Clinical trial NCT03140280
Conditions: Myelodysplastic Syndromes
Keywords: Black raspberries MDS Myelodysplastic Syndromes hypomethylating effects chemopreventive agent BRB pharmacokinetics
Sponsor: Ehab L Atallah
Start date: 2017-06-05; Completion date: 2021-05-28
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase II, single-group pilot study to evaluate efficacy and methylation. This study's overarching aim is to evaluate the systemic effects of black raspberries in patients with myelodysplastic syndrome or myelodysplastic syndrome/myeloproliferative neoplasm. Twenty-one patients with MDS will be treated with 25 gm (2x/day) of BRB powder taken orally.

Detailed description:
STUDY RATIONALE:

Hypomethylating agents (HMAs) such as azacitidine and decitabine are FDA approved therapies for MDS patients. Approximately 50% of patients respond to HMAs. In addition, HMAs have improved survival and quality of life of patients with MDS when compared with other therapies.

Preclinical research shows black raspberries (BRBs) have hypomethylating effects in the colon, blood, spleen, and bone marrow of mice treated with BRBs. The aim of this study is to evaluate the hypomethylating properties of BRBs in patients with MDS or MDS/MPN for three cycles (one cycle = 28 days) of BRB supplementation.

PRIMARY OBJECTIVE:

To evaluate the potential hypomethylating effects of freeze-dried black raspberries (BRBs) in the peripheral blood of patients with myelodysplastic syndrome or myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) after three cycles of BRB administration.

SECONDARY OBJECTIVE:

1. To evaluate the toxicity of BRBs in patients with MDS or MDS/MPN.
2. To evaluate the hematological response according to modified International Working Group (IWG) criteria (Appendix 2) in patients with MDS or MDS/MPN regardless of the initial blood count.

Arms: arm 1: Freeze-dried black raspberry powder administration.
Interventions: intervention 1: Freeze-Dried Black Raspberry Powder
Intervention descriptions: intervention 1: 25 gm (2x/day) of freeze-dried black raspberry powder taken orally in 8 ounces of water for 12 weeks. If the patient is tolerating BRBs well and is benefiting from therapy, he or she will continue treatment for a total maximum of 48 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
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CLINICAL STUDY PROTOCOL 
 
 
A Pilot Study to Investigate the Hypomethylating Properties of Freeze-dried Black 
Raspberries (BRB) in Patients with Myelodysplastic Syndrome or Myelodysplastic 
Syndrome/Myeloproliferative Neoplasm (MDS/MPN) 
 
Clinical Trials.gov Identifier: NCT03140280 
Funding Source: Kurtis R. Froedtert Clinical Trials Office Seed Grant 
 
 
Principle Investigator 
Ehab Atallah, MD 
 
 
Version No. 2 
December 29, 2017 
 
Protocol History 
Original Version No. 1 - October 7, 2016 
 
 
 
Proprietary and Confidential 
 
The information in this document is considered privileged and confidential, and may not 
be disclosed to others except to the extent necessary to obtain Institutional Review 
Board approval and informed consent, or as required by federal and state laws. Persons 
to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed. 


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Principal Investigator/ Sponsor- 
Investigator: 
Ehab Atallah, MD 
Associate Professor 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4600 
Email: eatallah@mcw.edu 
Sub-investigator: 
Li-Shu Wang, PhD 
Associate Professor 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
Translational & Biomedical Research Center 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-955-2827 
Email: liswang@mcw.edu 
Sub-investigator: 
Laura Michaelis, MD 
Associate Professor 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4600 
Email:  lmichaelis@mcw.edu 
Sub-investigator: 
Karen-Sue Barker Carlson, MD, PhD 
Assistant Professor 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4600 
Email:  kabarker@mcw.edu 
Sub-investigator: 
Parameswaran Hari, MD, MRCP, MS 
Armand Quick – William Stapp Professor of 
Hematology 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4600 
Email:  phari@mcw.edu 
Sub-investigator: 
Timothy Fenske, MD 
Associate Professor 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4600 
Email: 
tfenske@mcw.edu 
Sub-investigator: 
Steven H. Kroft, MD, FASCP 
Professor 
Director, Hematopathology Program 
Department of Pathology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-6986 
Email: skroft@mcw.edu 
Research Dietitian: 
Kara Sonntag, RD 
Clinical Dietician 
Froedtert and the Medical College of 
Wisconsin 
9200 W. Wisconsin Avenue 
Milwaukee, WI 53226 
414-805-4489 
Email: ksonntag@fmlh.edu 


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Biostatistician: 
Mei-Jie Zhang, PhD 
Professor 
Division of Biostatistics 
Medical College of Wisconsin 
9200 W Wisconsin Ave, 
Milwaukee, WI 53226 
Email: meijie@mcw.edu 
 
Investigational Drug Pharmacist: 
Kristin Busse, Pharm.D., BCPS 
Investigational Drug Pharmacist 
Froedtert & the Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Office: 414-805-3145 Pager: 414-314-7815 
Email: Kristin.Busse@froedtert.com 
Research Coordinator: 
Arielle Baim, BA, CCRP 
CRC III-Disease Team Lead 
Froedtert & the Medical College of Wisconsin 
Clinical Trials Office 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Telephone: 414-805-8745 
Fax: 414-805-0596 
Email: abaim@mcw.edu 
 
Research Coordinator: 
Hayden Krause, BS 
CRC l 
Froedtert & the Medical College of Wisconsin 
Clinical Trials Office 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Telephone: 414-805-8753 
Fax: 414-805-0596 
Email: hkrause@mcw.edu 
 
 
Postdoctoral Fellow:  
Pan Pan, PhD, RAC 
Department of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
Telephone:  414-955-2579 
Email: p p a n @mcw.edu   


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PROTOCOL SUMMARY 
 
Title 
A Pilot Study to Investigate the Hypomethylating Properties of 
Freeze-dried 
Black 
Raspberries 
(BRB) 
in 
Patients 
with 
Myelodysplastic 
Syndrome 
or 
Myelodysplastic 
Syndrome/ 
Myeloproliferative Neoplasm (MDS/MPN) 
Oncore Identifier 
IIT-ATALLAHBLACKRASPBERRY 
Principal Investigator/ 
Sponsor-Investigator 
Ehab Atallah, MD 
Study Site 
Froedtert & the Medical College of Wisconsin 
Clinical Trial Phase 
II 
Study Disease 
Myelodysplastic Syndrome or Myelodysplastic Syndrome 
/Myeloproliferative Neoplasm (MDS/MPN) 
Eligibility Criteria 
Inclusion Criteria 
Patients must have a confirmed diagnosis of myelodysplastic 
syndrome or myelodysplastic syndrome /myeloproliferative 
neoplasm (MDS/MPN) proven by bone marrow biopsy/aspirate. 
Patients with cytopenias (blood cell counts lower than the 
institutional lower limit of normal within the eight weeks prior to the 
study) who are receiving or received: 
• 
red blood cell transfusions 
• 
observation 
• 
platelet transfusions 
• 
erythropoietin 
• 
granulocyte colony-stimulating factors 
• 
granulocyte-macrophage colony-stimulating factors 
• 
hydrea  
 
Age >18 years. 
 
Predicted life expectancy of at least 12 weeks. 
Patients should be expected to stay on the same therapy for the 
period of the study. 
Patients who do not have an indication for and/or are believed to be 
unable to tolerate a hypomethylating agent are eligible for the trial. 
Reproductive requirements: 
• 
Female patients must meet one of the following: 
- 
Postmenopausal for at least one year before the screening 
visit, or 


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- 
Surgically sterile, or 
- 
If they are of childbearing potential, agree to practice two 
effective methods of contraception from the time of signing 
of the informed consent form through 30 days after the last 
dose of study drug, AND 
- 
Must also adhere to the guidelines of any treatment-specific 
pregnancy prevention program, if applicable, or 
- 
Agree to practice true abstinence when this is in line with the 
preferred and usual lifestyle of the subject. (Periodic 
abstinence [e.g., calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable 
contraception methods.) 
• 
Male patients, even if surgically sterilized (i.e., status 
postvasectomy), must agree to one of the following: 
- 
Practice effective barrier contraception during the entire 
study treatment period and through 30 days after the last 
study drug dose, OR 
- 
Must also adhere to the guidelines of any treatment-specific 
pregnancy prevention program, if applicable, OR 
- 
Agree to practice true abstinence when this is in line with the 
preferred and usual lifestyle of the subject. (Periodic 
abstinence [e.g., calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
Ability to understand a written informed consent document, and the 
willingness to sign it. 
Exclusion Criteria 
A potential subject who meets any of the following exclusion criteria 
is ineligible to participate in the study. 
Previously received hypomethylating agents. 
Allergy to black raspberries. 
Inability to swallow oral medication. 
Inability or unwillingness to comply with the BRB administration 
requirements. 
Uncontrolled intercurrent illness, including, but not limited to 
symptomatic congestive heart failure, or psychiatric illness/social 
situations, that, in the treating investigator’s discretion, would limit 
compliance with study requirements. 
 
Concurrent active malignancy is not an exclusion criterion. 


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Active infection not well controlled by antibacterial or antiviral 
therapy. 
Pregnant or lactating women. 
Participation in clinical trials with other investigational agents not 
included in this trial, within 14 days of the start of this trial and 
throughout the duration of this trial. 
Patients with allergies to other members of the Rosacea family 
including but not limited to: apple, almond, apricot, cloudberry, 
blackberry, etc. 
Study Rationale 
Hypomethylating agents (HMAs), such as azacitidine and 
decitabine, are FDA-approved therapies for MDS patients. 
Approximately 50% of patients respond to HMAs. In addition, HMAs 
have improved survival and quality of life of patients with MDS when 
compared with other therapies. 
Preclinical research shows black raspberries (BRBs) have 
hypomethylating effects in the colon, blood, spleen and bone 
marrow of mice treated with BRBs. The aim of this study is to 
evaluate the hypomethylating properties of BRBs in patients with 
MDS or MDS/MPN for three  cycles (one cycle = 28 days) of BRB 
supplementation. 
Primary Objectives 
To evaluate the potential hypomethylating effects of freeze-dried 
black raspberries (BRBs) in the peripheral blood of patients with 
myelodysplastic 
syndrome 
or 
myelodysplastic 
syndrome 
/myeloproliferative neoplasm (MDS/MPN) after three cycles of BRB 
administration. 
Secondary Objectives 
1. To evaluate the toxicity of BRBs in patients with MDS or 
MDS/MPN. 
2. To evaluate the hematological response according to modified 
IWG criteria (Appendix 2) in patients with MDS or MDS/MPN 
regardless of the initial blood count. 
Study Design 
This is a phase II single-group pilot study. This trial is designed to 
evaluate efficacy and methylation. This study’s overarching aim is to 
evaluate the systemic effects of BRBs in patients with MDS or 
MDS/MPN. 
Study Agent/ 
Intervention 
Description 
This protocol dictates the use of freeze-dried black raspberry 
powder. Twenty-five grams of freeze-dried BRBs will be mixed with 
approximately 8 ounces of water; subjects will consume 25 grams 
orally two times a day. 
Number of Patients 
The study team will enroll 18 patients with MDS or MDS/MPN. 
Subject Participation 
Duration 
After three and six cycles of treatment, if patients are benefiting from 
the regimen, they continue treatment for a total maximum of 12 
cycles. 


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Duration of Follow up 
Follow-up is required 30 days (+4 days) from treatment 
discontinuation. 
Estimated Time to 
Complete Enrollment: 
The study will reach accrual approximately 24 months from when 
the first patient is dosed. 
Safety Assessments 
Patients will be seen every cycle by the study staff for compliance 
and toxicity evaluation. No toxicity is expected from consumption of 
freeze-dried BRBs powder at a level of 50 grams per day. However, 
side effects are always a possibility. The NCI Toxicity Criteria version 
4.0 will be employed in this study to record any adverse events. 
Efficacy Assessments 
Peripheral blood samples will be collected day 1 of cycles 1–4, 7, 
10, and end of treatment for evaluation of methylation status of 
mononuclear cells. Assays will include plasma uptake of berry 
components, measurement of berry anthocyanins in urine, isolation 
of peripheral blood monocytes and analysis of DNA methylation. 
Unique Aspects of 
this Study 
This study will test the novel suppressive role of black raspberries. 


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E 
N 
R 
O 
L 
L 
M
E 
N 
T 
Research 
Labs 
Black 
Raspberries2 
(25 gm 2x/daily) 
  
Response 
assessment3 
O 
F 
F 
S 
T 
U 
D 
Y 
Eligibility 
Criteria 
All 
Screening 
Procedures 
Disease/ 
Survival 
Status4 
 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Refer to appendix 4. 
2. BRBs will be dispensed every cycle for a maximum of 12 cycles. 
3. If the patient is tolerating BRBs well and is benefiting from therapy after cycles 3 and 6, then, the patient will continue treatment for a total maximum of 12 cycles. 
4. A follow-up visit is required 30 days (+4 days) from treatment discontinuation. 
 
 
 
Screening 
Treatment 
Follow-Up 
 
Consent 
 
R 
E 
G 
I 
S 
T 
R 
A 
T 
I 
O 
N 


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STUDY CALENDAR 
The below study chart is described in detail in Sections 5 and 6. 
 
Study Calendar 
 
Period/Procedure 
Screening 
Treatment 
End of 
Treatment 
Study Day/Visit Day 
 Cycle=28 days 
-28 to 0 
Days1 
C1D1 
C2 & C3, D1 
(+/- 4 days) 
C4 & C7, D1 
(+/- 4 days) 
C10D1 
(+/- 4 days) 
C5-C6 & C8-C9 
& C11-C12, D1 
(+/- 4 days)10 
Follow-up2 
Informed consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Medical history/height 
X 
 
 
 
 
 
 
Medication history4 
X 
 
 
 
 
 
 
Drug Administration 
 
 
 
 
 
 
 
Black raspberries 25 gm (BID)3 
 
X 
X 
X 
X 
X 
 
Clinical procedures 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Diet assessment14 
 
X 
X 
X 
X 
X 
 
ECOG Performance Status16 
X 
 
 
X 
 
 
X 
Weight 
 
X 
 
X 
 
 
X 
AE assessment11 
 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
 
 
 
            
X 
Laboratory procedures 
 
 
 
 
 
 
 
Complete blood count (CBC) 
with differential and platelet 
count 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (serum or 
urine)5 
X 
 
 
 
 
 
 
Serum chemistry panel6 
X 
 
 
X 
 
 
X 
Research serum for 
anthocyanin level7, 15 
 
X 
 
 
 
 
 
Research blood 
methylation samples8, 15 
 
X 
X 
X 
X 
 
X 
Research urine samples9, 15 
 
X 
 
 
 
 
 
Disease Response 
Assessment12 
 
 
 
 
X 
 
 
X 
Transfusion history13 
 
X 
X 
X 
X 
X 
X 
 
1  Screening procedures should occur within 28 days prior to Day 1. BRB treatment should start within 14 days of enrollment. 
2  A follow-up visit is required 30 days (+/- 4 days) from treatment discontinuation. 
3 BRBs will be dispensed every cycle for a maximum of 12 cycles. BRB doses should be separated by at least six hours and the morning dose should be 
held when the methylation research samples are collected. Refer to appendix 5 for the drug diary. 
4  Capture medications taken within 30 days of day 1 of BRB treatment. 
5 For women of childbearing potential. This is defined as any woman whether or not they have undergone tubal ligation, that meets the following: has 
not undergone a hysterectomy or bilateral oophorectomy or has not been naturally postmenopausal for at least one year. 


