Conditions: Advanced Cancer Fatigue
Keywords: Advanced Cancer Fatigue Nursing Telephone Intervention NTI Methylphenidate Placebo Ritalin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 197
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if methylphenidate (Ritalin) can help to control fatigue caused by cancer. Its effect on other symptoms such as drowsiness, depression, sleeplessness, physical activity, and anxiety will also be studied. Another goal of this study is to learn if receiving a phone call by a nurse improves fatigue in patients.

Detailed description:
Fatigue is one of the most common problems in patients with advanced cancer. Currently, there are no treatments for managing fatigue. Methylphenidate is a stimulant that increases ability to pay attention, increases mental alertness, and decreases feelings of fatigue.

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the roll of dice) to one of 4 groups. You will have an equal chance of being placed in any of the 4 groups. You, the medical staff, and researchers will not know to which group you have been assigned.

Regardless of which group you are in, you will record your fatigue in a daily diary at breakfast, lunch, dinner, and before bedtime. Based on your level of fatigue, you will take the study drug as needed. You can take the study drug every 2 hours but you may not take more than 4 capsules a day.

Participants in Group 1 will take a methylphenidate capsule by mouth as needed to relieve symptoms of fatigue for 14 days. A nurse will call you 4-6 times in the first two weeks to ask about side effects and other symptoms. The phone calls should take about 10-20 minutes. The study nurse will set up a convenient time for you to take the phone call.

Participants in Group 2 will take a placebo capsule by mouth as needed for 14 days. A placebo is a capsule that does not contain any medication but looks just like the methylphenidate. A nurse will call you 4-6 times in the first two weeks to ask about side effects and other symptoms. The phone calls should take about 10-20 minutes. The study nurse will set up a convenient time for you to take the phone call.

Participants in Group 3 will take a methylphenidate capsule by mouth as needed for 14 days. Participants in this group will not receive any calls from a study nurse. However, A research staff member will call you 4-6 times in the first two weeks to ask about side effects and other symptoms. The phone calls should take about 10-20 minutes. The research staff member will set up a convenient time for you to take the phone call.

Participants in Group 4 will take a placebo capsule by mouth as needed for 14 days. Participants in this group will not receive any calls from a study nurse. However, A research staff member will call you 4-6 times in the first two weeks to ask about side effects and other symptoms. The phone calls should take about 10-20 minutes. The research staff member will set up a convenient time for you to take the phone call.

You will be asked to wear a wrist actigraph monitor (a wristwatch that keeps track of your physical activity and your sleep cycles) for the first 14 days.

You will keep a daily diary of your fatigue and other symptoms, the number and times pills are taken, and your fatigue rating before and 2 hours after taking methylphenidate.

On about day 15 (or within 3 days) you will return to the palliative care clinic at M. D. Anderson for tests. You will be asked about your level of drowsiness, pain, constipation, and fatigue. You will be asked about any side effects you may have experienced and the effectiveness of the drug. You will repeat the 6 minute physical test, the cognitive status test, and you will return the actigraph monitor to the research nurse. You will also be given the option to receive up to 4 capsules of methylphenidate per day until Day 36. You will not be told whether you were taking placebo or methylphenidate during Days 1-14. If you cannot come to the clinic on Day 15, all tests except the walking test, may be performed over the telephone. You will be asked to mail the actigraph back.

If you decide not to take methylphenidate on Days 15-36, you will be considered off-study and you will have end-of-study tests on Day 15. If you decide to take methylphenidate on Days 15-36, you will remain on study until Day 36. On Day 36, you will have end-of-study tests.

For end-of-study tests, you will repeat the physical and cognitive tests. You will be asked about your symptoms and any side effects you may be experiencing. You will then return to your primary physician who will discuss with you whether or not to continue on the methylphenidate based on your response to the drug.

Your participation in this study should end on either Day 15 or Day 36. However, if you develop intolerable side effects (including fatigue) while on this study, the medication will be stopped and you will be removed from the study.

This is an investigational study. Methylphenidate has been approved by the FDA and is a commercially available drug. It is FDA approved at this dose level. Its use in this study, for this purpose, is investigational. About 212 patients will take part in this multicenter study. About 142 patients will be enrolled at The University of Texas (UT) MD Anderson.

Arms:
arm 1: Methylphenidate 5 mg (one capsule) orally every two hours as needed up to a maximum of 20 mg per day for a period of 14 days + Nursing Telephone Intervention (NTI). NTI calls from study nurse 3 times weekly to ask about side effects and other symptoms. arm 2: Placebo capsule orally as needed for 14 days + NTI, calls from study nurse 3 times weekly to ask about side effects and other symptoms. arm 3: Methylphenidate 5 mg (one capsule) orally every two hours as needed up to a maximum of 20 mg per day for a period of 14 days + Non NTI, calls from research staff 3 times weekly. arm 4: Placebo capsules as needed with Non NTI, calls from research staff 3 times weekly.

Interventions: intervention 1: Methylphenidate intervention 2: Nursing Telephone Intervention intervention 3: Placebo intervention 4: Non NTI
Intervention descriptions: intervention 1: 5 mg (one capsule) orally every two hours as needed up to a maximum of 20 mg per day for a period of 14 days. intervention 2: Call from study nurse 3 times weekly to ask about side effects and other symptoms. intervention 3: One capsule, orally every two hours as needed up to a maximum of 4 capsules per day for a period of 14 days. intervention 4: Non NTI are calls from research staff 3 times weekly.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 1 of 34 
1.0  Objectives 
 
1)  Determine if methylphenidate 5 mg taken as needed is superior to placebo in the treatment of fatigue in 
advanced cancer patients as measured by the Functional Assessment of Chronic Illness Therapy-
Fatigue (FACIT-F) subscale.   
2) 
Secondary objective-1: Determine if a nursing telephone intervention (NTI) improves fatigue (measured 
by the FACIT-F subscale) as compared to standard care in patients receiving methylphenidate and 
placebo. 
3) 
Secondary objective-2:  Investigate the additive or synergistic effect of methylphenidate treatment plus 
NTI reduction of fatigue compared to either methylphenidate treatment or NTI alone.  
4)      Secondary objective-3:  To investigate the additive or synergistic effect of Methylphenidate treatment 
plus Nursing Telephone Intervention (NTI) in the reduction of other associated symptoms such as 
depression, sleep, anxiety, and health related quality of life. 
2.0 
 Grant Information 
The NIH grant for this protocol is # NIH R01 NR010162-01A1. 
3.0   Background 
Fatigue is a Major Problem in Cancer Patients.  Fatigue is reported by 60-90% of patients with advanced 
cancer as their most frequent and debilitating symptom [1-2].  Cancer related fatigue is defined as “an 
unusual, persistent, subjective sense of tiredness related to cancer or cancer treatment that interferes with 
usual functioning” [2].  Fatigue consists of three major components:  easy tiring and reduced capacity to 
maintain performance; generalized weakness (i.e., the anticipatory sensation of difficulty in initiating a certain 
activity); and mental fatigue, defined as the presence of impaired mental concentration, loss of memory, and 
emotional lability.  
 
Fatigue can interfere with a patient’s ability to perform physical and social activities [3].  It may also 
affect a patient’s decision-making regarding future treatment, leading to refusal of potentially curative or 
supportive treatment. In the majority of patients with advanced cancer, the etiology of fatigue is unclear but 
the effect is similar.  Fatigue is difficult on the patient and the family.  Fatigue interferes with activities of daily 
living (e.g., grooming, meal preparation) and robs patients of time and energy to engage in routine activities 
with there loved ones.  This greatly decreases a patient’s quality of life. In most patients with advanced 
cancer, fatigue is a multi-causal syndrome due to a number of physical and psychosocial mechanisms [4, 5].  
Cancer produces tumor by-products or induces immune cytokines capable of producing fatigue directly or 
indirectly by causing cachexia, muscle loss or deconditioning [6-7].  These mechanisms, in addition to 
medications to treat these conditions (i.e., opioid and other drugs), are capable of causing neurocognitive 
changes and hypogonadism [8-10].  Also, cancer patients frequently develop depression and anxiety [4-7].  
Fatigue is a major component of somatization in patients with mood changes and it has been found to 
strongly correlate with depression and anxiety.  Chemotherapy and radiation therapy can cause fatigue both 
directly and indirectly through the production of anemia [6].  
 
In patients with advanced cancer, fatigue is almost universal and severe even when hemoglobin is 
appropriately corrected and anemia is treated with erythropoietin or darbopoietin [4, 5] Most patients with 
advanced cancer have fatigue before receiving any treatment and fatigue persists after the discontinuation of 
chemotherapy and radiation, strongly suggesting that many of the other causative factors continue to have an 
impact on the brain’s perception of fatigue.  All of the available data suggest that despite the various 
mechanisms that have been identified as causing fatigue, one common denominator is that they all act on the 
brain to cause the subjective symptom of fatigue.  Thus, it is logical that an agent such as methylphenidate, 
with demonstrated central-stimulating activity, may reduce the severity of fatigue.  
 
Current Treatments for Cancer- Related Fatigue.  Most patients with advanced cancer do not receive 
specific treatment for fatigue [4,7].  Patients frequently under report fatigue as a symptom because of 
reluctance to distract providers from treatment of their tumor or other severe symptoms (e.g. pain).  In 
addition, because of the difficulty in treating fatigue, health care professionals may be reluctant to discuss it 
[6].  When patients report fatigue, physicians usually look for a number of reversible causes such as 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
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Page 2 of 34 
anemia, depression or anxiety, medications, or metabolic abnormalities [4-7].  Unfortunately, even when 
these abnormalities are identified and corrected, patients usually continue to report high levels of fatigue 
[5,6].  Our group and others have conducted randomized controlled trials of corticosteroids for the 
treatment of fatigue [11,12].  These drugs appear to have significant but transient effects (usually less than 
3-4 weeks) and are associated with adrenal suppression and major potential side effects, including 
infections, myopathy, osteoporosis, or Cushing syndrome.  Other pharmacological treatments of fatigue 
(e.g., testosterone and donepezil) have also been evaluated in preliminary investigations [13-16].  While 
testosterone replacement in patients experiencing hypogonadism may prove to be an effective treatment of 
fatigue [14], the effects of testosterone replacement in women are not understood and the side effects in 
men are still being debated and examined [17,18].  Although Donepezil has been found to alleviate fatigue-
related symptoms, this treatment can cause severe gastrointestinal side effects [13].  Thus, there is great 
need for effective symptomatic treatments for fatigue.  The National Comprehensive Cancer Network has 
established guidelines for the screening, evaluation, and intervention of cancer related fatigue [2].  These 
guidelines recommend the investigation of psychostimulants as a pharmacological therapy for cancer 
related fatigue.  Methylphenidate is a psychostimulant that has the potential to treat cancer-related fatigue.  
 
Methylphenidate and Fatigue.  Methylphenidate is a central nervous system (CNS) stimulant, and its 
mechanism of action is blockage of presynaptic dopamine re-uptake [19].  It presumably activates the brain 
stem arousal system and cortex to produce its stimulant effect.  Methylphenidate has a rapid onset of action, 
with peak plasma concentrations in one to three hours and a plasma half-life of 1.5 to 2.5 hours 
(concentrations in the brain exceed those in plasma).  The peak effect is at 2 hours, with duration of action of 
3 to 6 hours.  Methylphenidate is usually administered twice a day, at breakfast and at lunch, in order to 
minimize insomnia.  However, due to its rapid onset of action and short half-life, methylphenidate may be 
effective in relieving fatigue when taken on an as needed basis throughout the day.  This flexible 
administration regimen may significantly improve patient quality of life.  Methylphenidate is more frequently 
used for the management of attention deficit and hyperactivity disorder [20] and for depression, particularly in 
geriatric patients [21].   In patients with cancer, methylphenidate has been used successfully to manage 
opioid-induced sedation [22,23], cognitive failure associated with brain tumors [24], and depression [21, 25].  
 
Preliminary reports have suggested success with psycho-stimulants in treating fatigue in cancer 
patients as well as patients with other chronic illnesses [26-28].  Methylphenidate has been found to improve 
fatigue in ambulatory patients with human immunodeficiency virus [28]. In the palliative care setting, 
methylphenidate has been used in the management of opioid-induced sedation and depression [22, 25, 31].   
Sarhill and colleagues reported a rapid reduction of fatigue in 9 of 11 consecutively treated patients in an 
open-label study [29].  A pilot study of 14 evaluable patients with advanced cancer found that 
methylphenidate at a dose of 5-10 mg/day significantly improved fatigue after 7 days [30]. 
 
The side effects of methylphenidate are usually mild and generally well tolerated.  Nervousness and 
insomnia are the most common adverse reactions but are usually controlled by reducing dosage and omitting 
the drug in the afternoon or evening. Other reactions include hypersensitivity (including skin rash, urticaria, 
fever, arthralgia, exfoliative dermatitis, and erythema multiforme), anorexia, nausea, dizziness, palpitations, 
headache, drowsiness, and change of blood pressure, tachycardia, angina, cardiac arrhythmia, and 
abdominal pain.  There have been rare reports of Tourette’s syndrome. 
 
