Randomized Trial of Pegylated Interferon Alfa-2a Versus Hydroxyurea in Polycythemia Vera (PV) and Essential Thrombocythemia (ET)

• Sponsor: Ronald Hoffman (Other)
• Overall Status: Completed
• CT.gov ID: NCT01259856
• Collaborator: Myeloproliferative Disorders-Research Consortium (Other), National Cancer Institute (NCI) (NIH), Roche Pharma AG (Industry)
• Enrollment: 168
• Locations: 25
• Arms: 2
• Duration (Months): 69.9
• Patients Per Site: 6.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
High Risk Polycythemia Vera; High Risk Essential Thrombocythemia	Drug: PEGASYS; Drug: Hydroxyurea; Drug: Aspirin	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 168 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Trial of Pegylated Interferon Alfa-2a Versus Hydroxyurea Therapy in the Treatment of High Risk Polycythemia Vera (PV) and High Risk Essential Thrombocythemia (ET)
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Jun 30, 2017
• Actual Study Completion Date: Jun 30, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PEGASYS 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.	Drug: PEGASYS; 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.; Other Names: Pegylated Interferon Alfa-2a ; Drug: Aspirin; Subject will be asked to take 81 to 100mg per day for the 12 months of the study treatment.; Other Names: acetylsalicylic acid
Active Comparator: Hydroxyurea Subjects will receive a 500mg tablet to be taken twice daily for up to 12 months of treatment.	Drug: Hydroxyurea; Subjects will receive a 500mg tablet to be taken twice daily for up to 12 months of treatment.; Other Names: Hydroxycarbamide ; Drug: Aspirin; Subject will be asked to take 81 to 100mg per day for the 12 months of the study treatment.; Other Names: acetylsalicylic acid

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Complete Remission (CR) [12 months]

   Number of participants with Complete Remission after 12 months of therapy assessed by hematologic response rates two strata of patients with high risk polycythemia vera (PV) or high risk essential thrombocythemia (ET). Complete remission means no evidence of disease.

2. Number of Participants With Partial Remission (PR) [12 months]

   Number of participants with Partial Remission after 12 months of therapy assessed by hematologic response rates two strata of patients with high risk polycythemia vera (PV) or high risk essential thrombocythemia (ET). Partial Remission means decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment.

Secondary Outcome Measures

1. Number of Participants With Grade 3 and Grade 4 Hematological and Non-hematological Events [4 years]

   Number of Participants with Grade 3 and Grade 4 Hematological and Non-hematological Events using the Common Terminology Criteria for Adverse Events (CTCAE) 4.0 to assess the toxicity, safety and tolerability of therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea).

2. Change in the Total Symptom Score (TSS) [baseline and 12 months]

   Change in the Total Symptom Score which assessed improvement in disease symptoms measured by the change in TSS from the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) instrument being used in this study from baseline to 12 months. This 19 item instrument includes the 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. Each item is scored from 0-10 with full scale from 0-190, with higher scores mean worse symptoms.

3. JAK2 Allele Burden [4 years]

   To compare the impact of therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) on key biomarkers of the disease(s) by measuring the JAK2 allele burden.

4. Allele Burden [4 years]

   The impact of PEGASYS on JAK2 will be measured by the allele burden; hematopoietic cell clonality will be measured by whether patients with clonal disease return to polyclonal; bone marrow histopathology will be measured by going from abnormal to normal; cytogenetic abnormalities will be measured by seeing if the cytogenetics go from abnormal to normal.To compare the impact of therapy on JAK2-V617F (JAK2), CALR, hematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities.

5. Number of Participants With Progression of Disease or Death [4 years]

   Survival and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation after therapy To estimate survival and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation after therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) by capturing the rate of progression to a more advanced myeloid malignancy.

6. Number of Participants With Major Cardiovascular Events After Therapy [4 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• A diagnosis of Essential Thrombocythemia (ET) or Polycythemia Vera (PV) shall be made in accordance with the WHO (2008)criteria (Swerdlow 2008) as shown below.

• Diagnosis < 5 years prior to entry.

• 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.