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6 Including albumin, total protein, total bilirubin, ALT, AST, alkaline phosphatase, bicarbonate, sodium, potassium, chloride, creatinine, BUN, and glucose. 
7  Blood will be collected within three hours prior to BRB administration and at two hours (+/- 30 minutes) after first dose of BRBs. 
8  Study blood methylation samples will be collected within three hours prior to BRB administration. 
9  Urine will be collected within three hours prior to BRB administration and at three hours (+/- 30 minutes) after first dose of BRBs. 
10 If the patient is tolerating BRBs well and is benefiting from therapy, he or she will continue treatment for a total maximum of 12 cycles. 
11 All adverse events will be followed with appropriate medical management from the date the patient takes their first BRB dose until 30 days following 
the last dose of treatment. AEs are monitored continuously from the first dose of treatment to 30 days’ post last dose 
12 Benefiting from therapy (cycle 4 disease assessment) defined as CR, PR, HI, Stable disease with no disease progression (see appendix    
     2). Benefiting from therapy (cycle 7 disease assessment) defined as CR, PR, or HI (see appendix 2).) 
13 Capture transfusion history from eight weeks prior to day 1 of BRB treatment. 
14 Refer to appendix 6. 
15 Refer to appendix 4. 
16 Refer to appendix 1. 
 


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TABLE OF CONTENTS 
 
PROTOCOL SUMMARY ..................................................................................................................................... 4 
SCHEMA ............................................................................................................................................................. 8 
STUDY CALENDAR ........................................................................................................................................... 9 
TABLE OF CONTENTS .................................................................................................................................... 11 
LIST OF ABBREVIATIONS .............................................................................................................................. 14 
1  BACKGROUND ............................................................................................................................................ 16 
2  HYPOTHESIS AND OBJECTIVES ............................................................................................................... 20 
2.1  Primary Objectives ................................................................................................................................... 20 
2.2  Secondary Objectives .............................................................................................................................. 20 
3  STUDY DESIGN ............................................................................................................................................ 20 
3.1  General Description .................................................................................................................................. 20 
3.2  Number of Patients ................................................................................................................................... 21 
3.3  Primary Endpoint(s) .................................................................................................................................. 21 
3.4  Secondary Endpoint(s) ............................................................................................................................. 21 
3.5  Study Timeline .......................................................................................................................................... 21 
3.6  Study Completion ..................................................................................................................................... 21 
4  PATIENT SELECTION .................................................................................................................................. 21 
4.1  Inclusion Criteria ...................................................................................................................................... 21 
4.2  Exclusion Criteria ..................................................................................................................................... 22 
5  STUDY ENTRY AND WITHDRAWAL; STUDY PROCEDURES ................................................................... 23 
5.1  Screening Tests and Procedures ............................................................................................................ 23 
5.2  Enrollment Process .................................................................................................................................. 23 
5.3  Pretreatment Period .................................................................................................................................. 23 
5.4  Study Procedures During Treatment ....................................................................................................... 24 
5.5  Follow-up .................................................................................................................................................. 25 
5.6  Study Withdrawal Procedures ................................................................................................................. 25 
6  TREATMENT PLAN ...................................................................................................................................... 26 
6.1  Investigational Agent Administration ...................................................................................................... 26 
6.2  Dosing Delays/Dose Modifications .......................................................................................................... 26 
6.3  General Concomitant Medication and Supportive Care Guidelines ...................................................... 27 
6.4  Dietary Restrictions .................................................................................................................................. 27 
6.5  Prohibited Medications ............................................................................................................................. 27 


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6.6  Monitoring Subject Compliance .............................................................................................................. 27 
6.7  Follow-Up Period ...................................................................................................................................... 27 
7  ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS .................................................. 27 
7.1  Defining and reporting an Adverse Event ............................................................................................... 27 
7.2  Defining and reporting a Serious Adverse Event (SAE) ......................................................................... 28 
7.3  Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) .................................................. 29 
7.4  Procedure for Reporting Drug Exposure during Pregnancy and Birth Events ..................................... 29 
7.5  Common AE List ....................................................................................................................................... 30 
8  PHARMACEUTICAL INFORMATION ........................................................................................................... 31 
8.1  Black Raspberries .................................................................................................................................... 31 
9  REPORTING AND DOCUMENTING RESULTS (MEASUREMENT OF EFFECT) ........................................ 32 
9.1  Evaluation of Efficacy (or Activity) Definitions ....................................................................................... 32 
9.2  Methods for Evaluation ............................................................................................................................ 33 
9.3  Surrogate Endpoint Biomarkers .............................................................................................................. 33 
9.4  Response Criteria ..................................................................................................................................... 34 
9.5  Evaluation of Safety ................................................................................................................................. 34 
10  STATISTICAL CONSIDERATIONS ............................................................................................................ 34 
11  DATA AND SAFETY MONITORING PLAN (DSMP) ................................................................................... 35 
11.1  Data and Safety Management Overview ................................................................................................ 35 
11.2  Study Team ............................................................................................................................................. 35 
11.3  Quality Assurance .................................................................................................................................. 35 
11.4  Clinical Trials Office ............................................................................................................................... 35 
11.5  DSMC ....................................................................................................................................................... 35 
12  REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT .................................................... 36 
12.1  Ethical Standard ..................................................................................................................................... 36 
12.2  Regulatory Compliance .......................................................................................................................... 36 
12.3  Institutional Review Board ..................................................................................................................... 36 
12.4  Informed Consent Process .................................................................................................................... 36 
12.5  Prestudy Documentation ........................................................................................................................ 37 
12.6  Protection of Human Subjects ............................................................................................................... 37 
12.7  Investigator Compliance ........................................................................................................................ 37 
12.8  Onsite Audits .......................................................................................................................................... 38 
13  DATA HANDLING AND RECORD KEEPING ............................................................................................. 38 
13.1  Overview ................................................................................................................................................. 38 


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13.2  Case Report Forms ................................................................................................................................. 38 
13.3  Handling and Documentation of Clinical Supplies ............................................................................... 38 
13.4  Study Record Retention ......................................................................................................................... 39 
14  REFERENCES ............................................................................................................................................ 40 
APPENDIX 1.  PERFORMANCE STATUS CRITERIA ...................................................................................... 43 
APPENDIX 2.  MODIFIED IWG RESPONSE CRITERIA ................................................................................... 44 
APPENDIX 3.  BLACK RASPBERRIES NUTRIENT LEVELS AND POTENTIAL CHEMOPREVENTIVE 
COMPONENTS .......................................................................................................................... 46 
APPENDIX 4.  SPECIMEN COLLECTION ........................................................................................................ 48 
APPENDIX 5. DRUG DIARY ............................................................................................................................. 51 
APPENDIX 6. PHENOLIC-RICH FOOD DIARIES ............................................................................................. 52 
APPENDIX 7. PREGNANCY FORM ................................................................................................................. 53 
 
 


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LIST OF ABBREVIATIONS 
 
ACF 
aberrant crypt foci 
AE 
adverse event 
ALP 
alkaline phosphatase 
AML 
acute myelogenous leukemia 
AOM 
azoxymethane 
BELT 
bin-based enrichment level threshold 
BID 
bis in die or twice a day 
BRB(s) 
black raspberries 
BUN 
blood urea nitrogen 
CAD 
collisionally activated dissociation 
CBC 
complete blood cell (count) 
CpG 
—C—phosphate—G— 
CRC 
clinical research coordinator 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
CTO 
Clinical Trials Office 
DMR 
differentially methylated region 
DSMB 
Data and Safety Monitoring Board 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
 
 


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ESI 
Electrospray Ionization 
FAB 
French-American-British 
FCBP 
female of childbearing potential 
FDA 
Food and Drug Administration 
FDR 
false discovery rate 
GCP 
Good Clinical Practice 
gm 
gram 
HGB 
hemoglobin 
HIV 
human immunodeficiency virus 
HMAs 
hypomethylating agents 
HSCT 
hematopoietic stem cell transplantation 
ICH 
International Conference on Harmonization 
IND 
investigational new drug application 
IP 
investigational product 
IPSS 
International Prognostic Scoring System 
IRB 
Institutional Review Board 
IWG 
International Working Group 
iwCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IV 
intravenous 
LDH 
lactate dehydrogenase 
MBDCap Methyl-Binding-Domain–Capture 
MCW 
Medical College of Wisconsin 
MCWCC 
Medical College of Wisconsin Cancer Center 
MDS 
myelodysplastic syndrome 
MPN 
myeloproliferative neoplasm 
MS/MS 
mass spectrometry 


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NCI 
National Cancer Institute 
NMBA 
N-nitrosomethylbenzylamine 
PBS 
Phosphate-buffered saline 
PCNA 
proliferating cell nuclear antigen 
PO 
per os (by mouth, orally) 
QOL 
quality of life 
RBC 
red blood cell (count) 
SAE 
serious adverse event 
SIM 
selective ion monitoring 
TBRC 
Scientific Review Committee Translational biomedical 
research center 
TSS 
transcription start site 
UPIRSO 
unanticipated problems involving risks to subjects or others 
UPLC 
ultra-performance liquid chromatography 
WBC 
white blood cell (count) 
Wnt 
Wingless-type MMTV integration site family member 


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1  BACKGROUND 
Myelodysplastic Syndromes (MDS) 
 
Myelodysplastic syndromes (MDS) are a group of bone marrow disorders characterized by 
progressive cytopenias and progression to acute myeloid leukemia (AML). (1) Each year, an 
estimated 10,000 new patients with MDS above the age of 65 are diagnosed. (2) Clinicians use 
the French-American-British (FAB) and the World Health Organization (WHO) systems, in 
addition to the International Prognostic Scoring System (IPSS), to classify MDS. (3) The latter is 
the most commonly used prognostic scoring system, and it includes the percentage of 
blasts/morphology, number of cytopenias and cytogenetic abnormalities. The IPSS system 
divides patients into four prognostic groups — low, intermediate-1, intermediate-2 and high-risk 
disease. The median survival is 4.8, 2.7, 1.1 and 0.5 years for patients >60 years old with low, 
intermediate-1, intermediate-2 and high-risk disease, respectively. The median age at diagnosis 
for patients with MDS is 76 years and 86% of patients are above the age of 65. (2) As most 
patients with MDS are older, therapy with a low toxicity would be desirable for this patient 
population. 
 
Current therapy for MDS 
 
Hematopoietic stem cell transplantation (HSCT) remains the only cure for MDS. Clinicians also 
have other therapy options that correspond with disease risk in treating MDS. For example, 
supportive care, which may consist of transfusions and growth factors therapy, remains the 
backbone of low-risk MDS treatment. (4) 5q- syndrome patients are treated with antithymocyte 
globulin therapy and lenalidomide. (5) Azacitidine or decitabine (6,7) are first-line therapies for 
high-risk disease patients who can tolerate them. Azacitidine, decitabine, and lenalidomide are 
FDA-approved therapies for MDS treatment. The first two drugs are hypomethylating agents 
(HMAs). HMAs have yielded a response rate ranging from 30–50% for an average of 12 months 
in MDS patients. 
 
Treatment of MDS or MDS/MPN with Hypomethylating Agents 
 
Genetic and epigenetic alterations are the molecular hallmarks of cancer. Genetic alterations 
include mutations or deletions that alter the primary sequence of DNA. In contrast, epigenetic 
alterations result from biochemical modification of the composition of chromatin. DNA 
methylation and alteration of the histone code are two epigenetic changes that can result in 
transcriptional deregulation and gene silencing. Reversal of this process with hypomethylating 
agents results not only in gene expression reactivation but in killing of leukemic cells, a 
phenomenon that has been widely exploited in human clinical trials. (8–10) Hypomethylating 
agents 5-azacytidine (azacitidine) and 5-aza-2'-deoxycytidine (decitabine) are approved by the 
US Food and Drug Administration (FDA) for the treatment of myelodysplastic syndromes (MDS). 
Both agents were initially developed as cytarabine derivatives with initially disappointing results, 
especially at higher concentrations. However, in follow-up studies and with lower-dose 
schedules, both drugs have shown efficacy in MDS. 
 
In a randomized Phase III trial (AZA-001) conducted by Fenaux et al (6) in patients with high-risk 
MDS, patients were randomized to receive azacitidine (75 mg/m2 per day for seven days every 
28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive 
chemotherapy, as selected by investigators before randomization). At a median follow-up of 21.1 
months, the median overall survival was 24.5 months (9.9 – not reached) for the azacitidine 


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group versus 15.0 months (5.6 – 24.1 months) for the conventional care group (p=0.0001). 
Azacitidine was given for a median of nine cycles (4–15), and 86% of the patients who received 
azacitidine remained on 75 mg/m2 per day throughout the study with no dose adjustments. In 
patients with −7/del(7q), the median overall survival was 13.1 months (3.9 – 24.5 months) in the 
azacitidine group (n=30) compared with 4.6 months in the conventional care group. The median 
time to AML transformation was 17.8 months in the azacitidine group compared with 11.5 months 
in the conventional care group (CCR) (p < 0.0001). The duration of hematological response (CR, 
PR and any hematological improvement) was also significantly longer in the azacitidine group 
(median 13.6 months) than in the CCR group (5.2 months; p=0.0002). Median duration of CR 
plus PR in the azacitidine group was 3.2 months versus 3.0 months (p=0.48) in the CCR group. 
Factors affecting survival in that study were PS, presence of circulating blasts, RBC TD ≥ 4 units 
in eight weeks and cytogenetics. Based on these four factors, patients were subdivided into low- 
intermediate- and high-risk groups with median survival of not reached, 15 months and 6.1 
months, respectively. (11) This confirmed that treatment with azacitidine prolongs overall survival 
and lowers the risk of progression to AML in patients with higher-risk MDS compared with 
treatment with CCR. 
 
Decitabine was evaluated in two large phase III trials. (12,13) In the first study performed in the 
US, 170 patients were randomized to receive either BSC or decitabine 15 mg/m2 three times 
daily x 3 days repeated every six weeks. The ORR for patients receiving decitabine was 30% 
(9%CR, 8% PR and13% HI). (12) Using a similar decitabine schedule, Lubbert et al. reported an  
ORR of 34% (CR13%, PR 6%, and HI 15%). (13) However, in both studies there was no 
difference in overall survival in patients receiving decitabine in this schedule when compared to 
BSC. In order to better define the best dose schedule for decitabine, Kantarjian et al.  
randomized patients with MDS to one of three decitabine schedules: 20 mg/m2 intravenously 
daily for five days, 20mg/m2 subcutaneously daily for five days and 10 mg/m2 intravenously daily 
for 10 days. (14) In that study, patients randomized to the 20 mg/m2 intravenously daily for five  
days had the highest CR rate (39%) and this was chosen as the basis for a multicenter phase II 
study, the ADOPT trial. (7) In the ADOPT trial, decitabine 20 mg/m2 was administered to 99 
patients with MDS. As previously mentioned, the ORR was 51% (17% CR, 15 mCR and 18 HI). 
Most responses were seen after two cycles (82%), and the median duration of response was 10 
months. The -one-year survival was 66% and the median overall survival was 19.4 months. 
 
The myelodysplastic syndrome/myeloproliferative neoplasm category was introduced in the 
thirdrevision on the WHO classification. This group includes chronic myelomonocytic leukemia 
(CMML), atypical CML, MDS/MPN unclassified and juvenile myelomonocytic leukemia (JMML). 
Hypomethylating agents have shown in the therapy of those diseases (34-35).  
 
