Conditions: Breast Cancer
Keywords: Breast Cancer Chemotherapy Radiotherapy NF-kB DNA Binding Curcumin IL-6 TNF sTNFR2 IL-1-ra Fatigue Cytokine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
The main purpose of the investigation is to determine if curcumin reduces NF-kB DNA binding and ultimately its downstream mediator IL-6 in patients receiving XRT for their breast cancer after having completed chemotherapy. Patients who have received prior chemotherapy will be eligible, because we have found that this enriched population is at particular risk for exhibiting increased NF-kB DNA binding and IL-6 following XRT.

Detailed description:
As many as 60% of breast cancer (BrCA) patients receiving radiation are known to develop fatigue with about 30% suffering persistent fatigue several months to years after treatment completion (12-23). The physical, psychological, and molecular mechanisms by which patients develop fatigue are poorly understood and most likely multi-factorial. One pathway that has received considerable attention is nuclear factor-kappa B (NF-kB)(24). The NF-kB pathway has emerged as having an important role not only in cancer treatment resistance but in the development of fatigue. NF-kB activation leads to over expression of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, all factors related to inflammation and factors that have been found to be upregulated in patients receiving radiation as well as BrCA survivors with fatigue (25-29). A recently published study looking at TNF-alpha, fatigue and cachexia in cancer patients receiving docetaxol showed that NF-kB is upregulated in fatigued patients and that agents which inhibit TNF-alpha lead to better tolerance of chemotherapy dose escalation (30). Work by our group and others has shown that ionizing radiation increases NF-kB pathway activity in circulating immune cells (as well as within breast cancer cells) and that this effect is most pronounced in women previously treated with chemotherapy (31, 32). Our work has shown that the NF-kB pathway activity in circulating immune cells is also related to fatigue development in BrCA patients treated with radiation and that patients most at risk for persistent fatigue and NF-kB pathway activity are those who have received chemotherapy for their breast cancer (31).

Curcumin, a known inhibitor of NF-kB, has been shown to decrease NF-kB activation in human participants. In a recent study, 8 grams of curcumin by mouth daily for 8 weeks was well tolerated in patients with pancreatic cancer and other pre-malignant conditions with no associated toxicities (6, 8). Although there is concern over the body's absorption of curcumin, the bioavailability of curcumin in the study of pancreatic cancer patients was shown, with peak drug levels at 22 to 41ng/mL that remained relatively constant over the first 4 weeks of treatment with 8 grams of curcumin daily (8). Clinical trials with daily dosages of 1,125 to 2,500mg have also confirmed the safety of curcumin and also shown its ability to decrease inflammation in patients with rheumatoid arthritis and in post-operative patients (6, 33, 34). In vivo murine models of chronic fatigue syndrome have also shown that curcumin may also alleviate symptoms of fatigue (35). While these studies are promising, very little is known about the capacity of Meriva to inhibit NF-kB in women treated for BrCA. We hypothesize that oral Meriva, a known inhibitor of NF-kB, may be used to decrease levels of NF-kB activity in BrCA patients previously treated with chemotherapy who go on to receive radiotherapy (XRT), a carefully chosen group of patients at particular risk for high levels of NF-kB DNA binding (a direct measure of NF-kB pathway activity).

We have chosen to administer oral Meriva, 500mg BID, in our patient population based on the above data. Meriva-500 is a curcumin formulation that also contains phosphatidylcholine, derived from soy that has been shown to aid in absorption of curcumin (9), permitting a lower overall dose of curcumin. Of note, 1000 mg Meriva contains 200 mg curcuminoids (\>90% curcumin).

By decreasing activity of NF-kB and ultimately plasma IL-6, fatigue may improve in BrCA patients taking Meriva. Results from this study will contribute to the limited research available on the capacity of curcumin treatment, including Meriva, to inhibit NF-kB activation in vivo as well as symptoms of fatigue associated with excessive NF-kB pathway activity in BRCA patients.

Arms:
arm 1: Placebo arm 2: 500 mg BID

Interventions: intervention 1: Placebo intervention 2: Curcumin
Intervention descriptions: intervention 1: daily placebo for 6 weeks intervention 2: 500 mg BID

Protocol document:
Prot_SAP_000.pdf: 
Meriva for Treatment-induced Inflammation and Fatigue in Women With Breast Cancer 
IRB#00055328 
 
0 
 
 
 
 
 
 
  
     Meriva for Treatment-induced Inflammation 
and Fatigue in Women with Breast Cancer 
 
 
Protocol dated 12/22/2017 
 
 
NCT01740323 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Meriva for Treatment-induced Inflammation and Fatigue in Women With Breast Cancer 
IRB#00055328 
 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
     Meriva for Treatment-induced Inflammation and Fatigue in Women with Breast 
Cancer 
 
 
PI: Andrew H. Miller, M.D. 
Department of Psychiatry and Behavioral Sciences 
Emory Winship Cancer Institute 
Emory University School of Medicine 
 
Version:  (12/22/2017) 
  
 
 


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(i) 
Background and objectives 
 
As many as 60% of breast cancer (BrCA) patients receiving radiation are known to 
develop fatigue with about 30% suffering persistent fatigue several months to years after 
treatment completion (12-23).  The physical, psychological, and molecular mechanisms by 
which patients develop fatigue are poorly understood and most likely multi-factorial.  One 
pathway that has received considerable attention is nuclear factor-kappa B (NF-kB)(24). The 
NF-kB pathway has emerged as having an important role not only in cancer treatment 
resistance but in the development of fatigue.  NF-kB activation leads to over expression of 
interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, all factors related to 
inflammation and factors that have been found to be upregulated in patients receiving radiation 
as well as BrCA survivors with fatigue (25-29).  A recently published study looking at TNF-alpha, 
fatigue and cachexia in cancer patients receiving docetaxel showed that NF-kB is upregulated in 
fatigued patients and that agents which inhibit TNF-alpha lead to better tolerance of 
chemotherapy dose escalation (30).  Work by our group and others has shown that ionizing 
radiation increases NF-kB pathway activity in circulating immune cells (as well as within breast 
cancer cells) and that this effect is most pronounced in women previously treated with 
chemotherapy (31, 32). Our work has shown that the NF-kB pathway activity in circulating 
immune cells is also related to fatigue development in BrCA patients treated with radiation and 
that patients most at risk for persistent fatigue and NF-kB pathway activity are those who have 
received chemotherapy for their breast cancer (31).  
 
