Clinical trial NCT03186638
Conditions: Cognitive Impairment Malignant Neoplasm
Sponsor: University of Rochester NCORP Research Base
Start date: 2017-05-26; Completion date: 2022-06-01
Enrollment: 87 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well low-dose ibuprofen in improving cognitive impairment in patients with cancer. Anti-inflammatory agents, such as ibuprofen, may slow the decline of cognitive processes and diseases involving the brain.

Detailed description:
PRIMARY OBJECTIVES:

I. To provide preliminary data on the effect of ibuprofen on alleviating chemotherapy-related cognitive impairment (CRCI) in cancer patients receiving chemotherapy or who have received chemotherapy within the last 6 months compared to a placebo control, as assessed by the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog).

OUTLINE: Patients are randomized into 1 of 2 arms.

ARM I: Patients receive ibuprofen orally (PO) twice daily (BID) for 6 weeks.

ARM II: Patients receive placebo PO BID for 6 weeks.

After completion of study, patients are followed up periodically.

Arms: arm 1: Patients receive ibuprofen PO BID for 6 weeks. arm 2: Patients receive placebo PO BID for 6 weeks.
Interventions: intervention 1: Ibuprofen intervention 2: Placebo intervention 3: Questionnaire Administration
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
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Phase II Study of Low-Dose Ibuprofen for Cognitive Problems in Patients with Cancer   
URCC16092 
NCT #: NCT03186638 
 
URCC NCORP Research Base: 
Saunders Research Building 
265 Crittenden Blvd, Room 2.235 
CU 420658 
Rochester, NY  14642 
 
 
Phone:  585-275-1364 
Fax:  585-461-5601 
website:  http://urcc-ncorp.org/ 
Study Chair/Principal Investigator: 
Michelle C. Janelsins, Ph.D., M.P.H. 
URCC NCORP Research Base 
265 Crittenden Blvd, Room 2.230 
Box 658  
Rochester, NY  14642 
Michelle_janelsins@URMC.rochester.edu 
 
Study Co-Investigators:  
Karen M. Mustian, Ph.D., M.P.H. 
Luke Peppone, Ph.D., M.P.H. 
Gary R. Morrow, PhD, MS 
URCC NCORP Research Base 
 
Tim Ahles, Ph.D. 
Sloan Kettering Cancer Center 
 
Medical Monitors: 
Richard Dunne, M.D.  
Supriya Mohile, M.D.  
URCC NCORP Research Base 
 
NCORP Co-Investigators: 
Mark A. O’Rourke, M.D. 
Greenville Health System NCORP  
 
Jeffrey L. Berenberg, MD 
Hawaii Minority Underserved NCORP 
 
Biostatistician: 
 
Eva Culakova, PhD  
Huiwen Xu, Ph.D., M.A. 
URCC NCORP Research Base 
 
Participating Sites: 
Open to all NCORPs affiliated with the URCC 
NCORP Research Base 
 
IND: 
No IND Submission Required 
 
Agent/Supplier: 
Ibuprofen/University of Rochester Investigational Drug Service (UR IDS)   


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Document History 
Version Date  
Initial 
08/03/2016 
Initial Approval 
03/22/2017 
Amendment 1 
05/08/2017 
Amendment 2 
10/02/2017 
Amendment 3 
03/14/2018 
Amendment 4 
06/18/2018 
Amendment 5 
07/23/2018 
Amendment 6 
11/16/2018 
Amendment 7 
01/11/2019 
Amendment 8 
04/19/2019 
Amendment 8 
06/10/2019 
Amendment 9 
04/22/2020 
 
 
Protocol Contact Information 
 
Protocol Coordinator: 
Kari Gilliland 
585-275-6303 
URCC_16092@URMC.rochester.edu 
 
Adverse Event Reporting: 
Sarah Strause 
585-275-1398 
URCC_16092@URMC.rochester.edu 
 
Regulatory Contact: 
Cathy Lesniewski 
585-275-2282 
URCC_Regulatory@URMC.rochester.edu 
 
Website/Registration Contact: 
Sebastien Estaque 
585-275-2044 
URCC_Techsupport@URMC.rochester.edu 
 
Data Submission: 
Linda Spath 
URCC_16092@URMC.rochester.edu 
URCC NCORP Research Base  
Saunders Research Building 
265 Crittenden Blvd 
CU 420658 
Rochester, NY  14642 
585-275-1364 
 
Appendix: 
A. Study Calendar 
 
 


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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 Table of Contents 
 
 
INTRODUCTION AND BACKGROUND .................................................................................... 6 
 
Rationale and Literature Review ..................................................................................................................... 6 
 
Preliminary Data ............................................................................................................................................. 7 
 
Feasibility ....................................................................................................................................................... 8 
 
OBJECTIVES .................................................................................................................................. 8 
 
Primary Objective ........................................................................................................................................... 9 
 
Exploratory Objectives ................................................................................................................................... 9 
 
CHARACTERISTICS OF STUDY POPULATION....................................................................... 9 
 
Inclusion Criteria ............................................................................................................................................ 9 
 
Exclusion Criteria ......................................................................................................................................... 10 
 
Source of Study Participants ......................................................................................................................... 10 
 
Process of Consent ........................................................................................................................................ 11 
 
Recruitment and Retention Plan ................................................................................................................... 11 
 
REGISTRATION AND RANDOMIZATION .............................................................................. 12 
 
Investigator and Research Associate Registration with CTEP ..................................................................... 12 
 
CTSU Registration Procedures ..................................................................................................................... 13 
 
Enrolling Participants.................................................................................................................................... 14 
 
Randomization .............................................................................................................................................. 15 
 
RESEARCH PROTOCOL/STUDY PROCEDURES ................................................................... 15 
 
Overview of Study Plan and Coordinator Training ...................................................................................... 15 
 
Schedule of Activities ................................................................................................................................... 19 
 
Screening and Pre-Intervention Assessment ................................................................................................. 19 
 
Study Agent .................................................................................................................................................. 20 
 
Pre-Intervention Visit.................................................................................................................................... 21 
 
Mid-Intervention Assessments ...................................................................................................................... 28 
 
Post-Intervention Visit .................................................................................................................................. 28 
 
Potential Risks .............................................................................................................................................. 28 
 
Participant Withdrawal ................................................................................................................................. 29 
 Data & Specimen Storage for Future Research Use ..................................................................................... 30 
 Costs to the Participant ................................................................................................................................. 30 
 Payment for Participation ............................................................................................................................. 30 
 
INTERVENTION/STUDY AGENT ADMINISTRATION AND INFORMATION ................... 30 
 
Contraindications .......................................................................................................................................... 30 
 
Medications ................................................................................................................................................... 30 
 
Adherence/Compliance ................................................................................................................................. 30 
 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION ........................................... 31 
 
Primary Endpoint .......................................................................................................................................... 31 
 
Off-Agent Criteria ......................................................................................................................................... 31 
 
Off-Study Criteria ......................................................................................................................................... 31 
 
Study Agent/Device Distribution – IBUBROFEN/PLACEBO ..................................................... 31 
 
Availability ................................................................................................................................................... 31 
 
Distribution ................................................................................................................................................... 31 
 
Agent Accountability .................................................................................................................................... 32 
 
Packaging and Labeling ................................................................................................................................ 32 
 
Storage .......................................................................................................................................................... 32 
 
Blinding and Unblinding Methods ................................................................................................................ 32 
 
CORRELATIVE/SPECIAL STUDIES ......................................................................................... 33 
 
Rationale for Methodology Selection ........................................................................................................... 33 
 
Comparable Methods .................................................................................................................................... 33 
 
SPECIMEN MANAGEMENT ...................................................................................................... 33 
 Laboratories .................................................................................................................................................. 33 
 Specimen Storage ......................................................................................................................................... 33 
 
REPORTING ADVERSE EVENTS ............................................................................................. 33 
 Definitions .................................................................................................................................................... 34 
 Reporting ...................................................................................................................................................... 34 


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 Responsibilities for Expedited Reporting ..................................................................................................... 35 
 
STUDY MONITORING ............................................................................................................... 36 
 Data Management Summary ......................................................................................................................... 36 
 Records to be Kept ........................................................................................................................................ 38 
 Data and Safety Monitoring Plan .................................................................................................................. 38 
 Record Retention .......................................................................................................................................... 39 
 
STATISTICAL CONSIDERATIONS .......................................................................................... 39 
 Study Design ................................................................................................................................................. 39 
 Primary Objectives and Analysis Plans ........................................................................................................ 40 
 Exploratory Objectives and Analysis Plans .................................................................................................. 41 
 Interim Analysis ............................................................................................................................................ 41 
 Ancillary Studies ........................................................................................................................................... 41 
 
FINANCING, EXPENSES, AND/OR INSURANCE................................................................... 42 
 
REFERENCES .............................................................................................................................. 42 
 
 
 


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 INTRODUCTION AND BACKGROUND  
 
 Rationale and Literature Review 
 
Clinical Relevance. Chemotherapy-related cognitive impairment (CRCI) is characterized by 
difficulty in memory, attention, concentration and executive function. CRCI is most pronounced and severe 
during chemotherapy (in up to 80% of cancer patients); however, it can last for many years following 
treatment (up to 20 years) in up to 35% of survivors.1-3  With over 13 million cancer survivors in the US, up 
to 4 million could be living with long-lasting CRCI.4 CRCI is independent of other symptoms (e.g., 
anxiety, depression)5 and has a negative impact on quality of life (e.g., activities of daily living, work 
performance).6-10  CRCI influences treatment adherence; 80% of participants state that they would not 
choose a treatment if they knew it could interfere with their mental capacity.11 It is critically important to 
help participants with CRCI, by testing interventions to alleviate this burdensome side effect.  
 
CRCI affects patients with many different cancers. A majority of the research on CRCI has 
been conducted in breast cancer showing that CRCI is a pervasive problem during chemotherapy; however, 
CRCI affects patients with multiple cancer types that receive chemotherapy including those with colorectal 
cancer, prostate cancer, lymphoma, testicular cancer, multiple myeloma, and ovarian cancer.2,9,12-23  Of note, 
Dr. Janelsins has collected pilot data to indicate that, as Preliminary Study # 1 demonstrates, 78% of 
colorectal cancer patients report memory difficulty during chemotherapy. Recruitment of patients with 
colorectal cancer will be one of the key understudied groups included in this research.  
 
While studies have focused on developing CRCI interventions for breast cancer patients and survivors24-26, 
we are interested in studying interventions for CRCI more broadly; therefore, this study is novel and of 
potential clinical impact with more broad scope by addressing CRCI in those with different disease types.  
 
The preliminary link between CRCI and Inflammation forms the basis for testing ibuprofen 
intervention. Inflammatory processes play a role in a number of neurocognitive diseases.27-37 Dr. Janelsins 
and others have shown that chemotherapy increases production of pro-inflammatory cytokines including 
MCP-1, IL-6, IL-8, TNF-α, and receptor TNFR2 and these are correlated with CRCI (Preliminary Study # 
2).38-42 Elevated peripheral blood levels of these molecules can cause reduced neuronal plasticity and 
neuronal cell death which ultimately lead 
to cognitive impairments,27,30,37,43-50 and 
are thought to contribute to cognitive 
diseases including Mild Cognitive 
Impairment.39,51-53 Chronic expression of 
these pro-inflammatory cytokines leads to 
a cytokine cascade that may become 
chronic and contribute to and exacerbate 
CRCI, and may occur via similar 
neuronal degenerative pathways initiated 
by inflammation as in other cognitive disease settings.69,70 Conversely, anti-inflammatory cytokines are 
associated with neuroprotection (IL-10, sIL1Ra). Therefore, interventions that reduce inflammation, such 
as ibuprofen, that are associated with improved cognitive function in other disease settings and in healthy 
adults may reduce CRCI-induced inflammation and improve cognitive function in cancer patients receiving 
chemotherapy with CRCI (Fig. 1).  
Ibuprofen is an FDA-approved non-steroidal anti-inflammatory (NSAID) for treatment of 
conditions that involve pain, fever, and inflammation.54 Ibuprofen inhibits cyclooxygenase 1 and 2 activity, 
thereby inhibiting the synthesis of prostaglandins and consequently down-regulating inflammatory 
pathways involving IL-1β, MCP-1, IL-6, CRP and TNF-α 54-56 the same pathways involved in CRCI. 
NSAIDs, even at low doses, are neuroprotective among healthy female adults with long-term use.57 
Additional studies have shown the benefits of NSAIDs, including ibuprofen, on slowing cognitive decline 
in those with Alzheimer’s or Mild Cognitive Impairment (MCI).58-60, 61 Most recently, a protective effect of 


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ibuprofen in Parkinson’s risk was observed.62 Since low-dose ibuprofen is effective in these settings, we 
hypothesize that it may be beneficial for CRCI.63 Because CRCI develops quickly after chemotherapy, and 
because of the rapid effect of ibuprofen on inflammation, we hypothesize that noticeable improvements 
may occur with a brief (6-week) administration of low-dose ibuprofen. We observed benefits in a study 
where an NSAID was delivered to alleviate pegfilgrastim-induced bone pain (proposed inflammation 
mechanism); in that randomized clinical trial (RCT;N=510), we found a significant improvement with a 1-
week delivery of a low-dose NSAID on chemotherapy-related bone pain showing that it is feasible and safe 
to give an NSAID of 1000 mg/day during chemotherapy.64,65 Preliminary Study # 3 suggests that ibuprofen 
(200 mg twice a day for 6 weeks), is preliminarily safe and feasible for cancer patients receiving 
chemotherapy, and may be beneficial for CRCI. We arrived at the dosage of 200 mg twice a day for 6 
weeks and each dose 8 hours apart based on safety considerations.  
CRCI is a significant problem for cancer patients during chemotherapy and interferes with QOL. 
Dr. Janelsins also has preliminary data that participants on chemotherapy perform worse on the CANTAB 
memory task compared to similar age- and gender-paired controls (Preliminary Study # 5). If our 
hypothesis that intervening during chemotherapy may prevent post-treatment CRCI by reducing 
inflammation, the goal of future research is to follow participants for longer post-treatment times. 
 