Methylphenidate can be transformed from a therapeutic agent to an abused and addictive substance 
when this drug is taken in excessive amounts and used through intranasal and intravenous routes.  
Methylphenidate abuse produces psychiatric side effects similar to those of cocaine and amphetamines, such 
as nervousness, restlessness, agitation, suspiciousness, paranoia, hallucinations and delusions [32].  The 
potential for methylphenidate abuse has been addressed primarily through regulatory measures.  These 
include adding a higher level of surveillance by assigning it to schedule II status.  Other measures to reduce 
methylphenidate abuse include assessment of history of drug and substance abuse, tablet counts, and 
education about the abuse potential. 
 
Fatigue-Related Outcomes.  We know from the literature that methylphenidate has been found to reduce 
outcomes (e.g., depression, insomnia, physical activity) associated with fatigue.  In particular, 
methylphenidate has been reported to be an effective treatment for depression [21,25,31].  In a study of 30 


 
 
 
 
 
 
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Page 3 of 34 
depressed cancer patients, researchers found one-third demonstrated marked improvement and almost half 
(n =13) demonstrated moderate improvement when treated with methylphenidate [31].  In another study of 30 
cancer patients, Homsi and investigators [25], found that 21 of the patients studied reported that they were 
not depressed after only three days of treatment.  They also found that methylphenidate effectively and 
rapidly improved symptoms of depression in 10 advanced cancer patients [33].    
 
In another randomized, controlled trial, methylphenidate given to 32 adults with attention-deficit 
disorder also demonstrated improvements in depression, anxiety and irritability [34].  These findings suggest 
that methylphenidate will improve the mood of advanced cancer patients.  Though studies of cancer patients 
have observed improvements in depression after treatment with methylphenidate, many of these studies 
have had very small sample sizes.  Also, these studies have not been controlled, making it impossible to 
eliminate a placebo effect as an explanation for the findings.  However, studies with other patient populations 
have found that methylphenidate can be an effective treatment for depression.   
 
Sleep disturbance and insomnia, a frequent problem in patients with advanced cancer, are associated 
with fatigue.  While insomnia has been reported as a potential side effect of methylphenidate [35], some 
reports have indicated that methylphenidate can reduce insomnia, particularly in adults [36-38].  In a double-
blind crossover study of the effects of late-afternoon administration of methylphenidate in children with 
attention-deficit hyperactivity disorder, researchers did not find adverse effects on sleep latency when a third 
dose of methyl-phenidate was administered in the late afternoon (4 pm) [36].  In a double blind, placebo-
controlled six-week crossover study of 35 adults with traumatic brain injury, insomnia was not significantly 
related to methylphenidate [37].  Further, in our previous research we found that patient’s sleeping patterns 
were improved while taking methylphenidate [38].  We believe that methylphenidate may improve insomnia 
by reducing fatigue, lethargy, and depression symptoms and probably by also reducing daytime napping.  
This may lead to patients getting more adequate sleep at nighttime.   
 
As we have observed that methylphenidate improves activity [22], we hypothesize that patients with 
less fatigue and improved mood will increase their level of activity.  We expect that they will more frequently 
be able to perform their activities of daily living (such as self hygiene, food preparation, socialization, etc.) 
and they may even be able to spend more time outside their home.  Mini-Motionlogger™ Actigraph will be 
used to measure physical activity.  This device is worn on the wrist and unobtrusively monitors motion.  The 
actigraph can be used to record and evaluate sleep quantity and quality, daytime activity levels, and napping.  
Actigraphy is considered a useful method for measuring daily physical activity [39].  However, findings from 
some researchers suggest that changes in fatigue cannot be assumed to automatically correspond with an 
accompanying change in physical activity.  However, other findings indicate that physical activity may 
correspond with fatigue in ill patients.  While Dimsdale and colleagues found no correlation between fatigue 
expression and actigraph measurements in healthy controls [40], Roscoe found that actigraph measurements 
significantly correlated with fatigue in patients with breast cancer [41].   
 
Impact of Nurse Telephone Interventions on Fatigue and Other Symptoms.  In our studies, patients 
have responded favorably to nursing telephone interventions (NTI) in addition to methylphenidate treatment.  
Research has demonstrated that patients and their families’ welcome nurse telephone interventions, as a 
way of maintaining contact with healthcare professionals [42].  However, there is much debate regarding the 
effectiveness of these interventions on clinical outcomes.  One study found that nursing telephone 
interventions are able to augment the treatment of depression in primary care [43].  In this study, 302 patients 
with depression were randomized to usual physician care (123 patients), nurse tele-health care consisting of 
12-14 calls of approximately 10 minutes each over 16 weeks (117 patient), and combined nurse telehealth 
plus a peer support group (62 patients).  At 6 weeks and 6 months the nurse tele-health group had a 
significantly higher rate of improvement in the Hamilton Depression Rating Scale, Beck Depression 
Inventory, and treatment satisfaction score than the usual physician care group.  At week 6, the nursing 
telehealth group also had significantly higher improvement in the SF-12 mental functioning scale score than 
the usual physician care group [43].  The investigators did not find that adding peer support to the telehealth 
group further improved outcomes.  Other studies have found that nurse-led interventions for patients with 
ovarian cancer were perceived by patients as being helpful in regards to symptom management, assessment 
of side effects, and promotion of self care [44]. Ponica found that next day follow up calls in elderly patients 
after discharge resulted in a significant number of interventions in the form of advice or action to ensure 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 4 of 34 
patients well being [45].  Other findings regarding nurse phone interventions suggest that nursing 
interventions reduce unscheduled hospital visits [46-47].  For example, one study found that patients 
receiving pelvic radiotherapy and nurse-led follow up were able to reduce the number of emergency clinic 
visits [46].  In contrast, telephone support in the early post-discharge period following elective cardiac surgery 
was not able to reduce anxiety and depression levels [47] calling into question the efficacy and 
generalizability of nursing phone interventions.  A growing body of literature has explored integrating 
qualitative components in intervention research.  In a study that has similar features to what we are 
proposing in the qualitative component [48-50] tape recorded interventions were analyzed.  The qualitative 
data from the nursing intervention, designed to reduce pain, added insights into why the intervention was not 
effective for a subset of patients, and other aspects of the intervention that were helpful and not helpful were 
made more clear so that the intervention could be improved in future research and clinical applications.  This 
evidence as well as information we have obtained while conducting symptom management research leads us 
to believe that nurse phone calls may have a positive impact on patient’s symptom reduction and quality of 
life. 
 
Theoretical Model: Figure 1.  Model for the effects of methylphenidate and NTI for cancer related fatigue 
 
 
 
 
The model [Figure 1] guiding the research we are proposing is an adaptation and modification of the Middle-
Range Theory of Unpleasant Symptoms [51]. This theory describes the effects and interactions of symptom 
production. Methylphenidate, which will decrease sedation, improve cognition, and reduce pain, and the 
nursing telephone intervention (NTI), which will improve adherence to medications, such as analgesics, 
antiemetic, etc., both can influence physiological factors affecting fatigue.  Methylphenidate (improving 
depression) and NTI (providing educational and emotional support) can also influence psychological factors.  
Finally, covariates such as age, gender, socio-economic status and ethnicity can be interpreted as situational 


 
 
 
 
 
 
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Revised February 9, 2010  
 
 
 
 
 
 
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factors.  As described by Lenz et al, there is considerable interaction among different physiological, 
psychological, and situational influences on cancer fatigue.  In addition, both interventions can influence each 
other: the NTI can enhance the effects of methylphenidate by improving adherence, and methylphenidate 
can enhance the effects of NTI by reducing sedation and depression and by improving cognition and 
attention.  Both methylphenidate and the NTI will improve quality of life (FACT-G) by reducing fatigue, 
physiological symptoms, and psychological symptoms.  We will include the effect of covariates (situational 
factors) such as age, gender, socio-economic status, and ethnicity in all analyses. 
 
In the final analysis, we will need to determine; does the number of phone calls influence the response to 
NTI?  We will include the number of phone calls received, as a co-variate in analyses to adjust for possible 
effects on response.  In addition, if the number of phone calls received is a significant effect, we will further 
report and analyze the number of phone calls received in relationship to outcome responses to NTI.  
 
Summary.  Our previous research has indicated that methylphenidate can reduce fatigue, fatigue-related 
outcomes, and improve quality of life in advanced cancer patients.  Since we have found improvements in 
psychosocial outcomes in medication treatment studies that included a nurse phone call even in the placebo 
group, we expect that the nursing telephone interventions will interact with the treatment effects of 
methylphenidate to improve fatigue-related outcomes and overall quality of life above methylphenidate 
treatment alone.  As the synergistic effect between nursing telephone interventions and methylphenidate has 
not been evaluated in a randomized-controlled trial, we have no empirical information on this relationship.  
Our study will fill this gap and provide valuable information on the ability of nursing telephone interventions to 
enhance medication treatment effects and the effect of methylphenidate alone on fatigue-related outcomes. 
 
Significance.  Interventions that alleviate multiple sources of fatigue and fatigue-related symptoms are 
greatly needed in the clinical setting to treat the multiple fatigue-related symptoms experienced by advanced 
cancer patients.  Improving fatigue and treating fatigue-related symptoms will greatly improve the quality of 
life of advanced cancer patients.  Additionally, the interaction between methylphenidate and nurse telephone 
follow-up on cancer-related fatigue has not been studied.  Nurse telephone follow-up has the potential to 
reduce emergency visits and increase a patient’s adaptive coping responses to illness.  Combining nurse 
telephone follow-up with a pharmacological treatment may provide more effective management of symptoms 
experienced by patients at the end of life.  Thus, this treatment has the potential to help the patients better 
manage their symptoms, which improves their quality of life, and this treatment can be easily implemented in 
clinical practice.  If found effective, these two interventions will result in immediate changes in standard of 
care, as there is not yet an established, standard treatment for cancer-related fatigue. 
 
PRELIMINARY STUDIES 
Pharmacological Treatment of Fatigue.  The PI’s initial studies in symptom management in advanced 
cancer patients allowed us to establish the high frequency of fatigue in different patient populations [52-57].  
We conducted studies on different assessment methods for fatigue [55] and started the process of 
characterizing the association between fatigue and other complications of advanced cancer, including 
cachexia [52, 56-57] and hypogonadism [9-10].  These studies helped us better understand fatigue as a 
frequent, severe, and multi-causal syndrome. 
 
Initially, we evaluated the effects of corticosteroids on alleviating fatigue in cancer patients. In a 
randomized placebo-controlled study of 31 patients, we found that methylprednisolone improved subjective 
fatigue, pain, and appetite as compared to placebo in patients with advanced cancer [54]. However, the 
effects lasted less than 3 weeks and, as described earlier, corticosteroids had a variety of severe side effects.  
In later studies on the treatment of cancer cachexia, we observed mild improvement in fatigue in patients 
receiving megestrol acetate [11, 52] and polyunsaturated fatty acids [58] as compared to placebo.  However, 
these drugs were found to have limited efficacy for cancer cachexia and fatigue.  In a pilot study of 
Donepezil, a long-acting selective acetylcholinesterase inhibitor, 27 patients were provided 5 mg of this 
medication for 7 days to counteract opioid-induced sedation, we found a significant decrease in sedation and 
fatigue with this medication [13].  Seven patients had discontinued the study by day 7.  While two patients 
discontinued the study because of difficulties unrelated to the study drug, 5 patients experienced side effects 


 
 
 
 
 
 
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Revised February 9, 2010  
 
 
 
 
 
 
Page 6 of 34 
that may have been attributable to the study drug, with mild to moderate nausea being the most common 
reason for study discontinuation.  In the 20 remaining study patients, the FACIT-F (measure of subjective 
fatigue) scores of improved from 17.8 + 9.9 to 27.2 + 13.1 at day 7 (p = 0.0004).  Although these findings 
indicated that these drugs (corticosteroids or Donepezil) were not the most effective treatment for cancer-
related fatigue due to their side effects, they helped us further refine our methodology for pharmacological 
trials for treating fatigue.   
 
In conducting treatment studies of the efficacy of methylphenidate in decreasing opioid-induced 
sedation [22], we discovered that methylphenidate also decreases drowsiness and increases activity, leading 
us to believe that it might be an effective treatment for fatigue in cancer patients.  In a three-day trial of 32 
patients with cancer-related pain, we randomized patients to a group receiving 10 mg of methylphenidate 
with breakfast and 5mg with lunch or a group receiving placebo.  Patients received methylphenidate or 
placebo for 3 days and during day 4 a cross-over took place.  As can be seen in Table 1, there was a 
significant improvement in drowsiness, subjective activity and pain during the methylphenidate phase as 
compared to placebo [22].  In addition, there was no significant change in anxiety or hours of sleep. 
 
