A Phase III Randomized, Double-Blind Placebo Controlled Study of Armodafinil (Nuvigil®) To Reduce Cancer-Related Fatigue in Patients With High Grade Glioma
Phase: PHASE3
Conditions: Fatigue
Sponsor: Alliance for Clinical Trials in Oncology

 
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ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
ALLIANCE A221101 
 
 
A PHASE III RANDOMIZED, DOUBLE-BLIND PLACEBO CONTROLLED STUDY OF ARMODAFINIL 
(NUVIGIL®) TO REDUCE CANCER-RELATED FATIGUE IN PATIENTS WITH HIGH GRADE GLIOMA  
 
 
 
 
Study Chairs: 
 
Alyx B. Porter Umphrey, M.D.  (Research Base)* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Co-chairs:  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statisticians: 
 
 
 
 
 
 
Drug Availability  
Drug Company Supplied:  Armodafinil (Exempt IND 116927) 
 
*Investigator having NCI responsibility for this protocol 
√Study contributor(s) not responsible for patient care. 
 
 
ClinicalTrials.gov Identifier: NCT01781468 
 
Participating NCTN Organizations 
Alliance/Alliance for Clinical Trials in Oncology (lead) 
ECOG ACRIN/ ECOG-ACRIN Medical Research Foundation, Inc 
NRG/NRG Oncology Foundation, Inc 
SWOG/SWOG 
 

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Cancer Trials Support Unit (CTSU) Address and Contact Information 
For regulatory requirements: 
For patient enrollments:  
For study data submission  
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: (Sign 
in at 
,            and select 
the Regulatory Submission sub-tab 
under the Regulatory tab.)  
 
Institutions with patients waiting that 
are unable to use the Portal should 
alert the CTSU Regulatory Office 
immediately at 
 to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory Help 
Desk at 
 for 
regulatory assistance. 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN) 
which can be accessed at 
or 
. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
. 
. 
 
 
Legacy NCCTG sites will 
submit electronic CRFs via:  
NCCTG Remote Data Entry 
System. 
 
Sites not previously affiliated 
with NCCTG will submit 
paper CRFs to: 
 
 
 
 
 
 
Do not submit study data or 
forms to CTSU Data 
Operations. Do not copy the 
CTSU on data submissions.   
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at 
.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires user log on with 
CTEP-IAM username and password. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS. 
For clinical questions (i.e. patient eligibility or treatment-related) see the Protocol Contacts, Page 3. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 
, or
.  All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
The CTSU Web site is located at 
. 
 

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Protocol Resources 
 
Data Manager 
Protocol Coordinator 
 
 
 
 
 
 
 
 
 
Expedited Adverse Event Reporting 
 
OPEN (Oncology Patient Enrollment Network) 
 
 
A221101 Nursing Contacts 
 
  
 
 
 
 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Nursing Contact, Protocol 
Coordinator, and (where applicable) Data Manager 
Questions related to data submission or patient 
follow-up: 
Data Manager  
Questions regarding the protocol document and 
model informed consent: 
Protocol Coordinator 
Questions related to IRB review 
Alliance Regulatory Inbox 
 
Questions regarding CTEP-AERS reporting: 
Alliance Pharmacovigilance Inbox 
  
 
 

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Schema 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 length = 4 weeks  
Cycle 2 length = 4 weeks 
 
NOTE:  Cycle is a data management tool to facilitate consistent remote data entry. 
 
Generic name:    Armodafinil 
Brand name(s):  Nuvigil® 
Alliance Abbreviation:    
  
Availability:   Alliance Research Base pharmacy   
Generic name:   Placebo  
Brand name(s): 
Alliance Abbreviation:    
  
Availability:  Alliance Research Base pharmacy   
 
 
 
Unacceptable adverse events or patient refusal 
at any time  Off Study 
 
Randomization 
 
Armodafinil  
150mg q.d. x 8 weeks   
 
Placebo  
q.d.x 8 weeks  
 
Armodafinil  
250mg q.d. x 8 weeks  
 
Off Study  

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Table of Contents 
1.0 
INTRODUCTION ........................................................................................................................... 7 
1.1 
Background .................................................................................................................................................. 7 
1.2 
Evidence-Based Interventions ...................................................................................................................... 9 
1.3 
Mechanisms of Newer Psychostimulants and Rationale for Armodafinil (Nuvigil) .................................. 12 
1.4 
Study rationale ........................................................................................................................................... 14 
2.0 
GOALS........................................................................................................................................... 14 
2.1 
Primary ....................................................................................................................................................... 14 
2.2 
Secondary ................................................................................................................................................... 14 
3.0 
PATIENT ELIGIBILITY ............................................................................................................ 15 
3.1 
Inclusion Criteria ........................................................................................................................................ 15 
3.2 
Exclusion Criteria ...................................................................................................................................... 15 
4.0 
TEST SCHEDULE ....................................................................................................................... 18 
4.1 
Neurocognitive Testing .............................................................................................................................. 19 
5.0 
STRATIFICATION FACTORS .................................................................................................. 22 
5.1 
Concomitant Chemotherapy:  Yes vs. No .................................................................................................. 22 
5.2 
Age:  < 60 vs. ≥60 ...................................................................................................................................... 22 
5.3 
Corticosteroid use:  Yes vs. No .................................................................................................................. 22 
5.4 
Gender:  Male vs. Female .......................................................................................................................... 22 
6.0 
REGISTRATION/RANDOMIZATION PROCEDURES ........................................................ 22 
6.1 
Registration Requirements ......................................................................................................................... 22 
6.2 
CTEP Registration Procedures ................................................................................................................... 22 
6.3 
Site Registration Requirements – IRB Approval ....................................................................................... 23 
6.4 
Patient Randomization ............................................................................................................................... 25 
6.5 
Procedures for Double-Blinding the Treatment Assignment ..................................................................... 26 
7.0 
 PROTOCOL TREATMENT ...................................................................................................... 28 
7.1 
Treatment Schedule .................................................................................................................................... 28 
7.2 
Unblinding Procedures ............................................................................................................................... 28 
8.0 
DOSAGE MODIFICATION BASED ON ADVERSE EVENTS ............................................. 29 
9.0 
ANCILLARY TREATMENT/SUPPORTIVE CARE ............................................................... 29 
10.0 
ADVERSE EVENT (AE) REPORTING AND MONITORING .............................................. 29 
10.1 
Routine Adverse Event Reporting .............................................................................................................. 29 
10.2 
CTCAE Routine Study Reporting Requirements ....................................................................................... 30 
10.3 
Expedited adverse event reporting (CTEP-AERS) .................................................................................... 30 
10.4 
Contact Information for NCI Safety Reporting .......................................................................................... 33 
10.5 
Other Required Expedited Reporting ......................................................................................................... 34 
10.6 
Adverse events to be graded at each evaluation. ........................................................................................ 34 
11.0 
TREATMENT EVALUATION ................................................................................................... 34 
11.1 
Patient Self-Report Measures ..................................................................................................................... 34 
11.2 
Objective Cognitive Measures (Primary Cognitive Endpoint) ................................................................... 36 
12.0 
DESCRIPTIVE FACTORS ......................................................................................................... 37 
13.0 
TREATMENT/FOLLOW–UP DECISION AT EVALUATION OF PATIENT .................... 37 

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14.0 
BODY FLUID BIOSPECIMENS ................................................................................................ 37 
15.0 
DRUG INFORMATION .............................................................................................................. 37 
15.1 
Armodafinil (Nuvigil®) or placebo ........................................................................................................... 37 
15.2 
Placebo ....................................................................................................................................................... 39 
16.0  
STATISTICAL CONSIDERATIONS AND METHODOLOGY ......................................... 40 
16.1 
Study Design .............................................................................................................................................. 40 
16.2 
Sample Size ................................................................................................................................................ 40 
16.3 
Primary Endpoint ....................................................................................................................................... 40 
16.4 
Secondary Endpoints .................................................................................................................................. 41 
16.5 
Statistical Design ........................................................................................................................................ 41 
16.6 
Adverse Event Stopping Rule .................................................................................................................... 42 
16.7 
Study Monitoring ....................................................................................................................................... 42 
16.8 
Missing Data .............................................................................................................................................. 42 
16.9 
Inclusion of Women and Minorities ........................................................................................................... 43 
17.0  
PATHOLOGY CONSIDERATIONS/TISSUE BIOSPECIMENS ...................................... 45 
18.0 
RECORDS AND DATA COLLECTION PROCEDURES ....................................................... 45 
18.1 
Data collection and submission .................................................................................................................. 45 
18.2 
Submission Timetable ................................................................................................................................ 46 
19.0 
BUDGET ........................................................................................................................................ 46 
20.0 
REFERENCES .............................................................................................................................. 47 
APPENDIX I: 
 MODEL INFORMED CONSENT ......................................................................... 53 
APPENDIX II: 
 PATIENT INFORMATION SHEETS ................................................................... 61 
APPENDIX III:  BRIEF FATIGUE INVENTORY ........................................................................... 64 
APPENDIX IV: 
 PROMIS FATIGUE SHORT FORM .................................................................... 65 
APPENDIX V: 
 LINEAR ANALOGUE SELF ASSESSMENT (LASA) ....................................... 66 
APPENDIX VI: 
 FACT-COG .............................................................................................................. 68 
APPENDIX VII:  COGNITIVE TESTING ......................................................................................... 71 
APPENDIX VIII:  ADMINISTRATION PROCEDURES FOR THE NEUROCOGNITIVE TEST 
BATTERY 
78 
APPENDIX IX:  NEUROCOGNITIVE EVALUATIONS SUBMISSION FAX FORM ................ 85 
APPENDIX X: 
 BAYES SHADOW STATISTICAL DESIGN ....................................................... 86 
APPENDIX XI: 
 SITE DRUG ORDERING INSTRUCTIONS AND ORDER FORM ................. 88 
APPENDIX XII:  NURSE/CRA PHONE CONTACT ....................................................................... 91 
APPENDIX XIII:  GODIN LEISURE TIME EXERCISE QUESTIONNAIRE (GLTEQ) ........... 92 
APPENDIX XIV:  PRO-CTCAE.......................................................................................................... 93 
APPENDIX XV:  ECOG PERFORMANCE SCORE ........................................................................ 94 
APPENDIX XVI:  COPY OF FDA IND EXEMPTION LETTER ................................................... 95 
 

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1.0 
INTRODUCTION 
1.1 
Background 
1.1.1 Fatigue is one of the most common and most troublesome symptoms for primary 
brain tumor patients throughout the disease trajectory (1, 2). This condition has long 
been under-recognized, under-diagnosed, and undertreated (3-6).  
Cancer Related Fatigue (CRF) is a concerning issue in patients with cancer due to its high 
prevalence and negative effects on quality of life. Fatigue is a subjective experience.  
Sufferers may exhibit symptoms that are physical (physical weakness or tiredness), 
emotional (depression), motivational (lack of initiative or motivation), cognitive 
(impairment of cognitive function), and social (reduced ability to sustain social 
relationships) (7). In a survey evaluating Health-Related Quality of Life (HRQOL) in a 
variety of primary brain tumor patients at various times in the trajectory of their illness, 
42% reported “quite a bit low” or “very low” energy levels (8,9).   
Radiation therapy is the most common treatment modality for all brain tumor grades, and 
has been the treatment evaluated in the glioblastoma multiforme (GBM) patient population 
in relation to fatigue.  Lovely and colleagues reported that over 80% of primary brain tumor 
patients report fatigue during radiation therapy (10).  Fatigue has been reported to occur as 
early as within 1 week of the first radiation treatment and tends to increase with the number 
of radiation fractions (11).  Fatigue which occurs during radiation therapy may continue 
into the post radiation period.  Faithfull and Brada reported on the occurrence of a 
somnolence syndrome in the immediate post-radiation period (12).  This syndrome 
included fatigue, excessive drowsiness, feeling clumsy, and an inability to concentrate.  In 
this study, patients were followed during radiation and the immediate post-radiation period.  
Following completion of radiation therapy, the reported symptoms had a cyclical pattern, 
with increased severity between day 1-21 and then day 30-35 after treatment. Frequently, 
patients report that fatigue begins with treatment, continues during the course of treatment, 
and declines somewhat but persists at a higher-than-baseline rate after treatment is 
completed, sometimes lasting for months or even years (13-18).   
Besides treatment factors, fatigue is often due to the tumor itself.  The mechanism of direct 
tumor related fatigue is poorly understood and presumed to be a combination of the tumor 
biology itself, surrounding edema, and location.  A prospective trial assessing quality of 
life in high-grade glioma patients found one third of patients had clinically significant 
fatigue at baseline before initiation of radiotherapy.  In addition this study found fatigue to 
be an independent predictor of overall survival (19).   
Clinically, a variety of other factors may contribute to the frequency and intensity of 
fatigue.  These include concomitant medications such as chemotherapy, anticonvulsants, 
corticosteroids, metabolic disturbances, and psychosocial issues such as depression and 
anxiety. Most patients require corticosteroids to treat cerebral edema and anticonvulsants 
for seizure management. These medications have been reported to have a negative impact 
on fatigue in this patient population (11, 20). Recently, poor performance status, female 
gender, and active disease status were found to be associated with moderate to severe 
fatigue in patients with primary brain tumors (21).  For males, antidepressants and opioids, 
in addition to performance status predicted fatigue severity (22).  For women, variables 
that were most highly associated with fatigue severity were low-grade tumor diagnosis, 
steroids and active disease status (21).   

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1.1.2 Fatigue may also persist for years after diagnosis and completion of therapy.  
A recent report explored the occurrence of fatigue in 58 patients with low-grade gliomas 
who were at least eight years from completion of tumor therapy (22).  In this study, 39% 
of patients with a mean disease duration of 15 years, reported severe fatigue. 
Characteristics that differentiated those who were severely fatigued versus not severely 
fatigue included older age and anticonvulsant use (22).   
There are limited studies to date exploring the occurrence and correlates of fatigue in 
patients with primary brain tumors. In patients with other solid tumors, fatigue is often the 
most common and severe symptom associated with the disease and treatment (22, 23).  
Fatigue has been demonstrated to cluster with other symptoms, including pain, distress, 
insomnia, and depression and influence outcomes such as perceived health and functional 
status (24-28).  In the limited studies to date in patients with primary brain tumors, fatigue 
has been identified as a common symptom occurring in patients with both low and high 
grade tumors, to persist in long term survivors of low grade brain tumors, to be associated 
with both radiation and a variety of chemotherapies and to be more severe in women and 
in those with progressive disease.  
1.1.3 Brain tumors and treatment are associated with cognitive dysfunction.   
Normal cognitive functioning is the product of a complex interplay among multiple 
elements including attention span, learning and memory, visuospatial ability, mental 
flexibility, psychomotor activity and manual dexterity. The cholinergic neurotransmitter 
system is central for regulation of memory and learning, while the hippocampus is the 
primary region of the brain mediating cognitive function, primarily memory and attention. 
The basal forebrain is the major source of cholinergic innervation to the hippocampus. 
Derangement in any of these cognitive elements leads to a variety of cognitive and/or 
psychomotor problems which can range from hard-to-detect selective deficits to global 
impairments (28, 29).  
The effects of cancer treatments on cognitive function have commanded increasing 
attention from researchers in the past decade (28-32).  Cognitive deficits identified by 
cancer survivors consist of a range of difficulties including memory and concentration 
problems that can emerge during cancer treatment and/or months after completion (29). 
Cognitive deficits that occur as a result of cancer or its treatment vary widely and may be 
subtle or dramatic, temporary or permanent, and stable or progressive (33-36). Pathological 
evidence supports adverse effects of radiation on white matter tracts and cerebral 
vasculature of the brain secondary to damaged oligodendrocytes resulting in axonal 
demyelination, and, disruption of vascular endothelial cells contributing to coagulative 
necrosis, vessel wall thickening, and focal mineralization. Chronic radiation toxicity is also 
believed to involve alterations in neurogenesis as well as metabolic abnormalities and 
inflammatory responses (37-40).   
Subtle cognitive changes pose unique challenges to detection and management. First, the 
cause of subtle changes in cognitive function may not be readily apparent, and the 
impairments may not be evaluable with standard, objective neuropsychological measures. 
Second, subtle changes in cognitive function may also be confused with or confounded by 
other problems commonly associated with cancer and its treatment, such as depression, 
anxiety, and fatigue.  
Although the phenomenon is not understood completely, cognitive deficits in cancer 
patients are assuming greater significance as cancer survival improves. Advances in basic, 
imaging, and clinical sciences are beginning to unravel pathophysiologic mechanisms and 

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develop neuroprotective strategies. Conventional therapies soon may find new applications 
and pharmacologic options are borrowed from diverse diseases, including attention-
deficit/hyperactivity disorder and neurodegenerative diseases.  
1.2 
Evidence-Based Interventions  
The National Comprehensive Cancer Network (NCCN) has published clinical practice guidelines 
that encourage early identification and management of CRF during and after treatment (5).  
Physical activity is first-line therapy for CRF. However, an exercise program should be initiated 
cautiously in patients who have neurologic deficits, are deconditioned or experiencing 
comorbidities such as bone metastases, myelosuppression, fever, or treatment-related 
complications (5). Structured exercise training has been associated with significant improvement 
in quality of life and improved fatigue across numerous cancer populations, however have not 
studied the effect of exercise among cancer patients with neurologic and/or cognitive deficits or 
those with glioblastoma (41). Jones and colleagues found that the six minute walking test was 
well correlated with KPS and QOL in patients with glioma.  Their results then lead to the 
suggestion that interventions geared towards increasing their 6 minute walk timed test may cause 
considerable improvements in quality of life and fatigue in the recurrent glioblastoma patient 
population (42).   
A lack of sufficient evidence precludes the routine use of pharmacologic therapy in patients with 
moderate-to-severe fatigue. However, the NCCN does list pharmacologic intervention with 
psychostimulants as an option in cases in which other causes of fatigue have been ruled out (5). 
1.2.1 Clinical trials using methylphenidate for treatment of fatigue 
Methylphenidate is a central nervous system stimulant similar to amphetamine with a short 
plasma half-life of 2 hours, a rapid onset of action, and duration of action of 3 to 6 hours 
(43). The baseline dose is usually 5 mg in the morning and at noon with titration as needed 
with a maximum dosing of 1 mg/kg/d. The most frequent side effects are tachycardia, 
nervousness, insomnia, and anorexia, especially at higher doses. Open-label studies 
suggest an improvement in fatigue (44, 45). 
In a randomized controlled trial, 112 patients were assigned to 5 mg of methylphenidate or 
placebo and able to repeat dosing every 2 hours as needed to a maximum of 20 mg daily. 
At 7 days, significant improvement in fatigue compared to baseline was noted in both 
groups (46). The authors suggested that the observed benefits might be due to daily contact 
with the study nurse which may have had a major symptomatic or placebo effect.  
A more recent study conducted by Moraska et al, reports the results of a randomized, 
controlled trial comparing methylphenidate versus a placebo in a group of heterogeneous 
group of patients with CRF (47). Adults who were eligible for this trial had to have a history 
of CRF as defined by a score of 4 or more on a subjective fatigue level screening scale that 
ranged from zero (none) to 10 (as bad as it can be), for at least 1 month before registration. 
The authors found no significant differences in usual fatigue, current fatigue or worse 
fatigue during the course of the 4 week study. The primary end point of prorated Area 
Under the Curve for the usual fatigue question of the BFI did not show a statistically 
significant difference between the methylphenidate and placebo arms (P=.32). The 
methylphenidate treatment arm demonstrated a 3.2% better fatigue score on average, which 
was16%  the standard deviation of the fatigue scores (a small effect size) and not 
significantly different than that in the placebo arm. The authors did observe however, that 
patients with more advanced disease showed a significant response to methylphenidate as 
well as a trend for more improvement in usual fatigue for those who reported more severe 
fatigue at baseline with methylphenidate as opposed to placebo.  This study excluded 