 Preliminary Data  
 
Study 1: In a secondary analysis on 
69 colorectal cancer patients from a 
completed nationwide CCOP study 
originally designed to assess the 
effect of modafinil for cancer-
related fatigue (URCC2901), we 
found that 78% of these 
participants experience memory difficulty during chemotherapy Cycle 3 (Fig. 2). Difficulty at cycle # 3 
also predicts interference in quality of life items at cycle # 4 (mood, work, general activity, enjoyment of 
life; OR Range=2.16-3.43, p<0.05; Janelsins et al., Society for Behavioral Medicine Abstract). Colorectal 
cancer patients are one of the important groups we will recruit as they are underrepresented in CRCI 
intervention research.  
 
Study 2: We assessed levels of cytokines, MCP-1, IL-6 and IL-8, at two time-points during adriamycin-
based chemotherapy in breast cancer patients (n=54), and found that all three increased (IL-6 was 
significant, p<0.05).53  
 
Study 3: In preparation for the proposed Phase II RCT in cancer patients, we have collected feasibility data 
on an RCT conducted at Wilmot Cancer Institute which included Ibuprofen (200 mg twice a day for 6 
weeks) and EXCAP®© (tailored walking and resistance training program for 6 weeks) and in cancer 
patients receiving chemotherapy and reporting a least a mild/moderate level of CRCI via self-report score 
of 3 or higher on a MDASI CRCI question at cycles 3-5. These data have been collected as part of Dr. 
Janelsins’ ongoing NCI K07 Award and has an accrual closure date set for October 31, 2020. The 
feasibility data are based on 33 consented participants with 28 providing full evaluable pre/post data (67% 
breast cancer and 33% gastrointestinal (GI) cancer with 15% colorectal cancer). A majority of the patients 
with colorectal cancer received FOLFOX while one received Capecitabine. The goal of this feasibility 
phase of Dr. Janelsins’ K Award was to assess the feasibility of the interventions in a similar protocol 
design and procedures to help inform the proposed Phase II study.   
• 
Outcome Assessment: All randomized GI participants (to EXCAP©® or ibuprofen) completed the 
validated FACT-Cog, CANTAB neuropsychological tests, aerobic testing (6-minute walk test), 
strength testing (rep. max testing), symptom measures, diaries, and provided blood at pre- and post-
intervention. Note: EXCAP©® can lead to improvements in 6-minute walk test and rep. max testing 
over 6 weeks.66 In this pilot, we observed similar improvements with our study participants.   
Figure 2
% Colorectal Cancer Pts. with Difficulty
Problem Area
Cycle 2
Cycle 3
Cycle 4
Memory difficulty
75%
78%
74%
Difficulty thinking
55%
52%
48%
Unable to concentrate
62%
44%
58%


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• 
Adherence: Pill compliance was greater than 90% from all participants with the exception of one. 
Those in the EXCAP©® group had a 2,553 pedometer step increase moving participants from a 
sedentary to low-active level, and a 375 step increase in those not in EXCAP©®; those participants 
remained sedentary. 75% of participants reported using resistance bands with an average of 3 
days/week for 20 minutes at an average moderate RPE of 4.  
• 
Adverse Events: No study-related AEs occurred.  
• 
Satisfaction: 100% highly recommended the study.  
• 
Preliminary effect estimates of 0.4-0.7 on the Delayed Match to Sample CANTAB Task suggesting 
that exercise and ibuprofen are trending in the right direction; these are based on a very small 
number of patients and we only calculated these to get an idea of the sample size needed for the 
current Phase II study. 
• 
Beyond the feasibility phase of data collection highlighted above, Dr. Janelsins and colleagues are 
currently continuing her work with these interventions as part of her NCI K Award and this Phase 
II study at Wilmot Cancer Institute primarily in breast cancer patients. Eleven physicians worked 
with her and 10 allowed their patients to participate reaching an accrual of 110 patients to that 
study. We focused on recruiting from breast cancer and GI clinics and have also recruited from 
lung and prostate clinics. Of the 110 patients accrued to the study, 82 had breast cancer (including 
metastatic and non-metastatic cancer), 26 had GI cancers (16 colorectal cancer, 4 pancreatic, 2 
esophageal, 2 bile duct, 1 appendix, 1 liver), 1 prostate cancer patient, and 1 with lung cancer.  
• 
The current study will focus on the low-dose ibuprofen intervention for CRCI within the NCORP 
network.  
 
Study 5: In a large observational study (URCC10055) lead by Dr. Janelsins and conducted through the 
URCC NCORP Research Base and affiliates, we found that the FACT-Cog was a robust measure of CRCI, 
detecting clinically and statistically meaningful changes from pre- to post-chemotherapy as well as up to 6 
months post-chemotherapy.67 Using objective neurocognitive testing, Dr. Janelsins and colleagues showed 
that CRCI was a significant problem from pre- to post-chemotherapy and up to 6 months post-
chemotherapy.68 
 
Summary: Given the significance and innovation presented and our original preliminary data, the next 
logical step of investigating ibuprofen (200 mg twice a day—for cancer patients receiving  chemotherapy 
or who have received chemotherapy within the last 6 months and are experiencing CRCI, is a Phase II pilot 
RCT. The Phase II RCT, if promising, would support an eventual Phase III study.  
 
 Feasibility 
 
NCORP Community Sites and Minority/Underserved Community Sites have been involved in developing 
and reviewing this study concept. NCORP Investigators on this protocol played a role in reviewing and 
refining this protocol.  
 
The pilot study for this protocol was presented at the 2015 Annual NCORP Meeting by Dr. Janelsins with a 
majority of respondents indicating a high level of interest in this study. Conference attendees were given 
opportunities to discuss the concept with Dr. Janelsins, to provide written comments on the study concept, 
and to indicate their level of interest. A high level of participation from NCORP sites is anticipated based 
on data collected at the 2015 Annual NCORP Meeting. Representatives of nine of the NCORP community 
sites in attendance at the conference indicated a willingness to participate in this study. 
 
a. This study underwent peer review as part of an NCI study section and Dr. Janelsins was awarded 
funding under an NCI R21.  Feasibility was assessed as part of the peer review. 
b. The preliminary data in Section 1.2 solidifies study feasibility.  
 
 OBJECTIVES 
 


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 Primary Objective  
 
 To provide preliminary data on the effect of ibuprofen on alleviating CRCI in cancer patients 
receiving chemotherapy or who have received chemotherapy within the last 6 months 
compared to a placebo control, as assessed by the Functional Assessment of Cancer Therapy-
Cognitive Function (FACT-Cog). 
 
 Exploratory Objectives 
 
 To provide preliminary data on the effect of ibuprofen on alleviating CRCI in cancer patients 
receiving chemotherapy or who have received chemotherapy within the last 6 months 
compared to a placebo control by objective assessments of cognitive function. These are 
measured by validated neuropsychological assessment of verbal memory, attention, and 
executive function via CANTAB (computerized DMS, VRM, and RVP) and paper-based 
measures (CTMT and COWA). 
  
 To provide preliminary data on the effect of ibuprofen on alleviating CRCI in cancer patients 
receiving chemotherapy or who have received chemotherapy within the last 6 months 
compared to a placebo control on phone-based cognitive function measures (digit span, word 
recall, digits backward, CALVT, category fluency; all from BTACT). 
 
 To provide preliminary data on the effect of ibuprofen on alleviating CRCI in cancer patients 
receiving chemotherapy or who have received chemotherapy within the last 6 months 
compared to a placebo control on serum pro-inflammatory (MCP-1, IL-6, IL-8, TNF-α, 
sTNFR2, sTNFR1, IL-1β) and anti-inflammatory (sIL-1Ra, IL-10) cytokines/receptors in 
cancer patients receiving chemotherapy.  
 
 To provide preliminary data on the mediating effects of cytokine/receptor concentrations on 
the CRCI changes due to ibuprofen in cancer patients receiving chemotherapy or who have 
received chemotherapy within the last 6 months compared to placebo control. 
 
 CHARACTERISTICS OF STUDY POPULATION  
 
 Inclusion Criteria  
 
Study participants must: 
 
 Be ≥ 18 years of age 
 
 Have a diagnosis of cancer and are now receiving cytotoxic chemotherapy or have received 
cytotoxic chemotherapy within the last 6 months (i.e. are within a 6 month window of 
completion of chemotherapy). 
 
 Report cognitive difficulties or respond YES to the question: “Have you noticed any 
problems in your memory, attention, concentration, multi-tasking, or other cognitive 
functions?” 
 
NOTE: If a participant does not report cognitive difficulties or answers NO, they should be 
re-approached multiple times.  Patients should be re-screened at all subsequent 
chemotherapy treatments and multiple times during the six months following completion of 
chemotherapy via phone and in person.   
 
 Be able to swallow medication.  


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 Be able to read English.  
 
 Be able to give written informed consent. 
 
 Exclusion Criteria 
 
Study participants must not: 
 
 Have a confirmed brain tumor or confirmed brain metastases.  
 
 Be taking regular daily doses of an NSAID.  Note: Daily doses of 81 mg aspirin are 
permitted and higher doses of an NSAID on an ‘as needed’ basis are permitted.   
 
 Be diagnosed with dementia or severe neurodegenerative disease that would prohibit the 
ability to complete cognitive testing. 
 
 Have a contraindication to ibuprofen per physician or physician’s designee (e.g., allergy, 
worsening of ongoing medical problem due to NSAID, very low platelet count from 
chemotherapy, full-dose anti-coagulation/high risk of bleeding, as well as uncontrolled 
conditions such as hypertension, asthma, or peptic ulcer disease).  
 
 Have a hospitalization for treatment of a major psychiatric illness within the last five years. 
 
 Be pregnant.   
 
 Have a serum creatinine above 1.5 ULN. ULN is per institutional definition. If currently 
receiving chemotherapy, lab test must be collected within the 4 weeks prior to study 
enrollment. If not currently receiving chemotherapy, most recent labs tests may be used. 
 
 Be colorblind.  
 
 Have active substance abuse (e.g. alcohol, drugs) that would interfere with participation in 
this study per self-report or medical record. 
 
 Source of Study Participants  
 
Data will be gathered from patients, 18 years of age or older, undergoing chemotherapy treatment for 
cancer or have received chemotherapy within the last 6 months at participating sites. Pediatric patients will 
be excluded from this study. Women and members of minority groups and their subpopulations will be 
included in the study. 
 


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Planned Accrual: 
 
Ethnic Categories 
 
Racial Categories 
Not Hispanic or Latino 
Hispanic or Latino 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska Native 
0 
1 
0 
0 
1 
Asian 
2 
2 
0 
0 
4 
Native Hawaiian or Other Pacific Islander 
0 
1 
0 
0 
1 
Black or African American 
5 
7 
1 
0 
13 
White 
32 
33 
0 
1 
66 
More Than One Race 
1 
0 
0 
0 
1 
Total 
40 
44 
1 
1 
86 
 
 
 
 
 
 Process of Consent 
 
 Prior to study initiation, the informed consent document will be reviewed and approved by 
the NCI Central IRB (CIRB). Any subsequent changes to the informed consent will be 
approved by the NCI CIRB prior to utilization. 
 
 All potential study participants will be given a copy of the CIRB-approved Informed Consent 
to review. The investigator/investigator’s designee will explain all aspects of the study in lay 
language and answer all questions regarding the study. If the potential participant decides to 
participate in the study, s/he will be asked to sign and date the Informed Consent document. 
The study documents or interventions will not be released to a potential participant who has 
not signed the Informed Consent document. Potential participants who refuse to participate 
or participants who withdraw from the study will be treated without prejudice. 
 
 Participants will be provided the option to allow the use of blood samples for future research 
purposes. Statement of this option will be included within the informed consent document. 
 
 The eligibility checklist must be signed by the treating physician prior to study registration 
and initiation of any study procedures.  
 
 Recruitment and Retention Plan 
 
 Study personnel at participating NCORP sites with appropriate human subject protection 
certification and study-specific training will monitor patient visit schedules and inform 
treating physicians when a patient is potentially eligible for a study. If the treating physician 
deems the study appropriate for the potential participant, and, if the potential participant 
agrees to hear about it, the treating physician will introduce study personnel to the potential 
participant.  Study personnel will then explain the project to the potential participant and 
answer all questions. Treating physicians can also identify and approach potential participants 
about this study.  
 
