Clinical trial NCT01259856
Conditions: High Risk Polycythemia Vera High Risk Essential Thrombocythemia
Keywords: Polycythemia vera Essential thrombocythemia Hydroxyurea PEGASYS Pegylated Interferon Alfa-2a
Sponsor: Ronald Hoffman
Start date: 2011-09-01; Completion date: 2017-06-30
Enrollment: 168 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research is looking at two conditions, Essential Thrombocythemia (ET) and Polycythemia Vera (PV). ET causes people to produce too many blood cells called platelets and PV causes too many platelets and red blood cells to be made. Platelets are particles which circulate in the blood stream and normally prevent bleeding and bruising. Having too many platelets in the blood increases the risk of developing blood clots, which can result in life threatening events like heart attacks and strokes. When the number of red blood cells is increased in PV this will slow the speed of blood flow in the body and increases the risk of developing blood clots.

The purpose of this study is to look at the effectiveness of giving participants who have been diagnosed with ET or PV one of two different study regimens over time. The study subject will be followed for their condition for about 5 years. The subject will be randomized into one of two study regimens, either Pegylated Interferon Alfa-2a (PEGASYS) or Aspirin and Hydroxyurea (also called Hydroxycarbamide). The subject must be newly diagnosed or already receiving treatment for either PV or ET. Each of the study drugs used in this study is already being used to treat subjects with ET or PV currently, but the investigators are unsure which study drug is better.

Detailed description:
The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are a group of clonal hematological malignancies that are characterized by a chronic course which can be punctuated by a number of disease related events including thrombosis, hemorrhage, pruritis and leukemic transformation. These disorders include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PM). Recently an acquired somatic mutation in the intracellular kinase, JAK2 (JAK2V617F) has been observed in 95% of patients with PV, 50% of patients with ET and 50% of patients with primary myelofibrosis. At present the chemotherapeutic agent hydroxyurea is the standard of care for high risk patients with PV. Concern exists about prolonged use of this drug leading to leukemia and the inability of hydroxyurea to eliminate the malignant clone.

Interferon (rIFN -2b), is a drug that appears to be non-leukemogenic, and may have a preferential activity on the malignant clone in PV, as suggested by cytogenetic remissions obtained in patients treated with rIFN -2b. Several investigators recently reported that patients with PV treated with rIFN -2b had lower JAK2V617F allele burdens as compared to a control group that included patients treated with phlebotomy, hydroxyurea, or anagrelide, or who remained untreated. The results confirm the hypothesis that rIFN -2b preferentially targets the malignant clone in PV and raises the possibility that the JAK2V617F allele burden, and a reversion of clonal hematopoiesis monitored in females by expression of X-chromosome polymorphic alleles maybe useful in monitoring minimal residual disease in PV patients.

Pegylated Interferon Alfa-2a (PEGASYS) has been demonstrated in phase II trials of patients with PV and ET to have clinical efficacy as measured by normalization of myeloproliferation, lack of vascular events while on therapy, and a decrease in the JAK2V617F allele burden. Overall the tolerability of the therapy was good, with each of these trials having a dropout rate secondary to toxicity of less than 10% of those enrolled. Although dropout rates for toxicity were low, that is not to say the therapy was without symptomatic toxicity, and indeed a spectrum of toxicities might be encountered and need to be weighed in the analysis of the net clinical benefit patients experience on a clinical trial with Pegylated Interferon Alfa-2a.

A new MPN assessment form will be utilized in this study. This 19 item instrument includes a previously validated 9 item brief fatigue inventory (BFI), symptoms related to splenomegaly, inactivity, cough, night sweats, pruritus, bone pains, fevers, weight loss, and an overall quality of life assessment. The instrument yields an independent result for each symptom (fatigue is a composite score), as this methodology (of linear analog scale assessment \[LASA\]) has proven very valid in the past. This instrument was validated prospectively (by comparison to a panel of instruments each containing an aspect of the MPN-SAF) for administration at a single time point.

This is a randomized trial between hydroxyurea and Pegylated Interferon Alfa-2a, it is an open label clinical trial in two independent disease strata: (1) high risk polycythemia vera and (2) high risk essential thrombocythemia.

Arms: arm 1: The subject will begin receiving the PEGASYS at a dose level of 45 micrograms weekly and gradually get increased to the maximum dose of 180 micrograms per week. The dose will be administered by prefilled syringes that will be injected subcutaneously. Subjects will receive therapy for up to 12 months. arm 2: Subjects will receive a 500mg tablet to be taken twice daily for up to 12 months of treatment.
Interventions: intervention 1: PEGASYS intervention 2: Hydroxyurea intervention 3: Aspirin
Intervention descriptions: intervention 1: The subject will begin receiving the PEGASYS at a dose level of 45 micrograms weekly and gradually get increased to the maximum dose of 180 micrograms per week. The dose will be administered by prefilled syringes that will be injected subcutaneously. Subjects will receive therapy for up to 12 months. intervention 2: Subjects will receive a 500mg tablet to be taken twice daily for up to 12 months of treatment. intervention 3: Subject will be asked to take 81 to 100mg per day for the 12 months of the study treatment.

Protocol documents:
Prot_SAP_000.pdf: 
 
 Myeloproliferative Disorders-Research Consortium (MPD-RC)  
MPD-RC 112  
Randomized Trial of Pegylated Interferon Alfa-2a versus Hydroxyurea Therapy in the Treatment 
of High Risk Polycythemia Vera and High Risk Essential Thrombocythemia 
 
NCT01259856 
Version #8 12/21/2015 


MPD-RC 112 PEGHU-Phase 3 
MPD-RC 112 PEGHU-Phase 3 
 
Version #8  12/21/2015 
Myeloproliferative Disorders-Research Consortium (MPD-RC)  
MPD-RC 112 
Randomized Trial of Pegylated Interferon Alfa-2a versus Hydroxyurea Therapy in the 
Treatment of High Risk Polycythemia Vera and High Risk Essential Thrombocythemia 
Mandatory Companion Protocol MPD-RC 107 
EudraCT #2010-019501-41 
 
Study Chairs (United States) 
Ronald Hoffman, MD  
Icahn School of Medicine at Mount Sinai  
One Gustave L. Levy Place, Box 1079 
New York, NY 10029 
Phone: 212-241-2296 
Fax: 212-876-5276  
ronald.hoffman@mssm.edu 
Ruben Mesa, MD 
Mayo Clinic 
13400 E. Shea Blvd. 
Scottsdale, AZ 85259 
Phone: 480-301-8335 
Fax: 480-301-4675 
mesa.ruben@mayo.edu 
John Mascarenhas, MD 
Icahn School of Medicine at Mount Sinai 
One Gustave L. Levy Place, Box 1079 
New York, NY 10029 
Phone: 212-241-1948 
Fax: 212-876-5276 
john.mascarenhas@mssm.edu 
 
Study Chairs (Europe) 
Jean-Jacques Kiladjian, MD 
Hopitaux de Paris Assitance  
Publique– Hopitaux de Paris,  
Hopital Saint-Louis 
Centre d‟Investigation Clinique 
1 Avenue Claude Vellefaux 
75010 Paris, France 
Jean-jacques.kiladjian@sls.aphp.fr 
 
Mary Frances McMullin, MD  
Department of Hematology  
Belfast City Hospital 
C Floor Lisburn Road 
Belfast BT9 7AB 
Northern Ireland 
Phone: 02890263733 
Fax: 02890236870 
m.mcmullin@qub.ac.uk 
Claire Harrison, MD 
Department of Hematology  
St. Thomas’ Hospital  
Lambeth Palace Road 
London SE1 7EH 
Tel: 020 71882739 
Fax: 02071882728 or 02071882717 
Claire.harrison@gstt.sthames.nhs.uk 
 
Project 6 Chair 
Ronald Hoffman, MD  
Icahn School of Medicine at Mount Sinai  
One Gustave L. Levy Place, Box 1079 
New York, NY 10029 
Phone: 212-241-2296 
Fax: 212-876-5276  
ronald.hoffman@mssm.edu 
Project 6 Associate Chair 
John Mascarenhas, MD 
Icahn School of Medicine at Mount Sinai 
One Gustave L. Levy Place, Box 1079 
New York, NY 10029 
Phone: 212-241-1948 
Fax: 212-876-5276 
john.mascarenhas@mssm.edu 
 
Co-Investigator, Statistics 
Judith D. Goldberg, ScD 
New York University School of Medicine 
650 First Ave, 534 
New York, New York 10016, USA  
Phone: 212-263-0314 
Fax: 212-263-8570 
jd.goldberg@nyumc.org 
Data Management 
Giovanni Tognoni, MD 
IRCCS Istituto di Ricerche 
Farmacologiche  
Mario Negri 
Via La Masa, 19  
20156 Milano  
+39 02 390141  
+39 02 3546277  
mpdtrials@mpdrc.org 
www.marionegri.it 
Co-Investigator, Tissue Bank 
Rona Singer Weinberg, PhD 
New York Blood Center 
310 East 67th Street 
Room 2-46 
New York, New York 10065 
Phone: (212) 570-3488 
Fax: (212) 570-3495 
rweinberg@nybloodcenter.org  
 
 
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Date:  01/04/2013 
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Date:  6/05/2012 
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Date:  6/20/2011 
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Version #1 
 
Date:  3/16/2010 


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Trial Centers 
 
Belfast City Hospital, Belfast  
Mary Frances McMullin  
Department of Hematology  
Belfast City Hospital 
C Floor 
Lisburn Road 
Belfast, Northern Ireland BT9 7AB  
Tel: 02890263733 
Fax: 02890263870 
Email:  m.mcmullin@qub.ac.uk 
 
Emory Hospital 
Elliot Winton, MD. 
1365 Clifton rd. NE  
Atlanta, GA 30322 
Tel: 404-778-5871 
Fax: 404-778-5520 
Email: ewinton@emory.edu 
 
Geisinger Cancer Center 
Joseph Vadakara, MD 
1740 E. Broad St.  
Hazelton, PA 18201 
Tel: 570-271-6045 
Fax: 570-271-6195 
Email: jvadakara@geisinger.edu 
 
Georgetown University Medical Center 
Craig Kessler, MD 
3700 Reservoir Road NW  
Washington, DC 20007 
Tel: 202-444-8676 
Fax: 202-444-1229 
Email:  kesslerc@gunet.georgetown.edu 
 
Guy’s and St Thomas’ NHS Foundation 
Trust 
Claire Harrison, MD 
Consultant Haematologist  
Department of Hematology  
St. Thomas’ Hospital  
Lambeth Palace Road 
London SE1 7EH 
Tel: 020 71882739 
Fax: 02071882728 or 02071882717 
Email: Claire.harrison@gstt.nhs.uk 
Hopitaux de Paris 
Jean-Jacques Kiladjian 
Assitance Publique – Hopitaux de Paris,  
Hopital Saint-Louis 
Centre d‟Investigation Clinique 
1 Avenue Claude Vellefaux 
75010 Paris France 
Email: jean-jacques.kiladjian@sls.aphp.fr 
 
 
 
John H. Stroger Hospital of Cook County 
Rose Catchatorian, MD 
Administration Bldg. Rm. 751 
1900 W. Polk St. Chicago, IL 60612 
Tel: 312-864-7257 
Fax: 312-864-9002  
Email: rcatchator@ccbhs.org 
 
Mayo Clinic – Arizona 
Ruben A. Mesa, MD 
13400 E Shea BLVD  
Scottsdale, AZ 85259 
Tel: 480-301-8335 
Fax: 480-301-4675 
Email:  mesa.ruben@mayo.edu 
 
Memorial Sloan-Kettering Cancer Center 
Raajit Rampal, MD, PhD 
1275 York Ave., Box 443 
New York, NY 10065 
Tel: 212-639-2194 
Fax: 212-772-8550 
Email: rampalr@mskcc.org  
 
Icahn School of Medicine at Mount Sinai 
Ronald Hoffman, MD 
One Gustave L. Levy Place, Box 1079 
New York, NY 10029 
Tel: 212-241-2296 
Fax: 212-876-5276 
Email: ronald.hoffman@mssm.edu 
 
 
 


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Ospedale San Martino Genova 
Andrea Bacigalupo, MD. 
A.O. San Martino 
L.go R. Benzi, 10 
Genova, Italy 11632 
Tel: 39-010-555469 
Fax: 39-010-355583 
Email: andrea.bacigalupo@hsanmartino.it 
 
Azienda Ospedaliera Papa Giovanni 
XXIII 
Alessandro Rambaldi, MD.  
Piazza OMS- Organizzazione Mondiale della 
Sanità, 1  
24127 Bergamo 
Tel: +39 035-2673681 
Fax: +39 035-2674968 
Email: arambaldi@hpg23.it  
 
The Palo Alto Clinic 
David Liebowitz, MD. 
795 El Camino Real 
Palo Alto, CA 94301 
Tel: 650-853-2905 
Fax: 650-853-2966 
Email: leibowd@pamf.org 
 
Stanford Cancer Institute 
Jason Gotlib, MD 
875 Blake Wilbur Dr. 
Stanford, CA 94305 
Tel: 650-725-0744 
Fax: 650-724-5203 
Email: Jason.gotlib@stanford.edu  
 
Universita Cattolica del Sacro Cuore 
Giuseppe Leone 
Largo Agostino Gemelli   
Rome, 00168 Italy 
Tel: 390630154180 (Office) 
Mobile: 3932475014730 
Fax: 39-06-35503777 
Email: gleone@rm.unicatt.it 
 
Universitätsklinikum Freiburg 
Prof. Dr. Cornelius Waller 
Department of Hematology & Oncology 
Hugstetter Str. 55 
79106 Freiburg, Germany 
Tel: 49 0761 270 34220 
Fax: 49 0761 270 34180 
Email: Cornelius.waller@uniklinik-freiburg.de 
 
University Hospital of Aachen 
Prof. Dr. Steffen Koschmieder 
Department of Medicine IV 
Clinical Trials Office 
Pauweisstrasse 30, 52074 Aachen, Germany 
Tel: 49 0241 80 89713 
Fax: 49 0241 80 82 449 
Email: skoschmieder@ukaachen.de 
 
University Hospital Ulm 
Prof. Dr. Konstanze Doehner 
Department of Internal Medicine III 
University Hospital Medical Center 
Albert-Einstein-Allee 23 89081 Ulm, 
Germany 
Tel: 49 0731 50045500 
Fax: 49 0731 50045505 
Email: Konstanze.doehner@uniklinik-ulm.de 
 
University of Cambridge 
Anthony Green 
University of Cambridge 
Department of Hematology 
Cambridge Institute for Medical Research 
Hills Road 
Cambridge CB2 2XY  
Tel: 01223 762668 
Fax: 01223 762670 
Email: arg1000@cam.ac.uk 
 
University of Florence  
Alessandro Vannucchi, MD.  
Viale Morgagni, 85 – 50135 
Florence, Italy 
Tel: 39-055-7947-688 
Fax: 39-055-7947-688 
Email: a.vannucchi@unifi.it 
 


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University of Illinois at Chicago 
Damiano Rondelli, MD. 
909 S. Wolcott, Room 3099 
Chicago, IL 60612 
Tel: 312-996-6179 
Fax: 312-413-7963 
Email: drond@uic.edu 
 
University of Kansas Cancer Center 
Abdulraheem Yacoub, MD 
2330 Shawnee Mission Parkway 
Westwood, KS 66205 
Tel: 913-588-6029 
Fax: 913-588-8279 
Email: ayacoub@kumc.edu 
 
University of Utah 
Josef Prchal, MD. 
30 North 1900 East, Room 5C310 
Salt Lake City, UT 84132 
Tel: 801-581-4220 
Fax: 801-585-3432 
Email: Josef.Prchal@hsc.utah.edu 
 
USC/Norris Comprehensive Cancer 
Center 
Casey O’Connell, MD 
1441 Eastlake Avenue 
Los Angeles, CA 90033 
Tel: 323-865-3944 
Fax: 323-865-0060 
Email: OConnell_C@med.usc.edu  
 
Wake Forest University Baptist Medical 
Center 
Dmitry Berenzon, MD 
Medical Center Boulevard 
Winston-Salem, NC 27157 
Tel: 336-716-5847 
Fax: 336-716-5687 
Email: dberenzo@wfubmc.edu 
 
Weill Cornell Medical College 
Ellen Ritchie, MD 
525 East 68th Street, Box 581 
New York, NY 10065 
Tel: 212-746-6736 
Fax: 212-746-6645 
Email: ritchie@med.cornell.edu  
 
 
 
 
 


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MPD-RC Central Coordinating Office 
Ronald Hoffman, MD 
Mount. Sinai School of Medicine 
One Gustave L. Levy Place 
New York, New York 10029 
Tel: (212) 241-2297 
Fax: (212) 876-5276 
 
Adverse Event Reporting (North America) 
Crystal Miller, RN, BSN 
MPD-RC Central Coordinating Office 
Tel: (212) 241-4273 
Fax: (212) 876-5276 
                                                            E-mail: crystal.miller@mssm.edu  
 
Adverse Event Reporting (European Union) 
Alessandra Dilellio,MD 
IRCCS Istituto di Ricerche Farmacologiche  
Mario Negri 
Via La Masa, 19  
20156 Milano  
+39 02 390141  
+39 02 3546277  
mpdtrials@mpdrc.org 
www.marionegri.it 
 
MPD-RC Statistical Center 
Judith Goldberg, ScD 
New York University 
Tel: 212-263-0314 
Fax: 212-263-8570 
E-mail: jd.goldberg@nyumc.org 
 
MPD-RC Data Management Center 
Gianni Tognoni 
IRCCS Istituto di Ricerche Farmacologiche  
Mario Negri 
Via La Masa, 19  
20156 Milano  
+39 02 390141  
+39 02 3546277  
mpdtrials@mpdrc.org 
www.marionegri.it 
MPD-RC Tissue Bank North America 
Rona Singer Weinberg, PhD 
New York Blood Center 
Phone: (212) 570-3488 
Fax: (212) 570-3495 
E-mail: rweinberg@nybloodcenter.org 
Laboratory Phone: (212) 570-3412 
Laboratory Fax: (212) 570-3495 
E-mail: MPDLab@nybloodcenter.org 
 
MPD-RC Tissue Bank Europe 
Dr. Silvia Salmoiraghi 
Laboratorio Paolo Belli USC Ematologia  
Torre 7, Ingresso 55, piano 1 
Piazza OMS- Organizzazione Mondiale della Sanità,1  
24127 Bergamo 
Phone: +39 035-2673769 


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E-mail: lab.paolobelli@hpg23.it  
 
Patient Registration:  
Online Registration:  
www.mpdrc.org 


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List of Abbreviations 
ACD 
Acid Citrate Dextrose 
ALT 
Alanine transaminase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
BD 
Becton, Dickinson and Company 
BFI 
Brief Fatigue Inventory  
BM 
Bone marrow 
BPI 
Brief Pain Inventory 
BSP 
Bromsulphalein  
BUN 
Blood urea nitrogen 
C 
Celcius 
CALR 
Calreticulin 
CBC 
Complete blood count 
CML 
Chronic myelogenous leukemia 
CMV 
Cytomegalovirus 
COSMYD 
Collaborative Study of Myeloproliferative Disorders 
CR 
Complete response  
CRA 
Clinical research associate 
CRF 
Case report form 
CRP 
C-reactive protein 
CTSU 
Clinical Trials Service Unit 
CVA 
Cerebrovascular accident 
DARF 
Drug Accountability Record Form 
DLT 
Dose limiting toxicity  
DNA 
Deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
DVT 
Deep vein thrombosis 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
Ethylenediaminetetraacetic acid 
EKG 
Electrocardiogram 
ESRD 
End stage renal disease 
ET 
Essential thrombocythemia 
EU 
European Union 
F 
Fahrenheit 
FISH 
Fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B virus 
HCT 
Hematocrit 
HIV 
Human immunodeficiency virus 


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List of Abbreviations 
HU 
Hydroxyurea  
ICH 
International Conference on Harmonisation  
IMP 
Investigational medicinal product 
JAK2 
Janus kinase, type 2 gene 
LASA 
Linear analog scale assessment  
LFTs 
Liver function tests 
MDS 
Myelodysplastic syndrome 
MI 
Myocardial infarction 
MPD-RC   
Myeloproliferative Disorders Research Consortium   
MPN 
Myeloproliferative Neoplasm 
MPN-SAF 
Myeloproliferative Neoplasm Symptom Assessment Form 
MW 
Molecular weight 
NCI 
National Cancer Institute 
NDC 
National Drug Code 
PE 
Pulmonary embolism 
PEGASYS 
Peginterferon alfa-2a 
PIN 
Patient identification number 
pKa 
Acid dissociation constant  
PNH 
Paroxysmal nocturnal hemoglobinuria 
PR 
Partial response  
PT-1 
Primary Thrombocythemia-1 trial 
PV 
Polycythemia Vera  
QOL 
Quality of life 
RCM 
Red cell mass 
SAE 
Serious adverse event 
SC 
Subcutaneous  
SCE 
Sister chromatid exchange 
SUSAR 
Suspected unexpected serious adverse drug reaction 
TB ID 
Tissue bank ID number 
TIA 
Transient ischemic attack 
TIA 
Transient ischemic attack  
TIMI 
Thrombolysis in Myocardial Infarction 
USP 
United States Pharmacopeia 
WBC 
White blood cell count 
WHO 
World Health Organization 
 
 


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Protocol Summary 
Title of clinical trial 
PEGHU-Phase3 
Sponsor name 
Myeloproliferative Disorders Research Consortium 
Icahn School of Medicine at Mount Sinai 
One Gustave L. Levy Place 
Box 1079 
New York, New York 10029 
United States  
EudraCT number for trial 
2010-019501-41 
IND number for trial 
106,511 (Exempt) 
Medical condition or disease under 
investigation 
High Risk Polycythemia Vera and High Risk Essential 
Thrombocythemia 
Primary objectives:  
• To compare the complete hematologic response rates 
(by LeukemiaNet Criteria) in patients randomized to 
treatment with the Pegylated Interferon Alfa-2a 
(PEGASYS) vs. Hydroxyurea in two strata of patients 
with (1) high risk polycythemia vera or (2) high risk 
essential thrombocythemia.  
Secondary objectives:  
 
• To compare the toxicity, safety and tolerability of 
therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) 
in the study populations. 
• To compare the hematologic partial response rates on 
therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) 
by LeukemiaNet criteria. 
• To compare specific pre-defined toxicity and tolerance 
of therapy (Pegylated Interferon Alfa-2a vs. 
Hydroxyurea) and validate the utility of sequential 
structured symptom assessment package of patient 
reported outcome instruments. 
• To compare the impact of therapy (Pegylated Interferon 
Alfa-2a vs. Hydroxyurea) on key biomarkers of the 
disease(s) – JAK2V617F, CALR, hematopoietic cell 
clonality in platelets and granulocytes in females, bone 
marrow histopathology, and cytogenetic abnormalities. 
• To estimate survival and incidence of development of 
myelodysplastic disorders, myelofibrosis, or leukemic 
transformation while on active treatment or observation 
following end of treatment (Pegylated Interferon Alfa-2a 
vs. Hydroxyurea). 
• To estimate incidence of major cardiovascular events 
(defined as cardiovascular death, myocardial infarction, 
stroke, transient ischemic attack, pulmonary embolism, 
Budd Chiari syndrome, deep vein thrombosis, and any 
other clinically relevant thrombotic event) while on 
active treatment or observation following end of 
treatment (Pegylated Interferon Alfa-2a vs. HU). 


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Study Design  
A randomized open label clinical trial between hydroxyurea 
and Pegylated Interferon Alfa-2a in: (1) high risk 
polycythemia vera and (2) high risk essential 
thrombocythemia. 
Sample Size 
300 subjects 
Summary of eligibility criteria 
 
 
 
 
 
 
 
Inclusion Criteria: 
High risk PV ANY ONE of the following: 
• Age >60 years 
• Previous documented thrombosis, erythromelalgia or 
migraine either after diagnosis or within 10 years before 
diagnosis and considered to be disease related 
• Significant splenomegaly (i.e. > 5cm below costal 
margin on palpation) or symptomatic (pain, early 
satiety) splenomegaly  
• Platelets > 1000 x 109/L 
• Diabetes or hypertension requiring pharmacological 
therapy 
High risk ET ANY ONE of the following factors: 
• Age > 60 years 
• Platelet count > 1500 x 109/L 
• Previous thrombosis 
• Previous hemorrhage related to ET 
• Diabetes or hypertension requiring pharmacological 
therapy 
Other Inclusion criteria 
• Diagnosed less than 5 years prior to entry on trial 
• Never treated with cytoreductive drugs except 
hydroxyurea for up to 3 months maximum 
(phlebotomy, aspirin allowed, anagrelide allowed) 
• Age: ≥ 18 years (no upper limit) 
• Ability and willingness to comply with all study 
requirements 
• Signed informed consent to participate in this study. 
• Willing to participate in associated correlative science 
biomarker study 
• Serum creatinine ≤1.5 x upper limit of normal 
• AST and ALT ≤ 2 x upper limit of normal 
• No known PNH (paroxysmal nocturnal hemoglobinuria) 
clone 
• No concurrent hormonal oral contraceptive use 
Exclusion criteria: (ANY of) 
• Known to meet the criteria for primary myelofibrosis (as 
opposed to ET) by WHO 2008 
• Patients with a prior malignancy within the last 5 years 
(except for basal or squamous cell carcinoma, or in situ 
cancer of the cervix) 


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• Any contraindications to pegylated interferon or 
hydroxyurea 
• Presence of any life-threatening co-morbidity 
• History of active substance or alcohol abuse within the 
last year 
• Subjects who are pregnant, lactating or of reproductive 
potential and not practicing an effective means of 
contraception 
• History of psychiatric disorder (e.g. depression): 
Subjects with a history of mild depression may be 
considered for entry into this study, provided that a 
pretreatment assessment of the subject's affective status 
supports that the subject is clinically stable based on the 
investigator's normal practice for such subject.  
• History of active or uncontrolled autoimmune disorder 
(e.g. hepatitis) 
• Hypersensitivity to interferon alfa 
• Hepatitis B or C infection (HBV), or untreated systemic 
infection 
• Known HIV disease 
• Evidence of severe retinopathy (e.g. CMV retinitis, 
macular degeneration) or clinically relevant 
ophthalmological disorder (e.g. due to diabetes mellitus 
or hypertension) 
• History or other evidence of decompensated liver 
disease 
• History or other evidence of chronic pulmonary disease 
associated with functional limitation 
• Thyroid dysfunction not adequately controlled 
• Neutrophil count <1.5 x 109/L 
• JAK2 exon 12 mutation: PV that lacks the JAK2V617F 
mutation but is characterized by the exon 12 mutation. 
• Meets criteria for post PV or post ET-MF (see Appendix 
A) 
• Subjects with any other medical condition, which in the 
opinion of the investigator would compromise the 
results of the study by deleterious effects of treatment. 
• Previous exposure to any formulation of pegylated 
interferon 
• History of major organ transplantation 
• History of uncontrolled severe seizure disorder 
• Inability to give informed written consent 
• Total bilirubin >1.5 x ULN (patients that have an 
isolated indirect bilirubin that causes total bilirubin to be 
elevated beyond 1.5 x ULN due to documented 
Gilbert’s syndrome or hemolysis may be included).  