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patients with CNS malignancies, however.  Similar results have also been reported by 
Yennurajalingam et al (48). They conclude that higher levels of fatigue were predictors of 
response to methylphenidate in patients with advanced cancer in a randomized clinical trial 
conducted at MD Anderson. 
In terms of fatigue prevention, a phase III randomized, double blind study evaluating d-
THREO-methylphenidate HCL (MPH) in patients with brain tumors receiving radiation 
therapy was not able to show a benefit for the MPH in preventing fatigue. At the end of 
brain RT, there was no significant difference between groups taking MPH or placebo on 
the mean fatigue subscale score of the FACIT-F (49). The adjusted least squares estimate 
of the Mean Fatigue Subscale Score was 33.7 for the d-MPH and 35.6 for the placebo arm 
(p = 0.64).   
Methylphenidate has also been evaluated with respect to treating cognitive deficits in 
patients with brain tumors.  The first report was published in 1995 (50), in the treatment of 
neurobehavioral slowing associated with cancer and cancer treatment. Weitzner and 
colleagues described the effects of the psychostimulant methylphenidate on three patients 
who had cognitive deficits that had been caused by primary brain tumors or accompanying 
radiotherapy. Methylphenidate was expected to act as an indirect agonist, causing release 
of catecholamines that would control attention and memory. Arousal, attention, initiation 
speed of tasks, and mood were all improved.  
Subsequently, Meyers and colleagues evaluated methylphenidate in patients who had 
primary brain tumors and abnormal neuropsychological test scores. Mean test scores in 
several cognitive domains were significantly improved in the group of 26 patients, despite 
progressive disease and increasing radiation damage. There were also improvements in 
subjective cognitive functioning and mood (51).  
Based on its mechanism of action, methylphenidate is associated with a variety of adverse 
effects. Nervousness is among the most common adverse effects noted with general 
methylphenidate use (52, 53), while appetite loss and abdominal pain have been noted in 
many controlled clinical studies using this drug (54). This was noted in the study conducted 
by Moraska et al (47), where patients in the methylphenidate group reported adverse 
effects, including nervousness and appetite loss, compared with those in the placebo arm. 
Decreased libido and shakiness have also been noted as adverse effects in a small 
percentage of participants in placebo-controlled methylphenidate studies. Because of the 
adverse effect profile seen, future evaluations of methylphenidate should take into account 
the risk-benefit ratio from the patient’s perspective. 
Due to the poor side effect profile, the lack of positive data, and the potential for abuse, 
making this agent a Schedule II controlled substance, we do not wish to pursue 
methylphenidate as an agent for fatigue improvement in our brain tumor population.  
1.2.2 Clinical trials using modafinil for treatment of fatigue 
Newer psychostimulants with better side effect profiles and less potential for abuse are now 
available.  Modafinil is a unique wake-promoting agent. Preclinical studies indicate a 
mechanism of action which is distinct from that of amphetamine or methylphenidate. To 
compare the pharmacodynamic profiles of modafinil, methylphenidate, and placebo in 
humans, a double-blind Latin square crossover study was conducted in 24 male volunteers 
with a history of polysubstance abuse that included the stimulant cocaine. Each subject was 
given single oral doses of methylphenidate (45 mg or 90 mg), modafinil (200 mg, 400 mg 
or 800 mg) and placebo. Measures of subjective, behavioral, and physiological responses 
were evaluated at fixed intervals during 72h after each dosing occasion. Subjects 

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discriminated both modafinil and methylphenidate from placebo. Subjects liked the effects 
of both drugs. However, modafinil differed from methylphenidate in its lack of a significant 
response on the Amphetamine Scale of the Addiction Research Center Inventory. The 
profile of physiological effects for modafinil differed from methylphenidate in that it 
showed greater inhibition of observed and reported sleep, less facilitation of orthostatic 
tachycardia and less reduction of caloric intake. These findings are consistent with 
preclinical pharmacological data suggesting that modafinil is not an amphetamine-like 
agent (55).  
In an open-label trial conducted to evaluate the benefit of modafinil in managing CRF, 
patients who had completed treatment for breast cancer (chemotherapy, chemotherapy 
and/or radiation therapy), received modafinil 200 mg daily for 1 month (56). Upon 
completion of treatment with modafinil, mean fatigue severity decreased from 6.9 to 3.7 
(0-10 scale: 0 = fatigue not present and 10 = fatigue as bad as you can imagine). The mean 
rating on the patient-reported global effectiveness measured after therapy was 5.0 (with 1 
= no benefit and 7 = great improvement). This benefit rating supports the finding that 
participants perceived an improvement in fatigue with the use of open label modafinil. 
Furthermore, 51% of the patients reported improvement in sleep and 51% reported less 
daytime drowsiness. Additional benefits reported by a majority of patients (>60%) 
included improvements in general activity, mood, walking ability, normal work ability, 
relations with other people, and enjoyment of life. Four patients withdrew from the study: 
1 due to pregnancy and 3 due to "agitation" that developed after 1 week of treatment.  
Morrow et al (57) conducted a second open-label trial of modafinil, with the same purpose 
as the previous trial, in women with breast cancer who experienced fatigue levels of 2 or 
more on the Brief Fatigue Inventory (0-10 scale, 0 = no fatigue and 10 = fatigue as bad as 
it can be) at least 1 month following completion of radiation therapy. Patients received 
modafinil 200 mg once daily for 1 month. Of the 82 women enrolled, 76 completed the 
study. Reasons for discontinuation were pregnancy (n = 1), anxiety (n = 2), headache (n = 
2), and nausea (n = 1). Ninety percent of the women experienced an improvement in 
fatigue.  
One of the limitations of these studies is the design (56, 57). As open-label trials, they are 
subject to bias from a lack of randomization, lack of blinding, and lack of a control arm. 
Furthermore, with availability of only the published abstracts that contain an abbreviated 
methods section, it is unclear what the full inclusion/exclusion criteria were. Likewise, the 
authors did not indicate whether patients were assessed and treated for other causes of CRF, 
and it is unknown whether patients received prior or concurrent treatment for this 
condition. Patients who had received multiple prior treatments or concurrent therapy, 
including exercise, may have suffered from a more severe form of CRF. Therefore, 
observing a benefit from modafinil in these patients would strengthen the support that the 
drug provides a positive effect.  
Jean-Pierre et al have reported the results of a multi-center phase 3 randomized placebo-
controlled double-blind trial of the effect of modafinil on CRF among 631 patients 
receiving chemotherapy (58). Patients who reported fatigue were randomly assigned to 
receive either 200 mg of oral modafinil daily or a matching placebo. Treatment began on 
Day 5 of Cycle 2 and ended after Day 7 of Cycle 4. Fatigue and depression were assessed 
during Cycles 2 to 4 by using psychometrically valid measures. Group differences 
(treatment vs. control) in the worst level of fatigue during the previous week at Cycle 4 
were examined by using an analysis of covariance (ANCOVA) adjusting for baseline 
fatigue (Cycle 2). Patients reporting more severe fatigue (level >6 on a 10-point scale) at 
cycle 2 experienced greater improvement than patients reporting moderate or mild levels 

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(p = 0.017). Of the patients studied, 26 were noted to have a cancer primary other than GI, 
GU, breast, lung, gynecologic, or hematologic systems.  The authors do not report whether 
or not these patients had CNS malignancies and if so, the exact type. 
The authors conclude modafinil may be useful in controlling cancer-related fatigue in 
patients who present with severe fatigue but is not useful in patients with mild or moderate 
fatigue.   
More directly related to the needs of patients with brain tumors,  a randomized, dose-
controlled trial was conducted to assess the safety and efficacy of modafinil in 30 patients 
with cerebral tumors suffering from neurobehavioral dysfunction and/or fatigue post-
treatment (59), 8 (27%) with glioblastoma multiforme and 10 (33%) with anaplastic 
glioma. Unfortunately, to our knowledge the results of this study have not been published 
to date and therefore, besides the information reported in the abstract, we are unable to 
provide details on how large a study was conducted , whether it was blinded, used a placebo 
or how large the differences were between the active and control groups .  Fatigue levels 
were reported at baseline, week 8, and week 12 using the Fatigue Severity Scale (FSS; 
score range 1-7, lower score indicates less fatigue), Visual Analog Fatigue Scale (VAFS; 
score range 0-10, higher score indicates less fatigue), and the Modified Fatigue Impact 
Scale (MFIS; score 0-84, lower score indicates less fatigue). At baseline, 43% of patients 
were suffering from marked attention/memory impairment and/or fatigue, while 47% were 
identified as having severe illness by the Clinical Global Impressions Severity Scale, which 
rates the severity of illness as normal, borderline, mild, moderate, marked, severe, or 
extreme. Patients had been previously treated with neurosurgical resection (93%), radiation 
(87%), and/or chemotherapy (70%). Improvements were seen in fatigue outcome 
measures, with the greatest improvements noted 8 weeks after baseline. There was little, if 
any, difference between scores achieved at 8 weeks and those reported at the end of the 
trial. The authors concluded that modafinil is effective in improving fatigue with a low 
incidence of adverse reactions. However, the rigor and specifics of this study cannot be 
evaluated.  
Recent preclinical data suggest that modafinil (Provigil®) may have some cognitive 
enhancement capabilities as well. To our knowledge, the first study to address the effect of 
modafinil on cognition in patients with cancer was done by Kohli et al at the University of 
Rochester, NY.  They found that 200 mg of modafinil given to patients who had been 
treated for breast cancer, helped improve patient accuracy and speed of retention.  Patients 
treated with modafinil had improved verbal and visual memory storage, retrieval, and 
retention (60). 
The efficacy of modafinil in treating cognitive dysfunction in patients receiving treatment 
for glioblastoma is unknown.      
1.3 
Mechanisms of Newer Psychostimulants and Rationale for Armodafinil (Nuvigil) 
Modafinil is a central nervous system (CNS) stimulant approved by the Food and Drug 
Administration for the treatment of excessive sleepiness associated with narcolepsy, shift work 
sleep disorder, and obstructive sleep apnea (61, 62). Modafinil is theorized to cause neuronal 
activation in areas of the hypothalamus associated with normal wakefulness. This mechanism is 
unique from that of other centrally acting agents such as amphetamines, which cause widespread 
activation of the CNS. In comparison with other stimulants, modafinil has a low potential for 
abuse due to a lack of activity on dopamine receptors (6, 63). Important proposed differences 
between methylphenidate and modafinil are the primary effects on the cortical versus subcortical 
areas and the decrease in GABA, accompanied by adrenergic agonist effects; an increase in 
serotonin and histamine. Modafinil is generally well tolerated. Preliminary data demonstrate 

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benefits of modafinil use, with minimal toxicity and a low propensity for abuse, in patients who 
have received cancer treatment or are currently undergoing chemotherapy. The most frequent 
adverse events (5%) are headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, 
insomnia, dizziness, and dyspepsia (61).  
Armodafinil is the R-enantiomer of modafinil which is a mixture of the R- and S-enantiomers.  
Concentration-time profiles of the two enantiomers show the pure R-enantiomer to be  the longer 
lasting of the two enantiomers (10-14 hrs vs, 3-4 hrs), with a longer elimination half-life than 
modafinil.  The two medications are virtually identical clinically when adjusted for the 2 to 1 
greater dose level for modafinil.  The exact mechanism of action is unknown. Armodafinil 
belongs to a class of drugs known as eugeroics, which are stimulants that provide long-lasting 
mental arousal. Pharmacologically, armodafinil does not bind to or inhibit several receptors and 
enzymes potentially relevant for sleep/wake regulation. Armodafinil is not a direct- or indirect-
acting dopamine receptor agonist. However, in vitro, both armodafinil and modafinil bind to the 
dopamine transporter and inhibit dopamine reuptake. The side effect profile of the two 
medications appears to be similar and a slight difference noted on the package inserts generally 
favor armodafinil.  
While no studies to date have examined the benefits of armodafinil in reducing CRF, 
pharmacokinetic evidence suggests it will be at least the equivalent of modafinil in doing so.  The 
precise mechanism(s) through which armodafinil (R-enantiomer) or modafinil (mixture of R- and 
S-enantiomers) promote wakefulness is unknown.  Both armodafinil and modafinil have shown 
virtually identical pharmacological properties in nonclinical animal and in vitro studies (64)  Data 
held at Cephalon Inc. and reported on by Darwish and colleagues (65) shows that the S- and R-
isomers of modafinil exhibited similar inhibition of binding and functional activity at dopamine, 
norepinephrine and serotonin transporters.  They also reported that while the two isomers of 
modafinil have approximately equipotent pharmacological activity, the S-isomer is eliminated 
rapidly, having a half-life of 4-5 hours, whereas the R-isomer has a half-life of approximately 15 
hours.  Essentially, modafinil is the S-isomer and armodafinil is the R-isomer.   
A pharmacokinetic comparison of modafinil and armodafinil found that at steady state, 
armodafinil produces consistently higher plasma drug concentrations late in the day than 
modafinil when compared on a milligram to milligram basis (65).  The different pharmacokinetic 
profile of armodafinil may result in improved usefulness throughout the day in patients compared 
with modafinil (66). In other words, due to the longer acting R-isomer, armodafinil may result in 
better control of fatigue for a longer time throughout the day.  
Armodafinil is a novel psychostimulant that has shown promise as a cognitive enhancer in normal 
adults and patient populations, including schizophrenia and attention deficit hyperactivity 
disorder (67-70).  Commonly prescribed to treat MS-related fatigue (67), armodafinil is also an 
alertness-promoting agent that reduces lapses of attention and vigilance that are caused by sleep 
deprivation and fatiguing disorders (71-73).  Indeed, it has been suggested that the nootropic 
effects of armodafinil may be magnified among people with pronounced fatigue and pre-existing 
cognitive difficulties (74, 75).  As cancer patients frequently suffer from significant fatigue and 
neuropsychological deficits, armodafinil has strong potential as a highly efficacious cognitive 
enhancer in this population.  Despite this, no published studies have examined the use of 
armodafinil to treat fatigue or cognitive impairment in cancer patients. 
Both armodafinil and modafinil have been well tolerated in patients with significant fatigue 
complaints.  The adverse event profiles are similar between the two agents in head to head 
studies.  At the highest dosage, headache was the greatest adverse event noted with use of 
armodafinil compared to modafinil followed by nausea and abdominal pain as the most 
frequently encountered adverse effects (76). 

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1.4 
Study rationale 
As modafinil and armodafinil are newer drugs, there remains a paucity of research specifically 
in cancer.  However, data from other chronic illnesses that have symptoms of fatigue and 
cognitive impairment, as well as preliminary data with modafinil in patients with brain tumors 
(59), provides the impetus to study the newer psychostimulants in patients with high grade 
glioma. Although large RCT’s with modafinil and methylphenidate have not shown a significant 
impact on fatigue (47, 58), these trials did not focus on, and often did not include, patients with 
brain tumors, specifically glioblastoma.  These studies do provide data to hypothesize that 
patients with more severe fatigue (48, 58) may benefit from these agents.  Although data to date 
do not support using methylphenidate during radiation treatment (49), newer psychostimulants 
with broader CNS effects still need to be evaluated for effects on fatigue during and after 
radiation therapy, specifically in brain tumor populations. There are two clinical trials currently 
actively recruiting patients that involve armodafinil.  Both are using heterogeneous populations 
of people with brain tumors and both are using armodafinil during radiation therapy (77, 78).   
We conducted an extensive literature search and could find no published data on the effects of 
250mg of armodafinil in treating fatigue in brain tumor patients. Given the trend toward positivity 
of the studies ongoing with 150 mg dose (77,78) further investigation is needed to decipher if 
further benefit from a higher dose is plausible.  The 250 mg dose of armodafinil has been proven 
safe and efficacious in a study that showed positive results in patients with narcolepsy (109). In 
addition, there are ongoing trials listed on clinicaltrials.gov using 250mg of armodafinil in 
patients with results pending. Our proposed three-arm study complements both of those trials and 
other ongoing studies (110) by evaluating armodafinil in a more homogeneous population, 
specifically high grade glioma, and evaluating armodafinil for its effects on severe fatigue once 
radiation therapy has been completed. Given that fatigue is prevalent at the completion of 
radiation therapy, this seems the best endpoint to evaluate. Cognitive difficulties are one of the 
elements of fatigue and hence, these two problems are sometimes difficult to tease apart.  Fatigue 
measurement is more advanced than cognitive measurement, due to problems with practice 
effects for neuropsychiatric measures and the lack of understanding of how fatigue, sleep and 
mood impact cognition.  Therefore, we believe that evaluating fatigue as the primary endpoint 
and cognition as a secondary endpoint is well justified.  
2.0 
GOALS 
2.1 
Primary 
To determine preliminary efficacy measured by patient reported fatigue using the Brief Fatigue 
Inventory (BFI) at 8 weeks of two doses (150mg and 250mg) of armodafinil in treating moderate 
fatigue compared to placebo in patients with high grade glioma. 
2.2 
Secondary 
2.2.1 To evaluate the tolerability at 8 weeks of 150mg and 250mg armodafinil in this patient 
population  
2.2.2 To assess the effect of armodafinil at 8 weeks on cognitive function in patients with 
high grade glioma. 
2.2.3  To assess the impact of armodafinil on global quality of life and other fatigue 
endpoints in this patient population with high grade glioma. 
2.2.4 Explore the correlation between the BFI, PROMIS, and PRO-CTCAE measures, as 
well as, the relationship of fatigue and cognitive difficulties. 

