cancer. We 
hypothesize that MMT is capable of reducing SD as measured by the PSQI in these cancer patients 
(Fig. 1). To achieve this objective, we plan to use a randomized factorial design. 
    
 
 
 
 

2012-0120 
Rev. June 27, 2016 
3 
 
I. 
BACKGROUND 
 
SD is common and under diagnosed in patients with advanced cancer. SD is common in patients 
with advanced cancer, and its impact is not always recognized [1-3,30]. The prevalence of SD in patients 
with advanced cancer reported in the literature is variable with a range between 24% and 95% [1-3,30]. 
This wide range reflects the variability of diagnostic criteria, tools and methodologies used. In recent 
study at supportive care center at UT MD Anderson Cancer Center 75% (330/440) were diagnosed to 
have moderate to severe sleep disturbance(4). 
 
Patients who experience SD can experience significant distress due to decline in cognitive function, an 
inability to engage in work or recreational activities, loss of hedonic capacity and adverse changes in the 
immune and neuroendocrine functions [2,3,5-7. SD is also associated with worse quality of life and 
increase in the intensity of symptoms such as pain, depression and anxiety [2,3]. It has been suggested 
that sleep-wake and circadian rhythm disturbances are associated with increased mortality in patients 
with metastatic disease [31]. Despite its relevance, SD is frequently under diagnosed and undertreated 
in clinical oncology practice [2,25].  
 
A. Pathophysiologic mechanisms of SD in patients with advanced cancer 
 
Cancer patients are at an increased risk for altered sleep pattern and disruption of the normal 
behaviors and physiology that lead to a restful sleep [2,3,25]. Multiple physiologic mechanisms are 
altered in patients with advanced cancer. Patients with cancer have abnormalities in the circadian 
regulatory process, with alterations in the production of cortisol, melatonin and cytokines [2]. Recent 
research has recognized the role of the immune system and inflammatory mediators as an organic 
component in the disruption of the sleep cycle in patients with sleep disturbance [32-36]. Patients have 
changes in their daily routine, with decreased daytime activity and increased time in bed [37]. They also 
experience increased physical symptoms such as pain or dyspnea, which are associated with sleep 
disruption affecting both sleep onset and maintenance [25,30,31]. Finally, psychosocial stressors are 
frequent in cancer patients and can also contribute to sleep disturbances in this population. Hospice 
patients themselves recognize that physical symptoms, worries about the disease, the family and the 
future are the main causes of sleep disturbance [30]. All these mechanisms involved in sleep disturbance 
influence each other establishing an intricate network of interactions between them. This complex 
interaction makes the treatment of this distressing symptom very challenging.  
 
a. Immunity - Inflammation: Some cytokines regulate sleep under physiologic conditions, in the 
absence of infection or immune challenge [31,36]. Research during the last decade has described 
a close relationship between inflammation and sleep patterns, and this relationship seems to be 
bidirectional: impaired sleep can modify cytokine levels and inflammation itself can modulate 
wake-sleep pattern. Given the increased level of cytokines in patients with cancer it is possible 
that inflammation could have a role in the increased prevalence of SD in these patients. 
 
Sleep deprivation in normal subjects alters the immune system with decreased activity of natural 
killers (NK) cells and increased T-helper cells [25,31,34-36]. Healthy people exposed to modest 
sleep restriction are not only sleepier during the day and have impairment in psychomotor 

2012-0120 
Rev. June 27, 2016 
4 
 
performance tests, they also have increased secretions of cytokines [35,36]. Specifically, IL-1, 
TNFα and IL-6 are cytokines that have been identified as involved in altered sleep patterns. 
Chronic insomnia is also associated with cytokine changes. These patients have a shift in the 
peak levels of IL-6 and TNFα from nighttime to daytime, that could explain the fatigue and 
detrimental performance associated with insomnia [31,32]. It has also been suggested that 
chronic sleep impairment, as occur in patients with advanced cancer, could contribute to 
inflammation through desynchronization of circadian rhythms (e.g decreased rhythmic variation 
of cortisol) [31],  
 
On the opposite direction, inflammation may contribute to the development of behavioral 
alterations, such as SD, both in healthy and sick individuals. Studies in animals have shown that 
strong host defense responses are associated with suppression of REM sleep. Likewise, intense 
immune responses during infection are associated with increased non REM sleep and probably 
survival [34]. It is thought that immune cytokines induce behavioral changes through modulation 
of brain neurotransmitters, hypothalamic-pituitary-adrenal axis and regional brain activity [31]. 
Even though it has not been specifically studied, it is possible that inflammation could be an 
important trigger/mediator of altered sleep patterns in patients with advanced cancer.  
 
b. Behavioral factors: Conditions that maintain insomnia are maladaptive sleep habits and 
dysfunctional cognitions that patients develop in reaction to SD.  These two factors increase 
arousal and performance anxiety, which are opposite to the relaxation state required to initiate 
sleep. These maladaptive behaviors are particularly frequent in cancer patients. They are 
encouraged to rest and sleep as much as they can to recover from cancer treatments, impairing 
normal sleep habits. In this same direction, patients spend long time in bed doing wakening 
promoting activities, such as watching TV or listening to music, which in turn weaken the normal 
association between stimuli that promote sleep (e.g. like going to bed at bedtime, with sleeping 
itself) [37]. 
 
Increased time in bed and lack of exercise: Exercise improves sleep by direct brain effects and 
by modulating the inflammatory cytokines such as TNF-α, IL-6 levels [31]. Likewise CBT 
potentially reduce CBT by its action on IL-6, TNF-α [85, 90-93], 
 
c. Physical symptoms: Pain is a frequent symptom in patients with cancer [37]. Patients with 
severe pain often report more sleep disturbances [37, 38]. Pain affects both initiation and 
maintenance of sleep and one possible mechanism is increased arousal. It is thought/ has been 
demonstrated that patients with pain have increased adrenergic response, associated with 
activation of the HPA axis, which stimulates arousal and decreases sleep. 
 
Fatigue is one of the most important complains in patients with insomnia. Cancer patients often 
experience fatigue secondary to the cancer itself and to cancer treatment. 
 
Dyspnea is associated with frequent interruptions sleep [2,25,30,37]. Fatigue is associated to 
increased cytokines and changes in behavioral factors [25,31]. 
 

2012-0120 
Rev. June 27, 2016 
5 
 
d. Psychosocial stressors: Anxiety and Depression are associated to increased arousal. Sleep 
disturbance often coexists with psychiatric diseases such as depression and anxiety. These 
diseases can be both cause and consequence of insomnia [25].  
 
e. Aging: patients require less sleep as patient’s age (25). 
 
f. Other mechanisms: sleep apnea, restless leg syndrome (25) 
 
Figure 1: Conceptual model.  
 
SLEEP 
DISTURBANCE 
(PSQI) 
INFLAMATION 
BEHAVIORAL PROBLEMS 
-  Decreased daytime activity 
-  Increased time in bed 
PSYCHIATRIC SYMPTOMS 
-  Anxiety 
-  Depression 
PHYSICAL 
SYMPTOMS 
-  Pain 
-  Dyspnea 
-  Fatigue 
CANCER 
METHYLPHENIDATE 
MELATONIN 
LIGHT THERAPY 
CBT 
PATIENT CHARACTERISTICS 
-  Age, gender, race 
-  Comorbidities (obesity) 
-  Prior sleep disturbances 
-  Addictions (tobacco, coffee) 
BRAIN 

2012-0120 
Rev. June 27, 2016 
6 
 
 
 
 
 
B. Interventions for treatment of sleep disturbances in patients with advanced cancer 
Current treatments for SD in cancer patients are not effective. There are multiple interventions 
available to treat SD in patients with advanced cancer, but current treatments are not always effective. 
A reasonable first approach is to address underlying physical and psychological factors involved in 
sleep disturbances, such as pain, dyspnea or anxiety. At the same time, both non-pharmacological and 
pharmacological interventions can be implemented that directly treats this symptom. Both types of 
interventions have been studied. Among the non-pharmacologic interventions, cognitive based therapy 
and light therapy for SD in patients with cancer have been described in the literature with mixed results. 
Among the pharmacologic interventions, melatonin and methylphenidate have shown some 
improvement. However, the results have not been consistent, hence need for further studies.  
 
Type 
Intervention 
Effect in General Population 
Effect 
in 
Cancer 
Patients 
Non-
pharmacologic 
CBT 
 
Level 1 evidence for short-term effects. Reduces sleep onset 
latency and wake after sleep onset [39]. Includes: Stimulus 
control, progressive muscle relaxation, paradoxical intention, 
biofeedback and sleep restriction [40]. Multicomponent BT is 
effective. CBT is effective [41].  
Yes, likely to be effective 
[2,42]. 
Exercise 
Recommended by American Sleep Disorders Association, but 
there are still conflicting results [43].  
Positive trend to improve 
sleep [42].  
Light Therapy 
Yes, especially in patients with circadian rhythm disorders [44]. 
Yes, likely to be beneficial 
{12, 13} 
Pharmacologic 
Benzodiazepines  
Yes, reduce self-reported sleep onset latency time & number of 
awakenings and improve self-reported sleep duration, total sleep 
time and sleep quality. Reported increased daytime sleepiness, 
dizziness and lightheadedness [9]. Long term use can result in 
disrupted sleep pattern with fragmented sleep and dependence 
on the medication [20]. Also concern about drug interactions.  
Can be deleterious to the 
palliative care patients 
[37]. 
Non-
benzodiazepine 
hypnotics 
Yes, reduce self-reported sleep onset latency time & number of 
awakenings and improve self-reported sleep duration, total sleep 
time and sleep quality [9]. Same precautions as with 
benzodiazepines [20]. (More expensive than benzodiazepines). 
Yes, 
likely 
to 
be 
beneficial[25] 
Methylphenidate 
In healthy individuals who are experiencing sleep loss, 
methylphenidate improves psychomotor performance [38]. 
Yes, 
likely 
to 
be 
effective[22] 
Melatonin 
Yes, but minimal clinical benefits, with reduced sleep latency and 
increased sleep duration and sleep efficiency [39]. Demonstrated 
effect in patients with disruption of the circadian rhythm of 
melatonin secretion.  
Not 
demonstrated 
in 
patients with cancer. It 
could have a role as 
immunogenic agent [15]. 

2012-0120 
Rev. June 27, 2016 
7 
 
Antidepressants 
No strong evidence to favor its use in general population [20].  
Specific antidepressants 
recommended 
in 
patients with insomnia 
and 
depression 
or 
neuropathic pain [25].  
 