Azacitidine and decitabine are associated with significant toxicities 
 
Although both azacitidine and decitabine are effective therapies for patients with MDS, they are 
associated with significant toxicities. In the AZA-001 trial (6) previously mentioned, 91%, 85% 
and 57% of patients developed grade 3 or 4 neutropenia, anemia or thrombocytopenia,  
respectively. In the ADOPT trial, (7) 31%, 18% and 12% of patients receiving decitabine 
developed grade 3 or 4 neutropenia, thrombocytopenia and anemia, respectively. In addition, 
other nonhematologic toxicity occurring in > 10% of patients included fatigue, nausea, fever, 
diarrhea, constipation, pneumonia, vomiting and chills. 
 
Even though the quality of life of patients receiving azacitidine or decitabine is better when 
compared with patients receiving BSC only, (15) it is still significantly affected by frequent 
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month as long as the patient is responding and tolerating the therapy. Similarly, decitabine is 
administered for five consecutive days IV every month as long as the patient is responding and 
tolerating the therapy. Both those schedules place a large burden on patients and affect their 
quality of life. 
 
Black raspberries as hypomethylating agents 
 
Black raspberries have been shown to have hypomethylating effects in colon cancer patients.  
(16) In a study, 20 patients with colorectal cancer were treated with BRBs before surgical 
resection of the tumor. BRBs exerted hypomethylating effects in the adjacent normal mucosa in 
all patients and in carcinomas only in patients with > 4 weeks of therapy. (17) These 
observations on the hypomethylating effects of BRBs with prolonged therapy are consistent with 
what is seen in patients with MDS treated with hypomethylating agents. In almost all patients, two 
to three cycles are needed (up to six cycles) before a response is seen in patients receiving 
either azacitidine or decitabine. This hypomethylating effect in colon cancer is most likely due to 
local effect of the BRBs on colon cells. However, BRBs are systemically absorbed and have 
been shown to have a systemic hypomethylating effect. In the colon cancer study previously 
mentioned, none of the patients in that study had detectable urinary levels of BRB-derived 
anthocyanins before therapy, while all had detectable levels in urine after administration of BRBs, 
confirming the systemic absorption of BRBs. In addition, the systemic hypomethylating effects of 
BRBs have been demonstrated in IL-10 knockout mice. In that study, BRBs reversed aberrant 
promoter methylation of genes in the Wnt pathway in the colon, bone marrow and spleen of mice.  
(16) This confirmed the absorption and hypomethylation effect of BRBs in the colon, spleen and 
bone marrow of mice fed a 5% BRB powder diet for four weeks. (18)  
 
In a study by Silverman et al., the median time to any response was two cycles (range 1–16). 
Overall, 91% of patients achieved best response by six cycles. Based on that, we will discontinue 
therapy for patients who do not achieve a response after six cycles. Response defined as CR, PR 
or HI (see appendix 2). (364)  Our aim in this study is to evaluate the systemic effects of BRBs in 
patients with MDS or MDS/MPN. 
 
Black raspberry dose 
 
One of the most desirable features of a chemopreventive agent is little or no toxicity at 
concentrations producing chemopreventive efficacy. The toxicity of BRBs has been evaluated in 
rats fed a synthetic diet (AIN-76A diet) plus either 5% or 10% BRB powder by weight (w/w) for up 
to nine months. (19) These percentages of BRB powder in a rat diet would be equivalent to 
approximately 0.9 to 1.8 ounces (25.5 to 51 grams) of BRB powder in the daily human diet, as 
calculated on a body surface area basis. Histopathologic studies indicated that these BRB diets 
did not produce toxic effects in any major organs of the animals, and there were no significant 
differences in either body weight or food consumption between rats on either of the BRB- 
supplemented diets versus control rats on the AIN-76A-alone diet during the nine-month 
treatment. (19) 
 
In humans, a phase I trial evaluated the safety and tolerability of BRB powder (45 g as a slurry in 
water daily for seven days) in healthy participants and results suggested that berries were well 
tolerated. In a subsequent pilot study of oral BRB powder (32 or 45g/day for six months) in 
Barrett's esophagus patients, BRBs were tolerated as well. (20) In that study, three of the 20 
patients enrolled reported side effects that were likely related to BRBs. The reported side effects 
were epigastric pain, diarrhea and constipation; all were grade I. 
 
Further, the daily dose of BRBs at 60 g (20 g x 3) was well tolerated in colon cancer patients 


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(60g/day for one to nine weeks) and BRBs produced hypomethylating effects in colon cancer 
patients received average four weeks of BRBs in comparison to those received two weeks of 
BRBs; suggesting accumulating effects. (17) Also, using a daily dose of 60 g, BRBs were 
tolerated in patients with familial adenomatous polyposis (FAP) in a nine-month intervention 
study, and BRBs led to fewer and smaller polyps through hypomethylation. (21) The most recent 
unpublished data suggest that 50 g BRBs per day (25 g x 2) were tolerated in ulcerative colitis 
patients for a period of six months. Accordingly, we chose 50 g (25g x 2) daily BRBs to be tested 
in MDS patients. We anticipated that BRBs will be tolerated and exert hypomethylating effects in 
MDS patients. 
 
Preclinical Data 
 
As stated above, many berry components have demonstrated chemopreventive activity in animals. 
 
Kresty et al. reported in 2001 (22) that freeze-dried BRBs are a source of multiple nutrient and 
non-nutritive compounds, including vitamins A, C, E and folic acid; calcium; selenium; β- 
sitosterol, ellagic acid, ferulic acid, quercetin and certain anthocyanins (see Appendix 3). Many 
of these agents showed chemopreventive activity, both in vitro and in animal models. Their 
modes of action include inhibition of carcinogen activation and stimulation of carcinogen 
detoxification. In addition, they reduce the binding of the reactive metabolites of carcinogens to 
DNA, down regulate genes associated with cancer development, upregulate of genes involved 
in cell-cycle control and stimulate apoptosis and inhibit angiogenesis (19,23–25). 
 
In addition, ellagitannins in raspberries have been shown to inhibit phorbol ester-induced DNA 
synthesis and ornithine decarboxylase activity. (26) More specifically, the inhibition of 
mutagenesis and carcinogenesis by the ellagic acid in ellagitannins involves inhibition of 
carcinogen activation, stimulation of carcinogen detoxification, interference in the binding of 
reactive metabolites of carcinogens to DNA and downregulation of certain genes associated 
with cancer development. (25,27,28) 
 
Black raspberries’ chemopreventive effects were clearly demonstrated in a study by Harris et al. 
The investigators first induced colon tumors in the Fischer 344 rat by intraperitoneal 
administration of the chemical carcinogen azoxymethane (AOM). BRBs markedly decreased 
aberrant crypt foci (ACF), the precursor of invasive colon tumors, in the rat. ACF multiplicity 
decreased 36%, 24% and 21% in the 2.5%, 5% and 10% BRB diet groups, respectively, relative 
to the AOM-only group. Total tumor multiplicity declined 42%, 45% and 71% in these same 
groups, and decreases in overall tumor burden (28%, 42% and 75%) were observed (29). 
 
Other studies evidenced that dietary freeze-dried strawberries and BRBs inhibited N- 
nitrosomethylbenzylamine (NMBA)-induced tumors in the rat esophagus (22,30). Both berry 
types produced an approximate 40–60% reduction in esophageal tumor multiplicity and were 
capable of suppressing the development of preneoplastic lesions (hyperplasia and both low- 
and high-grade dysplasia) into papillomas. The inhibitory effects of the berries were associated 
with a reduction in the rate of proliferation of preneoplastic cells, as determined by 
immunohistochemical quantitation of the PCNA labeling index in the esophagi of rats treated 
with berries plus NMBA versus those treated with NMBA alone. Recently, a laboratory showed 
that BRBs downregulate COX-2 and iNOS expression and activities in NMBA-treated rat 
esophagus (31) and BRB extracts have been shown to downregulate the transcription 
activators, activator protein-1 (AP-1) and nuclear factor kappa B (NF-кB) in cultured mouse 
epidermal cells. (32) The protective effects of BRBs on esophageal tumorigenesis may be 
partially due to ellagic acid content, but cannot be attributed to ellagic acid alone. (22) 
 


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2  HYPOTHESIS AND OBJECTIVES 
2.1  Primary Objectives 
 
To evaluate the potential hypomethylating effects of freeze-dried black raspberries (BRBs) in 
the peripheral blood of patients with myelodysplastic syndrome or myelodysplastic syndrome/ 
myeloproliferative neoplasms(MDS/MPN) after three cycles of BRB administration. 
 
2.2  Secondary Objectives 
 
1. To evaluate the toxicity of BRBs in patients with MDS or MDS/MPN. 
 
2. To evaluate the hematological response according to modified IWG criteria (Appendix 2) 
in patients with MDS or MDS/MPN regardless of the initial blood count. 
 
3. To evaluate the anthocyanin concentrations in peripheral blood of patients prior to and 
after administration of BRB powder on Cycle 1 Day 1 of treatment. 
 
 
3  STUDY DESIGN 
3.1  General Description 
 
This is a phase II single-group pilot study. This trial is designed to evaluate efficacy and 
methylation. This study’s overarching aim is to evaluate the systemic effects of BRBs in 
patients with MDS or MDS/MPN. Eighteen patients with MDS or MDS/MPN will be treated with 
25 gm (2x/day) of BRB powder taken orally in 8 ounces of water. If the patient is unable to 
tolerate the taste of the BRB powder mixed in water, he or she may mix it with 8 ounces of milk, 
ice cream or a smoothie. 
 
Anthocyanins in the blood will be measured within three hours prior to BRB administration, and 
two hours (+/- 30 minutes) after the first dose. Urine anthocyanins will be measured within three 
hours prior to BRB administration and three hours (+/-30 minutes) after the first BRB dose. Both 
of those time points were chosen based on previous studies demonstrating that the maximum 
concentrations of anthocyanins and ellagic acid in plasma occurred at one to two hours, and 
maximum quantities in urine appeared from zero to four hours. (20) Methylation status will be 
measured within three hours prior to BRB administration in cycles 1–4, 7, 10 and at the end of 
treatment visit. 
 
Patients will receive oral BRBs while receiving their supportive care for a period of at least 
three cycles. At cycles 4 and 7, day 1, the patient will be assessed for response (Appendix 2) 
and toxicity. If the patient is tolerating BRBs well and is benefiting from therapy, he or she will 
continue treatment for a total maximum of 12 cycles. Tolerating well is defined as no grade 3 
or 4 toxicity. 
 
*Benefiting from therapy (for cycle 3 disease assessment) defined as CR, PR, HI, stable 
disease with no disease progression (see Appendix 2). 
**Benefiting from therapy (for cycle 6 disease assessment) defined as CR, PR or HI (see 
Appendix 2). 
 
 


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3.2  Number of Patients 
 
The study team will enroll 18 MDS or MDS/MPN patients. 
 
 
3.3  Primary Endpoint(s) 
 
To evaluate the potential hypomethylating effects of freeze-dried black raspberries (BRBs) in 
the peripheral blood of patients with myelodysplastic syndrome or myelodysplastic syndrome/ 
myeloproliferative neoplasms (MDS/MPN) after three cycles of BRB administration. 
 
3.4  Secondary Endpoint(s) 
 
1. To determine the toxicity of BRB by assessing the incidence of adverse events related to 
BRB. 
 
2. The patient’s best clinical response will be assessed, based on a modified International 
Working Group (IWG) response criteria (erythroid, platelet, neutrophil) (Appendix 2) in 
myelodysplastic syndrome or myelodysplastic syndrome/ myeloproliferative neoplasms 
(MDS/MPN). 
 
3. To evaluate the anthocyanin concentrations in peripheral blood of patients prior to and 
after administration of BRB powder on Cycle 1 Day 1 of treatment. 
 
3.5  Study Timeline 
 
Patients may continue BRB treatment for a maximum of 12 cycles from the time of study entry. 
 
3.6  Study Completion 
 
The study will reach accrual approximately 24 months from when the first patient is dosed. 
 
 
4  PATIENT SELECTION 
Eligibility Criteria 
 
The written informed consent must be obtained from the patient prior to enrollment and any 
study-specific procedures. Patients must have baseline evaluations performed prior to 
enrollment and the first study drug dose. The following criteria apply to all patients enrolled onto 
the study unless otherwise specified. 
 
4.1  Inclusion Criteria 
 
A potential subject must meet all the following inclusion criteria to be eligible to participate in 
the study. 
 
1. Patients must have a confirmed diagnosis of myelodysplastic syndrome or 
myelodysplastic syndrome/ myeloproliferative neoplasms (MDS/MPN) proven by bone 
marrow biopsy/aspirate. 


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2. Patients with cytopenias (blood cell counts lower than the institutional lower limit of normal 
within the eight weeks prior to the study) who are receiving or received: 
 
• 
red blood cell transfusions 
• 
observation 
• 
platelet transfusions 
• 
erythropoietin 
• 
granulocyte colony-stimulating factors 
• 
granulocyte-macrophage colony-stimulating factors 
• 
hydrea 
3. Age >18 years. 
4. Predicted life expectancy of at least 12 weeks. 
5. Patients should be expected to stay on the same therapy for the period of the study. 
6. Patients who do not have an indication for and/or are believed to be unable to tolerate a 
hypomethylating agent are eligible for the study. 
7. Reproductive requirements: 
Female patients must meet one of the following: 
 
Postmenopausal for at least one year before the screening visit, or 
 
Surgically sterile, or 
 
If they are of childbearing potential, agree to practice two effective methods of 
contraception from the time of signing of the informed consent form through 30 days 
after the last dose of study drug, AND 
 
Must also adhere to the guidelines of any treatment-specific pregnancy prevention 
program, if applicable, or 
 
Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable contraception methods.) 
 
Male patients, even if surgically sterilized (i.e., status postvasectomy), must agree to one of 
the following: 
• Practice effective barrier contraception during the entire study treatment period and 
through 30 days after the last study drug dose, OR 
• Must also adhere to the guidelines of any treatment-specific pregnancy prevention 
program, if applicable, OR 
• Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of contraception.) 
8. Ability to understand a written informed consent document, and the willingness to sign it. 
 
4.2  Exclusion Criteria 
 
A potential subject who meets any of the following exclusion criteria is ineligible to participate in 
the study. 
1. Previously received hypomethylating agents. 
2. Allergy to black raspberries. 
3. Inability to swallow oral medication. 


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4. Inability or unwillingness to comply with the BRB administration requirements. 
5. Uncontrolled intercurrent illness, including, but not limited to, symptomatic congestive heart 
failure, or psychiatric illness/social situations, that, in the treating investigator’s discretion, 
would limit compliance with study requirements. Concurrent active malignancy is not an 
exclusion criterion. 
6. Active infection not well controlled by antibacterial or antiviral therapy. 
7. Pregnant or lactating women. 
8. Participation in clinical trials with other investigational agents not included in this trial, within 
14 days of the start of this trial and throughout the duration of this trial. 
9. Patients with allergies to other members of the Rosacea family, including but not 
limited to apple, almond, apricot, cloudberry, blackberry, etc. 
 
5  STUDY ENTRY AND WITHDRAWAL; STUDY PROCEDURES 
5.1  Screening Tests and Procedures 
 
The study-specific assessments are detailed in this section and outlined in the Study Calendar. 
Screening assessments, unless otherwise specified, must be performed within 28 days prior to 
the day 1 visit. All on-study visit procedures are allowed a window of ± 4 days unless otherwise 
noted. Treatment or visit delays for public holidays or weather conditions do not constitute a 
protocol violation. 
 