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3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria  
3.1.1 Age ≥ 18 years. 
3.1.2 Diagnosed with glioblastoma, gliosarcoma, small cell or large cell glioblastoma, 
glioblastoma with oligo features, glioblastoma with primitive neuroectodermal tumor-like 
components 
(GBM-PNET) 
features, 
anaplastic 
astrocytoma, 
anaplastic 
oligodendroglioma, or anaplastic oligoastrocytoma who are clinically stable and have 
completed radiation therapy (excluding stereotactic radiosurgery) >21 days prior to 
registration. NOTE: Clinical stability will be defined as a stable or improved KPS 
compared to the prior month.  
3.1.3  ≥ 6 score on the worst fatigue question of the BFI (Brief Fatigue Inventory, see 
appendix III Question 3).  It is not required for the patient to complete the entire BFI to 
meet this criterion. 
3.1.4 Undergone surgery (gross total or subtotal resection) or biopsy and will have been 
treated with concurrent radiation therapy and chemotherapy as standard of care for 
Glioblastoma, gliosarcoma, small cell or large cell glioblastoma, glioblastoma with oligo 
features, glioblastoma with primitive neuroectodermal tumor-like components (GBM-
PNET) features, anaplastic astrocytoma, anaplastic oligodendroglioma, or anaplastic 
oligoastrocytoma patients. Note: radiation must be completed per Section 3.1.2, but 
chemotherapy is allowed. 
Patients who are currently using Optune® device will be eligible to participate in this trial. 
3.1.5 Negative serum pregnancy test done ≤ 7 days prior to registration only for women 
determined to be of childbearing potential by their treating physician. 
3.1.6 Ability to complete questionnaire(s) by themselves or with assistance.   
3.1.7 ECOG Performance Status (PS) of 0, 1, 2 or 3 (Appendix XV). 
3.1.8 Provide informed written consent. 
3.1.9 Willing to return to enrolling institution for follow-up (during the Active Monitoring 
Phase of the study). 
3.1.10 Stable dose of corticosteroid ≥ 14 days prior to registration. 
3.2 
Exclusion Criteria   
3.2.1 Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are 
unknown: 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ adequate 
contraception  
3.2.2 History of hypersensitivity to other psychostimulants. 
3.2.3 History of steroid psychosis. 
3.2.4 Currently taking medications for attention deficit hyperactivity disorder, history of 
or currently taking medications for severe anxiety disorder, schizophrenia, or 

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substance abuse by patient record and/or self-report. Note: Patients who had 
childhood ADHD and no longer require treatment will be eligible to participate.  
3.2.5 Currently using any other pharmacologic agents or nonpharmacologic interventions 
to 
specifically 
treat 
fatigue, 
including 
psychostimulants, 
antidepressants, 
acupuncture, etc. will be excluded. Note: Antidepressants used to treat items other than 
fatigue (such as hot flashes or depression) are allowed if the patient has been on a stable 
dose for ≥ 30 days prior to registration and plans to continue for the duration of the trial.  
Erythropoietin agents to treat anemia are allowed. Exercise is allowed.  
3.2.6 Anticipating surgery 
3.2.7 Uncontrolled hypothyroidism, profound anemia (hemoglobin level of <10 g/dL ≤ 28 
days prior to registration), or untreated clinical depression per physician discretion. 
Patients with stable, controlled depression or receiving treatment for hypothyroidism will 
be eligible, if they have been on a stable dose for the past 30 days and plan to continue for 
the duration of the trial. 
3.2.8 Any history of Tourrette’s syndrome or tic disorder. 
3.2.9 Any history of or active glaucoma. 
3.2.10 Any history of intractable epilepsy. 
3.2.11 Any of the following co-morbid systemic illnesses or other severe concurrent disease 
which, in the judgment of the investigator, would make the patient inappropriate for entry 
into this study or interfere significantly with the proper assessment of safety and toxicity 
of the prescribed regimens: 
• 
History of myocardial infarction 
• 
Unstable angina 
• 
Left ventricular hypertrophy 
• 
Mitral valve prolapse syndrome 
3.2.12 Receiving any medications or substances that are strong or moderate inhibitors of 
CYP3A4. 
Use of the following strong or moderate inhibitors are prohibited < 7 days prior to 
registration: 
Strong Inhibitors of CYP3A4:  
> 5-fold increase in the plasma AUC values or more than 80% decrease in clearance 
Indinavir (Crixivan®) 
Nelfinavir (Viracept®) 
Atazanavir (Reyataz®) 
Ritonavir (Norvir®) 
Clarithromycin (Biaxin®, Biaxin XL®) 
Itraconazole (Sporanox®) 
Ketoconazole (Nizoral®) 
Nefazodone (Serzone®) 
Saquinivir (Fortovase®, Invirase®) 
Telithromycin (Ketek®) 
Moderate Inhibitors of CYP3A4: 

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> 2-fold increase in the plasma AUC values or 50-80% decrease in clearance 
Aprepitant (Emend®) 
Erythromycin (Erythrocin®, E.E.S. ®, Ery-Tab®, Eryc®, EryPed®, PCE® 
Fluconazole (Diflucan®) 
Grapefruit juice 
Verapamil (Calan®, Calan SR®, Covera-HS®, Isoptin SR®, Verelan®, Verelan PM®) 
Diltiazem (Cardizem®, Cardizem CD®, Cardizem LA®, Cardizem SR®, Cartia XT™, 
Dilacor XR®, Diltia XT®, Taztia XT™, Tiazac®) 
3.2.13 Receiving any medications or substances that are inducers of CYP3A4. 
Use of the following inducers are prohibited < 7 days prior to registration 
Inducers of CYP3A4: 
Efavirenz (Sustiva®) 
Nevirapine (Viramune®) 
Carbamazepine (Carbatrol®, Epitol®, Equetro™, Tegretol®, Tegretol-XR®) 
Modafinil (Provigil®) 
Phenobarbital (Luminal®) 
Phenytoin (Dilantin®, Phenytek®) 
Pioglitazone (Actos®) 
Rifabutin (Mycobutin®) 
Rifampin (Rifadin®) 
St. John’s wort 
 
 
 
 
 
 

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4.0 
TEST SCHEDULE  
Test Schedule Table  
 
Active-Monitoring Phase 
≤28 days 
prior to 
registration 
Baseline6 
End of 
Week 47 
(Cycle 1) 
End of 
Week 87 
(Cycle 2) 
General neurological exam, 
weight, performance status 
X 
 
 
 
Pregnancy test 
X1 
 
 
 
Performance status 
 
 
X4,5 
X4,5 
Neurocognitive testing 
(Appendix VII) 
 
X3 
X3,5 
X3,5 
Adverse event assessment 
 
X 
X 
X 
Patient Questionnaire Booklet  
• Brief Fatigue Inventory (BFI) 
• PROMIS 
• PRO-CTCAE (for fatigue and 
cognition items) 
• Linear Analogue Self-
Assessment (LASA)  
• FACT-Cog  
• Godin Leisure Time Exercise 
Questionnaire (GLTEQ)  
(Appendices III-VI, XIII, XIV) 
 
X2 
X2,5 
X2,5 
Nurse/CRA Phone Contact 
(Appendix XII) 
 
 
X 
X 
1. If the treating physician determines that the woman is of childbearing potential, then a 
pregnancy test must be done ≤ 7 days prior to registration. 
2. Patient questionnaire booklets must be used; copies are not acceptable for this submission.   
3.  Must be administered by credentialed personnel.  See section 4.1 and appendices VIII and IX.  
4. PS will be collected via the Nurse/CRA Phone Contact.  
5.  Administered at the end of weeks 4 and 8. 
6. Baseline assessment must be done < 14 days after registration and no more than 7 days prior to 
1st day of study drug.  
7. +/- 3 days, timing for week 4 and 8 assessments should be measured from time of study drug 
administration – not baseline.  

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4.1 
Neurocognitive Testing 
The ‘Cognitive Testing’ and ‘Administration Procedures for the Neurocognitive Test Battery’ 
are included in this protocol as Appendices VII and VIII, respectively. Booklets must be used for 
submission; copies of the appendices are not acceptable. 
Note: Patients may not be registered to this study until at least one member from the site study 
team has received certification to perform neurocognitive testing. 
4.1.1 Credentialing to Perform/Administer Neurocognitive Testing 
Any individual member of a site study team who wishes to perform neurocognitive testing 
is required to be credentialed. Credentialing is specific to one individual person, it does 
not certify an entire study site or study team. 
For all Alliance sites, the following must be completed prior to registering a patient. This 
study requires that the member of the study staff who will administer the neurocognitive 
testing to patients be credentialed by 
 Each 
individual member of the study staff who will be administering the neurocognitive 
testing must be credentialed. 
Please order the “Neurocognitive Booklet for Certification Use Only” from the CTSU 
website (see Section 6.1.2) as the site prepares for IRB submission so the credentialing can 
be obtained prior to registering a patient.  
4.1.1.1 
Previously credentialed team members 
Members of site study teams are considered partially credentialed to perform 
neurocognitive testing for this study if they have previously been credentialed for 
any one of the following studies: NCCTG N0577; BN001, CC001, CC003 
 
Previously credentialed study team members will need to be partially re-
certified for this study.  Specifically, they need to do the following: 
1. Review procedures for the Symbol Digit Modalities Test (see Section 11.2.1) 
and the A221101 neurocognitive training video for this test which is posted on 
the CTSU website. The Symbol Digit Modalities Test was not included in the 
aforementioned protocols. 
2. Review Appendix VIII “Administration Procedures for Neurocognitive 
Testing” in the protocol, with special reference to the instructions for the 
Symbol Digit Modalities test.  
Note: Please have access to the Administration Procedures document while 
you view the brief A221101 neurocognitive testing training video for the 
Symbol Digit Modalities Test. 
Please allow enough time for the video to download. If you have difficulties 
downloading the video, please check with your institution’s computer 
support/help desk first before contacting the protocol coordinator at the 
telephone number or email address listed on the Protocol Resource page of the 
protocol. 
3. Obtain the “Neurocognitive Booklet for Certification Use Only” and complete 
the entire quiz.   

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4. Complete the practice test for Symbol Digit Modalities Test with a colleague 
(not a patient). You do not need to complete the practice portion for the other 
tests, just the Symbol Digit Modalities Test.  
5. Please be certain to complete and sign the certification page of the booklet. 
Also, include the CTEP site code for every site at which a patient may be 
enrolled along with your email address. 
6. Submit the entire booklet per section 4.1.1.3 below. Along with the booklet, 
be sure to include documentation of prior certification as follows: the 
name/number of the prior study and the approximate date of certification. 
4.1.1.2  
Not Previously credentialed team members 
If not previously credentialed, the study team member(s) must complete the 
following process:   
1. Review “Administration Procedures for Neurocognitive Testing” in Appendix 
VIII of this protocol and the A221101 neurocognitive testing training video 
posted on the CTSU website.  
Please have access to the Administration Procedures document while you view 
the A221101 neurocognitive testing training video.  
Please allow enough time for the video to download. If you have difficulties 
downloading the video, please check with your institution’s computer 
support/help desk first before contacting the protocol coordinator at the 
telephone number or email address listed on the Protocol Resource page of the 
protocol. 
2. Complete the “Neurocognitive Booklet for Certification Use Only.” The 
booklet includes a brief quiz and a practice test.  Complete the practice test 
with a colleague (not a patient).  
3. Please be certain to complete and sign the certification page of the booklet. 
Also, include the CTEP site code for every site at which a patient may be 
enrolled along with your email address. 
4. Submit the entire booklet per section 4.1.1.3 below. 
4.1.1.3 
Submitting certification booklets 
Scan and email a copy of the entire booklet to 
 at 
. OR 
Mail to the following: 
 
  
If mailing, be certain to keep a copy of the booklet at the site.  
Emailing directly to 
 is the most efficient path to certification. 
 
 

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4.1.1.4 
Team member certification review and confirmation 
 will review the certification booklet. If there are concerns, she will call 
or email the member of the site study team to review. If there are no concerns, 
confirmation of the team member's certification will be emailed to the team 
member. The site should then submit the Certification Confirmation Form to 
CTSU per Sections 6.4.4 and 6.4.5. 
Certification does not expire. However, if a number of months go by between 
administrations, please ensure readiness to test by reviewing Appendix VIII 
Administration Procedures for Neurocognitive Testing in the protocol and/or 
viewing the training video posted on the CTSU website and/or performing practice 
testing with a colleague. 
4.1.2 Neurocognitive Tests Format 
The credentialed site study team member will administer the neurocognitive tests to the 
patient using the patient questionnaire titled “Neurocognitive Examiners Booklet”. On 
follow-up visits, it is preferred that patients complete the neurocognitive test battery before 
seeing the physician since the emotional impact of the results of their follow-up brain scan 
may influence the patient’s performance on the neurocognitive assessments. The 
questionnaire booklet will take approximately 15 minutes to complete and includes the 
following tests: 
a) Symbol Digit Modalities Test (Smith, 1982). 
b) Controlled Oral Word Association. 
c) Trail Making Test A and B (Reitan 1958). 
4.1.3 Submission of the completed neurocognitive test questionnaires 
The neurocognitive tests must be administered in the order stated to every patient at every 
visit per testing instructions (see Appendix VIII).  
Note: For the ‘Symbol Digit Modalities Test’, DO NOT SCORE THIS TEST. Study 
staff administering this test should not make any corrections after the practice 
portion. Please leave it attached, make a copy for your records, and mail it still 
attached to the test booklet.  
Completed test forms must be signed by the credentialed site study team member 
administering the neurocognitive tests. Be sure to include the Alliance patient study ID on 
the Neurocognitive Booklet. Retain a copy of the completed Neurocognitive Booklet at the 
treating institution and mail the original of the completed booklet to: 
 
 
 
 
 
 
 

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5.0 
STRATIFICATION FACTORS  
5.1 
Concomitant Chemotherapy:  Yes vs. No 
5.2 
Age:  < 60 vs. ≥60 
5.3 
Corticosteroid use:  Yes vs. No  
5.4 
Gender:  Male vs. Female 
Stratification factors will be age, gender, concomitant chemotherapy, and corticosteroid usage. 
Balance will be achieved through established randomization procedures, which balances the 
marginal distributions of the stratification factors (102). These dichotomous variables involve a 
total of 16 different level combinations of stratification factors which is well below the group 
sample size as recommended by Therneau (101). We will also include these covariates in the 
modeling processes specified in the statistical considerations.   
6.0 
REGISTRATION/RANDOMIZATION PROCEDURES  
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
6.1 
Registration Requirements 
6.1.1 Informed consent:  
The patient must be aware of the neoplastic nature of his/her disease and willingly consent 
after being informed of the procedure to be followed, the experimental nature of the 
therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Current human 
protection committee approval of this protocol and a consent form is required prior to 
patient consent and registration. 
6.1.2 Ordering Questionnaires/Booklets 
Neurocognitive certification and patient assessment questionnaire booklets for 
A221101 must be ordered prior to the registration of any patients. Site staff should 
obtain all necessary neurocognitive certification and patient assessment questionnaire 
booklets before registering patients. Booklets can be ordered by downloading and 
completing the CTSU supply request form (located under the site registration documents 
section of the A221101 website) and faxing the form to the CTSU data operations center 
at 
. Samples of the booklets are found in Appendices III-VII, which are to 
be used for reference and IRB submission only. They are not to be used for patient 
completion. Note: The CTSU will not send questionnaire booklets until the site has 
submitted a copy of their IRB approval excerpt to the CTSU Regulatory Office. 
6.2 
CTEP Registration Procedures  
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account 
.  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) 
.  Documentation requirements per 
registration type are outlined in the table below. 

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Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP 
and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs 
must list all clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in 
RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional information can be found on the CTEP website at < 
>.  For questions, please contact the RCR Help 
Desk by email at 
 
6.3 
Site Registration Requirements – IRB Approval 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
6.3.1 IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data to 
make a determination of whether a site has fulfilled all regulatory criteria including but not 
limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 

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• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study 
are not required to submit IRB approval documentation to the CTSU Regulatory Office. 
For sites using the CIRB, IRB approval information is received from the CIRB and applied 
to the RSS in an automated process. Signatory Institutions must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB via IRB Manager to indicate their intent 
to open the study locally.  The CIRB’s approval of the SSW is then communicated to the 
CTSU Regulatory Office.  In order for the SSW approval to be processed, the Signatory 
Institution must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. 
6.3.2 In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually).  If the necessary documentation is 
not submitted in advance of attempting patient randomization, the randomization will not 
be accepted and the patient may not be enrolled in the protocol until the situation is 
resolved. 
6.3.3 When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the CTSU is no longer necessary. 
6.3.4 Downloading Site Registration Documents 
Site registration forms may be downloaded from the A221101 protocol page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed 
in the CTSU RSS. 
• 
Go to 
 and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the Alliance link to expand, then select trial protocol # A221101 
• 
Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided. 
Requirements of A221101 site registration: 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted). 
• 
The Certification Confirmation Form received from Dr. Cerhan (see Section 4.1.1.) 
6.3.5 Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS.  
Regulatory Submission Portal:
  (members’ area)  Regulatory Tab 
Regulatory Submission  
When applicable, original documents should be mailed to: 

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NCI Version Date: 9/24/2018 
Update #7 
25 
 
 
 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 
 in order to receive further instruction 
and support. 
6.3.6 Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU website. 
• Go to 
 and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab  
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
6.4 
Patient Randomization 
6.4.1 Patient randomization can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS. Patients 
must have signed and dated all applicable consents and authorization forms. 
6.4.2 Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account (check at < 
 and a 'Registrar' role on either the LPO or participating 
organization roster.  Registrars must hold a minimum of an AP registration type.     
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data.  OPEN can be accessed at 
 or from the OPEN tab on the CTSU members’ side of the website at 
  To assign an IVR or NPIVR as the treating, crediting, consenting, 
drug shipment (IVR only), or investigator receiving a transfer in OPEN, the IVR or NPIVR 
must list on their Form FDA 1572 in RCR the IRB number used on the site’s IRB approval.   
6.4.3 Prior to accessing OPEN, site staff must verify the following: 
• 
All eligibility criteria must have been met within the protocol stated timeframes. Site 
staff should use the randomization forms provided on the CTSU web site as a tool to 
verify eligibility. 
• 
All patients must have signed an appropriate consent form and HIPAA authorization 
form (if applicable). 
6.4.4 Access Requirements for Oncology Patient Enrollment Network (OPEN) 
• 
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM 
account.  This is the same account (user id and password) used for the CTSU members’ 
web site. 

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• 
To perform randomizations, the site user must have been assigned the ‘Registrar’ role 
on the relevant Group or CTSU roster. 
• 
To perform randomizations on protocols for which you are a member of the Lead 
Group, you must have an equivalent ‘Registrar’ role on the Lead Group roster.  Role 
assignments are handled through the Groups in which you are a member. 
• 
To perform randomizations to trials accessed via the CTSU mechanism, you must have 
the role of Registrar on the CTSU roster. Site and/or Data Administrators can manage 
CTSU roster roles via the new Site Roles maintenance feature under RSS on the CTSU 
members' web site. This will allow them to assign staff the "Registrar" role. 
NOTE:  The OPEN system will provide the site with a printable confirmation of 
randomization and treatment information.  Please print this confirmation for your records.  
Further instructional information is provided on the OPEN tab of the CTSU members’ side 
of the CTSU website at 
.  For any additional 
questions, contact the CTSU Help Desk at 
. 
6.4.5 Treatment on this protocol must commence at the accruing membership under the 
supervision of an Alliance member physician. 
6.4.6 Study participation cannot begin prior to registration and must begin within 14 days after 
registration. 
6.4.7 Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
6.4.8 Neurocognitive certification and neurocognitive patient testing questionnaire 
booklets must be used.  
Copies of questionnaires in the appendices of this protocol are to be submitted to the local 
IRB for review and approval only and are not acceptable for data submission. 
Note: Once the above conditions have been met, access the OPEN website and follow the 
instructions for enrollment. 
The factors defined in Section 5.0, together with the registering membership, will be used 
as stratification factors.  The values of the stratification factors will be recorded.  The 
patient then will be assigned to one of the following treatment groups using the Pocock and 
Simon65 dynamic allocation procedure which balances the marginal distributions of the 
stratification factors between the treatment groups. 
• 
Armodafinil  150 mgs 
• 
Placebo 
• 
Armodafinil  250 mgs 
6.5 
Procedures for Double-Blinding the Treatment Assignment 
To ensure that both the patient and the medical professionals who care for the patient are blinded 
to the identity of the treatment assignment, the below procedures must be followed. 
6.5.1 Each patient will be assigned a bottle number at the time of registration. This number can 
be found on the confirmation of registration. After the site has registered/randomized their 
patient in OPEN and received an Alliance subject number, the site will need to fax a drug 
order form (Appendix XI) to the Mayo Pharmacy fax number 
. The order 
form must include the patient’s subject number, the assigned bottle number, the patient’s 
initials, a complete shipping address, and the DEA Registration Number of the registering 

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investigator or the site’s pharmacy. This must be done for every patient registration. The 
Alliance Registration Office personnel will also be notified when a patient is 
registered/randomized in OPEN. As a double check, the registration office will also notify 
the pharmacy of the registered patient and the assigned bottle number.  
6.5.2 The number of the treatment bottle assigned to the patient will be recorded on the dosing 
form. 
6.5.3 The treatment assignment will be Armodafinil or placebo.  The dose will be prepared and 
labeled as “armodafinil OR placebo” so that the contents are not discernible to the 
individual administering the treatment. 
 
