A Double-Blind, Double-Dummy Phase 2 Randomized Study to Evaluate the Efficacy and Safety of Ruxolitinib Versus Anagrelide in Subjects With Essential Thrombocythemia Who Are Resistant to or Intolerant of Hydroxyurea (RESET-272)
Phase: PHASE2
Conditions: MPN (Myeloproliferative Neoplasms)
Sponsor: Incyte Corporation

Official Title: 
A Double-Blind, Double-Dummy Phase 2 Randomized Study to Evaluate the 
Efficacy and Safety of Ruxolitinib Versus Anagrelide in Subjects With 
Essential Thrombocythemia Who Are Resistant to or Intolerant of 
Hydroxyurea  
NCT Number: 
NCT03123588 
Document Date: 
Clinical Study Protocol Version 2: 02 August 2019 

Incyte Corporation 
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Protocol INCB 18424-272 Am 2 
Version 2 
02 AUG 2019 
 
Clinical Study Protocol 
 
INCB 18424-272 
 
A Double-Blind, Double-Dummy Phase 2 Randomized Study to 
Evaluate the Efficacy and Safety of Ruxolitinib Versus Anagrelide 
in Subjects with Essential Thrombocythemia Who Are Resistant to 
or Intolerant of Hydroxyurea 
 
 
Product: 
INCB018424 
IND Number: 
77,456 
Phase of Study: 
2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol (Version 0): 
22 JUL 2016 
Amendment (Version) 1: 
21 DEC 2016 
Amendment (Version) 2: 
02 AUG 2019 
 
 
 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, Good Clinical Practices as defined in Title 21 of the 
US Code of Federal Regulations Parts 11, 50, 54, 56, and 312, as well as ICH GCP consolidated guidelines (E6) and 
applicable regulatory requirements. 
 
The information in this document is confidential.  No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without the prior 
written consent of Incyte Corporation. 
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INVESTIGATOR'S AGREEMENT 
I have read the INCB 18424-272 Protocol Amendment 2 (Version 2 dated 02 AUG 2019) and 
agree to conduct the study as outlined.  I agree to maintain the confidentiality of all information 
received or developed in connection with this Protocol. 
 
 
 
 
 
(Printed Name of Investigator) 
 