 
Non - pharmacologic interventions: 
 
CBT: cognitive and behavioral interventions are defined as treatments that aim to improve sleep by 
changing poor sleep habits and challenging negative thoughts, attitudes and beliefs about sleep [39-
41]. The interventions include stimulus control, sleep restriction, sleep hygiene education, relaxation 
and cognitive therapy. The use of simultaneous interventions has proven more effective than 
interventions alone [37]. These interventions are clearly effective in patients with primary insomnia. 
There are some studies in patients with advanced cancer in which different multimodal interventions, 
including stimulus control, relaxation training, mindfulness practices, exercise and reducing levels of 
arousal and sleep hygiene, improved sleep and fatigue and enhanced ability to perform activities 
[42,48. However, few studies had a randomized control design or more than 100 patients. Hence, the 
evidence is not strong for the effectiveness of these interventions specifically in cancer patients [2].  
 
Light therapy: Evidence not clear[10-13].  
 Seasonal Affective Disorders and other disorders that involved chronobiological malalignments like 
circadian sleep phase disorder, jet lag and shift work syndrome showed similar benefits with light 
therapy.  Using the Litebook®, Ancoli-Israel et al. found that 1350 Lux of LED light for 30 minutes every 
morning improved sleep in patients with breast cancer undergoing chemotherapy compared to dim red 
light (13,Ancoli-Israel et al., personal communication).  Light therapy also has some effect in non-
seasonal depression (11,Tunainen Cochrane Database; Golden RN Am J Psychiatry). Exposure to 
bright light has been shown to improve sleep-wake quality.(12,Termin J Bio Rh  Bright light therapy also 
has been effective in sleep disturbances among nursing home patients with dementia. 50   Light, at 
intensity between 6,000 to 8,000 lux, was given for 2h/day during morning hours for 2 weeks, the only 
side effects reported were minor eye-irritation in the first 4-5 minutes of bight-light exposure, that 
gradually disappear after some days of treatment. 
Side effects are usually mild.  Terman et al. reported mild side effects of bright light therapy in the 
treatment of depression in 38 patients, receiving a dose of 10,000 lux daily for 30 minutes in the 
morning or evening[12].    These include jumpiness/jitteriness (9%), headache (8%) and 
nausea/vomiting (16%), and eye irritation (12%). 
Pharmacologic interventions 
Methylphenidate: evidence in patients with advanced cancer (21,22). 
Patient with advanced cancer have significant cancer related fatigue (CRF). Prior studies have found 
that SD and CRF are correlated. Prior studies of Methylphenidate for the treatment of sleep disturbance 
showed that sleep disturbance after treatment with methylphenidate showed significant improvement 
compared to baseline (see Table 1).  
 

2012-0120 
Rev. June 27, 2016 
8 
 
Table 1. Sleep Quality between Day 8 and Baseline in Patients taking Methylphenidate[22] 
 
 
• 
Melatonin: Evidence in patients with delayed sleep phase disorder onset no evidence in 
patients with advanced cancer (15-18)  
• 
In patients with primary sleep disorders: Melatonin decreased sleep onset latency in people 
with a primary sleep disorder (WMD: -10.7 min; 95-percent CI: -17.6 min, -3.7 min). SOL was 
decreased greatly in people with delayed sleep phase syndrome (WMD: -38.8 min; 95-percent 
CI: -50.3 min, -27.3 min). The magnitude of this effect appears to be clinically significant. SOL 
was decreased marginally in patients with insomnia (WMD: -4.3min; 95-percent CI: - 8.4 min, -
0.1 min.). The magnitude of this effect appears to be clinically insignificant. SOL was reduced 
more in children (less than age 17 years) (WMD: -17.0 min, 95-percent CI: -33.5 min, -0.5 min) 
than in adults (age 18-65 years) (WMD: -11.2; 95-percent CI: -27.7 min, 5.4 min) or elderly 
patients (greater than age 65 years) (WMD: -7.8 min; 95-percent CI: -17.4 min, 1.7 min). The 
effects of melatonin did not vary with dose or duration of treatment. If the analysis is approached 
using the Fixed Effects Model, melatonin does not have any effect on sleep onset latency in 
people with primary insomnia. 
• 
Melatonin did not have an effect on sleep efficiency in people with primary sleep disorders; the 
effects of melatonin did not vary by age, type of primary sleep disorder, dose, or duration of 
treatment. 
• 
Melatonin did not have an effect on sleep quality, wakefulness after sleep onset (WASO), total 
sleep time, or percent time spent in REM sleep. 
• 
Generally, these studies were of moderate-to-high quality. 
 
 
In patients with secondary sleep disorders:  
Melatonin did not have an effect on sleep onset latency in people with a secondary sleep 
disorder; the effects of melatonin did not differ between children and adults; the effect of 
melatonin did not vary with dose or duration of treatment. 
• 
Melatonin increased sleep efficiency in people with a secondary sleep disorder (WMD: 1.9 
percent; 95-percent CI: 0.5 percent, 3.3 percent); the effect of melatonin did not vary by age, 
dose or duration of treatment. The magnitude of this effect appears to be clinically insignificant. 

2012-0120 
Rev. June 27, 2016 
9 
 
• 
Melatonin did not have an effect on WASO or percent time spent in REM sleep in people with a 
secondary sleep disorder, but increased total sleep time in this population 
• 
Generally, these studies were of moderate-to-high quality. 
Most studies use fast-release melatonin, but sustained-release preparations are commercially 
available. The doses used in most studies range from 0.5 to 20 mg [15].  
Side effects 
In general, melatonin seems to be well-tolerated, and few serious side effects have been reported to 
date. However, there is a lack of long-term studies, and little is known about the possible drug 
interactions.  
 
Antidepressants can have a sleep induction profile, such as SSRIs and tricyclic antidepressants.  
 
Hypnotics are the most common drug used to treat SD in patients with cancer.  
Benzodiazepines: In general population, benzodiazepines are effective in short-term management of 
insomnia, decreasing sleep latency and mid night awakenings and increasing total sleep duration. 
There are no randomized controlled trials assessing the effectiveness of benzodiazepines on sleep 
initiation and sleep duration in cancer patients [37, 42]. Despite the evidence of this type of hypnotics in 
the short - term treatment of insomnia, little is known about long-term effect of benzodiazepines. A large 
number of side-effects are associated to the use of benzodiazepines, including drowsiness and 
dizziness, increased risk of falls and hip fractures, potentiation of hypoventilation in patients taking 
opioids and risk of tolerance and dependence [45].  
 
Therefore, it is unlikely that an isolated intervention will be effective in treating this symptom. 
 
C. Need for a Multimodal Therapy: 
It is possible, that given the multiple factors that influence sleep, the effect of an isolated intervention 
might not be as effective as an intervention in which multiple factors are simultaneously addressed and 
treated. This idea is supported by the fact that several pathophysiologic mechanisms have been 
identified as mechanisms associated with the presence of sleep disturbances, and that each of the 
interventions to improve SD targets partially the mechanisms involved. We believe that a multimodal 
intervention to treat SD in patients with cancer, targeting all the known pathophysiologic mechanisms 
involved will have a synergistic effect, decrease the intensity and frequency of SD among these 
patients and as a consequence patient’s quality of life.  
 
D. Potential for interactions and synergism:  
CBT, reduces SD by direct brain effects and by improving motivation and mood, which contribute to 
and exacerbate fatigue [2, 23-27]. MP will have a positive effect on SD via central mechanisms, that is, 
by blocking the reuptake of dopamine and norepinephrine, acting on the reticular activating system 
(arousal), and mood and by improvement of fatigue. We hypothesize that combinations of CBT with 
light therapy, melatonin and/or MP will confer additional benefits exceeding those conferred by each 
treatments alone (that is, that there will be a synergistic effect) [2, 10-22]. In patients with cancer and 
SD, melatonin improves fatigue direct brain effects related to fatigue, but also reduces fatigue by 
modulating the inflammatory cytokines such as TNFα, IL-6 levels [31]. Likewise CBT potentially reduce 
SD by its action on IL-6, TNFα [31,49,50], thus raising the possibility of synergism with melatonin. Prior 
findings also lead us to hypothesize that CBT has the potential for synergism with methylphenidate 
because of CBT’s ability to reduce anxiety and improve mood by enhancing the neurotransmission of 

2012-0120 
Rev. June 27, 2016 
10 
 
noradrenaline, seratonin, 5-hydroxytryptamine, and dopamine [31]. In addition Light therapy, MP 
combined with CBT may have a synergistic effect in improvement of fatigue and thereby enhancing 
patients’ SD [31,32-34,49-51]. 
   
E. Significance of the Study:  
Despite CRF’s prevalence, severity, and effects on cancer patients’ QOL, few treatment options are 
available that can reduce SD [2,3]. One reason for this lack of effective treatments is that few controlled 
studies targeting SD have been conducted in patients with advanced cancer population. Hence, further 
studies are needed [2,37]. The significance of this study is that it will allow us to obtain important 
preliminary data about the effects (i.e., clinical benefits) of safe, easily accessible and low cost 
interventions such as CBT, Light Therapy, Melatonin and MP and their combinations in the treatment of 
SD. The data collected from this novel randomized factorial design will enable us to assess the 
treatments used in this study[rapidly and efficiently], and but if more than one treatment combinations 
do appear effective, a larger study will be designed using estimates of intersubject variability and 
treatment efficacies estimated from this design. Our ultimate goal is to develop a single, effective, low-
cost, low-risk, easily accessible multimodal approach for the clinical management of SD that would 
potentially benefit many if not most cancer patients. 
 
II. 
Research design:  
 
 
A. Patient Recruitment:  
Eligible subjects will be recruited from MD Anderson Cancer Center. Potential participants will be 
approached by the research personnel and provided information about the study. Handouts that explain 
the study description and how subjects may benefit from participation will be provided to the patients. 
(See Appendix S) 
 
B. Feasibility  
Feasibility is based on the prior successful accrual in similar symptom control trials by our group 
[21,22,52,53] and on the great interest in complementary and alternative medicine in this population 
(83%) [54]. 
 