 

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7.0 
 PROTOCOL TREATMENT 
7.1 
Treatment Schedule 
Agent 
Dose Level 
Route 
Frequency 
Armodafinil 
150 mg (one tablet) 
Oral 
Every day in the 
morning for 8 weeks 
Placebo 
one tablet 
Oral 
Every day in the 
morning for 8 weeks 
Armodafinil 
250 mg (one tablet) 
Oral 
Every day in the 
morning for 8 weeks 
 
7.2 
Unblinding Procedures  
Unblinding can be done only in cases of an emergency or at the time of study completion. 
Follow the directions below to unblind patient treatment. Please note that if a treatment 
assignment is unblinded, the patient must discontinue protocol therapy. 
7.2.1 Emergency Unblinding Procedures: 
Unblinding can be done only in cases of an emergency or after the patient has completed 
protocol treatment. Follow the directions below to unblind patient treatment. Please note 
that if a treatment assignment is unblinded, the patient must discontinue protocol therapy. 
Emergency Unblinding Procedures: 
Examples of emergencies include 1) a life-threatening unexpected adverse event that is at 
least possibly related to the investigational agent and for which unblinding would influence 
treatment decisions; or 2) medication error, such as accidental overdose. Expected adverse 
events are listed in the “Toxicities” section below.  
Contact the Alliance Executive Officer on call by calling 
, pressing 1 to 
speak with an operator, and then asking for pager ID 8625 to return the call.  
The institution must provide the following information to the Alliance Executive Officer:  
• 
Alliance study ID (i.e., “A######”)  
• 
Alliance patient ID number (e.g., “999999”)  
• 
Patient initials (e.g., “L,FM”)  
• 
Institution name  
• 
Name and telephone number of treating physician  
• 
Name and contact information of person requesting the unblinding procedure  
• 
Name and contact information of person to inform of treatment assignment  
• 
Reason for emergency unblinding  
Please remember that emergency unblinding request may be authorized only by an Alliance 
Executive Officer, and emergency unblinding applies only if unblinding would influence 
management of the medical situation.  
After the Executive Officer deems unblinding is warranted, the treatment assignment will 
be provided to the contact person at the treating site.  
 
 

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7.2.2 Protocol-specified unblinding 
Trial participants may be unblinded upon study completion. Contact the Alliance 
Registration Office at 
 during regular business hours. Upon confirmation by 
the Primary Statistician (or designee) that all study completion requirements have been 
met, the treatment assignment may be unblinded. No Alliance Executive Officer (or 
designee) approval is required. 
8.0 
DOSAGE MODIFICATION BASED ON ADVERSE EVENTS  
The study medication dose should be stopped for any grade 3 or worse toxicities related to study 
agent, or at the patient’s discretion regarding toxicity.  Any of the above should be clearly recorded 
on the Adverse Event Form.  
Patients can be discontinued abruptly (no need to taper). 
9.0 
ANCILLARY TREATMENT/SUPPORTIVE CARE 
Patients who begin using any other pharmacologic agents or nonpharmacologic interventions after 
registration to specifically treat fatigue including psychostimulants, antidepressants, acupuncture, etc. 
will be taken off study. 
Note: Antidepressants used to treat items other than fatigue (such as hot flashes or depression) are 
allowed if the patient has been on a stable dose for ≥ 28 days and plans to continue for the duration 
of the trial. Erythropoietin agents to treat anemia are allowed.  
10.0 ADVERSE EVENT (AE) REPORTING AND MONITORING 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.0.  However, CTCAE v5.0 must be used for serious AE reporting 
through 
CTEP-AERS 
as 
of 
April 
1, 
2018. 
The 
CTCAE 
is 
available 
at 
. 
Attribution 
to 
protocol 
treatment for each adverse event must be determined by the investigator and reported on the required 
forms, using the codes provided. 
10.1 
Routine Adverse Event Reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the test schedule in Section 4.0. For this trial, the Adverse Events forms are 
used for routine AE reporting (see Section 18.2 for adverse event form submission details). 
 
 

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10.2 
CTCAE Routine Study Reporting Requirements 
* 
Combinations of CTCAE Grade & Attribution Required for Routine AE Data 
Submission on Case Report Forms (CRFs) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
 
a 
a, b 
a, b 
a, b 
Probable 
 
a 
a, b 
a, b 
a, b 
Definite 
 
a 
a, b 
a, b 
a, b 
a) Adverse Events: Other CRF - Applies to AEs occurring between registration and within 30 
days of the patient’s last treatment date, or as part of the Clinical Follow-Up Phase. 
b) Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the patient’s 
last treatment date. 
10.3 
Expedited adverse event reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined 
below. Alliance investigators are required to notify the Alliance Central Protocol Operations 
Program Office, the Study Chair, and their Institutional Review Board if a patient has an adverse 
event requiring expedited reporting. All such events must be reported in an expedited manner 
using the CTEP Adverse Event Reporting System (CTEP-AERS). In the rare occurrence when 
internet connectivity is lost, a 24-hour notification is to be made to the Alliance Central Protocol 
Operations Office. Once internet connectivity is restored, the 24-hour notification phoned in must 
be entered electronically into CTEP-AERS by the original submitter at the site. 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized for AE reporting beginning April 1, 2018. All appropriate treatment areas should have 
access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded 
from 
the 
CTEP 
web 
site:
  All reactions 
determined to be “reportable” in an expedited manner must be reported using the Cancer Therapy 
Evaluation Program Adverse Event Reporting System (CTEP-AERS). 
The Alliance requires investigators to route all expedited adverse event reports through the 
Alliance Central Protocol Operations Program Office for Alliance coordinated studies.  
Be sure to read this entire protocol section, as requirements are described in both the table and 
bullet points following the table. Note that the additional instructions or exclusions are protocol 
specific, and in the case of a conflict, the additional instructions or exclusions supersede the table.  
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality. Attribution to treatment or other cause should be provided. 
 
 

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10.3.1 Alliance A221101 Reporting Requirements   
Expedited reporting requirements for adverse events that occur on studies under an 
IND/IDE ≤ 30 Days of the last administration of the investigational agent/intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may 
be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour; 
5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
10 Calendar Days 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS ≤ 24 hours of 
learning of the AE, followed by a complete expedited report ≤ 5 calendar days of the initial 24-hour 
report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted ≤ 10 calendar days 
of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report ≤ 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs  
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
 
 

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• 
Expedited AE reporting timelines defined: 
 “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS ≤ 24 hours of learning of the event followed by a complete CTEP-AERS report 
≤ 5 calendar days of the initial 24-hour report. 
 “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted ≤ 
10 calendar days of the investigator learning of the event.  
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
Additional Instructions or Exclusions: 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
• 
Grade 3/4 hematosuppression and hospitalization resulting from such do not require CTEP-
AERS, but should be submitted as part of study results. All other grade 3, 4, or 5 adverse 
events that precipitate hospitalization or prolong an existing hospitalization must be reported 
via CTEP-AERS. 
• 
Treatment expected adverse events include those listed in Section 15.0 and in the package 
insert 
• 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.” 
Evidence that the death was a manifestation of underlying disease (e.g., radiological changes 
suggesting tumor growth or progression: clinical deterioration associated with a disease 
process) should be submitted. 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours. 
• 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, 
probably, or definitely related to the investigational agent/intervention. 
• 
All new malignancies must be reported through CTEP-AERS whether or not they are 
thought to be related to either previous or current treatment. All new malignancies should 
be reported, i.e., solid tumors (including non-melanoma skin malignancies), hematologic 
malignancies, myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), and 
in situ tumors.  
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe 
the event:  
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  

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33 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting unless otherwise specified. 
Whenever possible, the CTEP-AERS reports for new malignancies should include tumor 
pathology, history or prior tumors, prior treatment/current treatment including duration, any 
associated risk factors or evidence regarding how long the new malignancy may have been 
present, when and how it was detected, molecular characterization or cytogenetics of the 
original tumor (if available) and of any new tumor, and new malignancy treatment and 
outcome, if available. 
• 
Pregnancy loss  
• 
Pregnancy loss is defined in CTCAE as “Death in utero.” 
• 
Any Pregnancy loss should be reported expeditiously, as Grade 4 “Pregnancy loss” 
under the Pregnancy, puerperium and perinatal conditions SOC.  
• 
A Pregnancy loss should NOT be reported as a Grade 5 event under the Pregnancy, 
puerperium and perinatal conditions SOC, as currently CTEPAERS recognizes this 
event as a patient death. 
• 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under 
the General disorders and administration SOC. 
• 
The reporting of adverse events described above is in addition to, and does not supplant, 
the reporting of adverse events as part of the reporting of the results of the clinical trial, 
e.g. routine reporting. 
10.4 
Contact Information for NCI Safety Reporting 
Website for submitting expedited 
reports 
 
AEMD Help Desk (for CTEP)* 
 Monday through Friday,  
7:00 AM to 7:00 PM (US Eastern Time) 
Fax for expedited report supporting 
Medical Documentation for CTEP trials 
 
AEMD Help Email: 
 
Technical (e.g., IT or computer issues 
ONLY) Help Phone* 
 
CTEP-AERS Technical Help Email 
  
CTCAE v4 Help/Questions Email 
 
CTEP-AERS FAQs link 
CTEP-AERS Computer Based Training  
link 
  
Office phone and fax are accessible 24 hrs per day 7 days a week (The AEMD phone line is 
staffed from Monday through Friday, 7:00 AM to 7:00 PM ET.  Any phone call after these hours 
will go to voicemail.  Please leave contact information and the phone call will be returned the 
following business day. 

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34 
10.5 
Other Required Expedited Reporting 
EVENT TYPE 
REPORTING PROCEDURE 
Other Grade 4 or 5 
Events and/or Any 
Hospitalizations During 
Treatment Not 
Otherwise Warranting 
an Expedited Report 
Complete a Notification Form: Grade 4 or 5 Non-AER 
Reportable Events/Hospitalization Form electronically via the 
NCCTG Remote Data Entry System within 5 working days of 
the date the clinical research associate (CRA) is aware of the 
event(s) necessitating the form. 
If an CTEP-AERS report has been submitted, this form does 
not need to be submitted. 
10.6 
Adverse events to be graded at each evaluation.  
Pretreatment symptoms/conditions are to be evaluated at baseline per CTCAE v4.0 grading 
unless otherwise stated in the table below: 
System Organ Class (SOC) 
Adverse event 
Baseline 
Each evaluation 
Nervous System Disorder 
Headache 
X 
X 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as applicable) 
regarding the submission of late occurring AEs following completion of the Active Monitoring 
Phase. 
11.0 TREATMENT EVALUATION 
11.1 
Patient Self-Report Measures 
The Patient self-report measures will be given three times, baseline and after weeks 4 and 8 of 
treatment. These items together take approximately 20 - 25 minutes to complete. 
Fatigue is measured by multiple approaches in this protocol to not only provide a complete 
description of the type of fatigue experienced throughout treatment by the patients but also to 
inform future studies as to the relative merit (reliability, validity, responsiveness) the alternative 
methods impart in measuring fatigue. 
11.1.1 Brief Fatigue Inventory (BFI) 
The BFI is a 9-item instrument that allows for the rapid assessment of fatigue level in 
cancer patients and identifies those patients with severe fatigue.  Three items ask patients 
to rate their fatigue for “now,” and fatigue at its “worst” and “usual” for the last 24 hours.  
The 11-point scales are bounded by 0 = “no fatigue” and 10 = “fatigue as bad as you can 
imagine.”  Using the same type of scales, the remaining questions ask patients to rate how 
their fatigue interferes with several quality of life domains including general activity, 
walking, mood, work, and relations with others.  These scales are bounded by 0 = “does 
not interfere” and 10 = interferes completely.”  The reliability and validity of the BFI were 
demonstrated in a study of 305 cancer patients and 290 community-dwelling adults. An 
internal consistency coefficient (Cronbach’s alpha) = 0.96 was demonstrated when the BFI 
was administered to 305 patients with cancer (80). The BFI has been demonstrated as 
viable primary endpoints for numerous cancer clinical trials and has been translated into 
22 different languages (81).  
Single-question assessment is the most commonly used and the most useful methodology. 
A score of 1–3 indicates the presence of mild fatigue that does not require clinical 
intervention, and scores of 4–6 and 7–10 indicate moderate and severe fatigue, 
respectively, which require further evaluation and clinical intervention (82). 

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11.1.2 PROMIS  
The PROMIS fatigue short form is a 7-item assessment using 5 response categories similar 
to the initial FACT series of measures. It produces a single summated score for fatigue 
(91). It was recently endorsed by the NCI SxQOL Steering Committee for use in NCI-
sponsored cancer control trials. It produces a single summative score for the purposes of 
analysis. 
The PROMIS measure will be used mostly as an exploratory secondary measure.  We will 
look at its psychometric properties with the population in this study and also look at 
concurrent validity using the BFI as a gold standard.  There are two domains represented 
by the 7 items in the PROMIS fatigue short form; impact and experience.  In an exploratory 
manner, these will be evaluated as subscales but also the scale will be evaluated as a 
unidimensional measure.  Since the fatigue items have not been, to our knowledge, 
psychometrically validated in cancer populations, we do see the use of PROMIS fatigue as 
an exploration.  Since there is a desire to use a core set of measures in fatigue studies going 
forward and PROMIS has been cited as being a logical set of measures to use in this regard, 
we felt it was important to include these and begin generating some psychometric data, 
particularly in this, more rare population of high grade glioma patients. 
11.1.3 PRO-CTCAE  
PRO-CTCAE Symptomatic adverse events (AE) in cancer trials are reported by clinicians 
using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE). To integrate the patient perspective into AE reporting, NCI contracted 
(HHSN261201000043C) to create a patient-reported outcomes companion tool (PRO-
CTCAE). The validity and reliability of PRO-CTCAE’s 124 items reflecting 78 
symptomatic AEs is presently underway. The items being created and validated are 
intended to be complementary to existing symptom items in the NCI’s Common 
Terminology Criteria for Adverse Events (CTCAE). The CTCAE is an existing lexicon of 
clinician-reported adverse event items required for use in all NCI-sponsored trials. The 
goal of developing patient versions of CTCAE symptom items is to improve the accuracy 
and precision of adverse symptom assessment in cancer trials, and to bring the CTCAE 
into harmony with other areas of clinical research in which the gold standard for symptom 
evaluation is patient self-reporting. Information gathered through the PRO-CTCAE is 
intended to provide clinicians with more comprehensive information about the patient 
experience with treatment when trials are completed and reported. We are including six 
items from the PRO-CTCAE in this study for fatigue and cognitive function to provide 
further evidence of their reliability and validity and compare the PRO-CTCAE items to the 
other methods for assessing fatigue and cognitive function. 
11.1.4 LASA   
Linear Analogue Self-Assessment (LASA) items have been validated as general measures 
of global QOL dimensional constructs in numerous settings (83-88). A series of five LASA 
items have been constructed and validated at Mayo for use in cancer patients (89). The 5 
aspects measured will be global QOL, physical, emotional, spiritual, and intellectual well-
being.  Dr. Sloan and colleagues have done extensive research on the application of single-
item LASA measures for assessing a wide variety of PROs including fatigue, peripheral 
neuropathy, hot flash activity, and anxiety. These single-item assessments have become 
the most-used assessment in all NCI-sponsored cancer control studies (90).  As a result of 
recent research, this study includes LASA measures for global QOL and fatigue and will 
include these measures in all future phase II and phase III clinical trials as an independent 
prognostic factor independent of performance status. 