 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
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SYNOPSIS 
Name of Investigational Product:  INCB018424 (Ruxolitinib), JAKAFI® 
Throughout this Protocol, ruxolitinib or ruxolitinib placebo will be used to designate the drug substance 
(ruxolitinib phosphate) and drug product (ruxolitinib phosphate tablets) and matching placebo. 
Title of Study:  A Double-Blind, Double-Dummy Phase 2 Randomized Study to Evaluate the Efficacy 
and Safety of Ruxolitinib Versus Anagrelide in Subjects With Essential Thrombocythemia Who Are 
Resistant to or Intolerant of Hydroxyurea 
Protocol Number:  INCB 18424-272 
Study Phase:  2 
Indication:  Essential thrombocythemia that is resistant to or intolerant of hydroxyurea. 
Primary Objective: 
• To compare efficacy of ruxolitinib versus anagrelide as measured by the proportion of subjects 
demonstrating platelet and white blood cell (WBC) control.  
Secondary Objectives:  
• To evaluate the safety and tolerability of ruxolitinib compared with anagrelide in subjects with essential 
thrombocythemia (ET). 
• To compare complete remission (CR) and partial remission (PR) rates of ruxolitinib and anagrelide in 
subjects with ET. 
• To evaluate the duration of response. 
• To evaluate the proportion of subjects demonstrating platelet control. 
• To evaluate the proportion of subjects demonstrating WBC control. 
Primary Endpoint:  
• Proportion of subjects who achieve a simultaneous reduction of platelet counts to < 600 × 109/L with a 
reduction of WBC counts to < 10 × 109/L  for at least 80% of biweekly measurements for a consecutive 
12-week period between Weeks 32 and 52. 
Secondary Endpoints:   
• Safety and tolerability of ruxolitinib measured by adverse events (AEs) and laboratory values. 
• Proportion of subjects who discontinue study treatment because of AEs.  
• Time to treatment discontinuation. 
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• Proportion of subjects who achieve CR or PR at Week 32 based on European LeukemiaNet (ELN) 2013 
response criteria. 
− 
Analyses completed for subjects achieving CR plus PR. 
− 
Analyses completed for subjects achieving CR. 
− 
Analyses completed for subjects achieving PR. 
• Duration of response as measured from the onset of response to the loss of response for responders. 
Response is defined the same as in the primary endpoint.  
• Proportion of subjects who achieve reduction of platelet counts to < 600 × 109/L for at least 80% of 
biweekly measurements for a consecutive 12-week period between Weeks 32 and 52. 
• Proportion of subjects who achieve a reduction of WBC counts to < 10 × 109/L for at least 80% of 
biweekly measurements for a consecutive 12-week period between Weeks 32 and 52. 
Overall Study Design:  
This is a Phase 2, randomized, double-blind, double-dummy study in subjects with ET who are resistant 
to or intolerant of hydroxyurea (HU; according to modified ELN criteria) with a screening platelet count 
≥ 650 × 109/L and WBC count  ≥ 11.0 × 109/L.  Subjects will be randomized in a 1:1 ratio, stratified by 
Janus kinase (JAK) V617 mutation status (positive vs negative), platelet count at screening 
(≥ 1000 × 109/L or < 1000 × 109/L), and prior anagrelide use (yes vs no) to the following 2 treatment 
groups: 
• Group A:  ruxolitinib at a dose of 10 mg twice daily (BID) orally and anagrelide-placebo. 
• Group B:  anagrelide at a dose of 1 mg BID orally and ruxolitinib-placebo. 
Subjects will receive blinded study treatment for 52 weeks. 
Crossover and open-label extension:  After individual subjects reach the Week 52 visit (and data have 
been entered and cleaned), cross over to an open-label extension may occur.  Subjects originally 
randomized to ruxolitinib who are receiving benefit from therapy will continue receiving open-label 
ruxolitinib until the study is concluded.  Subjects originally randomized to anagrelide will be evaluated 
for eligibility to cross over to the open-label treatment phase according to investigator's decision, after 
consultation with the sponsor. 
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Study Population:  
Individuals, aged 18 years or older, who have been diagnosed with ET who are resistant to or intolerant of 
HU, with a platelet count ≥ 650 × 109/L and WBC count ≥ 11.0 × 109/L. 
Key Inclusion Criteria: 
• Men and women, aged 18 or older. 
• Subjects diagnosed with ET according to revised WHO 2016 criteria. 
• Subjects who are resistant to or intolerant of HU, that is, fulfilling at least 1 of the following criteria: 
− Platelet count > 600 × 109/L after 3 months of at least 2 g/day of HU (2.5 g/day in subjects with a 
body weight over 80 kg) OR at the subject's maximally tolerated dose if that dose is < 2 g/day. 
− Platelet count > 400 × 109/L and WBC count < 2.5 × 109/L or hemoglobin < 10 g/dl at any dose 
of HU. 
− Presence of leg ulcers or other unacceptable muco-cutaneous manifestations at any dose of HU. 
− HU-related fever. 
• Platelet count ≥ 650 × 109/L at screening. 
• WBC ≥ 11.0 × 109/L at screening. 
• ECOG performance status 0 to 2. 
• Known status of JAKV617F mutation. 
• Willingness to avoid pregnancy or fathering children based on the following criteria: 
− Woman of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral 
oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age). 
− Woman of childbearing potential who has a negative serum pregnancy test at screening and negative 
urinary test before the first dose on Day 1 and who agrees to take appropriate precautions to avoid 
pregnancy (with at least 99% certainty) from screening through safety follow-up.  Permitted methods 
that are at least 99% effective in preventing pregnancy should be communicated to the subject and 
their understanding confirmed. 
− Man who agrees to take appropriate precautions to avoid fathering children (with at least 
99% certainty) from screening through safety follow-up.  Permitted methods that are at least 
99% effective in preventing pregnancy should be communicated to the subject and their 
understanding confirmed. 
Key Exclusion Criteria:   
• Subjects who have previously been treated with JAK inhibitors. 
• Subjects being treated concurrently with anagrelide or HU. 
− Prior anagrelide use is allowed provided the reason for discontinuation is not AE-related and 
anagrelide is stopped at least 28 days before the start of study medications (ie, Day 1). 
− Treatment with HU can be stopped at any time once one of the inclusion criteria for HU 
refractoriness or resistance have been met, and up to the day before the first dose of study treatment 
(ie, Day 1). 
• Subjects with inadequate liver function at screening and Day 1 (before drug administration) as 
demonstrated by:  
− Total bilirubin > 1.5 × upper limit of normal (ULN) 
− Aspartate aminotransferase or alanine aminotransferase > 1.5 × ULN  
− Hepatocellular disease (eg, cirrhosis) 
• Subjects with inadequate renal function at screening as demonstrated by creatinine clearance 
< 40 mL/min calculated by Cockcroft-Gault equation. 
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• Subjects with clinically significant cardiovascular disease including uncontrolled cardiac disease, 
including unstable angina; acute myocardial infarction within 6 months from Day 1 of study drug 
administration; New York Heart Association Class III or IV congestive heart failure; and arrhythmia 
requiring therapy unless approved by medical monitor/sponsor (New York Heart Association Class III 
or IV). 
• History or presence of an abnormal electrocardiogram that, in the investigator's opinion, is clinically 
meaningful. 
• Subjects with impairment of gastrointestinal (GI) function or active GI disease that may significantly 
alter absorption of ruxolitinib or anagrelide (eg, active ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome, and small bowel obstruction). 
• Inability to swallow and retain oral medication. 
• Subjects with clinically significant bacterial, fungal, parasitic, or viral infection that requires therapy:  
− Subjects with acute bacterial infections requiring antibiotic therapy should delay 
screening/enrollment until the course of antibiotic therapy has been completed. 
− Subjects on chronic antibiotics for prophylaxis are allowed. 
• Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or risk of reactivation:  HBV 
DNA and HCV RNA must be undetectable.  Subjects cannot be positive for hepatitis B surface antigen 
or anti–hepatitis B core antibodies.  Subjects who have positive anti-HBs as the only evidence of prior 
exposure may participate in the study provided that there is both 1) no known history of HBV infection 
and 2) verified receipt of hepatitis B vaccine. 
• Known human immunodeficiency virus infection. 
• Subjects with diagnosed primary immunodeficiency syndromes, such as X-linked agammaglobulinemia 
and common variable immune deficiency.  
• Subjects with peripheral blood blast count of > 0% at screening.  
• Subjects with an active malignancy over the previous 2 years except treated cervical intraepithelial 
neoplasia, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or completely resected 
papillary thyroid and follicular thyroid cancers. 
• Pregnant or breastfeeding women.  
• Use of any potent cytochrome P450 3A4 inhibitors or inducers and CYP1A2 inhibitors within 14 days 
or 5 half-lives (whichever is longer) before the first dose of ruxolitinib or anagrelide or their anticipated 
use during the study (does not apply to topical ketoconazole). 
• Use of concomitant treatment of fluconazole at a dose > 200 mg. 
• Subjects being treated concurrently with any prohibited medications.  
• Subjects being treated concurrently with any medications that may prolong QTc interval of the 
electrocardiogram. 
• Subjects being treated concurrently with any investigational agent or who have had previously 
participated in an investigational study within 30 days before to the first dose of study drug or within 
5 half-lives of the previous investigational product, whichever is longer. 
• Subjects who are unable to comprehend or are unwilling to sign an informed consent form.  
• Subjects who are unwilling or incapable of complying with the requirements of the study. 
• Subjects with active alcohol or drug addiction that would interfere with their ability to comply with the 
study requirements.  
• Any condition that would, in the investigator's judgment, interfere with full participation in the study, 
including administration of study drug and attending required study visits; pose a significant risk to the 
subject; or interfere with interpretation of study data. 
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INCB018424/Study Drug, Dosage, and Mode of Administration:  
Ruxolitinib or ruxolitinib-placebo will be administered orally BID at a starting dose of 10 mg BID 
without regard to food. 
Reference Therapy, Dosage, and Mode of Administration:  
Anagrelide or anagrelide-placebo will be administered orally BID at a starting dose of 1 mg BID without 
regard to food.  Use of anagrelide will be consistent with approved prescribing information. 
Dose Titration Criteria (for Both Study Drug and Reference Therapy): 
Doses should be taken morning and evening, approximately 12 hours apart and without regards to food. 
Dose escalations up to the maximum allowed dose for ruxolitinib (25 mg BID) and anagrelide (2.5 mg 
BID) are permitted.  When modifications are made to the ruxolitinib dose, the dose of anagrelide will be 
modified concurrently.  A dose increase of 5 mg BID up to a maximum dose of 25 mg BID is permitted 
after 2 weeks of treatment for ruxolitinib, and a dose increase of 0.5 mg/day per week up to a maximum 
dose of 2.5 mg BID is permitted for anagrelide. 
Each dose escalation must be at least 1 week apart, and subjects must meet all of the following criteria: 
1. Platelet count ≥ 150 × 109/L. 
2. Hemoglobin ≥ 9 g/dL. 
3. ANC ≥ 1500 × 109/L 
4. One or more of the following:  
a. Platelet count > 600 × 109/L. 
b. WBC count > 10 × 109/L. 
c. Minimal improvement, no change, or worsening of vasomotor symptoms including headache, 
lightheadedness, syncope, atypical chest pain, acral paresthesia, livedo reticularis, 
erythromelalgia, and transient visual disturbances (eg, amaurosis fugax, scintillating 
scotomata, ophthalmic migraine).  
NOTE:  Dose decreases or interruptions for safety are required at any time throughout the study in 
accordance with Protocol requirements. 
A maximum of 8 weeks of dose interruption is permitted in the study; subjects who cannot tolerate the 
study medications must discontinue from the study. 
Study Schedule/Procedures: 
There will be study visits and laboratory-only visits in the study. 
Core Treatment Period 
Subjects will be randomized to receive blinded treatment with ruxolitinib plus anagrelide-placebo or 
anagrelide plus ruxolitinib-placebo on Day 1.  There is a 52-week dose administration period, but efficacy 
assessments will be measured between Weeks 32 and 52. 
Subjects will have regularly scheduled study visits at the clinical site at screening, baseline, Day 1 (before 
first dose intake), Day 8, Day 15, Day 22, Day 28, then Day 7 every 4 weeks from Week 4 through 
Week 32, where blood samples will be collected and assessments conducted. 
An efficacy assessment period will be defined by collection of blood samples (for hematology 
assessments of platelet count and WBC) every 2 weeks between Weeks 32 and 52 (Day 7 of Weeks 32, 
34, 36, 38, 40, 42, 44, 46, 48, 50, and 52).  Subjects will either have a brief laboratory visit at the clinic 
laboratory or at local laboratory (or as described in the laboratory manual). 
Study visits for clinical assessment will be performed every 4 weeks between Weeks 32 and 52. 
Hematology laboratory assessments and clinical assessments will occur on Day 7 of Week 56 and every 
12 weeks thereafter for subjects continuing treatment after Week 52. 
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All subjects will be required to have a bone marrow biopsy.  Bone marrow biopsy will be conducted at 
baseline and again at the Weeks 32 and 52 and/or end-of-treatment visits.  Optional additional biopsies 
will be requested at Week 104 and Week 156. 
 
 
 
 
 
 
 
 
 liver size will be measured at screening, baseline, and every study visit beginning at Week 4.  
The edge of the 
 liver shall be determined by palpation, 
 and liver length measured in 
centimeters using a soft ruler, from the costal margin to the point of greatest splenic protrusion. 
An end-of-treatment visit should be conducted when subjects are discontinued from study treatment, 
followed by a follow-up visit 30 to 37 days after the last dose of study drug. 
All hematology laboratory assessments, serum chemistries, and coagulation parameters will be analyzed 
by local laboratories.  Serology, urinalysis, and lipid panel will be analyzed by a central laboratory. 
Additional hematology assessments will be required if the subject has a dose modification or as clinically 
indicated. 
Options for the Open-Label Treatment Phase 
Subjects originally randomized to ruxolitinib with anagrelide placebo (Group A) who are receiving 
benefit from therapy can 1) continue receiving open-label ruxolitinib until the study is concluded or they 
meet discontinuation criteria, or 2) choose to discontinue therapy.   
Subjects originally randomized to receive anagrelide plus ruxolitinib placebo (Group B) have 3 options:  
1) they may cross over to begin receiving ruxolitinib if they meet eligibility criteria after consultation with 
the sponsor and may then continue until the study is concluded or they meet discontinuation criteria; 
2) they may continue receiving anagrelide until the study is concluded or they meet discontinuation 
criteria; or 3) they can choose to discontinue therapy.  Note that subjects originally randomized to 
Group B may cross over to receive ruxolitinib at any time during the open-label part of the study. 
Subjects who will continue with the same active agent to which they were randomized will have a study 
visit at Week 56, at which time study drugs will switch over to open-label supplies (ruxolitinib or 
anagrelide) and then study visits every 12 weeks (Week 68, 80, etc).  Subjects who were originally 
randomized to anagrelide (Group B) and who cross over to ruxolitinib will begin receiving ruxolitinib at 
the Week 56 visit.  These subjects will have study visits at Weeks 1, 2, 3, 4, and every 4 weeks up to 
52 weeks, then every 12 weeks thereafter.  Subjects who initially remain on anagrelide after unblinding 
but choose to cross over to receive ruxolitinib at a later time will have study visits at Weeks 1, 2, 3, 4, and 
every 4 weeks up to 52 weeks, then every 12 weeks thereafter. 
 