C. Patient Eligibility 
Patients: cancer patients currently on cancer therapy with a positive screening for SD (Screening PSQI 
score > 5). 
Inclusion criteria: 
1. 
Patients who are 18 years or older, cancer patients currently on cancer therapy with a positive 
screening for SD (Screening PSQI score > 5). 
2. 
Patients should have a Zubrod </= 2. 
3. 
Patients with no pain and with stable pain(defined as pain under control and on stable 
doses of opioids for 1 week) are eligible 
4. 
Memorial delirium assessment scale </= 13. 
5. 
Controlled pain and depression symptoms, if present (defined as no change in the Morphine 
equivalent dose of 30% or change in the dose of antidepressant medication in the past 2 weeks). 
6. 
All patients who are receiving chemotherapy and/or radiation therapy are eligible for study if 
they have completed > 1 week of radiation therapy, and if they have been approved to go on study by 
their primary oncologist. The PI/designated research staff of this study will obtain and document 
approval from the primary oncologist and principal investigator of the clinical trial in case the patient is 
on another clinical trial as referenced in the patient's study documents. 

2012-0120 
Rev. June 27, 2016 
11 
 
7.  
Laboratory test results within these ranges: Serum creatinine </= 2.0 mg/dL, Total bilirubin 
</=1.5 mg/dL, and AST (SGOT) and ALT (SGPT) </=2 x ULN or </= 5 x ULN if hepatic metastases are 
present. ULN= upper limit of normal. 
8. Patients on stable doses (defined as same dose for 2 weeks) of dexamethasone, mirtazapine, 
zolpidem,  benzodiazepines, phenothiazines are allowed to participate in the study. 
 
 
Exclusion criteria: 
(1) Have a major contraindication to methylphenidate (MP) (e.g., allergy/hypersensitivity to 
study medications or their constituents), light therapy (e.g., currently receiving UVA/UVB 
therapy), cognitive behavioral therapy (e.g., schizophrenia), or conditions making adherence 
difficult as determined by the attending physician.  
(2) Currently taking MP or have taken it within the previous 10 days. 
(3) Patients with a diagnosis of polysomnographically confirmed obstructive sleep apnea or narcolepsy. 
(4) Regularly used cognitive behavioral therapy in the last 6 weeks for sleep disturbance.  
(5) Unable to complete the baseline assessment forms or to understand the recommendations 
for participation in the study.  
(6) Currently with a diagnosis of major depression, manic depressive disorder, obsessive-
compulsive disorder, or schizophrenia). 
(7) Need monoamine oxidase inhibitors, tricyclic antidepressants, or clonidine.  
(8) Have glaucoma.  
(9) Symptomatic tachycardia and uncontrolled hypertension (determined to be clinically 
significant by the PI). 
(10) 
Currently receiving anticonvulsants (phenobarbital, diphenylhydantoin, primidone), 
phenylbutazone, clonidine, and/or tricyclic drugs (imipramine, clomipramine, or 
desipramine). 
(11) 
Unable to speak and understand English 
(12) 
Persons with congenital blindness and self-reported acquired blindness (independent of 
the cause) with no light perception 
(13) 
Patients with a history of retinal disease 
(14) 
Patients with >2 hours of direct exposure to outdoor natural light per day by interview with   
the Study Coordinator. 
(15) 
Patients with a diagnosis of obesity hypoventilation syndrome. 
(16) 
Positive pregnancy test for women of childbearing potential, as defined by intact uterus 
and ovaries, and a history of menses within the last 12 months.  Pregnancy test to be 
performed no greater than 14 days prior to consent in study. In cases of women with 
elevated b-HCG, these candidates will be eligible to participate so long as the level of b-
HCG is not consistent with pregnancy. Women of childbearing potential need to be on or 
use contraception, or be abstinent during the study period. Their male partners must also 
use contraception (condom) or maintain abstinence. Birth controls specifications: Women 
who are able to become pregnant must use birth control during the study and for 30 days 
after. 
(17) 
Women who are nursing. 
(18) 
Patients who have taken Melatonin within the past two weeks. 
 
D.  Clinical Trial Design:  

2012-0120 
Rev. June 27, 2016 
12 
 
For this study, we will use a randomized factorial design. Sixty-four patients will be randomized equally 
among the 8 possible treatment combinations, 8 per arm. The randomized assignment of intervention 
versus placebo will be obtained via the Department of Biostatistics, Clinical Trial Conduct Website. 
 
E.  Treatment Plan:  
Potential study subjects will be asked for verbal consent (Appendix Q) prior to completing the 
PSQI to determine eligibility. 
Patients who are eligible (PSQI score > 5)  and interested in participating will be asked to give written 
consent and then randomized into 1 of the 8 arms of the study that include possible combinations of the 
3 interventions or their corresponding placebo treatments. The length of treatment is 15 days with 
follow up at Day 29 (+/- 1 week). The research nurse/coordinator will conduct all baseline assessments 
and follow-up as shown Table 4. All patients will receive CBT. Patients will receive combination of light 
therapy, melatonin and methylphenidate or their placebos (Pharmacy Innovations) in addition to CBT 
as part of the multimodal therapy. The pharmacological treatment assigned to individual patients will be 
known to only the statistician and the investigational pharmacy. The research nurse will then provide 
instructions and prescriptions for the study medications (drug or placebo) and will make referrals to the 
counselor for CBT. The randomized assignment of intervention versus placebo will be obtained via the 
Department of Biostatistics, Clinical Trial Conduct Website. The research nurse/coordinator will then 
perform scheduled assessment as per Table 4. The research nurse/coordinator will check compliance 
during weekly telephone call or in person visit. Patients will be asked if they have been documenting 
the administration times on the patient diary/pill diary (See Appendix N).  
 
Table 2. Treatment Arm Combinations (please see page 26 for description of arm combinations) 
 
 
 

2012-0120 
Rev. June 27, 2016 
13 
 
 
 
Placebo and control.  
The matching placebo will consist of colored capsules of similar appearance and size, since 
methylphenidate has little or no odor that will need mimicking. The placebo will include the 
inactive excipient methylcellulose. A matching placebo will be used to eliminate the placebo 
effect as a result of intervention.  
 E.1 Light treatment: The active treatment is a Litebook device (The Litebook Company Ltd., 
Alberta, Canada).  The device consists of 60 LEDs with spectral emission peak at 
approximately 464nm and fluorescent phosphors that provide a broader, secondary spectral 
peak near 564nm. Of the energy emitted over the range 400 to 700nm, about 48% is emitted 
over the range 420 to 508nm, and 37% is emitted over the range 512 to 616nm. Collectively 
the emitted light appears white. This device produces approximately 1350 lux at 20 inches. 
The control red light device is also produced by Litebook (The Litebook Company Ltd), and is 
identical in appearance and dimensions to the bright light device, with the exception that it 
emits at wavelength 680nm (i.e. red light) and at an intensity of 50 lux. The manufacturer 
documentation of the shelf-life of the LiteBook device for both the placebo and active devices is 
5 years. 
 
While dim red light may not be the ideal control due to its different color, brightness and the fact 
that patients may find out that they are getting the control, we believe it is an appropriate 
choice for the following reasons: 

2012-0120 
Rev. June 27, 2016 
14 
 
 
1. Dim red light has been used as control intervention in multiple randomized trials 
studying the effect of bright light therapy.[51-53]  In fact, a cancer fatigue study that is actively 
recruiting patients is using dim red light as control  
(http://clinicaltrials.gov/ct2/show/NCT00478257?term=litebook&rank=1) 
 
2. In our supportive care outpatient clinic, a great majority of patients are not aware of 
the effect of bright light therapy and its potential therapeutic effects.   
 
3. We will not only check the blinding, but also plan to ask our subjects at day 15 
whether they have tried to look up information about the devices, if yes by what means and 
what were their conclusions.  If the blinding is not successful, we will need to treat this as an 
open label study. 
 
4. The red light given is significantly dimmer (<50 lux vs 1350 lux) and not expected to 
provide substantial therapeutic effect.  While we cannot exclude any benefit from dim red light 
(especially placebo response), multiple studies using dim red light as control have been 
positive.   
 
5. Some authors have suggested that an inactivated negative ion generator can be used 
as control [10].  However, negative ion generators do not provide any light at all, making them 
less ideal as a control.  Importantly, while there is some evidence to support the use of 
negative ion generators for SAD, we have not been able to find any beneficial effects for sleep 
specifically, making it more difficult to justify their use.  Thus, we feel they are less ideal than 
dim red light at this time. 
 
6. We discussed with the manufacturer of the Litebook device, and dim white light is not 
available. 
The Litebook Company Ltd. has previously applied to the US Food and Drug Administration (FDA) 
for a study approval using the same device in the current proposed study.  FDA concluded that 
this is a non-significant risk device, as it “does not meet the definition of a significant risk device 
under 812.3(m) of the investigational device exemptions (IDE) regulation (21 CFR 812, available 
on 
the 
internet 
at 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocscfcfr/showCFR.cfm?CFRPart=812)” 
(Appendix).  As such, an IDE application is neither required to be submitted nor approved by FDA 
for a NSR study. 
Both versions of the device feature compliance monitoring capabilities, using HOBOware® data 
loggers embedded in each device.  'On/off' data with time/date stamp is easily uploaded to a 
computer for analysis via a USB port.  The necessary software and USB cables are provided with 
the devices. 
Light treatment assignment will be determined at the time of CTC registration. Once enrolled, 
study participants will be issued an active or control treatment device by a research staff for the 
patients to bring home (different from the blinded staff who will be performing study assessments).  
Subjects assigned to this device will be carefully instructed to the proper use of the light box with 
regard to positioning, distance, and duration of therapy: 
• 
Positioned the device on a flat surface about an arm’s length away from the subject, with the 
participant situated at an angle of approximately 30 degrees to the light, with their eyes at 
mid-fixture level.  Do not directly stare at the light.   

2012-0120 
Rev. June 27, 2016 
15 
 
• Use the device for 30 minutes each morning within 2 hours of arising (to complete treatment 
before noon if possible).  The devices should be used daily (7 days per week) for 15 days.    
• They will be asked not to disclose to the blinded research staff which treatment device they 
were assigned.  
Blinding: Since symptom expression is a subjective outcome, we would like to minimize 
ascertainment bias by using a double-blind design (i.e. research staff conducting the 
assessments, and the research subject).  This is done by  
1. The consent form stating that we are studying “two types of light, one of which is 
expected to be beneficial and the other is not”, rather than stating our interest in the effect 
of bright light. While patients can see which color of light they are getting, they would not be 
given any information as to whether they are receiving the active intervention or control. 
 