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11.1.5 FACT-Cog (Secondary Cognitive Endpoint) 
Patients in this study will self-report their perceived cognitive functioning using the FACT-
Cog version 3 (92). For many cancer-related symptoms, given their subjective nature, self-
report is the only way an assessment can be conducted. The FACT-Cog is a useful measure 
of perceived cognitive deficits and related quality of life for adults undergoing 
chemotherapy, and is the first patient-reported outcomes measure to be developed and 
validated with a sample of cancer patients. The scale measures the frequency of positive 
and negative cognitive functioning events over the past seven days, based on self-report. 
The measure utilizes a five-point Likert-type scale (ranging from 0 = never to 4 = several 
times a day) to assess several different aspects of cognitive function. Lower scores are 
indicative of poorer perception of functioning. The FACT-Cog assesses a broad range of 
cognitive domains (not just those specifically related to work) and provides a 
multidimensional view of the cognitive deficits often experienced by patients with cancer.  
11.1.6 Godin Leisure Time Exercise Questionnaire (GLTEQ). 
The amount of leisure time spent in physical activity will be assessed using the Godin 
Leisure Time Exercise Questionnaire (GLTEQ) (103). The GLTEQ consists of two 
questions designed to assess the frequency within a typical 7 day week of mild, moderate, 
and strenuous exercise performed for a duration of at least 15 minutes during a participant’s 
free time.  The measure is easily administered and brief, with a retest coefficient of .62, a 
concurrent coefficient of .32 and an objective validity coefficient of .56 compared with 
CALTRAC accelerometry, estimated VO2 max and body composition (via hydrostatic 
weight).18  The GLTEQ has also been used successfully in populations of adult cancer 
patients (104-108).   
11.2 
Objective Cognitive Measures (Primary Cognitive Endpoint) 
The neuropsychological battery proposed for this study overlaps with batteries used in numerous 
North Central Cancer Treatment Group (NCCTG) multi-center trials for studies in patients with 
CNS tumors without any problems or complications. 
Clinicians and researchers must balance the often conflicting goals of obtaining valid PRO data 
while not burdening patients or interfering with the provision of care in a busy clinical setting. 
When surveyed about the preferred properties for an assessment battery for neurological and 
behavioral function, 191 experts in clinical and epidemiologic research reported it should be 
brief, precise, and easy to administer, score, and interpret (93). 
The Symbol Digit Modalities Test (SDMT; Smith, 1982) is a measure of attention, visual 
tracking, and psychomotor speed.  The task consists of a brief practice, followed by a 90-second 
test trial.  Subjects are given a key in which 9 symbols are paired with each of the digits 1 through 
9.  Below the key is a grid in which a random series of the symbols appear above empty boxes.  
The task is to fill in the correct digit under each symbol, without skipping boxes, as quickly as 
possible for 90 seconds.  This task has been found to be a particularly sensitive indicator of brain 
dysfunction (95).  
11.2.1 Controlled Oral Word Association 
This test requires subjects to generate words beginning with specified letters.  A brief 
practice is followed by three 60-second trials using three different first-letter cues.  This is 
a measure of processing speed and phonemic verbal fluency, and is a task widely used in 
neuropsychological assessment.   
11.2.2 Trail Making Test 

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Trail Making is a two-part sequencing task which requires subjects to connect numbered 
dots in order (Part A) and then to connect dots alternating between numbers and letters 
(Part B).  Score is time of completion, with each trial scored separately.  Part A measures 
psychomotor speed, concentration, and visual scanning.  Part B requires the cognitive 
functions required for Part A, with added recruitment of cognitive flexibility (executive 
function) (86).  This test has a long history of use in clinical neuropsychology, and has 
been found to be very sensitive to brain dysfunction in general (96, 97). 
12.0 DESCRIPTIVE FACTORS 
None. 
13.0 TREATMENT/FOLLOW–UP DECISION AT EVALUATION OF PATIENT   
If the patient discontinues the study agent prior to 8 weeks, the patient will go off study.  
A patient is deemed ineligible if after registration, it is determined that at the time of registration, the 
patient did not satisfy each and every eligibility criteria for study entry.  If the patient received 
treatment, all data up until the point of confirmation of ineligibility must be submitted.  If the patient 
never received treatment, on-study material must be submitted.  
A patient is deemed a major violation, if protocol requirements regarding treatment in cycle 1 of the 
initial therapy are severely violated that evaluability for primary end point is questionable.  All data 
up until the point of confirmation of a major violation must be submitted. 
A patient is deemed a cancel if he/she is removed from the study for any reason before any study 
treatment is given.  On-study material and the End of Active Treatment/Cancel Notification Form 
must be submitted.  No further data submission is necessary. 
14.0 BODY FLUID BIOSPECIMENS 
Not Applicable  
15.0 DRUG INFORMATION 
15.1 
Armodafinil (Nuvigil®) or placebo 
15.1.1 Background 
Armodafinil indicated as adjunctive therapy in the treatment of obstructive sleep apnea 
(OSA) and to improve wakefulness in patients with narcolepsy and shift work disorder 
(SWD).  Armodafinil is the R-enantiomer of modafinil, which is a mixture of the R- and 
S-enantiomers.  The precise mechanisms through which armodafinil and modafinil 
promote wakefulness are unknown.  Both agents have shown similar pharmacologic 
properties in nonclinical animal and in vitro studies. 
• 
At pharmacologically relevant concentrations, armodafinil does not bind to or inhibit 
several receptors and enzymes potentially relevant for sleep/wake regulation.  
Armodafinil is not a direct- or indirect-acting dopamine receptor agonist.  Armodafinil 
has wake-promoting actions similar to sympathomimetic agents, but the 
pharmacologic profile is not identical to that of the sympathomimetic amines. 
• 
Armodafinil has been classified as a Schedule IV controlled substance.  Investigators 
who prescribe this agent must have an up-to-date Controlled Substance Registration 
Certificate.  The agent must be stored in compliance with state and federal regulations 
related to Schedule IV controlled substances.    
15.1.2 Formulation 

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Commercial armodafinil (Nuvigil®) tablets contain 50, 150 or 250 mg of armodafinil and 
the following inactive ingredients: croscarmellose sodium, lactose monohydrate, 
magnesium stearate, microcrystalline cellulose, povidone, and pregelatinized starch. 
15.1.3 Preparation and storage:  
Armodafinil (Nuvigil®) tablets are stored at 20° to 25°C (68° to 77°F) 
15.1.4 Administration:   
Armodafinil will be taken as a single dose in the morning.  Food delays absorption, but this 
has minimal effects on bioavailability.  Armodafinil may therefore be taken without regard 
to food intake. If the patient misses a dose, the tablet can be taken that day as long as it is 
atleast 12 hours before the next dose.   
15.1.5 Pharmacokinetic information: 
a) Absorption – Readily absorbed. 
b) Distribution –Vd: 42L.  Approximately 60% protein bound, primarily to albumin 
(based on modafinil) 
c) Metabolism –Hepatic, via multiple pathways, including CYP3A4/5.  Metabolites 
include R-modafinil acid and modafinil sulfone.  Clearance is 33 mL/minute, mainly 
via hepatic metabolism.  Half-life elimination is 15 hours.  Steady state is reached at 
approximately 7 days.  The time to peak concentration (fasting) is 2 hours.  
d) Excretion – Urinary (80%, predominantly as metabolites); < 10% as unchanged drug. 
15.1.6 Potential Drug Interactions: 
Armodafinil is a major substrate of CYP3A4.  Dosage adjustment should be considered for 
concomitant medications that are substrates for CYP3A4/5, such as steroidal 
contraceptives, triazolam, and cyclosporine.  Armodafinil is a moderate inhibitor of 
CYP2C19.  Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, 
propranolol, and phenytoin may have prolonged elimination upon coadministration with 
armodafinil, and may require dosage reduction and monitoring for toxicity.   
15.1.7 Known potential toxicities 
The use of armodafinil is contraindicated in patients with hypersensitivity to armodafinil, 
modafinil, or any component of the formulation. 
Use is not recommended in patients with a history of angina, cardiac ischemia, recent 
history of MI, left ventricular hypertrophy, or patients with mitral valve prolapse, who have 
developed mitral valve prolapse syndrome with previous CNS stimulant use. 
Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm) have been 
observed with armodafinil. Small average increases in mean systolic and diastolic blood 
pressure were seen in patients with narcolepsy taking armodafinil when compared to 
placebo.  
Serious and life-threatening rashes including Stevens-Johnson syndrome, toxic epidermal 
necrolysis, and drug rash with eosinophilia and systemic symptoms have been reported 
with modafinil, the racemate of armodafinil.  Most cases have been reported within the 
first 5 weeks of therapy. 
In pre-approval narcolepsy, OSA and SWD controlled trials of armodafinil, anxiety, 
agitation, nervousness, irritability, and depression were reasons for treatment 

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discontinuation more often than for placebo. Cases of suicide ideation were also observed 
in clinical trials. 
The use of armodafinil may impair the ability to engage in potentially hazardous activities. 
The agent should be administered at a reduced dose for patients with severe hepatic 
impairment.  There is inadequate information to determine the safety and efficacy of dosing 
patients with severe renal impairment.  Elimination of the agent and its metabolites may be 
reduced in elderly patients.  Consideration should be given to the use of lower doses in this 
population. 
Headaches are dose related and reported in > 10% of patients.  Adverse reactions reported 
in 4 to 10% of patients include nausea (dose related), dizziness, insomnia (dose related), 
anxiety, and diarrhea. Adverse events reported in < 4% of patients include: depression 
(dose related), dyspepsia, fatigue, palpitations, rash (dose related), upper abdominal pain, 
agitation, anorexia, constipation, contact dermatitis, decreased appetite, depressed mood, 
attention disturbance, dyspnea hyperhidrosis,, increased heart rate, flu-like syndrome, 
loose stools, migraine, nervousness, pain, paresthesia, polyuria, pyrexia, thirst, tremor, 
xerostomia (dose related), and vomiting. 
15.1.8 Study agent procurement 
Armodafinil 150mg and 250mg tablets will be purchased for use in this trial.  The placebo 
tablets will be purchased from PharmOps Inc.  Armodafinil and placebo will be bottled, 
labeled, and distributed by the Alliance research base pharmacy.  The armodafinil/placebo 
will be provided in bottles containing 56 tablets.   
Each participating Alliance main membership or each participating affiliate site will order 
one patient-specific bottle of blinded armodafinil/placebo from the research base pharmacy 
each time a patient is registered in the trial.  Fax the completed Alliance Clinical Drug 
Order/Return Form to: 
 
 
See protocol Appendix XI for specific instructions. 
Outdated or remaining drug/product should be destroyed on-site per procedures in place at 
each institution.   
15.1.9 Nursing Guidelines    
• 
Patients must take drug in the morning, with or without breakfast. 
• 
Headaches are possibility.  Instruct patients to contact study staff if they develop new 
onset of headaches. 
• 
Instruct patient to monitor for hypersensitivity reactions such as rash and itching.  
Patients should immediately report any signs of fever, spreading rash, or joint aches. 
15.2 
Placebo 
Placebo tablets will be purchased from PharmOps, Inc., Phillipsburg, NJ.  The tablets will similar 
in appearance to the armodafinil tablets.  The tablets will contain anhydrous lactose (bulking 
agent), microcrystalline cellulose (bulking agent/binder), crospovidone (disintegrant), and 
magnesium stearate (lubricant). 

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16.0  STATISTICAL CONSIDERATIONS AND METHODOLOGY  
16.1 
Study Design 
This is a three-arm randomized clinical trial.  The primary goal of this study is to compare the 
response rate of patients randomized to one of two doses of armodafinil or placebo in terms of a 
clinically meaningful improvement in patient-reported fatigue of at least a two-point 
improvement in the 0-10 point Brief Fatigue Inventory usual fatigue item at eight weeks post-
treatment initiation.  Endpoints will be assessed per arm and compared across arms by comparing 
each armodafinil arm versus the placebo arm in turn. We make no adjustment for multiple 
comparisons as we want to err on the side of moving forward the appropriate dose into phase III 
testing upon the basis of promising information in the proposed trial. 
The three arm randomized trial will accrue a maximum of 330 patients to randomize a 100 
evaluable patients per arm based on a binary endpoint to armodafinil or placebo.   
Bayesian adaptive “shadow” design: Bayes clinical trial designs are becomingly increasingly 
more popular as alternatives to classic Fisherian designs, especially in the phase I context (110). 
They have not, however, been applied to cancer control cooperative group clinical trials. As a 
feasibility exercise, we will use the results of this trial to “shadow” what would have happened 
if the Bayes design would have been used. This will provide us insights into the relative utility 
of the Bayes design within the context of cooperative group cancer control clinical trials. The 
potential advantage of the Bayes approach is that the study likelihood of efficacy is constantly 
monitored allowing for the possibility of early study completion and therefore a smaller number 
of patients put at risk (see MD Anderson Cancer Center Technical Report UTMDABTR-002-06 
(98). There are a number of logistical and statistical issues that were raised in the review of the 
concept (which initially proposed a Bayes design) that we decided it would be more prudent to 
use a classic Fisherian design to run the trial and use a shadow design to obtain preliminary data 
for planning future cancer control clinical trials using a Bayes approach. The details for the Bayes 
design are attached as Appendix X. 
16.2 
Sample Size 
On average, we recruit six patients per month for GBM treatment trials.  For symptom control 
studies with heterogeneous populations, such as N05C7 (Concerta), we were able to average 25 
patients a month. We have found that symptom management trials targeting symptoms with a 
high prevalence have rapid accrual.  Therefore, for this study, a reasonable conservative estimate 
for this more homogeneous population would be 8 patients a month. With 330 patients, accrual 
would be completed in 41 months. 
The randomized design to be utilized is described below.  Based on our previous work, we 
estimate that the response rate for the placebo arm will be 10%.  We design the study with 100 
patients per arm so that the Fisher’s exact test will have 80% power to detect a response rate of 
25% with a two-tailed alternative and a 5% Type I error rate for each treatment comparison to 
the placebo. Again, we are not using a conservative multiple contrasts approach because we want 
to err on the side of accepting a modest armodafinil effect. We plan to accrue an additional 30 
patients to account for patient cancellations, ineligibility, or major treatment violations.  
Therefore, there will be a maximum of 330 patients accrued to this study unless undue adverse 
events are encountered. 
16.3 
Primary Endpoint 
The primary endpoint of this trial is the response rate in terms of a clinically meaningful 
improvement in patient-reported fatigue at 8 weeks.  A response is defined as an improvement 
of 2 points on the 0-10 scale of the usual fatigue on the BFI.  

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All patients meeting the eligibility criteria who have signed a consent form, have begun 
treatment, and have not had a major treatment violation within the 1st cycle of treatment will be 
evaluable for the primary endpoint.  Patients will be analyzed according to the arm in which they 
were randomized. 
Comparison of the primary endpoint between arms will be based on a binomial point estimate 
computed for each arm and a Fisher’s exact test will be the inferential hypothesis test. 
16.4 
Secondary Endpoints  
16.4.1  Other time points:  The same analyses carried out using the 8 week assessment data will 
be used for analysis of data from the other time point assessments. 
16.4.2 Other fatigue measures:  The other fatigue items (“usual”, “usual” and “now”) as well as 
the impact of fatigue items from the BFI, the PRO-CTCAE, and the summated score from 
the PROMIS fatigue measure will be analyzed separately in turn comparing the average of 
these variables for each treatment using Kruskal-Wallis testing for change from baseline 
to four weeks, AUC over the entire treatment period, and repeated measures ANOVA using 
all treatments and all time points. 
16.4.3 Cognitive function:  The same analyses outlined for the other fatigue measures will be 
carried out for each of the cognitive function tests.  
16.4.4 Quality of life: The same analytical approaches will be used to compare the three 
treatments in terms of QOL as was outlined for the other fatigue measures. 
16.4.5 Safety and tolerability of armodafinil:  Comparison of the proportion of patients 
reporting adverse events via the CTCAE items will be compared across treatment arms 
using a Fisher’s exact test. 
16.4.6 Area under the curve (AUC) and summary statistics:  For the continuous measures 
mentioned above, AUC summary statistics will be generated for each patient to represent 
the overall experience reported by patients for each endpoint (e.g. fatigue) by combining 
the data from baseline, weeks 4, and 8 assessment points. The average of these AUC 
variables will be compared between the two treatment arms using two-sample t-tests. 
Further summary statistics will be constructed for the categorical variables to indicate 
whether the patient ever responded over the entire treatment period. These categorical 
variables will be compared between treatment groups via Fisher’s exact tests. 
16.4.7 Repeated measures analysis: The overall experimental layout will be examined via the 
construction of a repeated measures model using data from all assessment time points 
involving the continuous variables described above. Tests for time by treatment interaction 
will be carried out by the profile analysis methods of Srivastava. Covariates such as age, 
gender and other clinical variables may be included to test their impact on the initial 
efficacy tests of the primary and secondary analyses described above. Use of the Optune® 
device will also be included as a descriptive factor.  
16.4.8 Logistic regression analysis: The overall experimental layout will be examined via the 
construction of a logistic regression model using the categorical response variables 
described above. This will allow for the characterization of the demographic and clinical 
variables’ impact on the identification of a patient as a responder per the above definition. 
16.5 
Statistical Design  
The primary endpoint for the trial is the response rate in terms of a clinically meaningful 
improvement in patient-reported fatigue, defined as at least a two-point improvement in fatigue 
as measured by the usual fatigue item from the Brief Fatigue Inventory at 8 weeks.  This change 

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will be from baseline to 8 weeks (after randomization).  The design proposed for this study will 
randomize a maximum of 330 evaluable patients to one of three treatment arms.   
Efficacy stopping rules:  This study will be monitored by Alliance Data and Safety Monitoring 
Board (DSMB) every 6 months for safely and efficacy. If at any time prior to full accrual the p-
value for the Fisher’s exact test that an arm is superior to the other arm given all available data 
falls below 0.001 then consideration will be given to stopping the trial early. 
16.6 
Adverse Event Stopping Rule  
The stopping rule specified below is based on the knowledge available at study development.  
We note that the Adverse Event Stopping Rule may be adjusted in the event of either 1. the study 
re-opening to accrual or 2. at any time during the conduct of the trial and in consideration of 
newly acquired information regarding the adverse event profile of the treatment(s) under 
investigation.  The study team may choose to suspend accrual because of unexpected adverse 
event profiles that have not crossed the specified rule below. 
Accrual will be temporarily suspended to this study if at any time we observe grade 4 or higher 
events considered at least possibly related to study treatment (i.e. an adverse event with attribute 
specified as  “possible”, “probable”, or “definite”) that satisfy the following: 
• 
If 3 or more patients in the first 20 treated patients (or 10% of all patients after 20 are 
accrued) experience a Grade 4 or higher non-hematologic adverse event and the adverse 
event rate is higher on either armodafinil arm than the placebo. 
We note that we will review Grade 4 and 5 adverse events deemed “unrelated” or “unlikely to be 
related”, to verify their attribution and to monitor the emergence of a previously unrecognized 
treatment-related adverse event. 
16.7 
Study Monitoring  
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are 
due January 31, April 30, July 31, and October 31.  Instructions for submitting data using the 
CDUS can be found on the CTEP web site 
 
The principal investigator(s) and the study statistician will review the study at least twice a year 
to identify accrual, adverse event, and any endpoint problems that might be developing.  This 
study will be monitored by the   Alliance Data and Safety Monitoring Board (DSMB), an NCI-
approved functioning body.  Reports containing efficacy, adverse event, and administrative 
information will be provided to the DSMB every six months as per NCI guidelines. 
16.7.1 We will further carry out a single interim analysis when 30 patients per treatment arm are 
evaluable for the primary endpoint. We will use this interim analysis to verify that the 250 
mg. dose arm is worthy of further accrual. If the conditional probability is less than 1% that 
the effect size is at least of moderate size given, the results (effect size) at that point, the 
250 mg. dose arm will be considered for closing.  
16.8 
Missing Data 
Routines developed by Mayo Clinic Cancer Center statisticians will be used to handle missing 
data in a number of ways including complete case analysis and imputation via nearest neighbor, 
mean value, last value, and zero value carried forward approaches.  Multiple approaches are used 
so that the sensitivity of results to alteration in imputational assumptions may be assessed. The 
extent of missing data on the primary and secondary endpoints will be explored for non-random 
influences. Sensitivity analysis will be performed using various imputation techniques, to ensure 

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results are not unduly influenced by the presence of missing data. Other endpoints will be handled 
in a similar fashion (99). 
16.9 
Inclusion of Women and Minorities 
This study will be available to all eligible patients regardless of race, gender, or ethnic group. 
There is no information currently available regarding differential agent effects of this regimen in 
subsets defined by race, gender, or ethnicity, and there is no reason to expect such differences to 
exist.  Therefore, although the planned analyses will, as always, look for differences in treatment 
effect based on racial and gender groupings, the sample size is not increased in order to provide 
additional power for such subset analyses.  A total of 120 patients may be enrolled. 
Based on prior studies involving similar disease sites, we expect about 6.7% of patients will be 
classified as minorities by race and about 50% of patients to be women.  Expected sizes of racial 
by gender subsets are shown in the following table: 
 
 

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Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or Latino 
Hispanic or Latino 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska Native 
1 
1 
0 
0 
2 
Asian 
4 
3 
0 
0 
7 
Native Hawaiian or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African American 
20 
18 
0 
 
38 
White  
157 
114 
8 
4 
283 
More Than One Race 
0 
0 
0 
0 
0 
Total 
182 
136 
8 
4 
330 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 

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17.0  PATHOLOGY CONSIDERATIONS/TISSUE BIOSPECIMENS 
None  
18.0 RECORDS AND DATA COLLECTION PROCEDURES  
Copies of forms and a data submission schedule are also available for download from the study page 
on the CTSU Web site. 
18.1 
Data collection and submission 
Patient assessment questionnaires and neurocognitive testing booklets for A221101 are to be 
ordered prior to the registration of any patients. Samples of questionnaires/booklets are available 
in the protocol appendices for reference and IRB submission only. They are not to be used for 
patient completion. Patient assessment questionnaire/booklets must be given to patients to 
complete and patients should be instructed to return the booklets to site staff either in person or 
by mail.  
See Section 4.0 for completion and submission of Neurocognitive Testing Booklets for all study 
sites.  
The accompanying tables in Sections 18.2 detail the forms completion and submission time 
points.  
18.1.1. Legacy NCCTG 
All legacy NCCTG sites will submit electronic CRFs and enter QOL/Patient Assessment 
Booklet data via the NCCTG Remote Data Entry System.  
18.1.2 Sites Not Previously Affiliated with NCCTG 
For sites that were not previously affiliated with NCCTG, all paper CRFs and QOL/Patient 
Assessment Booklets will be forwarded to the following address: 
 
 
  

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18.2 
Submission Timetable  
Data Submission Schedule 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At baseline 
evaluation 
(<2 weeks after 
registration ) 
At end of 
week 4 
At end of 
week 8 
On-Study Form 
X 
 
 
Nurse/CRA Evaluation/Treatment Form 
 
X 
X 
Baseline Adverse Event Form 
X 
 
 
Adverse Event Form 
 
X 
X 
Concomitant Steroid Medication Form 
X 
X 
X 
Patient Questionnaire Baseline Booklet 
X 
 
 
Patient Questionnaire Booklet (Cycle 1) 
 
X1 
 
Patient Questionnaire Booklet (Cycle 2) 
 
 
X1 
Patient Questionnaire Booklet Compliance Form 
 
X2 
X2 
Neurocognitive Booklet 
X 
X1 
X1 
Neurocognitive Testing Booklet Compliance 
Form 
 
X 
X 
End of Active Treatment/Cancel Notification 
Form 
 
 
X 
Notification Form – Grade 4 or 5 Non-AER 
Reportable Events/Hospitalization Form 
At each occurrence (see Section 10.0) 
1. Patient Questionnaire/Neurocognitive Testing Booklets must be used; copies are not acceptable 
for this submission. 
2. This form must be completed only if the patient Questionnaire Booklet contains absolutely NO 
patient provided assessment information. 
19.0 BUDGET  
• 
Costs charged to patient:  Routine clinical care 
• 
Tests to be research funded:  None  
• 
Other budget concerns:   Study agent/placebo will be provided to the patient free of charge.  