 
 
 
 
 
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Estimated Duration of Participation:  
Individual subject participation is expected to average 24 to 36 months, which includes the following: 
Screening period (Day -35 to Day -8):  Up to 28 days.  
Baseline (pretreatment) period (Day -7 to Day -1):  7 days before the first dose of treatment (required 
for all eligible subjects to complete the daily symptom diary for 7 days before the first dose of study 
medication. 
Treatment period (Day 1 through Week 52):  Begins with first dose of either ruxolitinib plus 
anagrelide-placebo or anagrelide plus ruxolitinib-placebo (Day 1).  The efficacy assessment period will be 
defined by collection of blood samples every 2 weeks between Weeks 32 and 52.  
Crossover and extension period:  Treatment with open-label ruxolitinib will continue until the study is 
concluded for subjects originally randomized to ruxolitinib who are receiving benefit from treatment or 
subjects originally randomized to anagrelide who cross over after unblinding treatment. 
Follow-up period:  30 to 37 days after last dose of blinded study treatment or open-label study treatment. 
Estimated Number of Subjects:  Approximately 120 subjects will be randomized in a 1:1 manner to 1 of 
2 treatment groups (approximately 60 subjects per group).  Approximately 85 clinical sites will be used in 
the United States. 
Principal Coordinating Investigator:  
, MD, PhD, MD 
 
 
Statistical Methods:   
When the last subject reaches Week 52 or discontinues, the database will be cleaned, locked and the final 
analyses will be conducted. 
Selection of Sample Size 
Based on a literature search and the Incyte Phase 2 study (INCB 18424-256) and a difference in response 
rate of 25% (30% vs 5%), a total of approximately 120 subjects (60 subjects per group) would provide 
approximately 90% power to detect a treatment difference of 25% in the primary endpoint at 2-sided 
chi-square test with an alpha level of 0.05. 
Primary Efficacy Analysis 
The primary efficacy endpoint is the proportion of subjects who achieve a simultaneous reduction of 
platelet counts to < 600 × 109/L with a reduction of WBCs to < 10 ×109/L for at least 80% of biweekly 
assessments for 12 consecutive weeks between Weeks 32 and Week 52.  The proportion of subjects who 
meet the response criteria will be estimated with a 95% confidence interval.  The Cochran-Mantel-
Haenszel test stratified by JAK2V617F mutation status, screening platelet count, and prior anagrelide use 
will be applied to compare the 2 treatment groups.  The test will be 2-sided at 5% significant level.  The 
overall stratum-adjusted odds ratio, along with its 95% confidence interval, will be presented. 
In the analysis of the primary efficacy endpoint, subjects who discontinue study treatment without 
meeting the response criteria will be considered as nonresponders.  Subjects who meet the primary 
endpoint criteria of a response but discontinue treatment before Week 52 will be considered as 
responders. 
Secondary Efficacy Analyses 
• Proportion of subjects who achieve CR or PR at Week 32, as defined by ELN 2013 response criteria.  
The analysis will be conducted in the same fashion as the primary analysis. 
• Duration of responses for subjects who achieve primary response as defined in the primary efficacy 
endpoint will be estimated using the Kaplan-Meier method.  The start of a response will be the first visit 
where both platelet control (defined as a reduction to < 600 × 109/L) and WBC control (defined as a 
reduction to < 10 × 109/L) are achieved.  Loss of response will be defined as 2 consecutive visits where 
either platelet count is ≥ 600 × 109/L or WBC is ≥ 10 × 109/L.  The earlier of the 2 consecutive visits 
will be used as the end of response time.  
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• Proportion of subjects who achieve a reduction of platelet count to < 600 × 109/L for at least 80% of 
biweekly assessments for a consecutive 12-week period between Weeks 32 and 52 will be estimated 
along with their 95% confidence interval. 
• Proportion of subjects who achieve a reduction of WBC counts to < 10 × 109/L for at least 80% of 
biweekly measurements for a consecutive 12-week period between Weeks 32 and 52 will be 
summarized along with their 95% confidence interval. 
 
  
All applicable efficacy parameters after crossover will be tabulated. 
Safety Analyses 
All clinical safety data (vital signs, laboratory tests and adverse events) will be tabulated and listed. 
The safety data collected after crossover will be summarized separately. 
Level of Significance and Testing Procedures 
The family wise alpha level will be controlled at 0.05 and will be controlled using a fixed sequential 
testing procedure.  The proportion of subjects who achieve CR or PR at Week 32, as defined by ELN 
2013 response criteria, will only be formally tested if the hypothesis for the primary endpoint is rejected. 
The duration of response for responders in both treatments will be estimated with 95% confidence 
intervals without comparison.  No alpha adjustment will be applied for the remaining endpoints. 
Data Monitoring Committee: 
An independent Data Monitoring Committee will be formed that consists of qualified individuals who are 
not involved in the conduct of the study.  The roles, responsibilities, and composition of the committee 
will be established in a charter. 
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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................18 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
Background and Overview on Essential Thrombocythemia ......................................21 
1.2. 
Product Information and Overview of Ruxolitinib .....................................................23 
1.2.1. 
Pharmacology .............................................................................................................23 
1.2.2. 
Nonclinical Drug Metabolism and Pharmacokinetics ................................................24 
1.2.3. 
Clinical Safety Summary ............................................................................................25 
1.2.3.1. 
Healthy Volunteers Study ...........................................................................................25 
1.2.3.2. 
Clinical Safety Data ....................................................................................................25 
1.2.3.3. 
Clinical Efficacy Data .................................................................................................27 
1.2.3.4. 
Proposed Indications ...................................................................................................28 
1.3. 
Product Information and Overview of Anagrelide .....................................................29 
1.3.1. 
Anagrelide ...................................................................................................................29 
1.3.1.1. 
Product Name and Application Number .....................................................................29 
1.4. 
Study Rationale ...........................................................................................................29 
1.4.1. 
Essential Thrombocythemia Symptoms and Treatment .............................................30 
1.4.2. 
Rationale for Study Design and Treatment and Dose Selection .................................30 
1.4.2.1. 
Double-Dummy Design ..............................................................................................31 
1.4.2.2. 
Prior Anagrelide Use ..................................................................................................31 
1.5. 
Potential Risks and Benefits of the Treatment Regimen ............................................31 
1.5.1. 
Risks Related to Ruxolitinib .......................................................................................31 
1.5.2. 
Risks Related to Anagrelide .......................................................................................32 
1.5.3. 
Potential Benefits of Ruxolitinib ................................................................................32 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................33 
2.1. 
Study Objectives .........................................................................................................33 
2.1.1. 
Primary Objective .......................................................................................................33 
2.1.2. 
Secondary Objectives .................................................................................................33 
 
33 
2.2. 
Study Endpoints ..........................................................................................................34 
2.2.1. 
Primary Endpoint ........................................................................................................34 
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2.2.2. 
Secondary Endpoints ..................................................................................................34 
 