TABLE 1.  Results after the completion of the double-blind study in 28 evaluable patients* 
Feature 
Baseline 
P value 
Placebo 
P value 
Methy
lpheni
date 
  
(B)† 
(B vs P) 
(P)† 
(P vs 
MP) 
(MP)† 
Pain intensity - Days 0,3,and 6 at 10:00am (VA 0-100) 
64±31 
P < 0.01 
55 ± 24 
P < 0.01 
43 ± 
27 
Pain intensity - Daily at 8:00am (VA 0-100) 
70 ± 30 
P < 0.05 
59 ± 28 
P < 0.01 
40 ± 
28 
Activity (VA 0-100) 
31 ± 29 
P < 0.15 
41 ± 26 
P < 0.05 
57 ± 
25 
Drowsiness (VA 0-100) 
36 ± 21 
P = 0.10 
45 ± 27 
P < 0.01 
58 ±  
24 
Depression (VA 0-100) 
59 ± 31 
NS 
64 ± 28 
NS 
69 ± 
25 
Anxiety (VA 0-100) 
58 ± 28 
NS 
60 ± 27 
NS 
65 ± 
25 
Hours of sleep  
6.5 ± 2 
NS 
6.3 ± 2 
NS 
6.5 ± 
2 
* VA = visual analogue; NS = not significant 
† Values are expressed as mean ± SD 
 
 
 
In an open study of 50 patients with opioid-induced sedation, we found that methylphenidate 
50mg/day improved sedation in 48 patients [53].  Although fatigue was not specifically measured in this 
study, patients anecdotally reported a reduction a fatigue.  In these studies there appeared to be an 
improvement in fatigue with methylphenidate as compared to placebo when measured as an ancillary 
outcome.  However, in a follow-up study on the neuropsychological effects of methylphenidate in patients 
receiving parenteral opioids, we did not observe an improvement in fatigue as compared to placebo [23].  
However, in this study, fatigue was only measured at one time point, two hours after receiving 
methylphenidate.  Our findings after multiple clinical trials and frequent clinical use of methylphenidate in 
patients with advanced cancer suggested that it was safe and effective for the management of opioid-induced 
sedation but it also appeared to have effects on fatigue and other fatigue-related outcomes.  However, our 
studies on the management of opioid-induced sedation did not allow us to appropriately characterize the 
effects of methylphenidate on fatigue and fatigue-related symptoms, as this study sample only included 
advanced cancer patients suffering from opioid induced sedation. 
 
Based on our preliminary observations, Breitbart and colleagues conducted a randomized controlled 
trial of methylphenidate 7.5 mg twice daily, pemoline 18.75 mg twice daily, or placebo capsule twice daily for 
the management of fatigue in 144 patients with AIDS [28].  Methylphenidate and pemoline were both superior 
to placebo.  These findings, in addition to our clinical observations of improvement in multiple symptoms in 
patients treated with methylphenidate for sedation, led us to design a pilot study of methylphenidate for the 
treatment of cancer fatigue. 


 
 
 
 
 
 
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We hypothesized that a treatment regimen allowing patients to titrate the administration schedule of 
methylphenidate to their level of fatigue and expected level of activity might be more efficacious than a fixed 
schedule regimen [37].  We postulated that given the rapid onset of action of methylphenidate and its short 
half-life, it might be possible to use 5 mg capsules on an as needed basis.  Thus, 31 participants with 
advanced cancer and fatigue who rated their fatigue as  > to 4 on a 0-10 rating scale were prescribed 
methylphenidate 5 mg capsules as needed every 2 hours for patient-described fatigue.  Patients were 
allowed to take a maximum of 4 capsules per day.  Patients received a daily nurse phone call for symptom 
assessment and support.  30/31 patients were evaluable by day 7.  Results from the first seven days of this 
study are summarized below in Table 2.  Overall, 28 of 30 patients (93%) had improved fatigue (defined as a 
decrease of more than 2 on a 0-10 scale) by Day 7. 
 
After the assessment at Day 7, all 30 patients (100%) chose to continue treatment with 
methylphenidate.  Twenty-eight patients (93%) took 3 or more methylphenidate capsules daily, and all 30 
patients took an afternoon or evening dose.  The findings remained stable in 21 patients who remained 
evaluable at Day 28. 
 
Methylphenidate was very well tolerated in these patients with advanced cancer and no patient 
required discontinuation due to side effects.  Two patients reported increased restlessness; 1 patient reported 
increased dizziness, 2 patients reported increased anorexia; 1 patient reported a 2-day self resolved skin 
rash; 1 patient reported intermittent vertigo for 2 days; and 1 patient reported self-resolved tachycardia for 3 
days.  In all cases, symptoms were mild and did not require treatment. 
 
Table 2. Comparison of Mean ESAS * FACT-G, FACIT-F at Baseline and Day 7 (n=30) and day 28 (n 
=21) 
Variable 
Symptom-Assessment 
Score (SD)  
 
 
 
 
Baseline 
(n=30) 
Day 7 
(n=30) 
P 
value** 
Baseline 
(n=21) 
Day28 
(n=21) 
P 
value***
* 
ESAS*  
 
 
 
 
 
 
  Fatigue 
7.2 (1.6) 
3.0 (1.8) 
<.001 
7.1 (1.5) 
3.1 (2.6) 
<0.001 
  Pain 
5.0 (2.4) 
3.8 (1.8) 
.005 
4.6 (2.6) 
3.9 (2.8) 
0.34 
  Depression 
3.6 (2.9) 
1.1 (1.5) 
<.001§ 
2.9 (2.9) 
1.7 (2.3) 
0.17 
  Anxiety 
3.5 (3.1) 
1.3 (1.5) 
.002§ 
2.7 (3.0) 
1.7 (2.2) 
0.14⁯ 
  Appetite 
4.5 (3.1) 
2.4 (2.0) 
<.001 
4.1 (3.1) 
2.8 (3.2) 
0.007⁯ 
  Sleep pattern 
5.3 (2.4) 
2.2 (1.8) 
<.001§ 
5.2 (2.5) 
3.3 (3.0) 
0.005 
FACT-G*** 
 
 
 
 
 
 
  Total sub score 
65.7 (17.1) 
81.4 (14.7) 
<.001 
68.1 
(16.8) 
79.4 (19) 
0.03 
FACIT-F*** 
 
 
 
 
 
 
   Fatigue sub 
score 
17.5 (11.3) 
34.7 (10.0) 
<.001 
18.4 (9.5) 
38.4 (14) 
<0.001 
Abbreviations: 
ESAS 
Edmonton Symptom Assessment Scale;  
FACIT-F  
Functional Assessment for Chronic Illness Therapy- Fatigue 
*Score: 0 = best; 10 = worst possible. 
**Comparisons were made between baseline and day 7, using a paired t test if the data were normally 
distributed and a sign test otherwise (noted by §). Since many statistical tests were made, we consider that 
statistical significance has been shown by p-value ≤ .005 instead of the usual value of .05. 
*** Higher scores indicate better functioning. 
**** Comparisons were made between baseline and day 28, using a paired t test if the data were normally 
distributed and a sign test otherwise (noted by ⁯). 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 8 of 34 
0
1
2
3
4
5
6
7
8
9
10
Day 1
Day 7
Level of fatigue*
 Breakfast
 Lunch
 Dinner
 Evening
 
In this study [38], patients maintained a daily diary in which they were required to record their fatigue, 
as one of the endpoints for this study, at breakfast, lunch, dinner and before bedtime.  We found that fatigue 
varied considerably during the course of the day, bolstering our belief that administering methylphenidate on 
“as needed basis” is the most effective treatment for fatigue in advanced cancer patients.  In ratings 
recording at baseline and at day seven, we found that fatigue progressively decreased from morning to 
evening.  We found significant differences in the amount of fatigue reported based on the time of day at day 1 
(p = 0.0023) and day 7 (p = 
0.0008).  This is illustrated in 
Figure 2.  
 
Our results indicate that 
methylphenidate is very well 
tolerated in the advanced 
cancer population [38].  In 
addition, our findings suggested 
that this drug is able to improve 
fatigue and a number of other 
symptoms, including the overall 
score, on our measure of 
quality of life (FACT-G) and the 
subscale score on a measure 
of fatigue (FACIT-F).  However, 
our pilot study had a number of limitations.  Fatigue is a subjective symptom and as such can only be 
appropriately tested in double blind trials.  As this was an open-label study, we could not rule out the 
possibility of a strong placebo effect.  As we found that several symptoms (i.e., depression, anxiety, 
insomnia, and pain) in addition to fatigue, improved, suggesting that the results might be partly attributable to 
placebo or to a response to the daily nurse phone calls.  However, the robust response for an observation 
period of 1 week followed by 4 weeks of treatment with maintained overall symptom improvement and 
satisfaction suggested that these results were genuine symptomatic effects.  Our study was also unable to 
establish whether methylphenidate effected fatigue directly or indirectly by influencing other symptoms such 
as depression, drowsiness, or anxiety.  
 
Nursing Telephone Interventions (NTI).  As illustrated in Table 2, we observed major clinical and 
statistically significant improvement in a large number of physical and psychosocial symptoms in our pilot 
study of methylphenidate [38].  This improvement was unexpected in the case of some symptoms such as 
insomnia, appetite, or anxiety, leading us to wonder if some of the effects that we noted were attributable to 
some factor other than the methylphenidate.  Considering that patients frequently expressed appreciation for 
the daily nursing telephone interventions, we speculated that the nursing telephone interventions might be 
another factor impacting patient symptom improvement.  We observed a similar expression of satisfaction 
with nursing telephone interventions in a previous pilot study of Donepezil [13] where we also observed 
significant improvement in a number of symptom variables, and previous studies on polyunsaturated fatty 
acids [58] and megestrol acetate [52] also provided evidence of patient satisfaction with the nursing 
telephone interventions.  
We also hypothesize that dramatic improvement in fatigue in both 
methylphenidate and placebo groups in our pilot randomized trial can be explained at least partially by the 
effects of the daily nursing telephone interventions.  In the process of conducting our clinical trials, we have 
developed expertise in conducting nursing telephone interventions. 
 
We recently completed a pilot randomized, double-blind controlled trial comparing patient controlled 
methylphenidate (PCM) versus placebo for cancer fatigue.  105 patients were randomized to receive PCM 5 
mg every 2 hours as needed for 7 days [maximum 20 mg/day] [n=52] or placebo [n=53]. All patients received 
a daily nursing telephone intervention (NTI).  The difference between baseline and day 8 are shown in table 
3. Fatigue and other symptoms improved dramatically by day 8 in both the PCM and placebo group (a mean 
improvement in FACIT-F fatigue subscale was 9.6 and 7.5 points, respectively). There was a trend favoring 
PCM over placebo, but it was not significantly different. In this study, we did not ask what patients believed 
they were taking but we asked how beneficial they found the drug at the end of the 7-day double-blind period.  
Figure 2.  Fatigue intensity according to time of the 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 9 of 34 
14/53 patients expressed a considerable and consistent benefit from placebo (26%).  We believe that these 
results can be explained by the fact that the nursing telephone intervention had such major impact on fatigue, 
and also because the duration of the study was only one week, thereby not allowing for enough time to 
observe a clear cut difference between methylphenidate and placebo effects.  Our proposed study will 
address these two issues by comparing PCM vs. placebo in a group not receiving nursing telephone 
intervention, and by extending the double blind phase of the study to two weeks.   
 
Table 3. Mean difference symptom intensity between baseline and day 8. 
    Symptom 
PCM + NTI 
(Day 8-
baseline) 
Placebo + NTI 
(Day 8-
baseline) 
P-value 
FACIT-F 
9.6 (± 9.8) 
7.5 (± 11.3) 
0.31 
FATIGUE 
-2.7 (±2.6) 
-1.9 (± 2.8) 
0.14 
PAIN 
-1.1 (±3.0) 
1.1 (±2.9) 
0.95 
DEPRESSION 
-1.4 (±2.6) 
-1.3 (±2.9) 
0.77 
DROWSINESS 
-1.4 (±2.9) 
-1.1 (±2.9) 
0.61 
SHORT OF BREATH 
-1.3 (±2.2) 
-0.4 (±3.1) 
0.08 
SLEEP 
-0.9 (±3.1) 
-0.9 (±2.9) 
0.95 
WELLBEING 
-1.7 (±2.7) 
-0.7 (±3.2) 
0.07 
                  FACIT-F: Positive value denotes improvement; other symptoms: negative value denotes 
improvement 
 
To better understand the NTI, Dr. Marlene Cohen has joined the research team.  Dr. Cohen's primary 
appointment is at the University Of Texas Houston School Of Nursing.  She also is a Professor at MD 
Anderson in the Department of Symptom Research and is a nurse researcher at LBJ Hospital, part of the 
Harris County Hospital District.  She has been investigating individuals' emotional responses to physical 
illness since 1981 and, specifically, among persons with cancer since 1990.  Cohen's early work found that 
practitioners' and family members' understanding of patients' experiences differed from patients' views in 
important ways.  Nurses focused their care on immediate problems and were preoccupied with their own 
approach (e.g., the best method to use to teach a patient about medication).  In contrast, patients were 
concerned about the outcomes of the hospitalization and how their lives would change after hospitalization 
(59-64).  
 
A study comparing cancer patients' and nurses' assessment of pain and pain relief (65) found that 
continued work is needed to ensure that pain is accurately assessed and relieved. A variety of nurse and 
patient characteristics altered the congruence of nurse assessment with patient self-assessment. The finding 
that pain management training in the nurses improved this congruence raises the potential for interventions 
to sensitize nurses to patient issues. Another aspect of this study was inclusion of an ethnically diverse group 
of patients with cancer. This study demonstrated the importance and feasibility of including an ethnically 
diverse sample. Pain ratings differed for African American and Hispanic patients but the differences were not 
statistically significant. However, this study had a small sample size with limited power to detect significant 
differences indicating the need for further research (65). 
Another study of pain assessment found that despite the JCAHO standards for pain assessment, many areas 
of this assessment were not documented (66). An additional study conducted with nurses and physicians in 
the Department of Palliative Care & Rehabilitation Medicine illustrated the complexity of symptom 
assessment and expression. Phenomenological interviews with persons who reported low levels of pain but 
many other symptoms that were relieved with pain medications revealed patterns of experiences that helped 
to explain why persons might not report pain (67).  
 