Curcumin, a known inhibitor of NF-kB, has been shown to decrease NF-kB activation in 
human participants.  In a recent study, 8 grams of curcumin by mouth daily for 8 weeks was well 
tolerated in patients with pancreatic cancer and other pre-malignant conditions with no 
associated toxicities (6, 8). Although there is concern over the body’s absorption of curcumin, 
the bioavailability of curcumin in the study of pancreatic cancer patients was shown, with peak 
drug levels at 22 to 41ng/mL that remained relatively constant over the first 4 weeks of 
treatment with 8 grams of curcumin daily (8).  Clinical trials with daily dosages of 1,125 to 
2,500mg have also confirmed the safety of curcumin and also shown its ability to decrease 
inflammation in patients with rheumatoid arthritis and in post-operative patients (6, 33, 34).  In 
vivo murine models of chronic fatigue syndrome have also shown that curcumin may also 
alleviate symptoms of fatigue (35).  While these studies are promising, very little is known about 
the capacity of Meriva to inhibit NF-kB in women treated for BrCA.  We hypothesize that oral 
Meriva, a known inhibitor of NF-kB, may be used to decrease levels of NF-kB activity in BrCA 
patients previously treated with chemotherapy who go on to receive radiotherapy (XRT), a 
carefully chosen group of patients at particular risk for high levels of NF-kB DNA binding (a 
direct measure of NF-kB pathway activity).    
We have chosen to administer oral Meriva, 500mg BID, in our patient population based 
on the above data. Meriva-500 is a curcumin formulation that also contains phosphatidylcholine, 
derived from soy that has been shown to aid in absorption of curcumin (9), permitting a lower 
overall dose of curcumin. Of note, 1000 mg Meriva contains 200 mg curcuminoids (>90% 
curcumin).  


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By decreasing activity of NF-kB, fatigue may improve in BrCA patients taking Meriva.  
Results from this study will contribute to the limited research available on the capacity of 
curcumin treatment, including Meriva, to inhibit NF-kB and its downstream mediators in vivo as 
well as symptoms of fatigue associated with excessive NF-kB pathway activity in BRCA 
patients.  
 
The primary objective of this protocol is to determine if Meriva reduces NF-kB 
DNA-binding and its downstream mediators in patients receiving XRT for their breast 
cancer after having completed chemotherapy.    Patients who have received prior 
chemotherapy will be eligible, because we have found that this enriched population is at 
particular risk for exhibiting increased NF-kB DNA binding following XRT. NF-kB DNA-binding is 
a direct measure of NF-kB pathway activity, while plasma concentrations of TNF-alpha and its 
soluble receptor sTNFR2, interleukin (IL)-1 receptor antagonist (IL-1ra), and C-reactive protein 
(CRP) are downstream indicators of NF-kB activity.  
Secondary objectives will be to 1) determine if Meriva decreases levels of fatigue as 
measured by the Multidimensional Fatigue Inventory (MFI) in BRCA patients, and 2)  determine 
longitudinal variances in skin changes measured by ultrasound in breast cancer patients 
undergoing XRT. Results from this study will contribute to the limited research available on the 
capacity of Meriva and curcumin to inhibit NF-kB and its downstream mediators in vivo. 
(ii) 
Study location, personnel, and Institutional Review Board 
Study location 
Studies proposed in the current application will take place either at the Emory Winship Cancer 
Institute, 1365-C Clifton Rd NE, Atlanta, GA 30322, or the Emory University Hospital Midtown, 
550 Peachtree St NE, Atlanta, GA 30308. 
Personnel 
Sponsor Investigator: Andrew H. Miller, MD; 1365-B Clifton Rd NE, Suite 5100, Atlanta, GA 
30322; Dr. Miller is the Director of Psychiatric Oncology at the Emory Winship Cancer Institute, 
has many years of experience studying the psychiatric changes in cancer patients as well as 
novel therapies to reverse these features. Please also see attached CV.  
Co-Investigator: Mylin Torres, MD; 1365-B Clifton Rd NE, Suite 5100, Atlanta, GA 30322; Dr. 
Torres is a radiation oncologist with multiple years of experience with breast cancer patients and 
study of fatigue symptoms experienced by women with BrCA. Please also see attached CV. 
Co-Investigator: Karen Godette, MD; 1365-B Clifton Rd NE, Suite 5100, Atlanta, GA 30322. Dr. 
Godette specializing in breast cancer. Please also see attached CV. 
Co-Investigator: Thaddeus Pace, PhD; Dr. Pace has multiple years of experience measuring 
inflammatory activation across a number of disorders including major depression and anxiety.  
He has worked with Drs. Miller and Torres for the last several years to measure NF-kB pathway 


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activation and other inflammatory biomarkers in women after treatment for BrCA with increased 
fatigue symptoms. Please also see attached CV. 
Co-Investigator: Tian Liu, PhD; 1365-A Clifton Rd NE, Suite 1313, Atlanta, GA 30322; Dr. Liu is 
a board certified in Therapeutic Radiologic Physics with expertise in quantitative assessment of 
radiation tissue toxicity using ultrasound imaging. Please also see attached CV. 
Institutional Review Board 
All procedures described in this protocol will take place under the supervision of the Emory 
University Institutional Review Board, 1599 Clifton Road, 5th Floor East, Atlanta, GA 30322, 
Telephone: (404) 712-0720, Fax: (404) 727-1358. 
(iii) 
Patients inclusion and exclusion criteria 
 
