Conditions: Breast Cancer
Keywords: polyphenolics anthocyanins n-3 fatty acids
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: no

Brief summary:
The purpose of this study is to examine the safety and influence of an intervention (COGNUTRIN) using nutritional supplements (n-3 fatty acids and blueberry anthocyanins) on cognitive performance in breast cancer survivors following chemotherapy. The investigators' goal is to treat or lessen the late effects of cancer treatment. The supplement to be used will be a combination of the following: (1) VitaBlue (40% polyphenolics, 12.5% anthocyanins from blueberries (BB) and (2) n-3 fatty acids - Lovaza.

Detailed description:
This pilot study will evaluate the feasibility of administration of the nutritional supplement and placebo in this patient population and performing cognitive function testing at baseline and post supplementation.

This is a randomized, double-blind pilot study of COGNUTRIN vs. Placebo.

Participants have an equal chance (like flipping a coin) of being in either of the study groups. Neither the participant nor the study doctor will be able to choose which study group the participant is in. Participants will not know and the study doctor will not know which study group the participants are in.

Arms:
arm 1: Participants will be provided with two bottles containing Lovaza and VitaBlue. Participants will be asked to take 1 tablet of Lovaza two times a day and 1 tablet of VitaBlue three times a day. arm 2: Participants will be provided with two bottles containing placebo. Participants will be asked to take 1 tablet of one placebo two times a day and 1 tablet of other placebo three times a day.

Interventions: intervention 1: VitaBlue™ intervention 2: Placebo intervention 3: Lovaza®
Intervention descriptions: intervention 1: Self administration of nutritional supplement COGNUTRIN for 3 months.

The supplement to be used will be a combination of the following: (1) VitaBlue (40% polyphenolics, 12.5% anthocyanins from blueberries (BB) and (2) n-3 fatty acids - Lovaza. intervention 2: Self administration of placebo for 3 months.

Investigators use a placebo to make sure that it really is the study medicine that is making a difference in the participant's condition. It does not have anything in it that would normally help or harm most people. intervention 3: Self administration of nutritional supplement COGNUTRIN for 3 months.

The supplement to be used will be a combination of the following: (1) VitaBlue (40% polyphenolics, 12.5% anthocyanins from blueberries (BB) and (2) n-3 fatty acids - Lovaza.

Protocol document:
Prot_SAP_000.pdf: 
 
 
Pilot Trial of COGNUTRIN in Breast Cancer Survivors 
 
NCT01823991 
 
Version 11.0 
October 7. 2015 


Amendment 11.0; 07 October 2015  
 
i
MCC Protocol #: 
17089  
Pilot Trial of COGNUTRIN in Breast Cancer Survivors 
 
Principal Investigator: 
Nagi Kumar, PhD, RD, FADA 
 
Senior Member/Professor 
 
Director, Cancer Chemoprevention 
 
Moffitt Cancer Center &Research Institute 
 
12902 Magnolia Drive 
 
Department of Population Sciences −MRC−216 
 
Tampa, FL 33612 
 
 
(813) 745 6885 
 
(813) 745 7185 fax 
 
Nagi.Kumar@moffitt.org 
 
MD PI: 
Susan Minton, D.O. 
 
Women’s Oncology 
 
Moffitt Cancer Center &Research Institute 
 
12902 Magnolia Drive 
 
Department of Population Sciences −MRC−216 
 
Tampa, FL 33612 
 
 
Susan.Minton@moffitt.org 
 
Primary Site 
Moffitt Cancer Center  
12902 Magnolia Drive 
 
Department of Population Sciences 
 
Tampa, FL 33612 
 
 
 
 
 
 
Co Investigators: 
John Arrington, M.D. 
 
David Evans, Ph.D. 
 
Heather Jim, Ph.D. 
 
Roohi Ismail-Khan, M.D. 
 
Hyo Sook Han, M.D. 
 
Hatem Soliman, M.D. 
 
Loretta Loftus, M.D. 
 
Julie Djeu, Ph.D. 
 
Collaborating Institution: 
University of South Florida 
 
Paula Bickford, PhD  
 
Brent Small, PhD 
 
 
Biostatistician: 
Brent Small, PhD 
 
Brent.Small@moffitt.org 
 
Clinical Research Coordinator: Adaixa Padron  
 
 Yvelise Rodriguez 
 
  
 
Data Manager:  
Karen Diaz, CCRP 
 


Amendment 11.0; 07 October 2015  
 
ii
IND Sponsor: 
Nagi Kumar, Ph.D. 
 
Moffitt Cancer Center &Research Institute 
 
Tampa, FL 33612 
 
 
Agent(s)/Supplier: 
 Anthocyanins (VitaBlue) & Lovaza (GSK) 
 
Original Protocol Date: 
October 3, 2012 
 
Protocol Amendment Date: 
February 14, 2013 (Amendment 1) 
 
May 20, 2013 (Amendment 1.1) 
 
June 25, 2013 (Amendment 1.2) 
 
July 16, 2013 (Amendment 2) 
 
January 30, 2014 (Amendment 3) 
 
February 10, 2014 (Amendment 3.1) 
 
March 5, 2014 (Amendment 4) 
 
April 4, 2014 (Amendment 5) 
 
April 8, 2014 (Amendment 5.1) 
 
May 1, 2014 (Amendment 6) 
 
July 16, 2014 (Amendment 7) 
 
November 17, 2014 (Amendment 8) 
 
January 22, 2015 (Amendment 9) 
 
February 25, 2015 (Amendment 10) 
 
October 7, 2015 (Amendment 11) 
 
Monitoring/Regulatory: 
Moffitt Cancer Center 
 
 
 


Amendment 11.0; 07 October 2015  
 
iii
CONFIDENTIAL 
 
This document is confidential and the property of the Moffitt Cancer Center & Research Institute. 
No part of it may be transmitted, reproduced, published, or used by other persons without prior 
written authorization from the study sponsor. 
 
 


Amendment 11.0; 07 October 2015  
 
iv
SCHEMA 
 
Pilot Trial of COGNUTRIN in Breast Cancer Survivors 
 
Screening (In person): 
(a) Within 6 months of  completing neoadjuvant or adjuvant treatment with anthracyclines and/or 
taxanes + or – radiation therapy (subjects on concurrent endocrine therapy (TAM, Aromatase 
inhibitors are also eligible to participate as this is standard of care for this patient population); (b) No 
evidence of dementia (MMSE >=23) but some evidence of cognitive impairment (each subject will be 
required to answer in the affirmative: ‘do you have problems with memory and attention since having 
chemotherapy, and do you believe chemotherapy contributed to the problems?’); (c) Collect blood for  
CBC/CMP/PT/PTT, LDL and antioxidant and biomarkers of inflammation; (d) Conduct Mini-Mental 
Status Exam 
If\yes- 
↓ 
Baseline/Randomization (In person):  
(a) Confirm eligibility based on screening tests; (b) Obtain baseline food records; (c) Complete 
Demographic and Godin Leisure-Time Exercise Questionnaires; (d) Conduct battery of cognitive 
tests including Weschler Test of Adult Reading, Hopkins Verbal Learning Test, Revised (Form 1), 
COWA (T1), Color Trails, Part 1 & 2,  Digit Span (Subset of WMS-IV), Symbol Digit Modalities 
Test, Brief Visuospatial Memory Test-Revised (Form 1), and Rey Complex Figure Copy; (e) 
Patient’s Assessment of Own Functioning Inventory (PAOFI); (f) Structural and resting-state 
functional magnetic resonance imaging (MRI/fMRI); (g) Complete questionnaires for symptoms of 
fatigue and depression (PHQ-9 and FSI); (h) Randomize and supply participant with one-month 
supply of nutritional supplement (COGNUTRIN) or placebo (n=20/arm), multivitamin, and study 
agent intake and symptom logs 
↓ 
Intervention: 
 
One of 2 arms, self-administration of nutritional supplement (COGNUTRIN) or placebo for 3 months 
 
plus multivitamin 
↓ 
Weeks 3, 7, & 11: 
Remind patient to complete diet records and schedule monthly visits 
↓ 
Weeks 4 & 8 (+/- 7 days) (In person): 
(a) Collect blood for CBC, CMP, PT/PTT; (b) Collect unused nutritional supplement/ placebo, 
multivitamin, and  completed study agent intake and symptom log form; (c) Collect completed diet 
survey; (d) Supply  participant with new one-month supply of nutritional supplement or placebo and 
study agent intake  and symptom logs 
↓ 
Week 12, 3 months or 90 days (+/- 7 days): End of Intervention (In person): 
(a) Collect blood for CBC/CMP/PT/PTT,LDL  & biomarkers (inflammation/antioxidant); (b) Collect 
unused nutritional supplement or placebo, multivitamin, and completed study agent intake and 
symptom log forms; (c) Collect completed diet survey; (d) Complete Godin Leisure-Time Exercise 
Questionnaire; (e) Conduct battery of cognitive tests Hopkins Verbal Learning Test, Revised (Form 
2), COWA (T2), Color Trails, Part 1 & 2,  Digit Span (Subset of WMS-IV), Symbol Digit Modalities 
Test, Brief Visuospatial Memory Test-Revised (Form 2), and Rey Complex Figure Copy; (f) Patient’s 
Assessment of Own Functioning Inventory (PAOFI); (g) Structural and resting-state functional 
magnetic resonance imaging (MRI/fMRI); (h) Complete questionnaires for symptoms of fatigue and 
depression (PHQ-9 and FSI) 


Amendment 11.0; 07 October 2015  
 
v
↓ 
 
Post-intervention Follow-up: (7 +/- 3 days post-treatment):  
Telephone contact to assess signs and symptoms and concomitant medications occurring post-treatment  
 
 
 
Endpoints: 
 
Primary:  
Changes in cognitive function: Number of impaired neuropsychological tests after 3 months 
of intervention with COGNUTRIN vs. placebo. Safety (Primary): Incidence and severity of 
adverse events 
 
Secondary:  
Changes in self-report measures of cognitive function. Changes in structural and resting-state 
  
functional magnetic resonance imaging (fMRI) after 3 months of intervention with 
  
COGNUTRIN vs. placebo. Changes in symptoms of  depression and fatigue with 
 
COGNUTRIN vs. placebo.  
 
Other:   
Changes in inflammatory and oxidative stress biomarkers from serum and plasma cytokine 
panel including IL1, IL6, IL8, IL10, IL12, GMCSF (Millipore Milleplex system) after 3 
months of intervention with COGNUTRIN vs. placebo 
 
 
 
 


Amendment 11.0; 07 October 2015  
 
vi
Table of Contents 
 
COVER PAGE……………………………………………………………………………………...
i 
 
SCHEMA……………………………………………………………………………………………
 
iv 
 
1  BACKGROUND………………………………………………………………………………… 
 
1 
    1.1  Disease Background………………………………………………………………………... 
1 
 1.2  Etiology of Cognitive Impairment in Breast Cancer Patients Treated with  
           Chemotherapy……………………………………………………………………………….
 
1 
1.3  Current interventions for the Treatment for Chemotherapy-induced Cognitive      
           Impairment…………………………………………………………………………………. 
 
1 
    1.4  Polyphenolic Antioxidants Agents and Cognitive Performance………………………… 
2 
    1.5  Anti-inflammatory agents (n-3 fatty Acids) and Cognitive Function…………………… 
3 
    1.6  Structural and Functional Imaging Markers of Cognitive Function…………………… 
4 
    1.7  Rationale……………………………………………………………………………………. 
4 
 
2  OBJECTIVES…………………………………………………………………………………… 
 
4 
    2.1  Pilot Trial Primary Objectives…………………………………………………………….. 
4 
 
3  SUMMARY OF STUDY PLAN………………………………………………………………... 
 
5 
 
4  PARTICIPANTION SELECTION……………………………………………………………. 
 
6    
    4.1  Inclusion Criteria……………………………………………………………………………
7 
    4.2  Criteria for Exclusion……………………………………………………………………….
7 
    4.3  Anticipated problems with subject recruitment and retention………………………….. 
8 
 
5  PHARMACEUTICAL INFORMATION……………………………………………………... 
 
9 
    5.1  COGNUTRIN………………………………………………………………………………. 
9 
           5.1.1  VitaBlueTM …………………………………………………………………………… 
9 
           5.1.2  Lovaza® (omega-3-acid ethyl esters)……………………………………………….. 
9 
    5.2  Rationale for Dose Selection and Administration………………………………………. 
10 
           5.2.1  Study Agent…………………………………………………………………………... 
10 
           5.2.2  Blueberry anthocyanins (VitaBlueTM)……………………………………………… 
10 
    5.3  Availability………………………………………………………………………………….. 
10 
    5.4  Agent Distribution………………………………………………………………………….. 
11 
    5.5  Agent Accountability……………………………………………………………………….. 
11 
 5.6  Packaging and Labels……………………………………………………………………… 
11 
    5.7  Drug Storage of Cognutrin (VitaBlueTM) and n-3 fatty acids…………………………… 
11 
    5.8  Registration and Randomization…………………………………………………………..
11 
    5.9  Blinding and Unblinding Methods……………………………………………………….
12 
 
6  AGENT ADMINISTRATION…………………………………………………………………. 
 
12 
    6.1  Dose Regimen and Dose Groups…………………………………………………………... 
12 
           6.1.1  Placebo Group……………………………………………………………………….. 
12 
           6.1.2  Nutritional Supplement Group (NS)……………………………………………….. 
12 
    6.2  Agent Administration………………………………………………………………………. 
12 
    6.3  Contradictions……………………………………………………………………………….
13 
    6.4  Concomitant Medications………………………………………………………………….. 
13 
    6.5  Dose and Toxicity Management.…………………………………………………………... 
13 


Amendment 11.0; 07 October 2015  
 
vii
    6.6  Adherence/Compliance…………………………………………………………………….. 
16 
    6.7  Agent Destruction/Disposal………………………………………………………………... 
16 
 
7  CLINICAL EVALAUTIONS………………………………………………………………….. 
 
16 
    7.1  Schedule and Sequence of Data Collection……………………………………………….. 
16 
    7.2  Evaluations during Screening visit……………………………………………………….
18 
    7.3  Evaluations During Baseline/Randomization Visit……………………………………..... 
18 
    7.4  Evaluations During Study Intervention…………………………………………………... 
19 
    7.5  Evaluations at Completion of Study Intervention…..…………………………………...
19 
  7.6  Post-intervention Follow-Up Period……………………………………………………... 
19 
7.7 Methods for Clinical Procedures……………………………………………………...... 
19 
           7.7.1  Demographic Data……………..…………………………………………………….. 
19 
           7.7.2  Anthropometric Measurements……………………………………………………. 
20
          7.7.3  Physical Activity (PA)………………………………………………….…..………. 
20 
           7.7.4  Dietary Intake………………………………………………………………………... 
20 
           7.7.5  Functional Markers (Eastern Cooperative Oncology Group:  ECOG)………….. 
20 
           7.7.6  Study Agent Intake and Symptom Log…………………………………………….. 
20 
           7.7.7  Pill Counts……………………………………………………………………………. 
20 
           7.7.8  Adverse Events Monitoring ……………………………….………………………... 
20 
           7.7.9  Assessment of Cognitive Performance………………………………………………
21
           7.7.10  Self-Report Measures…………………………………………………………… 
22 
            7.7.10.1  Depressive Symptomatology………………………………....... 
22 
           7.7.10.2  Fatigue Symptomatology……………………………………… 
22 
   7.7.10.3  Subjective Cognitive Function………………………….. 
23 
           7.7.11  Safety Markers………………………………………………………………………
23 
           7.7.12  Biomarkers of Oxidative Stress……………………………………………………. 
23 
           7.7.13  Inflammatory Markers – Cytokines………………………………………………. 
24 
7.7.14  Magnetic Resonance Imaging: Structural and Resting-state functional MRI….
24 
 
8  CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION……………………….. 
 
26 
    8.1  Primary Endpoint………………………………………………………………………….. 
26 
    8.2  Secondary Endpoints………………………………………………………………………. 
26 
    8.3  Off Agent Criteria………………………………………………………………………….. 
27 
    8.4  Off Study Criteria…………………………………………………………………………...
27 
 
9  SPECIMEN MANAGEMENT…………………………………………………………………. 
 
27 
    9.1  Blood Samples………………………………………………………………………………. 
27 
 
10  REPORTING ADVERSE EVENTS………………………………………………………….
 
28 
      10.1  Adverse Events (AEs)……………………………………………………………………. 
28 
               10.1.1  Reportable AEs…………………………………………………………………... 
28 
               10.1.2  Data Elements……………………………………………………………………. 
28 
               10.1.3  Severity of AEs…………………………………………………………………… 
28 
               10.1.4  Assessment of Relationship of AE to Treatment………………………………. 
29 
               10.1.5  Follow-up of AEs………………………………………………………………… 
29 
      10.2  Serious Adverse Events (SAEs)………………………………………………………...
29 
 
11  STUDY MONITORING………………………………………………………………………. 
 
30 
      11.1  Data Management……………………………………………………………………….. 
30 
      11.2  Case Report Forms……………………………………………………………… 
30 


Amendment 11.0; 07 October 2015  
 
viii
      11.3  Source Documents……………………………………………………………………….. 
30 
      11.4  Data and Safety Monitoring…………………………………………………………….. 
30 
      11.5  Sponsor or FDA Monitoring.………………………………………………………….....
30 
      11.6  Record Retention.............................................................................................................
30 
 
12  STATISTICAL CONSIDERATION…………………………………………………………. 
 
30 
    12.1  Study Design/Endpoints…………………………………………………………………...  
30 
    12.2  Sample Size/Accrual Rate………………………………………………………………… 
30 
    12.3  Randomization and Stratification………………………………………………………... 
31 
    12.4  Primary Endpoint…………………………………………………………………………. 
31 
    12.5  Secondary Endpoints……………………………………………………………………... 
31 
    12.6  Evaluation of Toxicity…………………………………………………………………….. 
32 
    12.7  Evaluation of Response………………………………………………………………….... 
32 
 
13  ETHNICAL AND REGULATORY CONSIDERATIONS…………………………………. 
 
32 
     13.1  Form FDA 1572…………………………………………………………………………... 
32 
     13.2  Other Required Documents……………………………………………………………… 
32 
     13.3  Informed Consent………………………………………………………………………… 
32 
     13.4  Confidentiality……………………………………………………………………………. 
33 
     13.5  Other………………………………………………………………………………………. 
33 
 
14  REFERENCES………………………………………………………………………………… 
 
34 
 
 
 
 


Amendment 11.0; 07 October 2015  
 
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1 
BACKGROUND 
 
1.1 
Disease Background   
Cognitive Impairment in Breast Cancer Survivors. Treatment-related neurocognitive impairment related to cancer 
treatment is most frequently reported in breast cancer patient population who comprise 22% of the 11 million survivors 
today in the US. 1 It is estimated that most of these women will be diagnosed with stage I to III disease, and a significant 
proportion will be treated with chemotherapy. Although the benefits of adjuvant chemotherapy are well established, many 
cancer survivors are at risk for developing physiological and psychological late effects of cancer treatment that might lead 
to premature mortality and morbidity2 and compromise their quality of life.  One of the most common adverse effects 
reported by breast cancer patients after treatment is “chemobrain”, a phenomenon of cognitive impairment (CI) that is 
reported in 30-75% of patients treated with chemotherapy for breast and other cancers and lasting anywhere from 6 
months to ten years.3-6 Although most standard chemotherapy regimens at standardized doses appear to not cross the 
blood-brain barrier, even mild toxicity to the Central Nervous System (CNS) has been shown to produce significant 
changes to cognitive function (CF).64 Additionally, although it was first thought that CI that is chemotherapy-induced is 
acute and reversible suggesting a transient nature of this phenomena, more recent studies have revealed cognitive 
impairment (CI) to be progressive and lasting anywhere from 6 months to 10 years post treatment in breast cancer 
survivors.2-6  Irrespective of baseline CF or type and duration of chemotherapy, there is consistent evidence of CI in 
patients receiving cytotoxic drugs for cancer treatment. 
 
1.2  
Etiology of Cognitive Impairment in Breast Cancer Patients Treated with Chemotherapy.  Several studies4-
10 in the past few years have hypothesized this phenomena of “Chemobrain” to be multifactorial and contributed by one or 
more of the following mechanisms - vascular injury, leukoencephalopathy, oxidative damage, cytokine-induced 
inflammatory response, direct injury to neuron, autoimmune responses, chemotherapy-induced anemia, abrupt steroid 
hormone deficit, hypothyroidism and the presence of the apolipoprotein gene.3, 7-9  We have reported prevalence of 
chemotherapy-induced loss of thyroid function8 which has been associated to decrements in working memory, and 
intentional and executive disturbances similar to those observed in breast cancer survivors. In addition to the biological 
plausibility, others have proposed psycho-social factors such as stress, anxiety, depression, fatigue, age, social support, 
education level and intelligence as other influential factors to CI.8 This study clearly demonstrates the multi-factorial 
nature of the etiology of this phenomenon and establishes the need for multifaceted approaches to the treatment as we 
have proposed in this trial.  
 
1.3 
Current interventions for the Treatments for Chemotherapy-induced Cognitive Impairment. Studies that 
hypothesize that CI may be attributed to symptoms of anemia have studied pharmacological interventions to treat anemia 
with recombinant human erythropoietin.55 Although these studies have demonstrated an increase in hemoglobin levels, 
decreased fatigue and improved CF in those cancer patients with anemia, the small sample sizes, use of cohorts with 
various cancers and treatment regimens and short duration of interventions fail to provide meaningful data as to the 
efficacy of this intervention.  In addition, new trials have provided further evidence against long-term use, cost-
effectiveness and side-effects with these agents, particularly thrombic events.  Others have evaluated psycho stimulant 
methylphenidate53-54 in brain tumor patients and other adults, including breast cancer patients for treatment-related CI and 
observed significant improvements in CF compared to a placebo group.  However, the long-term safety of these agents, 
including impact on neurochemistry and the amphetamines-like effects continue to be a concern. Most promising,  is a 
single arm pilot study of a brief cognitive-behavioral treatment aimed at managing cognitive dysfunction associated with 
adjuvant chemotherapy (Memory and Attention Adaptation Training; MAAT) 52, which  reported that participants 
reported high treatment satisfaction and rated MAAT as helpful in improving ability to compensate for memory problems. 
With the recent understanding of the multi-factorial etiology of CI, similar to those observed in CI related to aging and 
associated diseases, these structured CT strategies that have already demonstrated efficacy in aging and diseases related to 
CI, appear to offer promise for the treatment of chemotherapy-induced CI.  Over the past 25 years, several studies have 
demonstrated that among relatively healthy, older adults without dementia, cognitive abilities can be enhanced through a 
variety of cognitive intervention techniques. 12-16-18, 27   These cognitive training techniques are particularly promising in 
that transfer of training and have been demonstrated to performance of Timed Instrumental Activities of Daily Living 
TIADL, 19-20, safer on-road driving performance 21, and maintained health-related quality of life 22-23. Research has 
indicated that individuals, who exhibit slowed cognitive speed of processing as measured by UFOV, are most likely to 
benefit from and experience transfer of speed of processing training to functional outcomes 18.  


Amendment 11.0; 07 October 2015  
 
2
1.4 
Polyphenolic Antioxidants Agents and Cognitive Performance.  
Oxidative stress and inflammation contribute to several organ toxicities, including neurotoxicities, after common breast 
cancer chemotherapy regimen. Doxorubicin and other platinum-based therapies have been documented to cause the 
generation of free radicals and the induction of oxidative stress, associated with cellular injury.90  Although the debate 
continues as to the safety of antioxidant use during chemotherapy to reduce oxidative stress, the utility of these agents to 
ameliorate treatment-induced consequences post cancer treatment, including CI has not been examined.  Much of the 
work using antioxidant agents in treating CI comes from the aging literature.  However, interventions to treat CI using 
antioxidant therapies with Vitamins A, C and E have been disappointing as a treatment for markers of CI in cancer 
survivors, similar to those observed in the aging literature.56-61 Non-vitamin phytochemicals such as polyphenols, which 
are the most abundant antioxidants in our diets have been shown to possess strong anti-inflammatory properties, as well as 
stronger antioxidant activity,27, 36-38,48-51,65-84 as compared to traditional antioxidant vitamins that have never been tested 
before to improve CI in this cohort.   
 