In a study with BMT patients, these patients discussed their learning needs in phenomenological 
interviews.  Patients described a range of information needs, ranging from minimal to comprehensive and 
emphasized that information provided should be tailored to suit individual patient and family needs.  For 
example, some patients felt that staff members would tell them what they needed to know, so they had no 
questions.  Others wanted to know as much as possible about what to expect.  These patients often went to 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 10 of 34 
great lengths to obtain information, including searching the internet, contacting the National Cancer Institute, 
and searching in medical libraries.  There was also a group between these two extremes of patients who had 
some questions and fears and who were not always clear about what to ask, how to ask it, or what might 
provide the information or reassurance they wanted (68). This finding led the clinicians involved to revise their 
interventions to address learning needs, which show that such data can yield information needed to develop 
and modify effective interventions.  
 
A current study involves obtaining both phenomenological descriptions and symptom measures from 
patients at eight times over the first 100 days of their experience having blood and marrow transplantation 
(BMT).  These data are currently being analyzed, but indicate that symptom reports from measures and 
those obtained in the phenomenological interviews can be usefully compared and that the data augment 
each other and add to our understanding of symptoms and effective interventions (69-70).  
Cohen has also been involved in two studies of African American women (71-72), both of which involved 
interviewing African American women about their experiences with breast cancer screening.  Her current 
study with BMT patients included African American and Latino patients, and the majority of the Latino 
interviews were conducted in Spanish, transcribed and translated and then analyzed.  These studies 
demonstrated the ability to recruit African Americans and Latinos in research, and illustrate the willingness of 
Latinos and African Americans to participate in research that involves interviews.  
 
In summary, since patients vary in their ability to express their needs, and since professionals do not 
as a whole understand patients' views, those who are alerted to potential needs will be quicker to respond to 
the earliest cues. Patients described professionals who sometimes responded in unhelpful ways; those who 
were aware of the patients' perspective may be less likely to ignore important concerns or to respond in 
inappropriate ways. Knowledge of these patterns of needs will provide a more effective base for clinical 
interactions and decision making.  Cohen's prior research has shown that people are willing and able to 
describe their symptoms and health care experiences and that they can articulate the meaning of these 
experiences.  Subjects IN These studies have included African Americans and Latinos.  In addition, 
interventions have been suggested by these descriptions, and we expect in this study they will help us better 
understand the important aspects of the interventions being tested.  Descriptions obtained from Cohen's prior 
research have also been useful to health care professionals who have not had the experiences being 
described.  The "insider" experiences yield insights that provide a fuller understanding of the experiences, 
and our expectation is that the information obtained from analyzing the telephone interventions will add new, 
more detailed, understanding of the important aspects of fatigue and this intervention. 
 
 
Other Fatigue-Related Outcomes.   In conducting research on methylphenidate, we have found that it 
impacts other fatigue-related outcomes, particularly depression, activity, insomnia, and neurocognitive motor 
functioning.  Our pilot study suggested that methylphenidate had clinical effects on both fatigue and 
depression [38], as illustrated in Table 2. In one randomized, double-blind placebo-controlled trial, Breitbart 
and colleagues, in a study of 144 ambulatory HIV patients found that in addition to improvements in fatigue 
(their primary outcome), significant associations were found between improvements in fatigue and 
improvements in depression [28].   
 
As mentioned earlier, we found that methylphenidate improved activity levels in cancer patients 
receiving narcotics for the treatment of pain.  In our most recent pilot study, patients also demonstrated a 
significant improvement in sleep patterns at day 7 (see Table 1) and day 28 after taking methylphenidate.  At 
day 28 mean sleep scores for 21 patients were 3.3 (SD=3.0) as compared to 5.2 (SD = 2.5) at baseline, p = 
0.005.   
 
In researching the effectiveness of methylphenidate on reducing opioid-induced sedation, we 
discovered that methylphenidate also improves neurocognitive motor function [23].  In a double-blind 
crossover trial of twenty patients, we found that patients receiving methylphenidate were able to perform 
significantly better in neurocognitive motor functions such as finger taping and arithmetic [23]. These data are 
shown in the table 4 below. 
 
 
 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 11 of 34 
Table 4:  Effects of Methylphenidate on Neurocognitive Motor Tasks 
Neurocognitive Task 
Placebo Group 
Methylphenidate 
P 
Finger Tapping (speed = 10 sec) 
89 +12 
119 +16 
<0.001 
Finger Tapping (speed = 30 sec) 
98 +15 
130 +19 
<0.001 
Arithmetic 
108 +17 
78 +21 
<0.01 
Reverse Digits 
101 +17 
125 +28 
<0.001 
 
 
Breitbart also found that methylphenidate improves neurocognitive motor function as measured by the 
trail making test A & B in patients with AIDS [28]. Also, methylphenidate might reduce subjective fatigue and 
improve physical activity by its effects on psychomotor activation.   
 
RESEARCH DESIGN 
 
This is a 2x2 factorial design randomized controlled, double blind, parallel study investigating the 
interaction between methylphenidate and nurse phone calls in reducing fatigue and associated symptoms in 
212 patients diagnosed with metastatic, incurable cancer. Half of the patients will receive nursing telephone 
interventions (NTI) from 4 – 6 times in the first two weeks of study. Half will not.  Half of the patients will 
receive methylphenidate and half will receive placebo.  Patients will be assessed for fatigue, depression, 
anxiety, sleep disturbance, activity level, and neurocognitive motor function.  
 
Patient Recruitment.  Patients with advanced cancer will be recruited from The University of Texas M.D. 
Anderson Cancer Center (MDACC; a comprehensive cancer center) and Lyndon B. Johnson General 
Hospital (LBJ: a public hospital).  Both hospitals are located in Houston, Texas, and Drs. Vicente Valero and 
Marlene Cohen, co-investigators, have joint appointments at both facilities.  We currently conduct research 
protocols at both institutions.  We estimate that 2/3 of patients will be recruited from MDACC, and 1/3 from 
LBJ.  At MDACC, patients will be recruited from medical oncologists working in the genito-urinary, thoracic 
and head and neck, breast, gynecological centers, and the clinics based in our own outpatient center (pain, 
rehabilitation, and symptom control and palliative care clinics).  We have fully established ongoing 
relationships with the physicians operating these clinics and they regularly refer patients to our clinical 
studies.  
At LBJ hospital, patients will be recruited from M.D. Anderson Outreach Clinics.  We have fully 
established research links with this clinic and we have admitted patients, especially persons from ethnically 
diverse groups, to our pilot study, a randomized controlled trial of methylphenidate and the nursing telephone 
intervention with excellent recruitment and retention rates.  
MDACC’s patient population is comprised of 71%, Anglos, 11% African-Americans, 10% Hispanics, 
and 7% other.  The majority of patients have private insurance.  LBJ is part of the Harris County Hospital 
District (HCHD), and its patient population reflects that of the 2003 data from the HCHD community.  Active 
patients totaled 276,654, which was 11.89 % Anglo, 53.68% Hispanic, 30.39% Black, and 4.04% 
Asian/Other.  This population is primarily indigent and uninsured with a large number of immigrants.  More 
than half were under 200% of Federal Poverty Level in FY 2001.  Recruiting from two local, yet 
demographically-diverse hospitals will help produce a sample that is ethnically and socio-economically 
representative of advanced cancer patients.  Patients will be screened for eligibility criteria.  Patients who are 
eligible and who give written informed consent to participate in this research study will be admitted to the 
double blind phase of the study described below.  Consents forms and assessments will be available and 
administered in either English or Spanish (by Spanish speaking research nurse, and investigator). 
 
Patient Compensation 
Each patient that is willing to participate on this study and has signed the informed consent will receive a $10 
gift card for their time and participation. 
 
4.0  Patient Eligibility 
 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 12 of 34 
Inclusion criteria: 
 
      1.   Patients will be eligible to participate in this study if they have advanced cancer. 
2. Patients will be eligible to participate in this study if they rate fatigue on the ESAS during the last 24 
hours as  to 4 on a 0 to 10 scale, in which 0= no fatigue and 10= worst possible fatigue. 
3. Describe fatigue as being present every day for most of the day for a minimum of 2 weeks. 
4. Lack clinical evidence of cognitive failure, with normal Mini Mental State Examination (MMSE). A 
score of 24 is considered normal. 
5. Are 18 years or older. 
6. Are willing to keep a daily diary, engage in telephone follow up with a nurse every other day, and 
return for a follow-up visit after 14 days of treatment.   
7. Have telephone access to be contacted by the research nurse.  If patient is relocating within 5 weeks, 
patient will be asked to provide a new telephone number. 
8. Hemoglobin of >8 g/dL within 2 weeks of enrollment. If the patient has not had blood drawn for a 
hemoglobin level in the past two weeks, one will be done to determine the eligibility.  Patients with a 
hemoglobin <8 will be referred for treatment of their anemia. 
9. Able to understand the description of the study and give written informed consent. 
10. Able to understand the description of assessments, and able to complete baseline assessment 
11.  Patients on no erythropoietin or on a stable dose. 
 
Exclusion criteria: 
1. Major contraindication to methylphenidate i.e. hypersensitivity, anxiety, tension, agitation, or motor 
tics, glaucoma, severe angina pectoris, or hypertension, etc. 
2. Currently on methylphenidate or has been on methylphenidate within the last 10 days. 
3. Inability to complete the baseline assessment forms or to understand the recommendations for 
participation in the study. 
4. Major depression according to the S/CID DSM IV diagnostic criteria. These patients will be referred 
immediately to psychiatry for assessment and management. 
5. Pregnant or lactating women. 
6. Requirement for MAO inhibitors, tricyclic antidepressants or clonidine. 
7. Glaucoma, history of marked anxiety disorders. 
8. History of alcohol (CAGE questionnaire score for the last 2 years is 2 or above on a 0 to 4 scale) or 
substance abuse including illegal drugs and/or medications. 
9. Tourette's syndrome 
10.  Symptomatic tachycardia and uncontrolled hypertension 
11.  Currently receiving oral anticoagulants (Coumadin/warfarin), anticonvulsants (Phenobarbital, 
diphenylhydantione, primidone), phenylbutazone, MAOIs and tricyclic drugs (imipramine, 
clomipramine, desipramine). 
12. Patients with pacemakers 
13. Patients with symptomatic cardiac arrhythmias 
 
Randomization.  Patients will be randomized at the time of randomization by accrual site to ensure an 
approximately equal representation of patients in each arm, by site.  Separately for each site, patients will 
be randomized to one of the four treatment arms. The randomization schema will be based on parameters 
input into RANLST, a randomization program developed at MDACC and supported by an NCI grant.  
Initially a randomization list containing order information for all four arms will be made.  Information about 
drug assignment will then be deleted from the list given to research nurses and information about nurse 
phone calls will be deleted from the file given the pharmacists.   
 
Patient names in sequence will be recorded on each list as the patients are entered and both lists 
will match patient name and identification number.  Only the primary statistician will know the complete list 
of the order of randomization into the four arms until the end of the study.  In addition, the dispensing  
pharmacist at each site will know the randomization of drug treatment at their site and the research nurse(s) 
who call patients will know which patients to call.  However, the code for an individual patient as to drug 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 13 of 34 
treatment group may be disclosed early and the patient removed from the study in the case of a request by 
the primary treating physician due to adverse events.  Otherwise, no other persons will know about the 
assignment of patients to treatment arms until the end of the study. 
 
 
5.0  Study Plan and Assessment Measures 
 
 
5.1 Study Plan 
 
Clinical Trial Design. This will be a randomized controlled, double blind, parallel study investigating the 
interaction between methylphenidate and nursing telephone intervention in reducing fatigue and associated 
symptoms in advanced cancer patients.  An overview of the study design is illustrated in Figure 3.  
Double Blind Phase (Day 1-14):  Patients will be randomized to one of four experimental groups receiving the 
treatments detailed below. 
Group 1:   Methylphenidate 5 mg (one capsule) orally every two hours as needed up to a maximum of 20 mg 
per day for a period of 14 days with nursing follow up phone call (NTI)  4-6 times during the first 2 
weeks.  
Group 2:   Placebo, one capsule, orally every two hours as needed up to a maximum of 4 capsules per day 
for a period of 14 days with nursing follow up phone call (NTI) 4-6 times during the first 2 weeks.  
Group 3:   Methylphenidate 5 mg (one capsule) orally every two hours as needed up to a total of 20mg per 
day for 14 days with no specific phone calls (NSPC)4-6 times during the first 2 weeks. 
Group 4:   Placebo, one capsule, orally every two hours as needed up to a total of 20mg per day for 14 days 
with no specific phone calls (NSPC) 4-6 times during the first 2 weeks. 
 