 Retention of participants will be supported by flexible scheduling of study assessments and 
weekly phone contacts. Also, participants will be compensated a total of $100.00 for their 
time and travel upon the completion of study assessments. This is dispensed as follows: $25 
upon completion of Pre-Intervention requirements, $30 ($5/week x 6 weeks for completing 


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daily diaries/Mid-Intervention assessments) upon completion of the intervention and 
assessments on study, and $45 for completion of the Post-Intervention requirements. See 
Section 5.12. 
 
 REGISTRATION AND RANDOMIZATION 
 
 Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
individuals contributing to NCI-sponsored trials to register and renew their registration annually. To 
register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) account at https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration 
type of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete 
their annual registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr.    
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications such as 
the Roster Update Management System [RUMS], OPEN, Rave, acting as a primary site contact, 
or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with limited 
access to NCI-supported systems. 
RCR requires the following registration documents: 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, 
employment, license, and certification) 
✔ 
✔ 
✔ 
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 Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and NPIVRs 
must list all clinical practice sites and Institutional Review Boards (IRBs) covering their practice sites 
on the FDA Form 1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB approval), 
consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL must be rostered at 
the enrolling site with a participating organization.  


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Version Date:  04/22/2020 
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR Help 
Desk by email at RCRHelpDesk@nih.gov. 
 
 CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
 IRB Approval 
 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if the 
study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office 
following country-specific regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRBManager to indicate their intent to open the study 
locally. The NCI CIRB’s approval of the SSW is automatically communicated to the 
CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by email or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
 
Downloading Site Registration Documents 
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted based on person and site roster assignment. To participate, the 


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institution and its associated investigators and staff must be associated with the LPO or a 
Protocol Organization (PO) on the protocol. One way to search for a protocol is listed below.  
• 
Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password; 
• 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select URCC and 
protocol number URCC-16092 
• 
Click on Documents, select Site Registration, and download and complete the forms 
provided. (Note: For sites under the CIRB, IRB data will load automatically to the 
CTSU.)  
 
4.2.2. Submitting Regulatory Documents 
 
Submit your CIRB-approved Annual Signatory Institution Worksheet and Annual Principal 
Investigator Worksheet URCC_Regulatory@URMC.rochester.edu for the URCC 
Research Base study records 
 
4.2.3. Checking Your Site’s Registration Status: 
 
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the sites 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration requirements as 
outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
 
 Enrolling Participants 
 
To enroll a participant who meets the eligibility criteria and who has signed the informed consent 
document, log on to the URCC NCORP Research Base website at http://www.urcc-ncorp.org/, enter your 
NCORP’s username and password and enter the information outlined below. An email confirmation of 
registration will be forwarded by the URCC. Participants can be registered up to 3 weeks prior to their 
initiation of study procedures. If you are unable to log on, contact Kari Gilliland by phone at 585-275-6303 
or by email at URCC_16092@URMC.rochester.edu.  
 
The following information will be requested: 
a. NCORP name  
b. NCORP component name and CTEP#  
c. Enrolling physician name 
d. Enrolling physician CTEP Investigator ID 
e. Name and telephone number of person following study participant 
f. Verification that participant has met all inclusion and exclusion criteria listed in Section 3. 
g. Verification that consent form has been signed 
h. Participant’s identification 
• 
First name and last initial 
• 
Birth date (MM/DD/YYYY) 
• 
Gender 
• 
Race 


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• 
Five-digit zip code 
• 
Payment code 
• 
Other protocol-specific information, including: 
o Phone number 
o Best time to call 
o Permission to leave voicemail 
o Anticipated Intervention Start Date (i.e. Day 0 date) 
o 
Currently Receiving Chemotherapy? (Yes or No) 
o 
Date of first chemotherapy received while on this  study (If currently receiving 
chemotherapy) 
 
Note: must match day 0 date  
 
 
An email confirmation of registration will be forwarded by the URCC NCORP Research Base. Participants 
can be registered up to 3 weeks prior to their initiation of study procedures. The Eligibility Checklist must 
be signed and dated by the treating physician prior to registration. 
 
 Randomization 
 
Randomization will occur at the time of registration.  A computer-generated randomization schedule will 
be used to assign participants in equal numbers to the two arms, stratified by NCORP site and gender with 
a block size of 4.  The schedule will be prepared and maintained by the URCC NCORP Research Base 
biostatistician.   
 
The 2 study arms are as follows: 
 
Arm 1: 
Participants assigned to Treatment Arm 1 will receive a 6-week supply of ibuprofen (200 mg), 
which consists of 84 capsules of ibuprofen to be taken twice daily. 
 
Arm 2: 
Participants assigned to Treatment Arm 2 will receive a 6-week supply of placebo, which 
consists of 84 capsules of placebo to be taken twice daily. The placebo contains trace amounts 
of lactose (Approximately 0.32 grams per capsule). 
 
A total enrollment of 86 participants is planned, with 43 participants in each treatment group. Accounting 
for a 30% rate of incomplete data, we estimate 30 participants in each intervention group will yield fully 
evaluable data. It should take approximately 12 months to accrue all participants if 8 participants are 
accrued per month across NCORP sites.  
 
Treatment Arm 
N 
Evaluable 
Arm 1: Ibuprofen  
43 
30 
Arm 2: Placebo  
43 
30 
Total 
86 
60  
 
 RESEARCH PROTOCOL/STUDY PROCEDURES 
 
 Overview of Study Plan and Coordinator Training  
 
 Overview of Procedures and Study Timelines:  
 
This will be a phase II, multi-center, double-blind, placebo-controlled, 2-arm randomized 
clinical trial of an intervention examining the preliminary efficacy of the 2 treatment arms on 
perceived cognitive function. Participants in the study must have a diagnosis of cancer, be 


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currently receiving cytotoxic chemotherapy or have received chemotherapy treatment within 
the last 6 months, and report cognitive difficulties or respond yes to the question: “Have you 
noticed any problems in your memory, attention, concentration, multi-tasking, or other 
cognitive functions any time after initiation of cytotoxic chemotherapy cycle 1 (i.e. first 
infusion). Participants can receive other concurrent treatments (e.g. radiation, biologics) with 
cytotoxic chemotherapy or after cytotoxic chemotherapy. Therapeutic trial participants are 
also allowed as long as they are known to be receiving a cytotoxic chemotherapy agent. 
Participants can be enrolled up to 6 months after of completion of cytotoxic chemotherapy.  
 
Coordinators should provide an introduction to the concept of “chemo brain” and then 
ask the question above. An example introduction is below:  
 
Some patients experience changes in cognitive abilities during chemotherapy and 
within 6 months following chemotherapy treatments. These can be mild or more 
severe. Some examples of cognitive problems could include things like:  
 
• Feeling overall general “fogginess” 
• Trouble with details like names, events, dates 
• Trouble with learning new things 
• Trouble remembering common words - word is on the ‘tip of the tongue.’ 
• Trouble remembering things you usually have no trouble recalling, like directions 
• Trouble focusing on tasks and taking longer to accomplish a task 
• Trouble with multi-tasking at work or home 
 
If a caregiver is present at the time of screening they may be consulted during the discussion 
about changes in the participant’s cognitive function. However, to be eligible the participant 
themselves must agree to participate and report cognitive difficulties or respond yes to the 
screening question. Caregiver should be a person at least 21 years of age that provides 
support in any way to the participant. It is acceptable to ask a caregiver to provide input on 
the cognitive function of the participant and the participant’s problems with memory, 
attention, concentration, or multi-tasking.  
 
Participation in the study intervention will span 6 weeks (42 days) and participants will be 
evaluated at three time points during the study: Pre-Intervention (within Days -8 to 0), the 
study midpoint (Mid-Intervention; within Days 14-26), and Post-Intervention (Days 41 +/-3).  
 
Participants will complete brief daily diaries which include questions about symptoms, daily 
exercise, study agent use, and non-study agent drug usage. All participants will complete the 
Daily Diary on study Days 0 to 41. Time on this study could go up to approximately 7 weeks 
to allow for flexibility in scheduling the Pre-Intervention and Post-Intervention study visits. 
The intervention will begin on study Day 0. All Pre-Intervention visit assessments will be 
completed by participants within 8 days prior to or on Day 0. If Pre-Intervention visit occurs 
on Day 0 the assessments should be completed before the initiation of the study intervention. 
For participants currently receiving chemotherapy Day 0 will occur on the day of the first 
chemotherapy received while on the study. If Pre-intervention assessments are collected on 
the same day chemotherapy is given assessments must be completed prior to the 
chemotherapy infusion. The Post-Intervention visit will occur most often on Day 41 of the 
intervention. However, as scheduling issues can occur, the Post-Intervention visit may occur 
within Days 38 to 44. For participants currently receiving chemotherapy the Post-
Intervention visit must occur BEFORE the next administration of chemotherapy and not 
after. If Post-intervention assessments are collected on the same day chemotherapy is given 
assessments must be completed prior to the chemotherapy infusion.  
 


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All participants will be given a measure of cognitive functioning (Functional Assessment of 
Cancer Therapy with Cognition (FACT-Cog)) and other self-report measures evaluating 
depression (CES-D), fatigue (MFSI-SF), anxiety (STAI), Godin Exercise Leisure-time 
Questionnaire (Godin) and a symptom inventory (SI) to complete at the Pre-Intervention visit 
and Post-Intervention visit. Note: FACT-Cog is completed prior to computerized and 
paper-based testing. Participants will complete a FACT-Cog questionnaire at the Mid-
Intervention time point at home.  
 
At Pre-Intervention and Post-Intervention, all participants will be evaluated for cognitive 
performance on the CANTAB computerized neuropsychological assessment of memory 
performance on a delayed matching to sample task. This assessment measures memory 
across delay times (0, 4, 12 seconds) as well as reaction time. This assessment is non-
invasive and only requires touching a computer screen. It takes less than 10 minutes to 
complete. Two other CANTAB tests will be included for exploratory analyses: Verbal 
Recognition Memory (Immediate and Delayed Memory; ten minutes) and Rapid Visual 
Information Processing (a short 10 minute test of attention and working memory). Paper-
based assessment consisting of the WRAT-4 Reading (Pre-Intervention only), COWA, and 
CTMT will also be conducted. Study coordinators will complete the Behavioral Observations 
During Cognitive Testing form at the Pre-Intervention visit and Post-Intervention visit. 
               
After the cognitive testing, a follow-up call for a brief cognitive assessment (no more than 15 
min) with the Brief Test of Adult Cognition by Telephone (BTACT) will be conducted by 
research staff at the URCC NCORP Research Base for Pre-Intervention and Post-
Intervention. For all participants, the Pre-Intervention BTACT will be completed BEFORE 
the initiation of the study intervention. If the Pre-Intervention BTACT cannot be completed 
before the initiation of the study intervention, the assessment will be completed within 7 days 
after the in-person cognitive assessments completed at the Pre-Intervention visit.  
 
For participants currently receiving chemotherapy, Pre-Intervention BTACT should also be 
completed BEFORE the first administration of chemotherapy they receive while they are a 
participant on the study. If the Pre-Intervention BTACT cannot be completed before the first 
chemotherapy administered while on the study (for those receiving chemotherapy), the 
BTACT assessment may be completed within 7 days after the in-person cognitive 
assessments completed at the Pre-Intervention visit.  
 
For all participants, the Post-Intervention BTACT assessment will be collected AFTER the 
Post-Intervention in-person cognitive assessments have been completed. If the Post-
Intervention BTACT cannot be completed before the in-person cognitive assessments, the 
assessment may be completed within 7 days after the in-person cognitive assessments 
completed at the Post-Intervention visit. 
 
For participants currently receiving chemotherapy, Post-Intervention BTACT should be 
completed BEFORE the last administration of chemotherapy received while they are a 
participant on the study. If the Post-Intervention assessments are completed on the same day 
as the final chemotherapy administered while on study (for those receiving chemotherapy), 
the BTACT phone assessment will be performed AFTER in-person cognitive testing has 
been completed but before chemotherapy infusion, when possible. For participants receiving 
chemotherapy, the anticipated date of the last chemotherapy received while on the study will 
be communicated to the URCC Research Base by email when sending Post-Intervention 
CANTAB data files.  
 
Ibuprofen and placebo will be provided by the University of Rochester Medical Center 
Investigational Drug Service. Instructions for the study agent will be reviewed with all 
participants by the study coordinator at the Pre-Intervention visit. Participants will be given 


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one bottle containing 84 capsules. The placebo contains trace amounts of lactose 
(approximately 0.32 grams per capsule). Participants will take study agent (1 capsule twice a 
day separated by at least 8 hours) for approximately 42 days starting on Study Day 0. At 
sites, study agent is stored in a secured location that is locked at all times and only accessible 
by approved study personnel. Study pills will be over encapsulated in opaque gelatin 
capsules so that participants will not know whether they have ibuprofen or placebo.  
 