2. Study staff will be trained not to ask about the type/color of light. We also plan to 
document if at anytime there is an accidental breaking of the blinding. Study staff performing 
assessments will not provide the light boxes or know which arm the patients are randomized to. 
 
3. The light box will be provided by a separate research staff not involved in study 
assessments. This research staff member will show patients the device, but will not provide 
any information regarding the specific types of light, nor its potential effectiveness.  
 
4. We also plan to assess patients’ perception whether they received the active 
intervention or not at Day 15. If they were not generally successful in guessing the intervention, 
we will consider this a blinded study. Otherwise, we will consider the blinding to be 
unsuccessful.  Patients will also be instructed not to reveal which light they were assigned to the 
staff assessing their symptoms. This will improve the chances of maintaining the blinding.  
The research nurse/coordinator will check the compliance of the lightbook device usage during 
weekly telephone call or in person visit. 
Unblinding Procedure: 
1. The Statistician and the investigational pharmacist will have access to the codes/assignments. 
2. The codes will be revealed only If there is a safety issue and the treating physician needs to be 
aware of the treatment assignment. 
3. The PI should be contacted regarding the patient’s circumstances. 
4. Prior to unblinding a patient, the investigator or research team will inform the IND Office Medical 
Monitor.   
5. The Investigator will then give permission for the unblinding to the statistician and the investigational 
pharmacist. 
6. The investigator or research team will notify the DSMB and IRB of the unblinding. 
E.2 Methylphenidate Treatment.  
MP is very well tolerated when used in cancer patients, when used long-term in attention deficit 
disorder, and when used in the management of depression. A dose of 5 mg orally administered 
twice daily will be used. The last dose of the twice a day regimen should be prior to 3pm and 
the interval between doses should be at least 2 hours. This dose regimen has been well 
tolerated in these trials and in the current ongoing trial of methylphenidate for the treatment of 

2012-0120 
Rev. June 27, 2016 
16 
 
fatigue (a total 190 patients are enrolled to date).  We will instruct patients that methylphenidate 
may be taken without regards to meals and stored at room temperature. Patients will also 
receive a copy of the FDA-approved Medication Guide specific to methylphenidate. 
 
Contraindications.  Marked anxiety, tension, and agitation are contraindications to methylphenidate, 
since the drug may aggravate these symptoms. Methylphenidate is also contraindicated in patients’ 
known to be hypersensitive to the drug, in patients with glaucoma, motor tics or with family history or 
diagnosis of Tourette’s syndrome.  Methylphenidate is contraindicated during treatment with 
monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of a 
monoamine oxidase inhibitor.  Other contraindications include thyrotoxicosis, severe angina pectoris, 
and uncontrolled hypertension. 
Drug interactions.  The safety of using methylphenidate in combination with clonidine or other centrally 
acting alpha-2 agonists has not been systematically evaluated.  Methylphenidate may inhibit the 
metabolism of coumarin anticoagulants, anticonvulsants (Phenobarbital, diphenylhydantione, 
primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine).  Downward 
dosage adjustments of these drugs may be required when given concomitantly with methylphenidate.  
Serious adverse events have been reported in concomitant use with clonidine, although no causality for 
the combination has been established.  
Adverse reactions. Methylphenidate Side Effects 
 
It is not well known how often the side effects of methylphenidate may occur. 
 

2012-0120 
Rev. June 27, 2016 
17 
 
chest pain due to heart 
trouble  
irregular heartbeat 
abnormal heart sound 
fast, slow, or extra heartbeats 
bleeding in the brain 
blocked blood vessel in the 
brain (possible stroke)  
stroke 
blood vessel inflammation 
(possible bleeding and/or 
bruising) 
low blood pressure (possible 
dizziness/fainting) 
high blood pressure  
blood vessel disorder causing 
painful, cold, numb, and 
discolored fingers and/or toes 
hallucinations (seeing or 
hearing things that are not 
there) 
seizure 
mood changes (such as 
anger, anxiety, agitation, 
depression, aggressive 
behavior, mood swings, 
irritability, nervousness, 
and/or restlessness) 
confusion 
dizziness 
fatigue 
fever 
headache 
heightened alertness 
difficulty sleeping 
mood disorder with 
extremes of happiness 
and sadness 
obsessive-compulsive 
disorder  
neuroleptic malignant 
syndrome (possible high 
blood pressure, muscle 
stiffness, and/or fever) 
Tourette's syndrome 
(uncontrolled speech 
and/or muscle 
movements) 
physical tension  
psychosis (loss of contact 
with reality)  
tremors 
hair loss (partial or total) 
allergic skin reaction 
shedding and scaling of 
the skin (possible fatal 
loss of bodily fluids) 
increased sweating  
skin rash 
hives 
painful menstruation 
decreased sex drive 
impotence  
low red, white, and 
platelet counts  
abdominal pain 
loss of appetite 
constipation  
diarrhea 
upset stomach  
nausea 
vomiting 
weight loss 
dry mouth 
abnormal liver tests 
(possible liver damage) 
liver failure 
stunted growth 
joint pain 
uncontrolled movements  
muscle tightness  
abnormal sensation (such 
as pins and needles) 
dry eyes 
pupil dilation (possible 
light sensitivity) 
vision problems (such as 
double vision and blurry 
vision) 
cough 
difficulty breathing 
sore throat 
throat pain 
runny nose 
accidental injury related 
to physical activity  
life-threatening allergic 
reaction (such as difficulty 
breathing, low blood 
pressure, and/or organ 
failure) 
allergic reaction (possible 
swelling (ear),blisters, 
skin peeling, skin rash)  
grinding or clenching of 
teeth 
 
 
Methylphenidate may cause low blood cell counts (red blood cells, platelets, and white blood cells):  
• 
A low red blood cell count (anemia) may cause difficulty breathing and/or fatigue.  You may 
need a blood transfusion.  
• 
A low platelet count increases your risk of bleeding (such as nosebleeds, bruising, stroke, 
and/or digestive system bleeding).  You may need a platelet transfusion.   
• 
A low white blood cell count increases your risk of infection (such as pneumonia and/or severe 
blood infection).  Infections may occur anywhere and become life-threatening. 
Drug Dependence.  Methylphenidate has been abused and it has addictive potential. Our group has 
conducted five trials of methylphenidate, and we are not aware of any cases of abuse in cancer 
patients when treated with this drug. However, this drug has been abused by other patient 
populations, and therefore, patients will be informed about this risk and carefully monitored.  

2012-0120 
Rev. June 27, 2016 
18 
 
Information regarding abuse and all other side effects will be part of the research nurse-training 
program.   
Storage Information. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. 
Protect from light. 
 
All patients will be dispensed methylphenidate or placebo by the Investigational Pharmacy at MDACC.  
The medication will be provided free of charge. 
 
Disposal Information Any used methylphenidate or placebo will be returned to the research nurse or 
coordinator.  The research nurse or coordinator will then return the unused methylphenidate or placebo 
to Investigational Pharmacy and they will then dispose of the unused portion according to MDACC 
policy. 
 
Compliance for the use of the study drug will be documented by the research nurse/coordinator during 
their weekly telephone call or with an in person visit. 
 
E.3 CBT.  
Patients receiving CBT will receive 3 sessions between Baseline and Day 14+/- 3 days  (all by 
phone unless clinic time permits the first session to be in person); each session will last 
approximately 30 minutes each. Sessions will be led by a Master’s degree level counselor 
under Dr. Carmack’s supervision. The first session will cover sleep education and sleep 
hygiene. The second session will focus on cognitive strategies to target negative thoughts that 
could be contributing to or exacerbating sleep problems.  The final session will cover relaxation 
training including diaphragmatic breathing and guided imagery. Patients will be provided with a 
CD of relaxation exercises and will be encouraged to practice them daily for at least 10 
minutes. Patients will be provided with logs to monitor sleep, as well as record practice of the 
cognitive and behavioral skills taught in each session. These logs will be reviewed at each 
session. Telephone counseling sessions will be audiotaped for quality control. Dr. Carmack will 
review a random sample of audiotaped sessions to verify coverage of the weekly review, 
teaching of cognitive-behavioral skills, skills practice and discussion, and assignment of 
homework for practice.  
 
 
We do not expect any serious adverse events or adverse events associated with any of the 
treatment combinations. Any adverse event or serious adverse event deemed treatment-
related will trigger will be reviewed by MD Anderson Cancer Center’s Data Monitoring Safety 
Board and an assessment of whether one or more treatment combinations should be halted to 
ensure patient safety. 
 
E.4 Melatonin: The dose of 20mg orally and the modality of administration at bed time has 
been chosen because it was found to be effective based on prior studies [57] for fatigue related 
symptoms of sleep, cachexia and also well tolerated based on prior studies (15-18) in our RCT 
study ( NCT00513357).     
 
All patients will be dispensed melatonin or placebo by the Investigational Pharmacy at MDACC.  The 
medication will be provided free of charge. 
Contraindications: Melatonin may cause drowsiness. Patients are not to drive, operate 
machinery, or do anything else that could be dangerous until you know how you react to this 
product. Using this product alone, with certain other medicines or with alcohol may lessen their 
ability to drive or to perform other potentially dangerous tasks. Patients will be instructed to avoid 
drinking alcohol or taking other medications that cause drowsiness (eg, sedatives, tranquilizers) 

2012-0120 
Rev. June 27, 2016 
19 
 
while taking this product. This product will add to the effects of alcohol and other depressants. 
Patients will be asked to consult a pharmacist if they have questions about which medicines are 
depressants. This product has not been approved by the Food and Drug Administration (FDA) as 
safe and effective for any medical condition. The long-term safety of dietary supplements is not 
known. PREGNANCY and BREAST-FEEDING: Patients will be advised to not use this product if 
you plan to become pregnant. It may have a contraceptive effect. Melatonin is not recommended 
for use during pregnancy. Because of the potential risk to the infant, breast-feeding while using 
this product is not recommended.  
 
Adverse Reactions: Melatonin Side Effects 
 
It is not well known how often the side effects of melatonin may occur. 
 
headache 
drowsiness 
mood swings 
giddiness (abnormal 
excitement) 
worsening symptoms of 
existing depression 
depression 
nausea 
infection 
 
 
Storage Information: Store at room temperature away from heat, moisture, and light.  
 