 
Open Phase (Day 15-36):  The intervention phase will be followed by an open phase that will begin after the 
assessment at time point 2.  On Day 15, all patients will be provided the opportunity to receive 
methylphenidate 5 mg orally as needed up to a total of 20 mg per day until Day 36.  Patients will not be told 
whether they previously received placebo or methylphenidate.  Assessments of fatigue, physical activity, and 
psychosocial functioning will be conducted at day baseline, day 15 (±3 days), and day 36 (±3 days). On Day 
36 (±3 days) the study will be completed and patients will be referred back to their primary care physician 
who will discuss with the patient the appropriateness of continuing on methylphenidate. 
The open phase of the study will allow all participants to receive the potential benefits from 
methylphenidate, and will provide important preliminary information on longer term beneficial effects and side 
effects from methylphenidate. Our preliminary randomized controlled trial [132] found that the improvement in 
3 out of 4 items in the Functional Assessment for Chronic Therapy-General (FACT- G), and 7 out of 10 
symptoms of the Edmonton Symptom Assessment System (ESAS) was maintained during the open phase at 
day 36. In this study, if methylphenidate is found to be useful in the population under study, this drug will be 
used for weeks or months. We would like to gain preliminary data about the effectiveness and tolerability over 
time. Some specific questions regarding the longer term use of methylphenidate include: 1) Will dose 
escalation be needed for patients over time? 2) Will patients find the drug less useful and therefore decrease 
utilization over time? 3) Will the global assessment of treatment effectiveness decrease over time? 4) Will 
there be new or more severe side effects in this patient group over time? The preliminary information gained 
during the open phase will help us better delineate the overall role of methylphenidate in the long term 
management of fatigue in advanced cancer. 
 
 
 
 
Figure 3. Study Design 
 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 14 of 34 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Methylphenidate Treatment.  Methylphenidate is a central nervous system (CNS) stimulant.  This drug is 
usually very well tolerated when used in advanced cancer patients (38, 53-54), when used long term in 
attention deficit disorder (74-75) and when used in the management of depression in the elderly (25, 76). The 
dose of 5 mg orally and the modality of administration on an “as needed” basis has been chosen because it 
was found to be effective and well tolerated in our pilot study [38]. We also extended the double-blind 
treatment phase to 14 days to more effectively rule out placebo effects.  Breitbart’s findings [28] indicated 
differences between placebo and treatment groups after 14 days on a standardized comprehensive fatigue 
assessment scale (Piper Fatigue Rating Scale), similar in design to the fatigue measure (FACIT-F fatigue 
subscale) to be used in the proposed study.  However, considering the attrition rate in our pilot and 
Breitbart’s, we chose a study length that we believed would not be impacted by the attrition factors observed 
in previous studies with advanced cancer patients.  Placebos matching methylphenidate will be made in the 
pharmacy of MD Anderson Cancer Center.  In the double blind phase, capsules and lactose will be used for 
the placebos, and capsules and methylphenidate will be used for the study drug.  Both groups will receive a 
14-day supply of medication.  Patients will be instructed on how to take the medication.  They will also be 
provided dosage recommendations and potential side effects.  Patients will be given a diary to record daily 
dosage.  The research nurse will monitor the medication usage via diary records.  
 
During the double blind phase, all patients will be provided with a 14-day supply of methylphenidate or 
placebo by the pharmacy at MDACC.  The randomization code will be kept in the pharmacy and will only be 
broken for the final analysis upon completion of patient accrual.  In cases of serious toxicity the principal 
investigator will be able to request that the code be broken for a specific patient.  On Day 15, patients who 
choose to continue methylphenidate will be given a three-week supply.  The medication will be provided free 
of charge. 
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. 
Provision of Written Informed Consent 
Randomization to double-blind 
phase of study (Day 1-14) 
Group A 
Methylphenidate 
       5 mg as needed x 2 wks 
With 
NTI 4-6 times 
 Within 2 weeks 
Group B 
Matching Placebo  
as needed x 2 wks 
With 
      NTI 4-6 times  
Within 2 weeks  
Group C 
Methylphenidate 
5 mg as needed x 2 wks 
With 
NSPC 4-6 times 
Within 2 weeks 
Group D 
Matching Placebo  
as needed x 2 wks 
With 
NSPC 4-6 times 
Within 2 weeks 
Open phase of study 
(Day 15-36) 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 15 of 34 
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.  
 
It is not well known how often the side effects of methylphenidate may occur. 
 
chest pain (possibly due to 
heart trouble) 
high blood pressure 
low blood pressure 
irregular heartbeat 
fast heartbeat 
slow heartbeat 
extra heartbeats 
inflammation of arteries in 
the brain 
blocked blood vessels in 
the brain 
heart attack 
abnormal heart sound due 
to turbulent blood flow 
blood vessel disorder 
causing cold, numb, and 
discolored fingers and/or 
toes 
aggression, irritability, 
and/or anger 
agitation and/or anxiety 
confusion 
depression 
dizziness 
fatigue, drowsiness, and/or 
tiredness 
fever 
headache 
difficulty sleeping 
mood alterations 
nervousness, tension, 
and/or restlessness 
condition that results in 
muscle stiffness, high 
fever, and/or 
drowsiness 
stroke 
Tourette's syndrome 
(uncontrolled speech 
and/or muscle 
movements) 
psychosis (loss of 
contact with reality) 
hallucinations 
mood disorder with 
extremes of happiness 
and sadness 
seizures 
hair loss 
shedding and scaling of 
the skin 
increased sweating 
skin rash 
hives 
skin redness 
painful menstruation 
stunted growth 
abdominal pain  
decreased appetite 
grinding or clenching of 
teeth 
constipation 
diarrhea 
upset stomach 
nausea 
vomiting 
weight loss 
dry mouth 
spots under the skin 
caused by bleeding 
inability to have an 
erection 
decreased sex drive 
blood vessel 
inflammation (possible 
fever and/or fatigue)  
jaundice (yellowing 
and/or darkening of the 
skin) 
abnormal liver tests 
(possible liver damage) 
joint pain 
uncontrolled 
movements 
muscle tightness 
tickling/tingling 
sensation 
muscle twitching 
blurred vision 
dry eyes 
pupil dilation 
vision problems 
double vision 
cough 
difficulty breathing 
sore and/or painful 
throat  
inflammation in the 
nose 
inflammation of the 
sinuses 
head cold  
allergic reaction 
 
 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 16 of 34 
Methylphenidate may cause low blood cell counts (white blood cells, red blood cells, and platelets). 
This means that while you take the drug, there is more of a chance of getting an infection, including 
pneumonia. You may become anemic and/or have problems with bleeding, bruising, fatigue, and/or 
shortness of breath. You may need a blood transfusion. All patients will be provided with a toxicity-
recording sheet.  Patients will be instructed to record side effects daily.   
For those who receive NTI, the research nurse will assess toxicity during NTI. For those who receive NSPC, 
toxicity will be assessed by the research nurse once a week for 5 weeks. All patients will be provided with the 
research nurse contact phone number, MD Anderson Cancer Center emergency center telephone number, 
LBJ hospital emergency room telephone number, and will be asked to immediately call staff members if they 
perceive any serious or unusual side effect.   
Drug Dependence.  Methylphenidate has been abused and it has addictive potential [32].  Our group has 
conducted five trials of methylphenidate [22, 23, 38, and 54] and preliminary data reported above], 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.  Information regarding abuse and all other side effects will be part of the research nurse-
training program.   
 
Patients will be instructed that capsules should not be opened or crushed.  Methylphenidate should 
be taken only as prescribed and should be given cautiously to emotionally unstable patients, such as those 
with a history of drug dependence or alcoholism, because such patients may increase dosage on their own 
initiative.  Chronically abusive use can lead to marked tolerance and psychic dependence with varying 
degree of abnormal behavior.  Careful supervision is required during drug withdrawal, since severe 
depression as well as the effects of chronic over activity can be unmasked.  All patients on this study will be 
educated about the abuse potential of methylphenidate.  The research nurse as routine M.D. Anderson 
Cancer Center protocol procedure will conduct weekly pill count. During the double blind phase, only 2-week 
drug supply will be provided, and during the open phase, a 3-week drug supply will be provided.  
 
Potential withdrawal symptoms and intervention The most frequent problems associated with the withdrawal 
of methylphenidate are the return of the symptoms for which patients were originally treated. For example, 
there may be aggravation of symptoms of attention deficit hyperactivity disorder or depression. Other 
possible symptoms would include an aggravation of somnolence and/or fatigue [131]. However, our group 
has conducted five trials of methylphenidate (daily dose ranges from 10 mg to 20 mg) in cancer patients 
followed by discontinuation [22-23, 38, 53,132], we did not observe any cases of withdrawal symptoms. Other 
investigators also observed similar findings. Arnold et al. conducted a 2-week double-blind, placebo-
controlled withdrawal trial of methylphenidate in 76 evaluable children with attention deficit hyperactivity 
disorder (ADHD). They noticed no withdrawal signs and symptoms [128]. Nalon et al. switched from 
methylphenidate to placebo under double-blind conditions in 17 children with ADHD and chronic tic disorders 
[129], and found no signs of withdrawal. In a double-blind randomized placebo-controlled crossover study of 
60 patients with chronic fatigue syndrome, Blockmans et al. did not observe withdrawal symptoms after 
patients received 4-week methylphenidate and crossed over to 4-week placebo [130]. Breitbart and 
colleagues in their study of 109 HIV patients receiving methylphenidate versus pemoline for the treatment of 
fatigue found no withdrawal symptoms after 6-week trial [28]. 
 
Regardless, all patients are instructed to report to the research nurse if any of withdrawal symptoms 
develop, and appropriate interventions will be initiated by the research nurse. All patients who drop out of the 
study and all patients who discontinue methylphenidate after the completion of the open label phase will 
receive a weekly phone call from the research nurse regarding the presence of aggravation of depression, 
somnolence, fatigue, or other symptoms of withdrawal. These telephone calls will continue for a period of four 
weeks. If patients are found to develop any of these acute withdrawal symptoms, the patients will be 
immediately referred to their primary care physician and/or the emergency room at M. D. Anderson or Lyndon 
B. Johnson Hospital will be made, respectively, and the primary care physician and the emergency room 
physician will be notified of these findings for appropriate clinical management. 
 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 17 of 34 
Nursing telephone intervention (NTI).  All patients randomized to receive NTI will be contacted by a 
research nurse with training in palliative care 4-6 times during the first 2 weeks of the treatment. Those who 
are randomized to receive NSPC will be contacted by a non-nursing person 4-6 times during the first 2 
weeks.  The nurse will contact the patients at a time agreed upon during the initial meeting.  Conversations 
with nurses will be standardized in terms of questions that the nurses ask of patients, and attempts will be 
made to ensure consistency of time spent talking with patients.  The phone calls will begin with a brief 1-
minute introduction and statement of the purpose of the phone call.  NTI will include:  
1. Assessment of symptoms using M.D. Anderson Symptom Inventory (MDASI); 
2. Assessment of toxicity using a toxicity record sheet; 
3. Review of medication including regular and as needed medication; 
4. Provision of psychosocial support and patient education.   
 
MDASI is a brief, easily understood instrument, which provides a measure of the intensities of 13 
cancer-related symptoms.  Patients rate the intensity on 0 to 10 numerical scales from “not present” to “as 
bad as you can imagine.”  A Spanish version of the MDASI has been developed, by translating and back 
translating the instrument to check the translation.  Validation of the instrument has been completed (77).  
The research nurse will address main symptoms in the order of severity as recorded on the MDASI.  
Research nurse counseling will proceed according to the Methylphenidate and Nursing Intervention for 
Cancer Related Fatigue Study Manual (Appendix U).  Research nurses will ask what additional symptoms 
patients may have experienced during the last few days.  Patients will also be asked about any side effects 
they may have experienced and the severity of those side effects, based on NCI Common Toxicity Criteria, 
while taking methylphenidate.  The research nurse will review medications, including type and dose of all 
regular and “as needed drugs”, and provide educational advice as needed. The research nurse will also ask 
open-ended questions regarding general well being of the patient and family. The research nurse will provide 
empathetic listening, answer all the questions, and provide supportive statements and end the telephone call. 
 
If necessary or appropriate (i.e., in the case of severe symptoms), the nurse will contact a physician 
and phone the patient with recommendations or will recommend that the patient come to the hospital.  The 
total duration of the phone call is expected to be less than 30 minutes according to our experience in 
previous studies [38].   
 
In this study, 106 patients will be involved in the NTI, each called longitudinally at 4 to 6 times or 424 
to 636 calls.  The telephone conversation between the nurse and the patient will be recorded using a 
recording devise M. Cohen has used in prior research.  These calls will produce qualitative data that are 
useful to understand and identify interventions that are appropriate for phenomena that change over time, as 
do symptoms for persons with advanced cancer.  Content analysis will be conducted on transcripts of the 
telephone interviews with the nurses, and with the open-ended questions in the outcome assessment.  
Content analysis is one aspect of phenomenological work, with which Cohen has extensive experience.  
While the data obtained is not precisely the same as phenomenological data, there are many similarities, and 
we anticipate that data will elucidate the meaning of the experiences of both the symptoms and the 
intervention. 
 
As is done in phenomenological research, data analysis will occur simultaneously with data collection.  
The goal of analysis will be a thick description.  A thick description is one that captures the experience from the 
perspective of the informant in its fullest and richest complexity (78).  This analysis will provide a detailed 
description of the meaning of both intervention and patients’ symptoms.  
 
Data management: Cohen, with the help of the research nurses, will supervise and verify verbatim 
transcription of the audiotapes of each telephone intervention.  The transcriptionist will use a common editorial 
software program such as Microsoft Word for transcription.   
 