Fasting blood draws (6-8 hours) at three time-points will be done to measure cytokine, 
chemokine and receptor levels by appropriate ELISA/multiplex methods. These time-points 
coincide with Pre-Intervention (Day 0), Mid-Intervention (Day 14 to 26), and Post-
Intervention assessment (Days 41 +/- 3 days) time windows. Pre-Intervention blood will be 
collected prior to or on Day 0.  
 
For participants currently receiving chemotherapy, blood can be collected with pre-
chemotherapy labs but must be collected before the initiation of the first chemotherapy 
received while on study. Participants currently receiving chemotherapy must complete the 
Post-Intervention blood draw prior to the last administration of chemotherapy received while 
on study.  
 
Blood will still be collected if not fasted and this will be noted on the blood requisition form. 
Additionally, every effort should be made to make the Mid- and Post-Intervention blood 
draws the same time of day as the Pre-Intervention blood draw. Time of day is noted on the 
Blood Requisition Form. Blood will be drawn and processed using standardized kits supplied 
by URCC NCORP Research Base and using the standard processing procedure. All blood 
draws will occur at the NCORP sites and affiliated laboratories if blood is drawn off-site. 
 
If collected, blood counts measured by standard CBC with differential procedures will be 
abstracted from the participant’s medical record and entered into the Laboratory Data Form 
at Pre-Intervention and Post-Intervention time-points. Blood counts entered into the 
Laboratory Data form should be collected within 10 days of the associated time-point. If 
blood tests have not been completed within 10 days of the Pre-Intervention or Post-
Intervention visit the coordinator will document this on the Laboratory Data form. 
 
Study coordinators will complete weekly phone contacts. During phone contacts, 
coordinators will provide study reminders and participants will be questioned regarding 
compliance with the study interventions, completion of diaries, and occurrence of any 
adverse events. Information collected during weekly phone contacts will be recorded on the 
weekly Call Logs. 
 
  Coordinator Training  
 
All NCORP coordinators and staff must complete mandatory training conducted by URCC 
NCORP Research Base staff for this study.  
 
The training will be conducted via live video conference (or by watching a recorded training 
session followed by a short Q&A); content and training requirements vary by role.  NCORP 
site staff members must complete the appropriate URCC NCORP Research Base training 
prior to conducting study assessments and delivering study interventions. All phone-based 
cognitive assessment coordinators will also receive training at URCC. Coordinators must be 
trained on all study procedures (cognitive assessment, study data management, blood 
procedures) prior to conducting study procedures.  
 
All cognitive assessments must be conducted on a colleague prior to administering to a study 
participant and these documents should be sent to URCC_16092@URMC.rochester.edu for 


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review. A certification email will be sent to the coordinator from the Research Base after 
review.   
 
 
 
 Schedule of Activities 
 
Time-point 
Screening 
Pre-
Intervention 
Visit 
Day 0 
Mid-
Intervention 
Visit 
Post-
Intervention 
Visit 
Time window 
 
Day -8 to 0 
Intervention  
Start 
Day 14 to 26 
Day 412 
Screening  
X 
 
 
 
 
Informed Consent 
X 
 
 
 
 
Confirm eligibility/Register 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Adverse event review 
 
Weekly 
Weekly 
Weekly 
Weekly 
Medication Usage 
 
X 
 
 
 
Questionnaires 
 
X 
 
X 
X 
Cognitive Assessments  
(CANTAB and Paper-based 
Cognitive Tests) 
 
X 
 
 
X 
Brief Test of Adult Cognition by 
Telephone (BTACT; URCC Staff) 
 
 
X1 
 
X3 
Blood Draw  
 
X 
 
X 
X 
Laboratory Data  
(from medical record) 
 
X 
 
 
X 
Study Agent dispensed 
 
 
X 
 
 
Study Agent returned 
 
 
 
 
X 
Phone Contact 
 
Weekly 
Weekly 
Weekly 
Weekly 
Daily Diaries 
 
 
Daily 
Daily 
Daily 
1. For participants receiving chemotherapy, this will ideally be completed prior to first chemotherapy received while on 
study (Day 0) but can be completed within 7 days after the in-clinic cognitive assessments.  
2. If a participant cannot complete the Post-Intervention visit on Day 41 the visit may be completed on Days 38-44 as long 
as it is prior to the next administration of chemotherapy for participants currently receiving chemotherapy. 
3. Must be completed after computerized and paper-based cognitive tests are administered and before the participant 
receives the final chemotherapy while on the study if currently receiving chemotherapy. 
 
 
 Screening and Pre-Intervention Assessment 
 
 Screening and Consent 
 
All potentially eligible cancer patients that are currently receiving cytotoxic chemotherapy or 
have received cytotoxic chemotherapy treatment within the last 6 months and have been 
treated at NCORP communities affiliated with the URCC NCORP Research Base in the U.S. 
will be screened using an eligibility checklist. All screening data of potentially approached 
patients must be entered on the URCC screening log submitted monthly to the research base 
including those not eligible and those who declined to participate.  If the person meets all 
eligibility criteria, study personnel will go over the study in detail using the consent form.  
Both parties must sign the full study consent form, if the person agrees to be on study.  The 
eligibility checklist must be reviewed and signed by the participant’s oncologist prior to 
registering the participant. Contact Kari Gilliland at 585-275-6303 or email 
URCC_16092@URMC.rochester.edu with any questions regarding participant eligibility. 
 


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 Study Agent 
 
 Study Agent IND Exemption 
 
This clinical investigation of ibuprofen meets all criteria for an exemption from the IND 
requirements outlined in § 312.2(b). The study agent is a non-prescription oral medication 
lawfully marketed in the United States. The investigation is not intended to be reported to the 
FDA in support of a new indication, there is no intent to use this study to support any other 
significant change in ibuprofen labeling or to promote or commercialize the drug. This 
investigation does not involve any factors that significantly increase the risk associated with 
the use of ibuprofen. This investigation will be conducted in compliance with IRB 
regulations and policies. 
 
 The treatment arms will follow the guidelines listed below: 
 
 
The University of Rochester Investigational Drug Service (IDS) will supply the 
ibuprofen 200 mg in the form of pills over-encapsulated into opaque-colored capsules. 
A full six week supply of capsules will be given to the participants in a plastic vial by 
the study coordinator. Research participants will be instructed to take the ibuprofen 
once in the morning and once in the evening, where the doses are at least 8 hours apart.  
Participants will take 2 capsules /day for a total of 6 weeks.  They will be instructed to 
take capsules whole and not open the capsule. The IDS will keep all regulatory 
information regarding packaging of the study agent.  
 
 
The placebo capsule, which contains trace amounts of lactose (approximately 
0.32gm per capsule), will be supplied by the UR IDS and will be over-encapsulated 
into opaque-colored capsules to match the ibuprofen. A full six week supply of 
capsules will be given to the participants in a plastic vial by the study coordinator. 
Research participants will be instructed to take the capsules once in the morning and 
once in the evening, where doses are at least 8 hours apart.  Participants will take 2 
capsules/day for a total of 42 days (study Day 0 to Day 41). 
 
 
The study coordinator will contact each participant weekly to remind participants 
to take the study agent as directed. Review of diaries will occur at this time. The study 
coordinator will use this opportunity to assess any potential complications or toxicities 
due to the intervention and if any occur, they will be reported per the Adverse Events 
section (Section 11) of this protocol. Adherence and compliance is further detailed in 
Section 6.3  
 
 Obtaining Study Agent (Additional Study Agent Information in Section 8) 
 
Study agent will be shipped from the URCC NCORP Research Base to each participating 
site. In order for the sites to have interventions available upon enrollment, the URCC 
NCORP Research Base will ship study agent for each arm to each NCORP.  Bottles will be 
shipped to the designated pharmacy or investigator, who will be responsible for the receipt of 
the study agent from the Research Base, storage, and distribution to participants.  
Distribution and supply will be monitored and recorded using a modified version of the 
standard NCI Investigational Agent Accountability Record. Study agent can be requested by 
contacting Kari Gilliland at the URCC NCORP Research Base: 
 
 
PREFERRED CONTACT is e-mail: 
URCC_16092@URMC.rochester.edu 
Otherwise, call 585-275-6303 


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When ordering, the number of bottles of each arm and the study protocol number are 
required. Orders will be express mailed from the URCC within 2 working days unless 
notified otherwise.  
 
 Agent Disposal 
 
Any study agent returned by participants must be recorded on the Investigational Agent 
Accountability Record form and destroyed at the NCORP site per their institution’s 
guidelines.  At the completion of this investigation, any study agent left in stock (i.e., not 
dispensed to a study participant) will be destroyed at the NCORP site per their institution’s 
guidelines and recorded on the DARF. Investigational agents are NOT returned to URCC 
Research Base. 
 
 Pre-Intervention Visit 
 
 Questionnaires and Forms 
 
The On-Study Data/Participant Form is used to record demographic information (e.g., age, 
race, ethnicity, education).  Other clinical information (e.g., KPS or ECOG, diagnostic, 
planned and previous treatment (e.g., surgery, chemotherapy regimens, radiation, and 
hormone therapies)) will be abstracted from the participant’s chart and recorded on the 
Clinical Record Information form. The Laboratory Data form will be completed by the study 
coordinator using test results abstracted from the participant’s medical record. Lab values 
entered into the Laboratory Data form for the Pre-Intervention assessment should be 
collected within 10 days of the Pre-Intervention visit. If blood tests have not been completed 
within 10 days of the Pre-Intervention visit the coordinator will document this on the 
Laboratory Data form. 
 
The Medication Usage form, completed at the Pre-Intervention visit, will track the 
participant’s use of all prescription and non-prescription medications (e.g., stimulants, anti-
depressants, NSAIDs, vitamins; as cognitive aids or for other conditions) used at the time of 
enrollment. Participants will be asked about specific medications such as anti-depressants, 
stimulants, NSAIDs, and vitamins they may be taking.  This form will also specifically ask 
participants to report the use of any complementary and alternative medicine (CAM) 
modalities for any reason.  
 
All participants will complete the Daily Diary, which includes questions about symptoms, 
exercise, and drug usage, on Days 0 to 41.  
 
 Cognitive Functioning Assessments 
 
All coordinators must complete study-specific training in cognitive assessment prior to the 
conduct of assessments on study participants. Coordinators administering the cognitive 
assessments should use only the cognitive assessment manual and study-specific training 
provided by Dr. Janelsins’ team. After completing training, each coordinator will conduct at 
least one mock cognitive assessment. Results of the practice assessment should be submitted 
to the URCC Research Base for review at the study email 
URCC_16092@URMC.rochester.edu. A certification email will be sent to the coordinator 
from the Research Base after review.  Participants will first complete the FACT-Cog 
questionnaire and then all of the subsequent cognitive assessments.  
 
 Computerized Testing  
 


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Participants will complete three cognitive tests using Cambridge Neuropsychological Test 
Automated Battery (CANTAB), an objective and validated computerized testing tool for 
various cognitive functioning domains in the setting of multiple disorders, including 
cancer.69-78 All testing will be completed in a quiet, well-controlled environment at a flat 
workstation using a portable computer with a 20 inch touchscreen monitor provided to sites 
by the URCC NCORP Research Base. Cognitive tests will be administered in the 
following order: MOT, DMS, VRM (Immediate), RVP, CTMT (paper-based), COWA 
(paper-based), and VRM (Delayed), and WRAT-4 (Pre-intervention only) (paper-based). 
The VRM (Delayed) computerized cognitive test should be administered AFTER the 
completion of paper-based cognitive tests to meet the requirement for an approximate 20 
minute delay following the administration of the VRM (Immediate) test. The trained 
coordinator will describe each task to the participant prior to testing and provide scripted 
instructions throughout each task.  All computerized testing is anticipated to take about 30 
minutes to complete.  
 
 Participants will first complete a three-minute motor screening task (MOT) to 
confirm normal motor control and to get accustomed to using the computer. 
 
 Short-term visual memory will be assessed by the Delayed Matching to Sample 
(DMS) task. This test takes approximately 10 minutes to complete, and a total of 
three data points is obtained (at 0, 4, and 12 seconds). A participant is shown a 
complex visual pattern and then, after a brief delay (4 and 12 seconds), is shown 
four similar patterns. The participant is instructed to touch the pattern on the 
computer screen which exactly matches the sample. Speed to complete the task 
(latency in ms) is also assessed within the same measure which may indicate 
attention/motivation contributions to performance on the task. 
 
 Memory (verbal) will be assessed by the Verbal Recognition Memory (VRM) 
Task. In this task, the participant is asked to remember a list of words (presented 
to them on a screen) and then immediately recall them verbally. The participant is 
then asked to recall from a list if they previously saw the word (pressing yes or 
no). Following the next three tasks (i.e., the attention task, CTMT and COWA) 
approximately 20 minutes later, the participant is then asked to recall whether or 
not they recognize the word (pressing yes or no) from the original list of words. 
 
 Attention will be assessed by the Rapid Visual Information Processing (RVP) 
task. Errors will be recorded. A white box is displayed in the center of the 
computer screen, inside which digits, from 2 to 9, are displayed in a pseudo-
random order, at the rate of 100 digits per minute. The participant must detect 
consecutive odd or even sequences of digits (for example, 2-4-6) and respond by 
pressing the touch pad.  
 