34 
3. 
SUBJECT ELIGIBILITY ...........................................................................................35 
3.1. 
Subject Inclusion Criteria ...........................................................................................35 
3.2. 
Subject Exclusion Criteria ..........................................................................................36 
3.3. 
Subjects Who Fail to Meet Screening Criteria ...........................................................38 
4. 
INVESTIGATIONAL PLAN .....................................................................................39 
4.1. 
Overall Study Design ..................................................................................................39 
4.1.1. 
Options for the Open-Label Treatment Phase ............................................................40 
4.2. 
Measures Taken to Avoid Bias ...................................................................................40 
4.3. 
Number of Subjects ....................................................................................................40 
4.4. 
Duration of Treatment and Subject Participation .......................................................41 
4.5. 
Overall Study Duration ...............................................................................................41 
4.6. 
Study Termination ......................................................................................................41 
5. 
TREATMENT ............................................................................................................42 
5.1. 
Treatment Assignment ................................................................................................42 
5.1.1. 
Subject Numbering and Treatment Assignment .........................................................42 
5.1.2. 
Randomization and Blinding ......................................................................................42 
5.1.2.1. 
Blinding and Unblinding ............................................................................................43 
5.2. 
Study Drug ..................................................................................................................44 
5.2.1. 
Ruxolitinib ..................................................................................................................44 
5.2.1.1. 
Description and Administration ..................................................................................44 
5.2.1.2. 
Supply, Packaging, and Labeling ...............................................................................44 
5.2.1.3. 
Storage ........................................................................................................................44 
5.2.2. 
Anagrelide  (Non-Incyte Product) ..............................................................................44 
5.2.2.1. 
Description and Administration ..................................................................................44 
5.2.2.2. 
Supply, Packaging, and Labeling ...............................................................................45 
5.2.2.3. 
Storage ........................................................................................................................45 
5.2.3. 
Instruction to Subjects for Handling Study Drug Ruxolitinib and Anagrelide  
and Their Matching Placebo .......................................................................................45 
5.3. 
Treatment Compliance ................................................................................................45 
5.4. 
Treatment Modifications:  Increases, Interruptions, and Adjustments .......................46 
5.4.1. 
Dose Increases for Inadequate Efficacy .....................................................................46 
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5.4.2. 
Dose Interruptions or Decreases for Toxicity .............................................................47 
5.4.2.1. 
Hematologic Toxicities ...............................................................................................47 
5.4.2.2. 
Nonhematologic Toxicities .........................................................................................47 
5.4.2.3. 
Dose Reductions With Concomitant Cytochrome P450 Inhibitors ............................48 
5.4.3. 
Dose Discontinuation of Ruxolitinib or Ruxolitinib Placebo/Anagrelide or 
Anagrelide Placebo .....................................................................................................49 
5.4.3.1. 
Discontinuation of Study Drugs for Hematologic Toxicity .......................................49 
5.4.3.2. 
Discontinuation of Study Drug for Nonhematologic Toxicity ...................................49 
5.4.3.3. 
Dose Reduction Tapering Strategy (Optional) ...........................................................49 
5.4.4. 
Dose Modifications for Subjects Receiving Open-Label Treatment ..........................49 
5.5. 
Withdrawal of Subjects From Study Treatment .........................................................50 
5.5.1. 
Withdrawal Criteria ....................................................................................................50 
5.5.2. 
Withdrawal Procedures ...............................................................................................50 
5.6. 
Concomitant Medications ...........................................................................................51 
5.6.1. 
Permitted Medications ................................................................................................51 
5.6.2. 
Restricted Medications ...............................................................................................52 
5.6.3. 
Prohibited Medications ...............................................................................................52 
6. 
STUDY ASSESSMENTS ..........................................................................................53 
6.1. 
Screening ....................................................................................................................62 
6.2. 
Baseline .......................................................................................................................62 
6.3. 
Blinded Treatment ......................................................................................................62 
6.3.1. 
Transition Period Before Open-Label Period .............................................................63 
6.4. 
Open-Label Treatment ................................................................................................64 
6.4.1. 
Visits After Week 52 ..................................................................................................64 
6.5. 
End of Treatment ........................................................................................................64 
6.6. 
Safety Follow-Up ........................................................................................................64 
6.7. 
Unscheduled Visits .....................................................................................................65 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES ...........................65 
7.1. 
Administration of Informed Consent Form ................................................................65 
7.2. 
Interactive Response Technology Procedure ..............................................................65 
7.3. 
Demography and Medical History ..............................................................................65 
7.4. 
Prior and Concomitant Medications and Procedures ..................................................66 
7.5. 
Safety Assessments .....................................................................................................66 
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7.5.1. 
Review Inclusion and Exclusion Criteria ...................................................................66 
7.5.2. 
Adverse Events ...........................................................................................................66 
7.5.3. 
Physical Examinations ................................................................................................66 
7.5.3.1. 
Comprehensive and Targeted Physical Examinations ................................................66 
7.5.4. 
Vital Signs ..................................................................................................................67 
7.5.5. 
Electrocardiograms .....................................................................................................67 
7.5.6. 
Laboratory Assessments .............................................................................................67 
7.5.6.1. 
Pregnancy Testing ......................................................................................................67 
7.6. 
Efficacy Assessments .................................................................................................68 
7.6.1. 
Measurement of Platelet and White Blood Cell Control Between Weeks 32 
and 52 ..........................................................................................................................68 
7.6.2. 
Overall Response Assessment ....................................................................................68 
 
68 
7.6.4. 
Bone Marrow Biopsy ..................................................................................................68 
7.7. 
Performance and Quality-of-Life Assessments ..........................................................69 
7.7.1. 
Eastern Cooperative Oncology Group Performance Status ........................................69 
 
69 
 
69 
7.7.4. 
MPN-SAF Questionnaire............................................................................................69 
 
69 
 
69 
 
70 
 
70 
 
70 
 
70 
 
70 
 
71 
7.10. 
Other Study Procedures ..............................................................................................71 
7.10.1. 
Administration of Study Treatment ............................................................................71 
7.10.2. 
Dispensing of Study Treatment ..................................................................................71 
7.10.3. 
Assessment of Compliance With Study Drug ............................................................71 
7.10.4. 
Distribution of Subject Reminder Cards .....................................................................71 
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8. 
SAFETY MONITORING AND REPORTING .........................................................72 
8.1. 
Adverse Events ...........................................................................................................72 
8.1.1. 
Definitions ..................................................................................................................72 
8.1.2. 
Reporting ....................................................................................................................72 
8.2. 
Laboratory Test Abnormalities ...................................................................................73 
8.3. 
Serious Adverse Events ..............................................................................................74 
8.3.1. 
Definitions ..................................................................................................................74 
8.3.2. 
Reporting ....................................................................................................................74 
8.4. 
Emergency Unblinding of Treatment Assignment .....................................................75 
8.5. 
Pregnancy ...................................................................................................................76 
8.6. 
Warnings and Precautions ..........................................................................................76 
8.7. 
Data Monitoring Committee .......................................................................................76 
8.8. 
Adverse Events of Special Interest .............................................................................76 
8.9. 
Product Complaints ....................................................................................................77 
9. 
STATISTICS ..............................................................................................................77 
9.1. 
Study Populations .......................................................................................................77 
9.2. 
Selection of Sample Size ............................................................................................77 
9.3. 
Level of Significance ..................................................................................................78 
9.4. 
Statistical Analyses .....................................................................................................78 
9.4.1. 
Efficacy Analyses .......................................................................................................78 
9.4.1.1. 
Primary Efficacy Analyses .........................................................................................78 
9.4.1.2. 
Secondary Efficacy Analyses .....................................................................................78 
 
79 
9.4.2. 
Safety Analyses ..........................................................................................................79 
9.4.2.1. 
Adverse Events ...........................................................................................................80 
9.4.2.2. 
Clinical Laboratory Tests ...........................................................................................80 
9.4.2.3. 
Vital Signs ..................................................................................................................80 
 