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Investigational medicinal product 
and dosage 
Hydroxyurea (also known as Hydroxycarbamide).  Dosage 
of this is dependent on each individual’s hematocrit and 
platelet count. 
Aspirin in low doses is to be administered to all patients 
(unless patient is intolerant to this in which case substitution 
of alternative is permitted) 
Active comparator product(s) 
Pegylated Interferon Alfa-2a. Dosage is dependent upon 
achievement of therapeutic target and assessment of 
toxicity. 
Treatment Duration 
Patients will be treated for up to 12 months (with 3 months 
for confirmation -  therefore up to 15 months) to achieve 
CR or PR. Patients who achieve a CR or PR will be 
followed and remain on drug for up to a maximum of 6 
years from randomization. Minimum follow up is 2 years 
from the time the last patient is randomized.   
Route(s) of administration  
Subcutaneous – (pegylated interferon alpha 2a)  
or oral – (hydroxyurea) 
Maximum duration of treatment of a 
subject 
6.0 years  


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PROTOCOL SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*See Section 3.0 for Eligibility Criteria
Essential 
Thrombocythemia 
Polycythemia 
Vera 
Registration & 
Randomization 
Dose Titration  
Hydroxyurea 
Dose Titration  
PEGASYS 
Evaluate 
Evaluate 
Stable Dosing 
PEGASYS 
Stable Dosing 
Hydroxyurea 
Study 
Discontinuation 
Stopping Criteria 
Both Strata 
*See Section 5.7 
CR or PR 
CR or PR 
SD or No 
Response 
SD or No 
Response 
0 M 
Timeline 
(Months) 
1-6 M 
3 M 
12 M 
12 to 
(24-72) M 
In Pegasys arm: 
concurrent hydroxyurea 
must be stopped before 
beginning of 3 months 
Dose Titration 
*See Section 5.2.1 
Goal CR, 
Manageable Toxicity 
Observation/ 
Follow-up 
*See Section 5.8 


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TABLE OF CONTENTS 
 
TRIAL CENTERS 
LIST OF ABBREVIATIONS 
PROTOCOL SUMMARY 
PROTOCOL SCHEMA 
1.0 
OBJECTIVES .......................................................................................................... 20 
1.1 
Primary Objective: ................................................................................................. 20 
1.2 
Secondary Objectives: ........................................................................................... 20 
2.0 
INTRODUCTION AND RATIONALE ................................................................. 21 
2.1 
Introduction ........................................................................................................... 21 
2.2 
Rationale for Interventions .................................................................................... 22 
2.2.1 
JAK2V617F Status ......................................................................................... 22 
2.2.2 
Hydroxyurea ................................................................................................... 22 
2.2.3 
Interferons ....................................................................................................... 22 
2.2.4 
Aspirin ............................................................................................................ 24 
2.3 
Investigational Agents ........................................................................................... 24 
2.3.1 
Pegylated Interferon Alfa-2a (PEGASYS) ..................................................... 24 
2.3.2 
Hydroxyurea®/Hydroxyurea/Hydroxy Carbamide ........................................ 25 
3.0 
PATIENT ELIGIBILITY ....................................................................................... 32 
3.1 
Inclusion Criteria ................................................................................................... 32 
3.2 
Exclusion Criteria .................................................................................................. 33 
3.3 
Subject Recruitment and Screening ....................................................................... 34 
3.4 
Early Withdrawal of Subjects ................................................................................ 34 
3.4.1 
When and How to Withdraw Subjects ........................................................... 34 
3.4.2 
Data Collection and Follow-up for Withdrawn Subjects ............................... 35 
4.0 
REGISTRATION, MANDATORY SAMPLE SUBMISSION, AND DATA 
MANAGEMENT ................................................................................................................ 36 
4.1 
Registration Requirements .................................................................................... 36 
4.1.1 
Site Registration with MPD-RC ..................................................................... 36 
4.1.2 
Study Drug Shipment ..................................................................................... 36 


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4.1.3 
Correlative Biomarker Study (MPD-RC 107) ................................................ 36 
4.1.4 
Informed Consent ........................................................................................... 36 
4.2 
Patient Registration................................................................................................ 37 
5.0 
TREATMENT PLAN .............................................................................................. 38 
5.1 
Dose Titration and Study Duration ........................................................................ 38 
5.2 
Specific Dosing for Each Agent ............................................................................ 38 
5.2.1 
Dose Titration of Hydroxyurea ....................................................................... 38 
5.2.2 
Dose Titration of Pegylated Interferon Alfa-2a .............................................. 39 
5.3 
Phlebotomy Guidelines.......................................................................................... 40 
5.4 
Aspirin Therapy ..................................................................................................... 40 
5.5 
Pregnancy .............................................................................................................. 40 
5.6 
Intolerance or resistance to Hydroxyurea .............................................................. 40 
5.7 
Discontinuation of Treatment ................................................................................ 40 
5.8 
Treatment Failure/Observational Follow-up ......................................................... 42 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS ......................................................... 43 
7.0 
PHARMACEUTICAL INFORMATION .............................................................. 45 
7.1 
Pegylated Interferon Alfa-2a (IND #106,511) ...................................................... 45 
7.1.1 
Description...................................................................................................... 45 
7.1.2 
Packaging of Study Drug Pegylated Interferon Alfa-2a ................................. 45 
7.1.3 
Method for Assigning Subjects to Treatment Groups .................................... 45 
7.1.4 
Prior and Concomitant Therapy ..................................................................... 45 
7.1.5 
Receiving, Storage, Dispensing and Return of Study Drug pegylated 
interferon alfa-2a ............................................................................................ 45 
7.2 
Hydroxyurea .......................................................................................................... 46 
7.2.1 
Description...................................................................................................... 46 
7.2.2 
Packaging........................................................................................................ 47 
7.2.3 
Storage ............................................................................................................ 47 
7.2.4 
Method for Assigning Subjects to Treatment Groups .................................... 47 
7.2.5 
Prior and Concomitant Therapy ..................................................................... 47 
7.3 
Aspirin ................................................................................................................... 47 
8.0 
BIOMARKERS ........................................................................................................ 49 


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8.1 
Samples to be Collected ........................................................................................ 49 
8.2 
Collection of Biomarker Samples: ........................................................................ 52 
8.2.1 
Bone Marrow .................................................................................................. 52 
8.2.2 
Peripheral Blood ............................................................................................. 52 
8.2.3 
Nail Clippings ................................................................................................. 52 
8.3 
Central Morphological Review of Bone Marrow Aspirate Smears and Biopsies for 
Patients Entering MPD-RC Treatment Studies ..................................................... 52 
8.3.1 
Bone Marrow and Peripheral Blood Histopathology ..................................... 52 
8.3.2 
Cytogenetics and FISH Cytogenetic and FISH Requirements ....................... 54 
8.4 
Clonality ................................................................................................................ 55 
8.5 
Symptom Assessment Package ............................................................................. 55 
8.6 
Registration Procedure .......................................................................................... 55 
8.7 
Biomarker Evaluations .......................................................................................... 56 
9.0 
STUDY EVENTS ..................................................................................................... 57 
9.1 
Screening and Enrollment ..................................................................................... 57 
9.1.1 
Baseline Data .................................................................................................. 57 
9.2 
Study Calendar ...................................................................................................... 58 
9.3 
Procedures for the follow-up visit ......................................................................... 60 
9.4 
Interruption of Treatment ...................................................................................... 60 
9.5 
Drug Compliance ................................................................................................... 60 
9.6 
Symptom Assessment Package ............................................................................. 60 
10.0 DEFINITION OF RESPONSE CRITERIA .......................................................... 62 
10.1 
Primary Endpoints ................................................................................................. 62 
10.2 
Secondary Outcomes ............................................................................................. 63 
11.0 STATISTICAL CONSIDERATIONS ................................................................... 65 
11.1 
Safety Monitoring/ Stopping Rules ....................................................................... 65 
11.2 
Statistical Analysis ................................................................................................ 66 
11.3 
Additional Analyses (conducted within disease stratum) ...................................... 67 
11.4 
Quality of life analysis ........................................................................................... 67 
11.5 
Statement of Design............................................................................................... 68 
12.0 DURATION OF PATIENT PARTICIPATION ................................................... 69 


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12.1 
Termination of Treatment and/or Study Participation ........................................... 69 
12.2 
Required Data ........................................................................................................ 69 
13.0 ADVERSE EVENTS: ASSESSMENT OF SAFETY ........................................... 70 
13.1 
Definitions ............................................................................................................. 70 
13.2 
Expected Adverse Drug Reactions ........................................................................ 71 
13.2.1 
Hydroxyurea ................................................................................................... 71 
13.2.2 
Pegylated Interferon Alfa-2a/PEGASYS ....................................................... 72 
13.2.3 
Aspirin ............................................................................................................ 74 
13.3 
Expected Serious Adverse Events ......................................................................... 75 
13.3.1 
THROMBOTIC EVENTS ............................................................................. 75 
13.3.2 
OTHER VASCULAR OCCLUSIVE EVENTS............................................. 76 
13.3.3 
HAEMORRHAGIC EVENTS ....................................................................... 76 
13.3.4 
TRANSFORMATION ................................................................................... 76 
13.3.5 
DEATH ........................................................................................................... 77 
13.4 
Recording and evaluation of adverse events ......................................................... 77 
13.4.1 
Assessment of severity ................................................................................... 78 
13.4.2 
Assessment of causality .................................................................................. 78 
13.4.3 
Outcome.......................................................................................................... 78 
13.5 
Reporting of Serious Adverse Events .................................................................... 79 
13.5.1 
Study Sponsor Notification by Investigator ................................................... 79 
13.5.2 
EC/IRB Notification by Investigator .............................................................. 79 
13.5.3 
Notifications by Sponsor ................................................................................ 79 
13.6 
MPD-RC Reporting of Suspected Unexpected Serious Adverse Reactions ......... 80 
13.6.1 
MPD-RC Reporting of SUSARs. ................................................................... 80 
13.6.2 
When to report ................................................................................................ 80 
13.6.3 
How to report .................................................................................................. 80 
13.7 
Stopping Rules ....................................................................................................... 81 
13.8 
Medical Monitoring ............................................................................................... 81 
13.9 
Monitoring Plan and Period of Observation .......................................................... 81 
13.10 Procedures for Reporting Drug Exposure during Pregnancy and Birth Events .... 82 


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14.0 ADMINISTRATIVE REQUIREMENTS .............................................................. 83 
14.1 
Good Clinical Practice ........................................................................................... 83 
14.2 
Ethical Considerations ........................................................................................... 83 
14.3 
Patient Information and Informed Consent ........................................................... 83 
14.4 
Patient Confidentiality ........................................................................................... 83 
14.5 
Protocol Compliance ............................................................................................. 84 
14.6 
Management of Information .................................................................................. 84 
14.7 
Drug Accountability .............................................................................................. 86 
14.8 
Source Documents ................................................................................................. 86 
14.9 
Case Report Forms ................................................................................................ 86 
14.10 Premature Closure of the Study ............................................................................. 86 
14.11 Record Retention ................................................................................................... 87 
14.12 Endpoint Verification ............................................................................................ 87 
14.13 Data Safety Monitoring Board .............................................................................. 87 
15.0 MODEL CONSENT FORM ................................................................................... 88 
16.0 REFERENCES ....................................................................................................... 103 
 
APPENDICES 
 
Appendix A: Definitions of Events ........................................................................ 107 
Appendix B: ECOG Performance Status................................................................ 110 
Appendix C: NCI toxicity criteria .......................................................................... 111 
Appendix D: Symptom Assessment Package ......................................................... 112 
Appendix E: Medication Diaries ............................................................................ 117 
Appendix F: NCI DARF......................................................................................... 120 
 
 
 


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LIST OF TABLES 
 
Table 1 
Symptomatic toxicities at least possibly attributed to pegylated 
interferon alfa-2a therapy in patients with polycythemia vera (PV) or 
essential thrombocythemia (ET) ............................................................. 24 
Table 2 
Dose Levels of Hydroxyurea ................................................................... 39 
Table 3 
Dose Levels of Pegylated Interferon Alfa-2a .......................................... 40 
Table 4 
Depression Guidelines ............................................................................. 44 
Table 5 
Samples to be collected ........................................................................... 49 
Table 6 
Biomarker Evaluations ............................................................................ 56 
Table 7 
Criteria for Response in ET ..................................................................... 62 
Table 8 
Criteria for Response in PV .................................................................... 62 
Table 9 
Criteria for Response in Patients with Splanchnic Vein Thrombosis ..... 63 
Table 10 Definition of molecular response in ET and PV ..................................... 64 
Table 11 Criteria for histologic response in ET and PV ........................................ 64 
Table 12 O-Brien Fleming Stopping Boundaries to Reject Null (H0) or 
Alternative (H1 Futility) Hypotheses for Interim Analyses of 
Clinical Hematologic Response Rates (2-sided alpha =0.05, power 
=85%).  Complete Response Rate on Hydroxyurea Assumed =15%; 
on Pegylated Interferon Alfa-2a Assumed =30% ................................... 65 
Table 13 O’Brien Fleming Stopping Boundaries for Complication Free 
Survival: 300 Patients Randomized to Pegylated Interferon Alfa-2a 
vs. Hydroxyurea (2-sided overall alpha =0.05, power =80%) ............... 66 
 
 
 
    


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1.0 
OBJECTIVES 
1.1 
Primary Objective: 
To compare the complete hematologic response rates (By LeukemiaNet Criteria and revised 
ELN and IWG-MRT consensus criteria) with Pegylated Interferon Alfa-2a (PEGASYS) vs. 
Hydroxyurea in patients with (1) high risk polycythemia vera or (2) high risk essential 
thrombocythemia. 
1.2 
Secondary Objectives: 
• To compare the toxicity, safety and tolerability of therapy (Pegylated Interferon Alfa-
2a vs. Hydroxyurea) in the study populations. 
• To compare the hematologic partial response rates on therapy (Pegylated Interferon 
Alfa-2a vs. Hydroxyurea) by LeukemiaNet criteria and revised ELN and IWG-MRT 
consensus criteria. 
• To compare specific pre-defined toxicity and tolerance of therapy (Pegylated Interferon 
Alfa-2a vs. Hydroxyurea) and validate the utility of sequential structured symptom 
assessment package of patient reported outcome instruments. 
• To compare the impact of therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) on 
key biomarkers of the disease(s) – JAK2V617F, CALR, hematopoietic cell clonality in 
platelets and granulocytes in females, bone marrow histopathology, and cytogenetic 
abnormalities. 
• To estimate survival and incidence of development of a myelodysplastic syndrome, 
myelofibrosis, or leukemic transformation (Pegylated Interferon Alfa-2a vs. 
Hydroxyurea). 
• To estimate incidence of major cardiovascular events (defined as cardiovascular death, 
myocardial infarction, stroke, transient ischemic attack, pulmonary embolism, Budd 
Chiari syndrome, deep vein thrombosis, and any other clinically relevant thrombotic 
event) (Pegylated Interferon Alfa-2a vs. Hydroxyurea). 


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2.0 
INTRODUCTION AND RATIONALE 
2.1 
Introduction 
The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are a group of 
clonal hematological malignancies that are characterized by a chronic course which can be 
punctuated by a number of disease related events including thrombosis, hemorrhage, pruritis and 
leukemic transformation. These disorders include polycythemia Vera (PV), essential 
thrombocythemia (ET) and primary myelofibrosis. Recently an acquired somatic mutation in the 
intracellular kinase, JAK2 (JAK2V617F) has been observed in 95% of patients with PV, 50% of 
patients with ET and 50% of patients with primary myelofibrosis. At present the chemotherapeutic 
agent hydroxyurea is the standard of care for high risk patients with PV. Concern exists about 
prolonged use of this drug leading to leukemia and the inability of hydroxyurea to eliminate the 
malignant clone. Quantitation of the JAK2V617F allele burden provides for the first time the 
opportunity to follow the effect of potential therapeutic agents on the malignant clone in patients 
with PV.  Great enthusiasm has been expressed for the use of small molecule inhibitors of JAK2 
for the treatment of patients with MPN. Phase 1/2 trials have indicated greater than expected 
toxicity, non specificity of action and an inability of these compounds to dramatically alter the 
JAK2V617F allele burden. 
Interferon (rIFN -2b), is a drug that appears to be non-leukemogenic (contrary to 32P, alkylating 
agents, and possibly other cytotoxic drugs used to treat patients with PV), and may have a 
preferential activity on the malignant clone in PV, as suggested by cytogenetic remissions 
obtained in patients treated with rIFN -2b. Several investigators recently reported that patients 
with PV treated with rIFN -2b had lower JAK2V617F allele burdens as compared to a control 
group that included patients treated with phlebotomy, hydroxyurea, or anagrelide, or who remained 
untreated (Liu et al., 2003). The results confirm the hypothesis that rIFN -2b preferentially targets 
the malignant clone in PV and raises the possibility that the JAK2V617F allele burden, and a 
reversion of clonal hematopoiesis monitored in females by expression of X-chromosome 
polymorphic alleles may be useful in monitoring minimal residual disease in PV patients. 
Symptom Assessment and QOL in ET/PV:  Utilizing the information gathered from the internet 
based survey of MPN patients (Mesa, 2007) we created a new QOL instrument specifically for 
patients with MPNs, the MPN symptom assessment form (MPN-SAF). This 19 item instrument 
includes the previously validated 9 item brief fatigue inventory (BFI) (Mendoza,1999), symptoms 
related to splenomegaly, inactivity, cough, night sweats, pruritus, bone pains, fevers, weight loss, 
and an overall quality of life assessment (Appendix D). The instrument yields an independent 
result for each symptom (fatigue is a composite score), as this methodology (of linear analog scale 
assessment (LASA)) has proven valid in the past (Locke, 2007). This instrument was validated 
prospectively (by comparison to a panel of instruments each containing an aspect of the MPN-
SAF) for administration at a single time point (Mesa, 2009). 
Symptomatic Toxicities Specific to Pegylated Interferon Alfa-2a: Pegylated interferon-2 alpha 
(PEGASYS) has been shown in phase II trials of patients with PV (Kiladjian, 2008, Quintas-
Cardama, 2009) and ET (Quintas-Cardama, 2009) to have clinical efficacy as measured by 
normalization of myeloproliferation, lack of vascular events while on therapy, and a decrease in the 
JAK2V617F allele burden. Overall the tolerability of the therapy was acceptable, with each of these 
trials having a dropout rate secondary to toxicity of less than 10% of those enrolled.  This 
represents a potential improvement in tolerability as compared to other previous trials of standard 
interferon regimens. However randomized data does not exist to support the latter observation and 


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issues of dose and schedule are important before such a conclusion can be reached. Although 
dropout rates due to toxicity were low therapy was not without symptomatic toxicity (Table 1), and 
indeed a spectrum of toxicities (granted many < grade 3) might be encountered and need to be 
weighed in the analysis of the net clinical benefit patients experience with a clinical trial of 
Pegylated Interferon Alfa-2a. 
2.2 
Rationale for Interventions 
2.2.1 
JAK2V617F Status 
Data from the PT1 trial shows that JAK2V617F positive patients with ET have an MPN that 
resembles PV (Campbell, 2005), but crude comparisons show that JAK2V617F-positive ET has 
about 2/3 the rate of complications of PV patients in the ECLAP cohort (Marchioli, 2005) 
(although the ET patients were on average 5 years younger, and more likely to be female and 
receive aspirin). Preliminary data in approximately 150 patients with primary myelofibrosis 
showed that JAK2V617F positive patients had smaller transfusion requirements but poorer 
survival than JAK2V617F negative patients (Campbell, 2006a). 
JAK2V617F positive patients are therefore a logical group to include in a trial of a therapy which 
would have the potential to reduce the JAK2V617F level and to study if this therapy would 
improve disease control and affect the complication rate compared to standard therapy. 
2.2.2 
Hydroxyurea 
Hydroxyurea inhibits the enzyme ribonucleotide diphosphate reductase which has a rate-limiting 
role in DNA synthesis. It has been shown to be efficacious in PV in the PVSG-08 study (Donovan, 
1984). In this phase II study results of those who had not received any previous treatment were 
compared with a historical control group, the venesection only arm of the PVSG-01 study 
(Kaplan, 1986). The control group had a much higher rate of thrombotic events but did not 
experience a significantly greater incidence of leukemia.  The drug was effective in reducing blood 
counts. This and a number of small single center studies show that hydroxyurea controls blood 
counts and reduces the rate of thromboembolic events in PV. Reported side effects include fever, 
rash, stomatitis, gastrointestinal upset, leg ulcers, jaundice and elevated creatinine. 
Hydroxyurea has also been shown to be effective in ET. In a randomized study of hydroxyurea as 
compared to a control group the number of thrombotic episodes was significantly reduced 
(Cortelazzo, 1995) in the hydroxyurea treated group. Hydroxyurea in combination with aspirin it 
was also shown to be superior to anagrelide (Harrison, 2005). 
Potential leukemogenicity of hydroxyurea has been an ongoing concern.  In the non-clonal 
disorder sickle cell anemia a large numbers of patients have been treated for many years and there 
has not been an increase in the number of patients with leukemia (Halsey, 2003). An increase in 
acquired DNA mutations was not observed in patients with MPN exposed to hydroxyurea in vivo 
(Hanft, 2000) and in a series of patients with ET treated with hydroxyurea alone with 17p 
deletions the risk of leukemia was low at 3.5% (Sterkers, 1998). Overall, the case for the 
leukemogenicity of hydroxyurea therapy alone remains unproven although it would appear to be 
leukemogenic if used in combination with other cytotoxic agents or following other cytotoxic 
agents. 
2.2.3 
Interferons 
Interferon has been shown to be effective and tolerable in the treatment of PV, but is associated 
with a significant number of adverse events. Polyethylene glycol-conjugated pegylated derivatives 


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of interferon alpha-require less frequent dosing and may have a more tolerable toxicity profile. A 
recent phase 2 study has shown that following pegylated interferon alfa-2a therapy the malignant 
clone as quantitated by the percentage of the mutated allele JAK2V617F was reduced in treated 
patients (Kiladjian, 2006). Interferon was shown to reverse clonal to polyclonal hematopoiesis in 
some females (Liu, 2003).  However, these studies included only limited numbers of patients 
treated with IFN-alpha, at various dosages (from 1 MU 3 times weekly to 3 MU daily) and for 
very different periods (13-132 months). 
A subsequent trial was performed at the MD Anderson Cancer Center (Quintas-Cardama 2009).  A 
total of 76 patients were enrolled and treated thus far (36 ET, 40 PV).  The initial starting dose of 
PEG-IFN-{alpha}-2a was 450 micrograms/week, but that was modified to the current starting dose 
of 90 micrograms /week. Dose modifications were allowed according to response or toxicity. 
Patients received a variety of doses including: 450 micrograms (n=1), 270 micrograms (n=3), 180 
micrograms (n=14), 135 micrograms (n=8), 90 micrograms (n=27), and 45 micrograms (n=7). 
After a median follow-up of 23 months (range, 2-38), 63 (85%) of 74 eligible patients responded. 
The median time to response was 4 weeks (range, 0.5-26). Complete response (CR) was achieved 
by 60 (81%) patients (for ET: platelets <440x109/L in the absence of thromboembolic events; for 
PV: Hb <15 g/dL no phlebotomy, with absence of splenomegaly) whereas 3 (4%) patients (1 PV, 2 
ET) had a partial response ([PR]; no phlebotomy, but still had splenomegaly). Of 5 eligible 
patients with an abnormal karyotype at the start of the study, 2 reverted to a diploid karyotype. The 
mutant JAK2V617F to total JAK2 ratio was determined by  quantitative  pyrosequencing  assay  in  
all  76  patients  prior  to  PEG-IFN-{alpha}-2a and was repeated at least once during therapy in 41 
JAK2V617F- positive patients. Overall, 23 (56%) had >10% reduction in JAK2V617F expression, 
including 14 (34%) who had a >50% reduction. In 5 (11%) of the latter the mutant allele became 
undetectable. PEG-IFN-{alpha}-2a was well tolerated in most patients. Thirty-nine episodes of 
grade 3-4 toxicity were reported: neutropenia (n=15), elevated transaminases (n=5), infection 
(n=4), fatigue (n=3), pain (n=3), cardiac (n=2), and anemia, thrombocytopenia, depression, 
shortness of breath, pruritus, thrombosis, and dizziness in 1 case each (Table 1). Sixteen (21%) 
patients were taken off study after a median of 8 months (range, 2-26) on PEG-IFN-{alpha}-2a but 
only 7 (9%) of them due to therapy-related toxicities: grade 3 neutropenia, anorexia, depression, 
ischemic retinopathy, dyspnea, confusion, and pruritic rash. 
 


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Table 1 
Symptomatic toxicities at least possibly attributed to pegylated interferon 
alfa-2a therapy in patients with polycythemia vera (PV) or essential 
thrombocythemia (ET) 
  
MDACC Trial (Quintas-Cardama 2009) 
  
PV-NORD Trial (Kiladjian 2008) 
  
ET (N=39) 
PV (N=40) 
  
PV (N=40) 
Toxicity 
Grade 
1 
Grade 
2 
Grade 
3 
Grade 
4 
Grade 
1 
Grade 
2 
Grade 
3 
Grade 
4 
  
Grade 
1 
Grade 
2 
Grade 
3 
Grade 
4 
Fatigue 
31% 
31% 
3% 
0% 
28% 
45% 
5% 
0% 
  
  
25% 
0% 
0% 
Flu-like 
23% 
15% 
0% 
0% 
38% 
5% 
0% 
0% 
  
  
  
  
  
Dizziness 
13% 
0% 
3% 
0% 
10% 
10% 
0% 
0% 
  
  
0% 
0% 
0% 
Inj site rxn 
10% 
0% 
0% 
0% 
15% 
3% 
0% 
0% 
  
  
  
  
  
Dyspnea 
10% 
13% 
0% 
0% 
3% 
10% 
3% 
0% 
  
  
  
  
  
Pain 
8% 
23% 
7% 
0% 
18% 
38% 
3% 
0% 
  
  
5% 
0% 
0% 
Depression 
8% 
23% 
3% 
0% 
0% 
25% 
0% 
0% 
  
  
20% 
0% 
0% 
Blurred Vision 
8% 
3% 
0% 
0% 
8% 
5% 
0% 
0% 
  
  
0% 
0% 
0% 
Insomnia 
8% 
8% 
0% 
0% 
10% 
8% 
0% 
0% 
  
  
  
  
  
Anorexia 
5% 
3% 
0% 
0% 
3% 
5% 
0% 
0% 
  
  
  
  
  
Weight Loss 
3% 
3% 
0% 
0% 
3% 
3% 
0% 
0% 
  
  
3% 
0% 
0% 
Weakness 
3% 
13% 
0% 
0% 
5% 
15% 
0% 
0% 
  
  
  
  
  
Pruritis 
3% 
8% 
0% 
0% 
8% 
15% 
3% 
0% 
  
  
  
  
  
Sweating 
3% 
3% 
0% 
0% 
8% 
5% 
0% 
0% 
  
  
  
  
  
Fever 
0% 
0% 
0% 
0% 
0% 
0% 
0% 
0% 
  
  
18% 
0% 
0% 
Decreased 
Libido 
0% 
0% 
0% 
0% 
0% 
0% 
0% 
0% 
  
  
3% 
0% 
0% 
Hot Flashes 
0% 
0% 
0% 
0% 
0% 
0% 
0% 
0% 
  
  
3% 
0% 
0% 
Flushing 
0% 
5% 
0% 
0% 
0% 
5% 
0% 
0% 
  
  
  
  
  
 
2.2.4 
Aspirin 
The ECLAP study established the therapeutic benefit of aspirin in PV (Landolfi, 2004). Patients 
were randomized between aspirin 100mg daily and placebo. Aspirin significantly reduced the risk 
of the combined end-point of nonfatal thromboembolic events, or death from cardiovascular causes. 
The risk of major or minor thrombosis was also significantly decreased. A significant increase in 
hemorrhage was not observed. Thus there is evidence justifying the use of low dose aspirin in all 
patients with PV in the absence of a specific contra- indication. 
If the patient has a contra-indication to aspirin, an aspirin substitute may be prescribed but is not 
mandatory. 
2.3 
Investigational Agents 
2.3.1 
Pegylated Interferon Alfa-2a (PEGASYS)  
Data in this section is presented from the U.S. Package Insert. The dose titrations and modifications 
outlined in section 5.1 and 6.0 are to be used to adjust dose in this trial. 


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2.3.1.1 
DESCRIPTION 
PEGASYS, pegylated interferon alfa-2a, is a covalent conjugate of recombinant alfa-2a interferon 
(approximate molecular weight [MW] 20,000 daltons) with a single branched bis-monomethoxy 
polyethylene glycol (PEG) chain (approximate MW 40,000 daltons). The PEG moiety is linked at 
a single site to the interferon alfa moiety via a stable amide bond to lysine. Pegylated interferon 
alfa-2a has an approximate molecular weight of 60,000 daltons. Interferon alfa-2a is produced 
using recombinant DNA technology in which a cloned hydroxyureaman leukocyte interferon gene 
is inserted into and expressed in Escherichia coli. 
The study drug, pegylated interferon alfa-2a (PEGASYS), in North America will be provided by 
Mount Sinai to the individual sites participating in this study.  It will be shipped in prefilled 180 
microgram syringes or single-use vials. These syringes are the same as commercial supply with 
markings for 90, 135, and 180 microgram.    The local institutional pharmacist will be responsible 
for packing the study supply into individual containers and providing to the study subjects. 
The study drug (pegylated interferon alfa-2a; PEGASYS), in Europe, will be provided by Roche 
Pharmaceuticals or contracted drug distributors to the individual sites participating in this study.  It 
will be shipped in prefilled 135 or 180 microgram syringes or single-use pen devices. 
Subcutaneous (SC) administration of 1.0 mL delivers 180 micrograms of drug product (expressed 
as the amount of interferon alfa-2a), 8.0 mg sodium chloride, 0.05 mg polysorbate 80, 10.0 mg 
benzyl alcohol, 2.62 mg sodium acetate trihydrate, and 0.05 mg acetic acid. The solution is 
colorless to light yellow and the pH is 6.0 ± 0.01. 
Patients will self-administer a dose of Pegylated Interferon Alfa-2a as a subcutaneous injection 
once per week every week.  Doses will be adjusted according to response and adverse events (see 
section 5.2 and 6.0).  These doses will be administered at home.  Study staff will be instructing 
patients in self-injection at the appropriate dose level, proper handling of utilized syringes, return 
of used and unused syringes and medication, instructing the patient in how to properly fill out their 
diary, and provide the patient with education material on the aforementioned activities. See 
Appendix E for patient medication diaries. 
2.3.1.2 
CLINICAL ACTIVITY 
Clinical activity of PEGASYS in MPNs is presented in section 2.2.3. 
2.3.2 
Hydroxyurea®/Hydroxyurea/Hydroxy Carbamide 
2.3.2.1 
DESCRIPTION 
Hydroxyurea® (hydroxyurea capsules, USP), Hydroxycarbamide, is an antineoplastic agent 
available for oral use as capsules providing 500 mg hydroxyurea. Inactive ingredients: citric acid, 
colorants (D&C Yellow No. 10,FD&C Blue No. 1, FD&C Red 40, and D&C Red 28), gelatin, 
lactose, magnesium stearate, sodium phosphate, and titanium dioxide. 
Hydroxyurea/Hydroxycarbamide occurs as an essentially tasteless, white crystalline powder. Its 
structural formula is: 
 


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2.3.2.2 
CLINICAL PHARMACOLOGY  
2.3.2.2.1 
Mechanism of Action 
The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at 
present, be described. However, the reports of various studies in tissue culture in rats and humans 
lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis 
by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of 
ribonucleic acid or of protein. This hypothesis explains why, under certain conditions, 
hydroxyurea may induce teratogenic effects. 
Three mechanisms of action have been postulated for the increased effectiveness of concomitant 
use of hydroxyurea therapy with irradiation on squamous cell (epidermoid) carcinomas of the head 
and neck. In vitro studies utilizing  Chinese hamster cells suggest that hydroxyurea (1) is lethal to 
normally radioresistant S-stage cells, and (2) holds other cells of the cell cycle in the G1 or pre-
DNA synthesis stage where they are most susceptible to the effects of irradiation. The third 
mechanism of action has been theorized on the basis of in vitro studies of HeLa cells: it appears 
that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells 
damaged but not killed by irradiation, thereby decreasing their survival rate; RNA and protein 
syntheses have shown no alteration. 
2.3.2.2.2 
Pharmacokinetics 
Absorption 
Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1 to 4 
hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma 
concentrations and AUCs are observed. 
There are no data on the effect of food on the absorption of hydroxyurea. 
Distribution 
Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution 
approximating total body water. 
Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea concentrates in leukocytes and 
erythrocytes. 
Metabolism 
Up to 60% of an oral dose undergoes conversion through metabolic pathways that are not fully 
characterized. One pathway is probably saturable hepatic metabolism. Another minor pathway 
may be degradation by urease found in intestinal bacteria.  Acetohydroxamic acid was found in the 
serum of three leukemic patients receiving hydroxyurea and may be formed from hydroxylamine 
resulting from action of urease on hydroxyurea. 
Excretion 
Excretion of hydroxyurea in humans is likely a linear first-order renal process. 