 The coordinator will fill out a Brief Behavioral Observations During Cognitive 
Testing sheet about each study participant after each CANTAB assessment. This 
one page form will be used to determine the validity of the results. 
 
 Details for saving files are provided in the Cognitive Testing Manual. Upon 
completion of the computerized testing, data files (i.e., CANTAB files (html) and 
EXCEL files (.csv)) will be saved onto the CANTAB computer in the following 
format:  STUDY ID_Assessment #. Assessment 1 is Pre-Intervention and 
Assessment 2 is Post-Intervention. Back-ups will occur on each computer at 2 
week intervals; CANTAB will automatically ask you to back up the data, and the 
coordinator will follow the computer prompts as indicated.  
 


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URCC will provide USB flash drives that belong with each computer. The 
coordinator will transfer each of the files onto the flash drive to be transferred and 
saved on a HIPAA-compliant, regularly backed up network storage or computer. 
The EXCEL file (5 pages) will be printed and saved in the participant’s record, 
the CCLAR file will be uploaded to the URCC NCORP Research Base via 
Box.com. For participants receiving chemotherapy, the anticipated date of the last 
chemotherapy received while on the study will be communicated to the URCC 
Research Base by email when sending Post-Intervention CANTAB data files.   
CANTAB data must be submitted within 24 hours of each assessment. The 
CANTAB data file will be emailed to:  
 
URCC_16092@URMC.rochester.edu 
 
URCC will send an email response confirming receipt of the data. 
 
 Standard Paper-based Neuropsychological Testing 
 
All coordinators will be trained to administer and score neuropsychological tests 
as part of the computerized testing training and must submit a practice test for 
review prior to certification.   
 
Administration of the test battery takes approximately 20 minutes total. 
 
 Basic academic skills/cognitive reserve will be measured with the Wide Range 
Achievement Test-Fourth Edition (WRAT-4). The WRAT-4 Reading test 
involves the recognition and naming of letters and the pronunciation of words out 
of context. Participants are provided with the Green Wording list to read from. 
The administrator checks pronunciation carefully and scores the participant’s 
responses. This test will take approximately five minutes to complete. 
 
 Attention/scanning, speed/sequencing, and executive function will be assessed by 
the Trail Making Test (Comprehensive Trail Making Test Trails 1 and 5).79,80 In 
part A/Trail 1, participants draw a line connected to each number in sequential 
order. In part B/Trail 5, participants draw a line to connect numbers and letters in 
sequential order. Time to complete the test (in seconds) is recorded for both parts 
A and B.  Part A is stopped after 3 min, and Part B is stopped after 5 minutes.   
 
 Verbal fluency/executive function will be assessed by the Controlled Oral Word 
Association Test (COWA).81 Designed by Benton and colleagues, this test 
assesses fluency with naming words with C, F, and L.  Participants are asked to 
tell the administrator as many words as possible beginning with the letter C, 
excluding proper nouns and the same word with a different suffix. The participant 
has 60 seconds to list as many words as possible. The number of correct words 
will be recorded. This test takes less than five minutes to administer. Trials are 
repeated for the letter F and L. 
 
 
 Phone-based Cognitive Testing 
 
All phone-based cognitive testing will be conducted by trained research study 
staff at the URCC NCORP Research Base. Research study staff will contact 
participants by email or text messaging to schedule the phone-based cognitive 
testing if necessary. The adapted Brief Test of Adult Cognition by Telephone 
(BTACT) will be used and was originally developed at the Lifespan 


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Developmental Psychology Lab by Drs. Margie Lachman and Patricia Tun. This 
adapted telephone test battery was developed to be brief (taking no more than 20 
minutes to administer), to cover important domains of adult cognitive functioning, 
and to be easily administered by trained personnel. BTACT testing has resulted in 
similar cognitive scores as in-person testing. 82 
 
 Each participant will be asked to verify a short string of numbers (3,8,5) at the 
beginning of the call. 
 
 Memory will be assessed by the Rey Auditory-Verbal Learning Test81. One trial is 
administered at the beginning of the session and a second delayed trial is 
administered at the end of the session. One word per second is read aloud, and the 
participant recalls back as many of the words as possible within one minute. At 
the end of the session, participants are asked to recall as many words as possible 
from the list. The number of correct responses (one point) is totaled for the 
scoring of both immediate and delayed recall. The number of incorrect responses 
is also recorded for each.  
 
 Working memory/attention will be assessed with the backward digit span test 
from the WAIS-III (1997).83 The participant hears an increasingly longer series of 
digits read by the interviewer (starting with 2 digits leading up to 8 digits), and 
attempts to repeat them in reverse order. Two chances are given to complete each 
level. The test is stopped when the participant cannot get either trial for a 
particular number of digits. The score is the longest string (maximum of 8) that 
the participant can read in reverse order.  
 
 Executive function (verbal fluency) will be assessed by category fluency.  
Participants will be asked to list as many items in the category “animals” as they 
can within 60 seconds. The second executive function test is the Number Series 
test which involves a number series of increasing or decreasing length and pattern 
of numbers where the participant has to state what the next number would be. 
This is a 5-item measure. 
 
 Speed of Processing will be assessed by backward counting. Each participant will 
be asked to count backwards from 100 by one unit, and has 30 seconds to get as 
far as they can. The score is the total number of correct numbers reported. 
Skipped numbers and number of errors are also recorded.   
 
 Self-Reported Outcomes  
 
Note: FACT-Cog is completed prior to computerized and paper-based testing. 
After completion of computerized and paper-based cognitive assessments, all participants 
will complete the remaining questionnaires including the CES-D, Symptom Inventory, STAI, 
MFSI-SF, and Godin. Based on previous studies, we anticipate that these forms will take 
participants approximately 15 minutes to complete.   
 
 Self-reported cognitive functioning will be assessed by the Functional Assessment 
of Cancer Therapy with Cognition (FACT-Cog, ver 3). This measure includes 37-
items. The FACT-Cog addresses a wide range of cognitive functioning domains 
which allows one to separate specific domains of cognition. It was developed by 
Wagner and colleagues84 and is currently undergoing validation in studies with 
cancer patients.85  
 


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 Depressive symptoms will be measured with the Center for Epidemiological 
Studies Depression Scale (CES-D). The CES-D is a 20-item depression scale 
developed and validated for use with a variety of populations.  It is in a format 
similar to that of the Beck Depression Inventory, but with less emphasis on 
physical symptoms of depression that may be confounded with disease symptoms 
or treatment side effects.  It has been shown to reliably and validly measure 
depression in cancer populations,86 and we have successfully used this measure in 
previous studies.   
 
 General symptomatology will be measured with a Symptom Inventory, a list of 
symptoms modified from measures created at M.D. Anderson and Memorial 
Sloan-Kettering Cancer Centers.  It is a series of uniscales where the severity of 
each symptom is indicated on an 11-point scale, anchored by 0 = “Not Present” 
and 10 = “As Bad as You Can Imagine.”   
 
 Anxiety will be measured using the Spielberger State/Trait Anxiety Inventory 
(STAI Form).  In order to reduce the overall participant burden, we will use only 
the state portion of the questionnaire.  This one-page, self-administered 
questionnaire consists of 20 short statements which people may use to describe 
their feelings.  Participants are asked to fill in a numbered circle to indicate the 
degree to which they generally experience the particular feeling, ranging from 1 = 
“Not at all” to 4 = “Very much so” at that time.  It is one of the most widely-used 
assessments of anxiety.  Internal consistency coefficients > 0.90 have been shown, 
along with test/retest reliability coefficients > 0.70.  Concurrent, construct, 
convergent and divergent validity have also been demonstrated.87  We have 
successfully implemented this measure in previous studies. 
 
 Fatigue will be assessed via the Multidimensional Fatigue Symptom Inventory – 
Short Form (MFSI-SF).  The MFSI-SF is a 30-item fatigue scale developed 
specifically for documenting cancer-related fatigue.  In addition to a fatigue total 
score, the instrument includes subscales for assessing general, physical, 
emotional, mental and vigor domains of fatigue.  The self-report instrument was 
psychometrically validated among a sample of 304 cancer patients and has been 
shown to have good fit via confirmatory factor analysis, reliability and validity.88 
 
 The Godin is a brief two-part questionnaire used for assessing changes in leisurely 
exercise behavior over time and for assessing the impact of a physical activity 
program. 89 
 
   Blood Draw 
 
 Blood samples will be collected as part of the Pre-Intervention, Mid-Intervention, 
and Post-Intervention assessments. All study coordinators must perform training 
prior to any study procedures. Training can be organized by sending an email to 
the study mailbox (urcc_16092@URMC.rochester.edu). 
 
 Cytokines (i.e., MCP-1, IL-1 β, IL-6, IL-8, IL-10, sTNFR2 and sIL1Ra) can be 
reliably measured in the blood serum using a Luminex Multiplex Assay. Blood 
will be collected for banking of serum and plasma and whole blood for future 
protein, DNA and RNA analyses. An 8-hour fasting blood draw will be performed 
on all participants for the Pre-Intervention, Mid-Intervention, and Post-
Intervention assessments. Six tubes of blood (approximately 50ml) will be 
collected including:  two red top tubes for serum, two purple top EDTA tubes (1 
for plasma and 1 for DNA) and 2 Paxgene tubes for RNA.  All NCORPs will 


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handle all human biological materials and disposal of biohazard waste in 
accordance with biosafety level II guidelines at their respective institutions for 
blood collection, handling, disposal, storage and shipping.  All NCORP personnel 
handling human biological materials and laboratories used by NCORPs must have 
received appropriate biosafety certifications and meet routine inspection 
guidelines.   
 
 All requisitions, blood tubes, microfuge tubes, freezer boxes, pipettes, and labels 
for blood draws are provided by the URCC NCORP Research Base in the form of 
barcoded and pre-labeled participant kits. All participant kits are study specific.   
 
DO NOT MIX REQUISITIONS, BLOOD TUBES, MICROFUGE TUBES OR 
PIPETTES ACROSS PARTICIPANT BLOOD DRAW KITS EVEN IN THE 
SAME STUDY BECAUSE THE BARCODES AND LABELS ARE KIT 
SPECIFIC. 
 
DO NOT MIX THE FREEZER BOXES, LABELS OR EXTRA SUPPLIES 
PROVIDED ACROSS STUDIES EVEN URCC NCORP RESEARCH BASE 
STUDIES BECAUSE THEY ARE STUDY SPECIFIC. 
 
All study coordinators will fill in the appropriate participant information on the 
requisition form in each kit when it is assigned to the participant.  Every time a 
blood draw is performed a separate new kit is used and assigned to the study 
participant. Each NCORP is responsible for designating an individual that is 
certified by URCC and a lab or facility that meets the biosafety level II criteria to 
perform the blood draws and to handle, dispose, store and ship the blood samples 
appropriately.  The individual designated to coordinate the blood draws, handle, 
dispose, store and ship the samples must participate in the training provided by the 
URCC NCORP Research Base, and be approved by the study PI, Dr. Janelsins, 
prior to any blood collection at each NCORP site. 
 
 Serum will be extracted from the two red top tubes for estimation of cytokines 
(MCP-1, IL-1 β, IL-6, IL-8, IL-10, sTNFR2 and sIL1Ra).  Plasma will be 
extracted from one of the purple top EDTA tubes for estimation of cytokines 
(MCP-1, IL-1 β, IL-6, IL-8, IL-10, sTNFR2 and sIL1Ra).  To extract the serum 
and plasma, the tubes will first sit upright for 30 minutes at room temperature 
after blood collection.  Second, the tubes will then be put into a centrifuge (4°C if 
available) and spun for 15 minutes at 1600 x g.  After 15 minutes, there should be 
a clear separation of the serum or plasma (yellowish liquid on top) from the other 
cells.  If this is not evident, then centrifuge for 15 additional minutes.  The upper 
layer of serum (red top tubes) and plasma (purple top tube) is then gently 
aliquotted into the 2.0ml microfuge tubes provided in each URCC NCORP 
participant blood draw kit.  Serum from the red top blood tubes is to be placed 
into the pre-labeled pink microfuge tubes.  Plasma from the purple top tube is to 
be placed in the pre-labeled purple microfuge tubes.  All microfuge tubes are then 
placed in the pre-labeled freezer boxes provided by the URCC NCORP Research 
Base and the freezer box is then placed in either a -20°C freezer or a -80° C 
degree freezer (-80°C is preferred if available but not required) for storage until 
shipped to URCC NCORP Research Base.  Cytokines (MCP-1, IL-1 β, IL-6, IL-8, 
IL-10, sTNFR2 and sIL1Ra) will be assessed using Multiplex and ELISA 
methods as appropriate.  The remaining serum and plasma will be stored and 
banked for use in future research by Dr. Janelsins and her research team if 
participants have given permission.  
 