81 
 
81 
9.5. 
Analyses for the Data Monitoring Committee ............................................................81 
9.6. 
Interim Analysis ..........................................................................................................81 
10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ..........................................................................................................82 
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10.1. 
Investigator Responsibilities .......................................................................................82 
10.2. 
Accountability, Handling, and Disposal of Study Drug .............................................83 
10.3. 
Data Management .......................................................................................................84 
10.3.1. 
Data Collection ...........................................................................................................84 
10.3.2. 
Data Management .......................................................................................................84 
10.4. 
Study Monitoring ........................................................................................................84 
10.5. 
Protocol Adherence ....................................................................................................85 
10.6. 
Data Privacy and Confidentiality of Study Records ...................................................85 
10.7. 
Financial Disclosure ...................................................................................................86 
10.8. 
Quality Control and Quality Assurance ......................................................................86 
10.8.1. 
Sponsor Audits............................................................................................................86 
10.8.2. 
Inspection by Regulatory Authorities .........................................................................86 
10.9. 
Data Handling and Recordkeeping .............................................................................87 
10.9.1. 
Inspection of Records .................................................................................................87 
10.9.2. 
Retention of Records ..................................................................................................87 
10.9.3. 
Confidentiality ............................................................................................................87 
10.10. 
Publication Policy .......................................................................................................88 
11. 
REFERENCES ...........................................................................................................89 
APPENDIX A. REVISED WHO 2016 CRITERIA FOR ESSENTIAL 
THROMBOCYTHEMIA ...........................................................................................94 
APPENDIX B. DEFINITION OF MODIFIED CLINICAL RESISTANCE OR 
INTOLERANCE TO HYDROXYUREA ..................................................................95 
APPENDIX C. RESPONSE CRITERIA FOR ESSENTIAL THROMBOCYTHEMIA ...........96 
APPENDIX D. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS .......................................................................................97 
 
98 
99 
APPENDIX G. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS .............................................................................100 
APPENDIX H. CYTOCHROME P450 INHIBITORS AND INDUCERS ..............................101 
APPENDIX I. MYELOPROLIFERATIVE NEOPLASMS SYMPTOM 
ASSESSMENT FORM (MPN-SAF) .......................................................................109 
APPENDIX J. DRUGS THAT MAY PROLONG QT INTERVAL ........................................110 
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APPENDIX K. PROTOCOL AMENDMENT SUMMARY OF CHANGES .........................111 
 
LIST OF TABLES 
Table 1: 
Dose Interruptions for Hematologic Toxicities ..........................................................47 
Table 2: 
Dose Levels for Ruxolitinib and Anagrelide and Dose Reduction/Restart 
Guidelines ...................................................................................................................48 
Table 3: 
Schedule of Assessments ............................................................................................54 
Table 4: 
Schedule of Laboratory Assessments .........................................................................56 
Table 5: 
Schedule of Assessments for Subjects From Group B Who Cross Over to 
Open-Label Ruxolitinib ..............................................................................................59 
Table 6: 
Schedule of Laboratory Assessments for Subjects From Group B Who Cross 
Over to Open-Label Ruxolitinib .................................................................................60 
Table 7: 
Laboratory Tests:  Required Analytes ........................................................................61 
 
70 
Table 9: 
Criteria for Clinically Notable Vital Sign Abnormalities ...........................................80 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................39 
 
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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
AMP 
adenosine monophosphate 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BAT 
best available therapy 
BID 
twice daily 
CALR 
calreticulin 
CFR 
Code of Federal Regulations 
 
 
CMH 
Cochran-Mantel-Haenszel 
CML 
chronic myeloid leukemia 
CMML 
chronic myelomonocytic leukemia 
COX-1 
cyclo-oxygenase–1 
CR 
complete remission 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ECOG 
Eastern Cooperative Oncology Group 
ELN 
European LeukemiaNet 
EOT 
end of treatment 
ET 
essential thrombocythemia 
 
 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HBV 
hepatitis B virus 
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Abbreviation 
Definition 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
Hgb 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HU 
hydroxyurea 
IB 
Investigator's Brochure 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IN 
Investigator Notification 
IRB 
institutional review board 
ITT 
intent-to-treat 
IWG-MRT 
International Working Group-Myeloproliferative Neoplasms Research and 
Treatment 
IXRS 
interactive voice/web response system  
JAK 
Janus kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
myelofibrosis 
MPL 
myeloproliferative leukemia 
MPN 
myeloproliferative neoplasm 
MPN-SAF 
Myeloproliferative Neoplasm–Symptom Assessment Form 
NCI 
National Cancer Institute 
NSAID 
nonsteroidal anti-inflammatory drug 
PD 
pharmacodynamic  
PDEIII 
phosphodiesterase III 
PET-MF 
post–essential thrombocythemia myelofibrosis 
  
 
 