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20.0 REFERENCES 
1. 
Osoba D, Brada M, Prados MD, Yung WK. Effect of disease burden on health-related quality 
of life in patients with malignant gliomas. Neuro-oncology. 2000 Oct; 2(4):221-8. 
2. 
Osoba D, Aaronson NK, Muller M, et al. Effect of neurological dysfunction on health-related 
quality of life in patients with high-grade glioma. Journal of neuro-oncology. 1997 Sep; 
34(3):263-78. 
3. 
Winningham ML. Strategies for managing cancer-related fatigue syndrome: a rehabilitation 
approach. Cancer 2001; 92:988-97. 
4. 
Cella D, Davis K, Breitbart W, Curt G, Fatigue Coalition. Cancer-related fatigue: prevalence 
of proposed diagnostic criteria in a United States sample of cancer survivors. J Clin Oncol 
2001; 19:3385-91. 
5. 
National 
Comprehensive 
Cancer 
Network. 
Cancer-related 
fatigue. 
www.nccn.org/professionals/physician_gls/PDF/fatigue.pdf (accessed 2009 Jan 20). 
6. 
Morrow GR, Shelke AR, Roscoe JA, Hickok JT, Mustian K. Management of cancer-related 
fatigue. Cancer Invest 2005; 23:229-39. 
7. 
Mustian KM, Palesh O, Heckler CE, et al. Cancer-Related fatigue interferes with activities of 
daily living among 753 patients receiving chemotherapy: A URCC CCOP study.  J Clin Oncol 
2008;26:(May 20 suppl; abstr 9500): 
8. 
Osoba D, Aaronson NK, Muller M, et al. The development and psychometric validation of a 
brain cancer quality-of-life questionnaire for use in combination with general cancer-specific 
questionnaires. Qual Life Res. 1996 Feb;5(1):139-50. 
9. 
Heimans JJ, Taphoorn MJ. Impact of brain tumour treatment on quality of life. Journal of 
neurology. 2002 Aug; 249(8):955-60. 
10. Lovely MP, Miaskowski C, Dodd M. Relationship between fatigue and quality of life in 
patients with glioblastoma multiformae. Oncol Nurs Forum. 1999 Jun;26(5):921-5. 
11. Drappatz J, Schiff D, Kesari S, Norden AD, Wen PY. Medical management of brain tumor 
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APPENDIX I: 
 MODEL INFORMED CONSENT 
 
A221101 
 
A Phase III Randomized, Double-Blind Placebo Controlled Study of 
Armodafinil (Nuvigil®) To Reduce Cancer-Related Fatigue in Patients with 
High Grade Glioma 
 
This is an important form.  Please read it carefully.  It tells you what you need to know about this 
research study.  If you agree to take part in this study, you need to sign this form.  Your signature 
means that you have been told about the study and what the risks are.  Your signature on this 
form also means that you want to take part in this study. 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial 
to you.   Clinical trials include only people who choose to take part. Please take your time to 
make your decision about taking part.  You may discuss your decision with your friends and 
family.  You can also discuss it with your health care team.  If you have any questions, you can 
ask your study doctor for more explanation.  
You are being asked to take part in this study because you are experiencing fatigue that is related 
to your cancer. Cancer related fatigue is a very common symptom in people with cancer.   
 
Why is this study being done? 
The purpose of this study is to:   
• 
See if taking the study agent, armodafinil, at a dose of 150mg or 250mg, will improve 
problems with fatigue in patients who have been diagnosed with cancer and are experiencing 
fatigue.  
• 
See the effects (good and bad) of taking Armodafinil compared to placebo (an inactive agent) 
on cancer related fatigue.  
In this study, you will take either the study agent, armodafinil, or the placebo (inactive agent).  
You will not take both.   
Armodafinil (Nuvigil®) is a medicine that is currently FDA approved to promote wakefulness in 
people who have sleep disorders.  However, it is not been studied in people with cancer related 
fatigue.   
 
How many people will take part in the study? 
About 330 people will take part in this study.   
 
 

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What will happen if I take part in this research study?   
Before you begin the study… 
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  If you have had some of them recently, they may not need to be 
repeated.  This will be up to your study doctor. 
• 
Medical history (questions about your health and any medications you are taking), including 
weight and rating of how well you perform activities of daily living.  
• 
General neurological examination 
• 
Pregnancy test, if you have not already had one done and your doctor thinks this is needed  
(if you are a female and able to become pregnant) 
 
During the study…  
You will have already had radiation therapy or surgery for your cancer.   
Before you start taking the study agent, armodafinil or placebo, you will complete a booklet of 
questionnaires.  This booklet contains 6 brief questionnaires about the fatigue related symptoms 
you may be experiencing, and should take a total of 20-25 minutes to complete.   
You will also be asked to complete a cognitive test (memory and concentration skills test).  This 
will be done three times; once before you start taking the study agent, once at 4 weeks and once 
again at the end of the 8 week period, when you are finished taking the study agent.  This is to 
see how the study agent is affecting your memory and concentration. For the test, you will be 
asked some questions about your memory and concentration by someone with specialized 
training in this area.  This testing will be done at your doctor’s office, and will take about 20-30 
minutes to complete.   
You will be "randomized" into one of the study groups described below. Randomization means 
that you are put into a group by chance. A computer program will place you in one of the study 
groups.  Neither you nor your doctor can choose the group you will be in.  You will have a one 
in three chance of being placed in any group. 
If you are in group 1, you will take a dose of the armodafinil (150 mg) by mouth, every 
day in the morning.  You will take this every day for 8 weeks.   
If you are in group 2, you will take a dose of the placebo pill (inactive ingredient) by 
mouth, every day in the morning.  You will take this every day for 8 weeks.   
If you are in group 3, you will take a dose of the armodafinil (250 mg) by mouth, every 
day in the morning.  You will take this every day for 8 weeks.   
 
If you miss taking a tablet in the morning, you can take the tablet that day as long as you take it 
at least 12 hours before the next dose. 
You will also complete a booklet of questionnaires at the end of weeks 4 and 8.   This booklet 
contains the same 6 brief questionnaires about the fatigue, memory, and concentration that you 
completed before you started taking the study agent/placebo.  This should take a total of 20-25 
minutes to complete (as described above).   

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Someone from the study team will call you at the end of week 4 and week 8 and to see how you 
are doing and answer questions.   
 
When I am finished taking the study agent/placebo… 
You will complete the booklet of questionnaires (end of week 8) regarding your fatigue related 
symptoms, and undergo cognitive (memory and concentration skills) testing (as described 
above).  
 
How long will I be in the study? 
You will be asked to take the study agent or placebo for 8 weeks.    
 
Can I stop being in the study? 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about 
stopping or decide to stop.  He or she will tell you how to stop safely.  
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
study agent, armodafinil, can be evaluated by your doctor.  Another reason to tell your doctor 
that you are thinking about stopping is to discuss what follow-up care and testing could be most 
helpful for you. 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped. 
 
What side effects or risks can I expect from being in the study?  
You may have side effects while on the study.  Everyone taking part in the study will be watched 
carefully for any side effects.  However, doctors don’t know all the side effects that may happen.  
Side effects may be mild or very serious. Your health care team may give you medicines to help 
lessen side effects. Many side effects go away soon after you stop taking the study agent.  In 
some cases, side effects can be serious, long lasting, or may never go away.  
You should talk to your study doctor about any side effects that you have while taking part in the 
study.  

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Risks and side effects related to the study agent, armodafinil, include those which are: 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving armodafinil, from 4 to 20 may have: 
• Headache  
• Trouble sleeping 
• Nausea 
• Dizziness 
• Anxiety 
• Diarrhea 
 
RARE 
In 100 people receiving armodafinil, 3 or fewer may have: 
• 
Upper abdominal pain 
• 
Fatigue 
• 
Rash 
• 
Agitation, attention disturbance, or nervousness 
• 
Decreased appetite, anorexia 
• 
Constipation 
• 
Shortness of breath 
• 
Excessive sweating 
• 
Flu-like symptoms 
• 
Pain 
• 
Numbness and tingling 
• 
Frequent urination 
• 
Fever 
• 
Thirst 
• 
Tremor or shakiness 
• 
Dry mouth 
• 
Vomiting 
• 
High blood pressure 
 
RARE, AND SERIOUS 
In 100 people receiving armodafinil, 3 or fewer may have: 
• 
Severe headaches 
• 
Severe allergic reaction 
• 
Increased heart rate 
• 
Irregular heart beat 
• 
Depression 
• 
Increased risk of suicidal thoughts 
• 
Stevens-Johnson Syndrome (see below) 
 

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Stevens-Johnson syndrome is a rare, serious disorder in which your skin and mucous 
membranes react severely to a medication or infection. Often, Stevens-Johnson syndrome 
begins with flu-like symptoms, followed by a painful red or purplish rash that spreads and 
blisters, eventually causing the top layer of your skin to die and shed.  Stevens-Johnson 
syndrome is an emergency medical condition that usually requires hospitalization.  
Recovery after Stevens-Johnson syndrome can take weeks to months, depending on the 
severity of your condition. If you develop Stevens-Johnson syndrome and your doctor 
determines that it might have been caused by the study medication, you'll need to 
discontinue it.   
Armodafinil has not been shown to produce impaired judgment, thinking or affect motor skills, 
but due to the action of the medication, you should use caution when operating automobile or 
other hazardous machinery. 
Reproductive risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  Women should not breastfeed a baby 
while on this study.  It is important you understand that you need to use birth control while on 
this study.  Check with your study doctor about what kind of birth control methods to use and 
how long to use them.  Some methods might not be approved for use in this study.  
For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the study? 
Taking part in this study may or may not make your health better.  While doctors hope 
armodafinil will be helpful against cancer related fatigue, there is no proof of this yet. We do 
know that the information from this study will help doctors learn more about treatment for 
cancer related fatigue.  This information could help future cancer patients. 
 
What other choices do I have if I do not take part in this study? 
Your other choices may include: 
• 
Getting treatment or care for your cancer related fatigue without being in a study 
• 
Taking part in another study 
• 
Getting no treatment 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Will my medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
• 
Alliance Researchers 

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• 
The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people 
• 
The Cancer Trials Support Unit (CTSU), a service sponsored by the NCI to provide 
greater access to cancer trials 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results.  You can search this Web site at any time. 
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed by the local 
institution.  The regulations may or may not be included in the informed consent form depending on local 
institutional policy.] 
 
What are the costs of taking part in this study? 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment.  
You will not need to pay for tests and procedures which are done just for this research study.  
This test is: 
• 
Cognitive test 
The study agents, armodafinil and placebo, will be supplied at no cost to you. 
Even though it probably won’t happen, it is possible that the manufacturer may not continue to 
provide the armodafinil for some reason.  If this would occur, other possible options are: 
• 
You might be able to get the armodafinil from the manufacturer or your pharmacy but 
you or your insurance company may have to pay for it. 
• 
If there is no armodafinil available at all, no one will be able to get more and the study 
would close. 
• 
If a problem with getting armodafinil occurs, your study doctor will talk to you about 
these options.  
You will not be paid for taking part in this study. 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor 
in person or call him/her at __________________ [telephone number]. 

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You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.  The study will not pay for medical 
treatment.   
 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.   No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution.    
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.   
 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 
For 
questions 
about 
your 
rights 
while 
taking 
part 
in 
this 
study, 
call 
the 
________________________ [name of center] Institutional Review Board (a group of people who 
review the research to protect your rights) at __________________ (telephone number).  [Note to 
Local Investigator: Contact information for patient representatives or other individuals in a local 
institution who are not on the IRB or research team but take calls regarding clinical trial questions 
can be listed here.]   
 
Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or general 
information about cancer. You may also call the NCI Cancer Information Service to get the same 
information at: 1-800-4-CANCER (1-800-422-6237). 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
 

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Signature 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I have 
read it or it has been read to me.  I understand the information and have had my questions answered.  
I agree to take part in this study. 
 
Participant ________________________________ 
 
Date _____________________________________ 

Alliance A221101 
NCI Version Date: 9/24/2018 
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APPENDIX II:  PATIENT INFORMATION SHEETS 
 
Baseline Patient Information Sheet 
 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your quality of life and health status as a patient receiving treatment.  Your answers will help 
us to better understand how the treatment you are receiving is affecting the way you feel. 
 
 
 
1. The booklet contains six sets of questions: 
 
 
a. Brief Fatigue Inventory 
b. PROMIS Fatigue Short Form 
c. PRO-CTCAE 
d. Linear Analogue Self-Assessment Scale 
e. FACT-Cog 
f. Godin Leisure – Time Exercise Questionnaire 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3. Please return the booklet when you are finished 
 
 
Thank you for taking the time to help us. 
 
 

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Patient Information Sheet 
(First 4 weeks) 
 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your quality of life and health status as a patient receiving treatment.  Your answers will help 
us to better understand how the treatment you are receiving is affecting the way you feel. 
 
 
1. The booklet contains six sets of questions to be completed at the end of week 4: 
 
 
a. Brief Fatigue Inventory 
b. PROMIS Fatigue Short Form 
c. PRO-CTCAE 
d. Linear Analogue Self-Assessment Scale 
e. FACT-Cog 
f. Godin Leisure – Time Exercise Questionnaire 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3. A study nurse will call you on week 4 to answer any questions you might have.  You will be 
given the nurse’s name and telephone number.  You can call anytime with any concerns or 
questions. 
 
 
4. It is very important that you return the booklet to us, whether you finish the study or not. 
 
5. At the end of week 4, please return the booklet when you are finished 
 
Thank you for taking the time to help us. 
 
 

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Patient Information Sheet 
(End of Week 8) 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your quality of life and health status as a patient receiving treatment.  Your answers will help 
us to better understand how the treatment you are receiving is affecting the way you feel. 
 
 
 
1. The booklet contains six sets of questions to be completed at the end of week 8: 
 
 
a. Brief Fatigue Inventory 
b. PROMIS Fatigue Short Form 
c. PRO-CTCAE 
d. Linear Analogue Self-Assessment Scale 
e. FACT-Cog 
f. Godin Leisure – Time Exercise Questionnaire 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3. A study nurse will call you week 8 to answer any questions you might have.  You will be 
given the nurse’s name and telephone number.  You can call anytime with any concerns 
or questions. 
 
4. It is very important that you return the booklet to us, whether you finish the study or not. 
 
 
5. At the end of week 8, Please return the booklet when you are finished 
 
 
 
Thank you for taking the time to help us. 
 

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APPENDIX III:  BRIEF FATIGUE INVENTORY 
 

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APPENDIX IV:  PROMIS FATIGUE SHORT FORM 

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APPENDIX V: 
 LINEAR ANALOGUE SELF ASSESSMENT (LASA) 
 
LINEAR ANALOGUE SELF ASSESSMENT 
  
Directions: Please circle the number (0-10) best reflecting your response to the following that 
describes your feelings during the past week, including today. 
 
How would you describe: 
 
1. your overall Quality of Life? 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
It can be 
 
 
 
 
 
 
As good as 
It can be 
2. your overall mental (intellectual) well being? 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
It can be 
 
 
 
 
 
 
As good as 
It can be 
3. your overall physical well being?  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
It can be 
 
 
 
 
 
 
As good as 
It can be 
4. your overall emotional well being? 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
It can be 
 
 
 
 
 
 
As good as 
It can be 
5. your level of social activity? 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
It can be 
 
 
 
 
 
 
As good as 
It can be 
6. your overall spiritual well being? 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
It can be 
 
 
 
 
 
 
As good as 
It can be 
 
7. the frequency of your pain? 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
Constant Pain 
 
8. the severity of your pain, on the average? 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
Pain as bad as 
you can imagine 
9. your level of fatigue, on the average? 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No fatigue 
 
 
 
 
 
 
Constant tiredness 
 
 
 
 
 
 
 
 
10. your level of support from friends and family? 

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1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No support 
 
 
 
 
 
 
Highest level of 
support 
 
 
11. your financial concerns? 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Constant concerns 
 
 
 
 
 
 
No concern 
 
12. your legal concerns (will, advanced directives, etc.)? 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Constant concern 
 
 
 
 
 
 
No concern 
 
 
 
 

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APPENDIX VI:  FACT-COG  
FACT-Cog (Version 3) 
 
Below is a list of statements that other people with your condition have said are important. By circling one (1) 
number per line, please indicate how often each of the following has occurred during the past 7 days. 
 