Antioxidants, such as polyphenols, not only scavenge 
reactive oxygen species (ROS)91-92 but are also involved 
in modification of protein kinases, apoptosis signaling, 
and regulating signal transduction via modification of 
cellular redox reactions.33,86 Our group has shown that 
single and combination polyphenolic compounds have 
demonstrated improvements on cognitive tasks such as 
the Morris water maze, radial arm maze (water and land), 
t-maze passive and active avoidance tasks, as well as 
classical eye blink conditioning tasks. Dr. Bickford48 
established the precedent for cognitive improvement in 
normal aging rats with dietary supplementation of foods 
high in ORAC (Oxygen Radical Absorbance Capacity).  A combination of plant polyphenols containing a standardized 
formulation of grape, green tea and rich in blueberry extract  (NT-020) (Fig 1) increase actions on the progenitor cell 
populations and to reduce inflammation and oxidative stress to protect primary neuronal cultures as well as microglial cell 
cultures from oxidative stress, in addition to neuroprotective and neurogenic effects.26, 36, 48-51, 93-98  In a recent experiment, 
we examined the impact of this combination polyphenolic formulation rich in BB anthocyanins (NT-020) on Morris 
Water Maze performance among young animals (n =10), as well as older animals who received treatment of NT-020 (n = 
13) or a control diet (n – 13) for 3 weeks prior to behavioral testing.  All animals were tested on the Morris Water Maze 
test, four trials per day for five days.  Figure 2 on the top left shows learning on day 5, based upon the cumulative distance 
for individual rats on the last day of testing.  The animals in the NT-020 arm of study exhibited lower cumulative distance, 
as compared to the older control animals (p < .05).  Further, there was much less variability among the treated old 
animals, as compared to the control animals.  We then examined the brains of these rats for neurogenesis and markers of 
inflammation using unbiased serological measures.  As can be seen in Figure 2, there was a significant increase in the 
numbers of Ki67 and DCX labeled cells in the dentate gyrus of the NT-020 rats that was accompanied by a decrease in 
OX6 (MHC Class II) positive microglia indicating that there was a reduction in inflammatory mediators.  
 
Plant-derived compounds known as flavonoids may exert particularly powerful actions on mammalian cognition and may 
reverse age-related declines in memory and learning. In particular, evidence suggests that foods rich in three specific 
flavonoid sub-groups, the flavanols, anthocyanins 114-116 and/or flavanones, possess the greatest potential to act on the 
cognitive processes. For example, their specific interactions within the ERK and PI3-kinase/Akt signaling pathways, at 
the level of receptors or kinases, have been shown to increase the expression of neuroprotective and neuromodulatory 
proteins and increase the number of, and strength of, connections between neurons. Their effects on the vascular system 
may also lead to enhancements in cognitive performance through increased brain blood flow and an ability to initiate 
neurogenesis in the hippocampus. Additional mechanisms have been suggested for the ability of flavonoids to delay the 
initiation of and/or slow the progression of AD-like pathology and related neurodegenerative disorders, including a 
potential to inhibit neuronal apoptosis triggered by neurotoxic species (e.g., oxidative stress and neuroinflammation). 
Berry anthocyanins also improve neuronal and cognitive brain functions, ocular health as well as protect genomic DNA 
integrity.  Recent studies reported by Zafra-Stone S, et al 117 demonstrated that anthocyanins-rich OptiBerry exhibits high 
antioxidant efficacy as shown by its high oxygen radical absorbance capacity (ORAC) values, significantly inhibited basal 
MCP-1 and inducible NF-kappa-B transcriptions as well as the inflammatory biomarker IL-8.  Together, these processes 
 
Figure 1. Protection from oxidative cell induced death by blueberry, green 
tea, carnosine Vitamin D3or all 4 combined (NT-020).  


Amendment 11.0; 07 October 2015  
 
3
 
Figure 2. F344 rats of 3 or 20 months of age were treated with Control NIH21 diet 
or NIH21 diet plus NT-020 10X for 3 weeks prior to testing on a standard Morris 
water maze, 4 trials per day for 5 days of training. Top left: Cumulative distance 
scores for each individual rat on day 5 of training. It can be seen that there is a 
significantly reduced variance for the NT020 rats.  When you compare the 
learning impaired groups (cutoff = 3 SD from young) then the treated learning 
impaired rats perform at a higher level than the untreated impaired rats. After 
training brains were prepared for immunostochemistry and sectioned at 40 µm for 
unbiased stereological measures using the optical fractionator. Top Right: There 
is a significant increase in activated microglia in the aged dentate gyrus which is 
reduced in NT-020 treated rats. Bottom left: Numbers of proliferating cells at time 
of sacrifice (2 weeks post behavior) were estimated using Ki67+ immunolableling 
were significantly increased in the aged treated rats compared with control. 
Bottom right: Doublcortin (DCX) positive cells were also increased in the aged 
NT-020 treated rats suggesting that both proliferation of neural progenitors and 
cells that proceed to a neuronal lineage are increased by this dietary treatment. 
 
act to maintain the number and quality of synaptic connections in key brain regions and thus flavonoids have the potential 
to prevent the progression of neurodegenerative pathologies and to promote cognitive performance. 116,118. Preclinical 
evidence has demonstrated that these polyphenols protect vulnerable neurons and enhance the function of existing 
neuronal structures, two processes known to underpin neuro-cognitive function 116. Blueberry anthocyanins can decrease 
this vulnerability to oxidative stress as assessed in vivo by examining reductions in neuronal signaling and behavioral 
deficits and in vitro via H2O2-induced decrements in striatal synaptosomal calcium buffering. In preclinical studies, BB 
anthocyanin supplementations are effective in decreasing indices of inflammation and oxidative stress.  To date, the 
anthocyanins show the most efficacy in penetrating the cell membrane and in providing antioxidant protection. 119 More 
recent trials have demonstrated that polyphenolic 
components can be measured in serum and 
plasma, found to cross the blood brain barrier and 
are found in measurable levels within the brain.73   
For 
example 
NT-020 
contains 
blueberry, 
anthocyanins in blueberry are considered to be one 
of the major active fractions and can be found in 
the brain of several mammalian animal models.74-
76 
Our group has considerable experience 
and demonstrated the safety of polyphenolic67-72 
and n-3 fatty acids52-53, 84 supplementation in 
cancer patient cohorts.  Anthocyanins from BB 
thus hold the most promise to prevent or reverse 
normal or abnormal deteriorations in cognitive 
performance.  With the safety of anthocyanins 
well established, we predict this treatment regimen 
with 
anthocyanins 
can 
directly 
improve 
neurogenesis that is impacted with cytotoxic 
agents. 85-86   
 
1.5 
Anti-inflammatory agents (n-3 fatty 
Acids) and Cognitive Function: In view of the 
high omega-3 poly unsaturated fatty acid content 
of the brain, it is evident that these fats are 
involved in brain biochemistry, physiology and 
functioning; and thus in some neuropsychiatric 
diseases and in the cognitive decline of aging. 52-53, 
99-102 DHA (docosahexaenoic acid) is one for the 
major 
building 
structures 
of 
membrane 
phospholipids of brain and is absolutely necessary 
for neuronal function. Deficiency of DHA alters the course of brain development, perturbs the composition of brain cell 
membranes, neurones, oligodendrocytes and astrocytes, as well as sub cellular particles such as myelin, nerve endings 
(synaptosomes) and mitochondria. These alterations induce physicochemical modifications in membranes, lead to 
biochemical and physiological perturbations, and result in neurosensory and behavioral upset.99-102 The literature reveals 
growing mechanistic evidence that cognitive function of the aging brain can be preserved, or loss of function can be 
diminished with docosahexaenoic acid, a long-chain (n-3) PUFA. In addition, omega-3 polyunsaturated fatty acids (n-3 
PUFAs) 52-53, 84 have been shown to modulate levels of proinflammatory cytokines, hepatic acute phase proteins, 
eicosanoids, and tumor-derived factors in animal models of cancer. Omega-3 fatty acids can be detected in human 
serum/plasma, shown to cross the blood brain barrier and are the primary component of membranes of the nerve cells in 
the brain,  Deficits in Omega-3 fatty acids are associated with damage to brain biochemistry, structure and cognitive 
function.99-100 In contrast, a diet high in n-3 fatty acids reduced beta-amyloid (Abeta) and reduced the amount of plaque in 
the brain, especially in the hippocampus and parietal cortex, and reduced the amount of APP, the beta-amyloid precursor 
protein,101-102 improving CI.   
 
In summary, our team and others have demonstrated that the components of COGNUTRIN®, which includes standard 
formulations and extracts of blueberry anthocyanins and omega-3 fatty acids, can be detected in human serum/plasma, 


Amendment 11.0; 07 October 2015  
 
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shown to cross the blood brain barrier and localize in various brain regions important for learning and memory such as 
cerebellum, striatum and hippocampus in measurable quantities. Studies have correlated peripheral markers of 
inflammation, immune function and oxidative stress in serum/plasma with central inflammation and central nervous 
system functioning. Thus based on the etiologies of cognitive changes, animal and early clinical trial evidence of safety, 
bioavailability in blood and brain tissue and preliminary evidence of efficacy to improve CF, it is logical to test the 
effectiveness of a combination standard nutrition supplement that can provide anti-oxidant, anti-inflammatory nutrients 
critical to the physiochemical composition and functioning of the neurological system to “rescue” tissues from the effects 
of the oxidative damage and inflammation and reverse chemotherapy-induced cognitive impairment as we propose in this 
study.  
 
1.6 
Structural and functional imaging markers of cognitive function: Self-reported poor concentration or ‘chemo-
brain’ has been validated using neuropsychological tasks and more recently, neuroimaging studies have identified 
structural 123  and performance differences between patients (i.e. those treated with chemotherapy) and controls 122,124,126.  
For example, a recent functional Magnetic Resonance Imaging (fMRI) study has demonstrated that when compared to 
controls, chemotherapy treated patients show hyporesponsiveness in areas of the brain associated with impaired planning 
behavior and attentional abilities (i.e. paraphippocampal gyrus, left cuneus, right dorsal striatum, right inferior parietal 
cortex and left middle temporal gyrus). What is more, functional imaging studies have shown these disruptions last from 
one month following treatment 126 to 10 years following treatment .122  
 
To date, imaging studies have only focused on assessing cognitive disruption induced by chemotherapy. The proposed 
study aims to replicate these findings and extend them by testing the proposed interventions (e.g. COGNUTRIN®) ability 
to offset the changes in cognitive performance in breast cancer survivors post chemotherapy treatment.   
 
1.7 
Rationale Evidence from epidemiologic studies, as well as our experimental animal literature, suggests that 
antioxidant and anti-inflammatory agents promote cognitive health among older adults and early stages of Alzheimer’s 
disease.24-50  To date, interventions with cognitive training alone,51-52 pharmacological agents to treat chemotherapy-
induced anemia,55 psycho stimulants and antioxidant therapies with Vitamins A, C and E have not demonstrated efficacy 
or safety in treating CI in cancer survivors.53-54  In addition, new trials have provided further evidence against long-term 
use, cost-effectiveness and side-effects with these pharmacological agents, particularly thrombic events, that established 
the need to identify alternate approaches that can be implemented for a longer durations, with fewer side effects and an 
established safety profile.54-56  Both length and quality of survival are important end points.2  Our group and others have 
demonstrated the safety of the antioxidant57-63 and anti-inflammatory agents61 in high risk and cancer patient cohorts, 
including breast cancer patients during treatment and the effectiveness of the nutritional supplementation mixture to 
specifically improve cognitive function in preclinical studies.24, 45-48  In the current pilot proposal, we propose to examine 
the safety and influence of an intervention (COGNUTRIN®) using  nutritional supplements (n-3 fatty acids and blue 
berry anthocyanins) on longitudinal changes in cognitive performance in breast cancer survivors post chemotherapy. Our 
ultimate goal is to provide interventions, both therapeutic and lifestyle that carry the potential to treat or ameliorate these 
late effects of cancer treatment.  Based on the multiple etiology, the varying manifestation and extent of cognitive decline 
documented in this cohort, we hypothesize that interventions using a combination nutritional supplement with antioxidant 
and anti-inflammatory agents (COGNUTRIN®) can work synergistically to facilitate reductions in oxidative stress loads 
and inflammatory cytokines, with significant improvement in cognitive health resulting in improvements in quality of life 
of breast cancer survivors. 
 
2 
OBJECTIVES 
 
2.1  
Pilot trial Primary Objectives 
 
1. 
Specific Aim 1: Does nutritional supplementation facilitate cognitive function in adult breast cancer 
survivors, relative to persons who do not receive this supplementation? We predict that adult breast cancer 
survivors receiving nutritional supplementation will experience improved cognitive performance as assessed by a 
battery of standardized tests of cognitive function.  The current pilot study will evaluate the feasibility of 
administration of the nutritional supplement and placebo in this patient population and performing cognitive 
function testing at baseline and post supplementation. 


Amendment 11.0; 07 October 2015  
 
5
 
2. 
Specific Aim 2: Is the facilitation of cognitive function in the nutritional supplementation group mediated 
by changes in markers of oxidative stress and inflammation, relevant to cognitive performance? We predict 
that persons receiving nutritional supplementation will exhibit larger changes in antioxidant markers and that 
these changes will serve to mediate or explain differences in the cognitive performance of the two groups. The 
current pilot study will evaluate the feasibility of administration of the nutritional supplement and placebo in this 
patient population and testing antioxidant levels at baseline and after the supplementation.  
 
3. 
Specific Aim 3: Does nutritional supplementation facilitate cognitive function in adult breast cancer 
survivors, relative to persons who do not receive this supplementation as indicated by changes in structural 
and resting-state functional markers observed utilizing the MRI/fMRI? We predict that adult breast cancer 
survivors receiving nutritional supplementation will experience improved cognitive performance as assessed by a 
battery of structural and functional changes in imaging markers in the brain. The current pilot study will evaluate 
the feasibility of administration of the nutritional supplement and placebo in this patient population and performe 
structural and resting-state functional MRI to evaluate changes in these imaging markers at baseline and after the 
supplementation.  
 
 
3.0 
SUMMARY OF STUDY PLAN 
 
This pilot project is a randomized clinical trial of the feasibility of administering the nutritional supplement and 
placebo, performing a battery of cognitive function testing, structural and resting-state functional MRIs, and 
antioxidant levels at baseline and post supplementation in a target group of breast cancer survivors treated with 
chemotherapy. Prior to study initiation, the Human Subjects Committee will approve all study procedures.  This goal of 
this pilot feasibility study is to provide a comprehensive assessment of a clinical trial’s specific challenges as well as 
strategies to mitigate risks before a well- powered clinical trial can be proposed and implemented.   
 
Research teams that use feasibility studies experience faster clinical trial accrual and significantly fewer delays in 
enrollment than those that forgo this preliminary assessment.  A properly conducted clinical trial feasibility study can 
provide information regarding:  
 
 
Biomarker methodologies/estimations 
 
Effect size estimations 
 
Compatibility of the clinical trial treatments and assessments with current patterns of care  
 
Available patient population  
 
Likelihood of patients agreeing to participate in the clinical trial  
 
Potential modifications to clinical trial design and eligibility criteria to enhance enrollment  
 
Competing clinical trials  
 
Site capabilities  
 
Research infrastructure  
 
Personnel  
 
Equipment  
 
Regulatory requirements and timelines  
 
Local institutional review board/independent ethics committee (IRB/IEC) review timelines 
 
Investigator grant requirements and site contracts  
 
Projected patient enrollment rates. 
 
The current feasibility pilot trial is to inform the research team of all these above challenges that occur with clinical trials 
and can contribute to the proposal and conduct of a well powered clinical trial.    
 
 
 
 
 


Amendment 11.0; 07 October 2015  
 
6
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.0  
PARTICIPANT SELECTION 
Women who have been diagnosed with stage I-IIIB breast cancer (BCa) and who have completed neoadjuvant or 
adjuvant treatment with anthracyclines and/or taxanes + or – Radiation therapy within the past 6 months (+/- 7 
days) will be invited to be screened for eligibility to participate in this trial (subjects on concurrent endocrine therapy 
(TAM, Aromatase inhibitors are also eligible to participate as this is standard of care for this patient population). We will, 
in addition, expand our recruitment at the Moffitt Cancer Center to include the members of the Moffitt Cancer Center 
Affiliate Network (Total Cancer Care network consisting of 16 community hospital affiliates and 415 community 
oncologists statewide.  With this additional network to recruit this patient population from, we are confident that we will 
be able to recruit the number of subjects needed for this study from each site. Based on the number of subjects that can be 
recruited from Moffitt, we conservatively estimate that we will recruit and retain 40 subjects during the 6 months 
recruitment period. Throughout the recruitment, data collection and retention period of this study we will focus on 
retaining high participation rates of an ethnically diverse population.   
Screening/Baseline 
1) Women 30-70 years of age 
2)  Cases with Stage I-IIIB Breast Cancer  
3)  Completion of neoadjuvant or adjuvant 
 
treatment with anthracyclines, taxanes + or 
–  Radiation therapy (subjects on concurrent 
 
endocrine therapy (TAM, Aromatase 
 
inhibitors are also eligible to participate as 
 
this is standard of care for this patient 
 
population) 
4)  No more than 6 months post treatment (+/- 
7 days) 
5)  No evidence of dementia (MMSE >=23) 
 
but some evidence of cognitive impairment 
 
(each subject will be required to answer in 
 
the affirmative: ‘do you have problems 
 
with memory and attention since having 
 
chemotherapy, and  do you believe 
 
chemotherapy contributed to the problems 
6)  Structural and resting-state functional 
 
MRI/fMRI  
7)  Safety Labs (CBC, CMP, PT/PTT, LDL) 
8)  Plasma levels of oxidative markers 
9)  Cytokine panel 
10)  Completion of the following questionnaires
 
 
a.) Demographics 
 
 
 
b.) Cognitive Function Battery 
 
c.) Fatigue 
 
d.) Depression 
 
e.) Nutritional intake 
R 
A 
N 
D 
O 
M
I 
Z 
E 
Placebo 
Group 
+ 
Multivitamin  
 
N=20 
Endpoint Evaluation 
(3-months from baseline. +/- 7 
days) 
1) Functional and resting-state 
 
MRI/fMRI   
2) Safety Labs (CBC, CMP, 
PT/PTT,  
LDL) 
3) Plasma levels of oxidative 
markers 
4) Cytokine panel 
5)  Completion of the 
following  
 
 
questionnaires  
 
 
  
a.) Cognitive Function 
Battery 
 
   
b.) Fatigue 
 
   
c.) Depression 
 
   
d.) Nutritional intake 
 
   
e.) Physical activity 
 
 
Nutritional Supplementation (COGNUTRIN®) in Breast cancer Patients with 
Cognitive Impairment: Study Schema 
Nutritional 
Supplment 
(NS) Group 
+ 
Multivitamin  
 
N=20 


Amendment 11.0; 07 October 2015  
 
7
If women are already patients at Moffitt Cancer Center or one of its affiliates, they will be identified by one of the medical 
oncologists who are co-investigators in this trial based on the diagnosis and treatment received. Women who have been 
diagnosed with stage I-IIIB breast cancer (BCa) and who have completed neoadjuvant or adjuvant treatment with 
anthracyclines and/or taxanes + or – Radiation therapy within the past 6 months, (+/- 7 days) will be referred to 
the clinical research coordinator who will then invite these potentially eligible subjects to be screened for eligibility 
criteria to participate in this trial.  All subjects referred to the research team from affiliate sites will be screened for 
eligibility. In this pilot clinical trial, all subjects, if identified as eligible based on initial screening in any other site other 
than the Moffitt Cancer center, will be required to come to the Moffitt cancer center if willing to continue to participate. 
Although cognitive complaints are reported frequently after breast cancer treatments, their association with standardized 
neuropsychological (NP) test performance is not well-established. The lack of association between NP test performance 
and subjective cognitive complaints in prior studies with breast cancer patients 156-157,160 could reflect the lack of 
specificity and sensitivity of the self-report tools, or could be due to reliance on global measures rather than domain-
specific assessments. There is also a skepticism regarding the validity of cognitive complaints and their relationship to NP 
test performance in cancer patients.  A few more recent studies have suggested that patient self-report is associated with 
relevant domains of NP function, which is strongest for memory complaints. There is an emerging literature supporting 
the ability of individuals to subjectively detect changes in cognitive function that precedes statistically significant changes 
in NP performance or structural imaging abnormalities 158 . There is thus significant support for the value of patient-
reported outcomes as a central measurement in evaluation of cancer treatment-related morbidities 159, including domains 
of cognitive impairment.   
Therefore, based on the current body of research, the inclusion criteria in this trial will be based on subjective cognitive 
complaints in cancer survivors.  Inclusion criteria to identify women who met the inclusion criterion for chemotherapy-
induced cognitive impairment, we will use the most current approach described by Ferguson et al (2012) 160 where each 
subject will be required to answer in the affirmative: ‘do you have problems with memory and attention since having 
chemotherapy, and do you believe chemotherapy contributed to the problems?’  
4.1  
Inclusion Criteria. 1) Women 30-70 years of age 2) Cases with Stage I-IIIB Breast Cancer that have completed 
neoadjuvant or adjuvant treatment with anthracyclines and/or taxanes + or –Radiation therapy within past 6 
months (+/- 7 days) (subjects on concurrent endocrine therapy (TAM, Aromatase inhibitors are also eligible to participate 
as this is standard of care for this patient population) 3) Able to understand and sign the informed consent. 4) Fluent in 
reading, comprehension and communication in the English language. (Persons who are unable to meet this requirement 
are excluded from the current proposal because many of the cognitive tests that are administered are in English and 
translation of these instruments in other languages is currently unavailable)  5) No evidence of dementia (MMSE >=23) 
but some evidence of cognitive impairment (each subject will be required to answer in the affirmative: ‘do you have 
problems with memory and attention since having chemotherapy, and do you believe chemotherapy contributed to the 
problems?’);  6) Each subject must be aware of the nature of his current medical condition and must be willing to give 
consent after being informed of the experimental nature of therapy, alternatives, potential benefits, side-effects, risks and 
discomforts. 7) ECOG performance status of 0- 2 (8) Acceptable hemoglobin and hematocrit level based on CBC. (9) All 
subjects must be willing to be monitored for adequacy of nutritional intake during the intervention, as is the current 
standard of clinical practice.  
 