Female breast cancer patients over the age of 18 who were previously treated with 
standard anthracycline- and/or taxane-based chemotherapy will be recruited for this study.  
Patients enrolled in the study will meet standard criteria for whole breast XRT or chest wall XRT 
for patients who have had mastectomies.  Patients will be included if they have a National 
Comprehensive Cancer Network score for fatigue over 3 (NCCN>3) as determined by the 
standard fatigue scale of 0-10 unless otherwise approved by the principle investigator or PI’s 
designee. Participants will be excluded for medical conditions that are contraindications to XRT 
and/or might confound the relationship among fatigue and inflammation, including pregnancy, 
unstable major psychiatric disorders, autoimmune (active within the past 6 months) or 
inflammatory disorders, chronic infectious diseases (e.g. HIV, hepatitis B or C), neurologic 
disorders and uncontrolled cardiovascular, metabolic, pulmonary or renal disease (as 
determined by medical history, physical examination or laboratory testing) unless otherwise 
approved by the PI or PI’s designee.  Participants with an unstable major psychiatric disorder, 
as assessed by study clinician, or a diagnosis of Alcohol Abuse (more than 5 drinks in a 24 hour 
period) or Substance Dependence within the past 1 year (as determined by a standard 
psychiatric interview) will be excluded unless otherwise approved by the PI or PI’s designee.  
Participants with an IDS score > 32 or IDS #18 score 2> will be referred to Dr. Andrew Miller.  
Participants with uncontrolled or chronic pain, a score greater than 4 on the standard pain scale, 
will be excluded unless otherwise approved by the principle investigator or PI’s designee. 
Participants taking drugs known to affect the immune system (e.g. glucocorticoids, 
methotrexate, sulfasalazine and nonsteroidal anti-inflammatory agents) will also be excluded 
unless otherwise approved by the principle investigator or PI’s designee. To protect against 
possible side effects of the study drug, women who are pregnant or nursing a child may not take 
part in this study.  Subjects of childbearing ability must agree, with the study doctor, on a 
method of birth control to use throughout the study. Subjects who think they have gotten 
pregnant during the study must notify the study doctor immediately. Pregnant women will be 
taken out of the study.  Patients using over the counter supplements or other natural products 
within one week of treatment, excluding vitamins and calcium supplementation, or at the 
discretion of the enrolling physician, will be excluded.  Patients who have evidence of infection 
as determined by history, physical exam or laboratory testing (complete blood count and 
urinalysis) at baseline will be excluded unless otherwise approved by the PI or PI’s designee.  


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Patients with anemia (HEM < 10g/dl) at baseline will be excluded unless otherwise approved by 
the PI or PI’s designee.  In addition, patients who develop evidence of infection (as determined 
by history, physical exam or laboratory testing) during the study will be discontinued from the 
study unless otherwise approved by the PI or PI’s designee.  Patients will be asked to refrain 
from having more than one alcoholic beverage per day. 
This protocol proposes to enroll 60 total patients, with 30 randomized to the Meriva arm 
and 30 randomized to the placebo arm of the study.  
 
(iv)  
Design 
 
This double-blind, placebo controlled, randomized clinical trial will enroll BrCA patients 
seen at the Emory Breast Centers (Winship Cancer Institute of Emory University and Emory 
University Hospital Midtown) or in the community for XRT who were previously treated with 
chemotherapy.  These patients will be approached for enrollment on this therapeutic study 
during the first three weeks of receiving radiation therapy or one to three months post XRT. 
 
In patients previously treated with chemotherapy, we will administer placebo or Meriva 
daily for approximately 6 weeks, beginning immediately after the completion of XRT or up to 3 
months post-XRT. Patients will be randomized to placebo or Meriva-500 (500 mg PO BID) using 
a computerized system under the control of Emory Pharmacy. Randomization will occur in 
blocks of 10. Meriva-500 will be obtained from Thorne Research. Blood will be drawn at 
baseline and at the first follow-up appointment to determine NF-kB DNA-binding in peripheral 
blood mononuclear cells, expression of NF-kB regulated genes, and plasma cytokine 
concentrations. The final study visit will occur during the 6 week treatment period. Study 
Coordinator will make an effort to coincide the follow up visit and six week post-radiation follow 
up visit. Because placebo or Meriva is being given after XRT is complete, it is unlikely to alter 
the efficacy of the XRT or enhance side effects of XRT.   
 
Thirty patients 
will be enrolled per arm.  
NF-kB DNA-binding, 
downstream mediators 
of NF-kB activity and 
microarray analysis of 
NF-kB regulated genes 
will be used to 
determine NF-kB 
pathway activation. If 
any of these measures 
of NF-kB DNA binding 
activity (the primary 
outcome variables) 
decrease to the mean level of non-chemotherapy treated women who receive XRT, the 500 mg 
BID dose level will be considered successful.  
Patients will receive daily Meriva treatment for approximately 
6 weeks beginning immediately after radiation therapy (XRT) 
or up to 3 months post-XRT. Peripheral blood will be drawn 
during the last week of XRT and again after 6 weeks of Meriva 
(or Placebo) for assessment of NF-kB pathway activation. 


Meriva for Treatment-induced Inflammation and Fatigue in Women With Breast Cancer 
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(v) 
Dosing 
The 500 mg BID dose of Meriva that will be used in this protocol was selected after 
consulting with Stefano Togni, DVM, Head of Business Development at Indena S.p.A (Milan, 
Italy) and Giovanni Appendino, Chief Scientific Advisor, Indena S.p.A (Milan, Italy). The dose 
proposed for use here is similar to doses used in other studies investigating Meriva (1-4). For 
example, the single dose selection is also supported by a recent study by Cuomo and 
colleagues showing that 200-300 mg of curcumin as Meriva (i.e. a single Meriva dose of 1000-
1500 mg) resulted in 29-fold higher for Meriva than for its corresponding unformulated (non 
phosphatidylcholine) curcuminoid mixture. In terms of the length of Meriva treatment, 6 weeks 
was chosen because it is the period of time over which we have observed a significant increase 
in NF-kB pathway activity related to fatigue symptoms (31). 
We propose to increase the dose of Meriva 500 administered to patients randomized to 
the active arm of the study from 1 to 2g total per day (500mg to 1g BID, respectively).  This 
dose increase will be implemented 1) after 10 patients have completed the protocol (5 active 
and 5 placebo), 2) if no statistically significant differences are noted at the primary study 
endpoint (peripheral blood mononuclear cell NF-kB DNA-binding) between patients randomized 
to the active arm and patients randomized to the placebo arm, and 3) no dose-limiting side 
effects have been encountered. Dose-limiting side effects are considered to be a Grade 3 
(Based on NCI Common Terminology Criteria for Adverse Events) or higher adverse event that 
is deemed to be probably related to the drug. 
 