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2.3.2.2.3 
Special Populations 
Geriatric, Gender, Race 
No information is available regarding pharmacokinetic differences due to age, gender, or race. 
Renal Insufficiency 
As renal excretion is a pathway of elimination, consideration should be given to decreasing the 
dosage of hydroxyurea in patients with renal impairment. In adult patients with sickle cell disease, 
an open-label, non-randomized, single- dose, multicenter study was conducted to assess the 
influence of renal function on the pharmacokinetics of hydroxyurea. Patients in the study with 
normal renal function (creatinine clearance [CrCl] >80 mL/min), mild (CrCl 50–80 mL/min), 
moderate (CrCl = 30–<50 mL/min), or severe (<30 mL/min) renal impairment received 
hydroxyurea as a single oral dose of 15 mg/kg, achieved by using combinations of the 200 mg, 300 
mg, or 400 mg capsules. Patients with end- stage renal disease (ESRD) received two doses of 15 
mg/kg separated by 7 days; the first was given following a 4-hour hemodialysis session, the second 
prior to hemodialysis. In this study the mean exposure (AUC) in patients whose creatinine 
clearance was <60 mL/min (or ESRD) was approximately 64% higher than in patients with normal 
renal function. The results suggest that the initial dose of hydroxyurea should be reduced when 
used to treat patients with renal impairment. Close monitoring of hematologic parameters is 
advised in these patients. 
Hepatic Insufficiency 
There are no data that support specific guidance for dosage adjustment in patients with hepatic 
impairment. Close monitoring of hematologic parameters is advised in these patients. 
Drug Interactions 
There are no data on concomitant use of hydroxyurea with other drugs in humans. 
Animal Pharmacology and Toxicology 
The oral LD50 of hydroxyurea is 7330 mg/kg in mice and 5780 mg/kg in rats, given as a single 
dose. 
In subacute and chronic toxicity studies in the rat, the most consistent pathological findings were 
an apparent dose-related mild to moderate bone marrow hypoplasia as well as pulmonary 
congestion and mottling of the lungs. At the highest dosage levels (1260 mg/kg/day for 37 days 
then 2520 mg/kg/day for 40 days), testicular atrophy with absence of spermatogenesis occurred; in 
several animals, hepatic cell damage with fatty metamorphosis was noted. In the dog, mild to 
marked bone marrow depression was a consistent finding except at the lower dosage levels. 
Additionally, at the higher dose levels (140 to 420 mg or 140 to 1260 mg/kg/week given 3 or 7 
days weekly for 12 weeks), growth retardation, slightly increased blood glucose values, and 
hemosiderosis of the liver or spleen were found; reversible spermatogenic arrest was noted. In the 
monkey, bone marrow depression, lymphoid atrophy of the spleen, and degenerative changes in 
the epithelium of the small and large intestines were found. At the higher, often lethal, doses (400 
to 800 mg/kg/day for 7 to 15 days), hemorrhage and congestion were found in the lungs, brain, and 
urinary tract. Cardiovascular effects (changes in heart rate, blood pressure, orthostatic hypotension, 
EKG changes) and hematological changes (slight hemolysis, slight methemoglobinemia) were 
observed in some species of laboratory animals at doses exceeding clinical levels. 


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2.3.2.3 
INDICATIONS AND USAGE 
Hydroxyurea®/Hydroxycarbamide is currently the treatment of choice in patients with high risk 
polycythemia vera and essential thrombocythemia. Significant tumor response to hydroxyurea 
(hydroxyurea capsules, USP) has been demonstrated in melanoma, resistant chronic myelocytic 
leukemia, and recurrent, metastatic, or inoperable carcinoma of the ovary. 
Hydroxyurea used concomitantly with irradiation therapy is intended for use in the local control of 
primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip. 
2.3.2.4 
CONTRAINDICATIONS 
Hydroxyurea is contraindicated in patients with marked bone marrow depression, i.e., leukopenia 
(<2.5 x 109/L WBC) or thrombocytopenia (<100 x 109/L), or severe anemia.  (This information is 
a general guide from the manufacturer, but treatment parameters for this protocol are outlined in 
section 5.2 and 6.0 and are the operative guide for this study.) 
Hydroxyurea is contraindicated in patients who have demonstrated a previous hypersensitivity to 
hydroxyurea or any other component of its formulation. 
2.3.2.5 
WARNINGS 
Treatment with hydroxyurea should not be initiated if bone marrow function is markedly 
depressed. Bone marrow suppression may occur, and leukopenia is generally its first and most 
common manifestation. Thrombocytopenia and anemia occur less often and are seldom seen 
without a preceding leukopenia. However, the recovery from myelosuppression is rapid when 
therapy is interrupted. It should be borne in mind that bone marrow depression is more likely in 
patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents; 
hydroxyurea should be used cautiously in such patients.  (This information is a general guide from 
the manufacturer, but treatment parameters for this protocol are outlined in section 5.2 and 6.0 and 
are the operative guide for this study.) 
Peripheral neuropathy, which was severe in some cases, has been reported in HIV infected patients 
receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or 
without stavudine. 
Severe anemia must be corrected before initiating therapy with hydroxyurea. Erythrocytic 
abnormalities: megaloblastic erythropoiesis, which is self-limiting, is often seen early in the course 
of hydroxyurea therapy. The morphologic change resembles pernicious anemia, but is not related 
to vitamin B12 or folic acid deficiency. Hydroxyurea may also delay plasma iron clearance and 
reduce the rate of iron utilization by erythrocytes, but it does not appear to alter the red blood cell 
survival time.  (This information is a general guide from the manufacturer, but treatment 
parameters for this protocol are outlined in section 5.2 and 6.0 and are the operative guide for this 
study.) 
Elderly patients may be more sensitive to the effects of hydroxyurea, and may require a lower dose 
regimen.  (This information is a general guide from the manufacturer, but treatment parameters for 
this protocol are outlined in section 5.2 and 6.0 and are the operative guide for this study.) 
In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as 
polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown 
whether this leukemogenic effect is secondary to hydroxyurea or associated with the patient’s 


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underlying disease. 
Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in 
patients with MPN during therapy with hydroxyurea.  These vasculitic toxicities were reported 
most often in patients with a history of, or currently receiving, interferon therapy. Due to 
potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with 
MPN, hydroxyurea should be discontinued if cutaneous vasculitic ulcerations develop and 
alternative cytoreductive agents should be initiated as indicated. 
2.3.2.5.1 
Carcinogenesis and Mutagenesis 
Hydroxyurea is genotoxic in a wide range of test systems and is thus presumed to be a human 
carcinogen.  In patients receiving long-term hydroxyurea for MPN, such as polycythemia vera and 
thrombocythemia, secondary leukemia has been reported. It is unknown whether this 
leukemogenic effect is secondary to hydroxyurea or is associated with the patient’s underlying 
disease.  Skin cancer has also been reported in patients receiving long-term hydroxyurea. 
Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not 
been performed. However, intraperitoneal administration of 125–250 mg/kg hydroxyurea (about 
0.6–1.2 times the maximum recommended human oral daily dose on an mg/m2 basis) thrice 
weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving 
to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, 
and mammalian cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) 
and in vivo (SCE assay in rodents, mouse micronucleus assay). Hydroxyurea causes the 
transformation of rodent embryo cells to a tumorigenic phenotype. 
2.3.2.5.2 
Pregnancy 
Drugs which affect DNA synthesis, such as hydroxyurea, may be potential mutagenic agents.  The 
physician should carefully consider this possibility before administering this drug to male or 
female patients who may contemplate conception. 
Hydroxyurea can cause fetal harm when administered to a pregnant woman. Hydroxyurea has 
been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, 
hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose 
given on a mg/m2 basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially 
ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar 
vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on an 
mg/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human 
daily dose on an mg/m2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal 
viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta.  
Single doses of Y375 mg/kg (about 1.7 times the maximum recommended human daily dose on an 
mg/m2 basis) to rats caused growth retardation and impaired learning ability.  There are no 
adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or 
if the patient becomes pregnant while taking this drug, the patient should be apprised of the 
potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming 
pregnant. 


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2.3.2.6 
PRECAUTIONS  
2.3.2.6.1 
General 
Therapy with hydroxyurea requires close supervision. The complete status of the blood, including 
bone marrow examination, if indicated, as well as kidney function and liver function should be 
determined prior to, and repeatedly during, treatment. The determination of the hemoglobin level, 
total leukocyte count, and platelet count should be performed at least once a week throughout the 
course of hydroxyurea therapy. If the white blood cell count decreases to less than 2.5 x 109/L, or 
the platelet count to less than 100 x 109/L, therapy should be interrupted until the values rise 
significantly toward normal levels. Severe anemia, if it occurs, should be managed without 
interrupting hydroxyurea therapy. (This is information is a general guide from the manufactuer, 
but treatment parameters for this protocol are outlined in section 5.2 and 6.0 and are the operative 
guide for this study.) 
Hydroxyurea should be used with caution in patients with marked renal dysfunction. 
Hydroxyurea is not indicated for the treatment of HIV infection; however, if HIV infected patients 
are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, 
close monitoring for signs and symptoms of pancreatitis is recommended. Patients who develop 
signs and symptoms of pancreatitis should permanently discontinue therapy with hydroxyurea. 
An increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with 
hydroxyurea and in particular, in combination with didanosine and stavudine. This combination 
should be avoided. 
2.3.2.6.2 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Impairment of Fertility: Hydroxyurea administered to male rats at 60 mg/kg/day (about 0.3 times 
the maximum recommended human daily dose on an mg/m2 basis) produced testicular atrophy, 
decreased spermatogenesis, and significantly reduced their ability to impregnate females. 
2.3.2.6.3 
Pregnancy 
Pregnancy Category D. (See section 2.3.2.5.2) 
2.3.2.6.4 
Drug Interactions 
Prospective studies on the potential for hydroxyurea to interact with other drugs have not been 
performed. 
Concurrent use of hydroxyurea and other myelosuppressive agents or radiation therapy may 
increase the likelihood of bone marrow depression or other adverse events. 
Since hydroxyurea may raise the serum uric acid level, dosage adjustment of uricosuric medication 
may be necessary. 
2.3.2.7 
ADVERSE REACTIONS 
Adverse reactions have been primarily bone marrow depression (leukopenia, anemia, and 
occasionally thrombocytopenia), and less frequently gastrointestinal symptoms (stomatitis, 
anorexia, nausea, vomiting, diarrhea, and constipation), and dermatological reactions such as 
maculopapular rash, skin ulceration, dermatomyositis-like skin changes, peripheral and facial 
erythema. Hyperpigmentation, atrophy of skin and nails, scaling, and violet papules have been 


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observed in some patients after several years of long-term daily maintenance therapy with 
hydroxyurea. Skin cancer has been reported. Cutaneous vasculitic toxicities, including vasculitic 
ulcerations and gangrene, have occurred in patients with MPN during therapy with hydroxyurea. 
These vasculitic toxicities were reported most often in patients with a history of, or currently 
receiving, interferon therapy. Dysuria and alopecia occur very rarely. Large doses may produce 
moderate drowsiness. Neurological disturbances have occurred extremely rarely and were limited 
to headache, dizziness, disorientation, hallucinations, and convulsions. Hydroxyurea occasionally 
may cause temporary impairment of renal tubular function accompanied by elevations in serum 
uric acid, BUN, and creatinine levels. Abnormal BSP retention has been reported.  Fever, chills, 
malaise, edema, asthenia, and elevation of hepatic enzymes have also been reported. 
Adverse reactions observed with combined hydroxyurea and irradiation therapy are similar to 
those reported with the use of hydroxyurea or radiation treatment alone. These effects primarily 
include bone marrow depression (anemia and leukopenia), gastric irritation, and mucositis. Almost 
all patients receiving an adequate course of combined hydroxyurea and irradiation therapy will 
demonstrate concurrent leukopenia. Platelet depression (<100 x 109/L) has occurred rarely and 
only in the presence of marked leukopenia. hydroxyurea may potentiate some adverse reactions 
usually seen with irradiation alone, such as gastric distress and mucositis. 
The association of hydroxyurea with the development of acute pulmonary reactions consisting of 
diffuse pulmonary infiltrates, fever, and dyspnea has been reported rarely.  Pulmonary fibrosis also 
has been reported rarely. 
Fatal and nonfatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been 
reported in HIV-infected patients who received hydroxyurea in combination with antiretroviral 
agents, in particular, didanosine plus stavudine. Patients treated with hydroxyurea in combination 
with didanosine, stavudine, and indinavir in Study ACTG 5025 showed a median decline in CD4 
cells of approximately 100/mm3. 
2.3.2.8 
OVERDOSAGE 
Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at dosages 
several times the therapeutic dose. Soreness, violet erythema, edema on palms and soles followed 
by scaling of hands and feet, severe generalized hyperpigmentation of the skin, and stomatitis have 
also been observed. 
2.3.2.9 
HOW SUPPLIED 
Hydroxyurea ® (hydroxyurea capsules, USP) 
500 mg capsules in bottles of 100 (NDC 0003-0830-50). 
Storage 
Store at 25º C (77º F); excursions permitted to 15º–30º C (59º–86º F) Controlled Room 
Temperature. Keep tightly closed. 


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3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
• A diagnosis of ET or PV ≤ 5 years prior to entry shall be made in accordance with the 
WHO (2008) criteria (Swerdlow 2008) as shown below.  
o Polycythemia Vera (2 major criteria required)* 
1. Hb >18.5g/dl (♂) or 16.5g/dl (♀)  or 
HCT >99 percentile reference range  or 
Elevated red cell mass (>25% above mean predicted value)  or 
Hb >17g/dl (♂) or 15g/dl (♀) if associated with a sustained rise from baseline 
with no apparent cause (e.g. treated iron deficiency). 
2. Presence of JAK2V617F. 
* If source documentation of diagnostic criterion #1 cannot be obtained, then 
diagnosis can be made with (1) the addition of an erythropoietin level below the 
reference range of normal AND (2) bone marrow biopsy showing 
hypercellularity for age with trilineage (panmyelosis) with prominent erythroid, 
granulocytic, and megakaryocytic proliferation. 
o Essential Thrombocythemia (all 6 criteria required) 
1. Platelets count ≥ 450 x 109/L 
2. Megakaryocyte proliferation with large and mature morphology. No significant 
increase or left shift of neutrophil granulopoiesis or erythropoiesis. Patients may 
have up to and including 2+ marrow reticulin fibrosis (0, 1 or 2 on scale 0 -4). 
3. Not meeting WHO criteria for CML, PV, MDS, PMF or other myeloid 
neoplasms. 
4. Demonstration of clonal cytogenetic marker or no evidence of reactive 
thrombocytosis. 
5. Absence of a leukoerythroblastic blood picture. 
6. May participate in study without presence of JAK2V617F. 
 
• Patients must have high risk disease as defined below: 
o High risk PV ANY ONE of the following: 
1. Age ≥ 60 years 
2. Previous documented thrombosis, erythromelalgia or migraine (severe, 
recurrent, requiring medications, and felt to be secondary to the MPN) either 
after diagnosis or within 10 years before diagnosis and considered to be disease 
related 
3. Significant splenomegaly (>5 cm below the left costal margin on palpitation) or 
symptomatic splenomegaly (splenic infarcts or requiring analgesia) 
4. Platelets ≥ 1000 x 109/L 
5. Diabetes or hypertension requiring pharmacological therapy for > 6 months 
o High risk ET ANY ONE of the following: 
1. Age ≥ 60 years 
2. Platelet count ≥ 1500 x 109/L 
3. Previous documented thrombosis, erythromelalgia or migraine headaches 
(severe, recurrent, requiring medications, and felt to be secondary to the MPN) 


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either after diagnosis or within 10 years before diagnosis and considered to be 
disease related 
4. Previous hemorrhage related to ET 
5. Diabetes or hypertension requiring pharmacological therapy for > 6 months 
 
• Other Inclusion criteria (Both Strata) 
• Diagnosed less than 5 years prior to entry on trial 
• Never treated with cytoreductive drugs except hydroxyurea for up to 3 months 
maximum (phlebotomy, aspirin allowed, anagrelide allowed) 
• Age: ≥ 18 years (no upper limit) 
• Ability and willingness to comply with all study requirements 
• Signed informed consent to participate in this study. 
• Willing to participate in associated correlative science biomarker study 
• Serum creatinine ≤1.5 x upper limit of normal 
• AST and ALT ≤ 2 x upper limit of normal 
• No known PNH (paroxysmal nocturnal hemoglobinuria) clone 
• No concurrent hormonal oral contraceptive use 
3.2 
Exclusion Criteria 
Exclusion criteria: (ANY of the following, both strata) 
• Known to meet the criteria for primary myelofibrosis (as opposed to ET) by WHO 2008 
• Patients with a prior malignancy within the last 5 years (except for basal or squamous cell 
carcinoma, or in situ cancer of the cervix) 
• Any contraindications to pegylated interferon or hydroxyurea 
• Presence of any life-threatening co-morbidity 
• History of active substance or alcohol abuse within the last year 
• Subjects who are pregnant, lactating or of reproductive potential and not practicing an 
effective means of contraception 
• History of psychiatric disorder (e.g. depression): Subjects with a history of mild depression 
may be considered for entry into this study, provided that a pretreatment assessment of the 
subject's affective status supports that the subject is clinically stable based on the 
investigator's normal practice for such subject.  
• History of active or uncontrolled autoimmune disorder (e.g. hepatitis) 
• Hypersensitivity to interferon alfa 
• Hepatitis B or C infection (HBV), or untreated systemic infection 
• Known HIV disease 
• Evidence of severe retinopathy (e.g. CMV retinitis, macular degeneration) or clinically 
relevant ophthalmological disorder (e.g. due to diabetes mellitus or hypertension) 
• History or other evidence of decompensated liver disease 
• History or other evidence of chronic pulmonary disease associated with functional 
limitation 
• Thyroid dysfunction not adequately controlled 
• Neutrophil count <1.5 x 109/L 
• JAK2 exon 12 mutation: PV that lacks the JAK2V617F mutation but is characterized by the 
exon 12 mutation. 


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• Meets criteria for post PV or post ET-MF (see Appendix A) 
• Subjects with any other medical condition, which in the opinion of the investigator would 
compromise the results of the study by deleterious effects of treatment. 
• Previous exposure to any formulation of pegylated interferon 
• History of major organ transplantation 
• History of uncontrolled severe seizure disorder 
• Inability to give informed written consent 
• Total bilirubin >1.5 x ULN (patients that have an isolated indirect bilirubin that causes total 
bilirubin to be elevated beyond 1.5 x ULN due to documented Gilbert’s syndrome or 
hemolysis may be included). 
3.3 
Subject Recruitment and Screening 
Subjects will be recruited and screened for the study from the clinical services of the participating 
study centers. 
The sponsor may advertise in academic publications in order to raise awareness about the study. 
3.4 
Early Withdrawal of Subjects 
Withdrawal of the subject is defined as no longer participating in the study. This includes all 
remaining study visits and follow-up procedures.  Subjects who discontinue treatment will continue 
on study for observational follow-up (see section 5.8). 
3.4.1 
When and How to Withdraw Subjects 
In accordance with the Declaration of Helsinki and the guidelines of the country of the 
participating institution, each subject is free to withdraw from the study at any time.   An 
investigator also has the right to withdraw a subject from the study in the event of the patient 
suffering an intercurrent illness, adverse events, or other reasons concerning the health or well-
being of the patient, or in the case of lack of cooperation by the patient. All serious adverse 
reactions need to be followed up until resolution and information returned to study coordinators. 
Should a subject decide to withdraw after administration of study drug, or should the investigator 
decide to withdraw the subject, all efforts should be made to complete and report the observations 
up to the time of withdrawal as thoroughly as possible.  A final evaluation at the time of the 
subject’s withdrawal should be made on the last day the subject takes the study drug, or as soon as 
possible thereafter.  If a subject withdraws from the study beyond the time of the last clinical 
evaluation, then every effort should be made to evaluate the subject during the next scheduled 
visit.  The reason for and the date of withdrawal must be recorded on the CRF.  The study 
discontinuation/end-of-study visit will occur at 30 days after the patient withdraws from the study 
(±7 days). 
Subjects with clinically significant abnormal laboratory values as determined by the investigator or 
who have ongoing clinically significant treatment related adverse events during their last 
scheduled clinical evaluation will be monitored and treated until resolution or stabilization is 
achieved.  Or, in the event that the subject’s condition is not likely to improve because of disease 
progression, the subject will be monitored until the cause of the abnormal test result or adverse 
event can be determined. 


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3.4.2 
Data Collection and Follow-up for Withdrawn Subjects 
The reason for and date of withdrawal from study drug treatment and the reason for and date of 
withdrawal from the study will be recorded on the case report form (CRF).  If a subject withdraws 
consent, every attempt will be made to determine the reason.  If the reason for withdrawal is an 
adverse event or a clinically significant abnormal laboratory test result, monitoring will continue 
until the event has resolved or stabilized, until the subject is referred to the care of a local health 
care professional, or until a determination of a cause unrelated to the study drug or study 
procedure is made.  The specific event or test result(s) must be recorded on the CRF.  All 
evaluations will be performed, according to the protocol, 30 days after the patient withdraws from 
the study (±7 days).  A subject will be considered to be lost to follow-up if all of the following 
criteria have been met: 
1. More than 3 phone calls to the subject are unanswered. 
2. A next of kin is contacted and no information is available. 
3. The referring physician is contacted and no information is available. 
4. A telegram or certified letter is unanswered. 
 
 


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4.0 
REGISTRATION, MANDATORY SAMPLE SUBMISSION, AND DATA 
MANAGEMENT 
4.1 
Registration Requirements 
4.1.1 
Site Registration with MPD-RC 
Before an MPD-RC Institution can enroll patients, protocol specific regulatory documents must be 
submitted to the MPD-RC 112 Regulatory Coordinator via E-mail (PDF file preferred) or fax:  
   MPD-RC 112 Regulatory Coordinator 
Jane Lew 
                                                               Phone: (212) 241-0481 
Fax: (212) 876-5276 
E-mail: jane.lew@mssm.edu 
Required Protocol Specific Regulatory Documents (E-mailed by PDF format preferred):  
• Copy of IRB approval letter 
• Copy of IRB approved consent 
• US Centers ONLY: Completed Pharmacy Drug Order Sheet* 
• Copy of the CV of the Research Pharmacist 
• CV of the ordering physician 
• Completed Form FDA 1572 
 
* E-mail the completed drug order sheet directly to the regulatory coordinator.  The total amount 
of drug ordered with each order form will be determined based on the amount of study drug 
available at the time, onsite at the Icahn School of Medicine at Mount Sinai. 
4.1.2 
Study Drug Shipment 
Before Study Drug can be shipped to begin accruing patients the above regulatory documents will 
be required to be sent to the MPD-RC Central Office to the attention of the Regulatory 
Coordinator, as noted above. 
4.1.3 
Correlative Biomarker Study (MPD-RC 107) 
There is a correlative science biomarker study for which participation is mandatory (MPD-RC 
protocol 107).  The patient must be enrolled in the mandatory companion biomarker study in order 
to participate in this treatment study (MPD-RC 112). 
4.1.4 
Informed Consent 
The patient must willingly consent after being informed of the experimental nature of the therapy, 
alternatives therapies, potential benefits, side effects, risks, and discomforts.  Human Protection 
Committee approval of this protocol and of its consent form is required. 


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4.2 
Patient Registration 
This study uses the MPD-RC on-line Patient Registration system (http://www.mpd-rc.org).  
Registration will be accepted only through members of the MPD-RC institutions using the on-line 
Patient Registration system.   Registration must occur prior to the initiation of therapy. 
Confirm eligibility criteria (section 3.0).  Complete the Registration Worksheet. Access the on-line 
Patient Registration system via the patient registration icon on the MPD-RC Information Systems 
IS Application main menu.  If the registering clinical research associate (CRA) requires assistance 
he/she may consult the on-line help file located under the Help menu of the MPD-RC application.  
Enter the required information to submit the form. 
When the patient is registered, a patient identification number will be generated. Registration will 
not be completed if eligibility requirements are not met for the selected trial. 
The registering institution will receive a Confirmation of Registration that requires review by the 
registering institution and then either submission of acceptance or corrections to the MPD-RC 
Data Management Center. 
E-Mail MPD112@negrisud.it 
At the completion of the registration process, the assignment of the patient to the protocol 
treatment arm will be made on-line. 
Method for Assigning Subjects to Treatment Groups 
Patients in the high risk group of PV or ET will be randomized within disease strata to treatment 
with either pegylated interferon alfa-2a or hydroxyurea. Patients will be further stratified by prior 
treatment with hydroxyurea (in past 3 months, Stratum A) or no prior treatment with hydroxyurea 
(Stratum B). 
A confirmatory e-mail with the treatment assignment will be sent to the investigator.   


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5.0 
TREATMENT PLAN 
A treatment cycle is defined as a one calendar month period of treatment (i.e. January 15th, 
February 15th, March 15th, etc.) 
5.1 
Dose Titration and Study Duration 
Goal: The goal is to titrate up the dose of the therapeutic agent to the maximal tolerated dose 
(MTD), or that dose which achieves a complete response by LeukemiaNet criteria (see section 
10.0), unless the anticipated toxicity outweighs further clinical benefit. 
Treatment Duration: Patients will be treated for 12 months (with a 3 month confirmation period 
for a total of up to 15 months) to achieve CR or PR. Those not achieving at least a confirmed PR 
will stop therapy at the end of 15 months of treatment with pegylated interferon alfa-2a or 
hydroxyurea and continue on the observational follow-up. Length of therapy for responders will be 
determined by subject’s entrance onto the study.  The last subject to enter the study receive therapy 
for at most 24 months and the first subjects entered onto the study could receive therapy for up to 
72 months (assuming toxicity or loss of response does not intervene) (see section 9.2 for study 
calendar). 
Specific Goals for Efficacy: 
• Hematocrit ≤ 0.45 without phlebotomy (PV Only) and 
• Platelet count ≤ 400 x 109/L and 
• WBC ≤ 10 x 109/L and 
• Normal spleen size by imaging 
Limitation to further increases in dose of each agent, either pegylated interferon alfa-2a or 
hydroxyurea: 
• Hematologic: 
o Platelets <100 x 109/L 
o Neutrophil Count < 1.0 x 109/L 
o Development of new drug associated anemia (hemoglobin < 10.0g/dL) 
• Non-Hematologic (See section 6.0) 
5.2 
Specific Dosing for Each Agent 
5.2.1 Dose Titration of Hydroxyurea 
Specific Titration of hydroxyurea Dosing (1 cycle is 1 month for the purposes of titration) 
1. Stratum A: Patients randomized to hydroxyurea who enter the trial with < 3 months 
hydroxyurea will begin at 500mg twice daily* assuming: 
a. criteria for CR does not already exist and 
b. dose limiting toxicity (DLT) does not already exist 
* If at current dose the patient meets criteria for CR and DLT does not exist, patient can 
remain on that dose at trial entry. 
2. Stratum B: Patients randomized to Hydroxyurea who enter the trial naïve to hydroxyurea 
will begin at 500mg twice daily (or 500mg daily if clinically indicated). 
 


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3. Dose titration for both groups 1 and 2 will occur at each monthly visit (or dose reduction in 
between interval visits (but not dose increases) according to Table 2. Further fine tuning 
between dose levels is allowed at site investigators discretion. Levels above +4, or 
below -3 (if associated with toxicity) likely represent a failure of hydroxyurea in this trial. 
Table 2 
Dose Levels of Hydroxyurea 
Dose Level 
Dose of Hydroxyurea 
-3 
500 mg every other day 
-2 
500 mg every day 
-1 
500 mg day 1, 1000 mg day 2 - alternating 
0 
1000 mg daily (500 mg twice daily) 
+1 
1000mg day 1, 1500 mg day 2 - alternating 
+2 
1500mg daily (500 mg three times/ day) 
+3 
1500mg day 1, 2000 mg day 2 - alternating 
+4 
2000 mg/ day (1000 mg twice daily) 
5.2.2 Dose Titration of Pegylated Interferon Alfa-2a 
1. Stratum A: Patients randomized to Pegylated Interferon Alfa-2a and entering with < 3 
months hydroxyurea will begin at 45 micrograms per week. If patient is currently on 
hydroxyurea when entering therapy, patient will begin at 45 micrograms per week, and 
increases of pegylated interferon alfa-2a during the first 2 months will be made at a rate 
that will allow cessation of hydroxyurea prior to initiating treatment at the beginning of 
month 3.  
 
2. Stratum B: Patients randomized to Pegylated Interferon Alfa-2a who enter the trial naïve to 
hydroxyurea will begin at 45 micrograms/week. Dose can be increased after at least one 
month of therapy (as tolerated) if one of the following has not occurred. 
a. criteria for CR does not already exist  
b. dose limiting toxicity (DLT) does not already exist 
 
3. Dose titration for both strata A and B will occur at each monthly visit (or dose reduction in 
between interval visits according to Table 3). Dose escalations can only be done on the 
scheduled study visits until after 6 months, in which dose escalations can occur between 
study visits not less than a month apart. Interval Dose Levels (0.5, 1.5, and 2.5) are meant 
to allow for titration and can be used even if patient is not having side effects. Dose 
escalation to levels > 135 micrograms/ week will occur only after 3 months of therapy 
(unless part of Stratum A and needed for cessation of hydroxyurea). Levels below -3 (if 
associated with limiting toxicity) or above +3 likely represent a failure of Pegylated 
Interferon Alfa-2a in this trial. 
 