• Essential Thrombocythemia (all 6 criteria required)

1. Platelets count ≥ 450 x 10 to 9/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 neoplasm

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:

High risk PV ANY ONE of the following:

• Age ≥ 60 years

• 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

• Significant splenomegaly (> 5cm below the left costal margin on palpitation) or symptomatic splenomegaly (splenic infarcts or requiring analgesia)

• Platelets ≥ 1000 x 10 to 9/L

• Diabetes or hypertension requiring pharmacological therapy for > 6 months

High risk ET ANY ONE of the following:

• Age ≥ 60 years

• Platelet count ≥ 1500 x 10 to 9/L

• Previous documented thrombosis, erythromelalgia or migraine headaches (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

• Previous hemorrhage related to ET

• 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

• ST 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 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 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 10 to 9/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

• 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). No detectable PNH (paroxysmal nocturnal hemoglobinuria) clone where tested

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Scottsdale	Arizona	United States	85259
2	USC Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
3	The Palo Alto Clinic	Palo Alto	California	United States	94301
4	Stanford University School of Medicine	Stanford	California	United States	94305
5	Georgetown University Medical Center	Washington	District of Columbia	United States	20007
6	Emory Hospital	Atlanta	Georgia	United States	30322
7	John H. Stroger Hospital of Cook County	Chicago	Illinois	United States	60612
8	University of Illinois at Chicago	Chicago	Illinois	United States	60612
9	University of Kansas Cancer Center	Westwood	Kansas	United States	66205
10	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
11	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
12	Weill Cornell Medical College	New York	New York	United States	10065
13	Duke University Medical Center	Durham	North Carolina	United States	27710
14	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina	United States	27157
15	Geisinger Cancer Center	Danville	Pennsylvania	United States	17822
16	University of Utah	Salt Lake City	Utah	United States	84132
17	Hopitaux de Paris	Paris		France	75010
18	Ospedale Riuniti de Bergamo	Bergamo		Italy
19	University Of Florence	Florence		Italy
20	Ospedale San Maartino Genova	Genova		Italy	11632
21	San Matteo Hospital	Pavia		Italy	27100
22	Universita Cattolica del Sacro Cuore	Rome		Italy	00168
23	Belfast City Hospital	Belfast	Northern Ireland	United Kingdom	BT9 7AB
24	Heart of England NHS Foundation Trust	Birmingham		United Kingdom	B9 5SS
25	Guy's and St. Thomas' NHS Foundation Trust	London		United Kingdom	SE1 7EH

Sponsors and Collaborators

• Ronald Hoffman
• Myeloproliferative Disorders-Research Consortium
• National Cancer Institute (NCI)
• Roche Pharma AG

Investigators

• Study Chair: Ronald Hoffman, MD, Icahn School of Medicine at Mount Sinai
• Study Chair: Claire Harrison, MD, Guy's and St Thomas' NHS Foundation Trust
• Study Chair: Ruben Mesa, MD, Mayo Clinic
• Study Chair: Jean-Jacques Kiladjian, MD, Hopitaux de Paris
• Study Chair: Mary Frances McMullin, MD, Belfast Health and Social Care Trust
• Study Chair: John Mascarenhas, MD, Icahn School of Medicine at Mount Sinai

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 21, 2015

More Information

Publications

None provided.

• Responsible Party: Ronald Hoffman, Professor of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT01259856
• Other Study ID Numbers: GCO 09-1300-00002; P01CA108671; MPD-RC 112
• First Posted: Dec 14, 2010
• Last Update Posted: Apr 30, 2019
• Last Verified: Apr 1, 2019

• Keywords provided by Ronald Hoffman, Professor of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai: Polycythemia vera; Essential thrombocythemia; Hydroxyurea; PEGASYS; Pegylated Interferon Alfa-2a
• Additional relevant MeSH terms: Polycythemia Vera; Polycythemia; Thrombocytosis; Thrombocythemia, Essential; Aspirin; Interferons; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2a; Hydroxyurea

Study Results

Participant Flow

Recruitment Details	Enrollment period from Sept 2011 through June 2016

Arm/Group Title	PEGASYS	Hydroxyurea
Arm/Group Description	The subject received the PEGASYS at a dose level of 45 micrograms weekly and gradually increased to the maximum dose of 180 micrograms per week. The dose was administered by prefilled syringes and injected subcutaneously. Subjects received therapy for up to 12 months. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.	Subjects received a 500mg tablet to be taken twice daily for up to 12 months of treatment. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.
Period Title: Overall Study
STARTED	82	86
COMPLETED	13	12
NOT COMPLETED	69	74