 
PMF 
primary myelofibrosis 
PPV-MF 
post–polycythemia vera myelofibrosis 
PR 
partial remission 
PRO 
patient-reported outcome 
pSTAT 
phosphorylated signal transducer and activator of transcription 
PV 
polycythemia vera 
QD 
once daily 
RNA 
ribonucleic acid 
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Abbreviation 
Definition 
SAE 
serious adverse event 
STAT 
signal transducer and activator of transcription 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TXA2 
thromboxane A2 
TYK2 
tyrosine kinase 2 
ULN 
upper limit of normal 
WBC 
white blood cells 
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1. 
INTRODUCTION 
Ruxolitinib (previously known as INCB018424 phosphate, INC424, ruxolitinib phosphate) is a 
novel, potent, and selective inhibitor of Janus kinase (JAK) 1 and JAK2 with modest to marked 
selectivity against tyrosine kinase 2 (TYK2) and JAK3, respectively.  Ruxolitinib has been 
granted marketing authorisation approval for the treatment of myelofibrosis (MF) and 
polycythemia vera (PV) and is currently in development for the treatment of myeloproliferative 
neoplasms (MPNs; MF, PV, and essential thrombocythemia [ET]) and other hematologic 
malignancies.  
For a thorough discussion of the pharmacology of ruxolitinib, refer to the Investigator's Brochure 
(IB).  
1.1. 
Background and Overview on Essential Thrombocythemia 
The chronic MPNs are classified into subgroups, of which 4 are well characterized:  chronic 
myeloid leukemia (CML), PV, primary myelofibrosis (PMF), and ET.  Essential 
thrombocythemia is alone among the chronic MPNs in that it is diagnosed by excluding causes 
of reactive thrombocytosis and by excluding presence of the other MPNs (Arber et al 2016, 
Tefferi and Barbui 2015). 
Essential thrombocythemia represents one of the Philadelphia-chromosome negative MPNs and 
is associated with a mutation in the JAK2 tyrosine kinase domain estimated to be present in 
approximately 50% of ET patients (Levine et al 2007).  The majority of patients with essential 
thrombocytosis have mutations in 1 of 3 genes:  JAK2, calreticulin (CALR), or 
myeloproliferative leukemia (MPL) virus oncogene.  Rare cases involve mutations in the 
thrombopoietin gene, which are associated with autosomal dominant hereditary thrombocytosis, 
and somatic mutations in tet methylcytosine dioxygenase 2 (NIH 2016, Rumi et al 2014).  
Essential thrombocythemia is characterized by persistent thrombocytosis  (median platelet and 
white blood cell [WBC] counts at the time of diagnosis has been reported to range from 716 to 
1000 × 109/L and 8.6 to 9.6 × 109/L, respectively), excessive proliferation of megakaryocytes in 
the bone marrow (hyperplasia of enlarged mature with hyperlobulated nuclei megakaryocytes), 
splenomegaly (palpable spleen, enlargement below the costal margin in 16% to 25% of subjects 
at diagnosis; Montanaro et al 2014, Tefferi et al 2014a, Tefferi et al 2014b, Passamonti et al 
2012, Barbui et al 2011a) normal erythrocyte mass, the absence of bone marrow fibrosis and a 
clinical course complicated by thrombotic or hemorrhagic episodes, or both (Colombi et al 
1991). Although uncommon, thrombosis and hemorrhage are the life-threatening complications 
of ET.  Leukocytosis (WBC counts > 11 × 109/L) also increases the risk of thrombotic events 
and reduces survival in subjects with ET.  Predictors of arterial thrombosis include age 
> 60 years, history of thrombosis, presence of cardiovascular risk factors (eg, tobacco use, 
hypertension, diabetes mellitus), WBC count > 11 × 109/L, and presence of the JAK2V617F 
mutation.  The risk of significant bleeding is also associated with extreme thrombocytosis 
(platelet count > 1000 × 109/L), the use of aspirin in doses > 325 mg/day, or following treatment 
with nonsteroidal anti-inflammatory drugs (NSAIDs; Gangat et al 2007, Griesshammer et al 
1997, Colombi et al 1991, Bellucci et al 1986). 
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Leukemic and myeloid transformation into PV, PMF, or acute myeloid leukemia (AML) is 
another risk for patients with ET (Barbui et al 2011a, Cervantes et al 2002, Colombi et al 1991, 
Chistolini et al 1990, Fenaux et al 1990, Bellucci et al 1986) that is relatively low but increasing 
substantially after 10 years and 20 years (Wolanskyj et al 2006). 
Incidence of symptoms in ET is ill-defined, but reported to be in the range of 34% to 70% 
(Mesa et al 2007, Tefferi et al 2001, Fenaux et al 1990).  There exists a wide range in the 
reported incidence rates of symptoms in ET because of interstudy differences in patient selection 
and the definition of what constitutes a "vasomotor symptom."  Vasomotor manifestations 
include headache, lightheadedness, syncope, atypical chest pain, acral paresthesia, livedo 
reticularis, erythromelalgia, and transient visual disturbances (eg, amaurosis fugax, scintillating 
scotomata, and ophthalmic migraine).  These events are usually controlled by treatment with low 
or standard doses of aspirin (Pascale et al 2012, Michiels et al 2006, Michiels et al 1993).  
However, vasomotor symptoms in some patients may be resistant to antiplatelet therapy and may 
require cytoreductive therapy (Ruggeri et al 1998). 
The median age at diagnosis is approximately 50 to 60 years, and as many as 20% of the patients 
may be younger than 40 years of age (Tefferi et al 2015, Mehta et al 2014).  Five- and 10-year 
survival rates of 53% to 93% and 60% to 84%, respectively, have been reported in ET 
(Price et al 2014, Hultcrantz et al 2012, Maynadié et al 2013, Wolanskyj et al 2006).  The 
incidence rate for ET ranges from 0.2 to 3 new cases/100,000 in the population per year. 
Patients with ET can live many years after diagnosis but may have a reduced life expectancy 
compared with the normal population, particularly subjects with characteristics associated with 
an increased risk of thrombotic events or bleeding complications (Montanaro et al 2014, 
Hultcrantz et al 2012, Barbui et al 2011b, Finazzi and Barbui 2008, Schafer 2006).  The goal of 
cytoreductive therapy is the reduction and maintenance of the platelet and WBC counts to the 
normal range, which is associated with a reduction in the risk of hemorrhage or thrombosis 
(Tefferi and Barbui 2015, Campbell et al 2012, Regev et al 1997, Fenaux et al 1990).  
Hydroxyurea (HU), with or without aspirin, is considered first-line therapy in most subjects with 
ET (Cortelazzo  et al 1995, Harrison et al 2005).  Side effects of HU, which include oral ulcers, 
hyperpigmentation, skin rash, and nail changes, may lead to discontinuation of therapy and the 
need for alternative cytoreductive therapy.  A small percentage of subjects will develop leg 
ulcers, nausea, diarrhea, or alopecia (Gisslinger et al 2013, Barbui and Finazzi 2005, 
Latagliata et al 2012).  Thus, many subjects cannot remain on HU and require alternative 
cytoreductive therapies. 
Anagrelide is an oral imidazoquinazoline derivative that may interfere with megakaryocyte 
proliferation and maturation, resulting in platelet underproduction (Tomer 2002, Mazur et al 
1992).  Anagrelide is approved by the FDA for the treatment of patients with thrombocythemia, 
secondary to myeloproliferative disorders, to reduce the elevated platelet count and the risk of 
thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events.  In 
general, the drug is capable of reducing the platelet count to < 600 × 109/L in more than 80% of 
previously treated and untreated subjects in a similar manner to HU (Gisslinger et al 2013, 
Harrison et al 2005, Petitt et al 1997, Chintagumpala et al 1995, Balduini et al 1992).  Anagrelide 
has minimal effect on WBCs that may also be an important mediator of thrombotic risk 
(Harrison et al 2005, Bouchard and Tracy 2001, Falanga et al 2000).  Anagrelide also does 
not appear to stop the progression of bone marrow fibrosis and hypercellularity in ET or 
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PV (Hultdin et al 2007).  Toxicity of anagrelide is mainly related to the drug's direct vasodilatory 
and inotropic effects (Spencer and Brogden 1994, Abe Andes et al 1984).  Anagrelide use in 
patients with ET has been associated with acquired idiopathic cardiomyopathy and must be given 
with caution in patients with known or suspected heart disease, which may limit its utility in the 
older patient (Jurgens et al 2004, Amabile and Spencer 2004).  Thus, anagrelide is not tolerated 
or poorly tolerated in many subjects who would benefit from alternative options for platelet 
control. 
Alpha interferon controls the thrombocytosis associated with all MPNs, including ET.  An 
overview of the reported literature indicates a 75% to 88% hematologic response rate, associated 
with a 32% rate of reduction in spleen size (Kiladjian et al 2011, Kiladjian et al 2008, Saba et al 
2005, Radin et al 2003, Gilbert 1998, Elliott and Tefferi 1997).  The overall benefit to patients, 
compared with current treatment that usually consists of HU and low dose aspirin, is unknown.  
Similar efficacy along with marginally less toxicity has been observed with the use of the 
pegylated interferons alpha-2b and alpha-2a, which provide prolonged activity compatible with 
once weekly dose administration (Quintás-Cardama et al 2009, Jabbour et al 2007, Samuelsson 
et al 2006, Sacchi et al 1998).  Because of the toxicity issues, alpha interferon in ET should not 
be used in high-risk women of childbearing age and in those who are pregnant.  Considering the 
decreased tolerability associated with interferon therapy, a controlled study is needed before 
endorsing treatment with interferon as standard therapy in ET. 
Low-dose aspirin is especially effective in treating the vasomotor symptoms of ET, such as acral 
paresthesias and erythromelalgia (Fröhli et al 1983, Michiels et al 1993).  The optimal dose 
regimen of aspirin in ET is not known.  Whereas low-dose aspirin given once daily (QD) is 