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Table 3 
Dose Levels of Pegylated Interferon Alfa-2a 
Dose Level 
Dose of Pegylated Interferon Alfa-2a 
-3 
45 micrograms every fourth week (± 2 days) 
-2 
45 micrograms every third week (± 2 days) 
-1 
45 micrograms every other week (± 2 days) 
0 
45 micrograms/ week (± 2 days) 
0.5 
45 micrograms one week, 90 micrograms week 2 alternating (± 2 days) 
1 
90 micrograms weekly (± 2 days) 
1.5 
90 micrograms one week, 135 micrograms week 2 alternating (± 2 days) 
2 
135 micrograms weekly (± 2 days) 
2.5 
135 micrograms one week, 180 micrograms week 2 alternating (± 2 days) 
3 
180 micrograms weekly (± 2 days) 
 
5.3 
Phlebotomy Guidelines 
All patients will continue to receive venesection where required, the target hematocrit (HCT or 
packed cell volume) will be 0.45 for men and women. 
5.4 
Aspirin Therapy 
A standard dose of 81mg or 100mg of aspirin (depending on standard practice in each country) (to 
be taken with food) will be used in all patients. At this dosage side-effects are very uncommon. 
However, aspirin may be contraindicated in a few patients because they have a history of 
intolerance to aspirin, MPN-associated hemorrhage, recent peptic ulceration or aspirin sensitive 
asthma. 
5.5 
Pregnancy 
Neither agent used in this trial is indicated, not proven safe in pregnancy. Patients will be advised 
to use effective contraception and to avoid pregnancy while on the trial. In the event of pregnancy 
the patient will be removed from the study and alternative therapy (at the discretion of the treating 
physician) will be used. The patient and offspring will be followed monthly until 6 months after 
delivery. 
5.6 
Intolerance or resistance to Hydroxyurea 
Either Intolerant or resistant to HU according to established criteria as follows: 
Any ONE of the following: 
 
• Platelet count > 600 x 109/L after 3 months of at least 2g/day or maximally tolerated dose 
(MTD) of hydroxyurea (2.5 g/day in patients with a body weight > 80 kg) 
• Platelet count > 400 x 109/L and WBC less than 2.5 x 109/L at any dose of HU 
• Platelet count > 400 x 109/L and Hb less than10 g/dl at any dose of HU 
• Progressive splenomegaly or hepatomegaly (> 5cm from initiation of hydroxyurea) or the 


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appearance of new splenomegaly or hepatomegaly while on MTD of hydroxyurea. 
• Not achieving a Hct < 45% in order to eliminate the need for supplemental phlebotomies 
after 3 months of at least 2g/day or MTD of hydroxyurea 
• Not achieving a WBC of < 10 x 109/L after 3 months of at least 2g/day or MTD of 
hydroxyurea  
• Presence of leg ulcers or other unacceptable HU-related non-hematological toxicities, such 
as unacceptable mucocutaneous manifestations, gastrointestinal symptoms, pneumonitis or 
fever at any dose of HU. 
5.7 
Discontinuation of Treatment 
The following conditions are reasons to interrupt and discontinue the trial treatment: 
• The patient fails to achieve adequate response as defined by a platelet count> 600 x 109/L 
at the end of 12 months from trial entry. 
• If after the initial 12 months of therapy the patient cannot maintain a platelet count < 600 x 
109/L for a period of more than 3 months. (i.e. months 12 thru 15) 
• Major thrombosis (CVA, myocardial infarction, pulmonary embolism, DVT); Transient 
ischemic attack (TIA) is not for this purpose considered a major event. 
• Major hemorrhagic event (non-epistaxis, requiring medical intervention) 
• Progression to myelofibrosis (Appendix A) 
• Progression to Acute Leukemia (Appendix A) 
• The patient is progressing on the assigned treatment, i.e. blood counts (white blood cells or 
platelets) not controllable as dosage of drug is increased to the maximal tolerated or the 
maximum of 180 micrograms and patient is refractory 
• The patient decides it is in his/her best interest (patient unwilling to continue therapy) 
• Serious adverse experience(s) i.e.  bleeding,  irreversible  cytopenias, lower extremity 
ulceration, neuropsychiatric disturbances; pulmonary infiltrates, congestive heart failure, 
renal or hepatic insufficiency, colitis, pancreatitis and specific ophthalmological 
complications suspected to be treatment induced. Discretion is granted to the treating 
physician to determine, dependent on the severity, relationship to therapy of the adverse 
events in conjunction with the potential response to either reduce the dose of the study 
agent or stop treatment or withdraw the patient from the study. 
• Pregnancy 
• 
The patient is found to be intolerant or resistant to hydroxyurea as defined in section 5.2.4. 
• 
Non-Compliance 
Trial treatment should not be attempted where the patient meets criteria for failing to achieve and 
adequate response or in the event of serious adverse reactions which are related to pegylated 
interferon alfa-2a for example irreversible cytopenias, neuropsychiatric disturbances; pulmonary 
infiltrates, congestive heart failure, renal or hepatic insufficiency, colitis, pancreatitis and specific 
ophthalmological complications 
Patients with a treatment interruption should continue the protocol visit schedule and comply with 
all study procedures, except treatment. Patients with the above endpoints or the inability to 
continue on therapy will be considered off treatment at the time of the event and would be followed 
for the next 30 days only or until any drug related adverse events have resolved (even if more than 
30 days after the last dose of pegylated interferon alpha 2a). 


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5.8 
Treatment Failure/Observational Follow-up 
Patients who meet the criteria for treatment failure as defined in section 5.7 or by unwilling to 
continue therapy, will continue on study with observational follow-up.  The observational follow-
up will be conducted every 6 months from the time the patient goes off treatment until 6 years from 
the start of their treatment or 2 years after the last patient enters the study (whichever comes first). 
The following information will be collected during these observational follow-up time points: 
• Survival 
• Incidence of development of myelodysplastic disorders, myelofibrosis, or leukemic 
transformation 
• Incidence of cardiovascular events (defined as cardiovascular death, myocardial infarction, 
stroke, transient ischemic attack, pulmonary embolism, Budd Chiari syndrome, deep vein 
thrombosis, and any other clinically relevant thrombotic event) 
• Changes in treatment: treatments received after end of study drug while on observation  
 


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6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
The following grades and definitions of toxicity are used. Further details are available 
at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. 
Grades (General Definitions) 
0 = No adverse event or within normal limits 
1 = Mild adverse event 
2 = Moderate adverse event 
3 = Severe and undesirable adverse event 
4 = Life-threatening or disabling adverse event 
5 = Death related to adverse event 
Dose adjustments should be made as follows: 
• Grade 1 or 2 toxicity: should be maintained on the same dose where possible. For grade 2 
ALT or hematologic toxicities, follow instruction in the next bullet points 
 
• Grade 2 ALT: stop pegylated interferon alfa-2a then restart at one dose level lower per 
Table 2 or Table 3 when toxicity improves to grade 1 or better 
 
• Grade 2 hematologic toxicity: reduce one dose level lower per Table 2 or Table 3 
 
• Grade 3 or 4 toxicity: (for fevers, flu-like symptoms and chills consider restricting this to 
grade 4); stop pegylated interferon alfa-2a then restart at one dose level lower per Table 3 
when toxicity improved to grade 1 or better (caveat to this is a grade 3 or 4 AE that is 
unrelated to study drug and in the opinion of the investigator restarting or continuing 
therapy does not pose a safety risk), or discontinue at the discretion of the treating 
physician in the case of grade 4 toxicity; stop Hydroxyurea then restart at one dose level 
lower when toxicity improved to grade 1 or better, or discontinue at the discretion of the 
treating physician in the case of grade 4 toxicity.  In both instances reduce dose by at least 
1 dose level (see Table 2 and Table 3 above in section 5.2). 
If toxicity improves to grade 1 or better and the subject restarts at one dose level lower, the treating 
investigator may re-escalate following the guidelines in section 5.2. However, if the subject 
experiences the same toxicity a second time, the subject should be withdrawn from study. 
 
For non-hematological toxicities, the study drug can be held up to 3 months before it is considered 
a treatment failure (see section 5.8). For hematological toxicity, the study drug can be held 
indefinitely. When restarting study drug after the treatment interruption, the treating physician can 
re-escalate the dose as outlined in section 5.1. If the subject experiences the same toxicity that 
causes treatment interruption a second time, it should be considered a treatment failure (see section 
5.8). 


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Thyroid disease 
Prior to pegylated interferon alfa-2a:  
If patient has abnormal TSH and/or presence of thyroid antibodies, treat underlying thyroid 
condition before introducing pegylated interferon alfa-2a. 
During therapy with pegylated interferon alfa-2a: 
Hyperthyroidism – test Thyroid antibodies and Thyroid scan 
• if Graves, treat with standard therapy and consider withdrawal of pegylated interferon 
alfa-2a 
• if destructive thyroiditis, use beta blocker and consider withdrawal of pegylated 
interferon alfa-2a 
Hypothyroidism – thyroid replacement, continue pegylated interferon alfa-2a and monitor 
thyroid therapy 
Psychiatric: Depression 
Guidelines for modification or discontinuation of pegylated interferon alfa-2a (PEGASYS) and the 
scheduling of visits for patients with depression are provided in Table 4. 
 
Table 4 
Depression Guidelines 
Depression 
Severity  
(as defined by 
CTCAE v. 4.0) 
Initial Management 
(1-2 months) 
Depression 
Dose modification 
Visit schedule 
Remains stable 
Improves 
Worsens 
Mild 
No change 
Evaluate once 
weekly by visit 
and/or phone 
Continue weekly 
visit schedule 
Resume normal 
visit schedule 
(See moderate 
or severe 
depression) 
Moderate 
Decrease 
PEGASYS dose by 
one dose level per 
Table 3 
Evaluate once 
weekly (visit at 
least every other 
week) 
Consider 
psychiatric 
consultation. 
Continue reduced 
dosing 
Resume normal 
visit schedule 
(See severe 
depression) 
Severe 
Discontinue 
PEGASYS 
permanently 
Obtain immediate 
psychiatric 
consultation 
Psychiatric therapy necessary 
 
Renal Function and Liver 
Patients who qualify by eligibility criteria will be monitored for renal toxicity or hepatic toxicity.  
Guidelines for dose modifications will be made as described previously for Grade 3 or 4 non-
hematological toxicity. 


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7.0 
PHARMACEUTICAL INFORMATION 
7.1 
Pegylated Interferon Alfa-2a (IND #106,511) 
7.1.1 
Description 
PEGASYS, pegylated interferon alfa-2a, is a covalent conjugate of recombinant alfa-2a interferon 
(approximate molecular weight [MW] 20,000 daltons) with a single branched bis-monomethoxy 
polyethylene glycol (PEG) chain (approximate MW 40,000 daltons). The PEG moiety is linked at 
a single site to the interferon alfa moiety via a stable amide bond to lysine. Pegylated interferon 
alfa-2a has an approximate molecular weight of 60,000 daltons. Interferon alfa-2a is produced 
using recombinant DNA technology in which a cloned hydroxyureaman leukocyte interferon gene 
is inserted into and expressed in Escherichia coli.  
7.1.2 
Packaging of Study Drug Pegylated Interferon Alfa-2a 
The study drug pegylated interferon alfa-2a (PEGASYS), in North America will be provided by the 
Icahn School of Medicine at Mount Sinai to the individual sites participating in this study.  It will 
be shipped in prefilled 180 microgram/0.5mL syringes or 180 microgram/1.0mL single-use vials.  
The local institutional pharmacist will be responsible for packing the study supply into individual 
containers and providing to the study subjects. 
The study drug (pegylated interferon alfa-2a; PEGASYS), in Europe, will be provided by Roche 
Pharmaceuticals by Roche affiliates or contracted drug distributors located in each individual 
country in Europe participating in the trial to the individual sites participating in this study.  The 
delivery of study drug may vary in European countries, but could be made available as prefilled 
135 or 180 microgram syringes or single-use pen devices. 
7.1.3 
Method for Assigning Subjects to Treatment Groups 
Patients in the high risk group of PV or ET will be randomized to treatment with either pegylated 
interferon alfa-2a or hydroxyurea within strata defined by their disease and use of hydroxyurea 
(less than 3 months or never).  Registration and randomization is done through the MPD-RC Data 
Management website. 
7.1.4 
Prior and Concomitant Therapy 
Patients must have had PV or ET for not more than 3 years and not received more than 3 months 
of hydroxyurea therapy prior to study entry.  Patients cannot have any other form of 
chemotherapy, hydroxyurea, interferon, or JAK2 inhibitors. 
If a patient who is randomized to pegylated interferon alfa-2a is currently on hydroxyurea when 
entering the study, they should be tapered off hydroxyurea over a period of up to 2 months when 
pegylated interferon alfa-2a is started. 
7.1.5 
Receiving, Storage, Dispensing and Return of Study Drug pegylated interferon 
alfa-2a 
7.1.5.1 
Receipt of Drug Supplies 
Drug supply for the USA sites will be shipped from Genentech to the Mount Sinai Medical Center 
(New York), from which it will then be distributed to the sub-sites of the trial. It will be shipped in 


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180 microgram pre-filled syringes or single-use vials. 
European drug distribution will be provided by Roche Pharmaceuticals or contracted drug 
distributors to the individual sites participating in this study.  It will be shipped in prefilled 135 or 
180 microgram syringes or single-use pen devices, depending on the availability of Pegasys in the 
European regions. 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a drug 
receipt log filled out and signed by the person accepting the shipment.  It is important that the 
designated study staff counts and verifies that the shipment contains all the items noted in the 
shipment inventory.  Any damaged or unusable study drug in a given shipment should be 
documented in the study files.   The investigator must notify the MPD-RC of any damaged or 
unusable study treatments supplied to the investigator’s site. The site is required to maintain 
adequate accountability records that are equivalent to the NCI DARF. See Appendix F: NCI 
DARF. 
7.1.5.2 
Storage 
The study drug should be stored, under adequate security, in the pharmacy at the study center at a 
refrigerator at a temperature of 2°C to 8°C (36°F to 46°F) until taken by the study patients or until 
returned to Roche Pharmaceuticals. 
7.1.5.3 
Dispensing of Study Drug 
The study drug in North America may be requested from the Mount Sinai Medical Center (New 
York) by the Principal Investigator (or their authorized designee) at each participating site (See 
section 4.1.1 for required regulatory documentation).  In Europe, Roche Pharmaceuticals will ship 
the drug directly to the institution where the patient is to be treated. Transfer of drugs between 
MPD-RC member institutions is not permitted. 
7.1.5.4 
Return or Destruction of Study Drug 
At the completion of the study, there will be a final account of drug shipped, drug consumed, and 
drug remaining.  This accounting process will be logged on the drug accounting form, signed and 
dated.  Any discrepancies noted will be investigated, resolved, and documented prior to return or 
destruction of unused study drug.  Drug destroyed on site will be documented in the study files. 
7.2 
Hydroxyurea 
7.2.1 
Description 
Hydroxyurea® (hydroxyurea capsules, USP), Hydroxy Carbamide, is an antineoplastic agent 
available for oral use as capsules providing 500 mg hydroxyurea. Inactive ingredients: citric acid, 
colorants (D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red 40, and D&C Red 28), gelatin, 
lactose, magnesium stearate, sodium phosphate, and titanium dioxide. 


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Hydroxyurea/Hydroxycarbamide occurs as an essentially tasteless, white crystalline powder. Its 
structural formula is: 
 
 
 
 
 
 
A complete description is located in section 2.3.2. 
7.2.2 
Packaging 
Hydroxyurea is an FDA approved drug.  Patients or their insurance providers will be responsible 
for the cost of this drug. Hydroxyurea ® (hydroxyurea capsules, USP) 500 mg capsules in bottles 
of 100 (NDC 0003-0830-50). 
7.2.3 
Storage 
Store at 25º C (77º F); excursions permitted to 15º–30º C (59º–86º F) Controlled Room 
Temperature. Keep tightly closed. 
Hydroxyurea will be dispensed by physician prescription and is not provided specifically for use in 
this study. 
7.2.4 
Method for Assigning Subjects to Treatment Groups 
Patients in the high risk group of PV or ET will be randomized to treatment with either pegylated 
interferon alfa-2a or hydroxyurea within strata defined by their disease.  Within each disease 
stratum, patients will also be stratified by exposure to hydroxyurea (Stratum A (current 
hydroyxurea for 3 months or less) and Stratum B (no prior hydroxyurea)).  Registration and 
randomization is done through the MPD-RC Data Management website. 
7.2.5 
Prior and Concomitant Therapy 
Patients must have had PV or ET for not more than 3 years and not received more than 3 months of 
hydroxyurea therapy prior to study entry.  Patients cannot have any other form of chemotherapy, 
interferon, or JAK2 inhibitors. 
7.3 
Aspirin 
All subjects on this study, regardless of randomized medication, will receive aspirin as part of their 
therapy. 
Aspirin is an acetyl derivative of salicylic acid that is a white, crystalline, weakly acidic substance, 
with melting point 135°C. Acetylsalicylic acid decomposes rapidly in solutions  of ammonium 
acetate or of the acetates, carbonates, citrates or hydroxides of the alkali metals. Acetylsalicylic 
acid is stable in dry air, but gradually hydrolyses in contact with moisture to acetic and salicylic 
acids. In solution with alkalis, the hydrolysis proceeds rapidly and the clear solutions formed may 
consist entirely of acetate and salicylate. 
Synthesis 
The synthesis of aspirin is classified as an esterification reaction. Salicylic acid is treated with 
acetic anhydride, an acid derivative, causing a chemical reaction that turns salicylic acid's alcohol 
group into an acetyl group, (R-OH > R-OCOCH3). This process yields aspirin and acetic acid, 
which is considered to be a byproduct of this reaction.  Small  amounts  of  sulfuric  acid  (and  


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MPD-RC 112 PEGHU-Phase 3 
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Page 49 of 120 
Version #8  12/21/2015 
8.0 
BIOMARKERS 
The correlative biomarker study (MPD-RC 107-Appendix 10.2) will evaluate a series of 
biomarkers at baseline, after month 12, 24 and either at the time of relapse/progression or at 
termination of study, that is off study drug permanently for any reason (i.e. intolerance or 
completing required course of study drug). 
8.1 
Samples to be Collected 
The following samples noted in Table 5 are to be collected at baseline, the end of month 12, 24 and 
at the time of a bone marrow aspirate and biopsy to evaluate for relapse/progression or at off-
treatment, that is off study drug permanently for any reason (i.e. intolerance or completing required 
course of study drug).  
Table 5 
Samples to be collected  
Sample: 
Baseline 
After 
12 
Months 
After 
24 
Months 
Off-Treatment4 
Bone marrow 
aspirate 
 
 
Histopathology1 
 
 
Cytogenetics2 
 
 
 
Biomarkers3 
Copy of Local Institutional 
Histopathology Report  
 
Three (3) air dried unstained slides 
 
At local institution, upload data and 
karyotypes to website. If no aspirate, 
provide peripheral blood karyotypes2. 
 
2 to 5 mL of bone marrow aspirate in a 
green top, heparinized tube (BD catalog 
#366480) 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Bone marrow 
biopsy 
 
 
Histopathology1 
Copy of Local Institutional 
Histopathology Report  
 
One (1) H & E stain 
 
One (1) Iron stain 
 
One (1) Silver impregnated reticulin stain 
 
Three (3) Unstained paraffin-fixed slides 
each with at least 2 sections 
 
three (3) air-dried, unstained bone marrow 
aspirate slides (if available) 
 
If no aspirate, two (2) air dried unstained 
touch preps, 8 touches/slide, 2 horizontal 
rows of 4 touches. 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X  
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X  


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Page 50 of 120 
Version #8  12/21/2015 
Sample: 
Baseline 
After 
12 
Months 
After 
24 
Months 
Off-Treatment4 
Blood 
 
Histopathology1 
 
 
Cytogenetics2 
 
Biomarkers3 
 
 
Four (4) Unstained peripheral blood films, 
thin smears 
 
If no BM aspirate karyotypic analysis2 
 
Hematocrit  <  32,  37  mL  
Three (3) ACD: yellow (BD #364606; 8.5 
mL) 
 
One (1) EDTA: lavender (BD #366450; 
8.5 mL) 
 
One (1) sodium citrate: light blue (BD 
#366415; 4.5 mL) 
 
Hematocrit >= 32, 76 mL 
Five (5) ACD: yellow (BD #364606; 
8.5  mL) 
 
One (1) EDTA: lavender (BD #366450; 
8.5 mL) 
 
Four (4) sodium citrate: light blue (BD 
#366415; 4.5 mL) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
Nails3 
2 clippings (pre-treatment, at enrollment 
only) 
X 
 
 
 
 
1 
All slides must be registered via the MPC-RC website the day they are collected and prior to shipment.  
All slides MUST BE LABELED properly. Labels are to include the patient’s tissue bank ID number (TB ID), 
protocol number (e.g., Protocol 112), time of study (e.g., baseline, 6 months), type of specimen (e.g., BM biopsy, 
BM aspirate, blood), type of stain (e.g., Iron, H& E).  For unstained slides, use a pencil to label the slides.  All 
slides are to be shipped to the tissue bank laboratory in a labeled slide box.  The label on the box is to include the 
patient’s TB ID, protocol number, and time of study.    Slides may be shipped in batches together with the local 
institution’s histopathology report.  All slides are shipped to Dr. Rona Singer Weinberg. See Protocol 107, 
section 5.0 Procurement for additional labeling and shipping information. 
2 
Cytogenetic analyses are performed as a standard of care at the institution where the patient is being treated.  
Karyotypic analysis of unstimulated bone marrow after direct 24 and 48 hours, if available, or peripheral blood 
shall be performed.  Karyotypic analysis using G-banding technology is required. Data and karyotypes are 
uploaded to the website. See Protocol 107, section 5.0 Procurement for additional reporting information. 
3 
All tissue samples must be registered via the MPC-RC website the day they are collected and prior to 
shipment.  All tubes, and envelopes (nails) must be labeled with patient patient’s tissue bank ID number (TB 
ID), protocol number (e.g., Protocol 112), sample ID number (provided by the data bank at the time of 
registration), time of study (e.g., baseline, 6 months), type of specimen (e.g., BM biopsy, BM aspirate, blood) 
and date of collection. 
4 
Off-Treatment is defined as 30 (±7) days after patient permanently stops treatment for any reason at any time 
during the study (i.e. study drug intolerance, relapse/progression, study completion, etc.) 


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Page 51 of 120 
Version #8  12/21/2015 
 
Fresh blood and bone marrow are to be shipped at ambient temperature and must be shipped the 
day that they are collected. 
Nails are to be shipped at ambient temperature and may be shipped together with blood and bone 
marrow samples or subsequently.  
All slides are to be shipped to the tissue bank laboratory in a labeled slide box. The label on the 
box is to include the patient’s TB ID, protocol number, and time of study.    Slides may be shipped 
in batches together with the local institution’s histopathology report.  All slides are shipped to Dr. 
Rona Singer Weinberg. See Protocol 107 section 5.0 Procurement for additional labeling and 
shipping information. 
All shipments must be sent by overnight courier for delivery before 10 AM or morning 
delivery the next day.  For Friday shipments (to arrive on Saturday), notify the laboratory 
prior to collection of tissue and shipment.  For shipments sent on Friday for Saturday 
delivery be certain to request Saturday AM delivery directly to the lab.  It is not possible for 
lab personnel to go to the courier’s office for pick-up. 
Shipping: 
In North America ship to: 
Dr. Rona Weinberg 
New York Blood Center 
310 East 67th Street 
Second Floor 
New York, New York 10065 
Phone: (212) 570-3488 
Fax: (212) 570-3495 
rweinberg@nybloodcenter.org  
Laboratory Phone: (212) 570-3412 
Laboratory Fax: (212) 570-3495  
MPDLab@nybloodcenter.org  
Office hours: Monday through Friday 9AM to 5PM ET. For shipments to be received at other 
times, contact Dr. Weinberg in advance of collection of samples and shipment 
Or 
In Europe ship to: 
Dr. Silvia Salmoiraghi 
MPD-RC Tissue Bank 
Azienda Ospedaliera Papa Giovanni XXIII 
Laboratorio Paolo Belli USC Ematologia  
Torre 7, Ingresso 55, piano 1 
Piazza OMS- Organizzazione Mondiale della Sanità,1  
24127 Bergamo 
Phone: +39 035-2673769 
lab.paolobelli@hpg23.it  
Office hours: Monday through Friday 9AM to 5PM. For shipments to be received at other 
times, contact Dr. Silvia Salmoiraghi in advance of collection of samples and shipment. 


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Page 52 of 120 
Version #8  12/21/2015 
8.2 
Collection of Biomarker Samples: 
The samples obtained as noted in Table 5 will be separated as follows. (also see Protocol 107, 
Appendix 10.2 for the time points to obtain samples) 
8.2.1 
Bone Marrow 
Bone marrow samples will be collected for histopathology, biomarkers, and cytogenetics/FISH. 
For biomarkers (2-5 ml) and cytogenetics (1-2 ml) (performed at the local institution), obtain a 
total of 3-7 mL of aspirated bone marrow.  Samples are to be divided as follows: 
For Biomarkers: 2-5 mL of bone marrow in a green top, heparinized tube (BD catalog number 
366480).  Cytogenetics 1-2 ml. 
 
8.2.2 Peripheral Blood 
Up to 67 mL of blood (use sterile technique): 
• For hematocrit < 32, 37 mL of blood: three ACD (yellow top) tubes (BD catalogue number 
364606; 8.5 mL tubes), one EDTA (lavender top) tube (BD catalog number 366450), and 
one sodium citrate (light blue top) tube (BD catalogue number 366415, 4.5 mL). 
• For hematocrit > 32, 67 mL of blood: Five ACD (yellow top) tubes (BD catalogue number 
364606; 8.5 mL tubes), one EDTA (lavender top) tube (BD catalog number 366450), and 
four sodium citrate (light blue top) tubes (BD catalogue number 366415, 4.5 mL). 
 
8.2.3 Nail Clippings 
Two nail clippings are to be obtained from each patient during the initial entry onto the protocol. 
Clippings are to be placed in a paper envelope and the envelope is to be sealed.   The sealed 
envelope may be stored and shipped at room temperature. 
8.3 
Central Morphological Review of Bone Marrow Aspirate Smears and 
Biopsies for Patients Entering MPD-RC Treatment Studies 
8.3.1 
Bone Marrow and Peripheral Blood Histopathology  
(See protocol 107, Appendix 10.2, for more detailed information) 
At entry into the trial, after 12 months, after 24 months, and at off-treatment for any reason 
(completion of study, relapse, progression, intolerance to drug, etc.) the following bone marrow 
aspiration and biopsy specimens must be obtained and submitted for central review: 
 


MPD-RC 112 PEGHU-Phase 3 
MPD-RC 112 PEGHU-Phase 3 
Page 53 of 120 
Version #8  12/21/2015 
Bone marrow biopsy slides: 
• One (1) biopsy slide stained with H & E  
• One (1) biopsy slide stained for iron 
• One (1) biopsy slide stained with the silver for reticulin fibrosis stain should be submitted 
for confirmatory cytologic and cytochemical studies. 
• Three (3) unstained paraffin-fixed bone marrow biopsy slides each containing at least 2 
sections. 
• Two (2) air dried unstained bone marrow biopsy touch preps for patients with no aspirate 
sample (these are made with 8 touches per slide – 4 horizontal touches in 2 rows on the 
slide) 
 
Bone marrow aspirate slides: 
• Three (3) air-dried, unstained bone marrow aspirate slides (if available) 
 
Peripheral blood slides: 
• Four (4) unstained peripheral blood films (thin smears) 
 
Slides should be submitted together with the final institutional pathology, cytochemistry, and 
immunophenotyping reports (if possible).  Bone marrow studies should be repeated at 12 and 24 
months following treatment and aspirate and biopsy specimens as described above again submitted 
for central review. They should also be repeated if transformation to MDS, myelofibrosis or acute 
leukemia is suspected and if a patient goes off-treatment permanently for any reason (i.e. 
intolerance of drug, completion of study) after at least 6 months treatment. 
 
The histopathology slides may be batch shipped every 3 Months to Dr. Weinberg in North 
America or Dr. Salmoiraghi in Europe. 
There must be an adequate amount of marrow biopsy specimen in each smear.  The above 
requirements are considered minimal.  Contact the MPD-RC Study Chair with any questions. 
Identify each slide with the patient’s MPD-RC tissue bank ID number, protocol number, type of 
specimen (example: BM biopsy, BM touch prep, BM aspirate), type of stain (example: H&E, iron, 
reticulin), and time of study (example: baseline, 12 month, 24 month) pack carefully in protective 
slide boxes (not cardboard folders), and mail to: 
(North America) 
Dr. Rona Weinberg 
New York Blood Center 
310 East 67th Street 
Second Floor 
New York, New York 10065 
Phone: (212) 570-3488 
Fax: (212) 570-3495 
rweinberg@nybloodcenter.org  
Laboratory Phone: (212) 570-3412 
Laboratory Fax: (212) 570-3495  
MPDLab@nybloodcenter.org  
Monday through Friday Noon EST 
Or 


MPD-RC 112 PEGHU-Phase 3 
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Page 54 of 120 
Version #8  12/21/2015 
(Europe) 
Dr. Silvia Salmoiraghi 
MPD-RC Tissue Bank 
Azienda Ospedaliera Papa Giovanni XXIII 
Laboratorio Paolo Belli USC Ematologia  
Torre 7, Ingresso 55, piano 1 
Piazza OMS- Organizzazione Mondiale della Sanità,1  
24127 Bergamo 
Phone: +39 035-2673769 
lab.paolobelli@hpg23.it  
Monday through Friday Noon 
Send a copy of the institutional bone marrow aspiration and biopsy report generated at your 
institution as soon as it is complete to the MPD-RC central laboratory in New York or Bergamo, 
Italy.  This report must include differential cell counts on the marrow aspirate, if performed. 
8.3.2 
Cytogenetics and FISH Cytogenetic and FISH Requirements 
Diagnostic and follow up cytogenetics and or FISH will be performed by local institutional 
laboratories. All karyotypes will be centrally reviewed (see below).  To ensure uniformity of 
cytogenetic preparations all participating local laboratories must adhere to the following 
requirements established by the central karyotype review committee. 
General Inclusion Criteria for Conventional Cytogenetics 
1) 
Banding level 300 or more and structural aberrations are accepted at 400 or higher 
banding level or confirmed by FISH. 
2) 
Minimum requirements for baseline assessments:  From each patient, bone marrow (PV, 
ET) and or unstimulated PB (PMF) specimen must be set up into two, preferably three, 
different cultures (direct, 24 hrs with and without marrow max media). Every effort 
should be made to obtain the growth of cells that are cytogenetically abnormal. 
3) 
20 metaphase evaluated from two or more cell cultures or from marrow max culture 
only. 
4) 
Only G-banding of chromosomes is acceptable. Other banding methods are not 
acceptable. 
5) 
Analysis of cell at 300 band resolution, or low quality banding, irrespective of the 
findings, to be complemented with FISH screening for subtle aberrations, including 
del(20)(q11q13) with D20S108 probe. 
6) 
SCN 2009 must be used to describe the karyotype. 
7) 
Aberrations classified as clonal should be present in at least 2 cells by G-banding or 
confirmed by FISH. 
8) 
Unusual or novel findings should be fully characterized by FISH using appropriate 
probes. 
9) 
Three karyotypes (and metaphase cells) from each patient must be uploaded 
electronically into the MPD-RC data base to document the stated cytogenetic diagnosis.  
The karyotypes are uploaded either as TIFF or JPEG files. 
FISH studies, IF POSSIBLE and recommended 
10) Case normal by G banding, if possible, ought to be screened for cryptic changes by 
interphase FISH using a MPN panel of 12 probes: CEP1( or 1q12)/1q21, 
5p15.2/5q31(EGR1), CEP7/7q31, CEP8, CEP9/9p21, RB1 at 13q14, P53/CEP17, 
20q12/D20S108. 