A written, signed informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. 
 
All patients who are consented will be registered in OnCore®, the MCW Cancer Center Clinical 
Trial Management System. The system is password protected and meets HIPAA requirements. 
Once a patient has been consented, they will be assigned a screening ID by the clinical 
research coordinator that will be used to identify them throughout the study. The patient 
identifier will start with BRB and then chronologically numbered there after (BRB-001, BRB-002, 
BRB-003, etc.). 
 
5.2  Enrollment Process 
 
A subject will be considered enrolled onto the study once they have signed consent, have 
successfully met all screening criteria, the eligibility criteria has been reviewed and accepted by 
the PI or a sub-investigator, and entered into OnCore. Contact Dr. Atallah with any eligibility 
questions at eatallah@mcw.edu. 
 
5.3  Pretreatment Period 
 
The screening procedures and assessments must be completed within 28 days of the Day 1 
visit unless otherwise specified in the study parameter schedule. 
 
Refer to the study calendar for specifics: 
 
• 
Informed consent 
• 
Demographics 


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• 
Inclusion/exclusion criteria 
• 
Medical history 
• 
Medication history 
• 
Concomitant medications 
• 
ECOG performance status 
• 
Height 
• 
Physical examination 
• 
Complete blood count (CBC) with differential and platelet count 
• 
Serum or urine pregnancy test (for women of childbearing potential) 
• 
Serum chemistry panel, including: 
Alkaline phosphatase, aspartate aminotransferase/alanine aminotransferase (ALT/AST), 
total bilirubin, blood urea nitrogen (BUN), creatinine, total protein, albumin, potassium, 
sodium, chloride, bicarbonate, glucose. 
 
5.4  Study Procedures During Treatment 
 
Patients must meet eligibility criteria eligible on Day 1 and be enrolled prior to BRB treatment. 
BRB treatment should start within 14 days of enrollment. 
 
Study Procedures, Cycle 1 Day 1 (refer to study calendar for specifics) 
 
• 
Dispense BRB (Appendix 5) 
• 
Concomitant medications 
• 
Diet assessment (Appendix 6) 
• 
Weight 
• 
Adverse event assessment 
• 
Physical exam 
• 
Complete blood count (CBC) with differential and platelet count 
• 
Study serum sample for anthocyanin level 
• 
Study blood methylation samples 
• 
Study urine samples 
• 
Transfusion history 
 
Study Procedures, Cycles 2-3, Day 1 (refer to study calendar for specifics) 
 
These procedures must be completed cycles 2 - 3, day 1 (+/- 4 days). 
 
• 
Dispense BRB (Appendix 5) 
• 
Concomitant medications 
• 
Diet assessment (Appendix 6) 
• 
Adverse event assessment 
• 
Complete blood count (CBC) with differential and platelet count 
• 
Study blood methylation samples  
• 
Transfusion history 
 
Study Procedures, Cycles 4 & 7, Day 1 (refer to study calendar for specifics) 
 
These procedures must be completed cycles 4 and 7, day 1. (+/- 4 days). 
 
• 
Dispense BRB (Appendix 5) 


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• 
Concomitant medications 
• 
Diet assessment (Appendix 6) 
• 
ECOG performance status 
• 
Weight 
• 
Adverse event assessment 
• 
Complete blood count (CBC) with differential and platelet count 
• 
Serum chemistry panel, including: 
Alkaline phosphatase, aspartate aminotransferase/alanine aminotransferase (ALT/AST), 
total bilirubin, blood urea nitrogen (BUN), creatinine, total protein, albumin, potassium, 
sodium, chloride, bicarbonate, glucose 
• 
Study blood methylation samples 
• 
Disease response assessment (Appendix 2) 
• 
Transfusion history 
 
Study Procedures, Cycles 5-6 & 8-12, Day 1 (refer to study calendar for specifics) 
 
These procedures must be completed cycles 5–6 and 8–12, day 1 (+/- 4 days). 
 
• 
Dispense BRB (Appendix 5) 
• 
Concomitant medications 
• 
Diet assessment (Appendix 6) 
• 
Weight 
• 
Adverse event assessment 
• 
Complete blood count (CBC) with differential and platelet count 
• 
Study blood methylation samples (only cycle 10) 
• 
Transfusion history 
 
5.5  Follow-up 
 
Perform follow-up procedures 30 days (+4 days) after study treatment discontinuation. 
 
• 
Concomitant medications 
• 
ECOG performance status 
• 
Weight 
• 
Adverse event assessment 
• 
Physical exam 
• 
Complete blood count (CBC) with differential and platelet count 
• 
Serum chemistry panel, including: 
Alkaline phosphatase, aspartate aminotransferase/alanine aminotransferase (ALT/AST), 
total bilirubin, blood urea nitrogen (BUN), creatinine, total protein, albumin, potassium, 
sodium, chloride, bicarbonate, glucose 
• 
Study blood methylation samples 
• 
Disease response assessment 
• 
Transfusion history 
 
5.6  Study Withdrawal Procedures 
Patients may continue treatment for one year from the time of study entry. 
 
In the absence of treatment delays due to adverse events, treatment may continue until: 


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• 
Disease progression, as defined by the modified IWG criteria (Appendix 2) 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the investigator’s judgment. 
• 
Intercurrent illness that prevents further treatment administration 
• 
Patient decides to withdraw from the study 
• 
Significant patient noncompliance with protocol 
• 
Unacceptable adverse event(s) per PI discretion 
 
6  TREATMENT PLAN 
6.1  Investigational Agent Administration 
 
Treatment will be administered on an outpatient basis. MCW will obtain black raspberry powder 
directly from BerriProducts, Inc. in Corvallis, Oregon as study supply. Patients will be treated 
with 25 gm (2x/day) of BRB powder taken orally in 8 ounces of water. If the patient is tolerating 
and benefiting from treatment after three and six cycles, then, he or she will continue treatment 
for a total maximum of 12 cycles. 
 
Study Drug 
Dose 
Route 
Schedule 
Cycle 
Length 
Black 
Raspberries 
(Freeze-dried 
powder) 
25 grams 
Oral 
Twice a day 
(each dose 
separated by 
at least 6 
hours) 
4 weeks 
(28 days) 
 
6.2  Dosing Delays/Dose Modifications 
 
Treatment or visit delays for public holidays or weather conditions do not constitute a protocol 
violation. 
 
See the table below for dose modification requirements for nonhematological toxicities deemed 
clinically significant and related to BRB treatment by the treating physician. 
 
Dose Modifications 
Dose Level 
Dose of Study Drug 
0 
25 grams twice a day with each dose separated by at least six hours 
(mixed in 8 ounces of water)1 
1 
≥ grade 1 toxicity related to BRB treatment and unable to tolerate then 
dose reduce to 25 grams QD 
2 
≥ grade 2 toxicity or grade 3 allergic reaction related to BRB treatment 
and/or unable to tolerate, withdraw patient from study 
Footnotes1 
If unable to tolerate the taste, mix BRB with milk, ice cream or 
smoothie. 
 
Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse 
Events Version 4.0 (CTCAE v4.0). 
 
 
 


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6.3  General Concomitant Medication and Supportive Care Guidelines 
 
The treating physician will use standard supportive care to control symptoms and improve 
quality of life. These may include: 
 
 
Transfusions 
 
Use of growth factors 
 
Antibiotics 
 
6.4  Dietary Restrictions 
 
There are no dietary restrictions. Patients will take BRB powder orally in 8 ounces of water. If 
the patient is unable to tolerate the taste of the BRB powder mixed in water, then, he or she 
may mix it with 8 ounces of milk, ice cream or a smoothie. 
 
6.5  Prohibited Medications 
 
As noted in the eligibility section 4, patients should not be receiving hypomethylating agents. In 
addition, they should not be receiving other chemotherapy/radiation, or participating in clinical 
trials with other investigational agents not included in this trial, within 14 days of the start of this 
trial and throughout the duration of this trial. 
 
6.6  Monitoring Subject Compliance 
 
Black raspberries will be dispensed only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s). The appropriate study personnel will maintain 
records of product receipt and dispensing. The patient will complete a drug diary to ensure 
compliance. 
 
The patient will be seen every cycle by a healthcare professional or study staff for compliance. 
Patients will also be required to complete a food diary at home while taking BRBs and 
instructed to return the diary to clinic for assessment every cycle. 
 
6.7  Follow-Up Period 
 
Patients removed from the study treatment for unacceptable SAEs will be followed until 
resolution or stabilization of the adverse event. 
 
7  ADVERSE EVENTS: DEFINITIONS AND REPORTING 
REQUIREMENTS 
7.1  Defining and reporting an Adverse Event 
 
Definition. Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE. 
 
Prior to the trial. Planned hospital admissions or surgical procedures for an illness or disease 
that existed before the patient was enrolled in the trial are not to be considered AEs unless the 
condition deteriorated in an unexpected manner during the trial (e.g. surgery was performed 
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Reporting source. AEs may be spontaneously reported by the patient and/or in response to an 
open question from study personnel or revealed by observation, physical examination or other 
diagnostic procedures. 
 
For non-serious AEs, the investigator must determine both the intensity of the event and the 
relationship of the event to study drug administration. 
 
Signs or symptoms reported as adverse events will be graded and recorded by the investigator, 
according to the CTCAE version 4. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event. 
 
Follow-up of Adverse Events 
All adverse events will be followed with appropriate medical management from the first dose of 
BRBs until 30 days following the last dose of treatment. 
 
The investigator and his or her team will follow the Medical College of Wisconsin policies related 
to adverse event reporting. 
 
7.2  Defining and reporting a Serious Adverse Event (SAE) 
 
Serious Adverse Event (SAE) means any untoward medical occurrence that at any dose: 
• 
Death. Results in death. 
• 
Life threatening. Is life threatening (refers to an AE 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). 
• 
Hospitalization. Requires inpatient hospitalization or prolongation of an existing 
hospitalization (excluding planned hospitalization). 
• 
Disability/incapacity. Results in persistent or significant disability or incapacity. 
(Disability is defined as a substantial disruption of a person’s ability to conduct normal 
life functions). 
• 
Medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent one of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse; any 
organism, virus, or infectious particle (e.g., prion protein transmitting Transmissible  
• 
Spongiform Encephalopathy), pathogenic or nonpathogenic, is considered an infectious 
agent. 
 
Clarification should be made between a serious AE (SAE) and an AE that is considered severe 
in intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous. The 
general term severe is often used to describe the intensity (severity) of a specific event; the 
event itself, however, may be of relatively minor medical significance (such as a Grade 3 
headache). This is NOT the same as serious, which is based on patient/event outcome or action 
criteria described above, and is usually associated with events that pose a threat to a patient’s 
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serious. For example, a white blood cell count of 1000/mm3 to less than 2000 is considered 
Grade 3 (severe) but may not be considered serious. Seriousness (not intensity) serves as a 
guide for defining regulatory reporting obligations. 
 
Reporting SAEs 
 
Serious AEs must be reported from the first dose of BRBs through 30 days after completion of 
study treatment or until they are resolved or are clearly determined to be due to a patient’s 
stable or chronic condition or intercurrent illness(es). 
 
For serious AEs, the investigator must determine both the intensity of the event and the 
relationship of the event to study drug administration. 
 
Since this is an investigator-initiated study, the principal investigator, also referred to as the 
sponsor-investigator, is responsible for reporting serious adverse events (SAEs) to any 
regulatory agency and to the sponsor-investigator’s IRB when required. 
 
AEs which are serious must be reported to the Data Safety Monitoring Committee (DSMC) from 
the first dose of BRBs through 30 days after completion of treatment on the study. 
 
Reporting to the Data and Safety Monitoring Committee 
 
Regardless of expectedness or causality, all SAEs must also be reported to the DSMC as soon 
as possible, but no later than five calendar days of the sponsor-investigator’s observation or 
awareness of the event. 
 
Report Method: The investigator will use email to report SAEs to the DSMC. The SAE report 
must include event term(s), serious criteria, and the sponsor-investigator’s or sub-investigator’s 
determination of both the intensity of the event(s) and the relationship of the event(s) to study 
drug administration. Intensity for each SAE, including any lab abnormalities, will be determined 
by using the NCI CTCAE version 4 as a guideline whenever possible. 
 
The criteria are available online at http://ctep.cancer.gov/reporting/ctc.html. 
 
7.3  Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) 
 
The investigator and his or her team will follow the Medical College of Wisconsin policies related 
to unanticipated problems involving risks to subjects or others. This information may be found on 
the Human Research Protection Program website. 
 
7.4  Procedure for Reporting Drug Exposure during Pregnancy and Birth Events 
 
If a woman becomes pregnant, or suspects that she is pregnant, while participating in this study, 
she must inform the investigator immediately and permanently discontinue the study drug. The 
sponsor-investigator must notify the DSMC by email. The pregnancy must be followed for the 
final pregnancy outcome. 
 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor-investigator must also immediately notify the DSMC. Every effort should 
be made to follow the pregnancy for the final pregnancy outcome. 
 
Suggested Pregnancy Reporting Form: 


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• 
Pregnancy Report Form (a sample is provided in Appendix 7) 
 
7.5  Common AE List 
 
In a previous pilot study, healthy subjects consumed 45 g of freeze-dried berries for 14 days 
and the berries were well tolerated. 
 
However, side effects are always a possibility and patients will be asked to report any change in 
their health status or potential adverse events 
 
Expedited Reporting to the Food and Drug Administration 
 
If the study is being conducted under an IND, the sponsor-investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32). 
 
The investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected. The sponsor-investigator needs to ensure that the event meets all 
three definitions: 
 
Suspected adverse reaction 
 
Unexpected 
 
Serious 
 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 
 
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than seven calendar days after the investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)). 
 
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)). 
 
Suggested Reporting Form: 
 
US FDA MedWatch 3500A: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
Any other form deemed appropriate by the sponsor-investigator. 
 
 
 
 
 
 


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8  PHARMACEUTICAL INFORMATION 
8.1  Black Raspberries 
 
Product Description 
 
The freeze-dried black raspberry powder is available from BerriProducts, Inc. in 25-gram dosing 
packets. Each bag contains around 500 freeze-dried black raspberries. 
 
Black raspberries for this powder are grown, harvested mechanically when ripe, washed 
immediately after harvest and frozen at -20°C. 
 
They are freeze dried under Good Manufacturing Practice (GMP) conditions by Oregon Freeze 
Dry in Albany, Oregon, the largest U.S. freeze-drying company. After freeze drying, the berries 
are ground into a powder, and the powder is tested for contamination with fungi, e. coli, 
salmonella and listeria. In addition, the content of 26 different nutrients are measured in the 
powder on a routine basis, as described by Stoner. (19) 
 
Classification: 
 
Phytomedicine. 
 
Mechanism of Action: 
 
Their modes of action include inhibition of carcinogen activation and stimulation of carcinogen 
detoxification. In addition, they reduce the binding of the reactive metabolites of carcinogens to 
DNA, downregulate genes associated with cancer development, upregulate of genes involved in 
cell-cycle control and stimulate apoptosis and inhibit angiogenesis. 
 
Metabolism: 
 
Anthocyanins are excreted in intact forms and metabolized into methylated derivatives in human 
urine. The urinary excretion of anthocyanins reaches maximum concentration during the four- to 
eight-hour period after black raspberry ingestion. 
 
Contraindications: 
 
Allergic reaction to BRBs 
 
Side Effects: 
 
As noted, side effects are a possibility and potential adverse events (i.e., headache, dizziness, 
nausea, vomiting, diarrhea, cramping) will be monitored. 
 