 
Adherence: 
Patients with similar characteristics to those of patients we will admit to the study have 
demonstrated strong adherence to assessments of the same duration in studies conducted by 
our group [21,22,52,53,63]. These assessment tools have been validated and are reliable for 
use in the collection and analysis of data. Also, patients in this study will not undertake time-
intensive radiologic tests such as MRIs or drug pharmacokinetic studies, which are a common 
part of cancer clinical trials. This will help in completing the study in a timely manner and 
minimize attrition. 
 
Subject Burden:  The total time to complete the assessments will be approximately 30 
minutes. Many patients in our supportive care clinic are successfully prescribed CBT, light 
therapy and medications with excellent compliance (and therefore presumably low burden). 
Several aspects of the study design (e.g., scheduling around RT, using telephone 
interventions, administering methylphenidate on a simple dosing schedule) are also intended to 
minimize patient burden. Prior fatigue treatment trials conducted by our group have 
demonstrated strong adherence to assessments of the same duration [21,22,52,53,63]. A 
similar CBT trial by our group [59-62], found excellent adherence of approximately 83% at 6 
months and 84% at 12 months. As the counseling is done at patients’ home and on their own 
time schedule, we anticipate excellent adherence. This is based on similar current ongoing trial 
funded by NIH grant NR010162, which has a telephone counseling intervention with an 
adherence of 85% in 160 participants accrued to date. The MP schedule and dosing proposed 
here have been used in prior fatigue trials and in the current ongoing trial and it has been found 
to be well tolerated.  
 
III. Study Assessments 
i. Demographic Variables (APPENDIX A).  

2012-0120 
Rev. June 27, 2016 
20 
 
Include patient’s birth date, sex, marital status, ethnicity, education, job status, primary cancer, 
cancer treatment (s) within the last year, (surgery, chemotherapy, immunotherapy, or RT), and 
medications. 
 
ii. Outcome Measures:  
a) 
PSQI (APPENDIX B) The PSQI is a 19-item questionnaire that is an effective instrument in 
measuring the quality and patterns of sleep[64].It differentiates "poor" from "good" sleep by measuring 
seven areas: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep 
disturbances, use of sleeping medication, and daytime dysfunction over the last month.  Each area is 
rated from 0-3 with the higher score reflecting more severe sleep complaints.  The addition of all scores 
permits the analysis of the participant’s overall sleep experience. The PSQI can be used for both an 
initial assessment and ongoing comparative measurements across all healthcare settings.  The PSQI 
has internal consistency and a reliability coefficient (Cronbach's alpha) of 0.83 for its seven 
components.  Numerous studies using the PSQI have supported high validity and reliability.   The PSQI 
global score ranges from 0 to 21, with a score of 5 or greater indicating significant sleep disturbance.  
We will define response in this study using a reduction in PSQI global score at day 15 assessments of 
3 as compared to baseline. 
b) 
Functional Assessment of Chronic illness Therapy- Fatigue (FACIT-F): The FACIT-F forms the 
core of the FACT measurement system and consists of subscales assessing physical well being (PWB-
7 items), social/family well being (SFWB-7 items), emotional well being (EWB-6 items), functional well 
being (FWB-7 items), and relationship with doctor (RWD-2 items).  The FACIT-F yields a total score, as 
well as individual subscale scores, with higher scores reflecting better quality of life(66). The FACIT-F 
fatigue subscale has been used primarily in cancer patients to measure fatigue [66].  
The subscale consists of 13 items.  Patients rate the intensity of fatigue and its related 
symptoms on a scale of 0-4, from 0 "not at all" to 4 "very much".  Test-retest reliability 
coefficients for the fatigue subscale have ranged from 0.84-0.90.  This scale has demonstrated 
strong internal consistency (α = 0.93-0.95). 
c) 
Functional Assessment of Cancer Therapy: General (FACT-G): FACIT-F is a well-validated 
quality-of-life instrument widely used for the assessment of cancer-related fatigue and sleep 
disturbances in clinical trials. It consists of 27 general quality-of-life questions divided into four domains 
(physical, social, emotional, and functional). According to the scoring manual, the negatively worded 
items on the FACT were reverse scored so that the higher scores indicated more positive health states. 
Test-retest reliability coefficients for the FACIT-F subscale have ranged from 0.84–0.90 23. This scale 
has been shown to have strong internal consistency (α = 0.93–0.95). It has a sensitivity of 0.92 and 
specificity of 0.6923. 
Depression and anxiety:   
d) 
Depression and anxiety symptoms will be assessed by using the 14-item HADS (APPENDIX C) 
[67] questionnaire, which asks patients to underline the statement that most closely matches how they 
felt in the previous week. This questionnaire is valid and reliable in a number of clinical situations and 
has been widely used in cancer patients. 
Other common symptoms:  
e) 
The Edmonton Symptom Assessment Scale (ESAS) (APPENDIX D) [68] measures 10 common 
symptoms experienced during the previous 24 hours (pain, fatigue, nausea, depression, anxiety, 
drowsiness, shortness of breath, appetite, sleep, and feeling of well-being); this questionnaire has been 
found to be valid and reliable in cancer populations.  
Physical activity:  
f) 
Actigraphy: The Actiwatch 2 portable recorder (Mini Mitter Company, Inc. A Respironics, Inc., 
OR, USA) is a small wrist-worn device, sized 1 X 2 X 4 cm, containing an accelerometer that is 
optimized for highly effective sleep-wake inference from wrist activity that has been previously validated 
[25,42,69,70].   

2012-0120 
Rev. June 27, 2016 
21 
 
Data will be collected in 1-min epochs and transferred, via an interface, to a computer to be 
analyzed.  Actigraphy will be analyzed for Days 1 to 15 (+/- 3 days).   
 
 
Aim 3. To determine the safety of MMT (type, frequency, and severity of the adverse events). 
 
g.) Insomnia Severity Index: is a seven item questionnaire designed to evaluate insomnia severity on 
the basis of difficulties falling asleep, night-time awakening, early morning awakenings, impairment of 
daytime functioning due to sleep problems, noticeability of impairments, distress or worry caused by 
sleep difficulties, and dissatisfaction with sleep. Each item is rated using a five-point likert scale ranging 
from 0 (not at all) to 4 (very much), for a total score ranging from 0-28. The ISI has adequate 
psychometric properties and is sensitive to measure treatment response (71, 72). 
 
h.) The Memorial Delirium Assessment Scale (MDAS) is a clinician-rated, 10-item rating scale used 
to assess the severity of delirium over the past several hours. Each item is scored from 0 to 3 
depending on its intensity and frequency (possible range of total score, 0-30). The 10 items are 
anchored with statements reflecting the severity or intensity of the symptom and were reviewed by 
experienced clinicians to ensure ease of administration and the ability to generate accurate (reliable) 
ratings. The resulting scale, which requires approximately 10 minutes to administer, integrates 
behavioral observations and objective cognition testing. When items cannot be administered, scores 
can be prorated from the remaining items to an equivalent 10-item score. The MDAS is highly 
correlated with existing measures of delirium and cognitive impairment, yet offers several advantages 
over these instruments for repeated assessments, which are often necessary in clinical research. The 
cut of 13 has been used based on studies in cancer and non-cancer palliative care population (73, 74). 
 
i.) 
Global Symptom Evaluation. This instrument is to estimate the minimal important difference in 
symptoms before treatment and after treatment.  Patients will be asked about their symptoms (worse, 
about the same, or better) after starting study treatment. If their answer is better, patients will be asked 
to rate how much better their symptoms are (almost the same, hardly any better at all, a little better, 
somewhat better, moderately better, a good deal better, a great deal better, a very great deal better). If 
their answer is worse, patients will be asked to rate how much worse their symptoms are (almost the 
same, hardly worse at all, a little worse, somewhat worse, moderately worse, a good deal worse, a 
great deal worse, a very great deal worse). This evaluation will be performed on day 15 and day 29. 
 
CBT, Light Therapy, Melatonin and MP have been used in prior trials by our team and found to be safe. 
We do not expect any serious adverse events or adverse events associated with any of the treatment 
combinations.  However, we will monitor the safety of the interventions. 
 
MP and Melatonin: 
 Instructions for the administration of MP and Melatonin will be provided by the research 
nurse/coordinator. If the patients have questions in regards to administration and side effects, the nurse 
will answer and refer further questions to the PI (S.Y) or co-PI (E.B). The side effects will be monitored 
as per the toxicity assessment schedule at Day 8, 15, 29, and 45 (or 1 month after the last MP or 
Melatonin dose. 
 
 
 
CBT:  
This treatment plan has been successfully and safely used in cancer patients and in prior trials by our 
team [59-62]. However, in the event of severe emotional distress or mood disturbance, referral to the 

2012-0120 
Rev. June 27, 2016 
22 
 
psychiatry team will be made. We will monitor for any suicidal thoughts or ideation. The assessment of 
mood will be conducted during each CBT patient session.  
 
M. D. Anderson Cancer Center’s Data Monitoring Safety Board will review any adverse event or serious 
adverse event that is suspected to be treatment-related to ensure patient safety.  
 
Table 4. 
ASSESSMENTS 
BASELINE 
(± 1 week) 
DAY 
3 
(± 3) 
DAY 
8 
(± 3) 
DAY 15 
(± 3) 
Day 29 
F/U 
(± 1 week) 
Day 45 
Post 
Treatment 
F/U or 30 
Days 
After Last 
Treatment 
(± 5)  
History/Physical Exam 
X 
 
 
 
X* 
 
Zubrod score 
X 
X* 
 
 
X* 
 
Medication review 
X 
X* 
X* 
X* 
X* 
 
 
 
 
 
 
 
 
Edmonton Symptom 
Assessment Scale (ESAS) 
X 
X* 
X* 
X* 
X* 
 
FACIT-F, Functional 
Assessment of Cancer 
Therapy - General (FACT-G) 
,HADS, PSQI , Insomnia 
Severity Index 
X 
X* 
X* 
X* 
X* 
 
Light therapy compliance 
evaluation  
X 
 
X* 
X* 
 
 
Cognitive behavioral therapy 
X 
 
X* 
X* 
 
 
Actigraphy 
X** 
 
 
 
 
 
Hematology/chemistry 
(including Calcium and 
glucose if not done within the 
past 15 days) if not done in the 
past 4 months)   
X*** 
 
 
 
X 
 
Toxicity evaluation 
X 
X* 
X* 
X* 
X* 
X* 
Blinding Check 
 
 
 
X* 
 
 
Pregnancy Testing (for women 
of child bearing age) 
X 
 
 
 
 
 
Memorial Delirium 
Assessment Scale (MDAS) 
X 
 
 
 