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Page 55 of 120 
Version #8  12/21/2015 
11) FISH studies are performed on BM or PB on interphase cells processed directly (no 
culture) using Abbott Molecular FISH probes. A minimum of 200 cells at baseline 
should be scored by two individuals. Image of FISH results should be uploaded as JPEG 
or TIFF file into the MPD-RC data base. 
Central karyotype review committee consists of Vesna Najfeld, Ph.D., Director, Tumor 
Cytogenetics, The Mount Sinai Medical Center, NY (chair) Elisabeth Nacheva, MD, Ph.D, FRC 
Path, Director of Cytogenetics, UCL Medical School, Royal Free Campus, London, UK, Cristina 
Mecucci, MD, PhD, Director of Cytogenetic laboratory, University of Perugia, Perugia, Italy and 
Ursula Giussani, Ph.D., Director of Laboratorio di Genetica Medica, Bergamo, Italy. Central 
karyotype review committee will have biannual teleconferences and central karyotype review and 
will meet annually to resolve difficult karyotypes, perform QC, and discuss correlative studies 
with hematological response and other biomarkers. Karyotypes that were not uploaded or faxed 
pictures of karyotypes cannot be reviewed.  
One of the Quality Control indicators is a proper entry and submission of cytogenetic forms and 
karyotypes by the institutional cytogenetic laboratories. If the local laboratory fails two 
consecutive specimens (poor quality of chromosome banding, missed abnormality, wrong ISCN 
nomenclature) or lack of entering cytogenetic results into MPD- RC,  the laboratory will be 
informed, and the third  failure will result in placing the local laboratory on probation and the  
institutional PI will be informed. If required, either the central lab in NY or other 
MPD-RC approved cytogenetic lab will perform the studies from the institution whose cytogenetic 
lab is placed on probation. Each institution in the MPD-RC will receive quarterly information 
regarding the cytogenetic entry results on the MPD-RC data base. 
For any questions please call Joe Tripodi MS, Cytogenetic Research Coordinator, Mount Sinai 
Medical Center: 212 241-8801 or Dr. Vesna Najfeld at 212-241-8801. 
8.4 
Clonality 
Applicable to informative females = probable 50 – 60% of patients.  Sample amount for this test is 
already included in the samples being collected.  No further sample collection needs to be done for 
this test (already included in the sample collection). 
8.5 
Symptom Assessment Package 
The Symptom Assessment Package (MPN-SAF, EORTC-QLQ C30, Exploratory Questions, 
Pegylated Interferon Alfa-2a /PEGASYS Specific Questions) (see section 9.6) will be given to the 
patient to answer and complete.  At baseline these questionnaires will be given to the patient and 
completed by the patient and returned to the local investigator prior to being provided with 
information regarding the treatment assignment.  The time points for collection are at baseline 
(pre-randomization), month 4 day 1, after months 6, 9, 12, and then every 6 months while on 
study, and at off-treatment.  The data on the forms are to be electronically entered into the 
MPD-RC CRFs online in data web site. 
8.6 
Registration Procedure 
Register patients via the MPD-RC website:  http://www.mpd-rc.org. A summary and a schedule of 
the collection and distribution of tissue samples are provided in Table 5 above. 


MPD-RC 112 PEGHU-Phase 3 
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Page 56 of 120 
Version #8  12/21/2015 
8.7 
Biomarker Evaluations 
The biomarkers that will be monitored in this trial at baseline, after 12 and 24 months, and at 
time of a bone marrow to assess for relapse/progression or at the termination of the patients 
receiving study medication and are listed in Table 5. In each disease stratum the proportions 
of patients on each treatment arm who are abnormal at baseline will be estimated and changes 
over time will be examined.  The JAK2V617F allele burden will be monitored at baseline, 12, 
24 months and at time of a bone marrow to assess for relapse/progression or at the termination 
of the patients receiving study medication.  The presence of somatic mutations in CALR will 
be assessed at baseline, 12, 24 months and at relapse/progression or at the termination of the 
patients receiving study medication. The cytogenetics and bone marrow histopathology will 
be performed at 12, 24 months and at time of a bone marrow to assess for relapse/progression 
or at the termination of the patients receiving study medication. The hematopoietic cell 
clonality will be performed in select female patients who are informative at baseline and at 
remission, progression/relapse, 12 and 24 months and termination of the patients receiving 
study medication.  The anticipated effects of the treatments provided on the various 
biomarkers are summarized in Table 6: 
 
Table 6 
Biomarker Evaluations 
Test 
Result 
Modulation  
Clonality 
Clonal 
Polyclonal JAK2V617F 
CALR 
Abnormal 
Normal 
Allele Burden 
High 
Low or absent 
Cytogenics 
Abnormal 
Normal 
Bone Marrow 
Histopathology 
Abnormal morphology 
Normalization 


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9.0 
STUDY EVENTS 
9.1 
Screening and Enrollment 
Each subject must sign and complete an informed consent form prior to the performance of study-
specific procedures. Any procedures or tests during the screening period that are obtained as part of 
routine medical care can be used in lieu of the study specific evaluations. 
9.1.1 
Baseline Data 
Prior to randomization, all patients should be assessed for their eligibility of the study.  At this time 
the following procedures should be performed and appropriately recorded into the source notes. 
 
• Patient Informed Consent 
• History and physical examination 
• Fundoscopic Eye exam 
• Vital signs 
• Body Surface area 
• ECOG performance status 
• ECG 
• Splenic size by clinical examination and by ultrasound examination. 
• Complete blood count with differential and blood smear 
• Biochemistry screen (LFT, renal function and uric acid) 
• Thyroid function tests 
• Symptom Assessment Package (Appendix D) 
• Negative pregnancy test 
• Bone marrow aspirate and biopsy 
• Cytogenetics 
• Biomarker blood samples for MPD-RC 107 
• JAK2V617F (if not previously done) 
• Concomitant medication 
• Nail Clippings 
 
STUDY REQUIREMENTS MUST BE PERFORMED WITHIN 14 DAYS PRIOR 
TO REGISTRATION EXCEPT BONE MARROW AND CYTOGENETICS 
WHICH MUST BE DONE WITHIN 90 DAYS PRIOR TO REGISTRATION AS 
LONG AS THERE IS NO CHANGE IN CLINICAL STATUS OR CHANGE IN 
THERAPY. 
 


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Page 58 of 120 
Version #8  12/21/2015 
9.2 Study Calendar 
Every “Month” in the study calendar is defined as a calendar month. Subjects should come in on the same date of every study visit month (i.e. 
January 15th, February 15th, March 15th, etc.). 
 
 
Baseline 
PEGASYS1  or  Hydroxyurea 
Parameter 
Within 2 
weeks prior 
to 
registration 
Month 
1  
Days 
12, 153 
Month 
2-5 
Day 
13 
End of 
Month 
63,4 
End of 
Month 
93,4 
End of 
Month 
123,4 
Every 3 
Months While 
on Active 
Treatment3,4 
Off-Treatment9 Observational 
Follow-up 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Prior Diagnosis / Prior Treatment 
X 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X5 
X 
X 
X 
X 
X 
X 
 
Vital Signs 
X 
X5 
X 
X 
X 
X 
X 
X 
 
Physical Examination 
X 
X5 
X 
X 
X 
X 
X 
X 
 
Spleen Size by physical examination (cm) 
X 
X 
X 
X 
X 
X 
X 
X 
 
Spleen Size by Abdominal Ultrasound 
X 
12 months6, (and 15 months if necessary to confirm a CR ) at relapse/progression or 
off treatment for any reason 
 
ECOG Performance status 
X 
X5 
X 
X 
X 
X 
X 
X 
 
Serum or Urine HCG7 
X 
X5 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistries (sodium, potassium, creatinine, 
chloride, AST, Alk. Phosphatase, LDH, and uric 
acid) 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid Function T4, TSH 
X 
X5 
X 
X 
X 
X 
X 
X 
 
Thyroid Antibodies 
X 
 
 
 
 
 
 
X 
 
JAK2V617F mutation analysis 
X10 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
Fundoscopic Eye Exam8 
X 
 
 
 
 
 
 
 
 
Nail clippings 
X 
 
 
 
 
 
 
 
 
Symptom Assessment Packet 
X (pre-
randomization) 
 
Month 4 Day 1, After Months 6, 9, 12, every 6 months thereafter, and at off-
treatment. 
 


MPD-RC 112 PEGHU-Phase 3 
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Page 59 of 120 
Version #8  12/21/2015 
 
Baseline 
PEGASYS1  or  Hydroxyurea 
Parameter 
Within 2 
weeks prior 
to 
registration 
Month 
1  
Days 
12, 153 
Month 
2-5 
Day 
13 
End of 
Month 
63,4 
End of 
Month 
93,4 
End of 
Month 
123,4 
Every 3 
Months While 
on Active 
Treatment3,4 
Off-Treatment9 Observational 
Follow-up 
Bone Marrow biopsy and aspirate for 
-Cellularity 
-Morphology on H & E 
-Blast Percentage 
-Reticulin Fibrosis Grade 
X 
Months 126 and 24 and at time of relapse/progression or off treatment for any reason 
 
Cytogenetics 
X 
Months 126 and 24 and at time of relapse/progression or off treatment for any reason 
 
Biomarkers 
X 
 
Concomitant Medications 
X 
Ongoing 
 
Adverse Events NCI CTCAE v4.0 
X 
Ongoing 
 
Assessment of survival; development of 
myelodysplastic disorders, myelofibrosis, or 
leukemic transformation; cardiovascular events; and 
treatment changes 
 
Ongoing 
See section 
5.8 
 
1 
The subject will be taught how to administer the study drug injection to themselves by the research staff. The subject will inject the dosage amount needed and recap the syringe with the 
unused portion of the study drug, placing the capped syringe in a container and brought back to the clinic to be checked and recorded by the study staff. See Appendix E. 
2 
If Day 1 procedures were completed within 3 days of “Day 1”, they do not need to be repeated.  
3 
The month 1 day 15 visit may occur +/- 1 day. All other subsequent visits can occur +/- 7 days. 
4 
All subsequent study visits should occur at the end of the month (i.e. end of month 9, end of month 12, end of month 15, etc.). Note that there is a 2 month gap between “Month 5 Day 1” and 
“End of Month 6” 
5 
Day 1 Only 
6 
The Month 12 visit should be done at the end of month 12 +/- 7 days. 
7 
If the patient is a woman capable of having children. 
8 
Any patient complaining of decreased vision or loss of vision while receiving study drug must have a prompt and complete eye examination. 
9 
Off-Treatment is defined as 30 (±7) days after patient permanently stops treatment for any reason at any time during the study (i.e. study drug intolerance, relapse/progression, study 
completion, etc.) 
10 
JAK 2V617F test does not need to be repeated if previously performed. 


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9.3 
Procedures for the follow-up visit 
Refer to the study calendar (Section 9.2) for visit schedule and procedures to be 
completed. 
9.4 
Interruption of Treatment 
See Section 6.0. 
9.5 
Drug Compliance 
Patients will be given a diary to record drug usage and clinicians will be asked to confirm drug 
usage with patient. See Appendix E for patient medication diaries. 
9.6 
Symptom Assessment Package 
Given there is no currently validated instrument for QOL for serial administration in patients with 
ET or PV to be used in a clinical trial setting we have adopted a standard validation approach used 
for new QOL instruments. The MPN-SAF and EORTC-QLQ C30 will be given to patients at 
baseline, at month 4 day 1, after months 6, 9, 12, and then every 6 months (either previously or 
widely validated instruments to be used for cross-validation – see below). If the subject is 
randomized to pegylated interferon alfa-2a, the Pegylated Interferon Alfa-2a /PEGASYS Specific 
Questions will also be given and the same time points mentioned above. The symptom assessment 
package of instruments will be completed by enrolled patients on-site at the time of their study 
visits. 
MPN-SAF: The MPN-SAF (Appendix D) was created to address the constellation of symptoms 
most frequent in MPN patients based on the results of our internet based survey of 1179 MPN 
patients ((PV (N=405); ET (N=304); MF (N=456))(Mesa, et al 2007). Our survey demonstrated 
that the vast majority of the MPN patients have very significant fatigue compared to age matched 
published data. Given the central importance of this symptom, and need for accurate measurement 
on a trial, the previously validated Brief Fatigue Inventory is included as item 1-9 (Mendoza, et al 
1999), and a composite score is generated for the BFI (the score is the mean result of all 9 items). 
Items 10-13 address spleen related symptoms (early satiety, abdominal pain), inactivity, and 
cough.  Items 14-18 address the central MPN symptoms of night sweats, pruritus, bone pain, fever, 
and weight loss. Although some of the these symptoms are more frequent in PMF, they are still 
present in significant numbers of ET and PV patients and are of relevance in this trial given the 
high risk patients included on study will also include those who already have mild features of post 
ET/PV MF respectively.  Item 19 includes a single item overall quality of life measure. Items 10-
16 and 19 are measured on a linear analog scale assessment (LASA). The LASA methodology has 
proven very valid in the past (Locke, et al, 2007). Additionally, the lack of a composite score 
overall for the MPN-SAF is a positive attribute for this instrument for serial assessment in a 
clinical trial for MPN patients as individual symptoms may respond (or worsen) independently 
with therapy. 
The MPN-SAF has previously been validated for use at a single time point (Mesa, et al, 2009) by 
co-administration with previously validated instruments (the Memorial Symptom Assessment 
Scale), the Brief Pain Inventory (BPI). Measurement of individual symptoms which existed on 
other validated instruments was highly correlated with single item results on the MPN-SAF. 
Additionally, patient anonymous feedback demonstrated the MPN-SAF was easy to understand. 
Additionally patients were questioned to respond to any major symptoms which were not included 


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in the MPN-SAF, and no symptom was mentioned by more than one patient demonstrating the 
relatively comprehensive nature of the instrument for MPN patients. 
EORTC-QLQ C30 (Appendix D2): The EORTC-QLQ-C30 version 3.0 (Aaronson, et al 1993) is 
included as our main instrument for co-validation on these trials, and redundant capture of impact 
of information for impact of protocol therapy on patient’s symptoms, mood, and quality of life. 
The initial EORTC QLQ-C36 questionnaire, later shortened and validated with 30 questions, has 
the following advantages namely being a) cancer specific b) multidimensional in structure c) 
appropriate for self- administration d) applicable across a range of cultural settings. This 
instrument has been thoroughly validated for serial use in cancer clinical trial setting, and is 
available in standard and validated translations for Italian, French, Swedish, and German (all 
languages required for the enrolling centers on these trials). This instrument although highly valid 
for a portion of the symptom changes we wish to capture with this trial, nevertheless is not as 
comprehensive for MPN specific symptoms and hence the need for both instruments to be 
administered. 
Pegylated Interferon Alfa-2a /PEGASYS Specific Questions (Appendix D3): Analysis of the 
drug related toxicities from the 2 prior pegylated interferon trials in ET/PV, four toxicities possibly 
related to the drug were identified. These will be specifically addressed in the questionnaire, but 
only for this trial and not for the MPN- SAF as these toxicities are not core symptoms identified in 
patients with MPNs. The symptoms include flu like symptoms, injection site reaction, blurred 
vision or vision changes and flushing. 


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10.0 
DEFINITION OF RESPONSE CRITERIA 
10.1 
Primary Endpoints 
The following criteria for clinicohematologic will be used for ET and PV as designed by the 
European LeukemiaNet (Barosi 2008) (Table 7 and Table 8). The primary endpoint is CR or PR 
achieved by these criteria by the end of the first 12 months on treatment with duration confirmed of 
at least 3 months.  Alternative criteria will be used for patients with Splanchnic Vein Thrombosis 
(see Table 9) 
Table 7 
Criteria for Response in ET 
CRITERIA FOR RESPONSE IN ET 
Complete response 
o Platelet count < 400 x 109/L AND 
o No disease-related symptoms* AND 
o Normal spleen size on imaging AND 
o WBC < 10 x 109/L 
Partial response 
In patients who do not meet criteria for complete response 
Platelet count < 600 x 109/L OR >50% reduction from baseline 
No response 
Any response that does not satisfy partial criteria 
* Disease-related symptoms: microvascular disturbances, pruritis, headache 
 
Table 8 
Criteria for Response in PV 
CRITERIA FOR RESPONSE IN PV 
Complete response defined as 
o Hematocrit < 0.45 without phlebotomy AND 
o Platelet count < 400 x 109/L AND 
o WBC <10 x 109/L AND 
o Normal spleen size on imaging AND 
o No disease related symptoms* 
Partial response 
In patients who do not meet criteria for complete response, 
Hematocrit < 45% without phlebotomy OR 
response in any 3 of the remaining 4 criteria 
No response 
Any response that does not satisfy partial response 
* Disease-related symptoms: microvascular disturbances, pruritis, headache 
 


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Table 9 
Criteria for Response in Patients with Splanchnic Vein Thrombosis 
CRITERIA FOR RESPONSE IN PATIENTS WITH SPLANCHNIC VEIN 
THROMBOSIS: 
Complete response defined as: 
o Hematocrit <0.42 without phlebotomy AND 
o Platelet count 100-200 x 109/L AND 
o WBC 2-8 x 109/L  AND 
o No spleen enlargement from enrollment baseline AND 
o No disease related symptoms* 
Partial response  
In patients who do not meet criteria for complete response, Hematocrit < 45% 
without phlebotomy OR response in any 3 of the remaining 4 criteria 
No response 
Any response that does not satisfy partial response 
* Disease-related symptoms: microvascular disturbances, pruritis, headache 
 
In addition, the revised ELN and IWG-MRT consensus response criteria for PV and ET will 
be utilized (3). 
10.2 
Secondary Outcomes 
• To evaluate the toxicity and tolerability of therapy (Pegylated Interferon Alfa-2a vs. 
hydroxyurea) in the study populations 
• The ability of therapy (Pegylated Interferon Alfa-2a vs. hydroxyurea) to achieve a complete 
(CR) or partial response (PR) by LeukemiaNet criteria. 
• To evaluate specific pre-defined toxicity and tolerance of therapy (Pegylated Interferon 
Alfa-2a vs. hydroxyurea) through a sequential structured symptom assessment package of 
patient reported outcome instruments. 
• Observed survival and incidence of development of a myelodysplastic disorder, 
myelofibrosis, or leukemic transformation (Pegylated Interferon Alfa-2a vs. hydroxyurea). 
• Observed incidence of major cardiovascular events (defined as cardiovascular death, 
myocardial infarction, stroke, transient ischemic attack, pulmonary embolism, Budd Chiari 
syndrome, deep vein thrombosis, and any other clinically relevant thrombotic event) 
(Pegylated Interferon Alfa-2a vs. hydroxyurea). 
• To measure the impact of therapy (Pegylated Interferon Alfa-2a vs. hydroxyurea) on key 
biomarkers of the disease(s) – JAK2V617F, CALR, hematopoietic cell clonality in platelets 
and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities. A 
definition of a molecular response is provided in Table 10 and of a histologic response in 
Table 11. 
 


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Table 10 
Definition of molecular response in ET and PV 
Response Grade 
Definition 
Complete response 
Reduction of any specific abnormality to undetectable 
levels 
Partial response* 
(1) A reduction of >50% from baseline value in patients 
with <50% mutant allele burden at baseline OR 
(2) reduction of > 25% from baseline value patients with > 
50% mutant allele burden at baseline 
No response 
Any response that does not satisfy partial response 
* Applies only to patients with a baseline value of mutant allele burden greater than 10% 
 
Table 11 
Criteria for histologic response in ET and PV 
Essential Thrombocythemia 
Polycythemia Vera 
Bone marrow histologic remission 
Absence of megakaryocyte hyperplasia 
Bone marrow histologic remission 
Presence of age-adjusted normocellularity 
and no reticulin fibrosis  


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11.0 
STATISTICAL CONSIDERATIONS 
With 300 patients randomized to two treatment groups in two strata, we can detect a difference in 
complete clinical hematologic response rates of 15% from 15% to 30% with an overall two sided 
alpha of 0.05 and power of 85% for the two disease strata combined.  
Randomization will be carried out centrally within strata defined by disease (ET/PV). Within 
each of these disease strata, patients will be randomized within strata defined by current use of 
hydroxyurea or no current use within each center. 
Table 12 below provides the stopping boundaries for the difference in complete response rates 
between the two treatment arms at each of the two interim analyses and at the final analysis.  The 
first interim analysis will be performed when 75 patients (25% of total planned accrual) would 
have had sufficient time on study to be evaluable for response.  At that time, a blinded sample 
size re-estimation will be carried out to evaluate the underlying assumptions with respect to the 
anticipated overall CR+PR rate at 12 months and sample size will be adjusted, if necessary, 
should the study not be stopped for futility. The second interim analysis will be conducted when 
50% of randomized patients are evaluable for response. 
 
Table 12 
O-Brien Fleming Stopping Boundaries to Reject Null (H0) or Alternative 
(H1 Futility) Hypotheses for Interim Analyses of Clinical Hematologic 
Response Rates (2-sided alpha =0.05, power =85%).  Complete Response 
Rate on Hydroxyurea Assumed =15%; on Pegylated Interferon Alfa-2a 
Assumed =30% 
 
 
Critical Value of Z Statistic  
(p-value)  
 
Observed Difference in 
Proportions of Patients with 
Complete Response 
Analysis 
Number 
of 
Patients 
Reject Null 
Hypothesis 
Reject Alt. 
Hypothesis 
Reject Null 
Hypothesis  
Reject Alt. 
Hypothesis 
Interim 1 
75 
+/-4.333 
(0) 
+/-0.0029 
(≥0.998)) 
≥ |0.430| 
≤ |0.0003| 
Interim 2 
150 
+/-2.963 
(≤0.003) 
+/-0.269 
≥0.788 
≥ |0.208| 
≤|0.0189| 
Final 
300 
+/-1.957 
(≤0.0504) 
+/-1.957 
(˂0.0504) 
≥ |0.0971| 
˂|0.0971 
[Computations from EAST 6.2, Cytel, Inc., 2013.] 
11.1 
Safety Monitoring/ Stopping Rules 
The study is designed to allow for early stopping if the efficacy on either arm is much better or 
worse than the comparator or if the possibility of achieving the expected outcome is futile. In order 
to ensure that patients are not at excess risk of overall disease complications, we will also monitor 
the overall complication free survival rate in the total population under study.  We can detect a 
hazard ratio of 0.50 (Pegylated Interferon Alfa-2a /hydroxyurea) in overall complication free 
survival (free of major thrombotic event (definition 13.3.1), major hemorrhagic complications 
(definition 13.3.3), progression to myelofibrosis (definition 13.3.4), progression to acute leukemia 
(definition 13.3.4) or death) with 300 patients randomized into the trial with an unadjusted log rank 


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test with an overall power of 80.3% and 2-sided alpha of 0.05. If we enroll an average of 75 
patients/year over approximately 4 years, the expected maximum study duration would be 6 years.  
Table 13 below provides the stopping boundaries for this plan: 
Table 13 
O’Brien Fleming Stopping Boundaries for Complication Free Survival: 300 
Patients Randomized to Pegylated Interferon Alfa-2a vs. Hydroxyurea (2-
sided overall alpha =0.05, power =80%) 
Analysis Number of 
Events 
Approximate 
Expected 
Timing 
(months) 
Critical Value 
of 
Z-Statistic 
Hazard Ratio: 
Pegylated Interferon 
Alfa-2a /Hydroxyurea 
p-value (cumulative 
alpha spent) 
Interim 1 
26 
30 
+/-2.279 
≤0.405; ≥2.47 
≤|0.011| (0.023) 
Interim 2 
52 
48 
+/-2.295 
≤0.526; ≥1.902 
≤|0.011| (0.038) 
Final 
Analysis 
77 
67 
+/-2.296 
≤0.592; ≥1.691 
≤|0.011| (0.050) 
[Computations from EAST 6.2, Cytel, Inc., 2013.] 
Overall complication free survival will be monitored to ensure that the trial can be considered for 
early stopping if the hazard ratio for Pegylated Interferon Alfa-2a /Hydroxyurea is very favorable 
or very unfavorable.  The timing of these analyses (shown in section 9.2) is expected to occur at 30 
months when accrual has completed for the first analysis, and at 48 months when the study is 
scheduled to complete for the second analysis. These analyses will have no impact on study 
accrual, but will impact continuation on study should a major difference in complication free 
survival be observed. 
11.2 
Statistical Analysis 
Within each disease stratum, descriptive statistics will be used to compare the distributions of 
baseline patient and disease characteristics at randomization for patients treated with Pegylated 
Interferon Alfa-2a or hydroxyurea. Frequency distributions and chi-square tests will be used to 
screen for major imbalances in the two randomization groups for qualitative variables; graphical 
displays including and box plots and summary statistics (e.g., mean, median, standard deviation, 
ranges, etc.) will be used for quantitative variables with t-tests (after appropriate transformations if 
necessary to meet the assumptions of the methods). 
The primary analysis will be based on the comparison of the proportions of patients with complete 
clinical hematologic responses based on a 2-sided z-test for proportions. All patients randomized 
to the study will be included in this intent to treat analysis. The distribution of responses will also 
be summarized for each of the two treatment groups for each disease.  Cochran-Mantel log rank 
tests as well as logistic regression methods will be used to provide additional analyses that take 
into account any covariates that might potentially impact response to treatment within each disease 
stratum. 
Safety and toxicity will be summarized to compare the distributions of incidence and severity of 
adverse events and laboratory toxicities on the two treatment groups within each disease stratum. 
Frequency distributions and time to event analyses will be used to summarize the results. 


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11.3 
Additional Analyses  
The characteristics of patients at entry will be summarized within strata defined by disease. These 
characteristics include disease characteristics, biomarker levels, prior treatment, disease duration, 
demographic characteristics, comorbidity, and other covariates using summary statistics and 
graphical methods logistic regression models will be used to examine the associations of best 
response as defined above with these characteristics and biomarker levels within each of the 
disease classes.   The distributions of each of the biomarker measurements will be displayed 
graphically within strata defined by platelet level at entry as well as by other important features of 
disease history (disease duration, age, sex, and other potential covariates).  Similarly, for each 
biomarker, the proportions of patients who are normal at baseline (of each biomarker as defined by 
each of the laboratories) will be estimated.  Changes from baseline and summary statistics will be 
provided over time, along with t-tests (and analysis of variance F-tests) or chi square tests and 
odds ratios where appropriate to identify potential differences among subgroups of patients 
defined by clinical features at the time of registration. 
Additional analyses include comparisons of thrombotic complication free survival and survival 
using 2-sided log-rank tests of the hazard ratio of Pegylated Interferon Alfa-2a compared to 
hydroxyurea treated patients. Cox proportional hazards models will be used to examine the effects 
of covariates on outcomes. 
A major focus of this study is to examine biomarker normalization over time within a disease 
stratum. Rates of normalization for each individual marker and for one or more of these markers 
will be estimated at each time point.  Each of the biomarkers will be examined over time using 
methods for longitudinal data analysis. In particular, each of the markers shown in section 8.0 will 
be examined using Linear Mixed Effects Models with time as a fixed effect and a random effect to 
account for patient variability in the individual marker (Diggle, P.J., et al, 2002; Venables, W.N. 
and Ripley, B.D., 2002; Fitzmaurice, G., Laird, N., and Ware, J., 2004). General estimating 
equations (GEE) will also be used to address these issues. The effects of baseline characteristics as 
covariates will be incorporated into the models. Transformations of variables will be carried out if 
necessary to meet the assumptions of the proposed analyses.  
Correlations will also be examined within and across the strata to identify potential interactions 
and redundancies among variables. Data are expected to be missing in relation to treatment failure 
and/or disease complications. That is, missingness may be informative and related to treatment 
and/or outcome. Approaches to incorporate informative missing data into the longitudinal models 
such as those proposed by Verbeke, G. and Molenberghs, G. (2000) and Little and Rubin (2002) 
will be used. 
11.4 
Quality of life analysis 
Descriptive statistics will be used to summarize the individual items in the MPN-SAF as well 
overall scores on each of the quality of life instruments in each disease stratum at baseline and 
subsequent time points for each of the instruments described in Appendix D The changes in the 
specific components of the MPD-RC will be evaluated over time and the associations with 
changes in standard instruments will be summarized. These analyses will also include comparisons 
between the two treatment groups within each disease stratus. The MPN-SAF components and 
overall results at baseline and over time will also be compared with the presence/absence of 
toxicities and side effects of disease and treatment with Pegylated Interferon Alfa-2a or 
hydroxyurea.  Results will also be evaluated by best response outcome. 
Longitudinal data analysis methods will be used to evaluate patients’ quality of life over time for 


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the components of the MPN-SAF and other standard instruments. The objectives of these 
exploratory analyses will be to identify components of quality of life that are influenced by 
treatment with Pegylated Interferon Alfa-2a.  The limitations of these analyses will be evaluated. 
These issues include the potential effects of informative missing and data and patient 
perception/knowledge of response status. 
11.5 
Statement of Design 
The trial is a randomized Phase III study conducted in patients with high risk PV or ET. 


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12.0 
DURATION OF PATIENT PARTICIPATION 
Patients will be recruited for 4.0 years and will be followed-up for an additional 2.0 years following 
the last patient enrolled. 
12.1 
Termination of Treatment and/or Study Participation 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without compromising their medical care.  The investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
• Serious adverse event 
• Patient request 
• Non-compliance 
• Administrative reasons 
• Failure to return for follow-up 
• General or specific changes in the patient’s condition unacceptable to further treatment in 
the judgment of the investigator 
 
The primary reason for a patient’s withdrawal from the study is to be recorded in the source 
documents and on the “Off Treatment Notice” form available on the MPD-RC website. 
12.2 
Required Data 
Laboratory and clinical parameters during the treatment courses are to be followed using 
individual institutional guidelines and the best clinical judgment of the responsible physician. It is 
expected that participants will be cared for by physicians experienced in the treatment and 
supportive care of patients with MPN. 