Solution Preparation/ Investigational Agent Administration 
 
Twenty-five grams of freeze-dried BRBs will be mixed in 8 ounces of water and consumed twice 
daily at least six hours a part. If patient is unable to tolerate the taste, he or she may mix the BRB 
with milk, ice cream or a smoothie. 
 
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Black raspberries will be stored in Investigational Drug Pharmacy in a freezer at minus 20 
degrees Celsius and transported to the clinic in a cooler with an ice pack. Patients need to store 
BRBs in the freezer at home. 
 
Stability 
Freeze-dried products have the same size and shape as the original frozen material and have 
excellent stability and convenient reconstitution when placed in water. 
 
Route of Administration 
 
Oral administration. 
 
Nursing Implications 
 
Dispensing: Patients will receive oral black raspberries while receiving their supportive care. At 
office visits, patients will pick up black raspberry doses for the next cycle. 
 
Compliance: Clinical staff will collect phenolic-rich food diaries from patients which reflect the 
previous cycle. 
 
Handling 
 
No special handling instructions. 
 
Availability 
 
The supplier is BerriProducts, Inc. 
 
Agent Ordering 
 
MCW will obtain black raspberry powder directly from BerriProducts, Inc. in Corvallis, Oregon as 
study supply. 
 
Contact information: BerriProducts, Inc., 1325 NW Heather Drive, Corvallis, OR 97330. Phone 
number: 888-761-8407. 
 
Agent Accountability 
 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of black raspberries. 
 
9  REPORTING AND DOCUMENTING RESULTS (MEASUREMENT 
OF EFFECT) 
9.1  Evaluation of Efficacy (or Activity) Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first study 
drug treatment. 
 


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Evaluable for response: Only patients who have undergone at least three cycles of 
treatment are evaluable for response. 
 
9.2  Methods for Evaluation 
 
All baseline evaluations will be performed as closely as possible to the beginning of treatment. 
Please refer to the study calendar and Section 3 (study design). 
 
Physical Examination, Laboratory Values, Food Records 
 
After completing a dietary assessment, patients will undergo physical examination and 
laboratory tests (complete blood count (CBC) with differential, platelet count, and serum 
chemistry assessment). The treating physician will evaluate the patient every cycle. 
Peripheral blood samples will be collected cycles 1–4, 7, 10, and EOT for evaluation of 
methylation status.  
 
9.3  Surrogate Endpoint Biomarkers 
 
Plasma uptake and urine excretion of berry anthocyanins 
We will evaluate the uptake of berry compounds into plasma obtained at two hours after the first 
dose of BRBs. Urine samples will also be collected three hours after the first dose of BRBs. The 
content of each of the four major anthocyanins in BRBs (i.e., cyanidin-3-rutinoside, cyanidin-3- 
xylosylrutinoside, cyanidin-3-glucoside and cyanidin-3-sambubioside) will be measured, using 
HPLC, as described previously. (17) Briefly, separation of plasma and urinary anthocyanins will 
be conducted on a Symmetry C18 column (4.6 × 75 mm, 3.5 μm; Waters Corp.) using an HPLC 
system. Cyanidin-3-glucoside will be dissolved in deionized-distilled water containing 5% formic 
acid. All levels of anthocyanins analyzed in plasma and urine samples will fall within the 
standard curve range and will be expressed as cyanidin glucoside equivalents in pmol/mL 
plasma or urine. 
 
DNA methylation analysis by reduced representation bisulfite sequencing (RRBS) 
Peripheral blood will be used to isolate CD45+ leukocytes, using CD45 MicroBeads (Miltenyi 
Biotec). DNA will be extracted from isolated leukocytes (DNA extraction kit, Qiagen). Then, DNA 
samples will be used for RRBS analysis. In brief, first, genomic DNA is digested using a 
methylation-insensitive restriction enzyme. The next step is adding an extra adenosine to both 
the plus and minus strands. End repair and A-Tailing is done within the same reactions, with 
dCTP, dGTP and dATP deoxyribonucleotides. Then, methylated sequence adapters are ligated 
to the DNA fragments. The desired size of fragments is then selected to be purified. DNA 
fragments of 40-220 base pair are representative of the majority of promoter sequences and 
CpG islands. The DNA fragments are then bisulfite converted, which is a process that 
deaminates unmethylated cytosine into a uracil. The methylated cytosine remains unchanged, 
due to the methyl group protecting them from the reaction. The bisulfite converted DNA is then 
amplified, using PCR with primers that are complementary to the sequence adapters. The 
fragments are then sequenced. For Illumina sequencing, 36-base single-end sequencing reads 
are most commonly performed. Alignment to a reference genome allows the programs to identify 
base pairs within the genome that are methylated. The identified genes will be validated using 
pyrosequencing.  
 
The research samples will be batched and any leftover blood/urine will be banked for future 
research. The research samples will be processed and banked at Dr. Li-Shu Wang’s lab at the 
R4655 TBRC, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee WI 53226. 
 


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9.4  Response Criteria 
 
  The patient’s best clinical response will be assessed, based on the modified IWG response      
  criteria (Appendix 2) while receiving BRBs. 
 
9.5  Evaluation of Safety 
 
The study will use the CTCAE v4.0 for reporting of adverse events. Patients will be evaluated 
every cycle for toxicity. 
 
10  STATISTICAL CONSIDERATIONS 
Methods for berry components (ellagic acid and anthocyanins) 
A descriptive analysis will be performed for ellagic acid and anthocyanin data. Means, medians  
and confidence intervals will be calculated for all absolute and relative differences. 
 
Methods for analysis of methylation changes 
The primary analysis will consist of six mixed effect models with a random effect for patient, and 
4 pairwise comparison of baseline methylation to each treatment times. A Bonferroni correction 
for 24 total comparisons will be applied to maintain a 5% experimentwise error rate. The 
primary outcome will be analyzed as the relative methylation rate (difference/baseline). 
Absolute methylation will also be analyzed, if appropriate for this data. Missing data will be 
assumed to be missing at random (MAR). Patients with partial data before six6 cycles, e.g., 
from their visits at cycle 2 or 3, will be included in the analysis. 
 
Power calculation 
Strong changes in methylation levels have been observed in pilot data, with mean differences 
exceeding 20% difference, with standard deviations ranging from six to eight. This study calls 
for comparing the methylation differences from baseline to each treatment time points, and 
repeated over six different genes of interest, for a total of 24 comparisons. Based on a two-
sided paired t-test with 5% type I error rate with Bonferroni adjustment for 24 comparisons, a 
standard deviation of 8.0 and methylation difference of 12%, a sample size of 16 will be 
sufficient for 95% power. To date, seven patients were enrolled to the trial and they all finished 
three cycles of BRB treatment. Based on the current compliance to the treatment protocol, no 
one dropped and no one was noncompliant. Therefore, we assume that there will be no more 
than 5% non-compliance to the treatment protocol. An addition of 5% will be recruited, so power 
can be maintained using nonparametric methods (Wilcoxon Signed-Rank test). Therefore, this 
brings the final sample required sample size to 18 patients to maintain the power of the study. 
Toxicity monitoring plan (stopping rule) 
Severe toxicity is not expected with BRB. As a precaution for unexpected high toxicity, the trial 
enrolment will be pause and the protocol reviewed if a toxicity rate exceeding 15% is observed. 
The following table gives the stopping rule a Pocock-type boundary for 15% toxicity rate: 
 
# enrolled 
3 
5 
9 
12 
16 
18 
Pause 
if 
toxicities 
equal or greater than 
3 
4 
5 
6 
7 
8 
 
Ex: Five toxicities with 10 enrolled would call for a pause for review. 
 
 


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11  DATA AND SAFETY MONITORING PLAN (DSMP) 
11.1  Data and Safety Management Overview 
 
The Medical College of Wisconsin (MCW) Data Safety Monitoring Committee (DSMC) and the 
MCW Institutional Review Board (IRB) will approve protocol-specific DSM plans described 
below. A local, investigator-initiated trial will be required to be continuously monitored by the 
principal investigator of the study with regular safety and progress reports submitted to the 
DSMC. 
 
The DSMP for this study will involve the following entities: 
 
11.2  Study Team 
 
The study team minimally consists of the principal investigator, the clinical research coordinator, 
regulatory specialist and the study biostatistician. While patients are on treatment, the principal 
investigator will meet regularly with the research coordinator and the study biostatistician to 
review study status. This review will include but not be limited to reportable SAEs and UPIRSOs 
and an update of the ongoing study summary that describes study progress in terms of the 
study schema. The appropriateness of further subject enrollment and the specific intervention 
for a next subject enrollment is addressed. All meetings including attendance are documented. 
 
11.3  Quality Assurance 
 
The MCWCC Clinical Trials Office provides ongoing quality assurance audits 
Intermediate risk trials are reviewed every year 
• 
20% of subject files will be selected randomly for review (a maximum of 10 subjects at 
each monitoring time point). Consent/eligibility and objective-based data will be reviewed 
for those files selected. 
• 
One file will be selected randomly for a comprehensive review at each monitoring time 
point. 
• 
Regulatory documents (IRB submissions, reportable events, etc.) will be reviewed at 
each monitoring time point. 
 
11.4  Clinical Trials Office 
 
The MCWCC Clinical Trials Office [CTO] provides administrative assistance and support to the 
DSMC. 
 
11.5  DSMC 
 
The Medical College of Wisconsin Cancer Center places the highest priority on ensuring the 
safety of patients participating in clinical trials. Every cancer interventional trial conducted at 
MCW includes a plan for safety and data monitoring. 
 
This study will be reviewed by the Medical College of Wisconsin Cancer Center Data and Safety 
Monitoring Committee (MCWCC DSMC). A summary of the MCWCC DSMC activities are as 
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 
Review the clinical trial for data integrity and safety 
 
Review all unexpected grade 3, and all grade 4, and 5 adverse events, as well as any 
others requiring expedited reporting as defined in this protocol. (Grades 4 & 5 events 
must be reported to the DSMC within 5 calendar days of study staff’s knowledge.) 
 
Review all DSM reports 
 
Submit a summary of any recommendations related to study conduct 
 
Terminate the study if deemed unsafe for patients 
 
A copy of the MCWCC Data and Safety Monitoring Plan and membership roster will be 
maintained in the study research file and updated as membership changes. The committee will 
review reports from the study PI twice annually (or more frequently if needed) and provide 
recommendations on trial continuation, suspension or termination as necessary. 
 
Any available DSMC letters will be submitted to the IRB of record as required. 
 
12  REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT 
12.1  Ethical Standard 
 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
 
12.2  Regulatory Compliance 
 
This study will be conducted in compliance with: 
 
The protocol 
 
Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards) and §312 
(Investigational New Drug Application; and 45 CFR 46 Subparts A (Common Rule), B 
(Pregnant Women, Human Fetuses and Neonates), C (Prisoners), and D (Children), 
GCP/ICH guidelines, and all applicable regulatory requirements. The IRB must comply 
with the regulations in 21 CFR §56 and applicable regulatory requirements. 
 
12.3  Institutional Review Board 
 
The protocol, the proposed informed consent form and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the MCW Institutional Review Board. Prior to obtaining MCW approval, the 
protocol must be approved by the Medical College of Wisconsin Cancer Center Scientific 
Review Committee. The initial protocol and all protocol amendments must be approved by the 
IRB prior to implementation. 
 
12.4  Informed Consent Process 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and their families. 
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are given to the subject and written documentation of informed consent is required prior to 
starting intervention/administering study product. 
 
Consent forms will be IRB-approved and the subject (and Legally Authorized Representative, if 
necessary) will be asked to read and review the document. Upon reviewing the document, the 
investigator will explain the research study to the subject and answer any questions that may 
arise. In accordance with 46 CR 46.111, the subject will sign and date the informed consent 
document prior to any procedures being done specifically for the study. 
 
Subject confidentiality is strictly held in trust by the sponsor-investigator, participating 
investigators, and any staff. This confidentiality includes the clinical information relating to 
participating subjects, as well as any genetic or biological testing. 
 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the principal investigator. 
 
The conditions for maintaining confidentiality of the subjects’ records are required for the life of 
the data. These rules apply equally to any and all MCWCC projects. 
 
12.5  Prestudy Documentation 
 
Prior to implementing this protocol at MCWCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MCW IRB. 
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 
 
12.6  Protection of Human Subjects  
 
Protection from Unnecessary Harm 
 
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the IRB mechanism and the informed consent process. The IRB 
reviews all proposed studies involving human experimentation and ensures that the subject’s 
rights and welfare are protected and that the potential benefits and/or the importance of the 
knowledge to be gained outweigh the risks to the individual. The IRB also reviews the informed 
consent document associated with each study in order to ensure that the consent document 
accurately and clearly communicates the nature of the research to be done and its associated 
risks and benefits. 
 
Protection of Privacy 
 
As noted, patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this discussion, they 
will be asked to sign informed consent documents. The original signed document will become 
part of the patient’s medical records, and each patient will receive a copy of the signed 
document. 
 
12.7  Investigator Compliance 
 
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opinion by the IRB and the appropriate regulatory authority(ies). 
 
12.8  Onsite Audits 
 
Auditing is essential to ensure that research conducted at the Medical College of Wisconsin 
(MCW) Cancer Center is of the highest quality and meets MCW and regulatory agency 
standards. 
 
Regulatory authorities, the IRB and/or sponsor may request access to all source documents, 
data capture records and other study documentation for on-site audit or inspection. Direct 
access to these documents must be guaranteed by the investigator, who must provide support 
at all times for these activities. 
 
13  DATA HANDLING AND RECORD KEEPING 
13.1  Overview 
 
Every effort is made to uphold the integrity of the project, the research, the institution, and the 
researchers involved. Data collection guidelines and methodologies are carefully developed 
before the research begins. Investigators focus on the following to ensure data integrity: well- 
trained data collectors/recorders to ensure consistency and quality, well-designed data  collection 
protocols and ongoing monitoring. In this way, study rigor and validity are maintained. Data is 
protected from physical damage as well as from tampering, loss or theft. This project’s data 
management is a multidisciplinary activity that includes investigators, research coordinators and 
nurses, data mangers, support personnel, biostatisticians and database programmers. Quality 
control will be applied to each stage of data handling to ensure that all data are reliable and have 
been processed correctly. 
 
13.2  Case Report Forms 
 
The principal investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study- 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis. All study data will be entered into OnCore® via standardized 
CRFs, in accordance with the study calendar, using single data entry with a secure access 
account. 
 
All source documentation and data will be available for review/monitoring by the MCWCC 
DSMC and regulatory agencies. 
 
13.3  Handling and Documentation of Clinical Supplies 
 
The Investigational Pharmacy will maintain complete records showing the receipt, dispensation, 
return, or other disposition of black raspberries. The date, quantity and batch or code number of 
the agent, and the identification of patients to whom study drug has been dispensed by patient 
number and initials will be included. The sponsor-investigator will maintain written records of 
any disposition of the study drug. 
 
The principal investigator shall not make the agent available to any individuals other than to 
qualified study patients. Furthermore, the principal investigator will not allow the agent to be 
used in any manner other than that specified in this protocol. 


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13.4  Study Record Retention 
 
The principal investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity and use by subjects, as well as written records of the disposition of the 
drug when the study ends. 
 