4.2  
Criteria for exclusion will include: 1) Use of estrogens (oral, dermal or vaginal), progesterone (oral or topical), 
or androgens during the previous 3 months, 2) Use of over the counter steroid hormonal supplements 3) Patients with 
advanced or Stage IIIC or IV breast cancer or other cancers.  4) Use of n-3 fatty acids or high dose antioxidant 
supplements other than what is provided in the trial.  5) History of known allergy to components of the study supplements.  
6) Subjects with renal or liver disease (AST/ALT > 5.0 x upper limit of normal as evidenced by impairment of baseline 
laboratory values); Actual creatinine clearance of <60 utilizing the Cockroft-Gault formula (1976), which employs 
creatinine measurements and a patient's weight to predict the clearance. (The constant for women is 1.04). 7) Concurrent 
participation in another chemoprevention trial. 8) Evidence of bleeding diathesis or coagulopathy (PTT and/or either PT 
or INR > 1.5x upper limit of normal (except for subjects receiving anti-coagulation therapy). Concurrent use of Coumadin 
or Warfarin will be acceptable and monitoring patients on warfarin or Coumadin will follow the standard of care as 
dictated by the prescribing physician (PT/PTT).  If the prescribing physician is not a Moffitt MD, then the prescribing MD 


Amendment 11.0; 07 October 2015  
 
8
will be notified by the research staff of the subject participating in the study, and monitors for PT, PTT will be obtained 
from patient during the 3 month study visit for review.  9) Subjects with metabolic abnormalities (e.g. thyroid disorders, 
insulin dependent diabetes, rheumatologic disease etc.). Subjects with metabolic disorders (a) who are otherwise eligible, 
(b) treated for hypothyroidism by their primary MD with Synthroid (levothyroxine) and (c) with the approval of the 
Moffitt treating oncologist will not be excluded from the study. 10) Patients with known claustrophobia, presence of 
pacemaker and/or ferromagnetic material in their body that would prohibit MRI imaging (ex. tissue expanders). 11) 
Medical history of concussions 12) Other acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase risk associated with study participation or study drug administration, or may interfere with interpretation 
of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study.    
 
Our criteria for inclusion of subjects in this trial is that subjects recruited are able to understand and sign the informed 
consent. The subjects must also be fluent English-speaking (Persons who are not fluent English speakers are excluded 
from the current proposal because many of the cognitive tests that are administered are language-based and are heavily 
influenced by first language).  Subjects must also have no evidence of dementia (MMSE >=23) but some evidence of 
cognitive impairment (each subject will be required to answer in the affirmative: ‘do you have problems with memory and 
attention since having chemotherapy, and do you believe chemotherapy contributed to the problems?’);.  Each subject 
must be aware of the nature of his current medical condition and must be willing to give consent after being informed of 
the experimental nature of therapy, alternatives, potential benefits, side-effects, risks and discomforts. If a subject is 
determined to be cognitively impaired to the point of not meeting the above criteria at screening by the investigative team, 
they will not be included in this pilot phase of the clinical trial, making the use of proxy’s unnecessary. 
 
4.3  
Anticipated problems with subject recruitment and retention:  Our group has extensive experience 
conducting research with breast cancer patients as well as studies collecting neuropsychological data, questionnaires, 
blood samples, and MRI/fMRI.  Thus, we expect difficulties to be minimal.  As with all clinical trials, we anticipate that 
there will a 10% loss of subjects to follow up, although, in our experience, breast cancer survivors tend to be a highly 
motivated group and the time between assessments is short and subjects will be required to come in monthly for 
monitoring safety and compliance.  Moffitt Cancer center, as the only NCI designated Comprehensive cancer center in the 
State of Florida has a substantial number of subjects treated for breast cancer.   
 
The recruitment, intervention and retention team (PI, Dr. Kumar, Co-I Dr. Jim and CRC) will initiate, develop and 
implement procedures to deal with and solve problems with attrition. As we have with our previous and current 
intervention trials, we will take measures to ensure that loss to follow-up is minimal, implementing several strategies for 
recruitment and retention as follows:  
a. Contact with participants will be maintained by their preferred method or methods: phone numbers, primary 
and secondary mailing addresses, and e-mail addresses updated at each contact.  
b. At each visit, current contact information will be verified and an alternate means of contacting the person will 
be established with the permission of the participant. For example, friends, family members, and summer 
addresses will be maintained with the consent of the participant.  
c. Reminder calls and/or e-mails the day prior to the appointment. 
d. Monetary compensation for travel: Because of the importance of retaining participants for the duration of the 
study, participants will be provided $50 for each visit to cover travel expenses. Participants traveling more 
than 100 miles from their home to reach the research site will receive an additional $30 for transportation 
costs. 
e. Empathetic, warm and experienced clinical research coordinators and study staff who can establish rapport 
with participants.  
f. Telephone contact will be encouraged with calls from the research staff to the subject at least once a month 
between visits. 
g. Appointments will be made at the participants’ convenience including evenings or early mornings. 
h. Monthly and follow up visits will occur in the comfort of the Breast Program clinics to ensure familiarity of 
staff and environment. 
i. 
Valet parking for all subjects, free of charge. 


Amendment 11.0; 07 October 2015  
 
9
j. Weekly staff meetings will occur and case studies will be reviewed to observe patterns and etiology of 
attrition of participants will be discussed. 
 
5.0  
PHARMACEUTICAL INFORMATION:   
 
5.1  
COGNUTRIN: The choice of the supplement to use in this trial is based on relevant research supporting the 
various components as well as the use of a commercially available dietary supplement. The supplement to be used will be 
a combination of 2 standardized formulations (a) antioxidants from blueberry extracts - VitaBlue™ (40% polyphenolics, 
12.5% anthocyanins from blueberries (BB) and (b) omega 3-fatty acids - Lovaza®.  The standardized agent - Lovaza is 
manufactured by Glaxo Smith Kline and will be purchased for use in this study. However, the blue berry anthocyanins 
was purchased from a standard manufacturer and encapsulated at the dose for this specific study using FDA standards in a 
certified formulary and tested by an independent laboratory for composition (FDA IND 116424).  The matching placebos 
were also manufactured for this study using FDA standards- all of which have been evaluated and approved for use by the 
FDA.  As indicated in the protocol, these are 2 separate products administered separately (pages 8-11).  The combination 
that will be used has met the standards of the FDA and an IND has been approved by the FDA (FDA IND 116424) for use 
of this agent combination in this study. Our team took into consideration the high patient burden to the subjects due to 
large size if the agents were combined into one capsule and thus decided to keep them as 2 separate agents. 
 
The supplement COGNUTRIN is a term coined by the PI to denote the combination of 2 standardized formulations (a) 
VitaBlue™ (40% polyphenolics, 12.5% anthocyanins from blueberries (BB) and (b) n-3 fatty acids- Lovaza®.  We have 
obtained IND (FDA IND 116424) from the FDA for this current indication proposed from the FDA. We have not 
submitted a patent for this product but hope to explore the potential to license this combination if successful in the future. 
We are currently working on obtaining a registered trademark with this name that we coined –COGNUTRIN. Our goal is 
to develop this combination agent scientifically, maintain exclusivity and to not be confused with myriads of supplements 
in the market place.  
 
5.1.1 VitaBlue™ (BB Anthocyanins): VitaBlue™ is a freeze dried high potency extract from blueberries.  
VitaBlue™ is created using a unique proprietary process from VDF FutureCeuticals.  It comes as a standardized 
powder containing blueberry anthocyanins that is ready for encapsulation.   
 
VitaBlue™ provides concentrated amounts of healthy blueberry anthocyanins and polyphenols. Made from Wild 
Blueberry Extract (Lowbush Powder, VitaBlueTM, although no major adverse events have been observed with 
Vitablue, anecdotal evidence suggests that Blueberry can occasionally induce symptoms of food allergy in 
sensitized individuals; however, no studies have been reported to date. The lack of reported evidence may be due 
to the low allergenicity of this berry, the small amounts consumed, or the restricted time frame of consumption. 
Oftentimes a limited or low exposure to certain allergens might be the reason for the limited complaints reported.  
However, as the promotion of blueberry consumption continues, this situation may change (1). Nonetheless, 
based on adverse effects reported to other berries, and particularly to members of the same family, it can be said 
that blueberries may induce symptoms of food allergy in sensitized individuals (2).   
 
For example, a 25-year-old woman reported adverse reactions due to lingonberry (V. vitis-idaea). While eating 
lingonberry jam, she developed allergic symptoms including itching wheals around her mouth, however, the 
symptoms dissipated. During a second episode, when she ingested a very small amount of lingonberry jam several 
days later, she immediately noticed more-intense symptoms, including severe itching on the mouth, tongue and 
throat, and wheals over the mouth. Symptoms dissipated within an hour, however, it was noted that upon 
secondary exposure the symptoms were more severe and a skin reactivity test demonstrated a positive allergic 
response to lingonberry (3). Since there are no reported adverse effects of blueberries, we expect no adverse 
effects to occur with this agent during this study. 
 
5.1.2: Lovaza® (omega-3-acid ethyl esters): We plan to use a standardized product Lovaza® (omega-3-acid 
ethyl esters), an FDA-approved prescription omega-3 provides prescription-only potency and purity with each 1-
gram Lovaza® (omega-3-acid ethyl esters) gel capsule contains 90% omega-3-acid ethyl esters; 84% 


Amendment 11.0; 07 October 2015  
 
10
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ethyl esters. Lovaza® is provided by 
GlaxoSmithKline, who has authorized the FDA center for Drug Evaluation and Research, Division of Metabolic 
and Endocrine Drug Products to reference Lovaza® Capsules IND # 45,998.. Bottles are labeled to comply with 
study requirements and applicable regulations for investigational drug use. Bottles with study agent will be stored 
at controlled room temperature (15-30 0 C). The products are both standardized and examined for content, 
stability and bioavailability and the study will be conducted with an investigator-initiated new drug (IND) 
approval from the Food and Drug Administration (FDA) as mandated by the National Cancer Institute for Phase 
I-III clinical trials. Use of n-3 fatty acids may decrease platelet aggregation and subjects with evidence of bleeding 
diathesis or coagulopathy will not be included in this study and those with concurrent use of Coumadin or 
warfarin will be observed closely. The follow-up monitoring for PT, PTT for patients on warfarin and/or 
Coumadin will follow the standard of care as dictated by the prescribing physician.  The prescribing MD will be 
notified by the research staff of the subject participating in the study, and monitors for PT, PTT will be obtained 
from patients during the monthly clinic visits.  
 
5.2  
Rationale for Dose selection and Administration:  
 
5.2.1 Study Agent Lovaza® There is no established Dietary Reference Intake for n-3 fatty acids, yet the 
Adequate Intake (AI) is set at 1.6 and 1.1 grams/day for men and women respectively.  While intake in the United 
States occurs at much lower than the proposed AI and no signs of deficiency are observed, the AI is proposed to 
provide optimal health benefits associated with consuming n-3 fatty acids.  There is no Upper Limit established 
for n-3 fatty acids. In early studies using fish oil capsules, we and others have demonstrated the safety of 
administering 2-6 gms of EPA per day. Anticachectic effects were seen with these doses, with no adverse effects, 
however, there was no greater response with 6 gms per day relative to 2-4 grams/day. Therefore, the dose selected 
for this pilot clinical trial, 4 grams per day is comparable to the safe but effective dosage used in our preliminary 
studies and that of others. Currently prescription doses of 4 grams a day of Lovaza® is used and approved by the 
FDA to treat hypertriglyceridemia.  Furthermore, one, 3 to 4 oz serving of cold water fish such as salmon or 
sardines contains approximately 1.0-1.5 gms of n-3 fatty acids. The participant will be provided packages of the 
agent in a capsule form and instructed on compliance, intake, duration of intervention, and monitors to be 
completed by the research staff.  Subjects will be instructed to consume 4 gm Lovaza® in a divided dose (2 gm in 
the morning and 2 gm at night, to provide a total of 4 gm/day) with meals for a period of 3 months.  
 
5.2.2 Blueberry anthocyanins (VitaBlue):  Similarly, there is no established Dietary Reference Intake of the 
constituents of anthocyanins. The average daily consumption of anthocyanins in a western diet is estimated to be 
100 mgs/day. 120. Anthocyanins are rapidly absorbed and metabolized extensively following a moderate-to-high 
oral dose in humans. Studies have indicated anywhere from 4-6 hours half-life with complete excretion of parent 
compound as well as metabolites within 24 hours both in urine and plasma,  indicating the need for a dose every 
6- 8 hours to have consistent exposure 121. Similarly administration of anthocyanins at doses ranging from 0.5-2.0 
grams daily for 7 days in colorectal cancer patients with dose dependant concentrations detected in plasma and 
urine with no toxicities. 120.  Studies utilizing anthocyanins at doses of 1.4 grams/day (Mitroslect, Indena S.p.A.) 
administered as 0.47 grams/capsule  TID are currently in progress to provide active cellular antioxidant 
protection, inhibit inflammatory gene expression and consequently protect against oxidant-induced and 
inflammatory cell damage and cytotoxicity in obesity-induced inflammation and insulin resistance 
(NCT01180712) in 40-60 year old males for 21 days. In summary, repeated administration of anthocyanins exerts 
pharmacodynamic effects and generates concentrations of anthocyanins in human plasma as well as urine with no 
toxicity. We will thus use a dose of 0.47 grams/capsule dose of anthocyanins TID to total 1.4 grams per day, 
similar to the dose used in these chemoprevention trials.   
 
5.3  
Availability: VitaBlue will be obtained from VDF FutureCeuticals'. The product has earned self-affirmed GRAS 
(generally recognized as safe) status for use in food and beverages after a comprehensive review by an independent panel 
of experts.  Lovaza® is manufactured and distributed by Glaxo Smith-Kline laboratories and will be obtained from them 
for use in this study. The capsules have been manufactured by our team utilizing standards established by the FDA in a 
certified Compounding Center (Carrollwood Compounding Center and Pharmacy) and verified by the Center and by an 
independent testing group to assure consistent quality of the active agent contained in each capsule. The FDA has verified 
all these aspects of the agent as well as the placebo manufactured for this study and has provided us an IND approval of 


Amendment 11.0; 07 October 2015  
 
11
these agents used in this study. Dr. Kumar’s team currently holds 3 INDs for agents and placebos developed and approved 
by the FDA using the same methods for use in her research approved by this IRB. 
 
Placebo’s were also manufactured by Carrollwood Compounding Center and Pharmacy. 
 
5.4  
Agent Distribution: Agents will only be released by the Investigational pharmacy at MCC after documentation 
of IRB approval of the protocol and consent is provided and the collection of all essential documents is complete (e.g., 
signed 1572, current CV, medical license, and lab certifications, etc.) and new documents have been submitted to the FDA 
for the IND. 
 
5.5  
Agent Accountability: The PI, or a responsible party designated by the investigator (Investigational pharmacy at 
MCC), will maintain a careful record of receipt, disposition, and return of all study drugs on the Investigational Agent 
Accountability Record. All study drug supplies will be kept in a locked, limited access area. The study drug will not be 
used outside the context of the protocol. Under no circumstances will the investigator or other site personnel supply study 
drug to other investigators, patients, or clinics, or allow supplies to be used other than directed by this protocol. Study 
agent will not be transferred from one participant to another.  
 
The investigator will maintain records documenting the receipt, use, loss or other disposition of the investigational 
product, including batch or code numbers, and account for it’s disposition on a subject-by-subject basis, including specific 
dates and quantities. The source document, documenting the subject’s participation in this randomized clinical trial, must 
be documented in the medical and research records. Destruction will be documented in accordance with institutional 
practices. 
 
5.6  
Packaging and Labels: Bottles are labeled to comply with study requirements and applicable regulations for 
investigational drug use. Bottle labels include agent name, protocol number, dosing and storage instructions, required 
warnings for restricted, investigational use, and spaces for recording the subject registration and randomization number. 
The study agent to be used, Lovaza® (omega-3-acid ethyl esters), an FDA-approved prescription omega-3 provides 
prescription-only potency and purity with each 1-gram Lovaza® (omega-3-acid ethyl esters) gel capsule contains 90% 
omega-3-acid ethyl esters; 84% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ethyl esters. Lovaza® is 
provided by GlaxoSmithKline, who has authorized the FDA center for Drug Evaluation and Research, Division of 
Metabolic and Endocrine Drug Products to reference Lovaza® Capsules IND # 45,998. An investigator-initiated IND will 
be cross filed by the PI for this clinic trial  
 
5.7  
Drug Storage of COGNUTRIN (VITABLUE and n-3 fatty acids): All investigational agents will be received, 
stored and dispensed by the Investigational pharmacy at MCC. Bottles with study agent will be stored at controlled room 
temperature (15-30 0 C).The PI, or a responsible party designated by the investigator, will maintain a careful record of 
receipt, disposition, and return of all study agent on the Investigational Agent Accountability Record.  All study drug 
supplies will be kept in a locked limited access room. The study drug must not be used outside the context of the protocol.  
Under no circumstances will the investigator or .other site personnel supply study drug to other investigators, patients, or 
clinics, or allow supplies to be used other than directed by this protocol.  Study agent may not be transferred from one 
patient to another, from one participating center to another participating center or from one protocol to another.  All other 
transfers (i.e. patient or PI moves) must be approved in advance by the study PI. Every attempt will be made to collect all 
unused study agent supplies to be returned to the Moffitt Research Center PI office. The investigator will maintain records 
documenting the receipt, use, loss or other disposition of the investigational product, including batch or code numbers, 
and account for it’s disposition on subject-by-subject basis, including specific dates and quantities. The source document, 
documenting the subject’s participation in this clinical trial must be documented in the medical and research records.  
Destruction will be adequately documented.   
 
5.8  
Registration and Randomization: Potential subjects will be screened by the research coordinator using an 
Eligibility Checklist (Appendix I).   The initial screening visit will verify patient eligibility to the study.  A minimum of 
40 subjects will be randomized to the pilot clinical trial.  Within 6 months of completion of treatment with chemotherapy 
and radiation if applicable, we will screen the patients for cognitive function to determine the eligibility of participants to 
participate in the randomized trial portion of the study.  If found eligible based on the criteria established for cognitive 
impairment, subjects will be ready for baseline data collection.  


Amendment 11.0; 07 October 2015  
 
12
  
The research staff will use the Demographic Questionnaire Form to obtain baseline demographic data, medical and family 
history, and information regarding other health habits such as alcohol, tobacco and previous nutritional supplement use. 
Clinical Research Form (CRF): All medical record data (CRF) pertaining to the cancer diagnosis, tumor characteristics, 
node involvement, stage confirmation, medical history of cancer, menstrual cycle information, other medical history 
including renal or liver disease, concomitant medications including treatments for cancer and autoimmune diseases will be 
obtained from all subjects at baseline and changes in these variables monitored.  Once clinical eligibility is confirmed, and 
informed consent is signed, randomization of subjects takes place within the Moffitt SRARS program.  SRARS is a web 
delivered application that records subject registrations and provides randomization assignments.  Subjects will be 
randomized to one of 2 groups. An email is sent to a list of pre-determined recipients (clinical research coordinators) 
stating the treatment/randomization assigned to the subject.   
 
5.9  
Blinding and Unblinding Methods: All requests to unblind treatment assignment will be directed to the Protocol 
Lead Investigators (Kumar, Moffitt Cancer Center & Research Institute, telephone: 813-745-6885, fax: 813-745-7185, e-
mail: Nagi.Kumar@moffitt.org . Dr. Kumar   will determine if disclosure of treatment assignment is required after 
consultation with the Medical Doctor who is the primary MD for the subject.  If disclosure of the treatment would affect 
important medical decisions in a subject experiencing an AE, or could affect decisions regarding safe conduct of the 
clinical trial, unblinding might be allowed. If disclosure is warranted, the site will be directed to the product label found in 
the subject’s CRF binder or other designated research record. The label has a scratch-off area that will disclose the 
treatment assignment. Each site will document the unblinding process in the patient chart.  
 
6.  
AGENT ADMINISTRATION: 
 
6.1  
Dose Regimen and Dose Groups: Intervention groups  
 
6.1.1 Placebo Group: All participants in the placebo arm will receive the multivitamin supplement and the 
cognitive battery tests and structural and resting-state functional imaging at baseline and 3 months.  The placebo 
group used herein will allow us to generate information regarding the reliable change index, so information 
regarding the naturalistic change in cognitive performance, as well as the potential for practice effects to influence 
mean-level change data, across the follow-up period is important.  
 
6.1.2 Nutritional Supplement Group (NS).: The choice of the supplement to use in this trial is based on relevant 
research supporting the various components as well as the use of a commercially available standardized dietary 
supplement of anthocyanins and n-3 fatty acids.  The supplement to be used is a standardized formulation of 
blueberry extract VitaBlue® (40% polyphenolics, 12.5% anthocyanins from blueberries.  The supplement will in 
addition include Lovaza® (omega-3-acid ethyl esters), an FDA-approved prescription omega-3 provides 
prescription-only potency and purity with each 1-gram Lovaza® (omega-3-acid ethyl esters) gel capsule contains 
90% omega-3-acid ethyl esters; 84% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ethyl esters. 
Lovaza® is provided by GlaxoSmithKline, who has authorized the FDA center for Drug Evaluation and 
Research, Division of Metabolic and Endocrine Drug Products to reference Lovaza® Capsules IND # 45,998. An 
investigator-initiated IND has been obtained by PI for use of these agents in this clinical trial (IND # 116424).  
Subjects in the supplements treatment arm of the study will be given in the same fashion and time table to the 
“placebo” patients as the active treatment patients. 
 
6.2  
Agent Administration: Intervention will be administered to the patient on an outpatient basis and self-
administered by the participants. The daily dose of will be taken in divided doses (Lovaza® 2 tablet BID and VitablueTM 2 
tablet TID).  On the day of monthly follow-up visit, capsules should be taken within 4 hours of visit and blood draw for 
required lab work.   
 
Two bottles containing Lovaza and 1 bottle of anthocyanins capsules will be dispensed to all participants upon 
randomization with adequate number of capsules, to ensure that the subject has sufficient study drug to last until the next 
planned clinic visit.  At baseline and at each monthly visit up to the 3-month final visit, participants will receive these 
supplements in person to take home with them. At that point, participants will receive instructions regarding how many 
supplement pills they are to take a day.  


Amendment 11.0; 07 October 2015  
 
13
 
Schedule of dose administration of study agents 
Arm of Study 
Breakfast 
Lunch 
Dinner 
Treatment arm  
2 tablets Lovaza 
2 tablets Vitablue 
2 tablets Vitablue 
2 tablets Lovaza 
2 tablets Vitablue 
1 tablet multivitamin/mineral 
Placebo arm 
4 tablets matching 
placebo tablets 
2 tablets matching 
placebo 
4 tablets matching placebo tablets 
1 tablet multivitamin/mineral 
 
6.3  
Contraindications: COGNUTRIN ingredients - n-3 fatty acids may be contraindicated in subjects with bleeding 
disorders and anthocyanins may be contraindicated in people who are sensitive or allergic to berries.    
 
During study participation, subjects will be instructed to limit their consumption of the following berries to 1 cup per day: 
blackberry, blueberry, chokeberry, black currant, elderberry, and black raspberry. They will be asked to limit their 
consumption of the following omega 3’s to 2-3 servings (4 oz per serving) a week: walnuts, flaxseed oil, canola oil, fish 
oils, and fatty fish such as salmon, trout, mackerel, herring, sardines, pilchards, kipper, eel, whitebait, fresh tuna, 
anchovies, swordfish, bloater, cacha, carp, hilsa, jack fish, katla, orange roughy, and pangas.  
 
6.4  
Concomitant Medications: During study participation, subjects will be instructed to suspend consumption of 
additional supplements containing anthocyanins or omega 3’s. Subjects are considered enrolled in the trial from the time 
that the informed consent document is signed until the time that the subject is off study. All medications (prescription and 
over-the-counter), taken by the participant while on study will be documented on the concomitant medication CRF and 
will include: start and stop date, dose and route of administration, and indication.  
 
6.5  
Dose and Toxicity Management: We will ensure that our protocol and informed consent comply with FDA 
recommendations. In addition, we have planned monthly visits to monitor daily symptoms monitor and will perform an 
interview for adverse events, unusual symptoms, change in medical condition and concomitant medications use. Any 
abnormality observed will be communicated by the research coordinator to the study MD for evaluation and for 
continuation in the study.  Subjects in the study will be dropped from study until which time the symptom is determined to 
be unrelated to the study agent as determined by the study MD. We will provide each subject with a 24- hour contact 
phone number and specific instruction on contacting the research team including the MD in this study.  In addition, 
evaluation of safety in this subject population has been added as a specific aim of the trial with a formal comparison of 
safety between active and placebo arms, further illustrating our commitment to ensuring subject safety in this and future 
clinical trials. 
 