known to inhibit platelet thromboxane A2 (TXA2) synthesis by approximately 97% to 99% in 
healthy subjects through the irreversible inhibition of platelet cyclo-oxygenase–1 (COX-1), the 
same aspirin regimen is unable to fully inhibit TXA2 production in approximately 80% of 
patients with ET (Pascale et al 2012, Dragani et al 2010, Patrignani et al 1982).  This may be 
attributable to increased platelet turnover in ET, with the emergence of young platelets with 
intact COX-1 activity in the 24 hours between aspirin doses. 
Busulfan, in an uncontrolled study of 21 PV and 15 ET patients who were resistant to or 
intolerant of HU, was shown to be effective, but a significant rate of transformation was 
observed (Alvarez-Larrán et al 2014).  Radiophosphorus (32P) and plateletpheresis are 
alternative treatments for a limited number of subjects with ET because of the high rate of 
leukemic transformation following 32P and the transient results obtained by pheresis (reserved 
for those with limited life expectancy or acute, serious, thrombotic, or hemorrhagic events). 
1.2. 
Product Information and Overview of Ruxolitinib 
1.2.1. 
Pharmacology 
Ruxolitinib (previously known as INCB018424 phosphate, INC424, ruxolitinib phosphate) is a 
novel, potent, and selective inhibitor of JAK1 (inhibition concentration 50% [IC50] = 3.3 ± 
1.2 nM) and JAK2 (IC50 = 2.8 ± 1.2 nM) with modest to marked selectivity against TYK2 
(IC50 = 19 ± 3.2 nM) and JAK3 (IC50 = 428 ± 243 nM), respectively.  Ruxolitinib interferes with 
the signaling of a number of cytokines and growth factors that are important for hematopoiesis 
and immune function. 
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Ruxolitinib efficacy was demonstrated in several in vitro and in vivo models relevant to the 
increased inflammatory cytokine profile observed in patients with MF.  When combining 
ruxolitinib with the pan-deacetylase inhibitor panobinostat in a mouse model of 
JAK2V617F-driven PV-like disease, there was an added benefit on a number of endpoints.  
Efficacy was also demonstrated in mouse xenograft/allograft models, including models in which 
the most common mutation in MPNs, the JAK2V617F mutation, was expressed 
(Quintás-Cardama et al 2010). 
Ruxolitinib inhibited the splenomegaly and morbidity/mortality in mice resulting from 
intravenous inoculation of cells expressing the same mutated JAK2V617F implicated in the 
pathogenesis of the majority of Philadelphia chromosome–negative MPNs.  Ruxolitinib inhibited 
erythroid colony formation from mononuclear cells derived from PV subjects (IC50 of 223 nM 
compared with 407 nM for normal donors).  Growth factor–independent colony formation, a 
unique characteristic of PV and other MPNs, was inhibited more potently with an IC50 of 67 nM 
for ruxolitinib in cells bearing the JAK2V617F mutation compared with cells bearing the 
wild-type JAK2. 
Effects of ruxolitinib noted in 6-month rat and 12-month dog repeat-dose toxicology studies 
were primarily myelosuppressive in nature and are believed to be associated with the mechanism 
of action of ruxolitinib (inhibitor of JAK–signal transducer and activator of transcription [STAT] 
signaling).  Genetic toxicology assessments (evaluations of ruxolitinib in the bacterial 
mutagenicity assay, in vitro chromosome aberration assay, and in vivo micronucleus assay) in 
rats were negative.  In safety pharmacology evaluations, an adverse decrease in minute volume 
in a respiratory study in female rats only was noted at the highest dose.  In a cardiovascular 
evaluation of ruxolitinib in dogs, electrocardiogram (ECG) parameters and ventricular 
repolarization were unaffected at all doses, whereas the compound lowered blood pressure and 
increased heart rate compared with vehicle control at the highest dose evaluated.  In embryo-fetal 
assessments in rat and rabbit, maternal toxicity and minimal embryo-fetal toxicity were noted at 
the highest doses evaluated.  Ruxolitinib was not teratogenic in either rat or rabbit.  No effects 
were noted on reproductive performance or fertility in male or female rats.  Increases in 
postimplantation loss were noted at the higher doses. 
More detailed information on the pharmacology of ruxolitinib, single- and multiple-dose 
pharmacokinetic (PK) studies conducted in multiple species, and nonclinical safety evaluations 
can be found in the IB. 
1.2.2. 
Nonclinical Drug Metabolism and Pharmacokinetics 
After oral single-dose administration of ruxolitinib capsules in the fasted state, ruxolitinib was 
absorbed rapidly, typically attaining peak plasma concentrations within 1 to 3 hours after 
administration for all doses.  After attaining the maximum plasma concentration (Cmax), the 
ruxolitinib plasma concentrations declined, with a mean terminal-phase disposition half-life of 
approximately 3 to 5 hours.  The mean ruxolitinib Cmax and area under the curve (AUC) 
increased with approximately linear proportionality to dose for the entire dose range evaluated of 
5 to 200 mg.  There was no significant food effect on absorption or exposure. 
Ruxolitinib is metabolized in the liver by the cytochrome P450 (CYP) metabolizing enzyme 
system, predominantly by the 3A4 isozyme.  Systemic exposure of ruxolitinib was appreciably 
increased (AUC 2-fold higher) when given in combination with ketoconazole, a potent CYP3A4 
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inhibitor, with a similar effect observed on the pharmacodynamic (PD) activity 
(cytokine-induced STAT3 phosphorylation).  Cytochrome P450 3A4 inducers significantly 
decreased the exposure to ruxolitinib, with essentially no difference observed on the PD activity 
(cytokine-induced STAT3 phosphorylation).  This suggests that CYP3A4 induction with 
rifampin results in metabolism of ruxolitinib to active metabolites that also inhibit JAK. 
Ruxolitinib was given as a single 25 mg dose to subjects with varying degrees of renal function 
(Study INCB 18424-142) and to subjects with varying degrees of hepatic dysfunction or with 
normal hepatic function (Study INCB 18424-137).  Mild, moderate, or severe impairment of 
renal function had no statistically significant effect on PK or PD parameters; subjects requiring 
dialysis showed prolonged PD activity without a demonstrable effect on ruxolitinib clearance.  
The mean total AUCs of ruxolitinib were 87%, 28%, and 65% higher, respectively, in subjects 
with mild, moderate, and severe hepatic impairment than in subjects with normal hepatic 
function.  Terminal half-life of ruxolitinib was increased in subjects with hepatic impairment by 
approximately 2-fold compared with healthy controls.  The subjects with severe hepatic 
impairment showed modestly protracted PD activity compared with the other hepatically 
impaired subjects who displayed PD activity similar to the healthy controls. 
Additional details about clinical pharmacology of ruxolitinib may be found in the IB. 
1.2.3. 
Clinical Safety Summary 
1.2.3.1. 
Healthy Volunteers Study 
Ruxolitinib has been administered to over 180 healthy volunteers as single dose, repeat-single 
dose, or multiple doses of up to 10 days duration.  The clinical database (safety set) in solid 
tumor and hematologic malignancies consists of 787 subjects treated in 6 studies evaluating 
subjects with MF (n = 679), prostate cancer (n = 22), multiple myeloma (n = 13), and ET and PV 
(n = 73), of whom 617 received ruxolitinib. 
In healthy volunteer studies, a transient, reversible decrease in neutrophil count has been seen 
after doses of 25 mg to 50 mg, which reverses 12 to 24 hours after stopping ruxolitinib.  These 
neutropenia events were of Grade 1 or Grade 2 severity, with a single instance of severe Grade 4 
neutropenia that led to study drug discontinuation in 1 subject receiving 50 mg ruxolitinib twice 
daily (BID; highest dose).  The maximum tolerated dose in healthy volunteers was determined to 
be 25 mg BID or 100 mg QD. 
In a thorough cardiac QT study, it was shown that increasing plasma concentrations of 
ruxolitinib are not associated with increases in the QT interval.  
For a thorough review of ruxolitinib clinical safety, refer to the IB. 
1.2.3.2. 
Clinical Safety Data 
In the randomized period of the 2 pivotal studies in MF, COMFORT-I and COMFORT-II (cutoff 
01 MAR 2011, median duration of exposure = 10.8 months), discontinuation due to adverse 
events (AEs) regardless of causality was observed in 11.3% of subjects.  The most frequently 
reported adverse drug reactions were thrombocytopenia and anemia.  Hematological adverse 
reactions (any CTCAE Grade) included anemia (82.4%), thrombocytopenia (69.8%), and 
neutropenia (16.6%).  Anemia, thrombocytopenia, and neutropenia are dose-related effects.  
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The 3 most frequent nonhematological adverse reactions were bruising (21.6%), dizziness 
(15.3%), and headache (14.0%).  The 3 most frequent nonhematological laboratory abnormalities 
were raised alanine aminotransferase (ALT; 27.2%), raised aspartate aminotransferase (AST; 
18.6%) and hypercholesterolemia (16.9%). 
Long-term follow-up in subjects with MF (including 615 subjects treated with ruxolitinib during 
the controlled and extension period of studies INCB 18424-251 [cutoff 01 OCT 2012], 
COMFORT-I [02 SEP 2013], and COMFORT-II [cutoff 12 OCT 2015]) has shown that, as 
expected, the numbers and proportions of AEs and serious AEs (SAEs) has increased; however, 
no new safety signals have emerged (median duration of exposure for this 
population = 27.6 months, 1345.78 patient-years of exposure). 
Study INCB 18424-258 established 5 mg BID as a safe starting dose in patients with PMF,  
post–polycythemia vera myelofibrosis (PPV-MF), and post–essential thrombocythemia 
myelofibrosis (PET-MF) who have platelet count between 50 and 100 × 109/L. 