In accordance with FDA regulations, the investigator shall retain records for a period of two 
years following the date a marketing application is approved for the drug for the indication for 
which it is being investigated; or, if no application is to be filed or if the application is not 
approved for such indication, until two years after the investigation is discontinued and FDA is 
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14  REFERENCES 
1. 
Atallah, E., et al. (2008) Treatment strategies in myelodysplastic syndromes. 
Cancer Invest, 26, 208–16. 
 
2. 
Ma, X., et al. (2007) Myelodysplastic syndromes: incidence and survival in the United 
States. Cancer, 109, 1536–42. 
 
3. 
Greenberg, P., et al. (1997) International scoring system for evaluating prognosis in 
myelodysplastic syndromes. Blood, 89, 2079–88. 
 
4. 
Hellstrom-Lindberg, E., et al. (1997) Erythroid response to treatment with G-CSF plus 
erythropoietin for the anaemia of patients with myelodysplastic syndromes: proposal for 
a predictive model. Br J Haematol, 99, 344–51. 
 
5. 
List, A., et al. (2005) Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J 
Med, 352, 549–57. 
 
6. 
Fenaux, P., et al. (2009) Efficacy of azacitidine compared with that of conventional care 
regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, 
open-label, phase III study. Lancet Oncol, 10, 223–32. 
 
7. 
Steensma, D.P., et al. (2009) Multicenter study of decitabine administered daily for 5 
days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for 
outpatient treatment (ADOPT) trial. J Clin Oncol, 27, 3842–8. 
 
8. 
Jones, P.A., et al. (1980) Cellular differentiation, cytidine analogs and DNA methylation. 
Cell, 20, 85–93. 
 
9. 
Uchida, T., et al. (1997) Hypermethylation of the p15INK4B gene in myelodysplastic 
syndromes. Blood, 90, 1403–9. 
 
10. 
Yang, A.S., et al. (2006) DNA methylation changes after 5-aza-2'-deoxycytidine therapy 
in patients with leukemia. Cancer Res, 66, 5495–503. 
 
11. 
Itzykson, R., et al. (2011) Prognostic factors for response and overall survival in 282 
patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood, 117, 
403–11. 
 
12. 
Kantarjian, H., et al. (2006) Decitabine improves patient outcomes in myelodysplastic 
syndromes: results of a phase III randomized study. Cancer, 106, 1794–803. 
 
13. 
Lübbert, M., et al. (2011) Low-Dose Decitabine Versus Best Supportive Care in Elderly 
Patients With Intermediate- or High-Risk Myelodysplastic Syndrome (MDS) Ineligible for 
Intensive Chemotherapy: Final Results of the Randomized Phase III Study of the 
European Organisation for Research and Treatment of Cancer Leukemia Group and the 
German MDS Study Group. Journal of Clinical Oncology, 29, 1987–1996. 
 
14. 
Kantarjian, H., et al. (2007) Results of a randomized study of 3 schedules of low-dose 
decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic 
leukemia. Blood, 109, 52–7. 


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15. 
Kornblith, A.B., et al. (2002) Impact of azacytidine on the quality of life of patients with 
myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and 
Leukemia Group B study. J Clin Oncol, 20, 2441–52. 
 
16. 
Wang, L.-S., et al. (2013) Black Raspberries Protectively Regulate Methylation of Wnt 
Pathway Genes in Precancerous Colon Tissue. Cancer Prevention Research, 6, 
1317– 1327. 
 
17. 
Wang, L.S., et al. (2011) Modulation of genetic and epigenetic biomarkers of colorectal 
cancer in humans by black raspberries: a phase I pilot study. Clin Cancer Res, 17, 
598– 610. 
 
18. 
Wang, L.-S., et al. (2013) Dietary black raspberries modulate DNA methylation in 
dextran sodium sulfate (DSS)-induced ulcerative colitis. Carcinogenesis, 34, 2842–
2850. 
 
19. 
Stoner, G.D. (2009) Foodstuffs for preventing cancer: the preclinical and clinical 
development of berries. Cancer Prev Res (Phila), 2, 187–94. 
 
20. 
Stoner, G.D., et al. (2005) Pharmacokinetics of anthocyanins and ellagic acid in healthy 
volunteers fed freeze-dried black raspberries daily for 7 days. J Clin Pharmacol, 45, 
1153–64. 
 
21. 
Wang, L.-S., et al. (2014) A phase Ib study of the effects of black raspberries on rectal 
polyps in patients with familial adenomatous polyposis. Cancer Prev Res, 7, 666–674. 
 
22. 
Kresty, L.A., et al. (2001) Chemoprevention of esophageal tumorigenesis by dietary 
administration of lyophilized black raspberries. Cancer Res, 61, 6112–9. 
 
23. 
Kelloff, G.J., et al. (1999) Cancer chemoprevention: progress and promise. Eur J 
Cancer, 35, 1755–62. 
 
24. 
Mandal, S., et al. (1990) Inhibition of N-nitrosobenzylmethylamine-induced esophageal 
tumorigenesis in rats by ellagic acid. Carcinogenesis, 11, 55–61. 
 
25. 
Teel, R.W., et al. (1985) The effect of ellagic acid on the uptake, persistence, 
metabolism and DNA-binding of benzo[a]pyrene in cultured explants of strain A/J mouse 
lung. Carcinogenesis, 6, 391–5. 
 
26. 
Castonguay, A., et al. (1997) Antitumorigenic and antipromoting activities of ellagic acid, 
ellagitannins and oligomeric anthocyanin and procyanidin. Int J Oncol, 10, 367–73. 
 
27. 
Barch, D.H., et al. (1996) Structure-function relationships of the dietary anticarcinogen 
ellagic acid. Carcinogenesis, 17, 265–9. 
 
28. 
Teel, R.W., et al. (1986) Ellagic acid toxicity and interaction with benzo[a]pyrene and 
benzo[a]pyrene 7,8-dihydrodiol in human bronchial epithelial cells. Cell Biol Toxicol, 2, 
53–62. 
 
29. 
Harris, G.K., et al. (2001) Effects of lyophilized black raspberries on azoxymethane- 


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induced colon cancer and 8-hydroxy-2'-deoxyguanosine levels in the Fischer 344 rat. 
Nutr Cancer, 40, 125–33. 
 
30. 
Carlton, P.S., et al. (2001) Inhibition of N-nitrosomethylbenzylamine-induced 
tumorigenesis in the rat esophagus by dietary freeze-dried strawberries. Carcinogenesis, 
22, 441–6. 
 
31. 
Chen, T., et al. (2006) Chemopreventive properties of black raspberries in N- 
nitrosomethylbenzylamine-induced rat esophageal tumorigenesis: down-regulation of 
cyclooxygenase-2, inducible nitric oxide synthase, and c-Jun. Cancer Res, 66, 2853–
9. 
 
32. 
Huang, C., et al. (2007) Differential inhibition of UV-induced activation of NF kappa B 
and AP-1 by extracts from black raspberries, strawberries, and blueberries. Nutr Cancer, 
58, 205–12. 
 
33. 
Aggerholm, A., et al. (2006) Promoter hypermethylation of p15INK4B, HIC1, CDH1, and 
ER is frequent in myelodysplastic syndrome and predicts poor prognosis in early-stage 
patients. Eur J Haematol, 76, 23–32. 
 
 
34. 
Zeidan AM, Hu X, Long JB, Wang R, Ma X, Podoltsev NA, Huntington SF, Gore SD,  
Davidoff AJ. Hypomethylating agent therapy use and survival in older patients with 
chronic myelomonocytic leukemia in the United States: A large population-based study. 
Cancer. 2017 Oct 1;123(19):3754-3762Ye X, Chen D, Zheng Y, Zhu X, Fu J, Huang J.  
 
35. 
Effective treatment of low-dose decitabine in myelodysplastic syndrome/myeloproliferative 
neoplasms. Onco Targets Ther. 2017 Nov 13;10:5425-5428. 
 
 
36. 
Ye X, Chen D, Zheng Y, Zhu X, Fu J, Huang J. Effective treatment of low-dose 
decitabine in myelodysplastic syndrome/myeloproliferative neoplasms. Onco Targets 
Ther. 2017 Nov 13;10:5425-5428. 
 
37. 
Silverman LR, Fenaux P, Mufti GJ, Santini V, Hellström-Lindberg E, Gattermann N, Sanz 
G, List AF, Gore SD, Seymour JF. Continued azacitidine therapy beyond time of first 
response improves quality of response in patients with higher-risk myelodysplastic 
syndromes. Cancer. 2011 Jun 15;117(12):2697–702.  


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APPENDIX 1. PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Descriptions 
0 
Normal activity 
Fully active, able to carry on all 
pre-disease performance 
without restriction 
100 
Normal, no complaints, no evidence 
of disease 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease 
1 
Symptoms, but ambulatory 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry out 
work of a light or sedentary 
nature (e.g., light housework, 
office work) 
80 
Normal activity with effort; some 
signs or symptoms of disease 
70 
Cares for self, unable to carry on 
normal activity or to do active work 
2 
In bed < 50% of the time 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities 
Up and about more than 50% of 
waking hours 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs 
50 
Requires considerable assistance 
and frequent medical care 
3 
In bed > 50% of the time 
Capable of only limited self- 
care, confined to bed or chair 
more than 50% of waking hours 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization 
indicated 
Death not imminent 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
20 
Very sick, hospitalization indicated 
Death not imminent 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 


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APPENDIX 2. MODIFIED IWG RESPONSE CRITERIA 
 
Hematologic 
Improvement (HI) 
Response Criteria (responses must last at least 8 weeks) 
Erythroid response 
(pretreatment, 
< 11 g/dL) 
- 
Hgb increase by ≥ 1.5 g/dL. 
- 
Relevant reduction of RBC transfusion units by an absolute 
number of at least 4 RBC transfusions/8 wk compared with 
the pretreatment transfusion number in the previous 8 wk. 
- 
Only RBC transfusions given for an Hgb of ≤ 9.0 g/dL 
pretreatment will count in the RBC transfusion response 
evaluation. 
Platelet response 
(pretreatment, 
< 100 x 109/L) 
- 
Absolute increase of ≥ 30 x 109/L for patients starting with 
> 20 x 109/L platelet. 
- 
Increase from < 20 x 109/L to > 20 x 109/L and by at least 
100%. 
Neutrophil 
response 
(pretreatment, 
< 1.0 x 109/L) 
At least 100% increase and an absolute increase > 0.5 x 109/L. 
Progression or 
relapse after HI 
At least one of the following: 
- 
At least 50% decrement from maximum response levels in 
granulocytes or platelets. 
- 
Reduction in Hgb by ≥ 1.5 g/dL. 
- 
Transfusion dependence in transfusion independent 
patients. 


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Category 
Response criteria (responses must last at least 4 weeks) 
Complete 
remission 
Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines 
Persistent dysplasia will be noted 
Peripheral blood: 
Hgb ≥ 11 g/dL 
Platelets ≥ 100 × 109/L 
Neutrophils ≥ 1.0 × 109/L 
Blasts 0% 
Partial 
remission 
All CR criteria if abnormal before treatment except: 
Bone marrow blasts decreased by ≥ 50% over pretreatment but still > 
5% 
Cellularity and morphology not relevant 
Marrow CR 
Bone marrow: ≤ 5% myeloblasts and decrease by ≥ 50% over 
pretreatment 
Peripheral blood: if HI responses, they will be noted in addition to 
marrow CR 
Stable disease 
Failure to achieve at least PR, but no evidence of progression for > 8 
weeks. 
Failure 
Death during treatment or disease progression characterized by 
worsening of cytopenias, increase in percentage of bone marrow 
blasts, or progression to a more advanced MDS FAB subtype than 
pretreatment 
Cytogenetic 
response 
Complete: Disappearance of the chromosomal abnormality without 
appearance of new ones 
Partial: At least 50% reduction of the chromosomal abnormality 
Disease 
Progression 
For patients with: 
• Less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts 
• 5%-10% blasts: ≥ 50% increase to > 10% blasts 
• 10%-20% blasts: ≥ 50% increase to > 20% blasts 
• 20%-30% blasts: ≥ 50% increase to > 30% blasts 
Any of the following: 
• At least 50% decrement from maximum remission/response 
in granulocytes or platelets 
• Reduction in Hgb by ≥ 2 g/dL 
• Transfusion dependence 
World Health Organization (WHO) Classification-Based Prognosis Scoring System (WPSS 
calculator): http://www.myelodysplastischesyndrome.de/service/wpss_kalkulator/ 


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APPENDIX 3. BLACK RASPBERRIES NUTRIENT LEVELS AND 
POTENTIAL CHEMOPREVENTIVE COMPONENTS 
 
Berry Samples Analyzed (mg/100 g) 
Dietary Components 
BRB1 
BRB2 
Minerals 
Calcium 
245.0 
215 
Copper 
0.522 
0.554 
Iron 
13.2 
10.1 
Magnesium 
169.0 
153.0 
Manganese 
3.60 
4.68 
Phosphorus 
222.0 
170.0 
Potassium 
1200.0 
1300.0 
Zinc 
2.69 
2.17 
Selenium 
<5.0 
<5.0 
Folate 
0.07 
0.06 
Vitamins 
Ascorbic Acid 
<1.0 
4.4 
α-carotene 
<0.02 
<0.02 
β-carotene 
<0.02 
<0.02 
Sterols 
β-sitosterol 
89.1 
80.1 
Campesterol 
4.3 
3.4 
Stigmasterol 
<3.0 
<3.0 
Cholesterol 
<1.0 
<1.0 
Phenolics 
Ellagic Acid 
185.0 
166.3 
Ferulic Acid 
32.4 
17.6 
p-Coumaric Acid 
7.94 
9.23 
Abbreviations:  BRB, freeze-dried black raspberries. (components reported in mg/100 
g sample, except selenium levels reported in mcg/100g)]. BRB1 and BRB2 are two separate lots of 
freeze-dried BRBs obtained in 1998 and 1999, respectively. Subsequent lots obtained since 1999 have 
similar quantities of the components listed. 


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Food 
Category 
Specific Foods with High Phenolic Content 
Fruits 
Apples, apricots, berries (all), cherries, cranberries, currants, grapes, 
grapefruit, nectarines, oranges, peaches, peppers (bell and chili), 
plums, prunes, raisins, tangerines 
Vegetables 
Cucumbers, tomatoes 
Other foods 
Almonds, pickles, peanuts, walnuts 
Beverages 
Cider, coffee, fruit juices, tea, wine 
Spices 
Chili powder, cloves, paprika 
Other 
Cider and wine vinegar 


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APPENDIX 4. SPECIMEN COLLECTION 
Specimen Collection & Handling 
Anthocyanin collection: 
Collect a minimum of 5 ml of whole blood in an EDTA vacutainer (lavender top) tube on cycle 1 
day 1 within 3 hours prior to BRB administration and 2 hours (+/- 30 minutes) post BRB dose. 
No preprocessing is required. 
 
Urine sample collection: 
Collect in a urine collection container within three hours prior to BRB administration and at 
three hours (+/- 30 minutes) post BRB dose on cycle 1 day 1. No preprocessing is required. 
 
Methylation collection: 
Collect a minimum of 15 ml of whole blood in an EDTA vacutainer (lavender top) tubes within 
three hours prior to BRB administration on cycle 1 day 1 and day 1 of cycles 2–4, 7, 10 and at 
end of treatment. No preprocessing is required. 
 
Specimen Labeling: 
All tubes/containers must be labeled with the patient’s initials, patient study ID number, patient’s 
date of birth and date/time of specimen collection. 
 