Baseline Characteristics

Arm/Group Title	PEGASYS	Hydroxyurea	Total
Arm/Group Description	The subject received the PEGASYS at a dose level of 45 micrograms weekly and gradually increased to the maximum dose of 180 micrograms per week. The dose was administered by prefilled syringes and injected subcutaneously. Subjects received therapy for up to 12 months. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.	Subjects received a 500mg tablet to be taken twice daily for up to 12 months of treatment. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.	Total of all reporting groups
Overall Participants	82	86	168
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.8 (14.8)	61.8 (12.8)	59.4 (14.0)
Sex: Female, Male (Count of Participants)
Female	33 40.2%	37 43%	70 41.7%
Male	49 59.8%	49 57%	98 58.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	3 3.5%	3 1.8%
Native Hawaiian or Other Pacific Islander	0 0%	1 1.2%	1 0.6%
Black or African American	3 3.7%	4 4.7%	7 4.2%
White	76 92.7%	70 81.4%	146 86.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 3.7%	8 9.3%	11 6.5%
Age > 60 years (Count of Participants)
Count of Participants [Participants]	42 51.2%	56 65.1%	98 58.3%
The Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
0	65 79.3%	72 83.7%	137 81.5%
1	15 18.3%	13 15.1%	28 16.7%
2	0 0%	1 1.2%	1 0.6%
3+	2 2.4%	0 0%	2 1.2%
Disease Type (Count of Participants)
Essential thrombocythemia (ET)	39 47.6%	42 48.8%	81 48.2%
Polycythemia Vera (PV)	43 52.4%	44 51.2%	87 51.8%
Previous Thrombosis (Count of Participants)
Count of Participants [Participants]	26 31.7%	20 23.3%	46 27.4%
Previous Hemorrhage (Count of Participants)
Count of Participants [Participants]	3 3.7%	4 4.7%	7 4.2%
Splenomegaly (Count of Participants)
Count of Participants [Participants]	5 6.1%	6 7%	11 6.5%
Disease Duration (months) [Median (Full Range) ]
Median (Full Range) [months]	2.6	3.0	2.8

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Complete Remission (CR)
Description	Number of participants with Complete Remission after 12 months of therapy assessed by hematologic response rates two strata of patients with high risk polycythemia vera (PV) or high risk essential thrombocythemia (ET). Complete remission means no evidence of disease.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

there were 82 participants in PEGASYS arm 39 with ET and 43 with PV, 86 in Hydroxyurea arm 42 with ET and 44 with PV

Arm/Group Title	PEGASYS	Hydroxyurea
Arm/Group Description	The subject received the PEGASYS at a dose level of 45 micrograms weekly and gradually increased to the maximum dose of 180 micrograms per week. The dose was administered by prefilled syringes and injected subcutaneously. Subjects received therapy for up to 12 months. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.	Subjects received a 500mg tablet to be taken twice daily for up to 12 months of treatment. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.
Measure Participants	82	86
Essential Thrombocythemia	17 20.7%	19 22.1%
Polycythemia Vera	12 14.6%	13 15.1%

2. Primary Outcome

Title	Number of Participants With Partial Remission (PR)
Description	Number of participants with Partial Remission after 12 months of therapy assessed by hematologic response rates two strata of patients with high risk polycythemia vera (PV) or high risk essential thrombocythemia (ET). Partial Remission means decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

there were 82 participants in PEGASYS arm 39 with ET and 43 with PV, 86 in Hydroxyurea arm 42 with ET and 44 with PV

Arm/Group Title	PEGASYS	Hydroxyurea
Arm/Group Description	The subject received the PEGASYS at a dose level of 45 micrograms weekly and gradually increased to the maximum dose of 180 micrograms per week. The dose was administered by prefilled syringes and injected subcutaneously. Subjects received therapy for up to 12 months. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.	Subjects received a 500mg tablet to be taken twice daily for up to 12 months of treatment. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.
Measure Participants	82	86
Essential Thrombocythemia	10 12.2%	11 12.8%
Polycythemia Vera	25 30.5%	17 19.8%

3. Secondary Outcome

Title	Number of Participants With Grade 3 and Grade 4 Hematological and Non-hematological Events
Description	Number of Participants with Grade 3 and Grade 4 Hematological and Non-hematological Events using the Common Terminology Criteria for Adverse Events (CTCAE) 4.0 to assess the toxicity, safety and tolerability of therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea).
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PEGASYS	Hydroxyurea
Arm/Group Description	The subject received the PEGASYS at a dose level of 45 micrograms weekly and gradually increased to the maximum dose of 180 micrograms per week. The dose was administered by prefilled syringes and injected subcutaneously. Subjects received therapy for up to 12 months. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.	Subjects received a 500mg tablet to be taken twice daily for up to 12 months of treatment. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.
Measure Participants	82	86
Grade 3 Hematological event	3 3.7%	2 2.3%
Grade 4 Hematological event	0 0%	0 0%
Grade 3 Non-hematological event	27 32.9%	14 16.3%
Grade 4 Non-hematological event	2 2.4%	3 3.5%