Data collected in the course of the nursing telephone interventions will be used for the purposes of 
ensuring the quality and consistency of the nursing intervention, such as determining if education and 
psychosocial support are appropriate and consistent, and for qualitative analysis. 
Training of Nurses.  The research nurses conducting telephone interventions will undergo a training 
program conducted by the principal investigator [EB], the research manager [JW], and the nurse specialist 
[MC].  The training program will include 40 hours of structured training and consist of lectures, role play, and 
discussion in all aspects of the appropriate assessment of the different symptoms, how to follow the different 
guidelines for the management of the most common symptoms according to the Methylphenidate and 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 18 of 34 
Nursing Telephone Intervention for Cancer Fatigue Study Manual [Appendix U]. The manual includes 
Research Nurse Training Curriculum, Weekly Research Nurse Refresher Curriculum, and information on 
Methylphenidate, the Nursing Telephone Intervention information and Symptom Assessment and 
Management.  The training also includes elements for expressive supportive counseling as regularly 
conducted by our palliative care program.  Mock telephone interviews will be included in the training, and will 
be recorded, reviewed, critiqued, and discussed.  Training on the other study instruments will consist of 
several mock interviews that will be observed and critiqued.  The research nurses will evaluate study patients 
only after they have successfully completed training. 
 
Areas of interviewing that will be addressed in the training will include reducing interviewer bias, 
preventing the introduction of assumptions and leading statements, reflecting informants’ views rather than 
suggesting views, and helping informants elaborate on and clarify their perceptions.  M. Cohen will continue to 
review the audiotapes and discuss them with the interviewers throughout the project.  This procedure discussed 
by Tripp-Reimer (79) and used by Cohen in prior research, has been successful in obtaining rich 
phenomenological data.  The techniques in phenomenological interviewing are exactly what are required in the 
NTI.  
Weekly Research Nurse Refresher Curriculum.  Every week there will be a session of not less than two hours 
and 15 minutes with the project manager and the PI to discuss methylphenidate and pharmacy procedures, 
review the NTI, including quality assurance of tape recorded nursing interventions, discuss problems and 
solution related to symptom assessment and management, methylphenidate and the nursing intervention, 
patient drop outs and missing data. The research nurses will also discuss the progress of the different 
telephone calls and during these weekly meetings there will be booster sessions on different specific aspects 
of how to conduct symptom assessment, algorithms for symptom management, and expressive supportive 
therapy.  Nurses will be encouraged to ask questions and when appropriate other investigators will be invited 
to the weekly sessions for further clarifications. 
Quality Assurance.  All interviews will be tape-recorded.  The research manager will conduct weekly quality 
improvement with all the research nurses by discussing the content of the NTI.  Focus will be made on 
appropriate techniques for symptom assessment, appropriate advice based on the use of the algorithms, and 
the quantity and quality of expressive supportive counseling.  M. Cohen, who will be analyzing these 
transcribed interventions, will also alert the research manager and staff should problems be noted in the 
techniques the nurses are using.  She will meet with the research nurses to discuss any changes in the 
quality or consistency of these calls. 
 
5.2  The following assessment measures will take place at baseline and during the   study (see table 
5): 
 
Pre-Treatment Assessments. The assessment of demographic variables will include patient self-reported 
birth date, gender, marital status, ethnicity, education, and job status, primary cancer, cancer treatment within 
the last year, surgery, chemotherapy, immunotherapy or radiotherapy, and medications including opioid 
dosage. 
 
Baseline assessments of symptoms include FACIT-F (including FACT-G and Fatigue subscale), 
Hospital Anxiety & Depression Inventory (HADS), Edmonton Symptom Assessment System (ESAS), and Six-
Minute Walk test, Symbol Digit Modalities Test (SDMT), Pittsburgh Sleep Quality Index (PSQI). 
Outcomes Assessments: 
5.3  Fatigue. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) is a subscale of the 
Functional Assessment of Chronic Illness-General scale and has been used primarily in cancer patients to 
measure fatigue during the past 7 days.  The subscale consists of 13 items.  Test-retest reliability coefficients 
for the fatigue subscale have ranged from 0.84 – 0.90.  This scale has also demonstrated strong internal 
consistency (alpha = 0.93-0.95) [80].  This measure is available and validated in Spanish. 
5.4  Number of Pills Taken. The number of methylphenidate and placebo pills taken over the course of the 
study will be recorded.  As we expect the methylphenidate pills to have greater efficacy in the treatment of 
fatigue, we hypothesize that patients will take more methylphenidate pills than placebo pills. 
5.5  Depression and Anxiety.  Depressive and anxious symptoms will be assessed using the 14-item 
Hospital Anxiety and Depression (HADS) questionnaire [81].  This questionnaire has been found to be valid 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 19 of 34 
and reliable in a number of clinical situations and has been widely used in medically ill patients.  Although its 
use in cancer patients has been somewhat limited, we believe its proven validity in the clinical setting makes 
it well suited for our study.  This questionnaire asks patients to underline the statement that is closest to how 
patients have been feeling in the past week.  This measure is available and validated in Spanish. 
5.6  Other Common Symptoms. The Edmonton Symptom Assessment (ESAS) measures the patient’s 
response to ten common symptoms in the past 24 hours (pain, fatigue, nausea, depression, anxiety, 
drowsiness, and shortness of breath, appetite, sleep, and feeling of well being) in patients with cancer or 
other chronic illnesses.  This questionnaire has been found to valid and reliable in cancer populations [82] 
and it is available in Spanish. 
5.7  Sleep Disturbance.  Sleep disturbances will be assessed using the Pittsburgh Sleep Quality Index 
(PSQI) [83] and the Pittsburgh Sleep Diary (PghSD) [83].  The Pittsburgh Sleep Quality Index is an 18-item 
self-report measure.  Patients will be asked to report their usual sleep habit during the past 2 weeks.  This 
instrument provides a brief, clinically useful assessment of a variety of sleep disturbances that might affect 
sleep quality over a one-month period.  We will modify the time period to two weeks.  A total score is derived, 
as well as seven subscales consisting of subjective sleep quality, sleep latency, sleep duration, habitual 
sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction.  The PSQI has 
good internal (0.83) and test-retest reliability (0.65-0.85).  The PSQI was found to have good validity, and for 
distinguishing between patients with depression, disorder of initiating and maintaining sleep, disorder of 
somnolence, and healthy controls.  Validity of the PSQI is supported by significant differences between 
“good” and “poor” sleepers’ PSQI global and component scores; a sensitivity of 89.6% and specificity of 
86.5% using a cut-off score of 5 to identify a sleep disorder; and by similar group differences in terms of PSQI 
scores and polysomnographic sleep measures.  This assessment tool is available in Spanish. 
 
The PghSD was developed as a diary of sleep-wake behavior that could be used easily by research subjects 
and patients [79].  It comprises a bedtime and wake-time assessment.  We will collect sleep diary data for 7 
consecutive days during the time the actigraphy data are being collected.  The bedtime portion of the diary 
asks questions about the times of meals, naps, exercise, and medications, and about the consumption of 
caffeine and alcohol and tobacco use.  We have modified the diary to also include six common cancer-
related symptoms: fatigue, nausea, pain, anxiety/tension, blue/down, and difficulty thinking.  The wake-time 
portion of the diary asks the patient to record aspects of the previous nights sleep; symptoms they may have 
had during the night (nausea, pain, anxiety, and worry); and upon awakening a rating of whether they feel 
rested, blue/down, and anxious.  The PghSD has been used by the sleep laboratory in Pittsburgh for over a 
decade and has been adopted by several other researchers.  The PghSD is sensitive to differences between 
young and old individuals, and between patients with sleep disorders and healthy controls [84].  Sleep diary 
data will be used to quantify (1) subjective sleep quality; (2) self-reported sleep duration, latency, and 
fragmentation; and (3) sleep-related behaviors.  Data will also be used to help verify actigraphy-derived data 
regarding of sleep duration and fragmentation.  Summary scores will be calculated for diary data, although 
repeated measures analyses of daily data will also be done. The PghSD takes less than 2 minutes to 
complete upon awakening and each evening at bedtime. 
5.8  Physical Activity. The six-minute walk test will be used to assess physical function and has been 
recommended by the American Thoracic Society (ATS) as an objective measure of functional capacity [85].  
This test has been found to be an objective measure of functional capacity in patients with chronic respiratory 
conditions, fibromyalgia, stroke, and cancer [85].  Our group has used this methodology in the assessment of 
fatigue and dyspnea [86].  Assessment will occur at baseline, day 15 and day 36.  The standardized protocol 
for administering this test will be followed.  The Borg scale will be used to assess fatigue and shortness of 
breath prior to the six-minute walk and at the end of the walk [85].  Our previous study demonstrated that 6-
minute walk in patients with fatigue and dyspnea related to lung cancer was well tolerated.  33/33 (100%) 
patients were able to tolerate two episodes of 6-minute walks within half hour [86].  
 
In the proposed study establishing a baseline pattern of activity and sleep before the activation of the 
clinical trial would be optimal in order to compare changes in activity levels after the intervention, however, 
logistically this is not possible.  To establish baseline patterns would necessitate a delay in administering the 
intervention to eligible patients recruited during 2 clinic visits and would require an additional clinic visit to 
begin the intervention.  This would be an additional burden to the patient and might deter recruitment efforts.  


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 20 of 34 
Another way to address this problem might be to visit the patient in the home.  However, visiting the patient in 
the home would confound the testing of our hypothesis about the therapeutic value of nursing telephone 
interventions.  Thus, we will record activity over the fourteen-day intervention period.  Our group has 
conducted a pilot study with Actigraph and has extensively consulted with colleagues who have conducted 
this research. We believe that Actigraph has shown the ability to receive reliable 24-hour and awake/asleep 
data as well as overall activity.  We hypothesize that patients receiving methylphenidate will significantly and 
progressively increase their mean activity and decrease their percent sleep during the “out of bed” portion of 
the day as compared to the placebo group. 
 
All patients will carry a wrist actigraph monitor for the 14-day period of the double-blind phase.  Motion 
will be recorded 6 times per minute and the following measurements will be conducted:   
a. Mean activity during the “out of bed” portion of the day; 
b. Percent sleep during the “out of bed” portion of the day; 
c. Number of hours of “in bed” portion of the day. 
Actigraph record will be downloaded in the department specific database. 
In cases that patients are unable to walk, or unable to return to clinic on the scheduled days (15+/-, or 
36 +/-), 6-minute walk will not be performed. 
5.9  Neurocognitive Motor Function. The Symbol Digit Modalities Test (SDMT) will be used to assess 
neurocognitive motor function.  Our group has considerably experience with this tool.  SDMT requires 
examinees to match numbers to a series of different symbols presented randomly on a single test page, 
using a key found at the top.  There are 120 matches to be made in total, and each subject has to make as 
many as possible, working in a consistent order, within a 90 second period.  The score is the number of 
correct matches in the 90-second period, excluding the 10 practice items.  It is recorded as a proportion of 
the total number of responses, for example 36/39 indicates that the examinee made a total number of 39 
responses, 36 correct and 3 incorrect.  This gives a measure of both speed and accuracy. It is possible to 
convert the raw score into a standard score, with a mean of 100 and a standard deviation of 15.  It is a useful 
diagnostic tool, measuring clerical speed, visual search and memory, fine motor control and concentration 
(87). In our donepezil pilot study for opioids induced sedation [13] and a current randomized, double blind 
controlled trial for cancer fatigue, adherence to SDMT has excellent. SDMT will be performed at baseline, 
and on days 15 and 36 (+/-3 days). In cases that patient is not able to complete the assessment as 
scheduled (i.e. Unable to reach patient, SDMT form is not available, severity of symptoms or refusal), SDMT 
will not be performed.  
5.10 Quality of Life. The Functional Assessment of Cancer Therapy-General (FACT-G) is a self-report 
measure of quality of life in people with cancer.  Nearly all patients with a sixth-grade reading level can easily 
complete the measure without assistance.  The system contains a 27-item compilation of general questions 
divided into four primary QOL domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-
Being, and Functional Well-Being.  It is considered appropriate for use with patients with any form of cancer.  
Validation of a core measure allowed for the evolution of multiple disease, treatment, condition, and non-
cancer-specific subscales [88].  FACIT-F fatigue subscale has 13 items regarding patient’s fatigue during the 
last 7 days.  Patients rate the intensity of fatigue and its related symptoms on 0 to 4 numerical scales from 0 
“not at all” to 4 “very much,” This tool is available and validated in Spanish. 
5.11  Assessment of Blinding for Patient and Research Nurse.  At the end of week 1 and week 2, both 
patients and the research nurse will be asked about their belief of the treatment received by the patient: 1) I 
believe that I (my patient) received study drug (methylphenidate); 2) I believe that I (my patient) received 
placebo; and 3) I don’t know. 
5.12  Global Assessment of Effectiveness of the Treatment. This instrument will estimate the minimal 
important difference in patient’s overall symptom perception before treatment and after treatment.  Patients 
will be asked about their symptom perception after starting the new medication.  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 tool has been widely used in symptom research [89-90].  We will 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 21 of 34 
also use the “was it worthwhile?” assessment of participation in the clinical trial, developed by Sloan et al 
(91). 
5.13  Medication Review.  Patients receiving opioid analgesics (approximately 80% of patients with 
advanced cancer) will be eligible for this study.  The type, route, and daily dose of opioid analgesics will be 
recorded from information given by the patient on a weekly basis. This will include regular opioid dose and 
extra rescue dose.  Patients will be allowed to receive laxatives, antiemetics, and other symptom related 
medications.  They will be encouraged to carefully register in the diary the medications they have taken and 
to contact the research nurse before making major drug modifications.   
 