 
 
 
 
 
 
 
 
Never 
About 
once a 
week 
Two to 
three 
times a 
week 
Nearly 
every 
day 
Several 
times  
a day 
CogA1 
I have had trouble forming thoughts
 ............................................................................. 
0 
 
0 
1 
2 
3 
4 
CogA3 
My thinking has been slow
 ............................................................................. 
0 
0 
1 
2 
3 
4 
CogC7 
I have had trouble concentrating
 ............................................................................. 
0 
0 
1 
2 
3 
4 
CogM9 
I have had trouble finding my way to a familiar 
place
 ............................................................................. 
0 
1 
2 
3 
4 
CogM10 
I have had trouble remembering where I put 
things, like my keys or my wallet
 ............................................................................. 
0 
0 
1 
2 
3 
4 
CogM12 
I have had trouble remembering new 
information, like phone numbers or simple 
instructions 
0 
1 
2 
3 
4 
CogV13 
I have had trouble recalling the name of an 
object while talking to someone 
 ............................................................................. 
0 
1 
2 
3 
4 
CogV15 
I have had trouble finding the right word(s) to 
express myself
0 
1 
2 
3 
4 
CogV16 
I have used the wrong word when I referred to 
an object
 ............................................................................. 
0 
0 
1 
2 
3 
4 
CogV17
b 
I have had trouble saying what I mean in 
conversations with others
 ............................................................................. 
0 
0 
1 
2 
3 
4 

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CogF19 
I have walked into a room and forgotten what I 
meant to get or do there
 ............................................................................. 
0 
0 
1 
2 
3 
4 
CogF23 
I have had to work really hard to pay attention 
or I would make a mistake
 ............................................................................. 
0 
0 
1 
2 
3 
4 
CogF24 
I have forgotten names of people soon after 
being introduced
 ............................................................................. 
0 
0 
1 
2 
3 
4 
 
Page 1 or 3 
Below is a list of statements that other people with your condition have said are important. By circling one (1) 
number per line, please indicate how often each of the following has occurred during the past 7 days. 
 
 
 
Never 
About 
once a 
week 
Two to 
three 
times a 
week 
Nearly 
every 
day 
 
Several 
times a 
day 
CogF25 
My reactions in everyday situations have been 
slow
 ............................................................................. 
0 
 
0 
1 
2 
3 
4 
CogC31 
I have had to work harder than usual to keep 
track of what I was doing
 ............................................................................. 
0 
1 
2 
3 
4 
CogC32 
My thinking has been slower than usual
 ............................................................................. 
0
0 
1 
2 
3 
4 
CogC33
a 
I have had to work harder than usual to express 
myself clearly
 ............................................................................. 
0 
1 
2 
3 
4 
CogC33
c 
I have had to use written lists more often than 
usual so I would not forget things
 ............................................................................. 
0
0 
1 
2 
3 
4 
CogMT
1 
I have trouble keeping track of what I am doing 
if I am interrupted
 ............................................................................. 
0
0 
1 
2 
3 
4 
CogMT
2 
I have difficulty shifting back and forth between 
different activities that require thinking
 ............................................................................. 
0
0 
1 
2 
3 
4 
 

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Please answer the questions below with regard to all the above concerns that you have 
identified.  By circling one (1) number per line, please indicate how true each statement has been 
for you  during the past 7 days. 
 
 
 
Not  
at all 
A little 
bit 
Some-
what 
Quite a 
bit 
Very 
much 
CogQ35 
I have been upset about these problems
 ........................................................................ 
0 
 
0 
1 
2 
3 
4 
CogQ37 
These problems have interfered with my 
ability to work
 ........................................................................ 
0 
 
0 
1 
2 
3 
4 
CogQ38 
These problems have interfered with my 
ability to do things I enjoy
 ........................................................................ 
0 
 
0 
1 
2 
3 
4 
CogQ41 
These problems have interfered with the 
quality of my life
0 
1 
2 
3 
4 
 
 
 

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Page 2 or 3 
Below is a list of statements that other people with your illness have said are important. By circling one (1) 
number per line, please indicate how true each statement has been for you during the past 7 days. 
 
 
 
 
 
APPENDIX VII:  COGNITIVE TESTING 
 
Neurocognitive Testing 
 
Symbol Digit Modalities Test - copyright©   
 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
Cog
PC1 
I have been able to concentrate
............................................................................ 
0 
1 
2 
3 
4 
Cog
PV1 
I have been able to bring to mind words that I 
wanted to use while talking to someone
............................................................................ 
0 
1 
2 
3 
4 
Cog
PM1 
I have been able to remember things, like 
where I left my keys or wallet
............................................................................ 
 
0 
 
1 
 
2 
 
3 
 
4 
Cog
PM2 
I have been able to remember to do things, like 
take medicine or buy something I needed
............................................................................ 
0 
1 
2 
3 
4 
Cog
PF1 
I am able to pay attention and keep track of 
what I am doing without extra effort
............................................................................ 
0 
1 
2 
3 
4 
Cog
PCH
1 
My mind is as sharp as it has always been
............................................................................ 
0 
1 
2 
3 
4 
Cog
PCH
2
My memory is as good as it has always been
0 
1 
2 
3 
4 
Cog
PMT
1 
I am able to shift back and forth between two 
activities that require thinking
 
 
 
 
 
Cog
PMT
2 
I am able to keep track of what I am doing, 
even if I am interrupted
0 
1 
2 
3 
4 

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Allia nce A 2 2 1 1 0 1 
N CI Versi o n D ate: 9/ 2 4 / 2 0 1 8 
U p date  # 7  
7 8  
A P P E N DI X VIII:  
 A D MI NI S T R A TI O N P R O C E D U R E S F O R T H E N E U R O C O G NI TI V E T E S T B A T T E R Y  
 
A D MI NI S T R A TI O N P R O C E D U R E S F O R T H E N E U R O C O G NI TI V E T E S T B A T T E R Y  
 
Ple ase n ote:  All pers o n nel w h o a d mi nister t he c o g niti ve testi n g will nee d t o be certifie d.    
Ple ase see secti o n 4. 1    
 
1.  
Testi n g s h o ul d be c o m plete d i n o ne sessi o n. Test i nstr ucti o ns m ust be f oll o we d ver b ati m 
wit h e ver y p atie nt at e ver y st u d y visit. All tests s h o ul d be c o m plete d i n bl ac k pe n.  
 
P L E A S E N O T E:  If a p atie nt is u n a ble t o c o m plete t he test d ue t o c o g niti ve deteri or ati o n, it 
is best t o atte m pt t he test a n d pr ocee d u ntil t he p atie nt meets disc o nti n u ati o n criteri a.  T he n 
m ar k d o w n at t he b ott o m of e ac h test f or m “ Disc o nti n ue d ” a n d fill i n t he re as o n (e. g. c o ul d 
n ot u n derst a n d t he i nstr ucti o ns).  T his is m uc h preferre d t o n ot c o m pleti n g t he test at all 
a n d s h o ul d n ot be f r ustr ati n g t o t he p atie nt as it will o nl y t a ke a fe w mi n utes of t he p atie nt’s 
ti me.    
 
2.  
Ori gi n als of t he test b o o klets s h o ul d be m aile d t o  
 
 
 
 
 
 
 
 
 
3. 
Ple ase kee p c o pies of all ori gi n al test b o o klets. I n t he e ve nt of q uesti o ns, c o nt act t he R P S III 
or Q A S of t he st u d y (c o nt act i nf or m ati o n c a n be f o u n d i n t he pr ot oc ol o n t he Res o urce 
p a ge.  
 
4.  
P atie nts s h o ul d n ot be gi ve n c o pies of t heir tests t o a v oi d le ar ni n g t he m ateri al bet wee n test 
a d mi nistr ati o ns.  
  
 
Setti n g u p f or Ne ur o ps yc h ol o gic al Testi n g  
 
Set u p of testi n g sit u ati o n:  
 
 P ri v ate r o o m 
 D o or t h at cl oses 
 Q uiet  
 Al o ne wit h j ust t he p atie nt -- N o f a mil y me m bers  
 M a y w a nt t o h a n g a si g n t h at s a ys “ d o n ot dist ur b ”  
 S o me tests are ti me d – it is ver y i m p ort a nt n ot t o be i nterr u pte d  
 Des k f or y o u b ot h t o write o n (cli p b o ar d w or ks i n a pi nc h)  
 St o p w atc h  
 B l ac k i n k pe ns ( o ne f or y o u a n d o ne f or t he p atie nt) 
 
 
 
Pa ge 1 of 7 
 

Allia nce A 2 2 1 1 0 1 
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U p date  # 7  
7 9  
Testi n g ti ps  
 
 D o n ot i n dic ate t o t he p atie nt h o w well t he y are d oi n g  
 Hi de y o ur writi n g fr o m t he p atie nt s o t he y c a n n ot get fee d b ac k o n h o w t he y are perf or mi n g  
 H o we ver, it is O K t o be ge neric all y e nc o ur a gi n g ( m a ke s ure y o u m a ke t he s a me res p o nse 
w het her p atie nt is perf or mi n g well or n ot)  
 Ple ase d o n ot assist t he m i n a n y w a y if t he y str u g gle wit h a t as k; we nee d a n acc ur ate vie w 
of w h at t he y c a n d o t he msel ves.  
 
 
T E S T I N S T R U C TI O N S  
A d mi nister  t he tests i n t he f oll o wi n g or der t o e ver y p atie nt at e ver y visit 
 
1.  
S y m b ol Di git M o d alities Test  ( S mit h, 1 9 8 2) 
 
T he S D M T re q uires t he s u bject t o i nsert a n u m bers m atc hi n g t o ge o metric fi g ures 
prese nte d i n r a n d o m or der.  T he a p pr o pri ate n u m ber is s h o w n i n a ke y c o nt ai ni n g t he 
Ar a bic n u mer als 1 t hr o u g h 9, e ac h of w hic h is p aire d wit h a differe nt ge o metric s y m b ol.  
T o a d mi nister t he test, pl ace t he f or m i n fr o nt of t he e x a mi nee.  Re a d t he i nstr ucti o ns 
ver b ati m.  T hese are t a ke n directl y fr o m t he test m a n u al ( S mit h, 1 9 8 2) a n d re a d as 
f oll o ws:  
 
“ Ple ase l o ok at t hese b oxes at t he t o p of t he p a ge.  Y o u c a n see t h at e ac h b ox i n t he u p per 
r o w h as a little m ark i n it.  N o w l o ok at t he b oxes i n t he r o w j ust u n der ne at h t he m arks.  E ac h 
of t he b oxes u n der t he m arks h as a n u m ber.  E ac h of t he m arks i n t he t o p r o w is differe nt, a n d 
u n der e ac h m ark i n t he b ott o m r o w is a differe nt n u m ber.   
 
N o w l o ok at t he next li ne of b oxes (ex a mi ner p oi nts t o t he li ne of b oxes) j ust u n der t he t o p t w o 
r o ws.  N otice t h at t he b oxes o n t he t o p h ave m arks, b ut t he b oxes u n der ne at h are e m pty.  Y o u 
are t o fill e ac h e m pty b ox wit h t he n u m ber t h at s h o ul d g o t here acc or di n g t o t he w ay t hey are 
p aire d i n t he key at t he t o p of t he p a ge.  F or ex a m ple, if y o u l o ok at t he first m ark, a n d t he n 
l o ok u p at t he key, y o u will see t h at t he n u m ber 1 g oes i n t he first e m pty b ox.  S o write t he 
n u m ber 1 i n t he first b ox.  N o w, w h at n u m ber s h o ul d y o u p ut i n t he sec o n d b ox ? ( N u m ber 5) 
T h at’s ri g ht.  S o write t he n u m ber 5 i n t he sec o n d b ox.  W h at n u m ber g oes i n t he t hir d b ox ?  
( N u m ber 2)  T w o, ri g ht.  T h at is t he i de a.  Y o u are t o fill i n e ac h of t he e m pty b oxes wit h t he 
n u m bers t h at s h o ul d g o i n t he m acc or di n g t o t he key.  N o w f or pr actice, fill i n t he rest of t he 
b oxes u ntil y o u c o me t o t he d o u ble li ne.  W he n y o u c o me t o t he d o u ble li ne, st o p. ” 
 
T he e x a mi ner s h o ul d c hec k t o see t h at e ac h e x a mi nee u n derst a n d t he t as k.  A n y err ors 
m a de i n t he first 1 0 pr actice res p o nses ( bef ore t he d o u ble li ne) s h o ul d be i m me di atel y 
p oi nte d o ut b y t he e x a mi ner a n d c orrecte d b y t he e x a mi nee.  If a n e x a mi nee h as n ot 
u n derst o o d t he n at ure of t he t as k, t he i nstr ucti o ns are re pe ate d wit h f urt her e x a m ples 
u ntil t he n at ure of t he test is cle arl y u n derst o o d.  T he e x a mi nee t he n c o nti n ues wit h t he 
f oll o wi n g i nstr ucti o ns.   
 
Pa ge 2 of 7 
 
 

Alliance A221101 
NCI Version Date: 9/24/2018 
Update #7 
81 
“You will have a minute for each letter. The first letter is ‘___’ (see scoring sheet). 
 
**Allow exactly one minute for each letter** 
 
• If the patient discontinues before the end of the time period, encourage him/her to try to think of 
more words. 
• If he/she is silent for 15 seconds, repeat the basic instruction and the letter (e.g., “Tell me all the 
words you can think of that begin with a “c”). 
• No extension on the time limit is made in the event that instructions are repeated. 
• Continue the evaluation with the remaining two letters, allowing one minute for each. 
 
Recording and Scoring: 
•  
The COWA provides lines on which the patient’s responses can be entered (e.g.,write in 
the word that is said by the patient). If his/her speed of word production is too fast to 
permit verbatim recording, a “+” should be entered to indicate a correct response. 
•  
Incorrect responses either should not be recorded or, if recorded, should be struck through 
with a line. 
•  
If the patient provides more responses than there are lines on the record sheet, place check 
marks in the boxes to indicate correct responses only. 
•  
Count all the correct responses. The number of correct words should be indicated below 
each column. 
 
Comments on scoring: 
•  
Note: It can be helpful for the first several patients and for patients known to be fast with 
their word production to tape record the session for transcription at a later time. 
•  
The instructions include a specific prohibition against giving proper names or different 
forms of the same word. Therefore, inflections of the same word (e.g., eat-eating; mouse-
mice; loose-loosely; ran-run-runs) are not considered correct responses. 
•  
Patients often give both a verb and a word derived from the verb or adjective (e.g., fun-
funny; sad-sadness). These are not considered correct responses. On the other hand, if the 
word refers to a specific object (e.g., foot-footstool; hang-hanger), it would be counted as a 
correct answer. 
•  
Many words have two or more meanings (e.g., foot; can; catch; hand). A repetition of the 
word is acceptable IF the patient definitely indicates the alternative meaning to you. 
•  
Slang terms are OK if they are in general use. 
 
 
 
 
 
 
•  
Foreign words (for example, pasta; passé; lasagna) can be counted as correct if they can be 
considered part of the lexicon of the relevant language, the criterion being their listing in a 
standard dictionary of that language. All incorrect and repeated responses MUST be 
crossed out with one single line, initialed and dated. Additionally, all duplicate entries that 
have been verified to have different meanings must be marked “ok”, initialed and dated. 
Refer to the descriptions above for guidelines for acceptability. Add the total number of 
correct responses in each column and input the totals where indicated on the COWA 
worksheet. 
•  
If the test is discontinued or omitted, please mark this on the bottom of the test form. 
 
3.  
TRAIL MAKING TEST [Timed Test] 
 
 
 
Page 4 of 7 
 
Instructions are included verbatim in the test booklet 

Alliance A221101 
NCI Version Date: 9/24/2018 
Update #7 
82 
 
Part A – Sample:  
 
The Sample for Part A must be completed/attempted by each patient at every assessment. 
Place the Sample A worksheet flat on the table, directly in front of the patient (the bottom 
of the worksheet should be approximately six inches from the edge of the table). Give the 
patient a black pen and say: 
 
 
Examiner: “On this page (point) are some numbers. Begin at number 1 (point to 1) and draw a line 
from 1 to 2 (point to 2), 2 to 3 (point to 3), 3 to 4 (point to 4), and so on, in order, until you 
reach the end (point to the circle marked END). Draw the lines as fast as you can. Ready, 
begin.” 
 
 
If the patient completes Sample A correctly and in a manner demonstrating that s/he 
understands what to do, proceed immediately to Test A. If the patient makes a mistake on 
Sample A, point out the error and explain it. 
 
 
The following explanations of mistakes serve as illustrations: 
 
 
• “This is where you start (point to number 1)” 
 
 
• “You skipped this circle (point to the circle omitted)” 
 
 
• “You should go from number 1 to 2, 2 to 3, and so on, until you reach the circle 
 
marked END” 
 
 
If it is clear that the patient intended to touch a circle but missed it, do not count it as an 
omission.  Remind the patient, however, to be sure to touch the circles. If the patient still 
cannot complete Sample A, take his/her hand and guide him/her through the trail using 
the opposite end of the pen, lightly touching the worksheet to avoid making marks on the 
copy. Then say: 
 
Examiner: “Remember, begin at number 1 (point to 1) and draw a line from 1 to 2 (point 
to 2), 2 to 3 (point to 3), 3 to 4 (point to 4) and so on, in order, until you reach the circle 
marked END (point). Do not skip around, but go from one number to the next in proper 
order. Remember to work as fast as you can. Ready, begin.” 
 
 
If the patient does not succeed, or it becomes evident that s/he cannot do the task, 
DISCONTINUE testing and indicate the corresponding reason on the Trail Making A & B 
Scoring (TMABS) sheet. If the patient completes Sample A correctly and appears to 
understand what to do, proceed immediately to Part A. 
 
Part A – Test:  
 
After the patient has completed Sample A, place the Part A test worksheet directly in front 
of the patient and say: 
 
Examiner: “Good! Let’s try the next one. On this page are numbers from 1 to 25. Do this 
the same way. Begin at number 1 (point) and draw a line from 1 to 2 (point to 2), 2 to 3 
(point to 3), 3 to 4 (point to 4) and so on, in order, until you reach the circle marked END 
(point). Do not skip around, but go from one number to the next in proper order. 
 
Remember to work as fast as you can. Ready, begin.” 
 
 
Page 5 of 7 
 
 

Alliance A221101 
NCI Version Date: 9/24/2018 
Update #7 
83 
 
•  
Start timing as soon as the instruction is given to “begin.” 
•  
Watch closely in order to catch any errors as soon as they are made. If the patient makes 
an error, call it to his/her attention immediately and have him/her proceed from the point 
the mistake occurred (In other words, have them go back to the last correct circle). 
•  
The patient must complete the test in 3 minutes or less 
•  
DO NOT STOP TIMING UNTIL HE/SHE REACHES THE CIRCLE MARKED “END.” 
•  
If the patient does not complete the test within 3 minutes terminate the testing. The test can 
also be discontinued if the patient is extremely confused and is unable to perform the task. 
Complete the Trail Making A & B Scoring (TMABS) sheet indicating the reason the test 
was terminated and the last correct number reached on the test. 
•  
If the patient successfully completes the test, record the time to completion on the Trail 
Making A & B Scoring (TMABS) sheet in minutes and seconds. Then say, “That’s fine. 
Now we’ll try another one.” 
 