Transporting and Storage Requirements: 
For all transportations, a requisition should accompany all samples. A copy of the requisition will 
be retained at the site. Only transport samples Monday through Friday. Samples should be kept 
refrigerated until transport. The samples will need to be transported on ice. Samples should be 
packed and transported according to IATA regulations. Personnel from Dr. Li-Shu Wang’s Lab 
will pick up the study samples only Monday through Friday. Contact 414-955-2579 for sample 
pickup. 


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   Specimen Requisition Form 
 
 
A Pilot Study to Investigate the Hypomethylating Properties of Freeze-dried Black 
Raspberries in Patients with Myelodysplastic Syndrome or Myelodysplastic 
Syndrome/Myeloproliferative Neoplasm (MDS/MPN) 
 
 
Patient Information: 
 
Patient initials:   
 
 
Birth Date:   
 
Study ID #:   
 
 
 
 
Research Sample Information: 
 
Date of Collection: 
 Time of Sample Collection:    
 
Study time point: 
Physician:   
 
BRB administration time:    
 
 
 
 
Person Completing Requisition:   
 
 
Phone Number: 
Email:   
 
 
 
 
Sample Type: 
□ Anthocyanin 
□ Urine Sample 
□ Methylation 


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APPENDIX 5. DRUG DIARY 
 
Black Raspberry Drug Diary 
 
Patient #:  ________________      Cycle #: ______________ 
 
Directions: 
• 
Mix 25 gm of black raspberry powder in 8 ounces of water, twice a day, at least six hours 
a part. 
• 
Store black raspberry powder in the freezer. 
• 
Bring this diary to all oncology doctor visits. 
 
Date 
Time of AM Dose 
Time of PM Dose 
Comments 
 
Patient Signature & Date:   
 
 
 


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APPENDIX 6. PHENOLIC-RICH FOOD DIARIES 
 
Patient #: __________ 
Cycle #: ___________ 
Dates Tracked: 
Polyphenol Weekly Tracking 
Amount Consumed (in cups) 
Food Item 
Monday Tuesday Wednesday Thursday 
Friday 
Saturday Sunday 
Black chokeberry 
Dark chocolate 
Flaxseed meal 
Black elderberry 
Chestnut 
Lowbush blueberry 
Black currant 
Black olive 
Highbush blueberry 
Hazelnut 
Pecan nut 
Plum 
Green olive 
Sweet cherry 
Globe artichoke 
heads 
Blackberry 
Strawberry 
Red chicory 
Red raspberry 
Prune 
Black grape 
 
 
 
 
Patient Signature & Date:   
 


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APPENDIX 7. PREGNANCY FORM 
Pregnancy occurring in participant in a Clinical Trial of Investigational Medicinal Product, 
while not considered an adverse event or serious adverse event, requires monitoring and 
follow up. 
 
The investigator must collect pregnancy information for female trial subjects or female 
partners of male trial subjects. This includes subjects who become pregnant while 
participating in a clinical trial or during a stage where the fetus could have been exposed to 
the investigational medicinal product (e.g., if the active substance or one of its metabolites 
has a long half-life). 
 
Any pregnancy should be reported by the PI to the sponsor using either a study specific or 
generic pregnancy reporting form (see below). 
 
The pregnancy should be followed up by the investigator until delivery. It may be necessary 
to monitor the development of the newborn for an appropriate period post-delivery. Any 
occurrences that result in a Serious Adverse Event should be reported as per the SAE 
reporting procedure. 
 
The below form will be used. 


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Study Drug: 
Study/Protocol No: 
PATIENT ID 
 
Patient’s Initials 
1. 
2. fam. 
 
 
If applicable 
Centre No.  Patient No 
REPORT TYPE 
Initial 
Follow-Up 
STUDY PREGNANCY FORM 
Page 1 of 3 
1. Country: 
2. LOCAL CASE ID: 
I. 
MATERNAL INFORMATION 
3.  DATE OF BIRTH 
4.   AGE 
5. RACE 
6. HEIGHT 
7. WEIGHT 
day 
monthyear 
yrs./mo. 
Caucasian 
Oriental 
Black 
Other 
cm 
kg 
8. 
Date of Last Menstrual Period 
day 
month 
year 
9. 
Expected Date of Delivery 
day 
month 
year 
10. 
Method of Contraception 
11.  Contraception used as instructed 
yes 
no 
uncertain 
II. 
HISTORY 
12. PATIENT’S PAST MEDICAL HISTORY (include information on familial disorders, known risk factors or 
conditions that may affect the outcome of the pregnancy e.g. alcohol, smoking, other substance 
consumption, hypertension, eclampsia, diabetes including gestational, infections during pregnancy, 
environmental or occupational exposure that may pose a risk factor). 
13. 
PREVIOUS OBSTETRIC HISTORY – provide details on all previous pregnancies below, including abortion or stillbirth (use page 3 if 
needed) 
Gestation week 
Outcome including any abnormalities 
1 
2 
3 
4 
5 
14. 
DRUG INFORMATION – please list the Novartis drug(s) first and all other therapies taken prior to or during pregnancy 
Drug Names 
Daily Dose 
Route 
Treatment Dates 
Indication 
(specify week of pregnancy) 
Start 
Stop 
Start 
Stop 
 
 
 


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STUDY PREGNANCY FORM 
Page 2 of 3 
2. LOCAL CASE ID: 
III. 
PREGNANCY INFORMATION 
18. 
PRENATAL 
Have any specific tests, e.g. amniocentesis, ultrasound, maternal serum AFP, been performed during the pregnancy so far? 
No 
Yes 
Not known 
If yes, please specify test date and results: 
19. 
PREGNANCY OUTCOME
Delivery 
Normal 
Forceps/Ventouse 
Caesarean section 
Maternal complications or problems related to birth:  
_  
 
Abortion 
Therapeutic 
Planned 
Spontaneous 
Please, specify reason and any abnormalities (if known) 
 
Unspecified 
Date of abortion/delivery 
day 
month 
year 
at week   
 
20. 
MATERNAL PREGNANCY ASSOCIATED EVENTS: 
If the mother experiences a serious adverse drug reaction (ADR) during a pregnancy, please complete a SAE form and submit as requested. 
IV. 
CHILD INFORMATION 
21. 
Neonate 
Normal 
Abnormal 
Stillbirth 
please specify any abnormalities:    
 
Sex 
Height 
Weight 
Apgar Scores 
Head circumference 
Male 
Female 
i nches 
pounds 
1 min. 
5 mins. 
10 mins. 
inches 
For additional information, please use page 3 (please provide copies of relevant documentation) 
V. 
ASSESSMENT OF PREGNANCY OUTCOME 
22. 
SERIOUSNESS CRITERIA 
Non Serious 
day 
month  year 
day 
month  year 
Mother died 
Stillbirth / Neonate 
died 
Involved or prolonged inpatient hospitalization 
Life-threatening 
Results in persistent or significant disability/incapacity 
Other Seriousness Criteria: 
Congenital anomaly/birth defect 
Other significant medical events 
23. 
ASSESSMENT OF CAUSALITY 
Please indicate the relationship between pregnancy outcome and Novartis study drug 
Not suspected 
 Suspected 
INFORMATION SOURCE 
24. NAME, ADDRESS AND TELEPHONE NUMBER OF INVESTIGATOR 
Signature: 
25. REPORTING DATE BY INVESTIGATOR/PERSON REPORTING 
EVENT 
daymonthyear 
 


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STUDY PREGNANCY FORM 
Page 3 of 3 
2. LOCAL CASE ID: 
FOR ADDITIONAL INFORMATION: 
INFORMATION SOURCE 
32. NAME, ADDRESS AND TELEPHONE NUMBER OF INVESTIGATOR 
Signature: 
33. REPORTING DATE BY INVESTIGATOR/PERSON REPORTING 
daymonthyear 
PLEASE SEND FORM TO DSMC 
 

ICF_001.pdf: 
Medical College of Wisconsin & Froedtert Hospital  
 
Informed Consent for Research 
Clinical Interventions template - Version: October 31, 2016 
 
IRB Protocol Number: 28985 
IRB Approval Period: 05/08/2018 – 05/07/2019 
Page 1 of 10 
Version: 2/27/2018 
EFFECTIVE 
 
05/08/2018 
 
MCW/FH IRB
 
Medical College of Wisconsin and Froedtert Hospital 
CONSENT TO PARTICIPATE IN RESEARCH 
 
Name of Study Subject: ____________________________ 
 
A Pilot Study to Investigate the Hypomethylating Properties of Freeze-dried Black 
Raspberries (BRB) in Patients with Myelodysplastic Syndrome or Myelodysplastic 
Syndrome/Myeloproliferative Neoplasm (MDS/MPN) 
(The Black Raspberry Study) 
 
Ehab Atallah, MD 
Froedtert & the Medical College of Wisconsin 
Division of Hematology and Oncology 
9200 W. Wisconsin Avenue 
Milwaukee, WI 53226 
414-805-6700 
 
You are invited to take part in this research study. This form tells you why this research 
study is being done, what will happen in the research study, possible risks and benefits 
to you, your choices, and other important information. If there is anything that you do not 
understand, please ask questions. Then you can decide if you want to join this study or 
not.   
 
A1. INTRODUCTION – WHY ARE WE ASKING YOU ABOUT THIS STUDY? 
You are being invited to participate in this research study because you have been 
diagnosed with Myelodysplastic Syndrome or Myelodysplastic 
Syndrome/Myeloproliferative Neoplasm (MDS/MPN). The purpose of this study is to 
determine whether treatment with freeze-dried black raspberry powder (BRB) has an 
effect on your disease.  
 
A total of about 18 people are expected to participate in this study, at the Medical 
College of Wisconsin/Froedtert Hospital. 
 
The Director of the study is Ehab Atallah, MD in the Department of Medicine. A study 
team works with Dr. Atallah. You can ask who these people are.  
 
Froedtert Hospital Foundation is funding this study. 
 
A2. DO I HAVE TO BE IN THIS STUDY? 
You can decide whether to take part in this study or not. You are free to say yes or no. If 
you say no, your regular medical care will not change. Even if you join this study, you do 
not have to stay in it. You may stop at any time.  
 


Medical College of Wisconsin & Froedtert Hospital  
 
Informed Consent for Research 
Clinical Interventions template - Version: October 31, 2016 
 
IRB Protocol Number: 28985 
IRB Approval Period: 05/08/2018 – 05/07/2019 
Page 2 of 10 
Version: 2/27/2018 
EFFECTIVE 
 
05/08/2018 
 
MCW/FH IRB
A research study is different from routine medical care in three ways: 1) there are extra 
risks that we will tell you about in this form; 2) you may have some extra medical tests 
and visits; 3) the study procedures, tests and visits follow a set plan that must be kept. 
 
A3. WHY IS THIS RESEARCH STUDY BEING DONE? 
In this study we want to find out more about, BRB, in people with myelodysplastic 
syndrome or Myelodysplastic Syndrome/Myeloproliferative Neoplasm (MDS/MPN). We 
want to find out whether the, BRB, acts similarly to other agents currently used to treat 
MDS, and whether it causes any problems (side effects). Everyone in this study will 
receive BRB, which is experimental and is not approved by the U.S. Food and Drug 
Administration.  We are testing BRB to see what effect it has on people with MDS or 
MDS/MPN. We don’t know if this study will help you. Your condition may get better but it 
could stay the same or even get worse. We hope the information from this study will 
help us develop a better treatment for MDS or MDS/MPN in the future. 
 
B1. WHAT WILL HAPPEN IF I TAKE PART IN THE STUDY?   
STUDY PROCEDURES 
Before any study tests or procedures are done, you will be asked to sign this consent 
form. The study doctor will discuss the study with you and answer your questions. If you 
decide to join the study, some screening tests will be done first to see if you are eligible.  
 
Some of these tests and procedures are considered “standard of care” which means 
that they would be done even if you were not participating in this research study and 
some are considered “research” which means they are being done only because you 
have agreed to participate in this research study. 
 
Screening procedures:  
If you decide to join the study, some screening tests will be done first to see if you are 
eligible.  
 Complete Medical History: A complete medical history will be taken including 
transfusion history and medication history. 
 Demographics: age, gender, ethnicity 
 Physical Exam 
 Laboratory Tests: 
o Blood Tests: A small sample of your blood will be collected for routine 
safety tests  
o Pregnancy Test: If you are a female of child-bearing potential, you will be 
required to have a urine or serum pregnancy test done 
 
If the screening information shows that you meet the requirements, you will be able to 
participate in the study. If the screening information shows that you cannot be in the 
research study, the study doctors will discuss other options with you.  
 
 
 


Medical College of Wisconsin & Froedtert Hospital  
 
Informed Consent for Research 
Clinical Interventions template - Version: October 31, 2016 
 
IRB Protocol Number: 28985 
IRB Approval Period: 05/08/2018 – 05/07/2019 
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Summary of Study Procedures: 
After screening procedures are performed and you are deemed eligible, you will be 
enrolled on the study. Treatment will consist of 28 day (4 week) cycles. If, after 3 cycles 
of therapy, you are tolerating the BRB well, you will be allowed to remain on the study 
for an additional 9 cycles for a maximum of 12 cycles. You may be removed from the 
study at any time if you are not tolerating the BRB or if your treating physician decides it 
is in your best interest.  
 
On the first day of every cycle you will come to the study center for a lab draw of blood 
in the amount of approximately 20mL for an assessment of your overall health and to 
receive study drug for that cycle.  The following assessments will be performed unless 
otherwise specified: 
 Physical Exam: A physical exam will be performed only on Cycle 1 day 1 
 Blood Tests: 
o A small sample of your blood will be collected for routine safety tests  
o Research blood samples to look for evidence of the study drug in your blood 
will be collected only on day 1 of the first 4 cycles.  Samples will be collected 
within 3 hours prior to taking your dose and 2 hours after taking your dose. 
 Urine Tests: These research urine tests will be done prior to your first dose of 
BRB to determine baseline values of various chemicals of interest 
o Urine will be collected within 3 hours prior to your first dose of BRB and 3 
hours after your first dose.  This is only done on cycle 1 day 1. 
 Bone Marrow Aspirate/Biopsy: As part of your routine care, you may have a 
bone marrow aspirate/biopsy procedure to assess your disease if your doctor 
believes it is necessary. 
 
You will be asked to mix 25g of BRB powder with 8 ounces of water twice daily. You will 
drink the 25g BRB/water mixture in the morning and then again at night, separated by at 
least 6 hours. If you cannot tolerate the taste of the BRB with water mixture, you can 
combine the BRB with milk, ice cream, or in a smoothie. 
 
During the 28-day cycles, you will be asked to keep track of when you take each BRB 
dose (morning and evening) in a drug diary. You will bring your completed drug diary 
with you when you come for your next clinic visit. If you miss a dose, you will be asked 
to bring any missed doses back with you to your next clinic visit. Study drug must not be 
thrown away. If you do not follow the treatment schedule, or miss too many doses, you 
may be taken off the study. 
 
Follow-up: 
Approximately thirty days after your last dose, you will return to the study center to 
assess your overall health and disease.  The following assessments will be performed 
unless otherwise specified: 
 Physical Exam: A physical exam will be performed 
 Blood Tests: 


Medical College of Wisconsin & Froedtert Hospital  
 
Informed Consent for Research 
Clinical Interventions template - Version: October 31, 2016 
 
IRB Protocol Number: 28985 
IRB Approval Period: 05/08/2018 – 05/07/2019 
Page 4 of 10 
Version: 2/27/2018 
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05/08/2018 
 
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o A small sample of your blood will be collected for routine safety tests  
o Research samples to look for evidence of the study drug in your blood. 
 Bone Marrow Aspirate- This procedure may occur if your doctor believes that it 
is necessary.  
 