 
 
Global Symptom Evaluation 
 
 
 
X 
X* 
 
 
 
 
 
 
 
 
*In person or telephone evaluation 
**1st week after baseline assessment and 1 week prior to the primary end point 
***Hematology at Baseline only 

2012-0120 
Rev. June 27, 2016 
23 
 
 
 
Monitoring plan:  
All Grade≥ 2 toxic effects reported by patients in this trial will be evaluated by the principal investigator 
and treating physician or by an attending physician if the PI is not available, to determine whether the 
toxic effects were due to a study intervention. We will monitor for safety according to the procedures 
detailed in the section. Any treatment or treatment combination that is determined by the PI to have 
caused a significant toxicity (significant toxicity and toxic effects are defined as any Grade 3 or 4 toxicity 
that is intervention-related) in more than 1 of the first 6 patients to whom the treatment or treatment 
combination was administered (even if administered with other treatments) will be dropped from the 
study design. We will use the CTCAE version 4.0.  We will collect adverse events (including abnormal 
values) according to the Recommended Adverse Event Recording Guidelines on page 22. If a 
treatment or treatment combination is administered to more than 6 patients (possibly in conjunction with 
other treatments), it will be dropped from the design if it is determined by the PI to be responsible for 
2/6, 3/9, 4/12, 5/15, 6/18, 7/21, 8/24, 9/27, 10/30, 11/31 toxic effects. These stopping boundaries 
correspond to dropping treatment combinations from the study if the posterior probability that they 
result in greater than 33% DLT exceeds 0.5 when a non-informative (Jeffreys) prior is assumed for this 
probability a priori. For example, if it happens that the first two patients enrolled in the trial are assigned 
to receive light therapy and melatonin + MP, and if both patients experience grade 3 toxic effects that 
the PI determines were due to the light therapy, then all treatment combinations involving light therapy 
would be dropped from the factorial design because the 2/6 stopping boundary would have been 
reached for this treatment combination. The following toxicities are confirmed to count towards the 
stopping rule: dizziness, anorexia, restlessness, and tachycardia. 
 
The determination of whether a toxic effect (grade 3, 4) was due to the symptom treatment combination 
received by the patient (rather than by the primary chemotherapy agent or radiation therapy) will be 
made by the PI in consultation with the treating physician. In addition, toxic effects (grade 3, 4) will be 
counted against all higher-order treatment combinations whenever at least 1 toxic effect is observed for 
a specified treatment. For example, if (at least) one treatment toxic effect (grade 3, 4) is attributed to a 
patient who receives intervention melatonin and MP, then toxic effects observed in patients who receive 
intervention melatonin, CBT, and MP will also be attributed toward those experiencing toxic effects with 
the combination of intervention melatonin and MP alone. Patient toxic effects (grade 3, 4) will also be 
counted against lower-order treatment combinations when the principal investigator and treating 
physician determine that the toxic effect (grade 3, 4) could have been the result of one of the 
component treatments alone. For example, grade 3 diarrhea observed in a patient assigned to 
melatonin and CBT might also be counted against the single-agent treatment of cognitive behavioral 
therapy. Any adverse event or serious adverse event deemed treatment-related will trigger a review of 
the protocol and an assessment of whether one or more treatment combinations should be halted.   
 
Unblinding of the Light therapy, Melatonin and Methylphenidate arm: If unexpected serious side effect 
attributable to the study treatment occurs the blind code will be broken), patients will be taken off study, 
and appropriate interventions will be provided to the patient. 
Adverse events will be documented in the medical record and entered into the case report form 
according to the Recommended AE recording guidelines for Phase II protocols. 
 
The Investigator or physician designee is responsible for verifying and providing source documentation 
for adverse events and assigning the attribution for each event for all subjects enrolled on the trial. 
PDMS will be used as the electronic case report form (CRF) for this protocol and protocol specific data 
will be entered into PDMS. 
 

2012-0120 
Rev. June 27, 2016 
24 
 
Recommended Adverse Event Recording Guidelines 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
 
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase II  
 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
 
 
IV. Statistical Considerations:  
Factorial Randomization:  
A key component of this proposal is the use of a randomized factorial design to rapidly assess the 
efficacy of a large number of potential treatment(s) and treatment synergies [28,29]. This design 
exploits the fact that treatments evaluated during this project are known a priori to have neither minimal 
toxic effects nor toxic interactions with each other. In this sense, this trial differs from most clinical trials; 
in general, cancer treatments are associated with significant toxic effects, and these effects increase 
when the treatments are administered simultaneously with other potentially toxic treatments. Because 
the symptom treatments considered in this project do not share these features of standard cancer 
therapies, it will be possible to assign multiple treatments to the same patients. This in turn will allow us 
to assign treatments according to a randomized version of a factorial design. The primary advantage of 
the factorial design derives from the efficiency with which main treatment effects and second-order 
interactions between treatments can be evaluated. Assuming that there are n patients enrolled into the 

2012-0120 
Rev. June 27, 2016 
25 
 
trial, n/2 patients will be assigned to every treatment, and the remaining n/2 patients will be available to 
serve as controls. Ignoring higher-order interactions between treatments, this means that the main 
effects of each treatment will be estimable with the same precision as they would be in a two-arm trial 
involving only that treatment. Similar gains in efficiency will also be accrued in evaluating second-order 
synergies among treatments. 
 
Sixty-four patients will be randomized equally among the 8 possible treatment combinations, 8 per arm. 
Randomized block allocation with a block size of 8 will be used to ensure that the first 8 patients include 
1 with each treatment combination. The randomization will be performed by Dr. Kenneth R. Hess in the 
Department of Biostatistics in the Division of Quantitative Sciences. There will be a primary and a 
secondary statistical contact to ensure that the process proceeds smoothly. The trial will be placebo-
controlled. Because 8 patients are required for a single replication of the factorial design with 3 
treatments, a total of 64 patients will be used in this trial. 
 
 
 
 
Statistical Analyses Plan:   
Aim 1. The primary outcome variable for this study is the change in PSQI score. The value of this 
variable for patient i is denoted as fci. (PSQI change). The primary goal of this study is to assess (by 
PSQI score change) the three treatments used in this study(without the need of a second, larger study), 
but if one or more treatment combinations do appear effective, a larger study will be designed using 
estimates of intersubject variability and treatment efficacies estimated from this design. Estimates of 
treatment effects and combinations of treatment effects will be obtained by using standard linear 
regression techniques in which the change in PSQI values are regressed on indicator variables that 
represent treatment combinations that received 3 main effects for the primary treatments, 3 two-way 
interaction terms for each combination of two treatments, and 1 three-way interaction effects, which will 

2012-0120 
Rev. June 27, 2016 
26 
 
be included in the linear regression model. The resulting regression model can be expressed as 
follows: 
 
In this equation, 
 denotes assignment of patient i to treatment 1, and 
 denotes the 
mean effect of treatment 1 on a randomly selected patient’s PSQI score. 
denotes 
the assignment of treatments/interventions 1 and 2 to patient i, and 
 represents the 
average effect of this treatment on the fci. score. Similar notation applies to other treatment 
combinations. Note that the parameter
 represents the additional or synergistic treatment 
effect of treatments 1 and 2 when these treatments are assigned together, over and above the 
effects that these treatments have alone (i.e., 
+
). The term 
denotes random error in 
reported fci values, which is normally distributed with mean 0 and variance 
equal to 11.5^2 
= 132. 
 
Sample size justification:  
In this study, we will assess three treatments (Light therapy, Melatonin, MP) and their placebo 
treatments with CBT in 8 replications of a complete factorial design.  A total of 32 patients will receive 
each primary treatment (Light therapy, Melatonin, MP) and 32 will not. Within each group of 32, the 
allocation of the other treatment combinations will be balanced so that the additive effects of the other 
treatments cancel out; this means that we will be able to make comparisons between each of the 3 
main treatments with similar level of accuracy as if we had performed 3 trials, each with 64 patients. In 
other words, the variance of the estimate of the main treatment effects is similar as if the trial had been 
performed with 64 patients, 32 receiving treatment and 32 receiving placebo. For the three second-
order interactions, comparisons will have similar error variance that would have been estimated with 16 
patients assigned to the two-drug combination and 48 to placebo. The variance of the estimate of the 
effect of the three-drug combination will be similar to the variance that would be estimated if 8 of 64 
patients were receiving the three-drug combination and 56 were receiving the placebo. Thus data 
collected from this novel randomized factorial design will enable us to assess the three treatments used 
in this study(without the need of a second, larger study), but if one or more treatment combinations do 
appear effective, a larger adaptive randomized study will be designed using estimates of intersubject 
variability and treatment efficacies estimated from this design. 
 
Although the goal of this trial is to obtain preliminary estimates of the efficacy of various treatment 
combinations, for completeness we have provided a limited table of operating characteristics below. 
The entries in the table 6 represent the power that we would have in detecting treatment effects of the 
given magnitude based on the factorial design alone, assuming that no treatments are dropped from 
the study design due to feasibility considerations. All analyses are based on intent-to-treat, and patients 
dropping out before administration of the final PSQI score we would use the most recent PSQI score 
(even if it is baseline) as the estimated final score. All entries in the table are based on an assumption 
that tests for significance are performed at the 5% level. 
 
Table 5: Power to detecting treatment effects of the given magnitude based on the 
factorial design 
 
Treatment 
Power 
1) 
= 5 
12% 
fci = β0 + β1Ind(T1) + β2Ind(T2) + ...+ β1,2Ind(T1,T2) + ...+ β1,2,3Ind(T1,T2,T3 ) + εi
Ind(T1)
β1
Ind(T1,T2)
β1,2
β1,2
β1
β2
εi
σ 2
1
β

2012-0120 
Rev. June 27, 2016 
27 
 
2) 
= 7 
19% 
3) 
= 10 
33% 
4) 
= 12 
44% 
5) 
= 15 
62% 
6) 
= 5 
9% 
7) 
= 7 
12% 
8) 
= 10 
19% 
9) 
= 12 
25% 
10) 
= 15 
37% 
11) 
 = 5 
7% 
12) 
 = 7 
8% 
13) 
 = 10 
12% 
14) 
 = 12 
15% 
15) 
 = 15 
21% 
 
Aim 2. As a secondary objective of this project, we will perform exploratory data analyses to examine 
associations between patients’ change in PSQI score and the secondary measures of Insomnia 
Severity Index, FACIT-F, HADS, ESAS, and Actigraphy. Since each of these variables is also 
continuous and measured at the same points in time, we will perform multivariate regression analyses 
to determine the predictive relationship of each of these variables on PSQI and change in PSQI scores. 
With use of actigraphy, we would analyze differences between participants receiving the MMT or the 
placebo treatment. This analysis will be based on fitting mixed effect linear models with actigraphy data 
as the response variables, and treatment intervention, demographic variables, and treatment site as 
independent variables. 
 