A patient’s treatment will be discontinued in any of the following circumstances: (a) Allergic reaction to product; (b) 
Dramatic change in stool frequency; (c) Start of other treatments that may cause malabsorption; (d) Request of patient of 
MD or patient; (e) Unusual symptoms reported during follow-up or other unusual symptoms or blood work results 
observed during the study period; and, (f) Persistent nausea not controlled with antiemetics.  There are no reductions in 
the Cognutrin® dose. If adverse events occur that require holding Cognutrin ® (until etiology is determined), the dose 
will remain the same once treatment resumes. Any toxicities associated or possibly associated with Cognutrin ® treatment 
will be managed according to standard medical practice. Subjects will be assessed clinically for toxicity prior to, during 
intervention on a monthly basis and at end of intervention. If >grade III toxicity occurs because of Cognutrin ® at any 
time during the study, treatment with Cognutrin ® will be discontinued. We will also inquire about hypersensitivity to 
fish/and or shellfish and symptoms of atrial fibrillation at each visit. All subjects will be followed by their medical 
oncologists for their cancer treatment, using the routine surveillance guidelines as established by the Cancer Center during 
the study. 
There are no alternative agents that are currently available to treat or ameliorate cognitive impairment observed in this 
target population. To date, interventions with cognitive training alone, pharmacological agents to treat chemotherapy-
induced anemia, psycho stimulants and antioxidant therapies with Vitamins A, C and E have not demonstrated efficacy 
nor safety in treating CI.  We and others have demonstrated in preclinical and clinical trials that plant-based substances 
and n-3 fatty acids with potent antioxidant and anti-inflammatory properties can be detected in plasma and serum, cross 
the blood-brain barrier, localize in various brain regions important for learning and memory such as cerebellum, striatum 


Amendment 11.0; 07 October 2015  
 
14
and hippocampus and increase neurogenesis. However, these interventions have not been evaluated to ameliorate CI in 
cancer patients treated with chemotherapy.  The results of this study may inform the design of a well-powered clinical 
trial to test the effectiveness of this intervention to ameliorate these late effects of cancer treatment and ultimately improve 
quality of survival in this patient population.  However, no guarantee of personal benefit based on participation will be 
made to subjects recruited in this study. Instead, participants will be told that results are expected to contribute to 
increased knowledge about possible interventions to remediate chemotherapy-induced changes in cognitive performance. 
Among persons in the nutritional supplementation intervention conditions, based on existing evidence from the ageing 
literature, some improvements to cognitive performance are anticipated. 
On the other hand, the risks to participants of this study can be divided into three groups a) risk due to collection of blood, 
b) potential risk due to study agent intake; c) Magnetic resonance Imaging (MRI). We have taken careful steps to 
implement procedures for minimizing and protecting against potential risks: 
 
(a) Reduce risks of specimen collection:  Participants undergoing venipuncture typically experience brief pain during 
needle insertion; occasionally experience bruising or the need for additional needle sticks to access “good vein”, and 
rarely experience an infection at the site of needle insertion.  Sterile equipment, accepted clinical practices, and trained; 
experienced staff will be used to reduce the risks of specimen collection. In addition the site will be cleaned before 
drawing blood, pressure will be applied until the bleeding stops and a sterile dressing will be used to cover the puncture 
site.  
 
(b) Reduce risk due to study agent: Based upon our team’s considerable experience administering anthocyanins and n-3 
fatty acid supplementation in preclinical and clinical trials, we have proposed periodic monitoring of organ function 
(CBC, CMP) including liver function tests throughout the study.  Moreover, all of the substances in the nutritional 
supplements are found in everyday foods and are not at levels that greatly exceed a typical dietary intake.  We have 
obtained detailed information and potential side effects of each of the agents used in the study and paid attention to the 
criteria for inclusion and exclusion and dose to reduce side effects as follows: Study Agent Lovaza® There is no 
established Dietary Reference Intake for n-3 fatty acids, yet the Adequate Intake (AI) is set at 1.6 and 1.1 grams/day for 
men and women respectively.  While intake in the United States occurs at much lower than the proposed AI and no signs 
of deficiency are observed, the AI is proposed to provide optimal health benefits associated with consuming n-3 fatty 
acids.  There is no Upper Limit established for n-3 fatty acids. In early studies using fish oil capsules, we and others have 
demonstrated the safety of administering 2-6 gms of EPA per day. Anticachectic effects were seen with these doses, with 
no adverse effects, however, there was no greater response with 6 gms per day relative to 2-4 grams/day. Therefore, the 
dose selected for this pilot clinical trial, 4 grams per day is comparable to the safe but effective dosage used in our 
preliminary studies and that of others. Currently prescription doses of 4 grams a day of Lovaza® is used and approved by 
the FDA to treat hypertriglyceridemia.  Furthermore, one, 3 to 4 oz serving of cold water fish such as salmon or sardines 
contains approximately 1.0-1.5 gms of n-3 fatty acids. The participant will be provided packages of the agent in a capsule 
form and instructed on compliance, intake, duration of intervention, and monitors to be completed by the research staff.  
Subjects will be instructed to consume 4 gm Lovaza® in a divided dose (2 gm in the morning, 2 gm at night, to provide a 
total of 4 gm/day) with meals for a period of 3 months. Blueberry anthocyanins (VitaBlue):  Similarly, there is no 
established Dietary Reference Intake of the constituents of anthocyanins. The average daily consumption of anthocyanins 
in a western diet is estimated to be 100 mgs/day.  Anthocyanins are rapidly absorbed and metabolized extensively 
following a moderate-to-high oral dose in humans. Studies have indicated anywhere from 4-6 hours half-life with 
complete excretion of parent compound as well as metabolites within 24 hours both in urine and plasma,  indicating the 
need for a dose every 6- 8 hours to have consistent exposure 121. Similarly administration of anthocyanins at doses ranging 
from 0.5-2.0 grams daily for 7 days in colorectal cancer patients with dose dependant concentrations detected in plasma 
and urine with no toxicities.  Studies utilizing anthocyanins at doses of 1.4 grams/day .(Mitroslect, Indena S.p.A.) 
administered as 0.47 grams/capsule  TID are currently in progress to provide active cellular antioxidant protection, inhibit 
inflammatory gene expression and consequently protect against oxidant-induced and inflammatory cell damage and 
cytotoxicity in obesity-induced inflammation and insulin resistance in 40-60 year old males for 21 days. In summary, 
repeated administration of anthocyanins exerts pharmacodynamic effects and generates concentrations of anthocyanins in 
human plasma as well as urine with no toxicity. We will thus use a dose of 0.47 grams/capsule dose of anthocyanins TID 
to total 1.4 grams per day, similar to the dose used in these chemoprevention trials.   
 


Amendment 11.0; 07 October 2015  
 
15
Nevertheless, we will record adverse events and will develop a data safety and monitoring plan to ensure that study 
participants are not negatively affected by study compounds. We will in addition obtain symptoms and concomitant 
medications that may be potentially related to study agent intake using daily monitors. All of the substances in the 
nutritional supplements are found in everyday foods and are not at levels that greatly exceed a typical dietary intake. 
Nevertheless, we will observe and report adverse events and will develop a data safety and monitoring plan to ensure that 
study participants are not negatively affected by study compounds. Our group is currently involved in several active 
clinical trials where these agents are being used and under IND approval from the FDA. We will keep abreast of the 
literature in the area of potential drug-drug, drug-nutrient interactions and other contraindications in the evolving research 
and will amend the study appropriately to ensure subject safety. 
 
(c) Risks due to MRI: For most people, there is no danger associated with having an MRI scan.  However, there may be 
some risk of psychological distress for the individuals posed by the confining environment of the scanner. We will 
therefore verify that participants are not claustrophobic, thereby reducing the probability of claustrophobia. The scanning 
environment poses potential risk from the magnet; specifically that metallic objects brought into the scanning room are 
dangerous to the individual. However the well-established Moffitt Cancer Center and University Diagnostic Institute 
protocol for treatment of patients in this environment minimizes risk. 
 
Other: The research team has considerable experience with administering cognitive tests to young and older adults and in 
all cases, participants will be encouraged to do “their best”, which seems to minimize test taking anxiety. Experienced 
personnel will administer all self-report and cognitive performance measures. The research study staff will carefully 
monitor participants' reactions and provide information upon request. All participants will be provided with Dr. Kumar’s 
name and telephone number. 
 
Based on the unavailability of effective and safe treatments to ameliorate cognitive impairment resulting from 
chemotherapy and the potential benefit a study such as this can provide, combined with the careful attention paid 
to minimize and eliminate risks due to participation, the benefits outweigh the risks. 
 
Adverse events requiring delays or permanent discontinuation of Cognutrin® are listed in the table below: 
Event 
Action 
Grade 1 & 2 constitutional, dermatological, gastrointestinal 
(GI), metabolic and pain symptoms 
Examples: 
Rash 
Allergic rhinitis, cough, bronchitis.  
Abdominal Pain 
Belching/Gas 
Nausea/Vomiting 
Diarrhea 
No Action Required 
Inform MD 
Document event in research and medical record 
Grade 3 
Discontinue Cognutrin ®/Notify Study PI 
Grade 4 
Discontinue Cognutrin ®/Notify Study PI 
Grade 2, 3, or 4 abnormal liver function tests1,2 as 
determined by NCI CTC version 4.0    
Discontinue Cognutrin ®/Notify Study PI and  
Monitor until it returns to normal  
 
1. Tests used to monitor liver function include: albumin, total and direct bilirubin, alkaline phosphatase, AST, ALT, total 
 
protein, PT/PTT,) 
2. In the event that PT/PTT is abnormal due to anticoagulant therapy, treatment and/or drug discontinuation will be at 
 
the discretion of the site investigator/MD. 
 
Regardless of the reason for holding study drug treatment, the maximum allowable length of treatment interruption is 1 
week. Interruption of intake of >1 week will result in discontinuance of subject from the study. Patients who have an 
ongoing Cognutrin ®-related Grade 3-4 or serious adverse event at the time of discontinuation from study treatment will 
continue to be followed until resolution of the event or until the event is considered irreversible by the study MDs. 
 


Amendment 11.0; 07 October 2015  
 
16
In addition, a standard multivitamin/ mineral preparation will be provided free of charge during the study duration, to assure a 
consistent baseline intake of essential vitamins and minerals among all study participants during the study period and to 
encourage subjects from not using other supplements that may contain components of the study agents. Subjects in the 
treatment and placebo arms will be provided these multivitamin/mineral supplements and instructed to consume 1 tablet daily 
with the dinner meal.  
 
In our experience with cancer survivors both clinically and in research studies, over 75-85% of breast cancer survivors use a 
multivitamin/mineral supplement.   Several of these supplements have added ingredients including botanicals and biologics 
from unknown as well as known sources.  The quality, content, standardization techniques, safety as well as stability of the 
content of these supplements have been a challenge to our team.  In order to provide a standard dose to all subjects in the 
study .ensure safety and prevent any overdosing on other supplements, similar to the content of COGNUTRIN, we have 
provided a standard multivitamin/mineral to the subjects in our clinical trials with botanicals and biologics.  
  
Our group is currently involved in several active clinical trials where these agents are being used and under IND approval 
from the FDA. We will keep abreast of the literature in the area of potential drug-drug, drug-nutrient interactions and other 
contraindications in the evolving research and will amend the study appropriately to ensure subject safety. 
  
The research team has considerable experience with administering cognitive tests to young and older adults and in all cases, 
participants will be encouraged to do “their best”, which seems to minimize test taking anxiety. Experienced personnel will 
administer all self-report and cognitive performance measures. The research study staff will carefully monitor participants' 
reactions and provide information upon request. All participants will be provided with Dr. Kumar’s name and telephone 
number to clarify or answer any questions. 
 
6.6  
Adherence/Compliance: During study participation, subjects will be asked to: self-administer the study 
medication; complete diet recall forms at specified time periods (baseline, 1, 2 and 3 months); avoid consumption of 
additional nutritional supplements and multivitamins containing the recommended daily allowance (RDA) of Vitamin D. 
Subjects are expected to: maintain ≥85% compliance with study agent intake; comply with dietary, medication and 
supplement restrictions; and complete the diet recall forms to the best of their ability. Subjects will be interviewed at the 
monthly scheduled time points, at which time pill counts will be performed to verify compliance with study requirements. 
Subjects discovered not to be complying with study requirements will have the requirements re-explained to them.  
 
6.7  
Agent Destruction/Disposal 
 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and drug remaining. This 
reconciliation will be logged on the drug reconciliation form, signed and dated. Any discrepancies noted will be investigated, 
resolved, and documented prior to destruction of unused study drug. Drug destroyed on site will be documented in the study 
files. 
 
 
7 CLINICAL EVALUATIONS AND PROCEDURES 
 
7.1  Table 1: Schedule and Sequence of Data Collection 
 
 Assessment Schedule 
 
 
 
Screening 
Baseline/ 
Randomization 
 
M1 
+/- 7 days 
 
M2 
+/- 7 
days 
 
End of 
Treatment/M3 
+/- 7 days 
7 Day Follow Up 
 
 
W1 
W3 
W4 
W7 
W8 
W11 
W12 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
 
X 
 
X 
X 
Relevant Medical 
History/Current Medical 
Condition 
X 
 
 
 
 
 
 
 
 
Mini-Mental Status Exam, 
2nd Edition (MMSE) 
X 
 
 
 
 
 
 
 
 
Self-Reported Cognitive 
X 
 
 
 
 
 
 
 
 


Amendment 11.0; 07 October 2015  
 
17
Impairment Since 
Chemotherapy 
Wechsler Test of Adult 
Reading (WTAR) 
 
X 
 
 
 
 
 
 
 
Hopkins Verbal Learning 
Test, Revised (HVLT-R): 
Form 1 
 
X 
 
 
 
 
 
 
 
Hopkins Verbal Learning 
Test, Revised (HVLT-R): 
Form 2 
 
 
 
 
 
 
 
X 
 
Controlled Oral Word 
Association Test (COWA): 
T1 
 
X 
 
 
 
 
 
 
 
Controlled Oral Word 
Association Test (COWA): 
T2 
 
 
 
 
 
 
 
X 
 
Color Trails – Part 1 (Form 
A) 
 
X 
 
 
 
 
 
X 
 
Color Trails – Part 2 (Form 
A) 
 
X 
 
 
 
 
 
X 
 
Brief Visuospatial Memory 
Test – Revised (BVMT-R): 
Form 1 
 
X 
 
 
 
 
 
 
 
Brief Visuospatial Memory 
Test – Revised (BVMT-R): 
Form 2 
 
 
 
 
 
 
 
X 
 
Digit Span (subset of 
WMS-IV) 
 
X 
 
 
 
 
 
X 
 
Symbol Digit Modalities 
Test (SDMT) 
 
X 
 
 
 
 
 
X 
 
Rey Complex Figure Copy 
(Copy Trial Only) 
 
X 
 
 
 
 
 
X 
 
Demographic Questionnaire 
 
X 
 
 
 
 
 
 
 
Godin-Leisure Time 
Exercise Questionnaire 
 
X 
 
 
 
 
 
X 
 
Primary Care Evaluation of 
Mental Disorders Health 
Questionnaire (PHQ-9) 
 
X 
 
 
 
 
 
X 
 
Fatigue Symptom Inventory 
(FSI) 
 
X 
 
 
 
 
 
X 
 
Patient’s Assessment of 
Own Functioning Inventory 
(PAOFI) 
 
X 
 
 
 
 
 
X 
 
MRI-Resting state 
functional MRI and 
structural MRI. 
 
X 
 
 
 
 
 
X 
 
Anthropometric 
Measurements1 
 
X 
 
 
 
 
 
X 
 
ECOG 
X 
 
 
 
 
 
 
X 
 
2 Day Food Record2 
 
X 
 
X 
 
X 
 
X 
 
Hematology (CBC)3 
X 
 
 
X 
 
X 
 
X 
 
Blood Chemistry (CMP, 
PT/PTT, LDL)4 
X 
 
 
X 
 
X 
 
X 
 


Amendment 11.0; 07 October 2015  
 
18
Research Labs (Oxidative 
stress, Cytokine) 
X 
 
 
 
 
 
 
X 
 
Adverse Events 
 
 
 
X 
 
X 
 
X 
X 
Limited Physical Exam 
X5 
 
 
 
 
 
 
X 
 
Study Agent/Multivitamin 
Distribution 
 
X 
 
X 
 
X 
 
 
 
Study Agent Intake & 
Symptom Logs 
 
X 
 
X 
 
X 
 
X 
 
Pill Counts 
 
 
 
X 
 
X 
 
X 
 
Follow Up Phone Call 
 
 
 
 
 
 
 
 
X 
1 Height, Weight, BMI, Waist, & Hip Circumference  
2 Dietary recall forms and instructions will be distributed in person at the screening visit and collected at the baseline, 
week 4, week 8, and end of treatment visits 
3 Hematology labs do not need to be performed at screening visit if lab results are available within the previous 28 days 
 
(+/- 3 days)  
4 Blood Chemistry labs do not need to be performed at screening visit if lab results are available within the previous 28 
 
days (+/- 3 days)  
5 The initial limited physical exam can be done at either screening or baseline. 
 
7.2 
Evaluations during Screening Visit 
7.2.1 
All subjects will have the study fully explained to them and will sign an informed consent document prior 
to having any invasive procedures performed. They will also be assigned an identification number. 
 
7.2.2 
Within 6 months of completing chemotherapy, + or – radiation (+/- 7 days), patients will be screened for 
cognitive impairment. Evidence of cognitive impairment requires each subject answer in the affirmative: 
‘do you have problems with memory and attention since having chemotherapy, and do you believe 
chemotherapy contributed to the problems?’ 
 
 
7.2.3 
A limited physical exam will be performed which includes ECOG.  
 
NOTE: The limited physical exam can be done at either screening or baseline. 
 
7.2.4 
Concomitant medications, medical history, and current medical condition will be collected. 
 
7.2.5 
Mini-Mental State Examination, (MMSE will be administered to screen for and estimate the severity of 
cognitive impairment in order to determine participant’s eligibility to participate in the study. 
 
7.2.6 Blood will be drawn for CBC, CMP, PT/PTT, and LDL and measurement of plasma antioxidant 
biomarkers or oxidative stress and inflammation. 
 
7.3 
Evaluations during Baseline/Randomization Visit 
 
 
7.3.1  After eligibility has been confirmed based on screening tests using eligibility checklist, subjects will be 
randomized and supplied with a one-month supply of nutritional supplement (COGNUTRIN) or placebo 
(n=20/arm) and multivitamin . 
 
7.3.2 
Review of completed diet survey and concomitant medications. 
 
 
7.3.3 
Anthropometric measurements will be taken. 
 


Amendment 11.0; 07 October 2015  
 
19
 
7.3.4 
The following questionnaires will be completed:  Godin-Leisure Time Exercise, Patient’s Assessment of 
Own Functioning Inventory (PAOFI); Personal Health Questionnaire (PHQ-9), and Symptoms of Fatigue 
and Depression (FSI)  
 
7.3.5 
Cognitive testing will be administered (HVLT-R: Form 1, COWA: T1, Color Trails Part 1& 2, Digit 
Span, SDMT, BVMT-R: Form 1, and Rey Complex Figure Copy  
 
7.3.6  Subjects will also undergo a structural and resting-state functional magnetic resonance Imaging 
(MRI/fMRI)   
 
Subjects should not be randomized until eligibility has been confirmed. All components of eligibility will be 
confirmed (inclusion criteria and exclusion criteria). 
 
7.4  
Evaluations during Study Intervention 
7.4.1 
Weeks 3, 7, 11: Participants will be contacted reminding them to complete diet survey and to bring 
completed survey, study agent /symptom logs and all left over study agent (including multivitamin) to 
their next in person visit scheduled. 
 
7.4.2 
Weeks 4 & 8 ( +/- 7 days): Participants will come in person monthly for the following: 
7.4.2.1 
Review of completed diet surveys, study agent/symptom logs, adverse events and concomitant 
medications by CRC and verified with CRU RN. 
7.4.2.2 
Collection of any unused nutritional supplement/ placebo and multivitamin for pill counts 
7.4.2.3 
Safety labs (CBC, CMP, PT/PTT, and LDL) will be drawn 
7.4.2.4 
Participant will be supplied with a new one-month supply of nutritional supplement or placebo 
 
7.5  
Evaluations at Completion of Study Intervention (3 months, +/- 7 days) 
 
 
7.5.1  Blood will be drawn for CBC, CMP, PT/PTT, and LDL and measurement of plasma antioxidant  
biomarkers or oxidative stress and inflammation. 
 
7.5.2 
A limited physical exam will be conducted, including anthropometric measurements, ECOG, concomitant 
medications and adverse event collection by CRC and verified with CRU RN. 
 
7.5.3 
Food records and study agent and symptoms logs will be collected and reviewed with subject for 
clarification. 
 
7.5.4 
The following questionnaires will be completed:  Godin-Leisure Time Exercise, Patient’s Assessment of 
Own Functioning Inventory (PAOFI); Personal Health Questionnaire (PHQ-9), and Symptoms of Fatigue 
and Depression (FSI) will be completed.  
 
7.5.5 
Cognitive testing will be administered (HVLT-R: Form 2, COWA: T2, Color Trails Part 1& 2, Digit 
Span, SDMT, BVMT-R: Form 2, and Rey Complex Figure Copy. 
 
7.5.6 
Left over study agent will be collected and pill counts done. 
 
7.5.7  Subjects will also undergo a structural and resting-state functional magnetic resonance Imaging 
(MRI/fMRI).   
 
7.6 
Post-intervention Follow-up Period (7 days +/- 3 days) 
 
Subjects will be contacted by telephone 7 (+/-3) days after discontinuing study agent to capture any signs and 
symptoms occurring since stopping the study drug and changes to concomitant medications. The subject is 
considered off study after telephone contact is completed. 


Amendment 11.0; 07 October 2015  
 
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7.7  
Methods for Clinical Procedures: 
 
 
7.7.1  Demographic Data:  At baseline, in addition to the set of intake questionnaires designed to evaluate an  
 expanded set of demographic characteristics, self-reported health, lifestyle activity participation completed at 
screening, the following data will be collected at baseline (Appendix II). Data regarding menopausal status will 
also be obtained. (Pre-menopausal, post menopausal and CRA (Chemotherapy related amenorrhea will be defined 
as without menstrual periods for a period equal to or over 6 months in a patient who was premenopausal at 
diagnosis).  
 
7.7.2  Anthropometric measurements such as participant’s height, weight, BMI, waist and hip circumferences 
(Appendix III) will be obtained at baseline and at 3 months. These will be measured by a  trained CRC using 
standardized techniques utilized and validated in our previous trials,104-105 and used to calculate body mass index 
(Weight kg/ Height m2) and waist: hip ratio.  Our group has experience in the use of these methods in this patient 
population in clinical practice as well as in previous studies.   
 
7.7.3   Physical Activity (PA) will be obtained at baseline and at 3 months using the Godin-Leisure Time 
Exercise Questionnaire106 (Appendix IV).  They will be reviewed by the study staff to monitor for increase in 
physical activity and to ensure that subject in not participating in strenuous activities.  
 