The change to 2g/d dose is supported by Mantovani and colleagues who reported 
beneficial effects of 2g/d Meriva on inflammatory biomarkers in cancer patients taking Meriva for 
1 month (50). Also supporting this modification is a trial comparing the analgesic effects of 1.5g 
vs. 2g Meriva in a mixed patient group with different sources of pain (e.g. arthritis, neuropathy, 
recurrent headaches) (51). In general the results of this study suggest that Meriva at 2g/d may 
be more efficacious than Meriva at 1 g/d. Finally, a recent paper by Drobnic and colleagues 
found that 2g/d decreased inflammatory markers and muscular damage in healthy men 
undergoing intense physical exercise (52). No tolerability issues were noted in either of these 
studies except for mild nausea and heartburn in the report by Di Pierro et al. (51), which was 
attributed to the bulk of capsules consumed and not the content of the capsules. 
Of note, because of difficulty obtaining enough cells from the blood of the first 10 
subjects who completed the study, we were unable to measure peripheral blood NF-kB DNA 
binding. Therefore, because we could not statistically compare NF-kB DNA binding between 
groups, the Meriva dose of 1 g per day was maintained without an increase (as per protocol).  In 
addition, statistical consultation based on IL-6 values in the first 10 completed subjects 
suggested that continuing enrollment at the Meriva 1 mg dose would give sufficient power 
(>0.80) to detect a difference in this NF-kB-related inflammatory endpoint at study completion or 
after enrollment of at least 40 subjects. Similar findings were observed with fatigue.  For these 
reasons, the Meriva dose will be continued at 1mg per day for the entirety of the study for all 
subjects. 


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Although a maximum tolerated dose (MTD) for Meriva has not yet been identified in any 
population, most published studies have tested doses of either 1 or 2 g/d Meriva (containing 
200-400 mg curcuminoids )(53). By extrapolation of pharmacokinetic data (54,55), 2 g/d Meriva 
(containing 400 mg curcuminoids) dose may be bioequivalent to either 4 or 12 g/d non-
complexed curcuminoids, corresponding to the middle range of curcuminoid doses previously 
tested in humans.  Of note, the highest oral dose of Meriva being tested in humans is 4 g/d 
Meriva (containing 800 mg curcuminoids) (NCT01859858). However this study is ongoing, and 
information related to effectiveness and adverse events (AEs) is not available. All reported AEs 
for Meriva up to 2 g/d have been limited to grade 1 or 2 gastrointestinal symptoms and chronic 
toxicity studies in rats suggest that a human equivalent dose of 24 g/d Meriva is safe in humans 
(56).   
(vi) 
Observations and measurements 
Based on work performed in prior studies, we do not anticipate biomarker responses that would 
suggest adverse reactions to Meriva (1-4).  We will therefore not collect blood samples during 
the 6 week treatment with Meriva to monitor adverse biomarker responses. Research blood will 
be collected at baseline during the last week of XRT or up to three months post XRT and at the 
conclusion of the 6 weeks treatment with Meriva. Patients will be interviewed weekly by phone 
to ensure they are not experiencing side effects previously described for curcumin, including 
nausea and diarrhea. If they do report worsening of these symptoms compared to before they 
started Meriva, they will be asked to immediately discontinue taking Meriva and come to the 
clinic for full physical evaluation.  In the case that a patient experiences adverse side effects and 
stops taking Meriva, self-report information and blood samples will still be collected at the early 
termination visit. 
Curcumin Visit I: Screening  
 
Information regarding disease characteristics (including stage, tumor size, grade) 
 
Patient demographics (including age, race, co-morbidities, social history) 
 
Systemic treatment (including hormone therapy, systemic therapy), surgical treatment, 
and radiation treatment will be collected and recorded.   
 
Informed consent process 
 
Physician or NP evaluation or modified physical 
 
CBC with diff 
 
Serum quantitative pregnancy test 
 
 Urinalysis with microscopy 
 
Self-report of fatigue level and pain on a scale of 0-10, 0 being none and 10 being 
extreme. The patient’s self-report of fatigue at these visits will be used to assess the 
grade of their fatigue.   
 
Inventory of Depressive Symptomatology – Self Reported (IDS-SR)[41]- Participants 
with an IDS score > 32 or a score of 2 or higher on IDS item #18 will be referred to Dr. 
Andrew Miller 
 
PROMIS Fatigue Short form [49] 
 
Patient reimbursement 
 
Review labs for infection and anemia 
Curcumin Visit II: Baseline (XRT end – last week of XRT or within 3 months after)  
 
Inclusion criteria completed 


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 
Mediterranean diet survey, Inventory of Depressive Symptomatology – Self 
Reported(IDS-SR)[41], Pittsburgh Sleep Quality Index (PSQI) [42-45],  Perceived 
Stress Scale (PSS)[46], Godin Leisure-Time Exercise Questionnaire (GLTEQ)[48], 
Multidimensional Fatigue Index (MFI) (36) and PROMIS Fatigue Short form [49] 
 
Self-report of fatigue level and pain on a scale of 0-10, 0 being none and 10 being 
extreme. 
 
Fasting blood draw for research (two 4 ml purple tops, two 6 ml purple tops, and 1 
tempus tube) 
 
Ultrasound scan and photographs at PI’s discretion 
 
Randomization 
 
Dispense medications and medication diary 
 
Patient reimbursement 
 
Compliance: 
 
 
 
Patients will be asked to fill out a medication diary daily and report any missed doses 
during weekly telephone interviews. Patients who report taking less than 75% of their 
medication between interviews may be excluded from study participation at PI’s discretion.  
 
Curcumin Visit III: final evaluation of the last week of Meriva or placebo treatment  
 
Physician or NP evaluation or modified physical 
2/2/2016
date
date
date
During first 3 wks of XRT 
or up to 3 months post 
XRT
Discuss Curcumin Study and 
provide copy of ICF
Visit I - Boost Start or During Last 
2 wks of XRT or up to 3 months 
post XRT
Consent
ScreeningEvaluations
Visit III - Last week of 
medications
Final Evaluation
Return medications
Curcumin 
Study
Tx  wk 1 Call
Tx  wk 2  Call
Tx  wk  3 Call
Tx  wk 4 Call
Tx  wk 5 Call
R a d i a t i o n         T r e a t m e n t 
(up to 3 months post XRT)
M e d i c a t i o n s
Weekly phone interviews to assess adverse events.  
Visit II - Baseline - Last wk of RAD or up to 3 months post XRT
End RAD
Baseline Assessments
Blood draw
Randomization/Dispense Meds
Following Monday
Begin medication
date
Early Termination
Physical exam
Return medications
Blood draw
Questionnaires
date


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 
CBC with diff– review for infection and anemia 
 
Fasting blood draw for research ( two 4 ml purple tops, two 6 ml purple tops, and 1 
tempus tube) 
 
Ultrasound scan and photographs at PI’s discretion 
 
Self-report of fatigue level and pain on a scale of 0-10, 0 being none and 10 being 
extreme.  
 