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 One purple top EDTA tube and two Paxgene tubes will be prepared and stored for 
future DNA and RNA extraction.  The EDTA tube will be rocked 10 times and 
then placed upright in a -20° C freezer for a minimum of 24 hours.  After 24 
hours, the EDTA tube can then be transferred to a -80° C freezer if available.  The 
two Paxgene tubes will be rocked 10 times, stored upright for minimum of 2 
hours and a maximum of 24 hours at room temp and then placed upright in a -20° 
C freezer for a minimum of 72 hours.  After 72 hours, the Paxgene tubes can be 
transferred to a -80° C freezer if available.  After the tubes have been frozen 
upright for their designated time above, they can then be placed on their side in 
the pre-labeled freezer boxes provided by the URCC NCORP Research Base.  
(Storage in a -80° C freezer after 4 days is preferred if available but not required.)  
 
 
Shipping Supplies to NCORPs and Inventory Tracking:   
 
When the URCC NCORP Research Base receives notification that the NCORP has 
received CIRB approval, a starter blood drawing package, Blood Procedures 
Operations Manual, and an initial supply of barcoded and pre-labeled blood draw 
kits will be shipped to the NCORP for distribution and use.  
 
Each NCORP site will be responsible for designating someone on the research 
staff to be responsible for receiving the blood draw supplies and kits.  The staff 
member will verify that the shipment contains the correct number of supplies and 
kits and that the supplies and kits are in good condition.  The identification 
numbers need to be verified for accuracy and recorded.  The Investigational 
Device Accountability Record (DARF) will be used to track supplies and kits 
arriving from the URCC NCORP Research Base, kits given to participants, 
samples stored, and samples shipped to the URCC NCORP Research Base. 
 
 
Shipping Frozen Blood Samples to URCC NCORP Research Base: 
 
THE URCC NCORP RESEARCH BASE MUST BE NOTIFIED AND 
ARRANGEMENTS MADE TO RECEIVE SAMPLES AT THE URCC NCORP 
RESEARCH BASE 24 HOURS IN ADVANCE PRIOR TO SHIPPING ANY 
SAMPLES 
 
WE WILL NOT ACCEPT PACKAGES TO BE RECEIVED ON A FRIDAY. 
 
To arrange shipping samples, refer to the provided URCC16092 Blood Procedures 
Operations Manual. 
 
Ship Samples To: 
ATTN:  Cancer Control 
University of Rochester Medical Center 
CCPL Laboratory (2-3155) 
601 Elmwood Avenue 
Rochester, NY 14642 
 
NCORPs must ship the frozen samples to the URCC NCORP Research Base 
CCPL Lab every 3 months.  Samples cannot be kept at the NCORP location for 
longer than 3 months total.  Samples can be shipped sooner if storage space is 
limited.   
 
The NCORPs are responsible for shipping all samples to the URCC NCORP 
Research Base.  All samples must be shipped priority overnight and frozen on dry 


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ice.  Each NCORP is responsible for adhering to URCC NCORP Research Base 
biosafety level II guidelines (outlined in the Blood Procedures Operations Manual 
provided), their NCORP institutional biosafety level II guidelines and the shipping 
company guidelines when packing and shipping the frozen blood samples to the 
Research Base. 
 
 Mid-Intervention Assessments 
 
Between study Days 14 and 26 participants will complete Mid-Intervention assessment. At Mid-
Intervention, the study coordinator will collect and process blood samples and complete the Blood 
Requisition form, and store samples until shipping is required. Participants will complete a FACT-Cog 
questionnaire between study Day 14 and 26 on their own. 
 
 
 
 
 Post-Intervention Visit 
 
Ideally, the Post-Intervention visit will occur on Day 41. However, if a participant cannot complete the 
Post-Intervention visit on day 41, the participant can complete the visit on Days 38-44. For participants that 
are currently receiving chemotherapy, the Post-Intervention visit can occur on the same day as a 
chemotherapy treatment if assessments are completed prior to chemotherapy.   
 
At the Post-Intervention visit, participants will complete study questionnaires including the FACT-Cog, 
CES-D, MFSI-SF, STAI, and Symptom Inventory (SI), Godin, and feedback questionnaire. Study staff will 
complete the Investigational Agent Accountability Form after the participant returns unused study agent. 
 
Cognitive assessments to be performed at the Post-Intervention visit include the CANTAB computerized 
assessment, paper-based cognitive testing (COWA and CTMT), and phone-based Cognitive Testing 
administered by URCC staff. Note: FACT-Cog is to be completed prior to computerized and paper-based 
testing. For participants receiving chemotherapy, the anticipated date of the last chemotherapy received 
while on the study will be communicated to the URCC Research Base by email when sending Post-
Intervention CANTAB data files. Phone based-testing will be completed within 7 days of the in-clinic Post-
Intervention assessments.  
 
Blood samples will be collected during the Post-Intervention visit period, the Blood Requisition form will 
be completed, and processed samples will be shipped to the URCC NCORP Research Base when required 
per shipping requirements in Section 5.5.4. 
 
The Laboratory Data form will be completed using test results abstracted from the participant’s medical 
record. Lab values entered into the Laboratory Data form for the Post-Intervention time point should be 
collected within 10 days of the Post-Intervention visit. If blood tests have not been completed within 10 
days of the Post-Intervention visit the coordinator will document this on the Laboratory Data form. 
 
All cancer treatment records (e.g., chemotherapy, any biologic/targeted therapies, radiation) prior to going 
on study through the duration of the study must be submitted with protected health information redacted 
and labeled with Participant ID and NCI protocol number. 
 
Study coordinators will collect unused study agent and completed diary pages from study participants at the 
Post-Intervention visit.  
 
 Potential Risks  
 
 Ibuprofen 


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The potential risks and side effects of ibuprofen can include headaches, dizziness, 
drowsiness, rash, abdominal pain, nausea, diarrhea, constipation, renal insufficiency, and 
heartburn.  Since ibuprofen reduces the ability of blood to clot, bleeding may be increased 
after injury. Studies of high doses of ibuprofen (800 mg 3 times per day) have been 
associated with low incidence of gastroduodenal and gastric ulcers.90,91 The low dose for the 
proposed studies is not likely to cause ulcers; as a precaution, we are excluding those who 
have a history of ulcer disease during the past year. A full list of potential side effects of 
ibuprofen are located in the consent form and will be reviewed with the potential participant. 
Additionally, lactose is not an exclusion criteria due to trace amounts found in the placebo 
capsules (approximately 0.32 grams); however, this information is included in the consent 
form and will be reviewed with the potential participant and any concerns should be 
addressed with the provider.  
 
NSAIDs (e.g., ibuprofen) have been used in clinical studies in cancer patients receiving 
chemotherapy and have been safe and have not altered chemotherapy pharmacokinetics.92 
The doses of ibuprofen and time-frame of ibuprofen that we have chosen are similar to other 
ongoing studies of NSAIDs given in combination with chemotherapy (clinicaltrials.gov 
identifiers: NCT00520091, NCT00300729, NCT00064181, NCT00135018). 
 
 
Ibuprofen Toxicity Monitoring 
 
Participants should be removed from the study for any of the following reasons:  
 
1. Any grade ≥ 4 toxicity probably or definitely related to the study agent. 
2. Any grade >2 toxicity that persists for more than 2 weeks that is probably 
or definitely related to study agent. 
3. Any grade >2 GI bleeding. 
4. Primary treating physician deems it is unsafe for the patient to continue on 
the study for any reason. 
5. Withdrawal of consent. 
 
 
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 5.0 as described in Section 11.   
 
 Blood Collection 
 
There is a chance of bruising and a very slight chance of infection with blood collection.  
This will be minimized through the use of standardized hospital procedures for blood 
collection, use of a trained phlebotomist and sterile materials. 
 
 Participant Withdrawal  
 
If a participant decides to withdraw from the study, the study staff should clarify whether the participant 
wishes to withdraw entirely from the study or only from a component of the study. If a participant requests 
to be withdrawn from the study agent, research activities involving other components of the clinical trial, 
such as follow-up data collection activities, for which the participant previously gave consent, may 
continue. The study site staff may continue to follow the study participant for assessment data if the 
participant agrees and medical monitors feel it is safe for the participant to complete study assessments. 
Study participants may resume the study intervention if the participant agrees and medical monitors feel it 
is safe for the participant to receive study intervention. All communication (e.g., emails) with study medical 
monitors must be documented and recorded in the research record. Any withdrawals or partial withdrawals 
are documented on a Withdrawal and Study Status Form via REDCap with a physical copy of the form 


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filed in the participant binder. The REDCap Withdrawal and Study Status Form can be found on the URCC 
NCORP Research Base website. 
 
 Data & Specimen Storage for Future Research Use 
 
All human blood samples collected for the current study will be used in post hoc analyses as appropriate by 
Dr. Janelsins’ and her colleagues. The participant indicates on the consent form whether their blood is 
allowed to be used for future research. If a participant does not allow their blood to be used for future 
research, their blood will not be stored. Human samples collected for future research are stored in locked 
and alarmed freezers within Dr. Janelsins’ labs that are accessible by electronic card swipes or card swipe 
and key.  
 
 Costs to the Participant 
 
All study materials are provided without cost to participants.  
 
 Payment for Participation  
 
Participant Payment:  In order to improve study retention and compliance, participants will be compensated 
for their participation and completion of study procedures. Participants that complete all assessments will 
receive a total payment of $100.00. Participants will receive $25.00 after completing the Pre-Intervention 
assessment, $30.00 after completing the Mid-Intervention assessments ($5/wk x 6 weeks), and $45.00 after 
completing the Post-Intervention assessment.  Compensation has been pro-rated for participants that do not 
complete the full study.  Participants are only paid for the study assessments they actually complete.  Each 
NCORP will be responsible for dispersing the payments to study participants using methods appropriate for 
their sites.  Each NCORP will invoice the URCC Research Base monthly for payment expenses.  URCC 
will only reimburse for the cash value per assessment; no gift card or other fees will be reimbursed if 
NCORPs choose to use methods of payment that incur extra fees in lieu of cash. Contact Christine Lanceri 
to obtain an NCORP-specific invoice. 
 
Send invoices by email to: 
Mrs. Christine Lanceri 
Email: Christine_Lanceri@URMC.rochester.edu 
 
  INTERVENTION/STUDY AGENT ADMINISTRATION AND INFORMATION 
 
 Contraindications 
 
Participants must have approval of their treating physician to take the study agent. Participants should not 
take a regular daily NSAIDs in addition to their study agent during the intervention period. Higher doses of 
an NSAID on an ‘as needed’ basis are permitted. Daily doses of 81 mg aspirin are permitted. 
 
 Medications 
 
All medications (prescription and over-the-counter), vitamin and mineral supplements, and/or herbs taken 
by the participant will be documented on the Medication Usage form at the Pre-Intervention visit. 
Medications taken for a procedure (e.g., surgery) should also be included. 
 
 Adherence/Compliance 
 
 Intent to treat analysis will be used. All participants enrolled into the study will be included in 
the analysis. 
 


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 Adherence and compliance of participants to the study agent will be monitored via the Daily 
Diary. Also, during weekly phone calls, study coordinators will question participants on their 
study agent compliance and address any questions. Participants are also asked to return 
unused study agent at the end of the intervention period for an evaluation of study agent 
compliance. The Investigational Agent Accountability Form will be used to capture the 
number of capsules dispensed to and returned from participants. 
 
 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 
  
 Primary Endpoint 
 
The primary aim is to provide preliminary data on the effects of ibuprofen on alleviating cancer-related 
cognitive impairment in cancer patients that have received chemotherapy compared to placebo control, as 
assessed by the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog). 
 
 Off-Agent Criteria  
 
Participants may stop taking study agent for the following reasons: completed the protocol-prescribed 
intervention, adverse event or serious adverse event, inadequate agent supply, noncompliance, concomitant 
medications, or medical contraindication. Participants will continue to be followed, if possible, for safety 
reasons and in order to collect endpoint data according to the schedule of events.  
 
The participant will stop the study medication at the Post-Intervention visit (if visit occurs Days 38-41). If 
participants are 100% compliant with the study agent use instructions, there will be no capsules left in the 
bottle at the end of Day 41. Because there is flexibility in scheduling the post-intervention visit, the 
participant could end prior to Study Day 41 (i.e. 42 days of medication). In this case, the number of pills 
left will be noted on the Investigational Agent Accountability Form. If a participant is withdrawn or 
partially withdrawn from the study, coordinators will record the study day on which the study agent is 
stopped on the REDCap Withdrawal and Study Status Form.  
 
Study medication may be stopped at any time as determined by the treating physician if there is a reason 
they deem the intervention is unsafe for the participant as mentioned in the toxicity monitoring plan in 
Section 5.8.1.1.   
 
There are no dose modifications of the study agent. 
 
 Off-Study Criteria 
 
Participants may go ‘off-study’ for the following reasons: the protocol intervention and any protocol-
required follow-up period is completed, adverse event/serious adverse event, lost to follow-up, non-
compliance, concomitant medication, medical contraindication, withdraw consent, death, physician request, 
or pregnancy.  
 
 STUDY AGENT/DEVICE DISTRIBUTION – IBUBROFEN/PLACEBO 
 
 Availability 
 
Ibuprofen and matching placebo will be manufactured by the UR IDS and supplied by URCC NCORP 
Research Base. Both ibuprofen and placebo capsules will be packaged in bottles containing 84 capsules. 
 