4. Secondary Outcome

Title	Change in the Total Symptom Score (TSS)
Description	Change in the Total Symptom Score which assessed improvement in disease symptoms measured by the change in TSS from the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) instrument being used in this study from baseline to 12 months. This 19 item instrument includes the 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. Each item is scored from 0-10 with full scale from 0-190, with higher scores mean worse symptoms.
Time Frame	baseline and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PEGASYS	Hydroxyurea
Arm/Group Description	The subject received the PEGASYS at a dose level of 45 micrograms weekly and gradually increased to the maximum dose of 180 micrograms per week. The dose was administered by prefilled syringes and injected subcutaneously. Subjects received therapy for up to 12 months. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.	Subjects received a 500mg tablet to be taken twice daily for up to 12 months of treatment. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.
Measure Participants	82	86
Mean (Full Range) [score on a scale]	1.16	-1.0

5. Secondary Outcome

Title	JAK2 Allele Burden
Description	To compare the impact of therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) on key biomarkers of the disease(s) by measuring the JAK2 allele burden.
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

data not collected

Arm/Group Title	PEGASYS	Hydroxyurea
Arm/Group Description	The subject received the PEGASYS at a dose level of 45 micrograms weekly and gradually increased to the maximum dose of 180 micrograms per week. The dose was administered by prefilled syringes and injected subcutaneously. Subjects received therapy for up to 12 months. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.	Subjects received a 500mg tablet to be taken twice daily for up to 12 months of treatment. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.
Measure Participants	0	0

6. Secondary Outcome

Title	Allele Burden
Description	The impact of PEGASYS on JAK2 will be measured by the allele burden; hematopoietic cell clonality will be measured by whether patients with clonal disease return to polyclonal; bone marrow histopathology will be measured by going from abnormal to normal; cytogenetic abnormalities will be measured by seeing if the cytogenetics go from abnormal to normal.To compare the impact of therapy on JAK2-V617F (JAK2), CALR, hematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities.
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

data not collected

Arm/Group Title	PEGASYS	Hydroxyurea
Arm/Group Description	The subject received the PEGASYS at a dose level of 45 micrograms weekly and gradually increased to the maximum dose of 180 micrograms per week. The dose was administered by prefilled syringes and injected subcutaneously. Subjects received therapy for up to 12 months. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.	Subjects received a 500mg tablet to be taken twice daily for up to 12 months of treatment. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.
Measure Participants	0	0

7. Secondary Outcome

Title	Number of Participants With Progression of Disease or Death
Description	Survival and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation after therapy To estimate survival and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation after therapy (Pegylated Interferon Alfa-2a vs. Hydroxyurea) by capturing the rate of progression to a more advanced myeloid malignancy.
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PEGASYS	Hydroxyurea
Arm/Group Description	The subject received the PEGASYS at a dose level of 45 micrograms weekly and gradually increased to the maximum dose of 180 micrograms per week. The dose was administered by prefilled syringes and injected subcutaneously. Subjects received therapy for up to 12 months. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.	Subjects received a 500mg tablet to be taken twice daily for up to 12 months of treatment. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.
Measure Participants	82	86
Death	0 0%	1 1.2%
Progression to MF	0 0%	0 0%

8. Secondary Outcome

Title	Number of Participants With Major Cardiovascular Events After Therapy
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PEGASYS	Hydroxyurea
Arm/Group Description	The subject received the PEGASYS at a dose level of 45 micrograms weekly and gradually increased to the maximum dose of 180 micrograms per week. The dose was administered by prefilled syringes and injected subcutaneously. Subjects received therapy for up to 12 months. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.	Subjects received a 500mg tablet to be taken twice daily for up to 12 months of treatment. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.
Measure Participants	82	86
Count of Participants [Participants]	1 1.2%	1 1.2%