The primary analyses will include only information from baseline and Day 15, but other analyses will 
include information from all three time points (baseline Day 8, and Day 15). Finally, we will expand the 
regression equation to include patient demographic information (i.e., age, ethnicity, and baseline ESAS 
symptoms and referral site) to determine whether these variables are significant as predictors of 
change in the PSQI score. Note that because our primary outcome variable is change in the PSQI 
score, additive effects of the demographic and site variables can be expected to approximately cancel 
(i.e., if gender-female has the effect of adding c units to a PSQI score, by taking differences within 
subjects, the constant c cancels out). Similar comments apply also to potential referral site effects. 
Similarly we will summarize the PSQI change and secondary outcomes as detailed above at Day 29 
follow-up. 
1
β
1
β
1
β
1
β
2
,1
β
2
,1
β
2
,1
β
2
,1
β
2
,1
β
3,2
,1
β
3,2
,1
β
3,2
,1
β
3,2
,1
β
3,2
,1
β

2012-0120 
Rev. June 27, 2016 
28 
 
 
Feasibility and Adherence: Study treatments will be deemed to be feasible if ≥60% of patients assigned 
to each treatment are adherent.  Adherence to the CBT will be defined as the ability to complete ≥60% 
of the scheduled intervention. Adherence to the each of the medication arms will be defined as the 
ability to complete 60% of the scheduled study medication (methylphenidate, melatonin) or placebo 
regimen. Adherence to the Light therapy or its Placebo will be defined as the ability to complete ≥60% 
of the scheduled intervention. Logistic regression analyses will be used to explore factors related to 
adherence for treatments that are dropped from study.  
 
Aim 3. Information about toxic effects and tolerability will be summarized.  
 
V. Serious Adverse Event Reporting: 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the patient, in the 
view of the initial reporter, at immediate risk of death from the adverse experience as it occurred. It 
does not include an adverse experience that, had it occurred in a more severe form, might have caused 
death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered a serious adverse drug experience when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32). 
• Important medical events as defined above, may also be considered serious adverse events. Any 
important medical event can and should be reported as an SAE if deemed appropriate by the 
Principal Investigator or the IND Sponsor, IND Office. 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE must be 
reported to the IRB in accordance with the timeframes and procedures outlined in “The University of 
Texas M. D. Anderson Cancer Center Institutional Review Board Policy for Investigators on Reporting 
Serious Unanticipated Adverse Events for Drugs and Devices”.  Unless stated otherwise in the 
protocol, all SAEs, expected or unexpected, must be reported to the IND Office, regardless of 
attribution (within 5 working days of knowledge of the event). 
• All life-threatening or fatal events, that are unexpected, and related to the study drug, must have a 
written report submitted within 24 hours (next working day) of knowledge of the event to the Safety 
Project Manager in the IND Office.   
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety reporting to 
the IND Office and MDACC IRB.  

2012-0120 
Rev. June 27, 2016 
29 
 
• Serious adverse events will be captured from the time of the first protocol-specific intervention, until 
30 days after the last dose of drug, unless the participant withdraws consent. Serious adverse events 
must be followed until clinical recovery is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution of the event. 
• Additionally, any serious adverse events that occur after the 30 day time period that are related to the 
study treatment must be reported to the IND Office. This may include the development of a secondary 
malignancy. 
 
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager IND 
Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
    
 
VI. Future studies:  
At the end of this study, we will have obtained evidence on the combined interventions most likely to be 
effective for the management of SD, patient adherence, and side effect profiles. The magnitude and 
variance of treatment effects estimated from the outcomes of this trial will be used to design future 
trials, if needed, between promising treatments identified during this trial.  In addition, the effect sizes 
and interpatient variability of treatment effects estimated during this trial will be used to design future 
trials for similar treatments in other populations of cancer patients. In addition, this study will provide 
preliminary data for further studies exploring the biological and psychosocial mechanisms mediating 
SD. 
 
VII. Statement of Cancer Relevance:  
SD is the most common complaint of patients with Advanced Cancer. SD has detrimental effects on 
patients' physical, psychological, social, occupational functioning and ability to continue cancer 
treatment. However there are limited treatment options for SD. Preliminary data by our research team 
and others suggest that Cognitive behavioral therapy Melatonin and Methylphenidate play important 
role in reduction of SD. In this study, we propose the novel use of CBT in addition to multidimensional 
treatment combinations, MMT [Light Therapy, Melatonin and MP] to target the multifactorial SD in a 
well-defined population. An effective low cost low risk easily accessible treatment for SD would benefit 
a large number of cancer patients. 
 
 
 

2012-0120 
Rev. June 27, 2016 
30 
 
References 
 
1. Koopman C, Nouriani B, Erickson V, et al. Sleep disturbances in women with metastatic breast 
cancer. Breast Journal. 2002;8(6):362-370. 
2. Berger AM, Parker KP, Young-McCaughan S, et al. Sleep/wake disturbances in people with 
cancer and their caregivers: state of the science. Oncology Nursing Forum. 2005;32(6):E98-
126. 
3. Lianqi L, Ancoli-Israel S. Sleep Disturbances in Cancer. Psychiatric Annals. 2008;38(9):627-
634. 
4. Yennurajalingam.S, Chisholm.G, Palla S. L., Bruera. Sleep disturbance in patients with 
advanced cancer: Frequency and factors associated with response to specialist-based 
outpatient supportive care. J Clin Oncol 29: 2011 (suppl; abstr 9069). 
5. Redwine L, Hauger RL, Gillin JC, Irwin M. Effects of Sleep and Sleep Deprivation on Interleukin-
6, Growth Hormone, Cortisol, and Melatonin Levels in Humans. Journal of Clinical 
Endocrinology & Metabolism. October 1, 2000 2000;85(10):3597-3603. 
6. Davidson JR, MacLean AW, Brundage MD, Schulze K. Sleep disturbance in cancer patients. 
Social Science & Medicine. 2002;54(9):1309-1321. 
7. Lamberg L. Sleep Disorders, Often Unrecognized, Complicate Many Physical Illnesses. JAMA: 
The Journal of the American Medical Association. November 1, 2000 2000;284(17):2173-2175. 
8. Sateia M, Lang B. Sleep and cancer: Recent developments. Current Oncology Reports 
2008;10:309-18. 
9. Desan PH, Weinstein AJ, Michalak EE, et al. A controlled trial of the litebook light-emitting diode 
(LED) light therapy device for treatment of seasonal affective disorder (SAD). BMC Psychiatry. 
2007;7:38. 
10. Tuunainen A, Kripke DF, Endo T. Light therapy for non-seasonal depression. Cochrane 
Database Syst Rev. 2004;(2)(2):CD004050.  
11. Terman M, Lewy AJ, Dijk DJ, Boulos Z, Eastman CI, Campbell SS. Light treatment for sleep 
disorders: Consensus report. IV. sleep phase and duration disturbances. J Biol Rhythms. 
1995;10(2):135-147. 
12. Ancoli-Israel S, Martin JL, Kripke DF, Marler M, Klauber MR. Effect of light treatment on sleep 
and circadian rhythms in demented nursing home patients. J Am Geriatr Soc. 2002;50(2):282-
289. 
13. Golden RN, Gaynes BN, Ekstrom RD, et al. The efficacy of light therapy in the treatment of 
mood disorders: A review and meta-analysis of the evidence. Am J Psychiatry. 
2005;162(4):656-662. 
14. Buscemi N, Vandermeer B, Pandya R, Hooton N, Tjosvold L, Hartling L, Baker G, Vohra S, 
Klassen T. Melatonin for Treatment of Sleep Disorders. 
http://www.ahrq.gov/clinic/epcsums/melatsum.htm. Accessed as of Jan 2012.  
15. Garfinkel D, Laudon M,Nof D, Zisapel N. Improvement of sleep quality in elderly people by 
controlled release melatonin. Lancet.1995,Vol/Iss/Pg.346/89743(541-544).  
16. Oldani A Ferini-Strambi L Zucconi M Stankov B Fraschini F Smirne S Melatonin and delayed 
sleep phase syndrome:ambulatory polygraphic evaluation. Neuroreport. 6(1):132-4 1994 Dec 30 