 Distribution  
 


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The ibuprofen and placebo capsules will be supplied by the UR IDS and will be over-encapsulated. Agents 
will only be released by URCC NCORP Research Base affiliates approved to participate. URCC-supplied 
agents must be requested by the Investigator (or their authorized designees) at each site. URCC does not 
automatically ship agents; the site must make a request. Agents are requested by emailing the URCC 
NCORP Research Base and should include complete shipping and contact information): 
 
Kari Gilliland 
URCC_16092@URMC.rochester.edu 
585-275-6303 
 
 Agent Accountability 
 
The NCORP site, and responsible party designated at the site, must maintain a careful record of the 
inventory and disposition of all agents received from the URCC NCORP Research Base using the 
Investigational Agent Accountability Record. All receipt and dispensation of study agent should be 
recorded, including date, quantity and batch or lot number.  
 
 Packaging and Labeling 
 
UR IDS, under the direction of Steve Bean, PharmD, will package, label and oversee the distribution of 
ibuprofen and placebo to participating NCORP sites. Each bottle of study agent will contain 84 capsules. 
Each bottle will be labeled with a two-part label identifying study specific information, including study 
title, URCC protocol number, dosing instructions, recommended storage conditions, the name and address 
of the distributor, randomization number, and a caution statement indicating that the agent is limited by 
United States law to investigational use only and the agent should be kept out of reach of children.  
 
 Storage 
 
Store ibuprofen and placebo at room temperature, between 59°F and 86°F (15°C and 30°C). Store study 
agents away from heat, moisture, and light. Study agents should be stored in a secured location that is 
locked at all times and only accessible by approved study personnel. 
 
 Blinding and Unblinding Methods 
 
Participants, study coordinators, and investigators will be blinded to ibuprofen/placebo group assignments. 
The active study agent supplied to participants entered into arm 1 will be indistinguishable from the 
placebo supplied to participants entered into arm 2. Active agent and placebo treatments will be self-
administered by participants at the same dose and frequency (200 mg twice a day). Study agents supplied to 
sites will be labeled with a letter code that will be used to identify the assigned treatment arm for 
unblinding purposes.  
 
Unblinding of the study agent is ONLY permitted in the case of serious and unexpected adverse events that 
are definitely associated with the use of the study agent AND if knowledge of the study treatment arm 
received is necessary for interpreting the medical event and related treatment of that medical event. In this 
situation, only the treating physician will be made aware of the study agent dispensed and no other staff 
members will be notified. Research staff at NCORP sites can request unblinding of a participant’s study 
agent treatment group by emailing the URCC NCORP Research Base and should include participant ID 
number, site investigator, and reason for unblinding in the message: 
 
Kari Gilliland 
URCC_16092@URMC.rochester.edu 
585-275-6303 
 


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URCC Research Base staff will contact sites regarding unblinding requests within 24 hours of notification. 
Participants that require emergency study agent disclosure will discontinue the study agent. The research 
team may continue to follow the study participant for assessment data with participant and medical monitor 
approval.   
 
Any unblinding will be communicated to the CIRB in accordance with its reportable events policy. 
 
 CORRELATIVE/SPECIAL STUDIES 
 
 Rationale for Methodology Selection 
 
We will use standardized Millipore Luminex kits that have been used to analyze these or similar targets in 
hundreds of samples from NCORP samples in Dr. Janelsins’ laboratory. These are industry standard kits 
that have undergone R&D and validation at Millipore.  
 
 Comparable Methods 
 
Luminex kits are industry standard and well validated. We can replicate our results with ELISA in a subset 
of participants.   
 
 SPECIMEN MANAGEMENT  
 
 Laboratories 
 
All samples will be analyzed by the University of Rochester Medical Center Cancer Control and 
Psychoneuroimmunology Laboratory using the same Luminex machine with the same assay kits and 
reagents. This will limit biases in data output. The lab will conduct stability and selectivity analyses for our 
samples to assure data quality before running all samples.  Any remaining samples will be stored in the 
URCC NCORP Research Base secure and alarmed -80C freezer. 
 
 Specimen Storage 
 
After processing, the remaining blood samples will be stored for use in future research by Dr. Janelsins and 
her research team. Only specimens where participants have consented to future research will be used in any 
future research not included in this protocol.   
  
 REPORTING ADVERSE EVENTS 
 
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), version5.0. The CTCAE is available at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.html. 
 
CTCAE term (AE description) and grade:  CTCAE version 5.0 will be utilized for AE reporting.  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 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
The relationship to the study agent and the severity of each adverse event as judged by the investigator 
must be recorded.  Attribution to protocol treatment for each adverse event must be determined by the 
investigator and reported on the required forms, using the codes provided. 
 


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 Definitions 
 
Adverse event (AE) is any untoward medical occurrence associated with the use of a medical product, 
which does not necessarily have a causal relationship with its use.  An adverse event can be any 
unfavorable and unintended sign (including abnormal laboratory test results), symptom, or disease 
temporally associated with the use of the study product or not considered related to the study product.  The 
relationship of each adverse event to the study interventions must be recorded as one of the choices on the 
scale described below. 
 
Attribution:  An assessment of the relationship between the adverse event and study agent/intervention, 
using the following categories.  
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to the study agent  
Unlikely  
The AE is doubtfully related to study agent  
Possible 
The AE may be related to study agent 
Probable 
The AE is likely related to study agent 
Definite 
The AE is clearly related to study agent 
 
Serious Adverse Event (SAE):  A serious adverse event is defined as any adverse medical event 
(experience) that results in at least one of the outcomes listed below: 
1) Death 
2) Life-threatening 
3) Requires inpatient hospitalization or prolongation of existing hospitalization. 
4) Results in persistent or significant disability/incapacity with substantial disruption of the ability 
to conduct normal life functions. 
5) Congenital anomaly/birth defect. 
6) A medical event that may not result in death, be life threatening, or require hospitalization may 
be considered an SAE when, based upon medical judgment, it may jeopardize the patient or 
participant and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
 
Hospitalization (or prolongation of hospitalization):  For AE reporting purposes, a hospitalization is 
defined as an inpatient hospital stay equal to or greater than 24 hours. 
 
 Reporting 
 
At each participant visit the site study staff will assess adverse events by recording all voluntary complaints 
of the participant and by assessment of clinical and laboratory features.  At each study visit and weekly 
phone contact, the participant should be questioned directly regarding the occurrence of any adverse 
experience since his/her last contact with the study staff.   
 
All adverse events, whether observed by study staff or investigator, elicited from or volunteered by the 
participant, should be documented.  Each adverse event will include the date of onset, date of resolution, 
severity, and the relationship to the study agent or intervention, and any action taken with respect to the 
study agent or intervention. 
 
Recording of the adverse events will occur once the participant signs the consent form.  
 
Adverse events will be reported to the URCC NCORP Research Base using REDCap, which can be 
accessed from the URCC NCORP website.  The following table will be utilized to report adverse events: 
 
Adverse Event 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 


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Unrelated 
 
URCC-GI 
Bleed Only 
URCC 
URCC 
URCC 
Unlikely 
 
URCC-GI 
Bleed Only 
URCC 
URCC 
URCC 
Possible 
URCC 
URCC 
URCC 
URCC 
URCC 
Probable 
URCC 
URCC 
URCC 
URCC 
URCC 
Definite 
URCC 
URCC 
URCC 
URCC 
URCC 
 
Adverse events Grades 1 and 2 that the treating physician determines are unrelated or unlikely related to 
study participation do NOT require reporting with the exception of grade 2 gastrointestinal (GI) bleeding 
which will need to be reported to URCC via REDCap Adverse Event Reporting.  All other adverse events 
will be reported to the URCC NCORP Research Base using REDCap Adverse Event Reporting. Serious 
adverse events requiring expedited reporting via CTEP-AERS are described below in Section 11.3.  Serious 
adverse events not requiring expedited reporting through CTEP-AERS should be entered into REDCap and 
URCC notified within 10 calendar days of learning of the event. 
 
All recorded adverse events reported to the URCC Research Base will be reported to the Data Safety 
Monitoring Committee. 
 
All adverse events that in the opinion of the investigator are clinically significant will be documented and 
followed according to good medical practices. 
 
 Responsibilities for Expedited Reporting  
 
URCC NCORP Research Base affiliates are required to notify the URCC Research Base  if a participant 
has an adverse event requiring expedited reporting.  All SAEs that meet expedited reporting criteria defined 
in the reporting table below will be reported via CTEP-AERS, the Adverse Event Expedited Reporting 
System, accessed via the CTEP web site, https://eapps-ctep.nci.nih.gov/ctepaers/pages/task  
 
Commercial reporting requirements are provided in the table below.  The commercial agent used in this 
study is ibuprofen.   
 
Expedited reporting requirements for adverse events experienced by participants who have received 
study agent/intervention within 30 days of the last administration of commercial study 
agent/intervention.   
Attribution 
Grade 4 
Grade 5(a) 
 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated or Unlikely 
 
 
CTEP-AERS 
CTEP-AERS 
Possible, Probable, Definite 
CTEP-AERS 
 
CTEP-AERS 
CTEP-AERS 
 
CTEP-AERS:  Indicates an expedited report is to be submitted via CTEP-AERS within 10 calendar days 
of learning of the event (b). 
a) This includes all deaths within 30 days of the last dose of study agent with a commercial 
agent/intervention, regardless of attribution.  Any death that occurs more than 30 days after the 
last dose of study commercial agent/intervention and is attributed (possibly, probably or 
definitely) to the agent/intervention and is not due to cancer recurrence must be reported 
according to the instructions above. 
b) Submission of the on-line CTEP-AERS report plus any necessary amendments generally 
completes the reporting requirements.  You may, however, be asked to submit supporting 
clinical data to the Research Base in order to complete the evaluation of the event.   
For more information see: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
 


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Contact Information for NCI Safety Reporting: 
Website for submitting expedited reports 
http://eapps-ctep.nci.nih.gov/ctepaers  
AEMD Help Desk (for CTEP)* 
301-897-7497 Monday through Friday, 7:00 AM to 7:00 
PM (US Eastern Time) 
Fax for expedited report supporting 
Medical Documentation for CTEP Trials 
301-230-0159  
(Back-up FAX: 301-897-7404) 
AEMD Help Email: 
aemd@tech-res.com 
Technical (E.G., IT or computer issues 
ONLY) Help Phone * 
1-888-283-7457 or 301-840-8202 
CTEP-AERS Technical Help Email 
ncictephelp@ctep.nci.nih.gov 
CTCAE v 5 Help/Questions Email 
ncicctcaehelp@mail.nih.gov 
CTEP-AERS FAQs link 
https://eapps-
ctep.nci.nih.gov.ctepaers/help/webhelp/CTEP-
AERS%20FAQ.htm 
CTEP-AERS Computer based training link 
https://ctep.cancer.gov/protocolDevelopment/ 
electronic applications/adverse_events.htm 
 
Office phone and fax are accessible 24 hours 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. 
 
 STUDY MONITORING 
 
 Data Management Summary 
 
All participant data will be identified in the database by a study ID assigned by sequential numbering. This 
project will collect data in multiple formats:  paper documents, CANTAB csv files, electronic 
questionnaires (REDCap), and biospecimens (blood). 
 
All data forms must be sent to URCC within 30 days of completion from the participant.  
 
When paper data are received at the URCC NCORP Research Base, they are processed as follows: 
1. 
Data are visually checked line by line for missing, duplicate, ambiguous or unreasonable 
responses and if found, the originating site is queried for such data. 
2. 
When a query response is received, the form is amended per Good Clinical Practice, and 
the change is documented or the sites amend the form and submits it to the URCC 
Research Base. 
3. 
All paper forms are scanned via Teleforms software into tables in an Access database. 
Again, any missing, duplicate or ambiguous data found at this step generates a query to the 
originating site. 
4. 
The electronic database tables are visually checked, line by line, against the corresponding 
forms for accuracy. 
5. 
Queries are also generated if data are not received per the protocol timeline. 
6. 
When all data have been received on any given case, a chart audit is performed to ensure 
receipt and accuracy of all necessary data. 
7. 
All paper documents are stored in locked file cabinets or in locked, limited access file 
rooms. The electronic Access databases of those scanned documents are on password 
protected drives located behind University of Rochester firewalls, with limited access. 
 
Data submitted through REDCap are reviewed for accuracy and stored, protected by the University of 
Rochester firewalls with limited access. Queries are generated for any questionable or late data. 
 


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Biospecimens:  Blood kits sent from URCC have bar-coded tubes for collecting samples.  One kit is used 
for one data collection time point of one participant.  Samples are frozen on site and shipped frozen to 
URCC where they are stored in locked -80o freezers in Dr. Janelsins’ lab with limited access.  
 
CANTAB files are electronically sent to URCC by uploading to the URCC NCORP Research Base secure 
file servers via the University of Rochester’s Box.com system.  
1. 
The files are opened to confirm that the data in the file agrees with the site’s label of the 
file. 
2. 
These data are stored on password protected drives located behind University of Rochester 
firewalls, with limited access. 
 
Forms can also be emailed to the study email: 
URCC_16092@URMC.rochester.edu  
 
(Pages sent by email must be straight with all four Teleform brackets visible on the page). 
 