5.14 Assessment During Treatment.  During treatment, patients will maintain a daily diary of their fatigue 
and other symptoms, the number and times pills are taken, and the fatigue rating before and 2 hours after 
taking methylphenidate.  A research nurse will contact patients randomized to receive nursing telephone 
intervention 4-6 times for the first 14 days of the study.  Table 5 [next page] illustrates assessments 
performed during study.  Our preliminary data from our pilot study [38] as well as our pilot randomized 
controlled trial of methylphenidate plus nursing telephone interventions strongly support that patients comply 
with these assessments very well. (See table 5 below). 
 
 
 
 
 
 
 
Table 5.  Assessment Schedule  
Time Point 
Baseline 
Day* 
8 
(±3days) 
Day* 
15 
(±3days) 
Day** 
22 
(±3days) 
Day** 
29 
(±3days) 
Day** 
36 
(±3days) 
Instruments 
FACIT-F (including FACT-G)*** 
 
 
 
 
 
 
FACIT-F (subscale only)*** 
 
 
 
 
 
 
Hospital Anxiety & Depression 
Inventory (HADS)*** 
 
 
 
 
 
 
Edmonton Symptom Assessment 
Scale (ESAS)*** 
 
 
 
 
 
 
Six-Minute Walk Test 
 
 
 
 
 
 
Symbol Digit Modality Test 
 
 
 
 
 
 
Pittsburgh Sleep Quality Index*** 
 
 
 
 
 
 
Fatigue Diaries*** 
 
 
 
 
 
 
Toxicity Assessment*** 
 
 
 
 
 
 
Global Assessment 
 
 
 
 
 
 
Assessment of blinding (patient 
& nurse) 
 
 
 
 
 
 
Actigraph record 
 
 
 
 
 
 
Study drug count 
 
 
 
 
 
 
KEY: SHADED AREAS DENOTE ASSESSMENT GIVEN AT PARTICULAR TIMEPOINT. 
*Patient Diary is only provided to the patient for the first 2-week double blind phase of the study. 
** During open label phase, weekly assessment of FACIT-F, ESAS, Toxicity, drug count, and 
current opioid will be reviewed with the patient over the phone or in the clinic. 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 22 of 34 
*** These assessments are available in English and Spanish to allow recruitment and enrollment 
of Spanish-speaking patients. 
 
If the research nurse is unable to reach patient after 4 attempts, or patient is unable to answer 
questions due to severity of symptoms or refusal on the scheduled day (+/- 3 days), the research 
nurse will dictate in the progress notes detailing this effort, but assessments will not be 
performed. 
 
 
 
6.0   Statistical Considerations 
 
Prior to inferential procedures, extensive descriptive statistical analyses of the outcome and predictor 
variables will be conducted.  Standard descriptive statistics including means, standard deviations, ranges, 
and frequencies, together with 95% confidence intervals, will be computed where appropriate.  Distributional 
characteristics of relevant variables will also be more closely examined using box plots and histograms.  If 
the data do not appear to be approximately normally distributed, transformations will be made to the data.  
Bivariate associations will be explored using Pearson’s Product Moment correlation coefficients, scatter plots, 
and contingency tables. 
The primary endpoint of the study is the difference between the FACIT-F Fatigue Sub Score at 
baseline and 15 days later.  The goal of this study is to detect average difference scores of approximately 
33% from baseline for methylphenidate versus placebo or between every other day NTI versus no NTI or 
50% or more between any arms of the study.  The total sample size will be 212 patients. 
  We base this estimate in part on our previous study [38] that found close to 100% reduction in 
fatigue (baseline 17.5 to 34.7) by seven days in a group of 30 patients receiving methylphenidate and 
research nurse phone calls. We expect little reduction in fatigue for patients receiving placebo and no 
research nurse phone calls at 15 days, although there could be some placebo effect. We expect that the 
other two arms will fall somewhere in between.    
 
 As previously described, the four arms of the study are A) methylphenidate plus RN phone call, 4 – 6 
times in the first 2 weeks of study, B) placebo plus RN phone call 4 – 6 times in the first 2 weeks of study, C) 
methylphenidate plus no phone call, and D) placebo plus no phone call.  An advantage of the structure of our 
arms, which is a factorial treatment structure, is that it provides the opportunity for testing for significant 
differences between methylphenidate versus placebo and between 4 - 6 NTI versus no NTI; and also 
between all four arms of the study [92].  The design also allows us to test the synergistic effect of both phone 
calls and methylphenidate. 
 
 
The effect of the interventions on fatigue, physiological symptoms, and psychological symptoms will 
be tested using ANCOVA in SAS (SAS Institute, Cary, NC).  The fatigue outcome variable will be regressed 
onto the treatment group variables (two main effects of RN phone call and methylphenidate, each with two 
subgroups) with covariance adjustment for the baseline value of the outcome variable.  Standard residuals-
based diagnostic procedures will be used to test model assumptions and influential observations.  
Normalizing or variance stabilizing transformations will be made as necessary.  Although the randomization 
procedure will most likely ensure that these simple treatment comparisons are valid, additional covariance 
adjustments will be included in the models for age, gender, socioeconomic status, and ethnicity.  These 
variables will be forced in the model in a single step.  The magnitude and significance of the treatment 
condition variables will thus represent the effect of the interventions after adjustment for the covariates.  
Separate analyses will be conducted for the outcome measures for each follow-up time point.  To prevent 
inflated Type I error rates due to multiple comparisons, p-value adjustment will be conducted using the 
bootstrap resampling approach described by Westfall and Young (93).  This approach is less conservative 
than the standard Bonferroni approaches, while at the same time preserves the overall desired Type I error 
rate.  Algorithms for this procedure are currently available in SAS.   
 


 
 
 
 
 
 
Protocol #2005-0613 
 
 
 
 
 
 
Revised February 9, 2010  
 
 
 
 
 
 
Page 23 of 34 
 
Additional analyses will also be conducted in which all follow-up time points will be analyzed 
simultaneously using mixed model ANCOVA in SAS.  In mixed model ANCOVA, repeated measures data 
can be included by including random effect regression terms that provide adjustment for the correlation 
structure that exists across measures from the same individual.  At a minimum, a random effect term 
corresponding to the individual will be included in the model.  Additional covariance structure among 
observations from the same individual will be modeled by selecting the best fitting variance-covariance matrix 
using the procedure described by Wolfinger (94).  A separate time variable will be included in the model to 
allow simple trends to be tested.  An interaction term between time and treatment group will be added to test 
for differential patterns of change across time between the two treatment conditions.  Similar covariance 
adjustment for age, gender, socioeconomic status, and ethnicity will be included as described above.   
 
 
We will initially test for the main effects of treatment (methylphenidate versus placebo) and NTI (every 
other day versus none) and their interaction on fatigue. If there were a significant interaction, this would mean 
that the two factors were not independent. If this is found to be the case, four additional comparisons will be 
made: between NTI with methylphenidate, NTI with placebo, no NTI with methylphenidate, and no NTI with 
placebo. Although not independent, these F tests are essentially least significant difference comparisons [95].  
We will also use an analysis of variance to determine if any of the four arms of the study differ. If the overall F 
statistic from this test shows a statistical difference less than 0.05, we will then perform a set of additional pair 
wise comparisons using Duncan’s multiple range tests [96]. If the data appear to be non-normally distributed, 
we will use equivalent nonparametric tests; in this case the Kruskal-Wallis test with associated multiple 
comparison tests [97].   
 
In addition to fatigue, we will also test for differences between arms of the study for other continuous 
variables such as depression, pain, nausea, anxiety, insomnia, physical activity and neurocognitive motor 
function, using the same statistical methods as used for fatigue. Given the available sample size, changes 
between baseline and day 15 that are at least as large as 60% of the associated standard deviation will be 
declared statistically significant at a two-sided significance level with 80% power. When the arms for 
treatment/no treatment are combined or phone call/no phone call, the differences that can be detected 
between groups will be 42% or greater of the standard deviation.  
 
We will also have weekly information available for ESAS scores of fatigue, pain, etc. Therefore we will 
also test, on an exploratory basis, for trends over time for each of these variables using repeated measures 
analysis of variance. We will attempt to determine if there are differences by arm for these trends. However, 
since fatigue scores may not linearly decrease over time, this method of analysis may not be justified. We 
expect that fatigue scores will rapidly be reduced in the methylphenidate arms and that this reduction will be 
maintained over time. We also expect that fatigue scores in the placebo/no phone call arm will include some 
placebo effect of reduction in fatigue initially, but do not expect that this reduction will continue throughout the 
study. We expect that the other two arms will fall somewhere in between these two extremes. As summary 
measures, we will, at minimum, calculate average fatigue scores and standard deviations by group at each 
time point.   
 
We will also summarize the number of capsules taken by patients at days 8 and 15. We expect that 
patients randomized to placebo will be taking fewer capsules at these two times, due to realizing that the 
capsules are not working, than patients randomized to methylphenidate.  We will compare these numbers by 
arm using either an analysis of variance or a Kruskal-Wallis test, depending on the distribution of the data.   
 
Variables with percentage outcomes (such as percent sleep during the “out of bed” portion of the day) 
will be analyzed at specific time points (baseline and 15 days) using chi-square analyses or binomial tests to 
compare arms.   
 
We will also determine if number of phone calls (NTI or NSPC) or the group assignment (phone calls 
versus no phone calls) interacts when predicting quality of life, fatigue-related symptoms, and fatigue.  We 
believe that patients receiving phone calls will experience improved quality of life, reduced fatigue-related 
symptoms, and reduced fatigue while the patients not receiving phone calls will remain the same on these 
scores.  In this model we will also include the treatment group assignment to determine if these interactions 
differ by treatment group.   
 
Missing Data.  In order to allow for up to 15% of the patients to potentially drop out before completing the 


 
 
 
 
 
 
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study for 15 days, we will recruit a total of 53 patients per arm, or a total of 212 patients.  After 7 days of our 
open pilot study of methylphenidate [38] we found that 30 out of 31 eligible patients were evaluable (97%).  
By day 28, only 21-30 patients remained evaluable (70%).  Therefore, we estimate that the drop out rate 
could increase from 3% by day 7 to 30% by day 28.  Since the duration of this study is of 15 days, we 
conservatively estimate that the dropout rate will be approximately 15% upon completion of the double-blind 
phase. 
 
Information from the intervention phase (days 15-36), where all willing patients will receive study drug, 
will be summarized and exploratory analyses conducted to determine if patients in the treatment group 
continue to experience reduced fatigue and if patients previously assigned placebo improve.  However, the 
dropout rate after 15 days could be greater than 30% and sicker patients may be more likely to drop out 
early. Therefore the conclusions from these analyses may be preliminary only.  However, this data set will 
also be used to determine the impact of different methods of taking into account data that may not be missing 
at random. 
 
As an alternative analysis, subjects who drop out during the study will have their last available 
scores from the outcomes measures carried forward.  This procedure will be used because subjects may in 
some cases drop out because of worsening disease, which may be reflected in their fatigue measures.  
Failure to account for this might otherwise bias the treatment effect estimate.  
 
We will initially assume that missing data will give unbiased estimates of the intervention effects 
provided that the probability of having missing data depends only on the covariates in the model. We will 
check this assumption by looking at predictors of missing data. If the assumption is violated we will perform 
sensitivity analyses to determine the effect of varying the assumptions about the mechanisms for missing 
data. Other methods of accounting for missing variables will also be employed in sensitivity analyses (98).   
 
Model Analyses.  Structural Equation Modeling (SEM) will be used to test for mediation and or moderation 
of the interventions.  The model presented in Figure 1 will be formally evaluated, as will more complex forms 
of the same model that include repeated measures of the outcome variables across time.  To test mediation 
an approach based on the work of Kenny and colleagues (99-100) and further extended by MacKinnon (101) 
and Brown (102) will be used.  In order for the proposed mediators to mediate the effects of the interventions, 
four separate criteria must be met:  
1. the interventions must be significantly associated with the outcome measures of fatigue; 
2. the interventions must be significantly associated with the mediators;  
3. the mediators must be significantly associated with the physiological and psychological 
symptoms; and 
4. the association between the interventions and the outcome variables must decrease in the 
presence of the mediators.  
 
The mediation effect estimate will be computed according to MacKinnon (100) who describes 
mediation as the difference of the treatment condition with and without the presence of the mediators, or 
alternatively, the product of the effect of the treatment on the mediators and the mediators on the outcome 
controlling for the treatment.  Though mediation is often assessed using a sequence of independent 
regression equations, this practice becomes cumbersome in tests of complex theoretical models and is now 
often examined using SEM (102).  In accordance with the methodology detailed by MacKinnon (101) and 
Brown (102), the four criteria to assess mediation will be examined in simultaneous model and parameter 
tests using SEM software (e.g., EQS, Mplus, AMOS).   
 
Moderation will be examined by including interaction terms between the treatment group variable and 
the potential moderators.  SEM provides a flexible approach to modeling means, covariance, and correlation 
structures that yields relevant effect estimates (directional and non-directional; direct, indirect, and total) and 
standard errors for all of the parameters of interest in mediator analyses (101-103).  SEM also allows 
outcome measures obtained at all of the follow-up time points to be included in the same model.  In this 
approach, potential mediators can be evaluated at individual time points, or averaged across time, or can be 
grouped together with other mediators to evaluate combined effects.  Furthermore, beyond providing tests of 
model parameters, SEM also provides global measures of model fit (104); and permits the incorporation of 
latent variables into mediator models when appropriate (103-105). In addition, recent versions of software 


 
 
 
 
 
 
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such as EQS permit robust model and parameter assessment under varied distributional conditions (102-
106). 
 