7.7.4   Dietary intake (Appendix V) will be assessed at baseline and monthly by conducting random monthly, 
2-day, 24-hour dietary recalls (gold standard for collecting dietary data) using a 5-step multipass procedure 107-109 
and using the frequently updated NDSR database (for analysis of nutrient composition). At baseline and monthly 
for up to 3 months, subjects will be requested to complete this instrument and bring it to the scheduled study clinic 
visit for review and to monitor compliance. Food portion visuals will be provided at baseline in the participant 
folder to enhance the collection of accurate portion size information.  Protocols are established for training dietary 
interviewers and meticulous quality control procedures are established and supervised by Dr. Kumar. The 
University of Minnesota Nutrition Data System-Research version (NDS-R) is used for data entry and analysis.  
This is a microcomputer-based system for collection and analysis of dietary data that prompts the user to describe 
food intake at the level of detail such as food source, processing method, fat and salt used in preparation, and 
ingredients that contribute to fat and sodium intake.  The nutrient database contains over 19,000 foods, 7,800 
brand-name products, and many ethnic foods.  Although values are available for 108 nutrients and nutrient ratios, 
we will specifically analyze average intakes of energy and nutrient density. The database is derived from USDA, 
food manufacturers, foreign food composition tables, and scientific literature. Dr. Kumar’s group is currently 
using these instruments in the active and proposed chemoprevention trials and has experience working with the 
data using these instruments. The primary purpose of this instrument will be to (1) verify compliance to 
restrictions to not over consume other products containing similar agents and (2) to verify consumption of 
adequate calories, protein and other nutrients during the study.  A detailed list of products containing significant 
amounts of n-3 fatty acids and blueberry anthocyanins will be provided to each subject. Subjects will be instructed 
to avoid excess intake of these foods. 
 
7.7.5  
Functional markers (Eastern Cooperative Oncology Group: ECOG) 110 (Appendix VI):  Functional 
Markers allow subjects to be monitored for basic functional status and to monitor any functional impairment. 
Limitations in the activities of daily living have been identified secondary to fatigue and lethargy reported by this 
patient population. (Screening & 3 months) 
 
7.7.6  
Participants will also be provided with Study Agent Intake and Symptom log (Appendix VII) which 
they will be required to complete daily. Study agents and instructions for administration will be distributed to 
subjects at baseline and monthly during scheduled visits. Each batch will contain a supply for approximately 1 
month. The study intake log will require the subject to check that study agent has been taken and will be secured 
to the symptom monitoring scale to ease completion and to remind patients to monitor symptoms.  
 
7.7.7  
Pill counts will be completed at monthly visits prior to providing subject with a new batch of 
supplements. Working at a flat surface, the research coordinator applies a pair of latex gloves and then pours the 


Amendment 11.0; 07 October 2015  
 
21
bottle of study agent/placebo or multivitamin on to the pill count tray.  Using a gloved hand or sorter the pills are 
counted individually and returned to the empty bottle.  In the event of discrepancy between actual and expected 
count, the process is repeated.   
 
7.7.8  
Adverse events monitoring (Appendix VIII): 
All adverse events (AEs) that are reported by the subject, detected during a visit, physical examination, or 
laboratory work-up will be recorded in the participant’s study record and recorded on the CRF. All AEs that occur 
after the start of the study agent will be recorded on the AE CRF whether or not related to study agent. The 
following information will be captured for each AE: date reported; verbatim term; CTCAE Term (v 4.0); onset 
and resolution date; severity grade; attribution to study agent; whether or not the event was reported as an SAE; 
action taken; whether or not the subject dropped due to the AE; outcome; and comments. 
 
For each subject, AE’s will be collected at the screening, Month 1, Month 2, Month 3/EOT, visits as well as at the 
7-day post-treatment follow-up call by the clinical research coordinator. AE’s collected at the screening visit will 
be catalogued as baseline symptoms by the clinical research coordinator and the AE log will be reviewed and 
signed by either the patient’s medical oncologist or PI. AE’s collected during Month 1 and 2 visits will be 
reviewed with the patient by the nurse who drew their blood at CRU and the AE log will be signed by the 
principal investigator. Finally, at the Month 3 visit, the participant’s medical oncologist will review the AE log 
with the patient and sign-off on the reported symptoms; if the medical oncologist is unavailable to sign the AE log 
at this visit, then the PI will review and sign the form. AE’s reported at the 7-day follow-up call will be reviewed 
and signed by the PI. The participant’s reported symptoms at this time point will be documented on a powerchart 
telephone note by the clinical research coordinator. Serious adverse events (SAE’s) are reported to IRB and FDA. 
If a participant reports an SAE, the PI will immediately be informed and she will then report it to the IRB and 
FDA. AE logs will be scanned to patients’ medical records by the clinical research coordinator once they are off-
study.   
 
7.7.9 
Assessment of Cognitive Performance.   
 
Cognitive performance will be obtained using a battery of valid and reliable cognitive performance tests has been 
selected for administration based on the results of preliminary studies and previous research on the impact of 
cognitive training and nutritional supplementation on cognitive performance in older adults as well as previous 
research on cognitive deficits in breast cancer survivors. The tests will be used to derive composite indices for the 
domains of memory, executive functioning, processing speed, visual-spatial ability, and attention/concentration. 
The assessment of each domain with multiple measures is designed to more fully represent the domain and to 
minimize the possibility that scores reflect idiosyncratic performance on a single test. The assignment of measures 
to domains is based on accepted descriptions of their functional demands. We recognize that these measures are 
not pure tests of a domain and that some measures may draw on multiple domains. Nevertheless, the assignment 
of measures to domains as organized below can be considered a useful heuristic for characterizing cognitive 
functioning. To ensure the quality of the data collected, these tests will be administered and scored only by 
research personnel at Moffitt Cancer center qualified and trained by Drs. Heather Jim and Small before the start of 
the study and supervised by them during the course of the study.   
 
Cognitive Status. Mini-Mental State Examination, (MMSE) (Appendix IX). This domain will be used to screen for 
and estimate the severity of cognitive impairment in order to determine participant’s eligibility to participate in the 
study. The MMSE has demonstrated validity and reliability in psychiatric, neurologic, geriatric, and other medical 
populations. 
 
Estimated Intellectual Ability.  The Wechsler Test of Adult Reading (WTAR) 127 (Appendix X) requires 
participants to pronounce 50 irregular words that cannot be easily decoded phonetically.  Previous studies have 
shown that performance on the NART is highly correlated with general intelligence (factor ‘g’) as measured by 
the Wechsler intelligence scales127. (Accordingly, the WTAR will be administered to all participants at baseline 
only to obtain an estimate of overall intellectual ability).  WTAR scores will be used for descriptive purposes and 
as a covariate in all analyses comparing cognitive performance in the study samples.  
 


Amendment 11.0; 07 October 2015  
 
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Verbal Fluency. The Controlled Oral Word Association Test (COWAT) 144 is a measure of verbal fluency and is a 
subtest of the Multilingual Aphasia Examination (MAE; Benton, Hamsher, & Sivan, 1994). At baseline, the 
COWA uses the three letter set of F, A, S  (Appendix XI)to assess phonemic fluency. Individuals are given 1 min 
to name as many words as possible beginning with one of the letters. The procedure is then repeated for the 
remaining two letters. This is then repeated at the end of study using the letters P, R, W (Appendix XII). 
 
Memory.  This domain will be assessed with separate measures of visuospatial memory and verbal memory.  
Visuospatial memory will be assessed using the Brief Visuospatial Memory Test-Revised (BVMT-R) (Appendix 
XIII). Respondents are presented with six geometric figures printed in a 2 x 3 array.  In three learning trials, 
respondents view the array for 10 seconds and are then asked to draw as many of the figures as possible in their 
correct location.  After a 20 to 25-minute delay, the task is repeated. Then, the respondent is asked to identify the 
six figures from among 12 figures.  These procedures will be used to obtain two summary scores.  The immediate 
recall score represents the number of design features correctly reproduced across the three learning trials.  The 
delayed recall score represents the number of design features correctly reproduced 20-25 minutes following 
presentation. Form 1 will be used at the baseline visit (Appendix XIV) and Form 2 at the end of treatment visit 
(Appendix XV). Verbal memory will be assessed using Form 1 of Hopkins Verbal Learning Test-Revised 
(HVLT-R) 129,143 at baseline (Appendix XVI) and Form 2 at the end of study visit (Appendix XVII). Respondents 
are given three trials to learn a list of 12 concrete nouns organized into three taxonomic categories.  After a 20-25 
minute delay in which other tests will be administered, respondents will be given a delayed free recall task. 
Immediately following the free recall task, respondents will be asked to recognize the original 12 words from a 
list of 24 words.  In total, four measures of memory performance will be derived from this task: immediate recall, 
delayed free recall, retention (delayed free recall divided by best immediate recall trial), and recognition 
discrimination index (the total number of true-positive responses subtracted by the total number of false-positive 
errors, including semantically related and unrelated errors).   
 
Attention/Concentration.  This domain will be assessed using the Digit Span (Appendix XVIII) subtest of the 
Wechsler Memory Scale – Fourth Edition (WMS-III) at baseline and end of study 130 and Part 1 of the Color 
Trails Test (CTT-1) 131 at baseline and end of study (Appendix XIX).  The Digit Span assesses immediate verbal 
memory and auditory attention.  The examiner reads increasingly longer series of numbers and the respondent is 
required to repeat them in the same order.  The examiner then reads additional sequences of numbers and the 
respondent is required to repeat them in reverse order.  The Digit Span subtest yields one score, number of items 
completed correctly.  The CTT is an analogue of the original Trail Making Test without significant influence of 
language.  CTT-1 consists of a page with scattered circles numbered from 1 to 25.  Even numbered circles are 
colored yellow and odd-numbered ones are colored pink.  Respondents are instructed to connect the circles in 
consecutive numeric order with a continuous line as quickly as possible.  The alternating colors are not mentioned 
in the instructions.  A total score is determined by recording the number of seconds required to complete the task.   
Executive Functioning.  This domain will be assessed using Part 2 of the Color Trails Test (CTT-2) 131  (Appendix 
XX and the Symbol Digit Modalities Test (SDMT) 132  (Appendix XXI) at baseline and end of study. The CTT-2 
will be administered immediately following the CTT-1.  It consists of a page containing 25 pink circles and 25 
yellow circles numbered 1 to 50.  Respondents are instructed to connect the circles in consecutive order while 
alternating colors (1 pink, 2 yellow, 3 pink, etc.). A total scored is determined by recording the number of seconds 
required to complete the task.  Alternate forms will be used at the follow-up assessments.  The SDMT requires 
respondents to write the number that corresponds with each symbol for a series of 110 items in which the symbol 
but not the number appears. Respondents identify the correct number using a key provided in which a different 
abstract symbol is matched with a different number.  A total score is determined by calculating the number of 
items correctly completed in 90 seconds. 
 
Visual-Spatial Ability. At baseline and end of study, this domain will be assessed using the Rey Complex Figure 
Copy133 (Appendix XXII), which asks respondents to reproduce a complicated line drawing.  The time it takes a 
respondent to do so and the number of errors that she makes are used as the basis for scoring.  This test has been 
shown to be sensitive to impairments in visual-spatial ability in breast cancer survivors 7. 
 
Calculation of Domain Scores and Impairment Scores.  As in prior research incorporating a non-cancer 
comparison sample, data from the CA- sample will be used to convert raw scores on each test index into 


Amendment 11.0; 07 October 2015  
 
23
standardized z scores.  A domain score for each of the four domains listed above will be calculated by averaging 
the z scores of all the tests indices comprising a domain.  In addition to calculating continuous scores for each test 
index and domain, data from the CA- sample will be used to characterize performance on each individual test 
index as impaired or not impaired.  Consistent with previous research 134 , impairment will be defined as ≥1 
standard deviation below population norms. 
 
 
7.7.10 Self-Report Measures (Baseline and End of Study) 
 
7.7.10.1 Depressive Symptomatology.  The Primary Care Evaluation of Mental Disorders Health 
Questionnaire – 9 (PHQ-9)137  (Appendix XXIII) will be used to assess depressive symptomatology.  The 
PHQ-9 consists of 9 items assessing depression on a 4-point scale (0=not at all, 3=nearly every day).  
Items are summed for a total score ranging from 0 to 27 with higher scores indicating greater depressive 
symptomatology.  The PHQ-9 is a short self-report questionnaire that shows good sensitivity and 
specificity to assessment of depressive disorders by mental health professionals in primary care patients 
137-138 and cancer patients 139. 
 
7.7.10.2  Fatigue Symptomatology.  The Fatigue Symptom Inventory (FSI)140-141 (Appendix XXIV) is a 
14-item scale that assesses the frequency, severity, and disruptiveness of fatigue.  Frequency is measured 
in two ways: the number of days fatigue was experienced in the past week; and the portion of the day on 
average the respondents felt fatigued.  Severity in the past week is measured on an 11-point scale (0 = not 
at all fatigued; 10 = as fatigued as I could be).  Disruptiveness in seven different domains of daily 
functioning is also evaluated.  These domains are assessed on separate 11-point scales (0 = no 
interference; 10 = extreme interference).  Responses to these seven items are summed to provide a total 
interference score.  Previous research has demonstrated the reliability and validity of the FSI with 
individuals diagnosed with cancer. 
 
7.7.10.3  Subjective Cognitive Function.  The Patient’s Assessment of Own Functioning Inventory 
(PAOFI) 142 (Appendix XXV) will be used to assess patients’ perceptions of their cognitive functioning.  
The PAOFI consists of 33 items which assess cognitive functioning on a 6 point scale (1=almost always, 
6=almost never).  Items are summed to produce four subscales: memory, higher level cognition, language 
and communication, and motor sensory processing.   
 
7.7.11  Safety Markers: All safety markers will be performed at the Moffitt Cancer Center Clinical 
laboratories in real time. Non-fasting blood sample will be drawn at the screening visit (unless labs available 
within 7 days (+/- 3 days), and monthly, using sterile needles for the following studies:  
 
Comprehensive Metabolic Panel (CMP including LDL):  Approximately 10 ml of blood will be 
collected in a speckled red-top SST tube and processed at the clinic site by standing for 20–60 minutes to 
clot, then spinning for 20 minutes at 3200 rpm. The sample will be used for the CMP with LDL (Moffitt 
Cancer Center Labs). 
 
Complete Blood Count (CBC): Approximately 2.5 ml of blood collected in lavender top EDTA-
containing tubes will be used for CBC. A complete blood count (CBC) will be completed using electronic 
cell sizing sorting cytometry/microscopy. Tests performed as part of the CBC panel include the 
following: WBC; RBC; HgB; HCT; MCV; MCH; MCHC; RDW; PLT; MPV; absolute neutrophils; 
absolute bands; absolute lymphs; absolute monocytes; absolute eosinophils; and absolute basophils 
(Moffitt Cancer Center Labs).  
 
PT/PTT: Blood will be collected in one full 3.2% sodium citrate (light blue-top) tube. The correct blood 
to citrate ratio is critical—do not overfill or under fill the tube. Mix by inversion four times. Samples are 
stable for 24 hours at room temperature. If the sample will be stored longer than 24 hours, centrifuge 
specimen within one hour of collection at 2500–3000 rpm. Transfer plasma to a plastic screw-top vial and 
freeze at –20ºC immediately (Moffitt Cancer Center Labs). 
 


Amendment 11.0; 07 October 2015  
 
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7.7.12 Biomarkers of Oxidative Stress. A number of biomarkers of oxidative stress and inflammation have 
been shown to change with age and disease. For example the isoprostanes are a family of eicosanoidsformed in 
vivo from the free radical catalyzed peroxidation of arachodonic acid that is independent of cyclooxygenase 
activity. They appear to be reliable markers of lipid peroxidation. Levels of 8-isoprostane increase with age in 
some but not all studies, and are reduced by diets high in fruits and vegetables. Ideally measured with GC-mass 
spectroscopy, isoprostanes can also be measured by ELISA. Other markers of lipid peroxidation include 
malondiadehyde that can easily be measured, although it may reflect some enzyme dependent peroxidation and 
inflammation is still a valuable measure for comparison with other studies. Markers of protein oxidation and 
nitration have also been shown to increase with age and 2 markers routinely measured are protein carbonyls and 
3-nitrotyrosine (3-NT). Furthermore, oxidative DNA damage is another marker measured in aging as it is widely 
thought that oxidative damage to DNA is a significant contributor to age-related disease as well as cancer. 
Oxidative DNA damage markers are also decreased in humans following diets high in fruits and vegetables. 
Markers of inflammation are also useful and also show up-regulation with age and disease. Plasma samples will 
be analyzed for several biomarkers of inflammation and oxidative stress. These methods are in routine use in Dr. 
Bickford’s lab for rodent studies and will be adapted for human plasma: Isoprostanes (8-epi prostoglandin F2α) 
will be measured by ELISA (Cayman Chemical); 3-NT will also be measured by ELISA and we will make our 
own plates using routine methods for ELISA with commercially available antiserum (3-NT EIA antiserum from 
Cayman Chemical). Protein carbonyls are measured by oxy-blot techniques (Chemicon). 8-oxodeoxyguanisine is 
measured by ELISA (Cayman Chemicals). MDA is measured by HPLC, which is more specific for MDA than the 
TBAR assay. 
 
One 10 ml of blood will be collected in a green top vacutainer and centrifuged 3000 RPM /10 minutes/ RT to 
isolate the plasma portion of blood. Approximately 5 ml of plasma will be collected and transferred into 1 ml 
plasma aliquots. These will be stored in labeled screw cap tubes at -80C in the Tissue Core of the Moffitt Cancer 
Center until analysis. 
 
7.7.13 Inflammatory markers-Cytokines will be measured with a panel including IL-1, IL-4, IL-6, IL-8, IL-
10, IL-12, GM-CSF, IFN-gamma, TNFα, and CRP (BioRad-Bioplex). All of these biomarkers have been shown 
to increase with disease, aging and cytotoxic agents and will be used to monitor compliance with the dietary 
supplementation group and as a covariate in the analysis of cognitive function. The cytokine panel will be 
completed by Dr. Djeu in her research laboratories. 
 
One 10 ml of blood will be collected in a purple top (EDTA) vacuatiner and centrifuged at 3000 RPM /10 
minutes/ RT for isolation of PBMC, plasma and RBC. Approximately 5 ml of plasma will be collected and placed 
into one labeled screw cap tube and frozen at -80C. The Buffy Coat with adjacent layer of plasma & RBC with be 
harvested and transferred to 50 cc conical tube with 10ml of PBS. The remaining RBC will be harvested and 
washed 3 times with PBS and then re-suspended in equal volume of distilled water. Two,  1 ml RBC aliquots will 
be placed in labeled screw cap tubes and frozen in at -80C. Harvested BC will be harvested on Ficol for PBMC 
(no cell count required). PBMC will be washed once in PBS and the cells will then be re-suspend in 2ml of 
Freezing Media (40 ml FBS + 7 ml DMSO + 3 ml RPMI). Two, 1ml aliquots of PBMC will be placed in labeled 
cryovials, and frozen MR. Once frosty, they will be placed in storage. All samples will be stored in the Tissue 
Core at Moffitt Cancer enter until analysis. 
 
2 - 10 ml tube will be forwarded to Tissue Core labs at the Moffitt Cancer Center for processing and storage. 
Once labs specimens for 40 subjects (pre and post intervention) have been collected, they will be transported from 
Tissue to Dr. Bickford’s lab at USF and Dr. Djeu’s lab at MCC by the clinical research coordinators, using 
appropriate containers to preserve the temperature and thus integrity of the specimens for assay of oxidative stress 
markers.   
 
 
The plasma collected for assay of oxidative test markers and cytokines will be stored for a maximum of 12 
months at -80ºC. All specimens collected for assay of safety markers (CBC, CMP, PT, PTT, and LDL) will not be 
stored as they will be completed in real time. 
 
7.7.14 Magnetic Resonance Imaging: Structural and Resting-state functional MRI (fMRI):  


Amendment 11.0; 07 October 2015  
 
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Self-reported ‘chemo-brain’ has been validated using neuropsychological tasks and more recently, neuroimaging 
 
studies have identified structural 123  and performance differences between patients (i.e. those treated with 
 
chemotherapy) and controls 122,124,126.  For example, a recent functional Magnetic Resonance Imaging (fMRI) 
 
study has demonstrated that when compared to controls, chemotherapy treated patients show 
 
hyporesponsiveness in areas of the brain associated with impaired planning behavior and attentional abilities (i.e. 
 
paraphippocampal gyrus, left cuneus, right dorsal striatum, right inferior parietal cortex and left middle temporal 
 
gyrus). Specifically, longitudinal assessments of chemotherapy-induced structural changes in cerebral white 
 
matter and its correlation with impaired cognitive functioning have been reported in breast cancer patients 145-146. 
 
Differences in diffusion tensor imaging (DTI) white matter (WM) integrity parameters [fractional anisotropy 
 
(FA) and mean diffusivity (MD)] between patients and healthy controls were assessed using a voxel-based two-
 
sample-t-test. In comparison with healthy controls, the patient group demonstrated decreased FA in frontal and 
 
temporal WM tracts and increased MD in frontal WM 145-146. 
 
Research has demonstrated that an overall diffuse damage to white and gray matter of the brain is likely to disrupt 
overall brain organization, reducing efficiency of information transfer.  Previous studies have suggested  that 
breast cancer survivors show decreased efficiency of neural networks, requiring more functional activation across 
a range of brain regions to complete certain tasks compared to healthy women 152,155. The specific pattern  of brain 
changes following breast cancer and chemotherapy, including global versus local deficits, would have important 
implications for developing the most effective interventions for breast cancer-related cognitive  
deficits. 
Elucidation of large-scale brain network configuration in breast cancer may therefore contribute  important new 
information regarding the neurobiologic mechanisms of breast cancer-related cognitive  impairment. 
Research 
has demonstrated that an overall diffuse damage to white and gray matter of the brain is  likely to disrupt overall 
brain organization, reducing efficiency of information transfer.  Previous studies have  
suggested that breast 
cancer survivors show decreased efficiency of neural networks, requiring more functional  
activation 
across a range of brain regions to complete certain tasks compared to healthy women. 152,155 The  specific pattern 
of brain changes following breast cancer and chemotherapy, including global versus local  
deficits, would 
have important implications for developing the most effective interventions for breast cancer- 
related 
cognitive deficits. Elucidation of large-scale brain network configuration in breast cancer may therefore contribute 
important new information regarding the neurobiologic mechanisms of breast cancer-related cognitive 
impairment153.  
 
Resting-state fMRI measures spontaneous low-frequency fluctuations in the BOLD signal to investigate the 
functional architecture of the brain. Spatial patterns of spontaneous fluctuations in blood oxygenation level-
dependent (BOLD) signals reflect the underlying neural architecture. The study of the brain network based on 
these self-organized patterns is termed resting-state functional MRI (fMRI). Resting state functional connectivity 
MRI (rs-fcMRI), combined with structural connectivity mapping, has proven to be a useful probe for functional 
alterations in the brain as a consequence of changes in brain state, disease processes, neurodevelopment and 
aging, pharmacological interventions such as chemotherapy, and genetics 151-155. Additionally, several fMRI 
studies have demonstrated that some of these self-organizing, resting state networks coincide with brain regions 
that are found to be deactivated across several fMRI studies where an external stimulus or a cognitive paradigm is 
applied. Thus, these brain locations are more active at rest than during task performance. Resting state functional 
magnetic resonance imaging (fMRI) is a reliable, non-invasive method for examining the intrinsic topology of 
large-scale brain networks 154. Resting state fMRI networks are task-independent and thus less vulnerable to 
confounds due to performance variance. These observations have led to the hypothesis that the brain remains 
active in an organized fashion during the resting state, denoted the default mode network (DMN). The default 
mode hypothesis has been extensively studied, including direct electrophysiological measurement of default 
network areas, and its changes in different clinical states of consciousness. The concepts and exploration of the 
DMN has therefore been regarded as "a paradigm shift in functional brain imaging'' 147, 150, 148, 149, 153. 
Resting state fMRI connectivity studies are sensitive to abnormal global network organization, revealing changes 
in several clinical populations, including breast cancer patients treated with chemotherapy153.. Bruno et al (21012) 
applied resting state functional magnetic resonance imaging and graph theoretical analysis to examine the 
connectome in breast cancer survivors treated with chemotherapy relative to healthy comparison women. 