Inventory of Depressive Symptomatology – Self Reported  (IDS- SR)[41], Pittsburgh 
Sleep Quality Index (PSQI)[42-45], Perceived Stress Scale (PSS)[46], Godin Leisure-
Time Exercise Questionnaire (GLTEQ)[48], Multidimensional Fatigue Index (MFI) (36) 
and PROMIS Fatigue Short form [49] 
 
Collect unused medications and medication diary 
 
Patient reimbursement 
 
During the screening visit Curcumin Visit 1, a urinalysis, CBC with differential, serum 
quantitative pregnancy test, and physician evaluation or modified physical by the study NP will 
be performed. A subset of patients may have an ultrasound scan and photographs done by 
Radiation-Oncology research team. The lab tests will be processed in the Emory Medical 
Laboratory (EML) system.  The results of the evaluation or modified physical and urinalysis as 
well as the CBC with differential will be reviewed to rule out infection or anemia to verify 
eligibility.  If infection or anemia or pregnancy is detected, the patient will be withdrawn from the 
study.   
An ultrasound of the treated breast or chest wall and untreated breast and axilla may be 
performed at the baseline and final evaluation visits to assess cutaneous toxicity. These scans 
will be conducted based on the availability of research staff and space to conduct the scan. 
Each scan will take between 5 and 10 minutes to perform. Photographs of the treated breast (or 
chest wall) as well as the contralateral breast will also be taken.  Ultrasound data and 
photographs will be stored in a computer for later review.   
The patient will be randomized to Meriva or placebo at Curcumin Visit II.  Medications will 
be dispensed, to be started the following Monday. A physician evaluation or modified physical 
will also be performed at the final evaluation, Curcumin Visit III. A physical exam will be 
performed at the time of early termination as well as a CBC with differential, research bloods, 
and self-report forms.  
For safety precaution, patient will be asked to repeat Curcumin Visit I if a lapse of 30 days 
or greater occurs between Curcumin Visit I and Curcumin Visit II. 
See checklist below for details on Curcumin Study Visits. Laboratory Measures  
 
 
Sample Collection & Handling 
 
Blood will be collected using purple top vacutainers (containing EDTA additive) and a tempus 
tube.  The blood volume per tube will be 3 – 3.5 ml for the 4 ml tubes, and 5 – 5.5 ml for the 6 
ml tubes.  Four purple top tubes and a tempus tube will be collected at baseline and at the 
final evaluation under fasting conditions.  Prior to collection, study numbers will be 
determined and barcoded labels will be placed on collection aliquots. 
 


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Blood samples will be drawn at the same time of day between 9:00-11:00 am (to reduce 
potential circadian effects) under sterile conditions at each of these visits. Whole blood for 
plasma, buffy coat, and peripheral blood mononuclear cells (PBMCs) will be collected into 
EDTA vacutainer tubes. Two tubes will stored at 4°C for less than 45 minutes, after which 
plasma and buffy coat will be separated by centrifugation at 1000 x g for 10 minutes at 4ºC, 
aliquoted into siliconized polypropylene tubes and stored at -80ºC until assayed.  Two tubes 
will be kept at room temperature for less than 45 minutes, after which plasma will be replaced 
CLINIC VISIT
CLINIC VISIT
CLINIC VISIT
CLINIC VISIT
CLINIC VISIT
Procedure
Init ial 
Meet ing
Visit  I
Screening
Visit  II
Baseline
Tx wk 1
Call
Tx wk 2
Call
Tx wk 3
Call
Tx wk 4
Call
Tx wk 5
Call
Visit  III
Early 
Terminat ion
Curcumin ICF for review
x
Curcumin Consent
x
Inclusion Criteria
x
Demo Sheet
x
Physician/NP Evlauation
x
x
Physical Examination
x
Urinalysis
x
Serum quantitative pregnancy
x
CBC w/diff  
x
x
x
Review labs for infection and anemia 
x
x
x
Blood draw for research:
4 purple tops and 1 tempus
**
**
**
Randomize/dispense meds
***
Patient reimbursement
x
x
x
x
Phone Interview
*
*
*
*
*
Meds returned/counted
x
x
Meds diary returned
x
x
Concomitant Medications reviewed
x
x
x
x
x
x
x
x
x
Adverse Events Reviewed
x
x
x
x
x
x
x
Ultrasound scan and photographs 
x
x
Fatigue Level
x
x
x
x
Pain Level
x
x
x
x
Mediterranean Diet Survey
x
GLTEQ
x
x
x
MFI 20
x
x
x
PSS
x
x
x
IDS-SR
x
x
x
x
PSQI
x
x
x
PROMIS
x
x
x
x
*  Weekly phone interviews for Adverse Event Assessment/ Medication Compliance.  If indicated, stop medications and come in for physical exam.             
** Plasma analysis of inflammatory markers, PBMC analysis of NF-kB DNA binding, and gene expression.                                                                                                                                                   
*** Medication dispensed during treatment check by physician or nurse practitioner. Medication to begin the following Monday after medications are dispensed.                                                                    
v. 12/19/2017
Curcumin Study Checklist


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by saline for the isolation of PBMCs using density gradient centrifugation. PBMCs will be 
stored in freezing serum (90% fetal bovine serum, 10% DMSO) at -80ºC until nuclear 
extraction or mRNA isolation.  
 
Plasma Analysis of Inflammatory Markers  
Plasma concentrations of TNF alpha, sTNFR2, IL-ra, and IL-6 will be determined using 
sandwich ELISA according to manufacturer’s protocol (R & D Systems, Minneapolis, MN).  
Each determination (excluding the soluble cytokine receptors which require less sample) 
requires 100-150µl of sample, and all samples will be assayed in duplicate.  ELISA assays 
will be performed in Dr. Pace’s laboratory.  Quality control plasma of both low and high 
cytokine concentrations will be included with every assay.  The mean inter- and intra-assay 
coefficients of variation for control samples are reliably 10% or less.  High sensitivity CRP will 
be measured in the CLIA certified laboratory of the Emory University Hospital using a 
standard turbidimetric assay. 
 