Power Considerations.  The study is powered to be able to detect significant differences of change scores 
as large or larger than 33% or more from baseline to day 15 between methylphenidate versus placebo. For 
the first secondary objective, it will be able to detect significant differences of change scores as large or 
larger than 33% or more from baseline to day 15 between the 4-6 phone calls (NTI) with a nurse versus no 
phone calls with a nurse.  For the second secondary objective, it will be able to detect 50% or more change 
from baseline to day 15 between any of the four arms of the study.  Smaller differences will be able to be 
detected for the first comparisons since two arms will be combined for each of those comparison groups.   
The actual difference score related to a 33% or more change from a baseline of 17.5 is about 5.8, and 
a change of 50% or more is 8.75.  Previous research has shown that a difference of 5 or greater is the 
“minimally important difference” required to determine that the observed change in fatigue scores is 
significant [107].  Assuming that the standard deviations of these difference scores are approximately equal 
to the standard deviation of differences found in our previous study (13.96), we will require 45 evaluable 
patients per each of the four arms in order to detect these differences with 80% power and a two-sided 
significance level of 0.05.   
 
We also estimate power in terms of Effect Size Index (ESI), which renders the detectable difference in 
terms of population standard deviation units (108).  For example, an ESI of 0.5 represents an effect size of 
0.5 standard deviation units.  We anticipate that we will be able to recruit approximately 212 participants 
during the recruitment period.  With a maximum attrition rate of 15% by the 15-day follow-up, we will have 
approximately 45 participants per each of the four groups available for analysis. Using a simple t-test for two 
main effects comparisons at the 15-day follow-up and assuming a two-tailed type I error rate of 0.05 and a 
sample size of 90 participants per each main effects group, we will have 80% power to detect a true effect 
size of 0.42 standard deviation units.  By the end of the study, at 36 days, we may experience up to a 30% 
dropout rate, or have 74 patients per each main effects group remaining in the study. Using a simple t-test for 
two main effects comparisons at the 36-day follow-up and assuming a two-tailed type I error rate of 0.05 and 
a sample size of 74 patients per each main effects group, we will have 80% power to detect a true effect size 
of 0.46 standard deviation units.  ESIs of this magnitude are between what Cohen describes as a medium 
(0.5) effect.  These are consistent with what we found in our pilot study.  
 
Covariance adjustment for the baseline score of the outcome measure and other important covariates 
using ANCOVA will increase power, as will the use of all follow-up measures in the mixed-model ANCOVA 
analysis described above. 
 
Analyses Associated with Open Phase of the Study. We will track the number of patients who receive a 
dose escalation throughout the study. This information will be summarized for patients who receive 
methylphenidate to determine the number of patients who received a dose escalation by day 15 and by day 
36. We will test if these proportions are significantly different using the McNemar test, which takes into 
account the matching of the individuals over time.  
For the subset of patients who are randomized to receive methylphenidate, we will determine the 
proportion of patients who are still utilizing the drug at day 15 and at day 36.  We will determine if the proportion 
of patients who use the drug at day 15 differs from the proportion of patients who use the drug at day 36 by 
using the McNemar test.   
For the subset of patients who are randomized to receive methylphenidate, we will determine their global 
assessment of effectiveness of the treatment at day 15 and at day 36. We will determine if this value decreases 
over time by subtracting each patient’s day 15 value from their day 36 value and using a paired t test to test the 
null hypothesis that the difference between the two values is zero.    
We will summarize side effects for patients receiving methylphenidate and will present the information 
about side effects that occur before day 15 and that occur between days 15 and 36. We will be able to determine 
if the number of side effects increase for the two time periods using the sign test. The severity of the side effects 
will also be summarized, and if there are sufficient numbers to analyze, we will also determine if the number of 
severe side effects increase between the two time periods using the sign test.  
 


 
 
 
 
 
 
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Qualitative Analysis.  This study will involve telephone interventions with 106 persons, each called 
longitudinally at 4 - 6 times, or 424 - 636 calls.  In order to understand the essential elements in experience, 
sufficient numbers of informants must be selected to provide a detailed and clear description of the experience 
under investigation.  The usual way to determine sample size is through saturation, which means researchers 
conduct interviews until they no longer hear new statements from informants and the data are increasingly 
redundant.  For the purposes of operational and budgetary planning, we will use previous experience and 
research to project a point at which saturation and a detailed description might be expected.  Based on previous 
research that has obtained detailed description of other experiences, the sample size of this study should be 40 
to 60 at each time.  This number in fact exceeds the number of interviews and informants used in other research 
conducted by Cohen and others.  However, this will enable the research team to interview sufficient numbers of 
both genders and members of minority groups to accurately understand themes that vary by ethnicity or gender.  
This should allow phenomena to be captured in their complexity.   
 
In prior research, this has meant that the themes identified were present in the majority of informants' 
descriptions.  For example, Cohen and Ley (109) interviewed 20 BMT patients who were long-term survivors, 
Cohen and Sarter (110) interviewed 32 nurses to describe the experience of oncology nursing, and Cohen, 
Haberman, and Steeves (111) conducted a multi-site study of the meaning of oncology nursing with 76 
interviews with 38 nurses.  Bondas-Salonen (112) interviewed 40 women about the experience of having their 
partners present at the birth of their children.  Hanna's (113) study of the meaning of health involved 29 
informants.  Wilson and Morse (114) included data from 48 interviews with 15 husbands of women undergoing 
chemotherapy.  These numbers of informants were sufficient to obtain detailed descriptions of the experiences 
under study.  Analysis of 636 transcripts may well be more than is needed, but the analysis will be used for both 
to assure that the quality of the intervention does not change over time or differ among the nurses as well as to 
understand the intervention and patients’ experiences.  These calls are likely to be far shorter than traditional 
interviews so while the number may seem inordinately high, the data will be briefer than in prior research so the 
analysis of this number is feasible. 
 
Morse, Penrod, and Hupcey (115) recently described using qualitative data to identify interventions and 
evaluate outcomes.  While our project differs in many ways from what they describe, the idea that applies to 
this project is that qualitative data are useful to understand and identify interventions that are appropriate for 
phenomena that change over time, as do symptoms for persons with advanced cancer. Other strategies they 
describe as useful have been included here, such as including clinicians on the research team.  As they note, 
this strategy addresses both process and outcome and thus enhances the applicability to complex clinical 
experiences.  These strategies will enhance our ability to use these data to understand what is important in 
the nurse telephone interventions. 
 
The aim is to balance variability and homogeneity.  Limiting the sample to patients from two 
institutions will make it easier to describe the clinical context in detail.  However, the variability of the patients 
should provide enough heterogeneity to allow a wide exploration of the experience of having this nursing 
intervention.   
 
Analysis and Interpretation of Qualitative Data.  These analyses will help accomplish aim 3:  Investigate the 
additive or synergistic effect of methylphenidate treatment plus nurse telephone follow-up on reduction of 
fatigue compared to either methylphenidate treatment or nurse telephone follow-up alone.  
Analysis will follow the approach based on hermeneutic phenomenological approach, also called the Utrecht 
School of Phenomenology or simply phenomenological research [116-120].  Cohen and the research team will 
jointly conduct analysis using a process similar to what they used in prior research.  Cohen's prior research has 
demonstrated the advantages of having a team work together to analyze a large volume of data.  As in prior 
studies, once an understanding of the overall text is obtained, phrases in the text are underlined and tentative 
theme names are written in the margin of the text.  Data are examined line by line and all important phrases are 
labeled with tentative theme names.  An example from previous research is the analysis of the following 
passage: 
"I got the shingles.  I never knew what shingles were, and I didn't know and 
I got so scared.  And I come there and they're like, 'Oh, don't worry, that 


 
 
 
 
 
 
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usually happens to bone marrow transplants after.'  And I said, see, no one 
told me this.  You should have told me because I started stressing out...  I 
just think they should prepare people before they go in, of what is going to 
happen to you after, and what really a transplant is." 
 
This passage was identified as an exemplar and coded as "information needs."  Exemplars are 
defined as bits of textual data in the language of the informant that captures essential meanings of themes.  
As this example illustrates, analysis of data includes elements within themes.  This passage was included in 
the theme that was finally labeled "a range of needs for information."   Many passages were found in these 
interviews that dealt with patients’ needs for information.  Analysis made it clear that there were patients who 
felt staff would tell them what they needed to know, and that they need not ask any questions.  Another group 
wanted to know as much as possible.  They mobilized resources outside the hospital to obtain the 
information they wanted.  And finally, another group had questions and fears and was not always clear about 
what to ask, how to ask it, or who might provide the information or reassurance they wanted.  In addition to 
this range of needs for information, other themes emerged in the analysis that related to patients' information 
needs, which were described more fully in Tarzian, Iwata, and Cohen [68]. 
 
After exemplars are identified, they will be clustered according to observed similarities into themes for 
each individual informant.  Themes and exemplars will be compared for similarities and differences with each 
informant, across all informants. Important contextual features, such as ethnicity, and how the experiences vary 
with these features will be included in the analysis. This analysis will identify patterns and relationships among 
the various informants and form a coherent picture of the whole.  Data will also be analyzed to obtain an 
understanding of the meaning of symptoms and QOL.  The computer program Ethnograph or a similar one will 
be used to facilitate this thematic analysis. 
 
Central to phenomenological methods is the consideration and understanding of the contextual features 
that are meaningful to the informants.  At the outset of the project it is unclear precisely which features will be 
most meaningful to the informants.  Type of cancer, continuity of care, features of the particular professionals 
with whom they interact, or ethnic and other socio-demographic differences may be meaningful.  We will need to 
see what the data reveal.   
 
A process of writing and rewriting, which is crucial to phenomenology (119), will be used to move from 
identification and comparison of themes to a coherent picture of the whole.  As the research team gains insight 
into and a tentative understanding of the meaning of the experience of these patients as conveyed through the 
exemplars and in the themes, this understanding will be summarized in written memos that will be circulated 
among the members of the research team.  These memos will serve to document the process and drive the 
transformation of the field text to a coherent text through a reflective process of writing and rewriting.  All team 
members will write these memos about the whole of the data. Cohen will coordinate the logistics of the writing 
and rewriting process of analysis.   
Bias Control: The general rule for bias control in qualitative research, whether it is phenomenological or from 
another school or method, is to open all decision making to inspection by informants, peers and others who have 
no special attachment to or interest in the specific results of data analysis.  This will be accomplished through the 
use of several procedures developed by Cohen (121) and by Lincoln and Guba (122). 
 
The first procedure will be the use of the research team and the collaborators as a review panel.  This 
panel will be given interviews and asked to identify tentative themes in the text.  Next the panel will be given a 
sample of exemplars and a description of themes and asked to match the exemplars with a theme.  The level of 
agreement among the panel members will be determined.  Significant disagreements will be discussed and 
analysis refined until consensus is reached.  Cohen will coordinate this procedure.   
Finally, the procedures outlined above have been designed to create a written record of all the decisions made 
during the research project and justification for each decision.  This record will include E-mail communications 
among the co-investigators, minutes of team meetings, and minutes of the meetings and conference calls with 
the co-investigators, Cohen will maintain this record as part of the study archive along with all data and the 
analytic memos.  This decision record in conjunction with the other materials will provide an audit trail to answer 
any questions about the reasoning or justification of any decisions made during the study.   
 


 
 
 
 
 
 
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Triangulation:  Linking analysis of qualitative and quantitative data.  These techniques will help accomplish aim 
3:  Investigate the additive or synergistic effect of methylphenidate treatment plus nurse telephone follow-up 
on reduction of fatigue compared to either methylphenidate treatment or nurse telephone follow-up alone.  
 
Data will be analyzed with appropriate techniques (phenomenological data will be analyzed with 
phenomenological techniques, and statistical analysis will be conducted on quantitative measures) (123).  
Data will then be linked in several ways.  First, groups will be formed on the basis of scores on the structured 
measures (e.g., high, moderate, low fatigue).  In addition we will develop major qualitative themes or results 
(e.g., different meanings attached to symptoms) and examine how variation in the qualitative data link to 
variation in the quantitative date.  Matrices will be developed that combine and compare the qualitative and 
quantitative data groups (124-125).  In the quantitative analysis, patient profile plots will be constructed for 
each of the symptoms, and quality of life to describe the individual patient’s patterns of change over time.  
We will add the major phenomenological themes over time to these profiles to enhance our understanding of 
the factors associated with various patterns.  In addition, we will develop exemplar cases, for example, cases 
that illustrate different trajectories over time.  In these cases the diverse sources of data would provide a 
more comprehensive understanding of the recovery trajectory. We envision the data linking will serve multiple 
purposes.  These include understanding the meaning of the symptoms and quality of life in more detail than 
is possible without the qualitative data.  Marlene Cohen, our co-investigator, has experience with triangulation 
and will provide guidance for the processes used to link the qualitative and quantitative data. 
 
 
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Mock V, Piper B, Sabbatini P, Escalante C. National Comprehensive Cancer Network Fatigue 
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14. 
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Alban JP, Hopson MM, Ly V, Whyte J. Effect of methylphenidate on vital signs and adverse effects in 
adults with traumatic brain injury.  Am J Phys Med Rehabil.2004; 83:131-7. 


 
 
 
 
 
 
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38. 
Bruera E, Driver L, Barnes EA, Willey J, Shen L, Palmer JL, Escalante C. Patient-controlled 
methylphenidate for the management of fatigue in patients with advanced cancer: a preliminary 
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