Amendment 11.0; 07 October 2015  
 
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Compared to healthy females, the breast cancer group displayed altered global brain network organization 
characterized by significantly decreased global clustering as well as disrupted regional network characteristics in 
frontal, striatal and temporal areas. Breast cancer survivors also showed significantly increased self-report of 
executive function and memory difficulties compared to healthy females. These results suggest that topological 
organization of both global and regional brain network properties may be disrupted following breast cancer and 
chemotherapy. This pattern of altered network organization is believed to result in reduced efficiency of parallel 
information transfer. This is the first report of alterations in large-scale functional brain networks in this 
population and contributes novel information regarding the neurobiologic mechanisms underlying breast cancer-
related cognitive impairment 153-154. 
We thus propose to evaluate both chemotherapy-induced changes in structural and functional parameters by 
evaluating (a) differences in cerebral white matter integrity [fractional anisotropy (FA) and mean diffusivity 
(MD)] maps before and after treatment with COGNUTRIN by using magnetic resonance DTI; (b) we will 
perform resting state fMRI to determine changes in prefrontal executive functioning in breast cancer patients 
treated from baseline and post intervention with COGNUTRIN compared to placebo. To date, imaging studies 
have only focused on assessing structural and functional cognitive disruption induced by chemotherapy. The 
proposed study aims to replicate these findings and extend them by testing the proposed interventions ability to 
offset the changes in cognitive performance in breast cancer patients post chemotherapy treatment.   
 
 
Subjects will be provided prepared, specific and consistent instructions over the intercom prior to start of MRI as 
 
follows: “Keep your eyes closed, relax, try not to move, try to stay awake and just let your thoughts wander.” All 
 
subjects will be imaged on a 3T scanner with an eight channel phased- array head  coil.  Time in scanner for 
 
technician getting the imaging optimized for the patient is 5 minutes. 
 
The resting fMRI will be completed first prior to others.  Resting FMRI data will be acquired (Bruno et al, 2012) 
while participants rest in the scanner with their eyes closed using a T2* weighted gradient echo spiral pulse 
sequence: relaxation time = 2000 msec, echo time = 30 msec, flip angle = 80° and 1 interleave, field of view = 
220, matrix = 64×64, in-plane resolution = 3.125. Number of data frames that will be collected is 216. An 
automated high-order shimming method based on spiral acquisitions will employed to reduce field heterogeneity. 
To co register and normalize functional images with a standardized template, a high-resolution, 3 dimension 
inversion-recovery prepared fast spoiled gradient echo anatomical scan will be acquired: relaxation time: 
minimum, echo time: minimum, flip: 11 degrees, inversion time: 300 msec, bandwidth: +/−31.25 kHz, field of 
view: 24 cm, phase field of view: 0.75, slice thickness: 1.5mm, 125 slices, 256×256 at 1 excitation. The total 
scan time is estimated at 10 minutes. 
 
A T1- weighted whole brain 3D-TFE (182 contiguous coronal slices; 250 x 250 mm2 FOV; 4.6 ms TE; 9.7 ms 
TR; 1.2-mm slice thickness; 256 x 256 matrix; 0.98 x 0.98 x 1.2 mm3 voxel size). T2-weighted TSE (28 
transversal slices; 230 x184 mm2 FOV; 4-mm slice thickness; 3,000 ms TR; 80 ms TE), and a FLAIR (28 
transverse slices; 230 x 183 mm2 FOV; 125 ms TE; 11,000 ms TR; 2,800 ms IR delay; 4-mm slice thickness; 256 
x 256 matrix; 0.65 x 0.87 x 4 mm3 voxel size) will also be acquired to confirm absence of primary  brain 
pathology as an exclusion criterion. Scan time 10 minutes. 
 
A  whole  brain  DTI  SE-EPI (diffusion- weighted single shot spin-echo echoplanar imaging) will be acquired 
with  the following scanning parameters: 68 contiguous  sagittal slices, 112 x 109 matrix  size, 220 x 220 mm2   
FOV, 4,956 ms TR, 55 ms TE, 2.5 parallel  imaging factor, 2.2-mm slice thickness, 1.96 x 1.96 x 2.2 mm3  voxel 
size. Diffusion gradients will be applied along 45 noncollinear directions with a b-value of 800 s mm-2. 
Additionally one nondiffusion-weighted (b ¼ 0) set of images will be acquired resulting in a total scan time of 
10.34 min.  
 
We anticipated a total scan time of 30-45 minutes for both structural and resting functional MRIs, including time 
to prepare subject. 
 
 
8  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 


Amendment 11.0; 07 October 2015  
 
27
 
8.1  
Primary Endpoint 
The primary efficacy endpoint is to generate effect sizes for changes in the number of impaired neuropsychological tests. 
The planned intervention period is three months.  Neuropsychological outcomes will be examined using a 2 (group; 
COGNUTRIN, placebo) X 2 (time; baseline, three-months) repeated measures ANOVA to examine differences in the 
number of impaired neuropsychological tests.    Age, premorbid cognitive functioning, depression and fatigue will be 
evaluated for association with neurocognitive performance and entered as covariates in statistical analyses if a marginally 
significant association (p<.10) is observed.  
  
The primary safety endpoint is incidence and severity of AEs occurring during intervention with either COGNUTRIN or 
placebo. All AEs that are reported by the subject, detected during a visit, physical examination, or laboratory work-up will 
be recorded in the participant’s medical record and recorded on the CRF. All AEs that occur after the informed consent is 
signed will be recorded on the AE CRF whether or not related to study agent. 
 
The sample size proposed in the current protocol will not provide sufficient statistical power, but information regarding 
effect sizes will be gathered and used as motivation for future clinical trials. We estimate that a minimum evidence of 
improvement in cognitive function with the 3 month intervention as indicated by a score of 1 standard deviation or more 
above population norms on the Hopkins Verbal Learning Test – Revised, Controlled Oral Word Association Test, or 
Color Trails Test Part 1 or 2 will be considered adequate to justify progression to a larger study. 
 
8.2  
Secondary Endpoints 
The secondary endpoint will be improvement in subjective cognitive functioning as well as structural and resting state 
functional changes in MRI. 
  
 
 
 
 
 
 
 
 
                 
In addition we will examine the role of the cytokines and anti-oxidant biomarkers as mediators of reductions in the 
number of impaired cognitive tests. 
We will also examine if other factors such as fatigue, depression, physical and functional activities are affected by 
COGNUTRIN compared to placebo.  
The sample size proposed in the current protocol will not provide sufficient statistical power, but information regarding 
effect sizes will be gathered and used as motivation for future clinical trials. 
 
8.3  
Off Agent Criteria  
Participants may stop taking study agent for the following reasons: 
 
after completing the protocol-prescribed intervention 
 
at the discretion of the investigator  
 
AE or serious adverse events (SAE) requiring dose interruption 
 
inadequate agent supply 
 
noncompliance with study requirements  
 
medical contraindication. 
 
8.4  
Off Study Criteria 
If the subject never took study medication (e.g., does not meet eligibility criteria or withdraws consent prior to 
randomization) the only activity required to remove the subject from the study is to complete the Off Study CRF. If the 
subject was randomized to a treatment arm and received study medication, post-intervention procedures according to the 
schedule of events should be completed to the extent possible.  
 
not meeting randomization (eligibility) criteria 
 
the protocol intervention and any protocol-required follow-up period is completed  
 
experiencing an AE or SAE 


Amendment 11.0; 07 October 2015  
 
28
 
lost to follow-up 
 
taking a concomitant medication 
 
medical contraindication prohibiting further study participation 
 
discovery of a pre-existing condition not observed at baseline eligibility 
 
withdrawal of consent 
 
protocol non-compliance (i.e., visit schedule, dose administration, etc.) 
 
at the discretion of the investigator 
 
death 
 
Post-intervention procedures according to the schedule of events will be completed to the extent possible.  
9  
SPECIMEN MANAGEMENT  
 
9.1  
Blood Samples 
All samples once drawn must be processed and stored appropriately until pick-up by the designated courier to transport to 
the Moffitt Cancer Center clincial laboratories.  All safety labs will be forwarded to the Moffitt clinical labs in real time 
(CBC/CMP/PT/PTT). 2 - 10 ml tube will be forwarded to Tissue Core labs at the Moffitt Cancer Center for processing 
and storage. Once labs specimens for 40 subjects (pre and post intervention) have been collected, they will be transported 
from Tissue to Dr. Bickford’s lab at USF and Dr. Djeu’s lab at MCC by the clinical research coordinators, using 
appropriate containers to preserve the temperature and thus integrity of the specimens for assay of oxidative stress 
markers. 
10  
REPORTING ADVERSE EVENTS (AEs)  
 
DEFINITION: An adverse event is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be 
considered related to the medical treatment or procedure. An AE is a term that is a unique representation of a specific 
event used for medical documentation and scientific analyses. 
 
A list of AEs that have occurred or might occur (Reported AEs and Potential Risks) can be found in § 6.2, Pharmaceutical 
Information as well as the Investigator Brochure.  
 
10.1  
Adverse Events 
 
10.1.1  Reportable AEs 
 
All AEs that are reported by the subject, detected during a visit, physical examination, or laboratory work-up must 
be recorded in the participant’s medical record and recorded on the CRF. All AEs that occur after the start of 
study agent must be recorded on the AE CRF whether or not related to study agent. 
 
10.1.2  Data Elements  
 
AE reported date 
 
AE Verbatim Term 
 
CTCAE Term (v 4.0) 
 
Event onset date and event ended date 
 
Severity grade 
 
Attribution to study agent (relatedness) 
 
Whether or not the event was reported as a Serious AE (SAE) 
 
Action taken with the study agent 
 
Whether or not the subject dropped due to the event 
 
Outcome of the event 
 
Comments 
 
10.1.3  Severity of AEs 
Identify the AE using the NCI Common Terminology Criteria for AEs (CTCAE) version 4.0. The  


Amendment 11.0; 07 October 2015  
 
29
CTCAE provides descriptive terminology and a grading scale for each AE listed. A copy of the CTCAE can be 
found at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 
 
 
AEs will be assessed according to the CTCAE grade associated with the AE term. AEs that do not have a 
corresponding CTCAE term will be assessed according to their impact on the participant’s ability to perform daily 
activities as follows: 
 
 
 
Grade 
 
Severity 
 
Description  
 
 
1 
 
Mild 
 
Asymptomatic or mild symptoms, clinical or diagnostic 
observations only; intervention not indicated 
2 
 
Moderate 
 
Minimal, local or noninvasive intervention 
indicated; limited age-appropriate instrumental ADL* 
3 
 
Severe 
 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self care ADL**  
4 
Life threatening 
Life threatening consequences; urgent intervention indicated 
5 
Fatal 
Death related to AE 
 
 * Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using telephone, managing 
money, etc. 
** Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
 
10.1.4  Assessment of relationship of AE to treatment 
Relationship of the AE to study drug will be classified as one of the following:  not related, unlikely, possibly, 
probably, definitely. All AEs will be considered due to drug (AEs classified as unlikely, possibly, probably or 
definitely) unless clearly not related to therapy. The severity and seriousness of each AE will be assessed by the 
site investigators.  
 
10.1.5  Follow-up of AEs 
All AEs, including lab abnormalities that in the opinion of the investigator are clinically significant, will be 
 
followed until resolution, if possible. If an AE persists more than 30 days after the subject goes off study, the 
 
subject will be referred to their personal physician.  
 
10.2  
SERIOUS ADVERSE EVENTS (SAEs)  
DEFINITION: ICH Guideline E2A and Fed. Reg. 62, Oct. 7, 1997 define SAEs as those events, occurring at any dose, 
which meet any of the following criteria: 
 
Results in death 
 
Is life threatening (Note: the term life-threatening refers to an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe). 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital abnormality/birth defect 
 
Events that may not meet these criteria, but which the investigator finds very unusual and/or 
potentially serious, will also be reported in the same manner. 
 
Contact Dr. Kumar by phone or e-mail within 24 hours of knowledge of the event. A SAE regardless of relatedness or 
expectedness will be reported to the Principal Investigator by telephone within 24 hours of the PI/study team becoming 
aware of the event.  
 
 


Amendment 11.0; 07 October 2015  
 
30
FDA Notification by Sponsor:  Dr. Kumar will then notify the FDA by telephone or by facsimile transmission of any 
unexpected fatal or life-threatening experience associated with the use of the drug as soon as possible but no later than 
seven calendar days after the initial receipt of the information.  
 
IRB Notification by Investigator: Reports of all SAEs (including follow-up information) will be submitted to the all IRBs 
per state and federal guidelines. Copies of each report and documentation of IRB notification and receipt will be kept in 
the Clinical Investigator’s binder. AEs and/or laboratory abnormalities identified in the protocol as critical to safety 
evaluations will also be reported the IND sponsor.  
 
MCC and all participating organizations will comply with applicable regulatory requirements at the participating 
institution related to reporting SAEs to the IRB.   
 
Follow-up of SAE: 
 
Site staff should send follow-up reports as requested when additional information is available or to resolve queries. 
Additional information should be entered on the SAE form in the appropriate format. Follow-up information should be 
sent to the Principal Investigator as soon as possible. SAEs will be followed until resolved or stable, especially for those 
related to the study agent.  
 
 
 
 


Amendment 11.0; 07 October 2015  
 
31
11  
STUDY MONITORING 
 
11.1  
Data Management 
The Data Management team will consist of the PI, Biostatistician, and Data Entry Manager at MCC, Tampa, FL. As part 
of our efforts to ensure subject confidentiality, all names and other data, which might uniquely identify a subject, will be 
expunged from this data set. The database will be password protected and only the data entry person and project manager 
will have access to it. The computer that will house the database is part of a network that is backed up daily. The network 
also makes use of the latest in firewall technology to prevent unauthorized access or tampering and keeps up-to-date virus 
protection on each computer as well as the network. 
 
Computer files will be backed on regular intervals. Informed consent documents will be kept in files in an area designated 
by the principal investigator.  
 
The safety of the study will be monitored by the Principal Investigator according to the monitoring plan proposed in this 
Pilot clinical trial. The investigator will allocate adequate time for such monitoring activities. The investigator will also 
ensure that the monitor or other compliance or quality assurance reviewer is given access to all the above noted study-
related documents and facilities (e.g., pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct the 
monitoring visit. 
 
Internal Monitoring:  Data will be captured in Oncore, Moffitt’s Clinical Trial Database. The Case Report Forms will be 
reviewed by Moffitt’s Internal Monitors, periodically throughout the conduct of this trial. The monitoring will include 
source data verification, utilizing research subject’s medical records.  
 
11.2  
Case Report Forms 
Participant data will be collected using protocol-specific case report forms (CRFs).  
 
 
11.3  
Source Documents 
Original documents (i.e., informed consent forms) will be treated as source documentation for this clinical trial. 
 
11.4  
Data and Safety Monitoring  
Toxicities will be monitored continuously through the trial by the IRB, Moffitt and FDA. The PI and Biostatistician along 
with the MDs in the study will be responsible for reviewing AEs after 20 subjects have completed the study. If 50% of 
patients randomized to the treatment arm experience grade III or greater adverse events, we will discontinue this study. 
 
11.5  
Sponsor or FDA Monitoring 
The investigator will permit study-related monitoring, auditing, and inspection by the IRB and government regulatory 
bodies (FDA) of all study-related documents (e.g., source documents, regulatory documents, laboratory data, data 
collection instruments, etc.). 
 
11.6  
Record Retention 
Records for all participants will be retained, at a minimum, for two years after the approval of a New Drug Application 
(NDA) or as otherwise, directed by the Sponsor. The sponsor will be notified prior to the planned destruction of any 
materials. The records should be accessible for inspection and copying by authorized persons of the Food and Drug 
Administration. 
 
12  
STATISTICAL CONSIDERATIONS 
 
12.1  
Study Design/Endpoints  
The central hypothesis for this Pilot clinical trial is that adults who receive COGNUTRIN will exhibit reduction in the 
number of impaired cognitive tests, as compared to adults on the placebo. 
 
12.2  
Sample Size/Accrual Rate 
In this pilot trial, we plan to accrue 40 evaluable subjects. This is a feasibility clinical trial in preparation to inform the 
design of a well-powered randomized clinical trial.  


Amendment 11.0; 07 October 2015  
 
32
 
12.3  
Randomization and Stratification  
During the baseline/randomization visit, subjects will be randomized using block randomization.  The current design will 
ensure equal number of subjects in each arm receiving radiation therapy post chemotherapy and concurrent endocrine 
therapy. 
 
12.4  
Primary Endpoint 
The primary efficacy endpoint is to generate effect sizes for changes in the number of impaired neuropsychological tests. 
The planned intervention period is three months.  Neuropsychological outcomes will be examined using a 2 (group; 
COGNUTRIN, placebo) X 2 (time; baseline, three-months) repeated measures ANOVA to examine differences in the 
number of impaired neuropsychological tests. Age, premorbid cognitive functioning, depression and fatigue will be 
evaluated for association with neurocognitive performance and entered as covariates in statistical analyses if a marginally 
significant association (p<.10) is observed.   
 
The primary efficacy endpoint is to generate effect sizes for changes in the number of impaired neuropsychological tests. 
The planned intervention period is three months.  Neuropsychological outcomes will be examined using a 2 (group; 
COGNUTRIN, placebo) X 2 (time; baseline, three-months) repeated measures ANOVA to examine differences in the 
number of impaired neuropsychological tests.    Age, premorbid cognitive functioning, depression and fatigue will be 
evaluated for association with neurocognitive performance and entered as covariates in statistical analyses if a marginally 
significant association (p<.10) is observed.  The sample size of 20 patients per arm will allow us to generate useful 
information for future studies, in terms of anticipated effect size.  Although this pilot study is not designed to be fully 
powered, the current sample size will allow us to detect an effect size difference of .40 for a one-tailed paired sample t-
test, on account of the matched groups, at power of .80 and an alpha of .05.  Moreover, the sample sizes will enable us to 
detect a group X time interaction of .23, with an alpha of .05, power of .80, and a stability coefficient of .5. 
 
12.5  
Secondary Endpoint(s) 
 
12.5.1  Is the number of impaired neuropsychological tests in the COGNUTRIN supplementation group mediated 
by changes in cytokines and anti-oxidant markers?  In order to examine the mediation of the intervention group 
effects on number of impaired neuropsychological tests by changes in biomarkers, we will adopt a bootstrapping 
approach to this analysis.  Baron and Kenny's approach to regression-based statistical mediation. In this case, the 
95% confidence intervals around the bootstrapped indirect estimate will be examined to evaluate whether the 
mediation relationship is statistically significant.  Again, the analyses here are focused on generating information 
regarding the size of the effects, rather than statistical significance.  
 
 
 
12.5.2   We thus propose to evaluate both chemotherapy-induced changes in structural and functional parameters 
 
by evaluating (a) differences in cerebral white matter integrity [fractional anisotropy (FA) and mean diffusivity 
 
(MD)] maps before and after treatment with COGNUTRIN by using magnetic resonance DTI; (b) we will 
 
perform resting state fMRI to determine changes in the connectome in breast cancer patients treated from baseline 
 
and post intervention with COGNUTRIN compared to placebo. To date, imaging studies have only focused on 
 
assessing structural and functional cognitive disruption induced by chemotherapy. The proposed study aims to 
 
replicate these findings and extend them by testing the proposed interventions ability to offset the changes in 
 
cognitive performance in breast cancer patients post chemotherapy treatment.   
 
12.5.3 Evaluate the effects of COGNUTRIN on changes in subjective cognitive function.  We will evaluate the 
effect of COGNUTRIN on changes in subjective cognitive function; Compliance will be evaluated by standard 
pill counts, diet records and plasma levels of anthocyanins and erythrocyte n-3 index.  Any unusual patterns in 
compliance will be noted and apparent discrepancies between pill counts or diet records and plasma levels by will 
be summarized as well. The collected data will be entered through screens created by the Research IT analyst in 
ONCORE, the Research Data Management Systems used at the MCC. 
 
12.5.4  Evaluate the effects of COGNUTRIN on changes in symptoms of fatigue and depression. 
Additionally, we will evaluate the effect of COGNUTRIN on changes in symptoms of fatigue and depression.  
Medication use such as antidepressants, tranquillizers and anxiolytics will also be obtained at baseline and 


Amendment 11.0; 07 October 2015  
 
33
throughout the study. As with age and fatigue, we will evaluate the effect of these medications for association 
with neurocognitive performance and entered as covariates in statistical analyses if a marginally significant 
association (p<.10) is observed.   
 
12.6  
Evaluation of Toxicity 
The primary safety endpoint is incidence and severity of AEs occurring during intervention with either COGNUTRIN or 
placebo. All participants will be evaluated for toxicity from the time that the informed consent is signed up to the end of 
the intervention according to the NCI CTCAE version 4.0. Standard assessment of toxicity will also include interviews, 
clinical evaluation, and monitoring of laboratory values. All toxicity data will be summarized by category and grade in a 
standard fashion. Proportions experiencing most common types of toxicity in this trial will be estimated and exact 95% 
CIs calculated based on the exact binomial distribution for these proportions will be reported. Compliance will be 
evaluated by standard pill counts, diet records and plasma levels of anthocyanins and erythrocyte n-3 index.  Any unusual 
patterns in compliance will be noted and apparent discrepancies between pill counts or diet records and plasma levels by 
will be summarized as well.  
 
12.7  
Evaluation of Response 
 
All participants included in the study will be assessed for response to intervention, even if there are major protocol 
deviations.  We estimate that a minimum evidence of improvement in cognitive function with the 3 month intervention as 
indicated by a score of 1 standard deviation or more above population norms on the Hopkins Verbal Learning Test – 
Revised, Controlled Oral Word Association Test, or Color Trails Test Part 1 or 2 will be considered adequate to justify 
progression to a larger study. 
 
 
13 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
13.1  
Form FDA 1572 
Prior to initiating this study, the Principal Investigator at the participating organizations will provide a signed Form FDA 
1572 stating that the study will be conducted in compliance with regulations for clinical investigations and listing the 
investigators  at each site that will participate in the protocol. 
 
13.2  
Other Required Documents 
 
Signed and dated current (within two years) CV or biosketch for all investigators listed on the Form FDA 1572 for the 
PI and all co-investigators.  
 
Current medical licenses for all investigators listed on Form FDA 1572 for the PI and co-investigators 
 
Signed receipt of Investigator Brochure 
 
Delegation of Responsibility form 
 
IRB approval of protocol, informed consent, recruitment materials 
 
13.3  
Informed Consent 
All potential study participants will be given a copy of the IRB-approved Informed Consent to review. The investigator or 
other research staff will explain all aspects of the study in lay language and answer all questions regarding the study. If the 
participant decides to participate in the study, he will be asked to sign the Informed Consent document. The subject is 
considered enrolled in the study from the time the informed consent document is signed. The study agent(s) will not be 
released to a participant who has not signed the Informed Consent document. Subjects who refuse to participate or who 
withdraw from the study will be treated without prejudice. 
 
 
Participants must be provided the option to allow the use of blood samples, other body fluids, and tissues obtained during 
testing, operative procedures, or other standard medical practices for further research purposes. A separate signature area 
is required to allow participants to opt out of allowing tissue to be used for further research.  
 
 
The informed consent document must be reviewed and approved by the IRB at each organization at which the protocol 
will be implemented prior to study initiation. Any subsequent changes to the informed consent must be approved by each 
organization’s IRB for approval prior to initiation. 
 