Adverse Events

Time Frame	4 years
Arm/Group Title	PEGASYS		Hydroxyurea
Arm/Group Description	The subject received the PEGASYS at a dose level of 45 micrograms weekly and gradually increased to the maximum dose of 180 micrograms per week. The dose was administered by prefilled syringes and injected subcutaneously. Subjects received therapy for up to 12 months. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.		Subjects received a 500mg tablet to be taken twice daily for up to 12 months of treatment. Aspirin: Subject asked to take 81 to 100mg per day for the 12 months of the study treatment.
All Cause Mortality
	PEGASYS		Hydroxyurea
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/82 (0%)		1/86 (1.2%)
Serious Adverse Events
	PEGASYS		Hydroxyurea
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/82 (17.1%)		4/86 (4.7%)
Blood and lymphatic system disorders
Platelet disorders	1/82 (1.2%)		0/86 (0%)
Cardiac disorders
Cardiac arrhythmias	1/82 (1.2%)		0/86 (0%)
Cardiac disorder signs and symptoms	1/82 (1.2%)		0/86 (0%)
Gastrointestinal disorders
Exocrine pancreas conditions	1/82 (1.2%)		0/86 (0%)
Gastrointestinal haemorrahges NEC	1/82 (1.2%)		0/86 (0%)
Gastrointestinal signs and symptoms	1/82 (1.2%)		0/86 (0%)
General disorders
General system disorders NEC	1/82 (1.2%)		1/86 (1.2%)
Hepatobiliary disorders
Bile Duct Disorder	1/82 (1.2%)		0/86 (0%)
Gallbladder disorders	1/82 (1.2%)		0/86 (0%)
Infections and infestations
Infections - pathogen unspecified	0/82 (0%)		2/86 (2.3%)
Metabolism and nutrition disorders
Electrolyte and fluid balance conditions	1/82 (1.2%)		0/86 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified - Other	1/82 (1.2%)		0/86 (0%)
Respiratory and mediastinal neoplasms malignant and unspecified	0/82 (0%)		1/86 (1.2%)
Nervous system disorders
Headaches	1/82 (1.2%)		0/86 (0%)
Pregnancy, puerperium and perinatal conditions
Pregnancy, labour, delivery and postpartum conditions	1/82 (1.2%)		0/86 (0%)
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue infections and infestations	1/82 (1.2%)		0/86 (0%)
Other (Not Including Serious) Adverse Events
	PEGASYS		Hydroxyurea
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	79/82 (96.3%)		76/86 (88.4%)
Blood and lymphatic system disorders
Anaemias nonhaemolytic and marrow depression	10/82 (12.2%)		10/86 (11.6%)
Coagulopathies and bleeding diatheses (excl thrombocytopenic)	0/82 (0%)		1/86 (1.2%)
Haematopoietic neoplasms (excl leukaemias and lymphomas)	0/82 (0%)		1/86 (1.2%)
Lymphomas non-Hodgkin's T-cell	1/82 (1.2%)		0/86 (0%)
Neutrophils/granulocytes (ANC/AGC)	1/82 (1.2%)		0/86 (0%)
Platelet disorders	7/82 (8.5%)		8/86 (9.3%)
Spleen, lymphatic and reticuloendothelial system disorders	2/82 (2.4%)		0/86 (0%)
White blood cell disorders	15/82 (18.3%)		6/86 (7%)
Cardiac disorders
Cardiac Signs and Symptoms NEC	0/82 (0%)		1/86 (1.2%)
Cardiac arrhythmias	1/82 (1.2%)		3/86 (3.5%)
Cardiac disorder signs and symptoms	11/82 (13.4%)		6/86 (7%)
Chest pain	1/82 (1.2%)		0/86 (0%)
Coronary artery disorders	0/82 (0%)		1/86 (1.2%)
Heart failures	1/82 (1.2%)		1/86 (1.2%)
Myocardial disorders	0/82 (0%)		1/86 (1.2%)
Ear and labyrinth disorders
Aural disorders NEC	7/82 (8.5%)		4/86 (4.7%)
Hearing disorders	0/82 (0%)		1/86 (1.2%)
Inner ear and VIIIth cranial nerve disorders	5/82 (6.1%)		2/86 (2.3%)
Middle ear disorders (excl congenital)	0/82 (0%)		3/86 (3.5%)
Endocrine disorders
Endocrine disorders of gonadal function	1/82 (1.2%)		1/86 (1.2%)