NF-kB DNA Binding  
Peripheral blood mononuclear cells (PBMC) will be isolated on ficoll-hypaque gradients 
before nuclear protein extraction and DNA-binding analysis. DNA-binding of NF-κB will be 
determined by an ELISA kit as previously described by our group (Active Motif [Carlsbad, 
CA])(37, 38).  Like electrophoretic shift assays (EMSA), the enzyme-linked immunosorbent 
assay (ELISA)-based method measures transcription factor binding to their consensus DNA 
sequences.  The ELISA-based approach detects DNA-protein interaction by observing 
transcription factor consensus sequence binding in a 96-well plate.  The consensus 
sequence is fixed to the bottom of the well and specificity is demonstrated by adding a 
soluble consensus sequence to control wells.  We have demonstrated that the ELISA-based 
approach has high sensitivity and specificity for detecting activated transcription factors by 
running nuclear extracts in both EMSA and DNA-binding ELISA with the same effects 
observed (39). 
 
Gene Expression  
RNA will be isolated from PBMCs collected as described above using an RNeasy Mini Kit 
(Qiagen, Hilden, Germany).  The A260/A280 ratio will be used to assess RNA purity.  
Samples will be analyzed in the Biomarker Profiling Core at The Emory Winship Cancer 
Institute for gene expression analysis using an Illumina platform. Initial data analysis will be 
conducted using the BeadStudio software from Illumina, and the data will then be exported to 
the TELiS system available online (40).  The TELiS database in conjunction with the 
PromoterStats statistical tool will be used to identify transcription factors (i.e. NF-kB) driving 
gene expression detected in the microarray.  Of note, previous studies using the TELiS 
database have identified profiles of gene expression that reflect NF-kB signaling activity (40).  
Microarray Analysis 
Specimens collected in Tempus tubes will be used for microarray analysis. 2-8µg of high 
quality RNA may be extracted per 1mL of blood.  Tempus tubes contain up to 4mL of blood, 


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and therefore at least 8µg of RNA will be extracted for analysis and validation. RNA will be 
molecularly characterized using an Illumina BeadStation and will be run on the HumanHT-12 
Beadchips or a comparable chip. Specimens will have RNA extracted for expression profiling 
in a batched manner to allow for minimal variation in extraction, in vitro transcription (IVT) 
labeling, and hybridization to the Beadchips. The primary endpoint of the microarray data 
analysis will be to determine if genes regulated by NF-kB exhibit decreased expression when 
patients are treated with Meriva vs. placebo.   
Outcome Measures 
The primary outcome to be measured will be the change in NF-kB DNA binding and its 
downstream mediators (plasma concentrations of TNF-alpha, sTNFR2, IL-1ra, IL-6  and 
CRP)after six weeks of treatment with daily placebo or Meriva.  The secondary endpoint will 
be the change in fatigue from baseline to six weeks after treatment with Meriva or placebo. .  
Microarray analysis will also be performed before and after treatment to look at the 
expression of NF-kB response genes:  Primary Hypothesis: Patients responsive to 
Meriva will have decreased NF-kB DNA binding, decreased activation of NF-kB 
responsive genes and decreased downstream mediators of NF-kB pathway activation.   
Analytical Plan  
Power analysis: Based on a preliminary data, the mean change of NF-kB DNA binding from 
baseline among patients who underwent six weeks XRT was 8.2 ng NF-kB per assay well 
(SD = 9.0). We hypothesize that in this study the patients in the placebo group will have the 
similar response as in the preliminary data, and patients who receive Meriva, the mean 
change of NF-kB DNA-binding level from baseline to 6 weeks post XRT is 0.0 with a reduced 
SD of 4.5. Based on alpha of 0.05 and a n = 11 per group, we will have 82% power to detect 
the above hypothesized difference by one-sided two-sample t test.  We believe such a 
difference is clinically meaningful and is well within the range of differences observed in 
chemotherapy vs. no chemotherapy patients and fatigued vs. non-fatigued patients. 
Statistical analysis plan: Primary objectives: the mean changes of NF-kB DNA binding from 
baseline to Week 6 will be compared between two groups using two-sample t test. The 
change of plasma concentration of NF-kB downstream mediators from baseline will be 
compared between two groups using two-sample t-test/Wilcox sum rank test for continuous 
measures and using Chi-square test/Fisher’s exact test for categorical measures. Secondary 
objectives: The change of MFI over time in two groups will be compared by the GEE model. 
(vii) 
Chemistry, manufacturing, and control information 
a. Drug substance 
Curcumin, (1E,6E)-1,7-bis (4-hydroxy- 3-methoxyphenyl) -1,6- heptadiene-3,5-dione, is the 
major active ingredient in Meriva-500. Meriva also contains lesser amount of the other two 
curcuminoids, desmethoxycurcumin and bis-desmethoxycurcumin. Curcumin is the orange 
pigment in turmeric spice (the primary ingredient in many food curries). Meriva-500 also 
contains "phytosomes", or phosphatidylcholine (PC), that is extracted from soy. PCs are a major 


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component of animal cell membranes. The combination of PC with curcuminoids improves the 
absorption of curcumin. A recent article by Cuomo and colleagues indicates that absorption of 
curcuminoids was about 29-fold higher for Meriva than for its corresponding unformulated 
curcuminoid mixture (9). Information about preparation, acceptable limits and analytical 
methods used to insure identity, strength, quality, and purity of Meriva is provided in the 
Manufacturing Protocol provided by Thorne Research (see Appendix 3). We attest that research 
activities proposed under this IND will only administer batches of Meriva-500 that contain less 
than 10 µg/day of lead and not more than 1.5 µg/day of arsenic. 
b.  Drug product 
Details regarding components, the name and address of the drug product manufacturer, 
description of manufacturing and packaging procedures, acceptable limits and analytical 
methods used to assure identity, strength, quality, and purity of the drug product, and 
information about Meriva’s stability are all provided in the Manufacturing Protocol provided by 
Thorne Research (see Appendix 3). Component Certificates of Analysis, Meriva and placebo 
Letters of Formulation, and Manufacturing Flow Chart are presented in Appendix 4. 
c. 
Placebo 
Details about the placebo are provided in the Manufacturing Protocol provided by Thorne 
Research (see Appendix 3). Component Certificates of Analysis, Meriva and placebo Letters of 
Formulation, and Manufacturing Flow Chart are presented in Appendix 4. 
d. 
Labeling details 
Details about Meriva and placebo labeling are provided in the Manufacturing Protocol provided 
by Thorne Research (see Appendix 3). 
e. 
Environmental analysis requirements 
I claim categorical exclusion under 21 CFR 25.31(e) for the study under this IND. To my 
knowledge, no extraordinary circumstances exist.  
(viii)  Pharmacology and toxicology 
a.  Pharmacology and drug disposition 
Bioavailability of Meriva has been documented in both animal and human studies.  A published 
report on Meriva bioavailability in rats is presented in Appendix 5. An original report on 
absorption of Meriva in humans compared to a curcumin preparation without 
phosphatidylcholine is presented in Appendix 6.   On the whole bioavailability of curcuminoids 
after treatment with Meriva is good in both rats and humans. 
b. 
Toxicology 
Acute toxicity of Meriva has been examined in rats following a single oral administration (2000 
mg/kg body weight, see Appendix 1). After 3 days, there were no changes in body weight.  