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13.0 
ADVERSE EVENTS: ASSESSMENT OF SAFETY 
13.1 
Definitions 
Adverse event 
Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an investigational medicinal 
product, whether or not considered related to the investigational medicinal product. Such adverse 
events should be followed until resolution or until stabilization. 
Pre-existing conditions 
In this study, a pre-existing condition (i.e. a disorder present before randomization and noted on 
the medical history) should not be reported as an adverse event unless the condition worsens. A 
preexisting condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. At screening, any clinically significant 
abnormality should be recorded as a preexisting condition.  At the end of the study, any new 
clinically significant findings/abnormalities that meet the definition of an adverse event must also 
be recorded and documented as an adverse event. 
Study Disease 
Deterioration in the study disease should be reported as an adverse event. 
Procedures 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs. A medical condition for which an unscheduled procedure was performed, should 
however be reported if it meets the definition of an AE. For example the acute appendicitis should 
be reported as an adverse event rather than the appendectomy. 
Laboratory values 
A laboratory abnormality should be documented as a clinical adverse event if any one of the 
following conditions is met: 
• The laboratory abnormality is not otherwise corrected by a repeat test to confirm the 
abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
Adverse reaction of an investigational medicinal product (AR) 
All untoward and unintended responses to an investigational medicinal product related to any dose 
administered. All adverse events judged by either the reporting investigator or the sponsor as 
having a reasonable causal relationship  to  a  medicinal  product  qualify  as  adverse  reactions.  
The expression reasonable causal relationship means to convey in general that there is evidence or 
argument to suggest a causal relationship or no other reasonable etiology. 
Unexpected adverse reaction 
An adverse reaction, the nature, or severity of which is not consistent with the applicable product 
information (e.g. investigator's brochure for an unapproved investigational product or summary of 
product characteristics (SPC) for an authorized product). When the outcome of the adverse 
reaction is not consistent with the applicable product information this adverse reaction should be 


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considered as unexpected. The term “severe” is often used to describe the intensity (severity) of a 
specific event. This is not the same as “serious,” which is based on patient/event outcome or action 
criteria. 
Serious adverse event or serious adverse reaction 
Any untoward medical occurrence or affect that: 
• results in death 
• is life-threatening 
• requires hospitalization or prolongation of existing inpatient hospitalization 
• results in persistent or significant disability or incapacity 
• is a congenital anomaly or birth defect 
• other serious (important medical events) 
Life-threatening in the definition of a serious adverse event or serious adverse reaction refers to an 
event in which the subject was at risk of death at the time of event; it does not refer to an event 
which hypothetically might have caused death if it were more severe. 
Suspected unexpected serious adverse reactions (SUSARs) should be notified to MPD-RC office 
within 24 hours of the site becoming aware of the event occurring. 
13.2 
Expected Adverse Drug Reactions 
The medications used within the trial have been marketed for some time and consequently the 
following adverse drug reactions have been observed and reported. Consequently the following 
adverse reactions need not be reported as Suspected Unexpected Serious Adverse Reaction 
(SUSAR). 
13.2.1 
Hydroxyurea 
Bone marrow depression is the dose limiting toxicity. Gastrointestinal side effects are common but 
require rarely dose reduction or cessation of treatment. 
Common ≥1/100 to < 1/10 
Blood: Bone marrow depression, leucopenia, megaloblastosis. 
Gastrointestinal: Diarrhea, constipation. 
Uncommon (>1/1,000, <1/100) 
Blood: Thrombocytopenia, anemia 
Body as a whole: Nausea, vomiting, anorexia, stomatitis. Drug fever, chills, malaise. 
Skin: Maculopapular rash, facial erythema, aural erythema. 
Liver: Elevation of liver enzymes, bilirubin. 
Urogenital: Transient impairment of the renal tubular function accompanied by elevation 
in serum uric acid, urea and creatinine. 
Rare ≥1/10,000 to < 1/1000 
Body as a whole: Hypersensitive reactions 
Skin: Alopecia. 
Respiratory: Acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever 
and dyspnea, allergic alveolitis. 
Urogenital: Dysuria. 


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Neurological: Rare neurological disturbances including headache, dizziness, 
disorientation, hallucinations. 
Very rare: ( < 1/10,000) 
Skin: Dermatomyositis-like skin changes, Hyperpigmentation or atrophy of skin and nails, 
cutaneous ulcers (especially leg ulcers), Pruritus, actinic keratosis, skin cancer (squamous 
cell cancer, basal cell carcinoma), violet papules, desquamation. 
Urogenital: renal impairment. In rare cases dysuria or renal impairment, hypersensitive 
reactions. 
Blood: In the therapy with hydroxyurea megaloblastosis may occur which does not respond 
to treatment with folic acid or vitamin B12. The bone- marrow suppression subsides, 
however, when therapy is discontinued. In patients receiving long-term treatment with 
hydroxyurea for MPN, such as PV and thrombocythemia, secondary leukemia may 
develop. To what extent this relates to the underlying disease or to treatment with 
hydroxyurea is presently unknown.  Hydroxyurea can reduce plasma iron clearance and 
iron utilization by erythrocytes.   However, it does not appear to alter the red blood cell 
survival time. 
Gastrointestinal: Severe gastric distress (nausea, emesis, anorexia) resulting from 
combined hydroxyurea and irradiation therapy may usually be controlled by temporarily 
discontinuing hydroxyurea administration. Hydroxyurea may aggravate the inflammation 
of mucous membranes secondary to irradiation. It can cause a recall of erythema and 
hyperpigmentation in previously irradiated tissues. 
Skin: Erythema, atrophy of skin and nails, desquamation, violet papules, alopecia, 
dermatomyositis-like skin changes, actinic keratosis, skin cancer (squamous cell cancer, 
basal cell carcinoma), cutaneous ulcers (especially leg ulcers), pruritus and 
hyperpigmentation of skin and nails have been observed in isolated cases partly after years 
of long-term daily maintenance therapy with hydroxyurea. 
Neurological: High doses may cause moderate drowsiness. Rare neurological disturbances 
including headache, dizziness, disorientation, hallucinations, and convulsions have been 
reported. 
Respiratory: In individual cases allergic alveolitis. 
13.2.2 
Pegylated Interferon Alfa-2a/PEGASYS  
Very Common ≥1/10 
Metabolism and Nutrition Disorders: Anorexia 
Psychiatric disorders: Depression*, anxiety, insomnia* 
Nervous system disorders: Headache, dizziness*, concentration impaired  
Respiratory, thoracic and mediastinal disorders: Dyspnea, Cough  
Gastrointestinal disorders: Diarrhea*, nausea*, abdominal pain* 
Skin and Subcutaneous tissue disorders: Alopecia, dermatitis, pruritis, dry skin 
Musculoskeletal connective tissue and bone disorders: Myalgia, arthralgia  
General disorders and administration site conditions: Pyrexia, rigors*, pain*, asthenia, 
fatigue, injection site reaction*, irritability* 


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*These adverse reactions were common (≥1/100 to < 1/10) in Chronic Hepatitis B patients treated 
with Pegylated Interferon Alfa-2a /PEGASYS monotherapy 
Common ≥1/100 to < 1/10 
Infections and infestations:  Upper respiratory infection, bronchitis, oral candidiasis, herpes 
simplex, fungal, viral and bacterial infections 
Blood and lymphatic system disorders: Thrombocytopenia, anemia, lymphadenopathy 
Endocrine disorders: Hypothyroidism, hyperthyroidism 
Psychiatric disorders: Emotional disorders, mood alteration Aggression, nervousness, 
libido decreased 
Nervous system disorders:  Memory impairment, syncope, weakness, migraine, 
hypoesthesia, hyperesthesia, paraesthesia, tremor, taste disturbance, nightmares, 
somnolence 
Eye disorders: Vision blurred, eye pain, eye inflammation, xerophthalmia 
Ear and labyrinth disorders: Vertigo, earache 
Cardiac disorders: Tachycardia, palpitations, edema peripheral 
Vascular disorders: Flushing 
Respiratory, thoracic and mediastinal disorders: Dyspnea  exertional, epistaxis, 
nasopharyngitis, sinus congestion, nasal congestion, rhinitis, sore throat Gastrointestinal 
disorders: Vomiting, dyspepsia, dysphagia, mouth ulceration, gingival bleeding, glossitis, 
stomatitis, flatulence, dry mouth 
Skin and Subcutaneous tissue disorders: Rash, sweating increased, psoriasis, urticaria, 
eczema, skin disorder, photosensitivity reaction, night sweats Reproductive system and 
breast disorders: Impotence 
Musculoskeletal connective tissue and bone disorders: Back pain, arthritis, muscle 
weakness, bone pain, neck pain, musculoskeletal pain, muscle cramps  
General disorders and administration site conditions: Chest pain, influenza like illness, 
malaise, lethargy, hot flushes, thirst 
Investigations: Weight decreased 
Uncommon ≥1/1000 to < 1/100 
Infections and infestations: Pneumonia, skin infection  
Neoplasms benign and malignant: Hepatic neoplasm  
Immune system disorders: Sarcoidosis, thyroiditis 
Endocrine disorders: Diabetes 
Metabolism and Nutrition Disorders: Dehydration  
Psychiatric disorders: Suicidal ideation, hallucinations 
Nervous system disorders: Peripheral neuropathy 
Eye disorders: Retinal hemorrhage 
Ear and labyrinth disorders: Hearing loss 
Vascular disorders: Hypertension 


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Respiratory, thoracic and mediastinal disorders: Wheezing  
Gastrointestinal disorders: Gastrointestinal Bleeding  
Hepato-biliary Disorders: Hepatic Dysfunction 
Rare ≥1/10,000 to < 1/1000 
Infections and infestations: Endocarditis, otitis externa 
Blood and lymphatic system disorders: Pancytopenia 
Immune system disorders:   Anaphylaxis, systemic lupus erythematosus, rheumatoid 
arthritis 
Endocrine disorders: Diabetic ketoacidosis 
Psychiatric disorders: Suicide, psychotic disorder 
Nervous system disorders: Coma, convulsions, facial palsy 
Eye disorders:  Optic neuropathy, papilledema, retinal vascular disorder, retinopathy, 
corneal ulcer 
Cardiac 
disorders: 
 
Myocardial 
infarction, 
congestive 
heart 
failure, 
angina, 
supraventricular tachycardia, arrhythmia, atrial fibrillation, pericarditis, cardiomyopathy 
Vascular disorders: Cerebral hemorrhage, vasculitis 
Respiratory, thoracic and mediastinal disorders:  Interstitial Pneumonitis including fatal 
outcome, pulmonary embolism 
Gastrointestinal disorders: Peptic ulcer, pancreatitis 
Hepato-biliary Disorders: Hepatic failure, cholangitis, fatty liver  
Musculoskeletal connective tissue and bone disorders: Myositis  
Renal and urinary disorders: Renal insufficiency 
Injury and poisoning: Substance overdose 
Very rare <1/10,000 
Blood and lymphatic system disorders: Aplastic anemia 
Immune system disorders: Idiopathic or thrombotic Thrombocytopenic purpura 
Eye disorders: Vision loss 
Skin and Subcutaneous tissue disorders: Toxic epidermal necrolysis, Stevens- Johnson 
syndrome, angioedema, erythema multiform 
13.2.3 
Aspirin 
• Dyspepsia, nausea and vomiting. 
• Less commonly irritation of the gastrointestinal mucosa may lead to erosion, ulceration and 
gastrointestinal bleeding. 
• Hepatotoxicity, which occurs rarely. 
• Hypersensitivity reactions including urticaria, rhinitis, angioneurotic edema and severe 
bronchospasm. 
• Aspirin may enhance the effects of anticoagulants and may inhibit the action of uricosurics. 
• Aspirin may precipitate bronchospasm and may induce attacks of asthma in susceptible 
subjects. 


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• Aspirin may cause salt and water retention as well as deterioration in renal function 
13.3 
Expected Serious Adverse Events 
Within these patient populations the following serious adverse events are expected and need not 
be reported as a SUSAR. 
13.3.1 
THROMBOTIC EVENTS 
New infarction or recurrent myocardial infarction 
Myocardial  infarction  is  defined  as  the  presence  of  two  or  more  of  the following criteria: 
a) Symptoms of cardiac ischemia 
• Characteristic ischemic chest pain in the pericardium or associated referral areas, 
lasting for at least 20 minutes 
b) Significant cardiac enzyme elevations 
• Elevation of CPK, LDH, or AST to at least twice the upper limit of normal for the 
given laboratory in the absence of other explanation. 
c) EKG changes 
• Occurrence of new 40 msec Q waves in at least two adjacent ECG leads, or 
development of a new dominant R wave in V1 or of new ST elevation or depression 
or persistent (>48 hours) new T wave inversion. 
Stroke and stroke type 
A stroke is a new focal neurologic deficit of presumed vascular origin which persists for > 24 hours 
or results in death within 24 hours. 
 
Stroke type: 
• Hemorrhagic: A stroke caused by primary intracranial hemorrhage diagnosed by CT, MRI, 
or other objective means, or by autopsy. 
• Ischemic: A stroke of atherothrombotic or embolic origin as diagnosed by CT, MRI or other 
objective means, or by autopsy. 
• Uncertain: A stroke not otherwise classified by the above criteria. 
 
Transient cerebral ischemic attack (TIA) 
A Transient Ischemic Attack is defined as the abrupt onset of unilateral motor or sensory 
disturbance, speech defect, homonymous hemianopia, constructional apraxia, or transient 
monocular blindness (defined as the abrupt onset of unilateral decreased visual acuity involving a 
portion or the entirety of the visual field) that resolved completely in less than 24 hours. 
Deep vein thrombosis (DVT) 
A deep vein thrombosis (DVT) is defined as a typical clinical picture with positive investigation: 
i.e. phlebography, ultrasonography, CT in unusual sites. In case of suspected recurrence in a site of 
previous DVT (e.g. ipsilateral limb) diagnosis is accepted only if the investigation shows 
extension or recurrence of thrombosis as compared to a previous test. 
 
Pulmonary embolism 
A pulmonary embolism is defined as a typical clinical picture with positive angiography or high-
probability V/Q scanning. 
 
Thrombotic digital ischemia 
Characteristic purplish discoloration of toes/fingers, which may progress to infarction if untreated. 


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Digital ischemia may occasionally be associated with erythromelalgia. 
 
Unstable angina 
Defined in accordance with TIMI criteria as presence of prolonged angina or recurrent angina at 
rest, together with one of the following: new ST segment depression, requirement for 
revascularization procedure, cardiac enzyme rise to less than twice the upper limit of normal or 
past history of documented coronary artery disease. 
OR 
Ischemic discomfort at rest lasting 5 minutes or greater and associated with at least one of the 
following new/presumably new ST segment elevation > 0.5mm; T-wave inversion > 3mm in 3 
leads or left bundle branch block; cardiac enzyme rise to less than twice the upper limit of normal. 
Other thrombotic event 
Thrombosis in sites not covered above. In particular, characteristic symptoms of peripheral limb 
ischemia with evidence of thrombosis. In addition characteristic syndromes of abdominal 
thrombosis for example Budd Chiari syndrome. 
13.3.2 
OTHER VASCULAR OCCLUSIVE EVENTS  
Other transient neurological events 
This is defined as the abrupt onset of poorly or non-localizing neurological symptoms such as 
unsteadiness, blurred vision, hearing disturbance or unstable gait. 
Erythromelalgia 
Erythromelalgia is defined as the onset of pain at the extremities associated with temperature 
increase and redness of the skin. Erythromelalgia usually manifests in the lower extremities and/or 
rarely in the hands with frequent recurrences in the same areas. 
Other occlusive event 
Occlusion in sites not covered above. In particular, characteristic symptoms of cardiac, abdominal 
or peripheral limb ischemia supported by objective evidence of vessel disease and/or ischemia 
13.3.3 
HAEMORRHAGIC EVENTS  
Major hemorrhage 
Overt hemorrhage associated with either: 
• a decrease in hemoglobin level of at least 2g/dl or 
• a need for blood transfusion of 2 or more units of blood, or  
• if hemorrhage is retroperitoneal or intracranial. 
Minor hemorrhage 
Overt hemorrhage not meeting the criteria of major hemorrhage. 
13.3.4 
TRANSFORMATION 
Transformation to ET or PV myelofibrosis 
(Barosi 2008)  The criteria for Post PV/myelofibrosis are provided below. 
Required criteria: 
1. Documentation of a previous diagnosis of polycythemia vera as defined by the WHO 
criteria 
2. Bone marrow fibrosis grade 2–3 (on 0–3 scale) 3 or grade 3–4 (on 0–4 scale) 4 
Additional criteria (two are required): 
1. Anemia or sustained loss of requirement of either phlebotomy (in the absence of 


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cytoreductive therapy) or cytoreductive treatment for erythrocytosis 
2. A leukoerythroblastic peripheral blood picture 
3. Increasing splenomegaly defined as either an increase in palpable splenomegaly of 5 cm 
(distance of the tip of the spleen from the left costal margin) or the appearance of a newly 
palpable splenomegaly 
4. Development of 1 of three constitutional symptoms: 10% weight loss in 6 months, night 
sweats, unexplained fever (> 37.5º C) 
 
Criteria for post-ET myelofibrosis (Barosi 2008) 
Required criteria: 
1. Documentation of a previous diagnosis of essential thrombocythemia as defined by the 
WHO criteria 
2. Bone marrow fibrosis grade 2–3 (on 0–3 scale) 3 or grade 3–4 (on 0–4 scale) 4 
Additional criteria (two are required): 
1. Anemia and a ≥ 2 g/L decrease from baseline hemoglobin level 
2. A leukoerythroblastic peripheral blood picture 
3. Increasing splenomegaly defined as either an increase in palpable splenomegaly of 5 cm 
(distance of the tip of the spleen from the left costal margin) or the appearance of a newly 
palpable splenomegaly 
4. Increased LDH (above the baseline level and exceeding the normal reference range without 
other obvious cause) 
5. Development of 1 of three constitutional symptoms: 10% weight loss in 6 months, night 
sweats, unexplained fever (37.5º C) 
 
Transformation to leukemic phase is defined by: 
The threshold for a diagnosis of achieving blast phase is 20% blood or marrow blasts (persisting 
for 4 weeks) or the presence of an acute leukemia–defining karyotypic lesions despite blast 
percentage (t[8;21][q22:q22], inv[16][p13;q22], t[16;16][p13;q22], or t[15;17][q22;q12]). 
 
13.3.5 
DEATH 
The cause of death should be given, including post mortem findings where possible. Information 
about the death should be recorded immediately in the source document, and also in the 
appropriate adverse event module of the CRF.  All deaths must be reported to the MPD-RC 
Central Coordinating Office if it occurs within 30 days of receiving the study drugs. 
13.4 
Recording and evaluation of adverse events 
Individual adverse events should be evaluated by the investigator and, where indicated, they 
should be reported to the sponsor for evaluation on the annual follow up form. This includes the 
evaluation of its seriousness and the causality between the investigational medicinal product(s) 
and/or concomitant therapy and the adverse event. The sponsor has to keep detailed records of all 
AEs reported to them by the investigator(s) and to perform an evaluation with respect to 
seriousness, causality and expectedness. After each contact with the subject, the investigator must 
seek information on adverse events by specific questioning and, when appropriate, by 
examination.  Information about all adverse events should be recorded immediately in the source 
document, and also in the appropriate adverse event module of the CRF. All clearly related signs, 
symptoms, and abnormal diagnostic procedures results should recorded in the source document 
and should be grouped under one diagnosis. 


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All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause.   Serious adverse events that are still ongoing 
at the end of the study period must be followed to determine their final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
All unresolved adverse events should be followed by the investigator until the events are resolved, 
the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled 
visit, the investigator should instruct each subject to report any subsequent event(s) that the 
subject, or the subject’s personal physician, believes might reasonably be related to participation in 
this study.  The investigator should notify the study sponsor of any death or adverse event 
occurring at any time after a subject has discontinued or terminated study participation that may 
reasonably be related to this study.  The sponsor should also be notified if the investigator should 
become aware of the development of cancer or of a congenital anomaly in a subsequently 
conceived offspring of a subject that has participated in this study. 
13.4.1 
Assessment of severity 
Assessment of severity should be assessed according to The NCI Common Terminology Criteria 
for Adverse Events v 4.0. This is a descriptive terminology which can be utilized for Adverse 
Event (AE) reporting.  A grading (severity) scale is provided for each AE term. It can be found on 
the following website: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. 
All other adverse events should continue to be collected on the CRF pages. 
13.4.2 
Assessment of causality 
Definitely:  A causal relationship that can only be the result of the investigational medicinal 
product and there is no other plausible cause of the AE. 
Probable: A causal relationship is clinically / biologically highly plausible and there is a plausible 
time sequence between onset of the AE and administration of the investigational medicinal 
product and there is a reasonable response on withdrawal. 
Possible: A causal relationship is clinically / biologically plausible and there is a plausible time 
sequence between onset of the AE and administration of the investigational medicinal product. 
Unlikely: A causal relation is improbable and another documented cause of the AE is most 
plausible. 
Unrelated: A causal relationship can be definitely excluded and another documented cause of the 
AE is most plausible. 
13.4.3 
Outcome 
The outcome of the event should be recorded. Typically these will include the following: 
Resolved; Resolved with sequela; Death; or ongoing if not resolved at the end of the study. 


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13.5 
Reporting of Serious Adverse Events 
13.5.1 
Study Sponsor Notification by Investigator 
A serious adverse event must be reported to the MPD-RC Data Monitor within 24 hours of the 
event following the appropriate MPD-RC Standard Operating Procedures (SOP): 
• SOP 2-1: Serious Adverse Event (SAE) reporting – USA sites 
• SOP 2-2: Serious Adverse Event (SAE) reporting – EU sites 
• SOP 2-3: Serious Adverse Event (SAE) reporting – Canada site 
To ensure subject safety, every SAE, regardless of suspected causality must be reported per 
protocol to the MPD-RC Central Office within 24 working hours of learning of its 
occurrence.  The SAE should be reported in the Web-based data entry system (WBDES) on 
the “Immediate AE Reporting” (Part A) e-form and also on a Medwatch form 3500A. A 
signed and dated Medwatch 3500A should be emailed to the MPD-RC Data Monitor, Study 
Chair, Safety Officer, and PI of Project 6. At the time of the initial report the following 
information at minimum should be provided 
• Study Center 
• Subject number 
• A description of the event 
• Date of onset 
• Current status 
• Whether study treatment was discontinued 
• The reason why the event is classified as serious 
• Investigator assessment of the association between the event and study treatment 
• Study treatment dose 
 
Significant new information on ongoing serious adverse events should be provided promptly to the 
study sponsor by entering the information into the database on the “Intermediate (Part B) AE 
Reporting” e-form. Update on all SAEs must be provided every two weeks (15 days) by the 
investigators to the coordinating center using the “Intermediate (Part B) AE Reporting” e-form. 
The clinical course of the SAE is “concluded” when either the AE has reached a resolution or it 
becomes a chronic disorder not prone to further evolution. When the AE is “concluded”, the 
investigator is required to inform the coordinating center using the “Final (Part C) AE Reporting” 
e-form. 
13.5.2 
EC/IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) must be submitted to the 
local institutional EC/IRB within 10 working days. Copies of each report and documentation of 
EC/IRB notification and receipt will be kept in the Clinical Investigator’s binder. 
13.5.3 
Notifications by Sponsor 
FDA 
The study sponsor shall notify the FDA by telephone or by facsimile transmission (1-800-332-
0178) of any unexpected fatal or life-threatening experience associated with the use of the drug as 
soon as possible but no later than 7 calendar days from the sponsor’s original receipt of the 
information. All other unexpected, serious adverse events that are considered related to study 
treatment will be reported on a MedWatch form by the Study Sponsor to the FDA within 15 


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calendar days.   If a previous adverse event that was not initially deemed reportable is later found 
to fit the criteria for reporting, the study sponsor will submit the adverse event in a written report 
to the FDA as soon as possible, but no later than 15 calendar days from the time the determination 
is made. 
Europe 
The sponsor is responsible for the prompt notification to all concerned investigator(s), the 
Research Ethics Committees and competent authorities (e.g. MHRA) of each concerned Member 
State / Country of findings that could adversely affect the health of subjects, impact on the conduct 
of the trial or alter the competent authority’s authorization to continue the trial in accordance with 
Directive 2001/20/EC and other regulations as appropriate. In each country a PI designate will be 
utilized to facilitate this process. 
Roche 
The MPD-RC will report SUSAR and other serious adverse events to the safety office at Roche in 
parallel with submission to the FDA or equivalent European regulatory bodies. 
13.6 
MPD-RC Reporting of Suspected Unexpected Serious Adverse Reactions 
(SUSARs) Regulatory Bodies and Ethics Committees 
All suspected adverse reactions related to an investigational medicinal product (the tested IMP) 
which occurs in the concerned trial, and that are both unexpected and serious (SUSARs) are 
subject to expedited reporting. These events should be reported by the individual investigators to 
the MPD-RC with details as described in section 13.5.1. 
13.6.1 
MPD-RC Reporting of SUSARs. 
MPD-RC, or designee, should report all the relevant safety information previously described to the 
concerned competent authorities and to the Ethics Committee concerned. MPD-RC or designee 
shall inform all investigators concerned of relevant information about SUSARs that could 
adversely affect the safety of subjects. All SUSAR reports will also be reported to the FDA, 
European Research Ethics Committees and competent authorities (e.g. MHRA) of each concerned 
Member State / Country and Roche. 
13.6.2 
When to report 
Fatal or life-threatening SUSARs 
The MPD-RC should notify the Competent Authorities (CA) and the Research Ethics Committees/ 
IRBs as soon as possible but no later than 7 calendar days after the sponsor has first knowledge of 
the minimum criteria for expedited reporting. In each case relevant follow-up information should 
be sought and a report completed as soon as possible. It should be communicated to the Competent 
Authorities and the Ethics Committee within an additional eight calendar days. 
Non-fatal and non-life-threatening SUSARs 
All other SUSARs and safety issues must be reported to the competent authority and the Ethics 
Committee in the concerned countries as soon as possible but no later than 15 calendar days after 
the sponsor has first knowledge of the minimum criteria for expedited reporting. Further relevant 
follow-up information should be given as soon as possible. 
13.6.3 
How to report 
Minimum criteria for initial expedited reporting of SUSARs 
Information on the final description and evaluation of an adverse reaction report may not be 
available within the required time frames for reporting.  For regulatory purposes, initial expedited 


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reports should be submitted by the Sponsor within the time limits as soon as the minimum 
following criteria are met: 
a) a suspected investigational medicinal product, 
b) an identifiable subject (e.g. study subject code number), 
c) an adverse event assessed as serious and unexpected, and for which there is a reasonable 
suspected causal relationship, 
d) an identifiable reporting source, and, when available and applicable: 
• a unique clinical trial identification (EudraCT number or in case of non-European 
Community trials the sponsor's trial protocol code number) 
• a unique case identification (i.e. sponsor's case identification number). 
Follow-up reports of SUSARs 
In case of incomplete information at the time of initial reporting, all the appropriate information 
for an adequate analysis of causality should be actively sought from the reporter or other available 
sources. The sponsor should report further relevant information after receipt of follow-up reports. 
In certain cases, it may be appropriate to conduct follow-up of the long-term outcome of a 
particular reaction. 
Format of the SUSARs reports 
Electronic reporting should be the expected method of the Sponsor for expedited reporting of 
SUSARs to the competent authority. In that case, the format and content as defined by the 
Guidance of the Competent Authorities should be adhered to. The CIOMS-I form is a widely 
accepted standard for expedited adverse reactions reporting. However, no matter what the form or 
format used, it is important that the basic information/data elements described in annex 3 of the 
EU directive or as per country requirement, when available, be included in any expedited report 
(some items may not be relevant, depending on the circumstances). 
13.7 
Stopping Rules 
A patient may discontinue participation in the study at any time for any reason (e.g., lack of 
efficacy, consent withdrawn, adverse event).  The investigator and/or sponsor can withdraw a 
patient from the study at any time for a protocol violation or for noncompliance, adverse event or 
any other reason. The reason for early withdrawal will be recorded on the treatment withdrawal 
page of the CRF. 
13.8 
Medical Monitoring 
It is the responsibility of the local institutional Responsible Investigator to oversee the safety of the 
study at his/her site.  This safety monitoring will include careful assessment and appropriate 
reporting of adverse events as noted above, as well as the construction and implementation of a 
site data and safety-monitoring plan.  Medical monitoring will include a regular assessment of the 
number and type of serious adverse events. 
13.9 
Monitoring Plan and Period of Observation 
The monitoring plan for this study is maintained by the MPD-RC and contains the following 
elements: 
• This study will be conducted according to the policies and procedures of the MPD-RC; 
• All MPD-RC provided drug supplies will be returned to the MPD-RC or are to be disposed 
in accordance with procedure agreed to by investigator and the MPD-RC; 


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13.10 
Procedures for Reporting Drug Exposure during Pregnancy and Birth 
Events 
If a woman becomes pregnant or suspects she is pregnant while participating in this study, she 
must inform her treating physician immediately and permanently discontinue study drug.  The 
pregnancy must be followed through delivery for SAEs (See Section 13.5). 