Glucose metabolism disorders (incl diabetes mellitus)	4/82 (4.9%)		3/86 (3.5%)
Thyroid gland disorders	4/82 (4.9%)		2/86 (2.3%)
Eye disorders
Blurred vision	0/82 (0%)		1/86 (1.2%)
Eye disorders NEC	6/82 (7.3%)		3/86 (3.5%)
Ocular haemorrhages and vascular disorders NEC	2/82 (2.4%)		0/86 (0%)
Ocular infections, irritations and inflammations	9/82 (11%)		2/86 (2.3%)
Ocular sensory symptoms NEC	0/82 (0%)		1/86 (1.2%)
Ocular surface disease	1/82 (1.2%)		0/86 (0%)
Retina, choroid, and vitreous haemorrhages and vascular disorders	0/82 (0%)		1/86 (1.2%)
Vision disorders	8/82 (9.8%)		1/86 (1.2%)
Vision disorders	8/82 (9.8%)		3/86 (3.5%)
blurred vision	1/82 (1.2%)		0/86 (0%)
Gastrointestinal disorders
Abdominal Distenstion	0/82 (0%)		1/86 (1.2%)
Abdominal hernias and other abdominal wall conditions	0/82 (0%)		1/86 (1.2%)
Abdominal Pain	0/82 (0%)		1/86 (1.2%)
Benign neoplasms gastrointestinal	0/82 (0%)		1/86 (1.2%)
Constipation	0/82 (0%)		1/86 (1.2%)
Dental and gingival conditions	4/82 (4.9%)		5/86 (5.8%)
Diarrhea	1/82 (1.2%)		0/86 (0%)
Diarrhoea (excl infective)	0/82 (0%)		1/86 (1.2%)
Diverticular disorders	1/82 (1.2%)		1/86 (1.2%)
Exocrine pancreas conditions	1/82 (1.2%)		0/86 (0%)
Gastrointestinal conditions NEC	1/82 (1.2%)		0/86 (0%)
Gastrointestinal infections	0/82 (0%)		3/86 (3.5%)
Gastrointestinal inflammatory conditions	1/82 (1.2%)		1/86 (1.2%)
Gastrointestinal motility and defaecation conditions	16/82 (19.5%)		20/86 (23.3%)
Gastrointestinal signs and symptoms	24/82 (29.3%)		18/86 (20.9%)
Gastrointestinal stenosis and obstruction	1/82 (1.2%)		0/86 (0%)
Gastrointestinal vascular conditions	0/82 (0%)		1/86 (1.2%)
Gingival bleeding	0/82 (0%)		1/86 (1.2%)
Mucositis Oral	0/82 (0%)		2/86 (2.3%)
Nausea	0/82 (0%)		2/86 (2.3%)
nausea	1/82 (1.2%)		0/86 (0%)
Oral soft tissue conditions	3/82 (3.7%)		12/86 (14%)
Salivary gland conditions	5/82 (6.1%)		2/86 (2.3%)
Tongue conditions	3/82 (3.7%)		1/86 (1.2%)
Vomiting	0/82 (0%)		1/86 (1.2%)
General disorders
Administration site reactions	15/82 (18.3%)		0/86 (0%)
Body temperature conditions	4/82 (4.9%)		5/86 (5.8%)
Fatigue	3/82 (3.7%)		1/86 (1.2%)
Fatigue (asthenia, lethargy, malaise)	1/82 (1.2%)		0/86 (0%)
Fatigue or Tiredness	0/82 (0%)		1/86 (1.2%)
Fatigue or Tiredness	0/82 (0%)		2/86 (2.3%)
Flu-like symptoms	0/82 (0%)		1/86 (1.2%)
General malaise	1/82 (1.2%)		0/86 (0%)
General system disorders NEC	50/82 (61%)		42/86 (48.8%)
Non-cardiac chest pain	1/82 (1.2%)		1/86 (1.2%)
fatigue	1/82 (1.2%)		0/86 (0%)
flu like symptoms	1/82 (1.2%)		0/86 (0%)
Hepatobiliary disorders
Gallbladder disorders	1/82 (1.2%)		0/86 (0%)
Hepatic and hepatobiliary disorders	1/82 (1.2%)		1/86 (1.2%)
Hepatobiliary Disorders - Other	0/82 (0%)		1/86 (1.2%)
Immune system disorders
Allergic conditions	1/82 (1.2%)		2/86 (2.3%)
Infections and infestations
Bacterial infectious disorders	7/82 (8.5%)		4/86 (4.7%)
Fungal infectious disorders	1/82 (1.2%)		0/86 (0%)
Infections - Pathogen Unspecified	0/82 (0%)		1/86 (1.2%)
Infections - pathogen class unspecified	0/82 (0%)		1/86 (1.2%)
Infections - pathogen unspecified	12/82 (14.6%)		7/86 (8.1%)
Upper respiratory infection	0/82 (0%)		1/86 (1.2%)
Upper respiratory tract infections - pathogen class unspecified	1/82 (1.2%)		0/86 (0%)
Viral infectious disorders	3/82 (3.7%)		2/86 (2.3%)
Injury, poisoning and procedural complications
Administration site reactions	1/82 (1.2%)		0/86 (0%)
Bone and joint injuries	6/82 (7.3%)		0/86 (0%)
Bruising	0/82 (0%)		1/86 (1.2%)
Injuries NEC	3/82 (3.7%)		4/86 (4.7%)