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Necropsy revealed no internal or external abnormalities. This study concluded that there is very 
slight toxicity in rats after 2000 mg/kg Meriva. The LD50 was stated to be significantly greater 
than 2000 mg/kg 
c.  21 CFR Part 58 compliance 
The toxicology study was conducted in compliance with the good laboratory practice regulations 
in Part 58. 
(ix)  
Previous human experience 
While there are numerous studies in humans that have examined curcumin in various 
formulations, fewer exist that use the Meriva formulation (i.e. curcumin with phosphatidylcholine) 
specifically. Meriva has shown considerable disease-modifying promise in several disorders, 
including in type-2 diabetes (1), osteoarthritis (2, 3)(Appendix 2), and chronic anterior uveitis 
(4)(Appendix 2). In each of these studies toxicity and tolerability problems were not reported. 
 
With respect to cancer, 8 grams of curcumin (non phosphatidylcholine formulation) by 
mouth daily for 8 weeks was well tolerated in patients with pancreatic cancer and other pre-
malignant conditions with no associated toxicities (6, 8). In one of these studies a subgroup of 
patients exhibited a decrease in tumor mass that corresponded to inflammatory biomarkers, 
including plasma interleukin-6. Clinical trials with daily dosages of 1,125 to 2,500mg have also 
confirmed the safety of curcumin and also shown its ability to decrease inflammation in patients 
with rheumatoid arthritis and in post-operative patients (6, 33, 34). While these studies are 
promising, very little is known about the capacity of curcumin to inhibit NF-kB in women treated 
for BrCA. 
 
 
(x)    
Additional information 
Drug abuse potential 
A review of the literature reveals no potential risk of drug abuse for curcumin generally, and 
Meriva specifically.   
 
(xi)     Potential risks and benefits to subjects: 
Potential risks:  
The risk to patients is minimal. Blood draws will be performed at two different 
time points during the course of this study.   
 
All patients will be assigned a study number, and this number will be used in 
place of patient’s names or identification numbers so there should be minimal 
risk of loss of patient confidentiality.  The master sheet containing the patient 
number and study ID will be kept in a password protected database.   


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Curcumin doses up to 8 grams per day have been shown to be well tolerated 
with minimal side effects.  It is not expected that curcumin doses proposed in 
this study will cause untoward adverse effects.   
 
A recent literature review identified a study which suggested that curcumin may 
aggravate iron deficiency.  However, patients will be screened for evidence of 
iron deficiency as evidenced by their hemoglobin and hematocrit.  No patient 
with evidence of iron deficiency will be admitted to the study.  All patients will 
be evaluated for evidence of iron deficiency upon completion of the study as 
per protocol.   
Potential benefits: Patients undergoing this study may have improvement in their fatigue levels. 
 
(xii)    Data and Safety Monitoring Plan: 
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will oversee 
the conduct of this study. This committee will review all pertinent aspects of study conduct 
including patient safety, compliance with protocol, data collection and efficacy. The committee will 
review the charts of 10% of patients enrolled to the study and two of the first 5 patients entered 
to the study. Reviews will occur annually if categorized by the committee as a low to moderate 
risk study or biannually if considered a high-risk protocol. The committee will conduct additional 
audits if necessary at any time-point. The Principal Investigator will notify the DSMC about the 
accrual of patients when the first 5 have been entered to the study. The PI will also notify the 
DSMC of the study status within 2 months before the next annual review is due.  
(xiii)    Adverse Event Reporting 
Enrolled participants will be monitored closely by study clinicians for any adverse events. All 
adverse events will be collected using the NCI Common Terminology Criteria for Adverse 
Events version 4.0. If any overt study-related adverse events occur, a decision will be made 
about study continuation. Additionally, a record of adverse events for study participants will be 
reported to the DSMC on a regular basis. Subjects will be closely monitored during the course 
of the study for development of any serious or unexpected adverse reactions. Those events 
meeting Emory IRB criteria for a reportable event will be reported to the IRB or the Winship 
Cancer Institute DSMC according to standard regulations and procedures. The Emory IRB 
Reportable Events Guidelines are included in an attachment.  
 
 
(xiv)   Data Quality Monitoring Plan:  
 
Periodic chart monitoring will be conducted by study personnel to validate integrity of the 
data. Chart reviews will take place after each block of five subjects and may include, but 
not be limited to, the presence of a signed informed consent document, documentation that 
the informed consent was obtained prior to performance of any study-related evaluations, 
documentation related to billing compliance, treatment calendars, enrollment reported to 
OCR, enrollment recorded in Oncore ®, treatment order and/or prescription form copies, 
and source documentation as defined in the Winship Clinical Trials Office’s Standard 
Operating Procedure. 
 
The project will be subject to random chart audits conducted by the Winship Clinical 
Trials Office in accordance with Standard Operating Procedures. A minimum of 5 
subject charts may be randomly audited as requested by the PI, the Associate 


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Director for Clinical Research, the Director of the CTO, the IRB, the ORC, or other 
Emory research compliance personnel, or the assistant director on an as needed 
basis. 
 
1. Any of the above persons may request a random audit of clinical trials records for 
the subjects enrolled on any study managed by this office. 
 
2. When records are requested they will be made available to the person listed above 
within 2 hours. 
 
3. Chart review may include, but not be limited to, the presence of a signed informed 
consent document, documentation that the informed consent was obtained prior to 
performance of any study-related evaluations, documentation related to billing 
compliance, treatment calendars, enrollment reported to OCR, enrollment recorded 
in Oncore ®, treatment order and/or prescription form copies, and source 
documentation. 
 
4. Audit will be performed by the persons listed above in "Procedure" or the 
internal monitors. 
 
5. Audit results may be reviewed by the Winship CTO Director, the Assistant Director of 
Regulatory/Compliance, the Assistant Director for Clinical Research and the Office of 
Research Compliance.  Significant findings will be discussed with the nurse, 
coordinator, principal investigator, and Director. 
 