Amendment 11.0; 07 October 2015  
 
34
13.4  
Confidentiality  
 
Information about the study subjects will be kept confidential and managed according to the requirements of the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). Additionally, subject will not be identified by name, only 
subject identification numbers will appear on specimens and questionnaires. 
 
 
13.5  
Other 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA Title 21 part 
312 and International Conference on Harmonization guidelines), applicable government regulations and Institutional 
research policies and procedures. 
 
 


Amendment 11.0; 07 October 2015  
 
35
 
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17. Labouvie-Veif G, Gonda JN. Cognitive strategy training and intellectual performance in the elderly. J Gerontol. 
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34. Markesbery WR. Oxidative stress hypothesis in Alzheimer’s disease. Free Radical Biology & Medicine. 
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MRI acquisitions in a study of cognitive aging. Comput Methods Programs Biomed. 2012 Jun;106(3):328-41. doi: 
 
10.1016/j.cmpb.2011.03.010. Epub 2011 Jun 12. PubMed PMID: 21663993. 
 
151.  Kesler SR, Kent JS, O'Hara R. Prefrontal cortex and executive function impairments in primary breast cancer. Arch 
 
Neurol. 2011 Nov;68(11):1447-53. doi: 10.1001/archneurol.2011.245. PubMed PMID: 22084128; PubMed Central 
 
PMCID: PMC3239218. 
 
152. Kesler SR, Wefel JS, Hosseini SM, Cheung M, Watson CL, Hoeft F. Default mode network connectivity 
 
distinguishes chemotherapy-treated breast cancer survivors from controls. Proc Natl Acad Sci U S A. 2013 Jul 
 
9;110(28):11600-5. doi: 10.1073/pnas.1214551110. Epub 2013 Jun 24. PubMed PMID: 23798392; PubMed Central  
 
PMCID: PMC3710809. 
 
153.  Jennifer Bruno, PhD,1 SM Hadi Hosseini, PhD,1 and Shelli Kesler, PhD1,2 Altered resting state functional brain 
 
network topology in chemotherapy-treated breast cancer survivors. Neurobiol Dis. Dec 2012; 48(3): 329–338.  
 
154.  Zuo XN1, Di Martino A, Kelly C, Shehzad ZE, Gee DG, Klein DF, Castellanos FX, Biswal BB, Milham MP. 
 
The oscillating brain: complex and reliable. Neuroimage. 2010 Jan 15;49(2):1432-45. 
 
155.  Reuter-Lorenz PA, Cimprich B. Cognitive function and breast cancer: promise and potential insights from functional 
 
brain imaging. Breast Cancer Res Treat. 2013 Jan;137(1):33-43. doi: 10.1007/s10549-012-2266-3. 
 
156. Patricia A. Ganz, Lorna Kwan, Steven A. Castellon, Amy Oppenheim, Julienne E. Bower, Daniel H. S. Silverman, 
 
Steve W. Cole,Michael R. Irwin, Sonia Ancoli-Israel, Thomas R. BelinCognitive Complaints After Breast Cancer 
 
Treatments: Examining the Relationship With Neuropsychological Test Performance. J Natl Cancer 
 
Inst;2013;105:791–801 
 
157. Pullens MJJ, De Vries J, Roukema JA. Subjective cognitive dysfunction in breast cancer patients: a systematic 
 
review. Psycho-Oncology. 2010; 19(11):1127–1138. 
 
158.  Saykin AJ, Wishart HA, Rabin LA, et al. Older adults with cognitive complaints show brain atrophy similar to that 
 
of amnestic MCI. Neurology.2006; 67(5):834–842. 
 
159. Ganz PA. Doctor, Will the treatment you are recommending cause chemobrain? J Clin Oncol. 2012; 30(3):229–231. 
 


Amendment 11.0; 07 October 2015  
 
45
160. Robert J. Ferguson, RH, McDonald BC, Rocque MR, Furstenberg CT, Horrigan S, Ahles TA &  Saykin AJ. 
 
Development of CBT for chemotherapy-related cognitive change: results of a waitlist control trial. Psycho-
 
Oncology, 21: 176–186 (2012). 
 


 
MCC# 17089 
 
Amendment 11.0; 07 October 2015 
 
Pilot Trial of COGNUTRIN in Breast Cancer Survivors 
 
Principal Investigator:  Nagi Kumar, PhD, RD, FADA 
 
Summary of Changes: 
4.2  Criteria for exclusion 
 
Corrected actual creatinine clearance of >60 to <60. 
 
4.3  Anticipated problems with subject recruitment and retention 
 
Increased payment to participants from $25 to $50 for each visit to cover travel expenses. 
 
Added that participants traveling more than 100 miles from their home to reach the research 
site will receive an additional $30 for transportation costs. 


 
MCC# 17089 
 
Amendment 10.0; 25 February 2015 
 
Pilot Trial of COGNUTRIN in Breast Cancer Survivors 
 
Principal Investigator:  Nagi Kumar, PhD, RD, FADA 
 
Summary of Changes: 
4.2  Criteria for exclusion 
 
Added the following: 
Subjects with metabolic disorders (a) who are otherwise eligible, (b) treated for 
hypothyroidism by their primary MD with Synthroid (levothyroxine) and (c) with the 
approval of the Moffitt treating oncologist will not be excluded from the study. 
 
Added “(ex. tissue expanders)” as an example of ferromagnetic material that would prohibit MRI 
imaging. 
 
7.7.8  Adverse events monitoring (Appendix VIII) 
 
Added the following: 
For each subject, AE’s will be collected at the screening, Month 1, Month 2, Month 3/EOT, 
visits as well as at the 7‐day post‐treatment follow‐up call by the clinical research 
coordinator. AE’s collected at the screening visit will be catalogued as baseline symptoms by 
the clinical research coordinator and the AE log will be reviewed and signed by either the 
patient’s medical oncologist or PI. AE’s collected during Month 1 and 2 visits will be 
reviewed with the patient by the nurse who drew their blood at CRU and the AE log will be 
signed by the principal investigator. Finally, at the Month 3 visit, the participant’s medical 
oncologist will review the AE log with the patient and sign‐off on the reported symptoms; if 
the medical oncologist is unavailable to sign the AE log at this visit, then the PI will review 
and sign the form. AE’s reported at the 7‐day follow‐up call will be reviewed and signed by 
the PI. The participant’s reported symptoms at this time point will be documented on a 
powerchart telephone note by the clinical research coordinator. Serious adverse events 
(SAE’s) are reported to IRB and FDA. If a participant reports an SAE, the PI will immediately 
be informed and she will then report it to the IRB and FDA. AE logs will be scanned to 
patients’ medical records by the clinical research coordinator once they are off‐study. 
 


 
MCC# 17089 
 
Amendment 9.0; 22 January 2015 
 
Pilot Trial of COGNUTRIN in Breast Cancer Survivors 
Principal Investigator:  Nagi Kumar, PhD, RD, FADA 
 
Summary of Changes: 
7.7.9 Assessment of Cognitive Performance (pages 21‐22) 
 
Clarified the procedures in detail for memory testing.  




July 16, 2014 
 
Janelle Perkins, Pharm.D., Chairperson 
USF Institutional Review Board 
 
Re: Summary of Changes  
IRB#: Pro00009858 
Title: Pilot Trial of COGNUTRIN in Breast Cancer Survivors – MCC #17089 
 
Attached, you will find a tracked and clean copy of an amendment to the above application. Due to the 
complicated nature of breast cancer and the treatments associated with this disease, the inclusion criteria 
has been revised to allow sufficient time for patients to have any necessary surgeries (i.e. breast 
reconstruction)  after completing chemotherapy +/- radiation. Therefore the inclusion criterion has been 
revised as follows: 
 
 Completed neoadjuvant or adjuvant treatment with anthracyclines and/or taxanes + or –Radiation 
therapy within past 6 months (+/- 7 days) (subjects on concurrent endocrine therapy (TAM, 
Aromatase inhibitors are also eligible to participate as this is standard of care for this patient 
population) 
 
 
Please feel free to contact me if you have any questions regarding these changes. 
 
 
Thank you, 
 
 
Nagi B. Kumar, Ph.D., R.D., FADA 
Senior Member, Population Sciences Division 
Director, Cancer Chemoprevention, Moffitt Cancer Center 
Professor, Oncologic Sciences 
| tel: 8137456885 | fax:  8137457183 | email: nagi.kumar@moffitt.org 




MCC# 17089 
 
Pilot Trial of COGNUTRIN in Breast Cancer Survivors 
 
Principal Investigator:  Nagi Kumar, PhD, RD, FADA 
 
Amendment 5.1, 04/08/2014 
 
Summary of Changes: 
 
SCHEMA (page 3) 
• 
Revised to correct the questionnaires that will be completed at each visit. 
 
7 CLINICAL EVALUATIONS AND PROCEDURES (pages 24-26) 
• 
Added window (+/- 7 days) to week 4, week 8, and week 12 visits. 
1 
 


March 12, 2014 
 
Janelle Perkins, Pharm.D., Chairperson 
USF Institutional Review Board 
 
Re: Summary of Changes  
IRB#: Pro00009858 
Title: Pilot Trial of COGNUTRIN in Breast Cancer Survivors – MCC #17089 
 
Enclosed, please find a copy of an amendment to the above application.  This 
modification reflects no substantive changes in procedure.  Specific methods as well as 
inclusion/exclusion criteria have been modified to include the most current standards and 
evolving methods in the research literature. Modification of faculty in the study is also 
included based on turnover. 
 
The following are included with this submission:  
 
A. Tracked copy of the currently approved protocol, reflecting changes below 
B. Clean copy of the amended protocol  
 
Summary of changes and rationale:  
 
• Schema & Protocol Section 3.0: Clarification regarding the inclusion of women 
 
on concurrent endocrine therapy; Updated to reflect that all patients will now 
 
receive resting-state functional MRI in addition to structural MRI 
• Protocol Section 2.1: Specific Aim 3 updated to reflect the use of resting-state 
 
functional MRI in addition to structural MRI in order to evaluate changes in 
 
imaging markers 
• Protocol Sections 4.0 & 4.1: Clarification regarding the inclusion of women on 
 
concurrent endocrine therapy 
• Protocol Section 4.2: Clarification regarding the parameters for determining the 
 
exclusion of women with renal or liver disease 
• Protocol Sections 5.1.2, 5.6 & 6.1.2:  The removal of specific drug bottle 
 
descriptions in order to reflect that all study agents are bottled and labeled per 
 
investigational drug use regulations 
• Protocol Section 6.5:  Clarification regarding which labs determine abnormal 
 
liver function and the adverse event grades that will result in discontinuation of 
 
the study agent 
• Protocol Section 7.1: Updated to reflect that all patients will now receive resting- 
 
state functional MRI in addition to structural MRI; Removal of attention tasks 
 
during MRI 
• Protocol Section 7.3: Updated to reflect that all patients will now receive resting 
 
state functional MRI in addition to structural MRI 
• Protocol Section 7.6.6: Removal of additional 5 days of study agent being 
 
supplied to patient , agents were bottled based on a 30 day supply 
• Protocol Section 7.6.10: Functional MRI has been replaced with resting-state 


 
functional MRI, therefore working memory tasks to be performed in MRI has 
 
been removed from protocol 
• Protocol Section: 7.6.15: Functional MRI methods were replaced with resting- 
 
state functional MRI methods 
• Protocol Section 12.5.2: Secondary endpoint changed to reflect the use of a 
 
resting-state functional MRI versus a functional MRI 
• Protocol Section 14.0: References updated to include those used to support the 
 
use of resting-state functional MRI  
• Appendices:  Updated with the Teleform version of questionnaires 
 
 
 
Please feel free to contact me if you have any questions regarding these changes. 
 
 
Thank you, 
 
 
 
 
Nagi B. Kumar, Ph.D., R.D., FADA 
Senior Member, Population Sciences Division 
Director, Cancer Chemoprevention, Moffitt Cancer Center 
Professor, Oncologic Sciences 
University of South Florida College of Medicine 
 
12902 Magnolia Drive Tampa, FL 33612  
| tel: 8137456885 | fax:  8137457183 | email: nagi.kumar@moffitt.org 
 


January 30, 2014 
 
Janelle Perkins, Pharm.D., Chairperson 
USF Institutional Review Board 
 
Re: Summary of Changes  
IRB#: Pro00009858 
Title: Pilot Trial of COGNUTRIN in Breast Cancer Survivors – MCC #17089 
 
Enclosed, please find a copy of an amendment to the above application.  This 
modification reflects no substantive changes in procedure.  Specific methods as well as 
inclusion/exclusion criteria have been modified to include the most current standards and 
evolving methods in the research literature. Modification of faculty in the study is also 
included based on turnover. 
 
The following are included with this submission:  
 
A. Tracked copy of the currently approved protocol, reflecting changes below 
B. Clean copy of the amended protocol  
 
Summary of changes and rationale:  
 
• Schema: Updated to reflect changes regarding functional MRI (fMRI)  
• Schema: Updated to reflect removal of weekly phone calls 
• Protocol Section 2.0:  Objective 3 updated to reflect changes regarding fMRI   
Rationale for Change:  Although fMRI is one of the variables proposed in this 
clinical trial, there has been several installation issues with regard to the fMRI 
equipment in association with the MRI equipment current used in structural MRI 
studies. We anticipate that this will require several months before the equipment can 
be installed that ensures safety of the MRI.  Since funding was received in July of 
2013, we have been in the process of identifying  MRI equipment where the 
functional MRI equipment can be added without compromising the safety to the 
subjects/other patients.  We have learned that there will be further delay in the 
availability of the  fMRI. The delay in the availability of the functional MRI has 
serious implications on (a) bioavailability of the agent we have developed for this 
clinical trial; (b) cost of reproducing another batch of agent to match the current batch 
for consistency of  components and (c)  the funding for this clinical trial. Based on 
these major concerns, we have amended the proposal to include all other primary and 
secondary variables that we proposed to monitor in this pilot trial and will perform 
the functional MRI in the  second 10 pairs of subjects (10 from the Treatment arm 10 
from the placebo arm). 
• Protocol Section 7.1: Removal of weekly phone calls  
Rational for Change: Subjects will see a Nurse Practitioner (NP) at monthly visits 
for a limited physical exam assessing any adverse events. Subjects are instructed to 
contact coordinator, PI or physician should any adverse events occur prior to monthly 
visit.  


• Protocol Section 7.3: Addition of limited physical exam with NP to assess 
adverse events 
 
 
 
 
Please feel free to contact me if you have any questions regarding these changes. 
 
 
Thank you, 
 
 
 
 
Nagi B. Kumar, Ph.D., R.D., FADA 
Senior Member, Population Sciences Division 
Director, Cancer Chemoprevention, Moffitt Cancer Center 
Professor, Oncologic Sciences 
University of South Florida College of Medicine 
 
12902 Magnolia Drive Tampa, FL 33612  
| tel: 8137456885 | fax:  8137457183 | email: nagi.kumar@moffitt.org 
 





ICF_001.pdf: 
Subject’s Name  
 
 
Subject’s Medical Record #  
 
 
IRB# Pro00009858 
 
MCC# 17089 
Date Consent Signed  
[Original Approval Date: 05/13/2013] 
Informed Consent: Version #10     Version Date: 10/14/2015  
ICF Adult MCC-USF IRB Consent Template
Med Rev: 2010-09-03 [MCC Rev. 2012.10.03]
Informed Consent to Participate in Research and Authorization to Collect, 
Use and Share Your Health Information 
Moffitt Cancer Center/University of South Florida 
Information to Consider Before Taking Part in This Research Study 
Doctors and researchers at Moffitt Cancer Center study diseases and other health problems 
people may have.  Our goal is to try to find better ways to help treat these health problems.  To 
do this, we need the help of people who are willing to take part in a research study.
We are asking you to take part in a research study called:
Pilot Clinical Trial of COGNUTRIN in Breast Cancer Survivors
The person who is in charge of this research study is Nagi Kumar, PhD, RD, FADA.  This 
person is called the Principal Investigator.  However, other research staff may be involved and 
can act on behalf of the person in charge.
The research will be conducted at: 
H. Lee Moffitt Cancer Center & Research Institute, Inc. 
(Moffitt Cancer Center) 
12902 Magnolia Drive 
Tampa, FL  33612 
This research is being sponsored by The Gateway for Cancer Research.
Why are you being asked to take part? 
One of the most common adverse effects reported by breast cancer patients after treatment is 
“chemobrain”.  This is the term used to describe the mental cloudiness (i.e., thinking and 
memory problems) that patients sometimes notice during and after chemotherapy.
Chemobrain might last a short time, or it might go on for years. 
The purpose of this study is to examine the safety and effect of COGNUTRIN, a nutritional 
supplement, on memory and concentration tasks in breast cancer survivors following 
chemotherapy.  COGNUTRIN includes fatty acids (Lovaza®) and blueberry extracts (Vitablue).
Our goal is to treat or lessen the late effects of cancer treatment on thinking ability.  Lovaza® is 
currently approved for the treatment of patients with very high triglycerides 
(hypertriglyceridemia).
COGNUTRIN is an investigational drug.  An investigational drug is a drug that is being tested 
and is not approved for sale in the United States by the U.S. Food and Drug Administration 
(FDA).  In addition, this study will compare COGNUTRIN with a placebo to see if taking 
COGNUTRIN is better than taking a placebo.  A placebo is a pill that looks like COGNUTRIN 
but has no drug or other active ingredient in it. 
We are asking you to take part in this research study because you are a woman between the 
ages of 30 and 70, have been diagnosed with stage I-IIIB breast cancer, and have completed 
treatment with chemotherapy, + or - radiation, within the last 6 months (+/- 7 days). 
Study ID:CR4_Pro00009858 Date Approved: 5/13/2016 Expiration Date: 5/13/2017


Subject’s Name  
 
 
Subject’s Medical Record #  
 
 
IRB# Pro00009858 
 
MCC# 17089 
[Original Approval Date:  05/13/2013] Version #10 Version Date: 10/14/2015 
ICF Adult MCC-USF IRB Consent Template – Med Rev: 2010-09-03 [MCC Rev. 2012.10.03] 
Page 2 of 13
What will happen during this study?
Before you can start the study, the study doctor or study staff will talk to you about the study.
You must sign this form before any study procedures can be done. 
Screening: 
x You will be asked about your medical history, current medical condition, and other 
medications that you are taking. 
x You will have a limited physical exam. 
NOTE: The limited physical exam can be done at either screening or baseline. 
x Your ability to think, learn and remember will be evaluated using a variety of tests. 
x A sample of blood from your arm will be collected in 5 small tubes each holding about 1 
tablespoon of blood.  Three (3) of the tubes collected will be used to make sure that 
your organs (like your liver, heart, and kidneys) are functioning normally and to make 
sure that you can participate safely in this study.  The other two (2) tubes will be used to 
measure biomarkers of inflammation and oxidative stress. 
x A 2-day Food Record Recall will be given to you to complete and return at your baseline 
visit.
Baseline / Randomization:
x We will collect your 2-day Food Record Recall. 
x You will be asked about any changes in medications. 
x You will be asked to complete a demographic questionnaire.  You will also be asked to 
complete several questionnaires that look at your general well-being.  These will include 
exercise, depression, fatigue and a personal assessment of your ability to think, learn 
and remember. 
x Anthropometric measurements (such as height, weight, BMI, waist, and hip 
circumference) will be taken. 
You will undergo MRI scanning.  An MRI uses powerful magnets and radio waves to 
make pictures of body tissues and structure.  You will have a structural and a resting- 
state functional MRI.of your brain.  A structural MRI examines the physical structure of 
the brain, while a resting-state functional MRI looks at brain activity while you are 
resting. The MRI will be done at University Diagnostic Institute (UDI). 
If you meet all eligibility criteria, you will be randomized to one of two study groups: 
x COGNUTRIN 
x Placebo 
We use a placebo to make sure that it really is the study medicine that is making a difference 
in your condition.  The placebo does not have anything in it that would normally help or harm 
most people.
Sometimes people seem to feel better just because they are given something that looks like 
medicine.  We want to make sure that the COGNUTRIN we are testing really works.  We need 
Study ID:CR4_Pro00009858 Date Approved: 5/13/2016 Expiration Date: 5/13/2017


Subject’s Name  
 
 
Subject’s Medical Record #  
 
 
IRB# Pro00009858 
 
MCC# 17089 
[Original Approval Date:  05/13/2013] Version #10 Version Date: 10/14/2015 
ICF Adult MCC-USF IRB Consent Template – Med Rev: 2010-09-03 [MCC Rev. 2012.10.03] 
Page 3 of 13
to have some people take the placebo and some people take COGNUTRIN.  That way we can 
compare how well COGNUTRIN works to how well the placebo works. 
You have an equal chance (like flipping a coin) of being in either of the study groups.  Neither 
you nor the study doctor will be able to pick which study group you are in.  You will not know 
and the study doctor will not know which study group you are in, but the study doctor can find 
out if it is necessary to know for your health.  If this happens, the study doctor may not be able 
to tell you which study group you were in until everyone finishes the study. 
You will be provided with: 
x Two bottles containing Lovaza (or placebo) and one bottle containing VitaBlue (or 
placebo).  You will be asked to take 2 capsules of Lovaza (or placebo) two times a day 
and 2 capsules of VitaBlue (or placebo) three times a day.  On the days of study visits, 
we ask that you take the study drug within 4 hours of your visit.  You will be given 
instructions about how to take the study drug.  You will take the study drug for 3 
months.  You are the only one who should take the study drug.  You should make sure 
that no one else takes it. 
x Multivitamin – You will be asked to start taking the multivitamin daily with your evening 
meal.  You should not take any other nutritional supplements while you are in this study. 
x Study Agent Intake and Symptom Log 
x A 2-day Food Record Recall 
You will be asked to limit your intake of the following foods to 2 - 3 servings per week (4 oz. 
per serving) while you are in this study: 
x Walnuts 
x Sardines 
x Cacha 
x Flaxseed Oil 
x Pilchards 
x Carp 
x Canola Oil 
x Kipper 
x Hilsa 
x Fish Oils 
x Eel 
x Jack fish 
x Fatty Fish 
x Whitebait 
x Katla 
x Salmon 
x Tuna (fresh) 
x Orange roughy 
x Trout 
x Anchovies 
x Pangas 
x Mackerel 
x Swordfish 
x Herring 
x Bloater 
You will also be asked to limit your daily intake of the following berries to 1 cup total of all 
berries per day while you are in this study: 
x Blueberries 
x Chokeberries 
x Elderberries 
x Blackberries 
x Black Currants 
x Black Raspberries 
Weeks 3, 7, and 11: 
x You will be contacted and reminded to complete a 2-Day Food Record Recall and bring 
your remaining study drug, Study Agent Intake and Symptom Log, and 2-day Food 
Record Recall to your next study visit. 
Weeks 4 and 8: 
x We will collect your remaining study drug, Study Agent Intake and Symptom Log, and
2-day Food Record Recall when you come in for your week 4 and week 8 visits. 
Study ID:CR4_Pro00009858 Date Approved: 5/13/2016 Expiration Date: 5/13/2017


Subject’s Name  
 
 
Subject’s Medical Record #  
 
 
IRB# Pro00009858 
 
MCC# 17089 
[Original Approval Date:  05/13/2013] Version #10 Version Date: 10/14/2015 
ICF Adult MCC-USF IRB Consent Template – Med Rev: 2010-09-03 [MCC Rev. 2012.10.03] 
Page 4 of 13
x We will ask you about any changes in medications and review any adverse events. 
x A sample of blood from your arm will be collected in 3 small tubes each holding about 1 
tablespoon of blood.  The blood will be used to make sure that that the study agent is 
safe.
x We will provide you with a new one-month supply of study drug and multivitamin.  A 
new 2-day Food Record Recall and Study Agent Intake and Symptom Log will also be 
given to you to complete. 
Week 12 (End of Treatment): 
x Your remaining study drug, Study Agent Intake and Symptom Log, and 2-day Food 
Record Recall will be collected at your week 12 visit. 
x We will ask you about any changes in medications and review any adverse events. 
x Anthropometric measurements (such as height, weight, BMI, waist, and hip 
circumference) will be taken. 
x You will complete several questionnaires that look at your general well-being.  These 
will include exercise, depression, fatigue and a personal assessment of your ability to 
think, learn and remember. 
x A sample of your blood from your arm will be collected in 5 small tubes each holding 
about 1 tablespoon of blood.  Three (3) of the tubes collected will be used to make sure 
that that the study agent is safe.  The other two (2) tubes will be used to measure 
biomarkers of inflammation and oxidative stress. 
x You will have a limited physical exam. 
x You will undergo MRI scanning.  The MRI will be done at University Diagnostic Institute 
(UDI).
Post-intervention Follow-up (7 days after stopping study agent): 
x You will be contacted by telephone 7 days after stopping the study agent and asked if 
you have had any problems since stopping the study agent. 
x We will ask you about any changes in medications. 
If you are interested, The Gateway for Cancer Research would like permission to communicate 
with you regarding your experience and any other information you would like to share 
regarding the treatments you received while participating in this clinical trial. 
Please check one of the lines below.  Please note that giving The Gateway for Cancer 
Research permission to communicate with you is completely optional and will not affect your 
participation in the rest of this study.  
____ I give permission for The Gateway for Cancer Research to communicate with me. 
____ I do NOT give permission for The Gateway for Cancer Research to communicate with 
me.
Study ID:CR4_Pro00009858 Date Approved: 5/13/2016 Expiration Date: 5/13/2017


Subject’s Name  
 
 
Subject’s Medical Record #  
 
 
IRB# Pro00009858 
 
MCC# 17089 
[Original Approval Date:  05/13/2013] Version #10 Version Date: 10/14/2015 
ICF Adult MCC-USF IRB Consent Template – Med Rev: 2010-09-03 [MCC Rev. 2012.10.03] 
Page 5 of 13
How long will you be asked to stay in this study? 
 