Procedural related injuries and complications NEC	1/82 (1.2%)		0/86 (0%)
muscle, tendon, and ligament injuries	0/82 (0%)		1/86 (1.2%)
Investigations
Alanine aminotransferace increased	1/82 (1.2%)		0/86 (0%)
Blood Bilirubin Increased	0/82 (0%)		1/86 (1.2%)
Cardiac and vascular investigations (excl enzyme tests)	0/82 (0%)		3/86 (3.5%)
Elevated ALT	1/82 (1.2%)		0/86 (0%)
Enzyme investigations NEC	2/82 (2.4%)		0/86 (0%)
Haematology investigations (incl blood groups)	11/82 (13.4%)		12/86 (14%)
Hepatobiliary investigations	12/82 (14.6%)		5/86 (5.8%)
Investigations, imaging and histopathology procedures NEC	1/82 (1.2%)		0/86 (0%)
Lipid analyses	3/82 (3.7%)		1/86 (1.2%)
Lymphocyte count decreased	0/82 (0%)		1/86 (1.2%)
Metabolic, nutritional and blood gas investigations	2/82 (2.4%)		3/86 (3.5%)
Neutrophil Count Decreased	0/82 (0%)		1/86 (1.2%)
Physical examination topics	1/82 (1.2%)		1/86 (1.2%)
Renal and urinary tract investigations and urinalyses	3/82 (3.7%)		2/86 (2.3%)
Skin investigations	0/82 (0%)		1/86 (1.2%)
Urinary Tract Infection	0/82 (0%)		1/86 (1.2%)
Water, electrolyte and mineral investigations	2/82 (2.4%)		0/86 (0%)
Metabolism and nutrition disorders
Appetite and general nutrition disorders	7/82 (8.5%)		4/86 (4.7%)
Bone, calcium, magnesium and phosphorus metabolism disorders	1/82 (1.2%)		0/86 (0%)
Electrolyte and fluid balance conditions	4/82 (4.9%)		4/86 (4.7%)
Glucose metabolism disorders (incl diabetes mellitus)	4/82 (4.9%)		2/86 (2.3%)
Hyperuricemia	1/82 (1.2%)		0/86 (0%)
Lipid metabolism disorders	4/82 (4.9%)		2/86 (2.3%)
Metabolic/laboratory, other	1/82 (1.2%)		0/86 (0%)
Protein and amino acid metabolism disorders NEC	1/82 (1.2%)		0/86 (0%)
Purine and pyrimidine metabolism disorders	4/82 (4.9%)		3/86 (3.5%)
Vitamin related disorders	0/82 (0%)		2/86 (2.3%)
Musculoskeletal and connective tissue disorders
Back pain	1/82 (1.2%)		0/86 (0%)
Bone disorders (excl congenital and fractures)	3/82 (3.7%)		4/86 (4.7%)
Bone pain	0/82 (0%)		1/86 (1.2%)
Joint Disorders	16/82 (19.5%)		9/86 (10.5%)
Muscle disorders	9/82 (11%)		6/86 (7%)
Muscle spasms	0/82 (0%)		1/86 (1.2%)
Musculoskeletal and connective tissue deformities (incl intervertebral disc disorders)	0/82 (0%)		2/86 (2.3%)
Musculoskeletal and connective tissue disorders NEC	17/82 (20.7%)		17/86 (19.8%)
Musculoskeletal and connective tissue neoplasms	1/82 (1.2%)		0/86 (0%)
Neck pain	0/82 (0%)		1/86 (1.2%)
Pain	1/82 (1.2%)		1/86 (1.2%)
Spinal osteoarthritis	0/82 (0%)		1/86 (1.2%)
Synovial and bursal disorders	2/82 (2.4%)		2/86 (2.3%)
Tendon, ligament and cartilage disorders	2/82 (2.4%)		0/86 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm of colon	1/82 (1.2%)		0/86 (0%)
Renal and urinary tract neoplasms benign	0/82 (0%)		1/86 (1.2%)
Reproductive neoplasms female benign	0/82 (0%)		1/86 (1.2%)
Skin neoplasms malignant and unspecified	0/82 (0%)		1/86 (1.2%)
Nervous system disorders
Central nervous system vascular disorders	1/82 (1.2%)		0/86 (0%)
Cranial nerve disorders (excl neoplasms)	1/82 (1.2%)		1/86 (1.2%)
Dizziness	0/82 (0%)		2/86 (2.3%)
Dysgeusia	1/82 (1.2%)		1/86 (1.2%)
Dysgeusia	1/82 (1.2%)		1/86 (1.2%)
Headache	16/82 (19.5%)		11/86 (12.8%)
Mental impairment disorders	1/82 (1.2%)		2/86 (2.3%)
Migraine	1/82 (1.2%)		0/86 (0%)
Movement disorders (incl parkinsonism)	0/82 (0%)		1/86 (1.2%)
Nervous system disorders, unspecified	0/82 (0%)		1/86 (1.2%)
Neurological disorders NEC	17/82 (20.7%)		15/86 (17.4%)
Neurological signs and symptoms NEC	1/82 (1.2%)		0/86 (0%)