6. Deficiencies will be corrected within five working days and presented to the Assistant 
Director for review at that time. A corrective and preventive action  plan will be 
developed as indicated by the audit results. 
 
Quality Improvement 
 
Charts with significant deviations from Winship CTO policy will indicate the need for 
further audit of records belonging to the involved nurse or coordinator. Limited 
findings of noncompliance will signal a need for increased education and/or quality 
monitoring. Significant noncompliance can lead to disciplinary action. 
 
Failure to comply with this policy may be grounds for discipline by the University. Any 
disciplinary action taken by the University will follow the rules governing the 
individual's employment category. 
  
(xv) 
Payment to subjects: (Maximum compensation per participant=$250.00 or $300) 
Participants will be paid $50.00 at Visits I, II, and III. Participants will be compensated an 
additional study visit’s compensation of $50 per repeated study visit or, if indicated by the PI, 
repeated study visit procedures. They will also be paid $20.00 per weekly phone interviews 
completed, which they will receive at Visit III. If participant is asked to discontinue placebo or 
curcumin, he or she will be paid $50 for coming into the clinic for a full physical exam.  
Participants will be given a parking voucher for all study visits. Further compensation (up to an 
additional $25 per screening visit) will be provided to cover travel expenses for you if you live 
equal to or greater than 50 miles outside of the Atlanta city limits.  


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(xvi) 
Informed consent:  
A study investigator will obtain informed consent from every patient agreeing to 
participate in this study. 
 
(xvii) Confidentiality:  
Confidentiality will be protected by collecting only information needed to assess study 
outcomes, minimizing to the fullest extent possible the collection of any information that 
could directly identify subjects, and maintaining all study information in a secure manner. 
Any patient identifiers (patient name, medical record number, date of birth) will be 
removed from the database prior to analyzing the data, producing an anonymous 
analytical data set.  These same patient identifiers (name, medical record number, date 
of birth) will be removed from collected specimens before storing the samples in 
preparation for analysis.  A unique number will be used to link collected specimens with 
questionnaires collected for each patient but this number will not be traceable to the 
specific patient.  All data will be secured on password-protected computers accessible 
only to the investigators or support staff involved in the investigations (data manager 
and/or students), and will not be shared publicly. No reference to any individual 
participant will appear in reports, presentations, or publications that may arise from the 
study.  
 
(xviii) Recruiting Methods:  
Breast cancer patients previously treated with chemotherapy who are candidates for 
definitive radiation administered in one of the Emory Breast Centers or in the community 
will be approached for participation in this study. Social media marketing campaigns may 
be conducted for recruitment purposes. An overview of the study will then be provided in 
person or over the phone by study clinicians or trained study staff to prospective 
candidates.  A telephone prescreening interview may be conducted on candidates 
providing verbal consent. If a subject shows interest in the study, research staff 
members will describe the general procedures involved and will answer relevant 
questions. If a subject remains interested in participation, the detailed nature, purpose, 
procedures, benefits, risks of, and alternatives to this research study will be explained to 
each subject, and written informed consent will be obtained by the study clinician who 
provides this information. Informed consent will be documented on the Institutional 
Review Board-approved form. A copy of the signed consent form will be given to the 
participant and the original document filed in a central study consent binder. The consent 
binder(s) and subject casebooks containing information gathered as part of the study will 
be kept in a locked office and/or cabinet. 
 
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1. 
Appendino G, Belcaro G, Cornelli U, Luzzi R, Togni S, Dugall M, et al. (2012): Potential 
role of curcumin phytosome (Meriva) in controlling the evolution of diabetic microangiopathy. A 
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2. 
Belcaro G, Cesarone MR, Dugall M, Pellegrini L, Ledda A, Grossi MG, et al. (2010): 
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Belcaro G, Cesarone MR, Dugall M, Pellegrini L, Ledda A, Grossi MG, et al. (2010): 
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Emory IRB Reportable Events Guidelines 
 
1. The investigator must report the following events promptly to the IRB (report 
within 10 days of becoming aware of the event): 
a) Deaths at Emory-affiliated sites that are possibly, probably, or definitely 
related to the study procedure, drug, or device 
b) Unanticipated problems involving risks to participants or others 
(UPs), at both Emory affiliated and non-Emory-affiliated sites. Note: UPs 
are always possibly, probably, or definitely related to the research 
(otherwise it’s not a UP) 
c) Anticipated events at Emory-affiliated sites that occur with a greater 
frequency, duration, or severity than what is documented in the protocol, 
informed consent, and investigator’s brochure (these events become 
UPs because even though they are anticipated, it is unanticipated that 
the expected events are happening at a greater frequency, duration, or 
severity) 
d) Other unanticipated information, at both Emory-affiliated and non-
Emory-affiliated sites, that changes the risk benefit ratio or that indicates 
participants or others might be at greater risk of harm than was 
previously known (e.g. any change to the protocol taken without prior 
IRB approval in order to eliminate apparent immediate hazards to 
participants and any publication in the literature, DSMB report, or interim 
result that indicated an unexpected change to the potential risks of the 
study) 
e) Protocol deviations at Emory-affiliated sites in which there have been 
a substantive deviation from the IRB-approved protocol AND the 
deviation adversely affected 1) the rights, welfare or safety of subjects; 
2) the integrity of the research data; or 3) the subjects’ willingness to 
continue participation. 
f) Non-compliance or cases of alleged non-compliance for Emory-
affiliated sites 
 
2. The investigator must report the following events to the IRB periodically (usually 
at continuing review): 
a) Deaths at Emory-affiliated sites that are not related to the study 
procedure, drug, or device (for example, a death from cancer that is 
related to disease progression and NOT the intervention) need to be 
reported as a summary. The sponsor and PI should follow their data and 
safety monitoring plan to track trends using all available data. If in an 
aggregate analysis, the investigator and sponsor find some association 
of the deaths to the study, they must report these promptly to the IRB. 
b) A summary of UPs for both Emory-affiliated and non-Emory-affiliated 
sites 


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c) A summary of serious adverse events that are related to the 
research for Emory-affiliated sites 
 
3. The following events are NOT reportable to the IRB 
a) Anticipated or unanticipated events, whether serious or not, that are not 
related to the study procedure, drug, or device. 
b) Serious adverse events that are not related to the research  
 
 
Emory IRB  
9/9/2009