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14.0 
ADMINISTRATIVE REQUIREMENTS 
14.1 
Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).   The 
investigator should be thoroughly familiar with the appropriate use of the study drug as described 
in the protocol and Investigator’s Brochure.  Essential clinical documents should be maintained to 
demonstrate the validity of the study and the integrity of the data collected.  Master files should 
be established at the beginning of the study, maintained for the duration of the study and retained 
according to the appropriate regulations. 
14.2 
Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
This protocol and any amendments should be submitted to a properly constituted independent EC 
or IRB, in agreement with local legal prescriptions, for formal approval of the study conduct.  
The decision of the EC/IRB concerning the conduct of the study should be made in writing to the 
investigator and a copy of this decision should be provided to the MPD-RC Central Office before 
commencement of this study.  The investigator should provide a list of EC/IRB members and 
their affiliate to the MPD-RC Central Office. 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  See section 15.0 for a copy of the Subject Informed Consent Form.  This consent form 
should be submitted with the protocol for review and approval by the EC/IRB for the study.  The 
consent of a subject, using the EC/IRB-approved consent form, must be obtained before a subject 
is allowed to participate.  This consent form must be signed by the subject or legally acceptable 
surrogate, and the investigator obtaining the consent. 
14.3 
Patient Information and Informed Consent 
After the study has been fully explained, written informed consent should be obtained from either 
the patient or his/her guardian or legal representative prior to study participation.  The method of 
obtaining and documenting the informed consent and the contents of the consent should comply 
with ICH-GCP and all applicable regulatory requirement(s). 
14.4 
Patient Confidentiality 
Information about study subjects should be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
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subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the 
ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled 
study period. 
14.5 
Protocol Compliance 
The investigator should conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB and the appropriate regulatory authority(ies). Changes to 
the protocol will require approval of the MPD-RC and written IRB approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients.  The MPD-RC will submit all protocol modifications to the regulatory 
authority(ies) in accordance with the governing regulations. 
Any departures from the protocol must be fully documented in the source documents. 
14.6 
Management of Information 
The MPD-RC at the Icahn School of Medicine at Mount Sinai will maintain sponsorship 
authority at the Icahn School of Medicine at Mount Sinai and all other participating sites. 
Eligibility criteria will be confirmed using the electronic CRF. All inclusion and exclusion 
criteria are listed; the investigator is obliged to fill in all items. Subjects are enrolled in the study 
only if he/she fulfills all inclusion and no exclusion criteria. 
Before the site can enroll a subject, the site must be activated as described in section 4.1.1. 
Data Submission: Forms should be submitted to the MPD-RC Data Management Center.  Data 
must be entered electronically by logging onto the MPD-RC web site and locating the specific 
web-ready form.   
MPD-RC 
Form# 
MPD-RC FORM NAME 
SUBMISSION SCHEDULE 
00 
Parameter List 
@ Registration 
01 
Recruitment 
@ Registration 
02 
Baseline 
Within 1 week after registration 
03 
Follow-up visit 
Monthly X3, then every 3 months 
04 
Additional follow-up visit not 
planned in study protocol 
As needed 
05 
Follow-up visit after drug 
interruption 
Within 2 weeks of drug interruption 
06 
Adverse Event Form 
Immediately report all SAE’s and complete 
all non-reportable A/E’s Monthly 


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MPD-RC 
Form# 
MPD-RC FORM NAME 
SUBMISSION SCHEDULE 
07 
Outcome event Myocardial Infarction Monthly and when/if it occurs 
08 
Outcome event Stroke 
Monthly and when/if it occurs 
09 
Outcome event TIA 
Monthly and when/if it occurs 
10 
Outcome event DVT 
Monthly and when/if it occurs 
11 
Outcome event PAT 
Monthly and when/if it occurs 
12 
Outcome event PE 
Monthly and when/if it occurs 
13 
Outcome event Hemorrhage 
Monthly and when/if it occurs 
14 
Outcome event STP 
Monthly and when/if it occurs 
15 
Outcome event Pregnancy/Abortion 
Monthly and when/if it occurs 
16 
Outcome event Malignancy 
Monthly and when/if it occurs 
17 
Off treatment notice 
Within 2 weeks going off treatment 
18 
Death notification form 
Immediately 
19 
End of study 
Within 2 weeks of completing study 
20 
MPN-SAF 
Pre-registration, month 3, 6, 9, 12, then 
every 6 months 
21 
EORTC QLQ-C30 
Pre-registration, month 3, 6, 9, 12, then 
every 6 months 
22 
Exploratory questions and patient 
feedback 
Pre-registration, month 3, 6, 9, 12, then 
every 6 months 
23 
Bone marrow 
Baseline, month 12,24, @ time of 
relapse/progression and study termination 
for any reason 
24 
Cytogenetic 
Baseline, month 12,24, @ time of 
relapse/progression and study termination 
for any reason 
25 
Drug Administration 
Monthly 
 


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In addition, all protocol amendments will be generated through and distributed by the MPD-RC 
Central Coordinating Office, which will also maintain records of IRB approval, amendments, 
SAEs, and annual reviews. 
Serious adverse event reporting is detailed in section 13.5.  
The MPD-RC will monitor study progress on an on-going basis; this will include electronic and 
telephone correspondence between the central coordinating office and with individual 
investigators at other sites. 
14.7 
Drug Accountability 
Accountability for the study drug at all study sites is the responsibility of the MPD-RC.   The 
responsible investigator at each participating center will ensure that the study drug is used only in 
accordance with this protocol, drug accountability records indicating the drug’s delivery date to 
the site, inventory at the site, use by each patient, and return.  Accountability records will include 
dates, quantities, lot numbers, expiration dates (if applicable), and patient numbers. See NCI 
Drug Accountability Record Form (DARF) in Appendix F. 
14.8 
Source Documents 
Source data includes all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data 
are contained in source documents. Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic  negatives, microfilm or magnetic media,  x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in 
the clinical trial. 
14.9 
Case Report Forms 
The study CRF is the primary data collection instrument for the study. All data requested on the 
CRF must be recorded.  CRFs may be found online at the MPD-RC website under the address 
MPD112@negrisud.it. 
14.10 
Premature Closure of the Study 
This study may be prematurely terminated, if in the opinion of the Trial Steering Committee there 
is sufficient reasonable cause.  Written notification documenting the reason for study termination 
will be provided to the investigator by the terminating party. 
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients 
• Failure to enter patients at an acceptable rate 
• Insufficient adherence to protocol requirements 
• Insufficient complete and/or evaluable data 
• Plans to modify, suspend or discontinue the development of the study drug 


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14.11 
Record Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These documents 
must be retained at least 2 years following completion of the last follow-up on patients on active 
study.  These documents should be retained for a longer period if required by an agreement with 
the sponsor.  In such an instance, it is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. 
14.12 
Endpoint Verification 
The endpoint validation committee will centrally review and validate all end points following 
pre-defined criteria (Appendix A). All the clinical events included in the primary and secondary 
endpoints will be validated by an ad hoc committee of expert clinicians blinded to the treatment 
assigned. Copies of physicians’ and hospital records and death certificates will be reviewed by a 
Primary Endpoint Committee for event validation. Each event will be independently evaluated by 
two evaluators. Disagreement between the two evaluators will be addressed by the chairman of 
the committee. 
14.13 
Data Safety Monitoring Board 
An External Data and Safety Monitoring Board has been established.  All members have 
experience and expertise in clinical trials.  DSMB members are not directly involved in any phase 
of MPD-RC clinical trials and they have no major financial or intellectual conflict of interest that 
would prevent them from objectively reviewing the interim data and providing advice to the 
Trials Steering Committees and the Clinical Advisory Group.  They function independently of all 
other individuals, processes, and progress to ensure study integrity, monitor patient safety 
(providing quarterly safety reports), evaluate the results of interim analysis to assess efficacy, and 
make recommendations about protocol amendments and early termination to the Trials Steering 
Committees.  The External Data Safety and Monitoring Board must meet at least two times a 
year. 
The interim efficacy and safety analyses will be performed blinded to treatment assignment. 
The DSMB statistician will possess a copy of the treatment codes for unblinding purposes if 
required by the members of the board. 


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15.0 
MODEL CONSENT FORM 
(This consent template is meant as an aide in preparing your institution’s informed consent 
document.   You may alter the language to fit your IRB’s requirements.  You may add information 
to the various informative sections (e.g. “What is involved”, “Risks”, etc.) but not remove 
information because the minimum amount of disclosure has been provided to inform the subject 
adequately.) 
 
 
TITLE OF RESEARCH STUDY: 
 
 
Title: MPD-RC 112: Randomized Trial of Pegylated Interferon Alfa-2a versus Hydroxyurea 
Therapy in the Treatment of High Risk Polycythemia Vera and High Risk Essential 
Thrombocythemia 
 
 
PRINCIPAL INVESTIGATOR (HEAD RESEARCHER) NAME AND CONTACT 
INFORMATION: 
 
Name:  (Fill in this section with information for your institution) 
Physical Address:  
Mailing Address:  
Phone: 
 
WHAT IS A RESEARCH STUDY? 
 
A research study is when scientists try to answer a question about something that we don‟t know 
enough about.  Participating may not help you or others. 
 
People volunteer to be in a research study.   The decision about whether or not to take part is 
totally up to you. You can also agree to take part now and later change your mind. Whatever you 
decide is okay.  It will not affect your ability to get medical care at (Name of Institution). 
 
Someone will explain this research study to you. Feel free to ask all the questions you want 
before you decide.  Any new information that develops during this research study that might 
make you change your mind about participating will be given to you promptly. 
 
Basic information about this study will appear on the website http://www.ClinicalTrials.gov.  
There are a few reasons for this:  the National Institutes of Health (NIH) encourages all 
researchers to post their research; some medical journals only accept articles if the research was 
posted on the website; and, for research studies the U.S. Food and Drug Administration (FDA) 
calls "applicable clinical trials” a description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include 
information that can identify you. At most, the Web site will include a summary of the results. 
You can search this Web site at any time. 
 
PURPOSE OF THIS RESEARCH STUDY: 
 
This research looks at two conditions, Essential Thrombocythemia (ET) and Polycythemia Vera 


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(PV).  ET causes people to produce too many blood cells called platelets and PV causes too 
many platelets and red blood cells to be made.  Platelets are particles which circulate in the blood 
stream and normally prevent bleeding and bruising. Having too many platelets in the blood 
increases the risk of developing blood clots, which can result in life threatening events like heart 
attacks and strokes. When the number of red blood cells is increased in PV this will slow the 
speed of blood flow in the body and increases the risk of developing blood clots. 
The purpose of this study is to look at the effectiveness of giving participants who have been 
diagnosed with ET or PV one of two different study regimens over time. Your study doctor 
would want to follow your condition for about 6 years.  The study regimens are either 
“PEGASYS” (or Pegylated Interferon Alfa-2a) or “Aspirin and Hydroxyurea” (also called 
Hydroxycarbamide). All subjects participating in this study will also receive Aspirin as part of 
their study regimen regardless of which study drug they will receive.  More information on these 
study regimens will be described later in this information sheet. To enter this study you may be a 
newly diagnosed subject or a subject already receiving treatment for either ET or PV.  Each of 
the study drugs used in this study is already being used to treat subjects with ET or PV currently 
but we are unsure which study drug is better. 
 
You may qualify for this study because you have been diagnosed by your study doctor as having 
the condition ET or PV and are over 18 years of age. 
Funds for conducting this research are provided by the Myeloproliferative Disorders Research 
Consortium and the study drug (PEGASYS) is being supplied by Roche Pharmaceuticals. 
 
LENGTH OF TIME AND NUMBER OF PEOPLE EXPECTED TO PARTICIPATE 
 
 
Participation in this study is expected to last from 2 to 6 years depending upon your entry into the 
study.  Optimally you will receive study drug for 2 years (if you achieve a complete or partial 
response) and then you will be in follow-up, where you will come in every 3 months for a study 
visit, for an additional 4 years. 
 
The number of people at (Name of Institution) expected to participate in this study is 
approximately (number at institution) subjects, but because this is a cooperative group study 
approximately 300 subjects will be enrolled to the MPD-RC study throughout Europe and the 
United States. 
 
DESCRIPTION OF WHAT’S INVOLVED: 
 
If you agree to participate in this research study, the following information describes what may 
be involved. 
 
In order to participate in this study, you must also be participating in the mandatory Biomarker 
Study (107). Once you have signed the consent forms for both this study and the mandatory 
Biomarker Study to say you are willing to take part in these studies you will have a screening 
visit to make sure that you meet all of the requirements to participate in this study.  The 
following tests and procedures will be done during the screening visit: 
 
The following tests and procedures will be done during the screening visit: 
• Complete history and physical, including vital signs such as blood pressure, heart rate, body 
temperature, weight, body surface area, and a list of past and current medications. 
• ECOG performance status:  rating scale to rate your ability to perform daily functions. 


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• Spleen measurement: through palpation (feeling with the hands) or through ultrasound. 
Ultrasound technology uses sound waves to reflect off of soft tissues to create an image based 
upon the computer’s interpretation of the wave’s reflections.  The sonographer will use a gel 
to help transmit the sound waves through the wand.  It is cool and rather gooey – but not 
uncomfortable and the procedure does not last long. 
• Fundoscopic Eye Exam: examination that checks the retina of the eye. 
• Blood Tests: (Approximately a total of 7 ½ tablespoons of blood will be collected from a 
vein in your arm with a needle): 
o Complete blood count (approx. 1 ½ tsp. blood): complete blood count monitors the 
blood levels; red blood cells, white blood cells, platelets and other components of the 
blood. 
o Blood chemistries (approx. 1 ½ tsp. blood): tests the creatinine, glucose, bilirubin, 
and other chemicals in the blood that indicate how well the liver and kidneys are 
functioning and to check for side effects. 
o Thyroid Function (approx. 1 ½ tsp. blood): the thyroid is one of the largest 
endocrine glands in the body. This gland is found in the neck and controls how 
quickly the body uses energy, makes proteins, and controls how sensitive the body 
should be to other hormones.  This blood test checks how well the thyroid gland is 
functioning. 
o Plasma Viscosity (approx. 1 ½ tsp. blood): tests for how much water is present in the 
blood.  The less water, the thicker the blood and the more difficult it is for the blood 
to flow through the veins.  An increase in the viscosity level can reduce the amount of 
oxygen that is delivered to the body. 
o JAK2V617F: blood test to check for the JAK2V617F mutation in your blood (1 ½ 
tsp. blood) If you have PV and do not have the JAK2V617F mutation in your blood 
you may not participate in this study.  If you have ET and do not have the 
JAK2V617F mutation in your blood you may participate in this study. 
o Pregnancy test: for women of childbearing potential. (Approx. 1 tsp. blood) 
o Extra Blood and nail clippings: Up to 4 2/3 Tbsp. of blood will collected for 
research purposes for the biomarker study.  Nail clippings: 2 clippings will only be 
gathered once (at pre-study visit).  Your nail clippings will provide normal material, 
like DNA, for comparison with the abnormal material from your blood and/or bone 
marrow.  
• Bone marrow aspiration/biopsy/cytogenetics/clonality:  Bone marrow aspiration, also 
called bone marrow sampling, is the removal by suction (through a needle placed into the 
bone) of fluid from the soft, spongy material that lines the inside of most bones (marrow). 
(Approx.1½ tsp) During a bone marrow aspiration/biopsy an area of the hip is numbed and a 
needle is placed through the skin and into the hip bone.  A small sample of bone marrow and 
bone is withdrawn.  The bone marrow will be examined to see if it is abnormal.  Three 
teaspoons of additional bone marrow for the biomarker study will be collected prior to 
beginning the study drugs, again at the month 12 visit, then again at the month 24 visit, if the 
disease returns after a response to the medication, or if the study medications are 
discontinued for any reason. 
• EKG (electrocardiogram): for this test, you will be asked to lie down while 12 sticky pads 
are affixed to each of your arms and legs and to your chest.  The EKG will last about 10 
minutes.  An EKG records the electrical activity of the heart and is used to measure how fast 
and how regular the heart beats, as well as the size and position of the chambers, the presence 
of any damage to the heart, and the effects of study drugs or devices used to regulate the heart 


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(such as a pacemaker). An EKG is painless but sometimes the sticky pads can irritate your 
skin. 
• Quality of Life questionnaires: You will be asked to fill out three quality of life 
questionnaires.  Using a pencil you will be asked to circle answers on the questionnaires 
relating to how you feel.  Filling out all three questionnaires should take less than 15 minutes. 
 
Sometimes we don’t know which way of treating subjects is best. To find out, we need to 
compare different study regimens. We put people into groups and give each group a different 
study regimen. The results are compared to see if one is better. To try to make sure the groups are 
the same to start with, each subject is put into a group by chance (randomly-like flipping a coin) 
this is done because we currently think that the two study regimens under testing work equally 
well. We are aiming for 150 subjects to receive study drug PEGASYS and 150 to receive study 
drug Hydroxyurea for a total of 300 subjects. 
 
This means that you would have a 50% (1 in 2) chance of being treated with PEGASYS and a 
50% (1 in 2) chance of being treated with hydroxyurea. 
 
If you are already on Hydroxyurea when you start this study, and by chance you are assigned to 
Pegasys, your Hydroxyurea dose will be slowly lowered and stopped before the third month of 
the study. 
 
How often you need to visit your study doctor will depend on your blood results, which are used 
to measure how well you respond to the study drug.  At first you might need to visit weekly but 
once your study regimen is stable this should be less often. Your study doctor will need to see 
you at appropriate intervals for your care, on average every 3 months. During these visits your 
study doctor will take blood samples and ask you how you have been feeling. Some of these 
blood samples will be sent off to measure the amounts of different proteins in your blood as part 
of this study to compare your response to PEGASYS with hydroxyurea. Please use this time to 
report any problems you have had since your last visit.  During the study the following tests will 
be performed: 
• Complete physical, including vital signs such as blood pressure, heart rate, body 
temperature, weight, and a list of past and current medications.  This will be done at study 
visits on weeks 1 and 3, monthly for months 2, 3, 4, 5, 6, every 3 months while on active 
study drug, and at study discontinuation. 
• Spleen measurement: through palpation (feeling with the hands) or through ultrasound 
prior to starting the study drugs, at 12 or 15 months and when the study drugs are being 
discontinued.  Spleen measurements through palpation will be done at study visits on 
weeks 1 and 3, monthly for months 2, 3, 4, 5, 6, every 3 months while on active study 
drug, and at study discontinuation. 
• ECOG performance status:  rating scale to rate your ability to perform daily functions. 
This will be done at study visits on weeks 1 and 3, monthly for months 2, 3, 4, 5, 6, every 
3 months while on active study drug, and at study discontinuation. 
• Blood Tests: (Approximately a total of 2 tablespoons of blood will be drawn through a 
needle from a vein in the arm) (Months 12, 24 and at time of termination of study for any 
reason an additional 4 2/3 tablespoons will be drawn for the Biomarker Study)Blood 
Tests: 
 Complete blood count (approx. 1 ½ tsp. blood).  This will be done at study visits on 
weeks 1 and 3, monthly for months 2, 3, 4, 5, 6, every 3 months while on active study 


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drug, and at study discontinuation. 
 Blood chemistries (approx., 1 ½ tsp. blood).  This will be done at study visits on 
weeks 1 and 3, monthly for months 2, 3, 4, 5, 6, every 3 months while on active study 
drug, and at study discontinuation. 
 Thyroid Function (approx. 1 ½ tsp. blood) This will be done at study visits on weeks 
1 and 3, monthly for months 2, 3, 4, 5, 6, every 3 months while on active study drug, 
and at study discontinuation. 
 Extra Blood: Up to 4 2/3 Tbsp. of blood will collected for research purposes for the 
biomarker study.  This will be done at 12 and 24 months or at time of termination of 
study for any reason. 
• Bone marrow aspiration/biopsy: (Approx. 1 ½ tsp.)   An additional 3 teaspoons of bone 
marrow will be drawn for the biomarker study (#107) (research related).  This will be 
done after 12 and 24 months or at the time of a bone marrow for relapse or progression of 
disease or at termination of study treatment for any reason. 
• Quality of Life questionnaire: You will be asked to fill in a questionnaire called, 
“Quality of Life”. This will be done prior to receiving any study medication then after 
months 3, 6, 9, 12 and then every 6 months. The information from these will be compared 
with the one you did at the start of the study to see if how you have been feeling has 
changed over time. Filling out the questionnaire should take less than 15 minutes. 
 
Reproductive Information 
If you (or your partner) become pregnant or are thinking of having a baby you should speak to 
your study doctor so your medication can be carefully managed. If you are given Hydroxyurea as 
your medication you should make sure you use adequate contraception. Both men and women 
must not attempt pregnancy and women must not be pregnant or breast-feeding while 
participating in this study. If sexually active, both men and women must use an effective method 
of birth control while taking the study drug. Barrier contraceptives (condoms or diaphragm) with 
a spermicide, intrauterine devices, hormonal contraceptives (Depo-Provera, Norplant), oral 
contraceptive pills, and complete abstinence are examples of effective methods. Only methods 
that also use condoms provide adequate protection against sexually transmitted diseases. If you 
or your partner become pregnant while taking the study drug, it is important that you notify your 
study nurse/physician immediately. If you are pregnant you may be required to stop the study 
drugs at which time other treatment options will be discussed with you. 
 
Women who can still become pregnant must have a pregnancy test before taking part in this 
study. This pregnancy screening is standard practice at the (Name of Institution) in chemotherapy 
research studies and the results will be used to determine eligibility for the study. If you are a 
woman who can become pregnant, blood will be taken from a vein in your arm with a needle 
within 7 days before you enter the study.  You will be told the results of the pregnancy test.  If 
the pregnancy test is positive, you will not be able to take part in the study. 
 
Do not forget to tell your study doctor if you start taking any new medicines, feel unwell or want 
to take part in a new study run by another doctor. 
 
What is the drug being tested? 
Hydroxyurea is a form of chemotherapy. This means it stops the growth of abnormal tissue. It is 
a drug that has been shown to reduce the chance of blood clots in subjects with ET and PV who 
have high risk factors for forming clots. It is a tablet and must be taken on a continuous basis 
usually every day. 


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PEGASYS is a type of interferon, which is a form of a hormone produced naturally in the body 
which reduces the production of blood cells. It is a drug that has been shown to reduce the 
amount of a protein thought to be involved in causing ET and PV in some subjects. This protein 
is called JAK2V617F.  PEGASYS will be given by a subcutaneous injection (injected just under 
the skin) every week.  This is an injection similar to giving insulin to diabetics. You will begin 
receiving the medication at a dose level of 45 micrograms weekly and gradually get increased to 
the maximum dose of 180 micrograms per week.  You will be taught by the study staff how to 
give yourself the injection so that you can do the injections at home and reduce the number of 
visits needing to be made to the clinic.  You will receive a prefilled syringe or single-use vial 
containing 180 micrograms of the study drug.  You will be instructed by the study staff how to 
insert the needle under the skin to give yourself a subcutaneous injection (like diabetics receive 
their insulin). You will be instructed on how much of the medication to give yourself and then 
you will recap the syringe with the unused portion of the study medication and place the syringe 
in a container to bring back to the clinic with you.  The study staff will check and record the 
syringes that were used as well as any unused syringes. 
 
All subjects participating in this study will also receive aspirin as part of their study regimen 
regardless of which study drug they will receive. Aspirin (acetylsalicylic acid) works by stopping 
platelets from forming clots and is extensively used worldwide in patients at high risk of strokes 
and heart attacks. It has been shown to reduce risks of these events in PV but not directly in ET. 
 
A standard dose of 81mg or 100mg of aspirin (to be taken with food) will be used in all patients. 
At this dosage side-effects are very uncommon. However, a few patients may not be able to take 
aspirin because they have a history of intolerance to aspirin, MPN-associated hemorrhage, recent 
peptic ulceration or aspirin sensitive asthma.  You may be prescribed an aspirin substitute or 
nothing at all, an aspirin substitute not being mandatory for participation in the study. 
 
In your third year of the study your study doctor may ask to perform another bone marrow 
sample. This would help the study, but it is your choice if you want this taken or not.  This bone 
marrow procedure will be discussed with you when it comes time for the procedure and at that 
time you can either agree to have it done or refuse.  If you decide to not have the procedure done 
this will in no way effect your medical care. 
 
 
YOUR RESPONSIBILITIES IF YOU TAKE PART IN THIS RESEARCH: 
 
 
If you decide to take part in this research study you will be responsible for the following things: 
taking your medication as directed by your study doctor and attending the routine clinic 
appointments made for you. 
 
COSTS OR PAYMENTS THAT MAY RESULT FROM PARTICIPATION: 
 
 
There is no additional cost to you for participating in this research study other than those costs 
associated with the treatment of your disease. Please speak your study team and with the 
financial/billing representative to see if your insurance will cover the expenses associated with 
this study, before proceeding with this research study. The study drug, PEGASYS, will be 
provided at no cost to you by ROCHE Pharmaceuticals. You or your insurance company will be 


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responsible for the costs of your clinic visits and all of the standard study treatments and 
procedures, including standard of care blood tests, medication (hydroxyurea and aspirin), ECG, 
and bone marrow aspiration/biopsy.  This is because this standard care testing would be done 
even if you were not participating in this study. 
 
The sponsors of this study will pay for the biomarker sub-study blood tests and for the study 
medication, PEGASYS.  All  other  study  expenses  are  your  responsibility  or  that  of  your 
insurance carrier. 
 
Your insurance company must be contacted to pre-authorize all the study treatments in this study.    
If your insurance company does not authorize these study treatments, you may choose not to 
participate in this research study.  The study doctor will discuss these options with you.  If your 
insurance company does not authorize the study treatment, and no alternative payment 
arrangement is made, and you choose to go ahead with the study, you would be responsible for 
the bill.  Please speak to the study doctor and with the financial/billing representative before 
proceeding with this research study. 
 
 
POSSIBLE BENEFITS: 
 
The information gained from this study will help to give doctors a better idea of which 
medications minimize the risk of “life threatening events”, such as heart attacks and strokes in 
patients with ET and PV. We will also be using information from the additional blood samples 
taken in this study to see if either PEGASYS or Hydroxyurea reduce the amount of proteins in 
your blood that might be important in causing ET or PV, such as JAK2V617F.  Additionally, 
there may or may not be any direct medical benefit to you from participating in this study, but the 
knowledge gained through this research may help other patients with ET or PV in the future. 
 
REASONABLY FORESEEABLE RISKS AND DISCOMFORTS: 
 
While on the study, you are at risk for the side effects listed below. You should discuss these 
with the study doctor and/or your regular doctor. There also may be other side effects that we 
cannot predict.  Many side effects go away shortly after study drug is stopped, but in some cases 
side effects can be serious, long lasting, or permanent. It may be necessary for you to be admitted 
to the hospital for the treatment of these side effects. 
 
Each of the medicines in this study is licensed for treatment of medical conditions, but not 
necessarily ET or PV even though they are widely used for these conditions, and for each 
(PEGASYS and Hydroxyurea) further information can be found in the patient information sheet 
with the medication you would be given. Alternatively, information about these medicines is 
available at http://www.netdoctor.co.uk/medicines. 
 
Risks of Aspirin: 
The most common unwanted affect for aspirin is indigestion and heartburn, and so it should not 
be used (except on medical advice) in someone who has a peptic ulcer or has had one in the past. 
It is important that patients with Asthma should tell their doctor as aspirin can cause shortness of 
breath and may start an asthma attack. 
 
Where patients have increased levels of platelet counts, aspirin can also cause an increase in 


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bruising and bleeding. 
 
Although rare, kidney problems can develop in some patients. 
 
Risk of Hydroxyurea: 
Hydroxyurea is approved for treatment of medical conditions, but not ET or PV. However, it is a 
well-established treatment for these conditions and has been used for some time. A serious side 
effect of this medication may be to decrease your white and red blood cells as well as your 
platelet count. The decrease in white cells can lead to an increased risk of infection and possibly 
to a fever developing. If this happens it is important that you contact a doctor for medical advice.  
 
Some common side effects include tiredness, mouth ulcers, headaches and gastrointestinal upsets 
such as nausea, diarrhea or constipation. Rarely there might be skin rashes, leg ulcers or kidney 
problems. 
 
If Hydroxyurea is taken for a long time there can be redness, scaling or increased pigmentation of 
skin, or thinning of skin or nails in some people. 
 
There has been some controversy about whether Hydroxyurea increases the risk of ET or PV 
turning into acute leukemia in the long term (if taken for more than 10 years). This question has 
not yet been answered but if there is any increase in risk it is likely to be small, less than 3 in 100 
after 10 years. 
 
Risks of PEGASYS: 
PEGASYS can cause serious side effects including: 
• blood problems. PEGASYS can affect your bone marrow and cause low red blood cell, 
low white blood cell, and platelet counts 
• thyroid problems 
• blood sugar problems. Some people may develop high blood sugar or diabetes. 
• serious eye problems. PEGASYS may cause eye problems that may lead to vision loss 
or blindness 
• serious liver problems, worsening of liver problems, including liver failure and death 
• lung problems, including: 
o trouble breathing 
o pneumonia 
o inflammation of lung tissue 
o new or worse high blood pressure of the lungs (pulmonary hypertension). This 
can be severe and may lead to death 
• inflammation of your pancreas (pancreatitis) 
• inflammation of your intestines (colitis) 
• serious allergic reactions and skin reactions 
• nerve problems. People who take PEGASYS can develop nerve problems such as 
continuing numbness, tingling, or burning sensation in the arms or legs (peripheral 
neuropathy) 
• heart problems. Some people who take PEGASYS may get heart problems, including: 
o high blood pressure 
o fast heart rate or abnormal heart beat 


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o chest pain 
o heart attacks 
• Mental health problems and suicide. PEGASYS therapy may cause you to develop 
mood or behavioral problems, including: 
o irritability (getting upset easily) 
o depression (feeling low, feeling bad about yourself or feeling hopeless), and 
anxiety 
o aggressive behavior 
o former drug addicts may fall back into drug addiction or overdose 
o thoughts of hurting yourself or others, or suicide 
• Stroke or symptoms of a stroke. Symptoms may include weakness, loss of coordination, 
and numbness. 
• New or worsening autoimmune problems. Some people taking PEGASYS develop 
autoimmune problems (a condition where the body’s immune cells attack other cells or 
organs in the body), such as rheumatoid arthritis, lupus, and psoriasis. 
• Infections. Some people who take PEGASYS may get an infection. Symptoms may 
include: 
o fever 
o chills 
o burning and painful urination 
o urinating often 
o coughing up yellow or pink mucus (phlegm) 
 
The most common, but less serious, side effects of PEGASYS include: 
• flu-like symptoms (i.e. aches and pains, fever, chills, sweating, headache, fatigue and 
nausea. These tend to be worse at the start of study drug usage and improve with continued 
usage. You may want to take a medicine to reduce these symptoms - for example, 
paracetamol or ibuprofen - before the injection and for 24 hours after the injection) 
• tiredness and weakness 
• stomach problems 
• loss of appetite 
• skin reactions 
• hair thinning 
• trouble sleeping 
 
Risks of EKG: 
An EKG is painless. The electrodes placed on the skin detect only the electrical signals from the 
heart. No electricity is sent through the body, and there is no possibility of receiving an electric 
shock.  When first applied, the disks may be cold and in rare circumstances, you may develop a 
localized rash or irritation where the patches are placed. 
 