Peripheral neuropathies	5/82 (6.1%)		2/86 (2.3%)
Sensory Abnormalities NEC	1/82 (1.2%)		0/86 (0%)
Sleep disturbances (incl subtypes)	6/82 (7.3%)		4/86 (4.7%)
headache	1/82 (1.2%)		0/86 (0%)
Psychiatric disorders
Anxiety	1/82 (1.2%)		0/86 (0%)
Anxeity disorders and symptoms	4/82 (4.9%)		1/86 (1.2%)
Cognitive and attention disorders and disturbances	2/82 (2.4%)		1/86 (1.2%)
Depressed mood disorders and disturbances	11/82 (13.4%)		1/86 (1.2%)
Depression	1/82 (1.2%)		2/86 (2.3%)
Insomnia	0/82 (0%)		1/86 (1.2%)
Mood disorders and disturbances NEC	3/82 (3.7%)		0/86 (0%)
Sexual dysfunctions, disturbances and gender identity disorders	2/82 (2.4%)		1/86 (1.2%)
Sleep disorders and disturbances	0/82 (0%)		1/86 (1.2%)
Renal and urinary disorders
Bladder and bladder neck disorders (excl calculi)	0/82 (0%)		1/86 (1.2%)
Genitourinary tract disorders NEC	1/82 (1.2%)		1/86 (1.2%)
Renal disorders (excl nephropathies)	0/82 (0%)		1/86 (1.2%)
Urinary Incontinence	0/82 (0%)		1/86 (1.2%)
Urinary tract signs and symptoms	3/82 (3.7%)		3/86 (3.5%)
Urolithiases	1/82 (1.2%)		0/86 (0%)
kidney stone	0/82 (0%)		1/86 (1.2%)
Reproductive system and breast disorders
Male reproductive tract infections and inflammations	2/82 (2.4%)		0/86 (0%)
Menstrual cycle and uterine bleeding disorders	0/82 (0%)		1/86 (1.2%)
Penile and scrotal disorders (excl infections and inflammations)	0/82 (0%)		1/86 (1.2%)
Prostatic disorders (excl infections and inflammations)	1/82 (1.2%)		1/86 (1.2%)
Sexual function and fertility disorders	1/82 (1.2%)		1/86 (1.2%)
Respiratory, thoracic and mediastinal disorders
Cough	0/82 (0%)		1/86 (1.2%)
Dyspnea	0/82 (0%)		1/86 (1.2%)
Respiratory disorders NEC	20/82 (24.4%)		12/86 (14%)
Respiratory tract infections	4/82 (4.9%)		10/86 (11.6%)
Upper respiratory tract disorders (excl infections)	5/82 (6.1%)		5/86 (5.8%)
Skin and subcutaneous tissue disorders
Cutaneous neoplasms benign	1/82 (1.2%)		0/86 (0%)
Dermatitis and eczema	1/82 (1.2%)		0/86 (0%)
Dermatology/skin, other	1/82 (1.2%)		0/86 (0%)
Dry skin	0/82 (0%)		1/86 (1.2%)
Epidermal and Dermal Conditions	0/82 (0%)		1/86 (1.2%)
Epidermal and Dermal Conditions	24/82 (29.3%)		19/86 (22.1%)
Hair loss/alopecia (scalp or body)	0/82 (0%)		1/86 (1.2%)
Hyperhidrosis	0/82 (0%)		1/86 (1.2%)
Injection site reaction/extravasation changes	1/82 (1.2%)		0/86 (0%)
Skin disorders, Other	1/82 (1.2%)		0/86 (0%)
Pigmentation disorders	0/82 (0%)		3/86 (3.5%)
Rash maculo-papular	1/82 (1.2%)		0/86 (0%)
Skin and subcutaneous tissue disorders - Other	0/82 (0%)		1/86 (1.2%)
Skin and subcutaneous tissue disorders NEC	0/82 (0%)		1/86 (1.2%)
Skin and subcutaneous tissue infections and infestations	0/82 (0%)		2/86 (2.3%)
Skin appendage conditions	8/82 (9.8%)		7/86 (8.1%)
Skin vascular abnormalities	2/82 (2.4%)		2/86 (2.3%)
rashes, eruptions, and exanthems NEC	0/82 (0%)		1/86 (1.2%)
skin and subcutaneous conditions NEC	0/82 (0%)		1/86 (1.2%)
skin appendage conditions	0/82 (0%)		1/86 (1.2%)
skin appendage disorders	0/82 (0%)		1/86 (1.2%)
Vascular disorders
Arteriosclerosis, stenosis, vascular insufficiency and necrosis	1/82 (1.2%)		2/86 (2.3%)
Decreased and nonspecific blood pressure disorders and shock	2/82 (2.4%)		3/86 (3.5%)
Hypertension	1/82 (1.2%)		0/86 (0%)
Vascular disorders NEC	3/82 (3.7%)		0/86 (0%)
Vascular haemorrhagic disorders	1/82 (1.2%)		3/86 (3.5%)
Vascular hypertensive disorders	7/82 (8.5%)		3/86 (3.5%)
Venous varices	0/82 (0%)		1/86 (1.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.