On-site audits are conducted by the Research Base at least every three years in accordance with NIH/NCI 
CTMB Guidelines.  The primary objective of an on-site audit is to document compliance of the NCORP 
site with protocol and regulatory requirements, verify accuracy of data by comparing submitted data to 
source documents at the NCORP site, and to provide information on good clinical practice in study conduct 
and data management. 10% of cases accrued at each component site are audited.  The on-site pharmacy is 
visited and investigational agent records are reviewed at that time.  
 


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 Records to be Kept 
 
Evaluation/ Procedure 
Screening 
Pre-
Intervention 
Day 0 
Mid-
Intervention 
Post- 
Intervention 
Eligibility Checklist 
X 
 
 
 
 
Informed Consent Form  
X 
 
 
 
 
Screening Data on all approached 
subjects 
(Submitted electronically) 
X 
 
 
 
 
Clinical Trial Patient Registration  
X 
 
 
 
 
Clinical Record Information* 
 
X 
 
 
 
On Study Data/Participant Form 
 
 
X 
 
 
 
Medication Usage 
 
X 
 
 
 
Investigational Agent 
Accountability Form 
 
 
 
 
X 
Behavioral Observations During 
Cognitive Testing 
 
 
X 
 
 
 
X 
WRAT-4 Reading 
 
X 
 
 
 
CTMT 
 
X 
 
 
X 
COWA 
 
X 
 
 
X 
Laboratory Data  
 
X 
 
 
X 
Blood Requisition Form  
 
X 
 
X 
X 
BTACT Phone Interview Tests 
(URCC Conducts) 
 
 
X 
 
 
 
X 
FACT-COG 
 
X 
 
X 
X 
CES-D 
 
X 
 
 
X 
STAI 
 
X 
 
 
X 
MFSI-SF 
 
X 
 
 
X 
Symptom Inventory 
 
X 
 
 
X 
GODIN 
 
X 
 
 
X 
Feedback Questionnaire 
 
 
 
 
X 
Daily Diary  
 
 
Daily 
Daily 
Daily 
Call Logs 
 
Weekly 
Weekly 
Weekly 
Weekly 
Receipt for Participation 
 
X 
 
X 
X 
Withdrawal and Study Status Form 
(Completed as needed in REDCap) 
 
 
 
 
 
* All cancer treatment records (e.g., chemotherapy and other biologic therapy-radiation summary) prior to going on study 
through the duration of the study must be submitted with the Post-Intervention forms (with protected health information 
redacted). 
 
 
 Data and Safety Monitoring Plan 
 
All adverse events reported to URCC are per Section 11.   
 
The James P Wilmot Cancer Center Data Safety Monitoring Committee (DSMC) will serve as the DSMC 
of record for this study. The DSMC provides oversight of study progress and safety by review of accrual 
and events at regularly scheduled meetings.   
 
Study investigators conduct continuous review of data and patient safety. The Wilmot Cancer Center Peer 
Review Committee has determined that progress reports of these data will be submitted annually to the 
DSMC for review. These reports will include: the number of participants enrolled, withdrawals, any 


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significant toxicities, and serious adverse events both expected and unexpected. The study chair maintains a 
database of all adverse events with toxicity grade and information regarding treatment required, 
complications, or sequelae.  A copy of the AE spreadsheet is submitted with the annual progress report to 
the DSMC for review. Actual review dates will be assigned when the 1st patient is accrued. 
 
• 
Any adverse event that is serious, related AND unexpected must be reported within 10 
calendar days from notification to the DSMC safety coordinator and DSMC chair.  The 
NCORP sites will report to the URCC NCORP Research Base in REDCap and if applicable 
CTEP AERS per Section 11 of the protocol.  The NCORP Research Base will be responsible 
for reporting to the DSMC. The DSMC Chair will determine whether further action is required, 
and when patient safety is of concern, may call an interim meeting. 
 
• 
Serious adverse events that are related AND expected or unrelated AND unexpected will be 
reported to the Committee for review at the annual meeting. SAE reports are expected to 
include sufficient detail so that the DSMC can determine the severity, toxicity grade, 
expectedness, treatment required, and a follow up report documenting resolution or if there are 
sequelae. Unless otherwise specified in the protocol, serious adverse events that require 
reporting (but not necessarily expedited) are expected, related, non-hematologic toxicities of 
grades 3, 4 or 5. See Section 11 for specific reporting requirements for this protocol.  
 
The DSMC Safety Coordinator administratively coordinates reports and data collection and prepares 
documents for the DSMC Chair and committee review.  The Safety Coordinator will administratively monitor 
adverse event rates utilizing the report from the study database.  If the study has had two or more of the same 
SAE’s reported in a month or more than six of the same SAE’s in six months, the DSMC will review the 
summary of SAEs, discuss events with Study Chair, and conduct a more detailed review with the Study 
Chair. The Data Safety Monitoring Chair will determine if further action is required. 
 
The URCC will notify the NCORP sites immediately of any serious safety concerns identified by the 
DSMC.  DSMC reports will be available for download on the research base website. 
 
 Record Retention 
 
Clinical records for all participants, including CRFs, all source documentation (containing evidence to 
study eligibility, history and physical findings, laboratory data, results of consultations, etc.), as well as IRB 
records and other regulatory documentation will be retained by the originating NCORP site in a secure 
storage facility in compliance with Health Insurance Portability and Accountability Act (HIPAA), Office of 
Human Research Protections (OHRP), Food and Drug Administration (FDA) regulations and guidance, and 
NCI/DCP requirements, unless the standard at the site is more stringent. Records will be retained at the 
NCORP site for at least five years after the completion of the research. The records should be accessible for 
inspection and copying by authorized persons of the Food and Drug Administration. 
 
 STATISTICAL CONSIDERATIONS 
 
 Study Design 
 
This is a phase II, multi-center, double-blind (based on ibuprofen), placebo-controlled, two-arm 
randomized clinical trial of an intervention to determine the preliminary efficacy of the two treatment arms 
on perceived cognitive function using intent to treat principles. 
 
 Data Handling 
Data will be analyzed as intent-to-treat. Since this is phase II trial all individual 
tests will be performed at the two tailed 10% significance level.93,94 The 
assumptions underlying all statistical analyses will be thoroughly checked. In the 


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case of serious violations of distributional assumptions, appropriate nonparametric 
methods or transformations will be attempted. If outliers or influential data are 
detected, the accuracy of the data will be investigated; analyses may be done 
without these cases to evaluate their impact on the results. We will also conduct 
exploratory analyses on a subset of participants that provided data for both Pre- 
and Post-Intervention and will also conduct analyses of the outcomes based on 
compliance. 
 
13.1.2 
Missing Data 
Every effort will be made to avoid dropout, but dropout is inevitable.  In keeping 
with intent to treat, we will apply multiple imputation to all our analyses, thereby 
including all randomized subjects irrespective of whether they has post-
intervention data.  These results will be compared with the complete case results.  
If they are similar, we will report the complete case results.  If we believe that the 
mechanism for missing data is missing not at random (MNAR), we will perform a 
sensitivity analysis using pattern-mixture models.95 
 
13.1.3 
Sample Size and Power 
We do not know what the possible effect sizes of the interventions might be which 
is the reason for conducting this RCT; this is, therefore, not a fully powered study. 
We will target 43 per group to account for 30% dropout and anticipate 30 
evaluable per group.  We have used this N per group for several similar 2 year 
R21/Phase II-level studies in the past.  This sample size will be sufficient for 
informing the design of a possible Phase III study. Assuming a correlation of 0.65 
between the pre- and post- treatment measures of FACT-Cog (calculated using the 
data in Study 5), this sample size allows for detecting effect sizes ≥ 0.5 comparing 
each individual arm with control at the two-sided 10% type I error with 80% 
power. These calculations are based on contrast estimates from an ANCOVA. 
  
 Primary Objectives and Analysis Plans  
 
Primary Objective: To provide preliminary data on the effect of ibuprofen on alleviating CRCI in cancer 
patients who have received chemotherapy compared to a placebo controls as assessed by the Functional 
Assessment of Cancer Therapy-Cognitive Function (FACT-Cog).  
 
Primary Hypothesis: Ibuprofen will lead to more improvement in FACT-Cog scores from Pre- to Post-
Intervention in cancer patients who have received chemotherapy compared to the control group (placebo).  
 
Primary Statistical Analyses: Means, standard deviations, and 95% confidence intervals will be 
determined in order to estimate preliminary population variances and effect sizes in preparation for a larger 
R-01 investigator-initiated efficacy trial for cognitive scores as described in the measures. These statistical 
measures will be calculated by group for the Pre and Post measures of the FACT-Cog scores as well as the 
change (Post-Pre) in the scores using the subjects that completed the study (complete case estimation). The 
complete case estimates will be compared to multiple imputation estimates based on all subjects that 
completed Pre-Intervention as outlined in 13.1.2 above.  
 
Additional Primary Aim Analyses:  In addition to the above descriptive statistics, an ANCOVA will be 
run using FACT-Cog Post-Intervention as the response with group (ibuprofen/placebo) as the fixed effect 
and baseline FACT-Cog as a covariate. NCORP Site will also be entered in the model initially as a fixed 
effect and removed if not statistically significant.  The mean Post-Pre changes in Fact-Cog for Ibuprofen 
vs. placebo will be estimated from the model (the main effect).  The ANCOVA results including the main 
effect estimate will be used to inform the design of the future R-01 study.  We will also construct models 
controlling for relevant covariates (e.g., age, gender, education, menopausal status, medications, WRAT-4 
Reading score, chemotherapy type, fatigue, anxiety, and depression, number of cycles of prior 


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chemotherapy, treatment regimen and cycles, and expectancy/beliefs); non-significant factors will be 
removed. We will also conduct ANCOVA analyses stratified by 1) cancer type (i.e. colorectal, breast, 
other), and 2) by treatment status (i.e. completed chemotherapy (yes/no)) to compare the main effect 
estimates across cancer types and treatment status, respectively. 
 
 Exploratory Objectives and Analysis Plans  
 
1. To provide preliminary data on the effects of ibuprofen on alleviating CRCI in cancer patients who have 
received chemotherapy compared to placebo controls by objective assessments of cognitive function as 
measured by validated neuropsychological assessment of verbal memory, attention, and executive function 
via CANTAB (computerized DMS, VRM, RVP) and paper-based measures (CTMT and COWA) 
respectively. 
  
2. To provide preliminary data on the effects of ibuprofen on alleviating CRCI in cancer patients who have 
received chemotherapy compared to placebo controls on phone-based cognitive function measures (digit 
span, word recall, digits backward, CALVT, category fluency; all from BTACT). 
For 1 and 2, ANCOVA will be used as with the primary aim analyses to assess mean differences between 
cognitive function assessed by the remaining objective total scores at Post-Intervention. 
  
3. To provide preliminary data on the individual effects of ibuprofen on alleviating CRCI in cancer patients 
who have received chemotherapy compared to placebo controls on serum pro- (MCP-1, IL-6, IL-8, TNF-α, 
sTNFR2, sTNFR1, IL-1β) and anti-inflammatory (sIL-1Ra, IL-10) cytokines/receptors. We will also assess 
the effects of the interventions on cytokines, hypothesizing that each intervention will reduce pro-
inflammatory cytokines and increase anti-inflammatory cytokines using the same ANCOVA analysis as 1.  
  
4. To provide preliminary data on the mediating effects of cytokine/ receptor concentrations on the CRCI 
changes due to ibuprofen, in cancer patients who have received chemotherapy compared to placebo 
controls. 
 
To assess these aims, we will use the techniques of mediation analysis, popularized by Baron and Kenny96, 
described by Kraemer97 in clinical trials contexts, and methodologically updated by MacKinnon et al.98   
Specifically, we will use path modeling to estimate indirect (mediation) effects, and bootstrapping to 
estimate the 95% confidence intervals.  We will use the MPlus software.99 We will evaluate whether 
cytokines mediate the effect of the intervention on cognitive scores.  This will involve a separate analysis 
for each cytokine, using linear models with Arm, Pre-Intervention cognitive score and with/without 
cytokine post-pre change scores as model predictors (to be used for hypothesis-generation/aid in the R01 
design). In addition, we will attempt to do a structural equation model (SEM) where the mediator is a latent 
variable measured by changes in all the cytokines, and the response is a latent variable representing CRCI 
using the FACT-Cog subscales.  
 
5. We will also verify adherence to the study medication (pill counts) and determine if it was similar 
between all groups. In addition, we will review non-study NSAID medication usage (tracked on the Daily 
Diary) and determine if there is a difference between arms. Specifically, we will assess total counts and 
differences between groups on number of days of non-study medication on the Daily Diary and number of 
days a week of ibuprofen and other NSAID use on the Medication Usage Form.  
 
 Interim Analysis 
 
There will be no interim analysis for this protocol.  
 
 Ancillary Studies 
 
Ancillary studies could include exploratory data analyses and use of blood samples for future research.   
 


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 FINANCING, EXPENSES, AND/OR INSURANCE 
 
This study is supported by the URCC NCORP Research Base grant UG1CA189961 and NCI R21CA187500. There 
are no expenses to the participant for participating in this study. Compensation for participants is described in 
Section 5.15.  
 
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