Part B – Sample:  
 
The Sample for Part B must be completed/attempted by each patient at every assessment. 
Place the Sample B worksheet flat on the table, directly in front of the patient (the bottom 
of the worksheet should be approximately six inches from the edge of the table) and say: 
 
Examiner: “On this page (point) are some numbers and letters. Begin at number 1 (point 
to 1) and draw a line from 1 to A (point), A to 2 (point to 2), 2 to B (point to B), B to 3 
(point to 3), 3 to C (point to C) and so on, in order, until you reach the end (point to the 
circle marked END). Remember, first you have a number (point to 1), then a letter (point 
to A), then a number (point to 2), then a letter (point to B), and so on. Draw the lines as fast 
as you can. Ready, begin.” 
 
 
If the patient completes Sample B correctly, and in a manner demonstrating that s/he 
understands what to do, proceed immediately to Part B. If the patient makes a mistake on 
Sample B, point out the error and explain it. 
 
The following explanations of mistakes serve as illustrations: 
• “You started with the wrong circle. This is where you start (point to number 1)” 
• “You skipped this circle (point to the circle omitted)” 
• “You should go from number 1 (point) to A (point), A to 2 (point to 2), 2 to B (point to B), B to 3 
(point to 3) and so on, until you reach the circle marked END (point)” 
 
 
If it is clear the patient intended to touch a circle but missed it, do not count it as an 
omission.  Remind the patient, however, to be sure to touch the circles. If the patient still 
cannot complete Sample B, take their hand and guide them through the trail using the 
opposite end of the pen, lightly touching the worksheet to avoid making marks on the copy. 
Then say: 
 
Examiner: “Now you try it. Remember, begin at number 1 (point to 1) and draw a line 
from 1 to A (point to A), A to 2 (point to 2), 2 to B (point to B), B to 3 (point to 3) and so on, 
in order, until you reach the circle marked END (point). Ready, begin.” 
 
 
If the patient does not succeed or it becomes evident that s/he cannot do the task, 
DISCONTINUE testing and indicate the corresponding reason on the Trail Making A & B 
Scoring (TMABS) sheet. If the patient completes Sample B correctly and appears to 
understand what to do, proceed immediately to Part B. 
Page 6 of 7 

Alliance A221101 
NCI Version Date: 9/24/2018 
Update #7 
84 
Part B – Test:   
 
After the patient has completed Sample B, place the Part B Worksheet directly in front of 
the patient and say: 
 
Examiner: “ Good! Let’s try the next one. On this page are both numbers and letters. Do 
this the same way. Begin at number 1 (point) and draw a line from 1 to A (point to A), A to 
2 (point to 2), 2 to B (point to B), B to 3 (point to 3), 3 to C (point to C) and so on, in order, 
until you reach the circle marked END (point). Remember, first you have a number (point 
to 1), then a letter (point to A), then a number (point to 2), then a letter (point to B), and so 
on. Do not skip around, but go from one circle to the next in the proper order. Draw the 
lines as fast as you can. Ready, begin.” 
•  
Start timing as soon as the instruction is given to “begin.” 
•  
Watch closely in order to catch any errors as soon as they are made. If the patient makes 
an error, call it to his/her attention immediately and have him/her proceed from the point 
the mistake occurred (In other words, have them go back to the last correct circle). 
•  
The patient must complete the test in 5 minutes or less. 
•  
DO NOT STOP TIMING UNTIL HE/SHE REACHES THE CIRCLE MARKED “END.” 
•  
Record the time to completion on the Trail Making A & B Scoring (TMABS) in minutes 
and seconds. 
•  
If the patient does not complete the test within 5 minutes terminate the testing. The test can 
also be discontinued if the patient is extremely confused and is unable to perform the task. 
Complete the Trail Making A & B Scoring (TMABS) sheet indicating the reason the test 
was terminated and the last correct number or letter reached on the test. 
•  
If the patient successfully completes the test, record the time to completion on the Trail 
Making A & B Scoring (TMABS) sheet in minutes and seconds. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 7 of 7 
 

Alliance A221101 
NCI Version Date: 9/24/2018 
Update #7 
85 
APPENDIX IX:  NEUROCOGNITIVE EVALUATIONS SUBMISSION FAX FORM 
 
Neurocognitive Evaluations Submission Fax Form 
 
Fax completed form to: 
 
 
 
 
 
From: 
__________________________ 
 
Date: 
__________________________ 
 
Re: 
Neurocognitive Evaluations Booklet Submission  
 
Attention:  A completed Neurocognitive Evaluations booklets (completed Patient and Examiner 
Questionnaire Booklets) have been sent to you via surface mail, as of 
__________________________(date). 
 
 
 
   
 
Contact Information: 
 
 
Person administering test: 
 
 
Name of site: 
 
 
Phone: 
 
 
Email: 
 
 
Patient’s study ID #:  
 
 
 

 
NCI Version Date: 9/24/2018 
Update #7 
86 
APPENDIX X: 
 BAYES SHADOW STATISTICAL DESIGN 
Bayes Shadow Statistical Design 
 
The primary endpoint for the trial is the response rate in terms of a clinically meaningful 
improvement in patient-reported fatigue, defined as at least a two-point improvement in fatigue as 
measured by the worst fatigue item from the Brief Fatigue Inventory at 8 weeks, and the design 
proposed for this study will randomize a minimum of 30 evaluable patients and a maximum of 120 
evaluable patients to one of three treatment arms The Bayesian adaptive randomization design  (98) 
will work as follows The first 30 patients will be randomized in a 1:1:1 fashion to the three 
treatment arms (block size of 30 will be used to guarantee an equal number of patients are 
randomized to each treatment arm).  After the 30th patient has been randomized, the adaptive 
randomization procedure will begin. As a shadow design, we will use the data from the completed 
Fisherian design and then assess the different assignations that would have been made via the Bayes 
design and its impact on the trial results. 
 
Adaptive randomization:  We assume that the fatigue response outcome, denoted Xi,j, of patient i 
on treatment j derives from a Binomial(πj) distribution (j=1 for placebo; j=2 for armodafinil 150 
mg).  We assume that πj derives from a Beta (αj, βj) distribution.  Given limited historical data, we 
use a uniform non-informative prior for each arm (α1=α2=1; β1=β2=1). We repeat this calculation 
for the comparison of the placebo versus the armodafinil 250 mg arm and normalize the result to 
get three probabilities for treatment assignation. 
 
As each patient is enrolled, the randomization probability for each treatment arm is recomputed 
using all currently available fatigue response data from already accrued patients.  The 
randomization procedure computes the posterior probability for each treatment of being the best 
between the two treatments (where pj = probability that treatment j is better than the other treatment) 
and assigns the patient to arm j with probability pj (i.e., λ=1 in the notation of Cook [100]).  This 
procedure uses all observed fatigue response data at the time of the patient’s randomization to 
unbalance the randomization probabilities in favor of the treatment arm having comparatively 
superior symptom response outcomes. 
 
Efficacy stopping rules:  If at any time prior to full accrual the probability that an arm is superior 
to the other arm given all available data falls below 0.05 (PL in the notation of the Adaptive 
Randomization software used below), that arm is suspended (though it potentially could reopen 
should the results on the other arm substantially worsen).  If at any time prior to full accrual the 
probability that an arm is superior to the other arm given all available data rises above 0.95 (PU in 
the notation of the Adaptive Randomization software used below), that arm is declared the winner 
and the trial is stopped early. 
 
Decision rule:  If the trial runs through completion without early stopping and if the largest 
probability for the two armodafinil treatment arms is better than that for the placebo arm is greater 
than 0.80 (PU* in the notation of the Adaptive Randomization software used below), then that 
treatment is declared the winner of the trial.  
 
 
 
Page 1 of 2 
 
 

 
NCI Version Date: 9/24/2018 
Update #7 
87 
Operating characteristics:  Operating characteristics of a clinical trial with the above parameters 
and accrual rate were simulated (10,000 replicates) using software developed by the M. D. 
Anderson 
Cancer 
Center 
Department 
of 
Biostatistics 
(available 
at:http://biostatistics.mdanderson.org/SoftwareDownload/): 
 
Arm1 
True 
Confirmed 
Fatigue 
Response 
Rate 
Pr(Selected)2 
Pr(Selected 
Early)3 
Pr(Stopped 
Early)4 
Average 
Number of 
Evaluable 
Patients 
Treated 
Average 
Trial 
Duration 
1 
10% 
0.20 
0.07 
0.07 
34 
27.6 mo 
2 
10% 
0.20 
0.07 
0.07 
34 
1 
10% 
0.09 
0.04 
0.21 
29 
26 mo 
2 
15% 
0.41 
0.19 
0.04 
36 
1 
10% 
0.03 
0.02 
0.39 
24 
23.5 mo 
2 
20% 
0.63 
0.36 
0.02 
35 
1 
10% 
0.02 
0.01 
0.57 
20 
20.4 mo 
2 
25% 
0.80 
0.54 
0.01 
33 
1 
10% 
<0.01 
<0.01 
0.73 
18 
17.4 mo 
2 
30% 
0.90 
0.69 
<0.01 
29 
1. 1=placebo, 2=best of armodafinil arms. 
2. The overall probability that the given arm is selected as being the best treatment after the trial 
has ended. 
3. The probability that the given arm is selected as being the best treatment arm early (prior to all 
patients being enrolled). 
4. The probability that the given arm is dropped for any reason (due to futility or another arm being 
selected).  
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 
 

 
NCI Version Date: 9/24/2018 
Update #7 
88 
APPENDIX XI:  SITE DRUG ORDERING INSTRUCTIONS AND ORDER FORM  
 
Site Ordering Instructions and Order Forms: 
Armodafinil and Placebo 
 
 
  
Background:  The NCCTG/Alliance research base pharmacy will deviate from their standard operational 
policy of supplying study agent to the main NCCTG, CALGB and ACOSOG memberships.  For this trial, 
the research base pharmacy will send one patient specific supply (one bottle) directly to each participating 
main membership or each participating affiliate site upon receipt of an order from the participating site. 
This order must be completed each time a study participant is enrolled. 
 
 
Starter Supplies:   Each treating location, must request one patient-specific bottle each time a patient 
is registered in the trial by completing the Alliance Clinical Order/Return Form located on page 2 of 
this appendix. Note a sample form is included (page 3 of this appendix) 
 
Please be certain to include a complete shipping address for the treatment site.   
 
Please include your patient’s registration number and initials on the form.  Please also include the DEA 
Registration Number of your Pharmacy or investigator on the order form. 
 
The site must also complete the Alliance clinical drug order/return form located on page 2 of this appendix, 
and fax it to the number listed on the form. 
 
Note:  Allow three business days for the delivery of the order.  
The shipment of Armodafinil/placebo will be provided in bottles, with each bottle containing 56 tablets.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 3 
 

 
NCI Version Date: 9/24/2018 
Update #7 
89 
                                                                                                                                                                                                                                  Page 2 of 3 
A221101 CLINICAL DRUG ORDER FORM 
 The drugs listed below are requested for the use of (please type or print): 
  
  
  
Gonda 10 USE 
  
Alliance  
  
 
 
 
 
 
 
 
 
 
 
  
ONLY 
  
  
  
  
  
 Dr. 
  
 
 
 
 
  
  
  
 FAX orders to: 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
  
  
  
Cancer Treatment Pharmacy Svc. 
 Designee/Requester (if other than investigator) (please type or print): 
 
 
 
  
filled by 
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
  
  
Name: 
  
Title: 
  
 
  
checked by 
  
 MAIL orders/returns to: 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
  
Telephone Number: 
  
Fax Number: 
  
 
  
date 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
 
 
 
 
  
  
  
  
Site DEA Registration Number: ______________ 
 
 
 
 
  
  
 Investigator/Designee Signature 
 
  
(Example: FM1234567)    
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
  
Date 
(dd/Mon/yyyy): 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Protocol 
Patient Study 
ID Number  
 
Patient 
Initials 
Drug 
Strength 
Quantity 
Date 
------ 
  
  
  
Bottle # 
Number 
 
 
Name 
& Dosage Form 
Ordered 
Needed 
 
 
  
 
  
  
  
  
  
  
(vials, tablets, etc.) 
(vials, bottles, etc.) 
  
  
  
  
  
  
  
 A221101 
2XXXXXX  
Example 
ABC  
Armodafinil 150mg or 
armodafinil 250mg or 
placebo tablets    
56 tablets per 
bottle  
 One bottle 
XX/XX/XXXX  
  
        
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
 
 
 
 
 
 
  
 INSTRUCTIONS: 
  
  
  
  
  
  
  SHIPPING ADDRESS: 
 
  
 NOTE:  Urgent Shipments must be accompanied by 
 1. One item or protocol per line 
  
 
 an express courier account number. 
 
  
 2. When requesting drugs: Fill in all sections completely,  
  
 
 
 
 
 
 
  
except shaded areas. 
 
  
  
 Express Courier Name: 
 
  
 
  
 
 
 
 
 
 
  
3. Must include official shipping address, site DEA registration 
number, patient initials, and patient study ID. 
 
  
  
 Express Courier Acct No.:   __  __  __  __ - __  __  __  __ - __   
 4. Sign and date the order/return. 
  
  
 
 
 
 
 
 
  
 
  

 
NCI Version Date: 9/24/2018 
Update #7 
90 
 
A221101 CLINICAL DRUG ORDER/RETURN FORM 
 The drugs listed below are requested for the use of (please type or print): 
  
  
  
Gonda 10 USE 
  
Alliance  
  
 
 
 
 
 
 
 
 
 
 
  
ONLY 
  
  
  
  
  
 Dr. 
Investigator Name 
 
 
 
 
  
  
  
 FAX orders to: 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
  
  
  
Cancer Treatment Pharmacy Svc. 
 Designee/Requester (if other than investigator) (please type or print): 
 
 
 
  
filled by 
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
  
  
Name: 
Ordering Designee  
Title: 
 As needed 
 
  
checked by 
  
 MAIL orders/returns to: 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
  
Telephone 
Number: 
Complete number  
Fax 
Number: 
 Complete number 
 
  
date 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
  
  
  
  
  
  
  
COMMENTS: 
  
  
  
  
  
 
 
 
 
  
  
  
  
 Site DEA Registration Number:  
 
 
 
 
  
  
 Investigator/Designee Signature 
 
  
 
 
 
 
  
  
 
 
 
 
 
  
  
 
 
 
 
  
Date 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Protocol 
Patient 
Patient 
Drug 
Strength 
Quantity 
Date 
------ 
  
  
  
 
Number 
Study ID 
Initials 
Name 
& Dosage Form 
Ordered 
Needed 
 
Bottle# 
  
Number 
  
  
  
  
  
  
(vials, tablets, etc.) 
(vials, bottles, etc.) 
  
  
  
  
  
  
  
A221101  
2XXXXXX 
 Example: 
ABC  
armodafinil 150mg or 
armodafinil 250mg or 
placebo tablets    
 56 tablets per 
bottle  
  
One bottle 
XX/XX/XXXX 
  
        
  
  
  
  
  
 
   
  
  
  
        
  
  
  
  
  
  
  
  
  
        
  
 
 
 
  
 
 
 
 
 
 
  
 INSTRUCTIONS: 
  
  
  
  
  
  
SHIPPING  ADDRESS: 
 
  
NOTE:  Urgent Shipments must be accompanied by 
1. One item or protocol per line 
  
Site Name: 
 an express courier account number. 
 
  
2. When requesting drugs: Fill in all sections completely, except shaded             areas. 
Facility: 
 
 
 
 
 
 
  
3. When returning drugs: Fill in all sections completely, including         
shaded areas. 
 
  
Department:  
 Express Courier Name: 
 
  
4. Must include official shipping address. 
Street Address: 
 
 
 
 
 
 
  
5. Sign and date the order/return. 
 
  
City, State:                          
 Express Courier Acct No.:   __  __  __  __ - __  __  __  __ - __   
 
  
 Zip: 
 
 
 
 
 
 
 
  
 
  
Page 3 of 3 

 
N CI Versi o n D ate: 9/ 2 4 / 2 0 1 8 
U p date  # 7  
9 1  
A P P E N DI X XII:   N U R S E / C R A P H O N E C O N T A C T  
 
N urse/ C R A P h o ne C o nt act G ui de  
 
Patie nt P h o ne N o. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Best Dates/ Ti mes t o call _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
F O L L O W U P:  
 
  
 
P h o ne call sc he d ule:  Call patie nt at h o me t he e n d of st u d y wee ks 4 a n d 8. T his is t o re mi n d patie nt t o 
ta ke t he st u d y a ge nt as i nstr ucte d, d oc u me nt c o m plia nce, e nc o ura ge c o m pleti o n of t he b o o klet, a n d 
a d dress pr o ble ms.   If t he patie nt is see n i n cli nic, t his p h o ne call ca n be o mitte d.  
•        
3. Ite ms t o d oc u me nt: 
 Date of p h o ne call  
 St u d y  wee k 
 Q ues ti o ns/ C o m me nts 
 Perf or ma nce Stat us Sc ore  
 A E assess me nt e n d of wee ks 4 a n d 8  
 
If t he patie nt re p orts a n y si de effects, please d oc u me nt:  
o  
Si de effects:  
  Hea d ac he  
 A n y ot hers - Se verit y a n d attri b uti o n, if a p plica ble. 
 
4. Rei nf orce c o m plia nce wit h st u d y me dicati o n.   
 
5. Rei nf orce c o m pleti o n of q uesti o n naires a n d re q uest ret ur n of t he m at e n d of t he m o nt h.  
 
 
 

 
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APPENDIX XIII:  
GODIN LEISURE TIME EXERCISE QUESTIONNAIRE (GLTEQ)  
 
 
 
 

 
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APPENDIX XIV: 
 PRO-CTCAE  
 
PRO-CTCAE Questionnaire 
 
 
 
 
PRO-CTCAE items for fatigue and cognitive function 
 
 
1.  
In the last 7 days, what was the SEVERITY of your fatigue, tiredness, or lack of energy 
 
at its WORST: 
 
 
 
 
None / Mild / Moderate / Severe / Very severe 
 
 
2.  
In the last 7 days, how much did fatigue, tiredness, or lack of energy INTERFERE with 
 
your usual or daily activities: 
 
 
 
 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
 
3.  
In the last 7 days, what was the SEVERITY of your problems with concentration at their 
 
WORST: 
 
 
 
 
None / Mild / Moderate / Severe / Very severe 
 
 
4.  
In the last 7 days, how much did problems with concentration INTERFERE with your 
 
usual or daily activities: 
 
 
 
 
 
 
 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
 
5.  
In the last 7 days, what was the SEVERITY of your problems with memory at their 
 
WORST: 
 
 
 
 
None / Mild / Moderate / Severe / Very severe 
 
 
6.  
In the last 7 days, how much did problems with memory INTERFERE with your usual or 
 
daily activities: 
 
 
 
 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
 
 
 

 
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APPENDIX XV:  ECOG PERFORMANCE SCORE 
 
 
 
ECOG PERFORMANCE STATUS 
 
Grade 
 
0 
Fully active, able to carry on all predisease activities without restriction 
(Karnofsky 90-100). 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work (Karnofsky 
70-80). 
2 
Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50 percent of waking hours (Karnofsky 50-
60). 
3 
Capable of only limited self-care, confined to bed or chair 50 percent or more of 
waking hours (Karnofsky 30-40). 
4 
Completely disabled. Cannot carry on any self-care.  Totally confined to bed or 
chair (Karnofsky 10-20). 
5 
Dead 
 
 

 
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APPENDIX XVI:  
COPY OF FDA IND EXEMPTION LETTER 
 

 
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