Risks of Bone marrow aspirate/biopsy: 
A bone marrow aspiration/biopsy is a procedure in which an area of the hip is numbed and a 
needle is placed through the skin and into the hip bone.  A small sample of bone marrow and 
bone is withdrawn. There may be some temporary pain or discomfort associated with these 
routine procedures. The risks therefore include bleeding which rarely requires blood transfusions, 


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pain at the site of the biopsy, and a small possibility of a local infection which may lead to 
antibiotic therapy.  In extremely rare cases, an allergic reaction to the local anesthetic used to 
numb the hip can occur.  In addition, tissue swelling around the aspiration/biopsy site may occur. 
 
Risks of clipping nails: 
There are no risks to clipping nails. 
 
Side Effects of Blood Being Drawn: 
Blood withdrawal may cause pain and bruising at the site of vein puncture, inflammation of the 
vein and infection; lightheadedness and/or fainting; care will be taken to minimize these risks. 
 
Reproductive Health/Sexual Activity: 
Both men and women must not attempt pregnancy and women must not be pregnant or breast- 
feeding while participating in this study. If sexually active, both men and women must use an 
effective method of birth control while taking the study drug. Barrier contraceptives (condoms or 
diaphragm) with a spermicide, intrauterine devices, and complete abstinence are examples of 
effective methods. Only methods that also use condoms provide adequate protection against 
sexually transmitted diseases. If you or your partner become pregnant while taking the study 
drug, it is important that you notify your study nurse/physician immediately. If you are pregnant 
you may be required to stop the study drugs at which time other treatment options will be 
discussed with you. 
 
Women who can still become pregnant must have a pregnancy test before taking part in this 
study.  This pregnancy screening is standard practice at (Name of Institution) in chemotherapy 
research studies and the results will be used to determine eligibility for the study. If you are a 
woman who can become pregnant, blood will be taken from a vein in your arm with a needle 
within 7 days before you enter the study.  You will be told the results of the pregnancy test.  If 
the pregnancy test is positive, you will not be able to take part in the study. 
 
Risk of loss of confidentiality: 
There is the risk for the potential loss of confidentiality.  This means that the risk of release of 
private information from your health records can occur.  Release of this private information 
might affect you in the future. 
 
In addition to these risks, this research may hurt you in ways that are not known.  The unknown 
risks might be minor or might be major (death). 
 
OTHER POSSIBLE OPTIONS TO CONSIDER: 
 
 
An option is not to participate and if you choose not to take part in the study this will not affect 
your level of care. Your study doctor will discuss with you what will be the best treatment and 
you will be seen at routine clinic appointments. 
 
 
IN CASE OF INJURY DURING THIS RESEARCH STUDY: 
 
 
If you are injured or made sick from taking part in this research study, medical care will be 
provided. Generally, this medical care will be billed to you and/or your health care insurance. In 
some cases, the costs of this care may be paid by someone else. In the event of injury, contact the 


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Principal Investigator. 
 
 
ENDING PARTICIPATION IN THE RESEARCH STUDY: 
 
You may stop taking part in this research study at any time without any penalty. This will not 
affect your ability to receive medical care at (Name of Institution) or to receive any benefits to 
which you are otherwise entitled. 
 
If you decide to stop being in the research study, please contact the Principal Investigator or the 
research staff 
 
If you stop being in the research study, already collected information may not be removed from 
the research study database and will continue to be used to complete the research analysis.  You 
may be asked whether the investigator can collect information from your routine medical care. If 
you agree, this data will be handled the same as research data. 
 
You may also withdraw your permission for the use and disclosure of any of your protected 
information for research, but you must do so in writing to the Principal Investigator at the address 
on the first page. Even if you withdraw your permission, the Principal Investigator for the 
research study may still use the information that was already collected if that information is 
necessary to complete the research study. Your health information may still be used or shared 
after you withdraw your authorization if you should have an adverse event (a bad effect) from 
participating in the research study. 
 
Withdrawal without your consent: The study doctor, the sponsor (MPD-RC) or the institution 
may stop your involvement in this research study at any time without your consent. This may be 
because the research study is being stopped, the instructions of the study team have not been 
followed, the investigator believes it is in your best interest, or for any other reason. If specimens 
or data have been stored as part of the research study, they too can be destroyed without your 
consent. 
 
CONTACT PERSON(S): 
 
If you have any questions, concerns, or complaints at any time about this research, or you think 
the research has hurt you, please contact the office of the research team and/or the Principal 
Investigator at phone number (XXX-XXX-XXXX). 
 
This research has been reviewed and approved by an Institutional Review Board. You may reach 
a representative of the Program for Protection of Human Subjects at (Name of Institution) at 
telephone number (XXX-XXX-XXXX) during standard work hours for any of the following 
reasons: 
 
• Your questions, concerns, or complaints are not being answered by the research team. 
 
• You cannot reach the research team. 
 
• You are not comfortable talking to the research team. 
 
• You have questions about your rights as a research subject. 
 
• You want to get information or provide input about this research. 
 
DISCLOSURE OF FINANCIAL INTERESTS: 
 


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None. 
 
MAINTAINING CONFIDENTIALITY – HIPAA AUTHORIZATION: 
 
As you take part in this research project it will be necessary for the research team and others to 
use and share some of your private protected health information. Consistent with the federal 
Health Insurance Portability and Accountability Act (HIPAA), we are asking your permission to 
receive, use and share that information. 
 
What protected health information is collected and used in this study, and might also be 
disclosed (shared) with others? 
As part of this research project the researchers will collect your name, address including zip 
code, telephone number, date of birth, sex, race, and ethnicity. 
 
The researchers will also get information from your medical record (includes hospital record 
from (Name of Institution) and referring physician’s records) 
 
During the study the researchers will gather information by: 
• taking a medical history (includes current and past medications or therapies, illnesses, 
conditions or symptoms, family medical history, allergies, etc.) 
• doing a physical examination that generally also includes blood pressure reading, 
heart rate, breathing rate and temperature 
• completing the blood tests, procedures such as ECG, bone marrow aspiration/biopsy, 
biomarker testing as explained in the description section of this consent. 
 
Why is your protected health information being used? 
Your personal contact information is important to be able to contact you during the study. Your 
health information and the results of any tests and procedures being collected as part of this 
research study will be used for the purpose of this study as explained earlier in this consent form. 
The results of this study could be published or presented at scientific meetings, lectures, or other 
events, but would not include any information that would let others know who you are, unless 
you give separate permission to do so. The Principal Investigator may also use and share the 
results of these tests and procedures to treat you. 
 
The research team and other authorized members of (Name of Institution) workforce may use and 
share your information to ensure that the research meets legal, institutional or accreditation 
requirements. For example, the (Name of Institution) Program for the Protection of Human 
Subjects is responsible for overseeing research on human subjects, and may need to see your 
information. If you receive any payments for taking part in this study, the (Name of Institution) 
Finance Department may need your name, address, social security number, payment amount, and 
related information for tax reporting purposes.  If the research team uncovers abuse, neglect, or 
reportable diseases, this information may be disclosed to appropriate authorities. 
 
Who, outside (Name of Institution), might receive your protected health information? 
As part of the study, the Principal Investigator, study team and others in the (Name of Institution) 
workforce may disclose your protected health information, including the results of the research 
study tests and procedures, to the following people or organizations: (It is possible that there may 
be changes to the list during this research study; you may request an up-to-date list at any time by 
contacting the Principal Investigator.) 


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• Research data coordinating office and/or their representative(s) who will be 
responsible for collecting results and findings from all the centers: 
Myeloproliferative Disorders Research Consortium Data Management Center 
• Outside laboratory who will be performing laboratory analysis for all the research 
centers involved in this project: Myeloproliferative Disorders Central Laboratory 
located at the New York Blood Center in North America and at MPD-RC Tissue 
Bank, Laboratorio Paolo Belli in Europe. 
• The manufacturer of the drug PEGASYS, Roche Pharmaceuticals. 
• The  sponsoring  government  agency  and/or  their  representative  who  need  to 
confirm the accuracy of the results submitted to the government or the use of 
government funds: In the USA this is the National Cancer Institute (NCI), in 
Europe this will be the individual regulatory authorities for examples the MHRA. 
• A Data Safety Monitoring Board or other committee that will monitor the study 
on an ongoing basis for safety. This will include the (Institution’s Name) 
Institutional Review Board (IRB) and the Myeloproliferative Disorders Research 
Consortium Data and Safety Monitoring Board. 
• The United States Food and Drug Administration. 
• United States Department of Health and Human Services and the Office of Human 
Research Protection. 
 
In all disclosures outside of (Name of Institution), you will not be identified by name, social 
security number, address, telephone number, or any other direct personal identifier unless 
disclosure of the direct identifier is required by law. Some records and information disclosed may 
be identified with a unique code number. The Principal Investigator will ensure that the key to 
the code will be kept in a locked file, or will be securely stored electronically. The code will not 
be used to link the information back to you without your permission, unless the law requires it, or 
rarely if the Institutional Review Board allows it after determining that there would be minimal 
risk to your privacy. It is possible that a sponsor or their representatives, a data coordinating 
office, a contract research organization, will come to inspect your records. Even if those records 
are identifiable when inspected, the information leaving the institution will be stripped of direct 
identifiers.  Additionally, the monitors, auditors, the IRB, the Food and Drug Administration will 
be granted direct access to your medical records for verification of the research procedures and 
data. By signing this document you are authorizing this access. We may publish the results of 
this research. However, we will keep your name and other identifying information confidential. 
 
For how long will (Name of Institution) be able to use or disclose your protected 
health information? 
 
Your authorization for use of your protected health information for this specific study does not 
expire. 
 
Will you be able to access your records? 
During your participation in this study, you will have access to your medical record and any 
study information that is part of that record. The investigator is not required to release to you 
research information that is not part of your medical record. 
 
Do you need to give us permission to obtain, use or share your health information? 
NO! If you decide not to let us obtain, use or share your health information you should not sign 
this form, and you will not be allowed to volunteer in the research study. If you do not sign, 
it will not affect your treatment, payment or enrollment in any health plans or affect your 


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eligibility for benefits. 
 
Can you change your mind? 
You  may  withdraw  your  permission  for  the  use  and  disclosure  of  any  of  your  protected 
information for research, but you must do so in writing to the Principal Investigator at the address 
on the first page. Even if you withdraw your permission, the Principal Investigator for the 
research study may still use your protected information that was already collected if that 
information is necessary to complete the study. Your health information may still be used or 
shared after you withdraw your authorization if you should have an adverse event (a bad effect) 
from being in the study.  If you withdraw your permission to use your protected health 
information for research that means you will also be withdrawn from the research study, but 
standard medical care and any other benefits to which you are entitled will not be affected. You 
can also tell us you want to withdraw from the research study at any time without canceling the 
Authorization to use your data. 
 
If you have not already received it, you will also be given the Notice of Privacy Practices that 
contains more information about how (Name of Institution) uses and discloses your protected 
health information. 
 
It is important for you to understand that once information is disclosed to others outside (Name of 
Institution), the information may be re-disclosed and will no longer be covered by the federal 
privacy protection regulations. However, even if your information will no longer be protected by 
federal regulations, where possible, (Name of Institution) has entered into agreements with those 
who will receive your information to continue to protect your confidentiality. 
 
If as part of this research project your medical records are being reviewed, or a medical history is 
being taken, it is possible that HIV-related information may be revealed to the researchers.  If 
that is the case, the information in the following box concerns you.  If this research does not 
involve any review of medical records or questions about your medical history or conditions, 
then the following section may be ignored. 


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Signature Block for Capable Adult 
Your signature below documents your permission to take part in this research and to the use and 
disclosure of your protected health information. A signed and dated copy will be given to you. 
 
 
DO NOT SIGN THIS FORM AFTER THIS DATE 
 
 
 
Signature of subject 
Date and Time 
 
 
 
Printed name of subject 
 
Person Explaining Study and Obtaining Consent 
 
 
 
Signature of person obtaining consent 
Date and Time 
 
 
 
Printed name of person obtaining consent 
 
 
 
Witness Section: For use when a witness is required to observe the consent process 
document below (for example, subject is illiterate or visually impaired, or this 
accompanies a short form consent): 
My signature below documents that the information in the consent document and any other 
written information was accurately explained to, and apparently understood by, the subject, and 
that consent was freely given by the subject. 
 
 
 
Signature of witness to consent process 
Date and Time 
 
 
 
Printed name of person witnessing consent process 


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16.0 
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5. Bretscher M, Rummans T, Sloan J, Kaur J, Bartlett A, Borkenhagen L, et al. Quality of 
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6. Campbell PJ, Scott LM, Buck G, et al. Definition of subtypes of essential 
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7. Campbell PJ, Griesshammer M. The V617F mutation in JAK2 is associated with poorer 
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8. Cannon CP, McCabe CH, Wilcox RG et al Oral glycoprotein IIb/IIIa inhibition with 
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9. Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential 
thrombocythemia and a high risk of thrombosis. N Engl J Med 1995;332,1132-6 
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11. Diggle PJ, Heagerty P, Liang K-Y and Zeger SL (2002)  Analysis of Longitudinal Data 
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12. Donovan PB, Kaplan ME, Goldberg JD, et al. Treatment of polycythemia vera with 
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14. Halsey C, Roberts IA. The role of hydroxyurea in sickle cell disease. Br J Haematol 
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risk essential thrombocythemia. N Engl J Med 2005;353,33-45. 
17. Ishii T, Bruno E, Hoffman R, Xu M. Involvement of various hematopoietic-cell lineages 
by the JAK2V617F mutation in polycythemia vera. Blood 2006;108, 3128-24. 
18. Jabbour E, Kantarjian H, Cortes J et al. PEG-IFN-alfa-2b therapy in BCR-ABL-negative 
myeloproliferative disorders. Cancer 2007;110, 2013-2018. 
19. Jenkinson C, Layte R, Jenkinson D, Lawrence K, Petersen S, Paice C, et al. A shorter form  
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20. Jenkinson C, Layte R. Development and testing of the UK SF-12 (short form health 
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Lawrence K, Petersen S, Paice C, et al. A shorter form health survey: can the SF-12 
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22. Kiladjian JJ, Cassinat B, Turlure P, et al. High molecular response rate of  polycythemia 
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24. Kopec JA, Willison KD. A comparative review of four preference-weighted measures of 
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26. Landolfi  R,  Marchioli  R,  Kutti  J,  et  al.  Efficacy and  safety  of  low-dose aspirin  in 
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27. R. Kralovics, S. S. Teo, S. Li, A. Theocharides, A. S. Buser, A. Tichelli, and R. C. Skoda. 
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30. Little R and Rubin D (2002)  Statistical Analysis of Missing Data (2nd Ed).  Wiley, New 
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Appendix A: Definitions of Events  
 
A. THROMBOTIC EVENTS 
1. New infarction or recurrent myocardial infarction 
Myocardial infarction is defined as the presence of two or more of the following criteria: 
a. Symptoms of cardiac ischemia 
• Characteristic ischemic chest pain in the pericardium or associated referral 
areas, lasting for at least 20 minutes 
b. Significant cardiac enzyme elevations 
• Elevation of CK, LDH, or AST to at least twice the upper limit of normal for 
the given laboratory in the absence of other explanation. 
c. EKG changes 
• Occurrence of new 40 msec Q waves in at least two adjacent EKG leads, or 
development of a new dominant R wave in V1 (R>1mm >S in V1) or of new 
ST elevation or depression or persistent (>48 hours) new T wave inversion. 
 
2. Stroke and stroke type 
A stroke is a new focal neurologic deficit of presumed vascular origin which persists for 
>24 hours or results in death within 24 hours. 
 
Stroke type 
• Hemorrhagic: A stroke caused by primary intracranial hemorrhage 
diagnosed by CT, MRI, or other objective means, or by autopsy. 
• Ischemic: A stroke of atherothrombotic or embolic origin as diagnosed 
by CT, MRI or other objective means, or by autopsy 
• Uncertain: A stroke not otherwise classified by the above criteria. 
 
3. Deep vein thrombosis 
A deep vein thrombosis (DVT) is defined as a typical clinical picture with positive 
investigation: i.e. phlebography, ultrasonography, CT in unusual sites. In case of suspected 
recurrence in a site of previous DVT (e.g. ipsilateral limb) diagnosis is accepted only if the 
investigation shows extension or recurrence of thrombosis as compared to a previous test. 
4. Pulmonary embolism 
A pulmonary embolism is defined as a typical clinical picture with positive angiography or 
high- probability V/Q scanning. 
 
5. Thrombotic digital ischemia 
Characteristic purplish discoloration of toes/fingers, which may progress to infarction if 
untreated. Digital ischemia may occasionally be associated with erythromelalgia. 
 


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6. Unstable angina 
Defined in accordance with TIMI criteria as presence of prolonged angina or recurrent 
angina at rest, together with one of the following: new ST segment depression, requirement 
for revascularization procedure, cardiac enzyme rise to less than twice the upper limit of 
normal, or past history of documented coronary artery disease. 
 
OR 
 
Ischemic discomfort at rest lasting 5 minutes or greater and associated with at least one of the 
following new/presumably new ST segment elevation >0.5mm; T-wave inversion >3mm in 3 
leads or left bundle branch block; cardiac enzyme rise to less than twice the upper limit of 
normal. (40) 
 
7. Other thrombotic event 
Thrombosis in sites not covered above. In particular, characteristic symptoms of peripheral 
limb ischemia with evidence of thrombosis. In addition characteristic syndromes of 
abdominal thrombosis for example Budd Chiari syndrome. 
 
B. OTHER VASCULAR OCCLUSIVE EVENTS (Not major) 
 
1. Other transient neurological event 
This is defined as the abrupt onset of poorly or non-localizing neurological symptoms such 
as unsteadiness, blurred vision, hearing disturbance or unstable gait. 
 
2. Erythromelalgia 
Erythromelalgia is defined as the onset of pain at the extremities associated with 
temperature increase and redness of the skin. Erythromelalgia usually manifests in the 
lower extremities and/or rarely in the hands with frequent recurrences in the same areas. 
 
C. HEMORRHAGIC EVENTS 
 
1. Major hemorrhage 
Overt hemorrhage associated with either: 
• a decrease in hemoglobin level of at least 2g/dl, or 
• a need for blood transfusion of 2 or more units of blood, or 
• if hemorrhage is retroperitoneal or intracranial. 
 
2. Minor hemorrhage 
Overt hemorrhage not meeting the criteria of major hemorrhage 
 


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D. TRANSFORMATION 
 
1. Transformation to Post ET or Post PV myelofibrosis is defined by: 
Criteria for post-polycythemia vera myelofibrosis (Barosi 2008) 
Required criteria: 
1. Documentation of a previous diagnosis of polycythemia vera as defined by the WHO 
criteria 
2. Bone marrow fibrosis grade 2–3 (on 0–3 scale) 3 or grade 3–4 (on 0–4 scale) 4 
 
Additional criteria (two are required): 
1. Anemia or sustained loss of requirement of either phlebotomy (in the absence 
of cytoreductive therapy) or cytoreductive treatment for erythrocytosis 
2. A leukoerythroblastic peripheral blood picture 
3. Increasing splenomegaly defined as either an increase in palpable splenomegaly of 5 
cm (distance of the tip of the spleen from the left costal margin) or the appearance of 
a newly palpable splenomegaly 
4. Development of 1 of three constitutional symptoms: 10% weight loss in 6 
months, night sweats, unexplained fever (> 37.5C) 
 
Criteria for post-essential thrombocythemia myelofibrosis 
Required criteria: 
1. Documentation of a previous diagnosis of essential thrombocythemia as defined by the 
WHO criteria 
2. Bone marrow fibrosis grade 2–3 (on 0–3 scale) 3 or grade 3–4 (on 0–4 scale) 4 
 
Additional criteria (two are required): 
1. Anemia and a ≥ 2 g/L decrease from baseline hemoglobin level 
2. A leukoerythroblastic peripheral blood picture 
3. Increasing splenomegaly defined as either an increase in palpable splenomegaly of 5 
cm (distance of the tip of the spleen from the left costal margin) or the appearance of 
a newly palpable splenomegaly 
4. Increased LDH (above the baseline level and exceeding the normal reference range 
without other obvious cause) 
5. Development of 1 of three constitutional symptoms: 10% weight loss in 6 
months, night sweats, unexplained fever (37.5C) 
 
2. Transformation to leukemic phase is defined by: 
The threshold for a diagnosis of achieving blast phase was 20% blood or marrow blasts 
(persisting for 4 weeks) or the presence of a acute leukemia–defining karyotypic lesions 
despite blast percentage (t[8;21][q22:q22], inv[16][p13;q22], t[16;16][p13;q22], or 
t[15;17][q22;q12]) 
 
E. DEATH 
 
The cause of death should be given, including post mortem findings where possible. 


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Appendix B: ECOG Performance Status 
 
Eastern Cooperative Oncology Group (ECOG) Performance Score Ratings 
 
At each clinic visit after the screening visit, the investigator will assess each subject’s ECOG 
performance status according to the following scale: 
0 Fully active, able to carry on all pre-disease performance without restriction 
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house-work, office work 
2 Ambulatory and capable of all self-care but unable to carry out any work activities.  Up 
and about more than 50% of waking hours 
3 Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair 
5 Dead 


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Appendix C: NCI toxicity criteria 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 


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Appendix D: Symptom Assessment Package 
 
Appendix D1: MPN Symptom Assessment Form (MPN-SAF) 
 
Instructions: Please fill out all questions, as best able, reflecting how these symptoms 
affected you over the LAST WEEK unless directed otherwise. Complete forms until the 
STOP instruction toward the end of the packet. 
 
Symptom 
1 to 10  (0 if absent) ranking* 
1 is most favorable and 10 least favorable 
Please rate your fatigue 
(weariness, tiredness) by circling 
the one number that best 
describes your fatigue right NOW 
(No Fatigue)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Please rate your fatigue 
(weariness, tiredness) by circling 
the one number that best 
describes your USUAL Level of 
fatigue during past 24 hours 
 
(No Fatigue)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Please rate your fatigue 
(weariness, tiredness) by circling 
the one number that best 
describes your WORST level of 
fatigue during past 24 hours 
 
(No Fatigue)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Circle the one number that describes how, during the past 24 hours, fatigue has interfered with 
your 
• General Activity 
(Does not Interfere) 0 1 2 3 4 5 6 7 8 9 10 (Completely Interferes) 
• Mood 
(Does not Interfere) 0 1 2 3 4 5 6 7 8 9 10 (Completely Interferes) 
• Walking ability 
(Does not Interfere) 0 1 2 3 4 5 6 7 8 9 10 (Completely Interferes) 
• Normal Work (includes 
work both outside the 
home and daily chores) 
(Does not Interfere) 0 1 2 3 4 5 6 7 8 9 10 (Completely Interferes) 


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• Relations with other 
people 
(Does not Interfere) 0 1 2 3 4 5 6 7 8 9 10 (Completely Interferes) 
• Enjoyment of life 
(Does not Interfere) 0 1 2 3 4 5 6 7 8 9 10 (Completely Interferes) 
 
Circle the one number that describes how, during the past Week how much difficulty you have had 
with each of the following symptoms 
 
Filling up quickly when you 
eat (Early Satiety) 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Abdominal pain 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Abdominal discomfort 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Inactivity 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Problems with Headaches 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Problems with Concentration - 
Compared to prior to my MPD 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Dizziness/ Vertigo/ 
Lightheadedness 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Numbness/ Tingling (in my 
hands and feet) 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Difficulty sleeping 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Depression or sad mood 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Problems with Sexual Desire 
or Function 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Cough 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Night Sweats 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Itching (pruritus) 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Bone Pain (diffuse not joint 
pain or arthritis) 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
Fever (>100 F) 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Daily) 
Unintentional weight loss last 
6 months 
(Absent)   0  1  2  3  4  5  6  7  8  9  10   (Worst Imaginable) 
What is your Overall Quality 
of Life? 
(As good as it can be)  0  1  2  3  4  5  6  7  8  9 10  (As bad as it can be) 
 


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Appendix D2: EORTC 
 
 
 
 
 


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Appendix D3: Symptomatic Questions Specific for Toxicities of Pegylated interferon alfa-2a 
 
Answer these questions in reference to how these issues affected you during the Last Week 
 
 
 
I feel like I have the flu 
(Absent)  0  1  2  3  4  5  6  7  8  9  10  (Worst Imaginable) 
Irritation at the site I receive my 
injections 
(Absent)  0  1  2  3  4  5  6  7  8  9  10  (Worst Imaginable) 
I have developed blurring in my vision 
(Absent)  0  1  2  3  4  5  6  7  8  9  10  (Worst Imaginable) 
I have developed a change in my vision 
(Absent)  0  1  2  3  4  5  6  7  8  9  10  (Worst Imaginable) 
I have developed flushing 
(Absent)  0  1  2  3  4  5  6  7  8  9  10  (Worst Imaginable) 


 
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MPD-RC 112 PEGHU-Phase 3 
Appendix E: Medication Diaries


 
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MEDICATION DIARY 
PATIENT NAME: ____________________________ 
 
STUDY DRUG: PEGASYS  
 
PATIENT INSTRUCTIONS: Use this calendar to record your dose of PEGASYS and Aspirin weekly.  All additional medications must be approved by your treating 
physician. 
Week 1 
Week 2 
Week 3 
Week 4  
Week 5 
Week 6    
 
 
 
EXAMPLE ONLY 
Day: Monday 
Date: 5/2/2011 
Amount of PEGASYS: 
45mcg 
Aspirin: 80mg 
()Mon () Tues 
()Wed ()Thurs 
() Fri   () Sat 
() Sun   
 
 
 
EXAMPLE ONLY 
 
 
 
EXAMPLE ONLY 
 
 
 
EXAMPLE ONLY 
 
 
 
EXAMPLE ONLY 
 
Day: _______________ 
 
Date:_______________ 
Amount of 
PEGASYS:_________mcg 
 
Aspirin:______mg 
(   )Mon (   ) Tues 
(   )Wed (   )Thurs 
(   ) Fri   (   ) Sat 
(   ) Sun 
 
Day: ______________ 
 
Date:______________ 
Amount of 
PEGASYS:_________mcg 
 
Aspirin:______mg 
(   )Mon (   ) Tues 
(   )Wed (   )Thurs 
(   ) Fri   (   ) Sat 
(   ) Sun 
 
Day: ______________ 
 
Date:______________ 
Amount of 
PEGASYS:_________mcg 
 
Aspirin:______mg 
(   )Mon (   ) Tues 
(   )Wed (   )Thurs 
(   ) Fri   (   ) Sat 
(   ) Sun 
 
Day:_______________ 
 
Date:______________ 
Amount of 
PEGASYS:_________mcg 
 
Aspirin:______mg 
(   )Mon (   ) Tues 
(   )Wed (   )Thurs 
(   ) Fri   (   ) Sat 
(   ) Sun 
 
Day:______________ 
 
Date:_____________ 
Amount of 
PEGASYS:_________mcg 
 
Aspirin:______mg 
(   )Mon (   ) Tues 
(   )Wed (   )Thurs 
(   ) Fri   (   ) Sat 
(   ) Sun 
 
Day: ______________ 
 
Date:______________ 
Amount of 
PEGASYS:_________mcg 
 
Aspirin:______mg 
(   )Mon (   ) Tues 
(   )Wed (   )Thurs 
(   ) Fri   (   ) Sat 
(   ) Sun 
Week 7 
Week 8 
Week 9 
Week 10 
Week 11 
Week 12 
 
Day: ______________ 
 
Date:______________ 
Amount of 
PEGASYS:_________mcg 
 
Aspirin:______mg 
(   )Mon (   ) Tues 
(   )Wed (   )Thurs 
(   ) Fri   (   ) Sat 
(   ) Sun 
 
Day: ______________ 
 
Date:______________ 
Amount of 
PEGASYS:_________mcg 
 
Aspirin:______mg 
(   )Mon (   ) Tues 
(   )Wed (   )Thurs 
(   ) Fri   (   ) Sat 
(   ) Sun 
 
Day: ______________ 
 
Date:______________ 
Amount of 
PEGASYS:_________mcg 
 
Aspirin:______mg 
(   )Mon (   ) Tues 
(   )Wed (   )Thurs 
(   ) Fri   (   ) Sat 
(   ) Sun 
 
Day:______________ 
 
Date:_____________ 
Amount of 
PEGASYS:_________mcg 
 
Aspirin:______mg 
(   )Mon (   ) Tues 
(   )Wed (   )Thurs 
(   ) Fri   (   ) Sat 
(   ) Sun 
 
Day:______________ 
 
Date:_____________ 
Amount of 
PEGASYS:_________mcg 
 
Aspirin:______mg 
(   )Mon (   ) Tues 
(   )Wed (   )Thurs 
(   ) Fri   (   ) Sat 
(   ) Sun 
 
Day:______________ 
 
Date:_____________ 
Amount of 
PEGASYS:_________mcg 
 
Aspirin:______mg 
(   )Mon (   ) Tues 
(   )Wed (   )Thurs 
(   ) Fri   (   ) Sat 
(   ) Sun 
 
PATIENT SIGNATURE: _______________________________ 


 
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MEDICATION DIARY 
 
PATIENT NAME: ____________________________ 
 
STUDY DRUG: Hydroxyurea 
 
Start Date: ______/______/_______  
End Date: ______/______/_______ (MM/DD/YYYY) 
PATIENT INSTRUCTIONS: Use this calendar to record your dose of Hydroxyurea and Aspirin daily.  All additional medications must be approved by your treating 
physician. 
SUNDAY 
MONDAY 
TUESDAY 
WEDNESDAY 
THURSDAY 
FRIDAY 
SATURDAY 
 
 
EXAMPLE ONLY 
Hydroxyurea: 500mg 
____3_____(capsules) 
 
Aspirin:___80___mg 
Hydroxyurea: 500mg 
____3_____(capsules) 
 
Aspirin:___80___mg 
Hydroxyurea: 500mg 
____3_____(capsules) 
 
Aspirin:___80___mg 
 
 
 
EXAMPLE ONLY 
 
 
 
EXAMPLE ONLY 
 
 
 
EXAMPLE ONLY 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
Hydroxyurea: 500mg 
 
__________(capsules) 
 
Aspirin:________mg 
 
PATIENT SIGNATURE: _______________________________


 
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MPD-RC 112 PEGHU-Phase 3 
Appendix F: NCI DARF