2012-0120 
Rev. June 27, 2016 
31 
 
17. Zhdanova IV Wurtman RJ Lynch HJ Ives JR Dollins AB Morabito C Matheson JK Schomer DL 
Sleep-inducing effects of low doses of melatonin ingested in the evening. Clinical Pharmacology 
and Therapeutics. 57(5): 552-8, 1995 May. 
18. Kooij JJ, Middelkoop HA, van Gils K, Buitelaar JK. The effect of stimulants on nocturnal motor 
activity and sleep quality in adults with ADHD: an open-label case-control study. J Clin 
Psychiatry. 2001 Dec;62(12):952-6. 
19. Sobanski E, Schredl M, Kettler N, Alm B. Sleep in adults with attention deficit hyperactivity 
disorder (ADHD) before and during treatment with methylphenidate: a controlled 
polysomnographic study. Sleep. 2008 Mar;31(3):375-81. 
20. Bruera E, Driver L, Barnes EA, et al. Patient-Controlled Methylphenidate for the Management of 
Fatigue in Patients With Advanced Cancer: A Preliminary Report. Journal of Clinical Oncology 
2003;21:4439-43. 
21. Bruera E, Valero V, Driver L, et al. Patient-Controlled Methylphenidate for Cancer Fatigue: A 
Double-Blind, Randomized, Placebo-Controlled Trial. Journal of Clinical Oncology 
2006;24:2073-8. 
22. Savard J, Simard S, Ivers H, Morin CM. Randomized Study on the Efficacy of Cognitive-
Behavioral Therapy for Insomnia Secondary to Breast Cancer, Part I: Sleep and Psychological 
Effects. Journal of Clinical Oncology 2005;23:6083-96. 
23. Espie CA, Fleming L, Cassidy J, et al. Randomized Controlled Clinical Effectiveness Trial of 
Cognitive Behavior Therapy Compared With Treatment As Usual for Persistent Insomnia in 
Patients With Cancer. Journal of Clinical Oncology 2008;26:4651-8. 
24. Ancoli-Israel S. Recognition and Treatment of Sleep Disturbances in Cancer. Journal of Clinical 
Oncology. December 10, 2009 2009;27(35):5864-5866. 
25. Epstein DR, Dirksen SR. Randomized trial of a cognitive-behavioral intervention for insomnia in 
breast cancer survivors. Oncology Nursing Forum. 2007;34(5):E51-59. 
26. Morin CM, Vallières A, Guay B, et al. Cognitive Behavioral Therapy, Singly and Combined With 
Medication, for Persistent Insomnia. JAMA: The Journal of the American Medical Association. 
May 20, 2009 2009;301(19):2005-2015. 
27. Fisher. R.A. The design of experiments (1935). 
28. Wu J, and Hamada M. Experiments: Planning, Analysis, and Parameter Design 
29. Mystakidou K, Parpa E, Tsilika E, et al. Sleep quality in advanced cancer patients. Journal of 
Psychosomatic Research. 2007;62(5):527-533. 
30. Miller, A.H., et al., Neuroendocrine-immune mechanisms of behavioral comorbidities in patients 
with cancer. J Clin Oncol, 2008. 26(6): p. 971-82. 
31. Vgontzas, A.N., et al., Circadian interleukin-6 secretion and quantity and depth of sleep. J Clin 
Endocrinol Metab, 1999. 84(8): p. 2603-7. 
32. Morgan, K., Daytime activity and risk factors for late-life insomnia. J Sleep Res, 2003. 12(3): p. 
231-8. 
33. Opp, M.R., Cytokines and sleep. Sleep Med Rev, 2005. 9(5): p. 355-64. 
34. Vgontzas, A.N., et al., Adverse effects of modest sleep restriction on sleepiness, performance, 
and inflammatory cytokines. J Clin Endocrinol Metab, 2004. 89(5): p. 2119-26. 
35. Patel, S.R., et al., Sleep duration and biomarkers of inflammation. Sleep, 2009. 32(2): p. 200-4. 
36. Savard, J. and C.M. Morin, Insomnia in the context of cancer: a review of a neglected problem. J 
Clin Oncol, 2001. 19(3): p. 895-908. 

2012-0120 
Rev. June 27, 2016 
32 
 
37. Grond, S., et al., Prevalence and pattern of symptoms in patients with cancer pain: a prospective 
evaluation of 1635 cancer patients referred to a pain clinic. J Pain Symptom Manage, 1994. 9(6): 
p. 372-82. 
38. Montgomery, P. and J. Dennis, Cognitive behavioural interventions for sleep problems in adults 
aged 60+. Cochrane Database Syst Rev, 2003(1): p. CD003161. 
39. Chesson, A.L., Jr., et al., Practice parameters for the nonpharmacologic treatment of chronic 
insomnia. An American Academy of Sleep Medicine report. Standards of Practice Committee of 
the American Academy of Sleep Medicine. Sleep, 1999. 22(8): p. 1128-33. 
40. Morin, C.M., et al., Psychological and behavioral treatment of insomnia:update of the recent 
evidence (1998-2004). Sleep, 2006. 29(11): p. 1398-414. 
41. Berger, A.M., Update on the state of the science: sleep-wake disturbances in adult patients with 
cancer. Oncol Nurs Forum, 2009. 36(4): p. E165-77. 
42. Santos, R.V., S. Tufik, and M.T. De Mello, Exercise, sleep and cytokines: is there a relation? 
Sleep Med Rev, 2007. 11(3): p. 231-9. 
43. Chesson, A.L., Jr., et al., Practice parameters for the use of light therapy in the treatment of sleep 
disorders. Standards of Practice Committee, American Academy of Sleep Medicine. Sleep, 1999. 
22(5): p. 641-60. 
44. Bruera, E., et al., Rapid discontinuation of hypnotics in terminal cancer patients: a prospective 
study. Ann Oncol, 1996. 7(8): p. 855-6. 
45. Bonnet, M.H., et al., The use of stimulants to modify performance during sleep loss: a review by 
the sleep deprivation and Stimulant Task Force of the American Academy of Sleep Medicine. 
Sleep, 2005. 28(9): p. 1163-87. 
46. Brzezinski, A., et al., Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev, 
2005. 9(1): p. 41-50. 
47. Simeit, R., R. Deck, and B. Conta-Marx, Sleep management training for cancer patients with 
insomnia. Support Care Cancer, 2004. 12(3): p. 176-83. 
48. Andersen BL, Farrar WB, Golden-Kreutz DM, Glaser R, Emery CF, Crespin TR, Shapiro CL, 
Carson WE 3rd. Psychological, behavioral, and immune changes after a psychological 
intervention: a clinical trial. J Clin Oncol. 2004;22:3570–80. 
49. Atanackovic D, Kro¨ger H, Serke S, Deter HC. Immune parameters in patients with                  
anxiety or depression during psychotherapy. J Affect Disord. 2004;81:201–9. 
50. Cooper NJ, Keage H, Hermens D, et al. The dose-dependent effect of methylphenidate on 
performance, cognition and psychophysiology. J Integr Neurosci. 2005 Mar;4(1):123-44.  
51. Bruera E, Strasser F, Palmer JL, et al. Effect of fish oil on appetite and other symptoms in patients 
with advanced cancer and anorexia/cachexia: a double-blind, placebo-controlled study. J Clin 
Oncol. 2003;21:129-34. 
52. Bruera E, El Osta B, Valero V, et al. Donepezil for cancer fatigue: a double-blind, randomized, 
placebo controlled trial. J Pain Symptom Manage. 2003 Nov;26(5):1049-54. 
53. Richardson MA, Sanders T, Palmer JL, et al. Complementary/alternative medicine use in a 
comprehensive cancer center and the implications for oncology. J Clin Oncol. 2000 
Jul;18(13):2505-14. 
54. Martiny K, Lunde M, Unden M, Dam H, Bech P. The lack of sustained effect of bright light, after 
discontinuation, in non-seasonal major depression. Psychol Med. 2006;36(9):1247-1252. 
55. Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, Van Someren EJ. 
Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of 
group care facilities: A randomized controlled trial. JAMA. 2008;299(22):2642-2655. 
56. Badr H, Carmack Taylor CL. Social constraints and spousal communication in lung cancer. 
Psycho-Oncology. 2006;15:673-683.  

2012-0120 
Rev. June 27, 2016 
33 
 
57. Badr H, Carmack Taylor CL. Effects of relationship maintenance on psychological distress and 
dyadic adjustment among couples coping with lung cancer. Health Psychology. 2008;27(5):616-
627.  
58. Badr H, Carmack Taylor CL. Effects of relationship talk on the psychological and marital 
adjustment of lung cancer patients and their partners. Journal of Cancer Survivorship. 
2008;2(1):53-64.  
59. Carmack Taylor CL, Gritz ER, Basen-Engquist K. Active for Life after cancer: A randomized trial 
examining a lifestyle physical activity program for prostate cancer patients. Psycho-oncology 
2006;15:847-62.  
60. Carmack Taylor CL, Smith MA, de Moor C, Dunn AL, Pettaway C, Sellin R, et al. Quality of life 
intervention for prostate cancer patients: design and baseline characteristics of the Active for 
Life after cancer trial. Controlled Clinical Trials 2004;25:265-85.  
61. Carmack Taylor CL, de Moor C, Basen-Engquist K, Smith MA, Dunn AL, Badr H, et al. 
Moderator analyses of participants in the Active for Life after cancer trial: implications for 
physical activity group intervention studies. Ann Behav Med 2007;33(1):99-104.  
62. Bruera E, Strasser F, Palmer JL, et al. Effect of fish oil on appetite and other symptoms in patients 
with advanced cancer and anorexia/cachexia: a double-blind, placebo-controlled study. J Clin 
Oncol. 2003;21:129-34. 
63. Buysse DJ, Reynolds CF,3rd, Monk TH, Berman SR, Kupfer DJ. The pittsburgh sleep quality 
index: A new instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193-
213. 
64. Buysse DJ, Ancoli-Israel S, Edinger JD, Lichstein KL, Morin CM. Recommendations for a 
standard research assessment of insomnia. Sleep. 2006;29(9):1155-1173. 
65. Cella D. Manual of the Functional Assessment of Chronic illness Therapy (FACIT) Measurement 
System. Center on Outcomes, Research and Education (CORE), Evanston Northwestern 
Healthcare and Northwestern University. Version 4, 1997. 
66. Johnston M, Pollard B, Hennessey P. Construct validation of the hospital anxiety and depression 
scale with clinical populations. J Psychosomatic Res. 2000; 48:579-584. 
67. Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. The Edmonton Symptom Assessment 
System(ESAS): a simple method for the assessment of palliative care patients. J Palliat Care. 
1991;7:6-9. 
68. Gibbins J, McCoubrie R, Kendrick AH, Senior-Smith G, Davies AN, Hanks GW. Sleep-wake 
disturbances in patients with advanced cancer and their family carers. J Pain Symptom Manage. 
2009. 
69. Tonetti L, Pasquini F, Fabbri M, Belluzzi M, Natale V. Comparison of two different actigraphs with 
polysomnography in healthy young subjects. Chronobiol Int. 2008;25(1):145-153.  
70. Reuben, J.M., Lee, B.-N., Johnson, H., et al. Restoration of Th1 cytokine synthesis by T cells of 
patients with chronic myelogenous leukemia in cytogenetic and hematologic remission with 
interferon-α. Clin Cancer Res. 2000; 6: 1671-7. 
71. Morin CM; Belleville G; Bélanger L; Ivers H. The insomnia severity index: psychometric indicators 
to detect insomnia cases and evaluate treatment response. SLEEP 2011;34(5):601-608. 
72. Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an outcome 
measure for insomnia research. Sleep Med. 2001;2(4):297–307, pmid:11438246. 

2012-0120 
Rev. June 27, 2016 
34 
 
73. Breitbart W, Rosenfeld B, Roth A, Smith MJ, Cohen K, Passik S. The memorial delirium 
assessment scale. Journal of Pain and Symptom Management. 1997;13(3):128-137. 
74. Grassi L, Caraceni A, Beltrami E, et al. Assessing Delirium in Cancer Patients. The Italian Versions 
of the Delirium Rating Scale and the Memorial Delirium Assessment Scale. Journal of Pain and 
Symptom Management. 2001;21(1):59-68.