You will come to the study center approximately 15 times during the study (including 
this visit). The study staff will tell you when to come in for your study visits.  
 
B2. HOW LONG WILL I BE IN THE STUDY? 
You will be in this research study for about one year (approximately 52 weeks). 
 
B3. CAN I STOP BEING IN THE STUDY?   
You are free to withdraw from the study at any time. If you leave, your regular medical 
care will not change. If you are thinking about leaving, please tell the study doctor.  
 The doctor can tell you about the effects of stopping, and you and the doctor can 
talk about what follow-up care would help you the most. 
 You might be asked to come back for one more visit to check your health. 
 You might be asked to return your research drug containers. 
 
The study doctor may take you out of this study at any time. This would happen if: 
 
They think it is in your best interest. 
 
You do not follow the study rules. 
 
The whole study is stopped. 
 
If this happens, the study doctor will tell you. 
 
B4. ARE THERE ANY SPECIAL INSTRUCTIONS WHILE I AM IN THE STUDY?  
You will complete a drug diary for each cycle to document when you took each dose of 
study drug and bring it with you for each clinic visit. 
 
You will be asked to keep a food diary of when you eat foods that contain compounds 
that are similar to the study drug.  You will need to bring this diary with you for each 
clinic visit.  The diary contains a list of foods that will need to be tracked on a daily basis 
during each cycle.  You will also meet with a nutritionist on day 1 of every cycle to 
discuss your diet habits as they relate to the study drug. 
 
C1. WHAT HEALTH RISKS OR PROBLEMS CAN I EXPECT FROM THE STUDY? 
There are risks to taking part in any research study. There is a risk that the study drug, 
BRB, will not help your condition or may make it worse.  There also may be problems 
(side effects) we do not know about yet, from BRB itself, or how it combines with other 
drugs you are taking. If we learn about new important side effects, we will tell you.  
 
We watch everyone in the study for problems (side effects). You need to tell the study 
doctor or a member of the study team immediately if you experience any 


Medical College of Wisconsin & Froedtert Hospital  
 
Informed Consent for Research 
Clinical Interventions template - Version: October 31, 2016 
 
IRB Protocol Number: 28985 
IRB Approval Period: 05/08/2018 – 05/07/2019 
Page 5 of 10 
Version: 2/27/2018 
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05/08/2018 
 
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problems, side effects, or changes in your health.  If you have severe side effects, 
call Dr. Atallah immediately at 414-805-6700. In an emergency, call 911. 
 
C2. RISKS OF FREEZE-DRIED BLACK RASPBERRY POWDER (BRB) 
The BRB itself may cause problems (side effects).  Side effects may be mild or very 
serious.  Some can last a long time or never go away.   
 
Drugs can affect individuals in different ways. In a previous study, subjects consumed 
45g of BRB for 14 days and it was well tolerated with no reported side effects. However, 
side effects are always a possibility and you should report any changes to your health 
while taking the BRB drug to your study doctor. 
 
C3. OTHER RISKS OF THIS RESEARCH STUDY 
Other procedures that are part of the study also involve some risks. 
 
Blood Samples: Blood draws may cause pain, bleeding, and/or bruising. You may faint 
and/or get an infection with redness and irritation at the place where the needle enters 
your vein. 
 
Bone Marrow Aspirate/Biopsy Collection – Bone marrow is collected using a needle 
under local anesthesia to aspirate (draw out) marrow tissue from the inside of your bone 
(usually pelvic or hipbone).  The risks on bone marrow biopsy and aspirate include pain, 
bleeding, bruising, and/or discomfort at the biopsy site.  Infection is also possible but 
rare. 
 
C4. REPRODUCTIVE RISKS 
Risks to women who could become pregnant 
The drug in this study might affect a baby, before or after the baby is born. We do not 
know if the drug causes harm to a baby, so we do not want anyone who might be 
pregnant to enter the study. You should not become pregnant or nurse a baby while in 
this study. You must tell the study doctor right away if you think you are pregnant. You 
will be asked to have a pregnancy test to be sure you are not pregnant at the start of the 
study.  
 
Risks of fathering a child 
You should not father a baby while taking part in this study because it is unknown if the 
drug in this study could affect a baby. If your partner is able to become pregnant, one or 
both of you must use some form of effective birth control.  You must tell the study doctor 
right away if you think your partner is pregnant. 
 
Birth control methods for all subjects 
Check with the study doctor about the birth control methods needed for this study and 
how long to use them. Some methods might not be good enough for this study. If you 
are having sex that could lead to pregnancy, you should use birth control while you are 
in this study.   


Medical College of Wisconsin & Froedtert Hospital  
 
Informed Consent for Research 
Clinical Interventions template - Version: October 31, 2016 
 
IRB Protocol Number: 28985 
IRB Approval Period: 05/08/2018 – 05/07/2019 
Page 6 of 10 
Version: 2/27/2018 
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05/08/2018 
 
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This may include: 
 Not having vaginal sex (abstinence) 
 Taking birth control pills orally 
 Having birth control shots or patches such as Depo-Provera 
 Surgical sterilization (hysterectomy or tubal ligation) 
 Use of an intrauterine device (IUD) 
 Use of diaphragm with contraceptive jelly 
 Use of condoms with contraceptive foam 
 Use of diaphragm with condoms (“double barrier”) 
 Limiting sexual activity to a male partner who has had a vasectomy 
 
You should continue using birth control for 30 days after stopping the study drug. 
 
C5. ARE THERE ANY BENEFITS TO TAKING PART IN THE STUDY? 
We don’t know if this study will help you. Your condition may get better but it could stay 
the same or even get worse. We hope the information from this study will help us 
develop better treatments for MDS. 
 
D1. ARE THERE ANY COSTS TO BEING IN THE STUDY? 
Most of the medical care that you will receive in this study is considered routine care for 
your condition and would be recommended whether you join the study or not.  Costs for 
routine care will be billed to you or your insurance carrier.  
 
Activities / costs that are part of the study will not be billed to you or your insurance 
company. These are the study drug, BRB, and the processing and shipping of research 
samples.  Some insurers will not pay for drugs, tests or hospitalization that are part of 
research studies, so check with your insurer before you join this study. If you have 
questions regarding study costs, please contact Dr. Atallah. 
 
If you participate in this research study, the costs of any necessary emergency medical 
treatment in the event of a research-related injury will be billed to you or your health 
insurance. 
 
D2. WILL I BE PAID FOR PARTICIPATING IN THE STUDY? 
There is no payment for being in this study  
 
D3. WHAT OTHER HEALTHCARE CHOICES DO I HAVE? 
You do not have to join this study. You are free to say yes or no. If you do not join this 
study, your doctor can discuss other healthcare choices with you.  
 
Your other choices may include: 
 Getting treatment or care for your cancer without being in a research study. 
 Taking part in another research study. 


Medical College of Wisconsin & Froedtert Hospital  
 
Informed Consent for Research 
Clinical Interventions template - Version: October 31, 2016 
 
IRB Protocol Number: 28985 
IRB Approval Period: 05/08/2018 – 05/07/2019 
Page 7 of 10 
Version: 2/27/2018 
EFFECTIVE 
 
05/08/2018 
 
MCW/FH IRB
 Getting no treatment. 
 
The study doctor can explain both the possible benefits and the risks of other options 
that are available to you. 
 
D4. WILL I BE GIVEN NEW INFORMATION ABOUT THE STUDY? 
If we learn any important new information about the study drug, that might change your 
mind about being in the study, we will tell you about it right away.  You can then decide 
if you want to stay in the study. 
 
D5. WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THE STUDY?  
Emergency medical treatment for injuries directly related to your participation in this 
research study will be provided to you. You or your health insurance will be billed for the 
costs of this emergency treatment.  MCW will decide on a case by case basis if they will 
reimburse you or your insurer for emergency treatment costs.  If your research-related 
injury requires medical care beyond this emergency treatment, you or your insurer will 
be responsible for the costs of this follow-up care.  
 
At this time, there is no plan for any additional financial payments. 
 
If you believe that you have been injured because of your participation in this study, 
contact the study doctors right away.  Contact information: Dr. Atallah, 414-805-6700.  
 
Nothing in this consent form affects any legal rights you may have nor does it 
release the investigator, the sponsor, the institution, or its agents from liability for 
negligence. 
 
D6. WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? 
 
If you have more questions about this study at any time, you can call Dr. Atallah at 
414-805-6700. 
 
If you have questions about your rights as a study participant, want to report any 
problems or complaints, obtain information about the study, or offer input, you can 
call the MCW/Froedtert Hospital Research Subject Advocate at 414-955-8844. 
 
E. PERMISSION TO COLLECT, USE AND SHARE HEALTH INFORMATION 
 
E1. What health information will be collected and used for this study? 
To be in this research study, the study team needs your permission to access, collect 
and use some of your health information. If you say no, you cannot be in the study. This 
information may come from questions we ask, forms we ask you to fill out, or your 
medical record, as described below. We will only collect and use information needed for 
the study. 
 
The protected health information (PHI) originates from services you will or have 
received at one or more of the following locations: the Medical College of Wisconsin 


Medical College of Wisconsin & Froedtert Hospital  
 
Informed Consent for Research 
Clinical Interventions template - Version: October 31, 2016 
 
IRB Protocol Number: 28985 
IRB Approval Period: 05/08/2018 – 05/07/2019 
Page 8 of 10 
Version: 2/27/2018 
EFFECTIVE 
 
05/08/2018 
 
MCW/FH IRB
(MCW); BloodCenter of Wisconsin (BCW); Children’s Hospital of Wisconsin (CHW); any 
Froedtert Health Affiliate- Froedtert Memorial Lutheran Hospital (FMLH), Inc.; 
Community Memorial Hospital (CMH) Menomonee Falls, Inc.;  St. Joseph’s Community 
Hospital (SJH) West Bend, Inc.;  Froedtert & The Medical College of Wisconsin 
Community Physicians Clinics, Inc. (FMCWCP); the West Bend Surgery Center, LLC; 
and the Froedtert Surgery Center, LLC.  
 
The health information to be collected and used for this study is:  
 Hospital/Medical Records 
 Physician/Clinical Records 
 Lab and/or Pathology Reports 
 Radiology Reports 
 Biological Samples 
 
E2. Who will see the health information collected for this study? 
The only MCW/Froedtert Hospital employees allowed to handle your health information 
are those on the study team, those on the Institutional Review Board (IRB) and those 
who check on the research activities to make sure the hospital’s rules are followed. 
 
If the costs of any necessary emergency medical treatment in the event of a research-
related injury are billed to your health insurance, your health information may need to be 
disclosed to the insurer for billing purposes. 
 
The study team may share your information with people who don’t work at 
MCW/Froedtert Hospital because they planned, pay for, or work with us on this study.  
The federal Privacy Rule may no longer protect your health information once it leaves 
MCW/Froedtert Hospital.  For this study, we plan to share information with those 
doctors, researchers or government representatives working with us on this study at the 
institutions or companies listed here: 
 Any federal, state, or local governmental agency that regulates the study (such 
as the U.S. Food and Drug Administration (FDA)  
 The U.S. Department of Health & Human Services (DHHS) 
 The Office for Human Research Protections (OHRP) 
 Other government agencies in this or other countries 
 The designated Data Safety Monitoring board and Institutional Review Board 
which is a committee that has reviewed this research study to help ensure that 
your rights and welfare as a research participant are protected and that the 
research study is carried out in an ethical manner, and Privacy Boards and their 
related staff that have oversight responsibilities for this study.  
 Personnel from the study site that provide study related treatment or procedures 
 Those required by law 
 
Because this study involves the use of drugs and/or devices, the FDA also has the right 
to inspect all study records. 


Medical College of Wisconsin & Froedtert Hospital  
 
Informed Consent for Research 
Clinical Interventions template - Version: October 31, 2016 
 
IRB Protocol Number: 28985 
IRB Approval Period: 05/08/2018 – 05/07/2019 
Page 9 of 10 
Version: 2/27/2018 
EFFECTIVE 
 
05/08/2018 
 
MCW/FH IRB
 
We may record your research information, including results of tests and procedures 
done for research, in your Froedtert Hospital and/or Medical College of Wisconsin 
medical record.  As a result, this research information may be seen by people allowed 
to see your medical records for healthcare operations or treatment, by those you allow 
to see your medical records by giving written permission, and by others when required 
by law. 
 
We will not use your personal health information for a different study without your 
permission or the permission of a hospital research review board (IRB). Once all 
personal identification is removed, the information might be used or released for other 
purposes without asking you. Results of the study may be presented in public talks or 
written articles, but no information will be presented that identifies you. 
  
E3. What are the risks of sharing this health information? 
One risk of taking part in a research study is that more people will handle your personal 
health information collected for this study. The study team will make every effort to 
protect the information and keep it confidential, but it is possible that an unauthorized 
person might see it. Depending on the kind of information being collected, it might be 
used in a way that could embarrass you or affect your ability to get insurance. If you 
have questions, you can talk to the study doctor about whether this could apply to you.  
 
E4. How long will you keep the health information for this study? 
If you sign this form, we plan to keep your information without any end-date in case we 
need to check it again for this study. 
 
E5. Can I cancel my permission to share this health information? 
If you change your mind later and do not want us to collect or share your health 
information, you need to send a letter to: 
Ehab Atallah, MD 
Froedtert Hospital & the Medical College of Wisconsin 
Division of Hematology and Oncology, 
9200 W Wisconsin Avenue 
Milwaukee, WI 53226. 
 
The letter must say that you have changed your mind and do not want the researcher to 
collect and share your health information. At that time, we may decide that you cannot 
continue to be part of the study. We may still use the information we have already 
collected.  
 
F1. FOR MORE INFORMATION ABOUT THE STUDY 
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. 


Medical College of Wisconsin & Froedtert Hospital  
 
Informed Consent for Research 
Clinical Interventions template - Version: October 31, 2016 
 
IRB Protocol Number: 28985 
IRB Approval Period: 05/08/2018 – 05/07/2019 
Page 10 of 10 
Version: 2/27/2018 
EFFECTIVE 
 
05/08/2018 
 
MCW/FH IRB
 
You can look up this study by referring to the ClinicalTrials.gov number NCT03140280 
or by asking the study team for a printed copy.    
 
 
CONSENT TO PARTICIPATE IN THE STUDY 
 
By signing my name below, I confirm the following: 
 I have read (or had read to me) this entire consent document.  All of my questions 
have been answered to my satisfaction. 
 The study’s purpose, procedures, risks and possible benefits have been explained to 
me.   
 I agree to let the study team use and share the health information and other 
information gathered for this study. 
 I voluntarily agree to participate in this research study.  I agree to follow the study 
procedures as directed.  I have been told that I can stop at any time. 
 
IMPORTANT: You will receive a signed and dated copy of this consent form.  Please 
keep it where you can find it easily.  It will help you remember what we discussed today. 
 
 
 
 
Subject's Name please print  
Subject's Signature 
Date 
 
 
 
 
 
Name of Witness (if applicable) 
please print  (for short form consent 
process, or consent of blind or illiterate 
subject) 
Signature of Witness 
 
Date 
 
 
 
* Name of person discussing/ 
obtaining consent please print  
Signature of person 
discussing/obtaining consent 
Date 
* A member of the study team trained and authorized by the Principal Investigator to act on her/his behalf 
in obtaining informed consent according to the protocol.  In all research study protocols the Principal 
Investigator is responsible and accountable for the study.