You will be asked to spend about 3 months in this study.  You will need to come for 5 study 
visits in all – screening, baseline, 4 weeks, 8 weeks, and 12 weeks.  All visits will take place at 
Moffitt Cancer Center and University Diagnostic Institute (UDI) and will last approximately 2-3 
hours.  The follow-up phone call will take approximately 10 minutes. 
How many people will take part in this study? 
Approximately 40 people will take part in this study at Moffitt Cancer Center.  
What other choices do you have if you do not participate? 
You do not have to be in this study to get help for your decreased ability to think, learn and 
remember.  The study doctor will talk to you about other things you can do to possibly improve 
your ability to think, learn and remember, including the important risks and benefits.  Your 
participation in this study is voluntary.  You can decide not to be in the study and you can 
change your mind about being in the study at any time.  There will be no penalty to you, and 
you won’t lose any benefits.  Your regular medical care at Moffitt Cancer Center will not 
change if you decide not to be in the study. 
Will you be paid for taking part in this study? 
We will pay you $50 for each of the 5 study visits (screening, baseline, 4 weeks, 8 weeks, and 
12 weeks) for transportation costs that you may incur during the time you volunteer while being 
in this study.  This will be paid to you by check, which will be mailed to your home after each 
visit.  If you complete all five study visits, you will receive a total of $250.  If you are traveling 
more than 100 miles from your home to reach the research site, you will receive an additional 
$30 for the transportation costs that you may incur. 
The findings from this research may result in the future development of products that are of 
commercial value.  There are no plans to provide you with financial compensation or for you to 
share in any profits if this should occur. 
Will it cost anything to be in this study?
You and/or your insurance company will be financially responsible for hospital inpatient, 
outpatient and follow-up visits that would normally or routinely occur in the management of 
your disease.  Inpatient and outpatient visits could include charges for treatments, 
medications, physician visits, laboratory tests and procedures.  You and /or your insurance 
company will be responsible for paying for the charges which are considered routine, since you 
would have received these services even if you were not participating in this study. 
You will be responsible for any costs not covered by your insurance company, including 
deductibles, co-payments and all out-of-pocket expenses.
You and/or your insurance company will not be responsible for paying for the following testing 
and procedures that are specifically required for this research study and are not considered 
part of the routine management of your disease, if these procedures are performed at Moffitt 
Cancer Center and University Diagnostic Institute (UDI).
x Screening Visit:  CBC, CMP, PT, aPTT, LDL, Study Clinic Visit 
Study ID:CR4_Pro00009858 Date Approved: 5/13/2016 Expiration Date: 5/13/2017


Subject’s Name  
 
 
Subject’s Medical Record #  
 
 
IRB# Pro00009858 
 
MCC# 17089 
[Original Approval Date:  05/13/2013] Version #10 Version Date: 10/14/2015 
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x Baseline Visit:  MRI Brain 
x Week 4 and Week 8:  CBC, CMP, PT, aPTT, LDL 
x Week 12:  CBC, CMP, PT, aPTT, LDL, MRI Brain, Study Clinic Visit 
During your participation in this study, we will provide you with the study drugs COGNUTRIN, 
containing VitaBlue (VDF FutureCeuticals) & Lovaza (GSK), and a multivitamin mineral at no 
additional charge to you.  
What are the potential benefits if you take part in this study? 
The study drug may help your ability to think, learn and remember, but there is no guarantee 
that being in this study will help you.  Your ability to think, learn and remember might not get 
better or may even get worse while you are in this study.  You may get placebo, which means 
you will not be receiving active drug.  Information from this study might help researchers to 
come up with new tests or medications to help others in the future. 
What are the risks if you take part in this study? 
The study drug might not help. 
Right now we do not know for sure if COGNUTRIN will help.  If it does not help, your 
condition/disease may get worse. 
There may be side effects. 
You may have problems because of the study drug used in this study.  These problems are 
called side effects.  Some side effects are just bothersome. Others could harm you.  There 
may be some side effects that we don’t know about yet. The research might involve risks to 
you that are currently unforeseeable.  Your health care team may give you medicines to help 
lessen side effects.  Many side effects go away soon after you stop taking the study drug.  In 
some cases, side effects can be serious, long lasting, or may never go away.  There may also 
be the risk of death. 
The risks to participants of this study are those associated with blood draws, MRI (magnetic 
resonance imaging test that uses powerful magnets and radio waves to make pictures of body 
tissues and structure), and study drug.
x
Blood draw:  Risks associated with blood draw are minimal.  However, it is possible to 
have infection or bleeding or bruising at the needle site.  To minimize risk, the site will 
be cleaned before drawing blood, pressure will be applied until the bleeding stops and a 
sterile dressing will be used to cover the puncture site.
x
MRI/fMRI:  For most people, there is no danger associated with having an MRI scan.
However, there may be some risk of psychological distress (i.e., anxiety, 
claustrophobia) caused by the confining environment of the scanner (MRI).  If you have 
claustrophobia, you cannot be in this study.  In addition, an MRI could be very 
dangerous if you have certain objects or devices implanted in your body, such as a 
pacemaker, insulin pump, ear implant, joint replacement, permanent dentures, or 
shrapnel.  You must tell the study doctor about any objects that you know are implanted 
or imbedded in your body.
x
VitaBlue:  VitaBlue is made from Wild Blueberry Extract.  There is evidence to suggest 
Study ID:CR4_Pro00009858 Date Approved: 5/13/2016 Expiration Date: 5/13/2017


Subject’s Name  
 
 
Subject’s Medical Record #  
 
 
IRB# Pro00009858 
 
MCC# 17089 
[Original Approval Date:  05/13/2013] Version #10 Version Date: 10/14/2015 
ICF Adult MCC-USF IRB Consent Template – Med Rev: 2010-09-03 [MCC Rev. 2012.10.03] 
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that blueberry can occasionally cause a food allergy in sensitive individuals.
x
Lovaza:  In previous studies with Lovaza, the most commonly reported side effects 
were feeling of fullness, fatty stools, nausea, and abdominal pain. 
Risks and side effects related to Lovaza include: 
Possible Risk/Side 
Effect
How often is it 
expected to 
occur? 
How serious will 
it be? 
Will it go away? 
Gastrointestinal Upset 
(diarrhea, abdominal 
bloating, abdominal 
pain) 
Common  
Can be treated 
Yes – once dose is 
stopped 
Decreased Blood 
Pressure
Occasionally  
Can be treated 
Yes – once dose is 
stopped 
Increase in bleeding 
time
Occasionally  
Can be treated 
Yes – once dose is 
stopped 
Mild elevation of liver 
function tests 
Rarely 
It will not impact 
your overall 
health
Yes – once dose is 
stopped 
Chest Pain 
Rarely 
Can be treated 
Yes – once dose is 
stopped 
Flu like symptoms 
Rarely 
Can be treated 
Yes – once dose is 
stopped 
Infection 
Rarely 
Can be treated 
Yes – once dose is 
stopped 
Change in sense of taste Rarely 
Can be treated 
Yes – once dose is 
stopped 
There is always a chance that any medical treatment may cause you some discomfort or harm 
and the study drug/procedures in this study are no different.  We will do everything possible to 
keep you from being harmed.  You should talk to your study doctor when you experience any 
side effects that you have while taking part in the study. 
It is not uncommon for the medical treatment that you would receive as your standard care to 
also cause problems.  However, these adverse effects will be communicated to you, specific to 
the treatment you receive. 
We will tell you as soon as we can, if we find out more information about the side 
effects that are caused by COGNUTRIN.  During the course of this study, we may find more 
information that could be important to you.  This includes information that, once learned, might 
cause you to change your mind about your willingness to be in this study.  We will notify you as 
soon as possible if such information becomes available. 
Is there any risk to your unborn children if you take part in this study? 
If you are pregnant, you may not participate in this study, because there may be risks to you 
and your unborn baby.  Breastfeeding (nursing) mothers will not be included in this study, 
since it is not known whether the drugs in this study will be passed on to the baby in mother’s 
milk.  If you are currently breastfeeding and wish to continue, your study doctor may 
Study ID:CR4_Pro00009858 Date Approved: 5/13/2016 Expiration Date: 5/13/2017


Subject’s Name  
 
 
Subject’s Medical Record #  
 
 
IRB# Pro00009858 
 
MCC# 17089 
[Original Approval Date:  05/13/2013] Version #10 Version Date: 10/14/2015 
ICF Adult MCC-USF IRB Consent Template – Med Rev: 2010-09-03 [MCC Rev. 2012.10.03] 
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recommend another treatment.
If you are a female of childbearing potential (able to become pregnant), you will be given a 
pregnancy test at no cost to you before beginning any study treatment. 
Tell one of the study doctors right away if: 
x You are pregnant. 
x You get pregnant. 
x You are breastfeeding. 
There may be risks to your unborn children that we don’t know about ahead of time; they are 
unforeseeable.
If you take part in this study, you must use an effective birth control method as discussed with 
your study doctor. 
Examples of birth control methods include: 
x Oral birth control pills 
x Birth control patch 
x Implanted (injectable contraceptive hormones or mechanical products such as 
intrauterine device) 
x Barrier methods (diaphragm, condoms, spermicidal) 
x Tubal ligation or vasectomy 
x Abstinence (no sexual intercourse)  
You should discuss the method of birth control which is best for you to use both during study 
treatment and for a period of time after treatment. 
You should tell your study doctor immediately if you become pregnant. 
The long-term effects of the study drug on fertility are unknown.  This means that it is unknown 
if treatment with these medications will affect your ability to have children in the future.  If we 
find COGNUTRIN might harm your fertility, we will notify you as soon as possible. 
What if you get sick or hurt while you are in the study?  
If you need emergency care:  
x
Call 911 or go to your nearest emergency room right away.  Moffitt Cancer Center 
does not have an emergency room or the facilities to provide emergency care.
If you do NOT need emergency care: 
x Call or go to your regular doctor.  It is important that you tell your regular doctor that you 
are participating in a research study.  If possible, take a copy of this consent form with 
you when you go.   
If you experience an adverse event or unanticipated problem, call Nagi Kumar, PhD, RD, at 
(813) 745-6885. 
Moffitt Cancer Center Injury Statement 
If you believe you have been injured as a result of your participation in this study or if you have 
Study ID:CR4_Pro00009858 Date Approved: 5/13/2016 Expiration Date: 5/13/2017


Subject’s Name  
 
 
Subject’s Medical Record #  
 
 
IRB# Pro00009858 
 
MCC# 17089 
[Original Approval Date:  05/13/2013] Version #10 Version Date: 10/14/2015 
ICF Adult MCC-USF IRB Consent Template – Med Rev: 2010-09-03 [MCC Rev. 2012.10.03] 
Page 9 of 13
questions about your rights as a person who is taking part in a research study, you may call 
the Moffitt Cancer Center Risk Manager at 813-745-4219.  Florida law (Statute 768.28) limits 
the liability of Moffitt Cancer Center.  Moffitt Cancer Center cannot pay for lost wages, 
disability, or discomfort.  A copy of this statute is available upon request at 813-745-1869.  This 
statute provides that damages are available only to the extent that negligent conduct of a 
Moffitt Cancer Center employee caused your injuries.  The damages available in this situation 
are limited by law.  The Moffitt Cancer Center and investigators have made no provision for 
monetary compensation in the event of physical illness or injury resulting from this study.
Be aware that your health care payer/insurer might not cover the costs of study-related injuries 
or illnesses. 
The use and disclosure of your personal health information 
We understand that information about you and your health is personal, and we are committed 
to protecting the privacy of that information.  Because of this commitment, we must obtain your 
written authorization before we use or disclose your information for this study.   
Research at the Moffitt Cancer Center may be undertaken jointly with the University of South 
Florida or other persons or entities under an organized health care arrangement.  By signing 
this form, you are permitting researchers at Moffitt Cancer Center to use personal health 
information for research purposes within its organized health care arrangements.  You are also 
allowing the Moffitt Cancer Center to disclose your personal health information to outside 
organizations or individuals that participate in this study.  We may publish what we find out 
from this study.  If we do, we will not let anyone know your name.  We will not publish anything 
that would let people know who you are. 
If you do not agree to the use and disclosure described above, you cannot be in the study.
Who will disclose, receive, and/or use your information? 
Federal law says we must keep your study records private.  We will keep the records of this 
study private by keeping them in a locked area or on a secure computer.  To do this research, 
the following people and/or organization(s) will be allowed to disclose, use, and receive your 
information, but they may only use and disclose the information to the other parties on this list, 
to you or your personal representative, or as permitted by law: 
x Every research site for this study, including the Moffitt Cancer Center, and each site’s 
study team, research staff and medical staff; 
x Any person who provides services or oversight responsibilities in connection with this 
study;
x Every member of the Moffitt Cancer Center workforce who provides services in 
connection with this study; 
x The person who is responsible for the study nationwide or worldwide (study 
chairperson);
x Any laboratories and other individuals and organizations that use your health 
information in connection with this study; 
x Any sponsor of the study, including the following sponsors: The Gateway for Cancer 
Research;
Study ID:CR4_Pro00009858 Date Approved: 5/13/2016 Expiration Date: 5/13/2017


Subject’s Name  
 
 
Subject’s Medical Record #  
 
 
IRB# Pro00009858 
 
MCC# 17089 
[Original Approval Date:  05/13/2013] Version #10 Version Date: 10/14/2015 
ICF Adult MCC-USF IRB Consent Template – Med Rev: 2010-09-03 [MCC Rev. 2012.10.03] 
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x Any federal, state, or local governmental agency that regulates the study (such as the 
Food and Drug Administration (FDA), Florida Department of Health (FDH), the U.S. 
Department of Health & Human Services (DHHS), and Office for Human Research 
Protections (OHRP)); 
x Other government agencies in this or other countries; 
x The designated Protocol Review and Monitoring Committees, Institutional Review 
Boards, Privacy Boards, Data and Safety Monitoring Board and their related staff that 
have oversight responsibilities for this study; 
x The National Cancer Institute in evaluating the ongoing research of the Moffitt Cancer 
Center as a Comprehensive Cancer Center. 
The organizations and people listed above may employ or pay various consultants and 
companies to help them understand, analyze and conduct this study.  All of these people may 
not be known now, but if you would like to have more specific information about this at any 
time during the study, you may ask the study doctor and your questions will be answered. 
Moffitt Cancer Center cannot guarantee the privacy of your information, or block further use or 
distribution, after the information has left the Moffitt Cancer Center.  Others listed above may 
further disclose your information, and may no longer be covered by federal privacy regulations. 
If all information that does or can identify you is removed from your records, the remaining 
information will no longer be subject to this authorization and may be used or shared for other 
purposes.
You might have the right to see and copy your health records related to this research.  You 
might not be able to see or copy some of your records until after all participants finish the 
study.  If it is necessary for your care, your records will be provided to you or your regular 
doctor.
What information will be used or disclosed? 
By signing below, you authorize the use and disclosure of your entire study record and any 
medical or other records held by Moffitt Cancer Center, including, but not limited to, HIV/AIDS, 
mental health, substance abuse or genetic information. The purpose for the uses and 
disclosures you are authorizing is to conduct the study explained to you during the informed 
consent and research authorization process and to ensure that the information relating to that 
study is available to all parties who may need it for research purposes. 
Your authorization to use your health information will never expire unless and until you 
expressly revoke it in writing to the investigator on the first page of this form.  If you revoke 
your authorization, you will not be able to continue in the study. 
By signing this form, you authorize the use and/or disclosure of your protected health 
information described above.  Your information may also be used as necessary for your 
research-related treatment, to collect payment for your research-related treatment (when 
applicable), and to run the business operations of the Moffitt Cancer Center. 
Any data collected prior to your letter will continue to be used as necessary to preserve the 
integrity of the study, however no additional information will be collected after you withdraw 
your authorization. 
Study ID:CR4_Pro00009858 Date Approved: 5/13/2016 Expiration Date: 5/13/2017


Subject’s Name  
 
 
Subject’s Medical Record #  
 
 
IRB# Pro00009858 
 
MCC# 17089 
[Original Approval Date:  05/13/2013] Version #10 Version Date: 10/14/2015 
ICF Adult MCC-USF IRB Consent Template – Med Rev: 2010-09-03 [MCC Rev. 2012.10.03] 
Page 11 of 13
You will receive a signed copy of this form. 
What happens if you decide not to take part in this study? 
You should only take part in this study if you want to volunteer.  You should not feel that there 
is any pressure to take part in the study to please the study doctor or the research staff. If you 
decide not to take part: 
x You will not be in trouble or lose any rights you normally have.  
x You will still have the same health care benefits. 
x You can still get your regular treatments from your regular doctor. 
You can decide after signing this informed consent document that you no longer want 
to take part in this study.  We will keep you informed of any new developments which might 
affect your willingness to continue to participate in the study.  However, you can decide you 
want to stop taking part in the study for any reason at any time.  If you decide you want to stop 
taking part in the study, tell the study staff as soon as you can.
We will tell you how to stop safely.  We will tell you if there are any dangers if you stop 
suddenly.
x If you decide to stop early, we will require final lab testing to assure safety.
Are there reasons we might remove you from the study later on? 
Even if you want to stay in the study, there may be reasons we will need to take you out of it.
Your study doctor has the right to take you out of the study at any time with or without your 
agreement.  Your participation may be ended without your consent for different reasons, 
including the following. 
x If the study doctor believes, for any reason, that it is in your best interest. 
x If at any time while you are taking the study drug the study doctor discovers that your 
health has worsened. 
x If you develop side effects that the study doctor considers unacceptable. 
x If you refuse to take the study drug or return for follow-up as recommended by your 
study doctor, or do not follow the study doctor’s instructions. 
x If you refuse to have tests that are needed to determine whether the study drug is safe 
and effective. 
x If you require treatment with drugs that are not allowed on this study. 
x If other causes prevent you from continuing in this study.
x If the Sponsor decides to end the study. 
You can get the answers to your questions, concerns, or complaints. 
If you have any questions, concerns or complaints about this study, call Nagi Kumar, PhD, at
(813) 745-6885. 
If you have questions about your rights as a research patient at Moffitt Cancer Center, call the 
Division of Research Compliance in the Corporate Compliance Department at The Moffitt 
Study ID:CR4_Pro00009858 Date Approved: 5/13/2016 Expiration Date: 5/13/2017


Subject’s Name  
 
 
Subject’s Medical Record #  
 
 
IRB# Pro00009858 
 
MCC# 17089 
[Original Approval Date:  05/13/2013] Version #10 Version Date: 10/14/2015 
ICF Adult MCC-USF IRB Consent Template – Med Rev: 2010-09-03 [MCC Rev. 2012.10.03] 
Page 12 of 13
Cancer Center at (813) 745-1869.
If you have questions about your rights as a participant in this study, general questions, or 
have complaints, concerns or issues you want to discuss with someone outside the research, 
call the USF IRB at (813) 974-5638. 
WHERE CAN I GET MORE INFORMATION? 
You may call the National Cancer Institute’s (NCI) Information Service at: 1-800-4-CANCER 
(1-800-422-6237).
Visit the NCI’s Websites at: 
x CancerTrials: comprehensive clinical trial information at: http://cancertrials.nci.nih.gov
x CancerNet: accurate cancer information including PDQ at: http://cancernet.nci.nih.gov
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you.  At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
Statement Of Participation in Research and Authorization for the 
Collection, Use and Disclosure of Health Information 
It is up to you to decide whether you want to take part in this study.  If you want to take part, 
please read the statements below and sign the form if the statements are true.  A 
representative of the Moffitt Cancer Center must answer your questions completely before 
providing this form to you. You or your personal representative should read this form and 
understand it before signing below. 
I freely give my consent to take part in this study and authorize that my health 
information as agreed above, be collected/disclosed in this study.  I understand that by 
signing this form I am agreeing to take part in research.  I have received a copy of this form to 
take with me. 
  
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Taking Part in Study 
 
 
Date 
Printed Name of Person Taking Part in Study 
Statement of Person Obtaining Informed Consent / Research Authorization 
I attest that the participant named above had enough time to consider this information, had an 
opportunity to ask questions, and voluntarily agreed to be in this study. 
Signature of Person Explaining Informed Consent / Research Authorization 
Date 
Printed Name of Person Explaining Informed Consent / Research Authorization 
Study ID:CR4_Pro00009858 Date Approved: 5/13/2016 Expiration Date: 5/13/2017


Subject’s Name  
 
 
Subject’s Medical Record #  
 
 
IRB# Pro00009858 
 
MCC# 17089 
[Original Approval Date:  05/13/2013] Version #10 Version Date: 10/14/2015 
ICF Adult MCC-USF IRB Consent Template – Med Rev: 2010-09-03 [MCC Rev. 2012.10.03] 
Page 13 of 13
Consent to store blood samples for future research 
We are asking you to allow us to store samples of your blood for use in the future.  These 
samples may be used for a variety of purposes, but those purposes will be related to breast 
cancer and/or cognition.
This means that we will store some of the blood samples taken at screening and week 12 for 
later testing.  This will not increase the time it takes to complete the blood draw. 
We may use these samples to help us: 
 
x Learn more about breast cancer and/or cognition. 
x Learn how COGNUTRIN works.
x Find new ways to help improve cognition in breast cancer patients following 
chemotherapy.
You can decide if you want us to store and use your samples in the future. 
You do not have to agree to this in order to take part in the study that has been previously 
explained to you.
Please initial one of the lines below:   
____ I agree for my blood samples to be stored for future research studies related to breast 
cancer and/or cognition. 
____ I DO NOT agree for my blood samples to be stored for future research studies related to 
breast cancer and/or cognition. 
Study ID:CR4_Pro00009858 Date Approved: 5/13/2016 Expiration Date: 5/13/2017