Study INCB 18424-261 showed that 10 mg BID was an effective starting dose by providing 
symptomatic benefit and reducing palpable spleen length in the majority of subjects while having 
less of an impact on hematologic parameters than seen in the pivotal Phase 3 studies.  
In Study INCB 18424-260, a sustained release formulation as administered provided safety and 
efficacy results generally comparable to results reported previously for the immediate release 
(IR) formulation. 
Up to Week 32 of the randomized portion in the RESPONSE trial (cutoff 25 SEP 2014, median 
duration of exposure = 7.8 months), ruxolitinib was generally well-tolerated in subjects with PV, 
and only a small proportion of subjects discontinued ruxolitinib due to AEs (6.4%).  Most of the 
AEs have been managed by dose modifications and/or supportive care.  Hematological toxicities 
were less frequent and less severe in patients with PV than those observed in patients with MF.  
Analysis of Week 80 data did not identify any new safety findings, and the frequency of AEs 
remained comparable to Week 48 data.  
In INCB 18424-256, a Phase 2, open-label dose-ranging clinical study to determine the safety 
and efficacy of INCB018424 in subjects with advanced ET refractory to or intolerant of 
hydroxyurea, subjects with ET were randomized to receive oral ruxolitinib at a dose of 10 mg 
BID (n = 8), 25 mg BID (n = 9), or 50 mg QD (n = 9).  No unexpected safety signals were 
observed compared with treatment in subjects with MF.  Exposure-response analyses and 
population PK/PD models were developed for dose change and time courses in platelet count, 
absolute neutrophil count (ANC), WBC count, and hematocrit to support the starting dose 
selection.  The majority of subjects in the 25 mg BID and 50 mg QD groups did not have dose 
increases over their starting dose, suggesting that total daily of 50 mg may be a maximum 
tolerated dose for this population.  However, subjects receiving starting doses of 2 mg BID or 
50 mg QD commonly required dose reduction for anemia, suggesting that 10 mg BID is an 
appropriate starting dose. 
No new safety signals emerged from a study in pancreatic cancer in combination with 
capecitabine. 
The AE profile of the compound has been assessed in more than 370 healthy volunteers, in 
subjects with various degrees of renal (n = 32) or hepatic (n = 24) impairment, and in subjects 
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with RA (n = 59) receiving ruxolitinib:  AEs were, in general, mild and resolved without 
interventions. 
A thorough QT study was conducted in 50 healthy subjects.  There was no indication of a 
QT/QTc prolonging effect of ruxolitinib in single doses up to a supratherapeutic dose of 200 mg, 
indicating that ruxolitinib has no effect on cardiac repolarization. 
1.2.3.3. 
Clinical Efficacy Data 
As of 22 FEB 2016, approximately 10,350 patients had been evaluated in sponsored clinical 
studies and 5932 patients in third-party studies, and an estimated 37,166 patient-years of 
postmarketing experience have accrued since the initiation of global marketing of ruxolitinib 
(refer to the Ruxolitinib Development Safety Update Report). 
More than 70 interventional or observational studies sponsored by third parties are ongoing or 
completed.  These indications include the following: 
• Hematologic malignancies:  PV, Chuvash PV, MF (in combination with either 
panobinostat, azacytidine, danazol, lenalidomide, or pomalidomide), MF patients 
eligible for allogeneic hematopoietic stem cell transplantation, high-risk ET patients 
resistant to or intolerant of HU, MPNs in accelerated or blast phase (in combination 
with decitabine), MDS (single treatment or in combination with azacytidine), AML, 
CML (single treatment or in combination with nilotinib), chronic myelomonocytic 
leukemia, relapsed or refractory leukemia, relapsed or refractory Hodgkin lymphoma, 
B- or T-cell non-Hodgkin lymphoma, or chronic lymphocytic leukemia. 
• Solid malignancies:  phosphorylated STAT3 positive breast cancer, triple-negative 
breast cancer, ER-positive advanced breast cancer (in combination with exemestane), 
EGFR-mutant lung adenocarcinoma (in combination with erlotinib), advanced solid 
cancers (in combination with afatinib), or cancer-related cachexia. 
Ruxolitinib is also being examined in pediatric patients with hematologic malignancies. 
The results from 2 Phase 3 studies in MF (COMFORT-I, Verstovsek et al 2012; COMFORT-II, 
Harrison et al 2012) demonstrate the effectiveness of ruxolitinib in subjects with PMF, PPV-MF, 
and/or PET-MF.  The results of these 2 studies were consistent, demonstrating statistically 
significant (p < 0.0001) differences in the proportion of subjects who demonstrated ≥ 35% spleen 
volume reduction, when compared with either placebo or an investigator's selection of best 
available therapy (BAT).  Ruxolitinib was associated with prolonged survival compared with 
placebo (COMFORT-I) and BAT (COMFORT-II).  
Consistent with its activity in MF, ruxolitinib demonstrated efficacy in a related MPN, PV, in the 
RESPONSE study (Vanucchi et al 2015).  A significantly greater proportion of subjects who 
were randomized to ruxolitinib met the primary endpoint of the study, which was a composite 
endpoint of hematocrit control in the absence of phlebotomy and spleen volume reduction 
≥ 35%, when compared with subjects randomized to BAT (22.7% vs 0.9%, p < 0.0001).  Of the 
subjects meeting the primary endpoint at Week 32, 88% maintained their response at Week 48, 
and 80% maintained their response for at least 48 weeks from initial response. 
An open-label Phase 2 dose regimen ranging clinical study to determine the safety and efficacy 
of ruxolitinib with advanced PV or ET refractory to HU (Study INCB 18424-256) is currently 
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ongoing in United States and Italy.  The last ET subject was randomized on 07 APR 2009.  As of 
22 FEB 2016, 39 subjects with ET were enrolled in the study, and 19 subjects (48.7%) withdrew 
from the study.  The median duration of exposure was 358.6 weeks (range:  13-384 weeks), and 
the most frequently reported reasons for withdrawal from the study for subjects with ET was lack 
of response (17.9%) and AEs (17.9%).  In this study, ruxolitinib is well-tolerated and is 
associated with platelet and WBC control in most subjects.  The median baseline platelet count 
in subjects with ET is 849 × 109/L, with 35 subjects (89.7%) having counts > 600 × 109/L.  The 
median baseline WBC count was 8.15 × 109/L with 11 subjects (28.2%) having counts 
> 10 × 109/L.  Of the subjects with baseline platelet count > 600 × 109/L, 60.0% achieved platelet 
count ≤ 600 × 109/L at the Week 32 visit and 57.1% at the Week 192 visit, which was similar at 
Week 364 (56.3%) and demonstrating durability of response.  In the initial (dose-finding) portion 
of the study, subjects were randomized to receive oral ruxolitinib at a dose of 10 mg BID (n = 8), 
25 mg BID (n = 9), or 50 mg QD (n = 9).  The majority of ET subjects received ruxolitinib in 
total daily doses of 10 mg to 20 mg BID or of 30 mg to 50 mg QD. 
1.2.3.4. 
Proposed Indications 
The FDA approved ruxolitinib in the United States under the trade name, JAKAFI®, in 
NOV 2011 for the treatment of patients with intermediate or high-risk MF, including PMF, 
PPV-MF, and PET-MF.  This approval was based on the demonstration in 2 Phase 3 studies 
(COMFORT-I and COMFORT-II) that treatment with ruxolitinib in all 3 subtypes of MF (PMF, 
PPV-MF, and PET-MF) resulted in rapid, significant, and durable reduction in spleen size and 
improvement in disease-related symptoms when compared with either placebo in COMFORT-I 
or BAT in COMFORT-II.  On 04 DEC 2014, ruxolitinib was approved for the treatment of 
patients with PV who have had an inadequate response to or are intolerant of HU.  This approval 
was based on data from the pivotal Phase 3 RESPONSE trial, which was conducted under a 
Special Protocol Assessment and demonstrated superior hematocrit control and reductions in 
spleen volume compared with BAT.  In addition, a greater proportion of subjects in the 
ruxolitinib treatment group achieved complete hematologic remission, which was defined as 
achieving hematocrit control and lowering platelet and WBC counts. 
The most commonly observed adverse drug reactions in subjects with MF taking ruxolitinib 
were anemia and thrombocytopenia.  The most commonly observed nonhematological adverse 
drug reactions were dizziness and headache, which were mainly CTCAE Grade 1.  Incyte 
successfully collaborated with the FDA to develop and implement a 'fit for purpose' 
patient-reported outcome (PRO) instrument (modified Myelofibrosis Symptom Assessment 
Form version 2.0) used in a Phase 3, double-blind, placebo-controlled registration trial 
(COMFORT-I) to evaluate the safety and effectiveness of ruxolitinib in subjects with MF.  This 
resulted in the inclusion of symptom improvement data in the Jakafi label.  In a pivotal Phase 3 
study (CINC424B2301; The RESPONSE Trial), the most common nonhematologic AEs for PV 
subjects (incidence >10%) were headache, abdominal pain, diarrhea, dizziness, fatigue, pruritus, 
dyspnea, and muscle spasms. 
In MAR 2010, orphan-drug designations for ruxolitinib were granted by the FDA for the 
"Treatment of Essential Thrombocythemia" (22 MAR 2010).  In the present study, Jakafi 
(ruxolitinib) tablets will be used for the treatment of subjects with ET who are resistant to or 
intolerant of HU. 
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1.3. 
Product Information and Overview of Anagrelide 
1.3.1. 
Anagrelide 
1.3.1.1. 
Product Name and Application Number 
Anagrelide hydrochloride, USP is a platelet-reducing agent.  Its chemical name is 6,7-dichloro-
1,5-dihydroimidazo[2,1-b] quinazolin-2(3H)-one monohydrochloride monohydrate, and it has 
the following structural formula:  C10H7Cl2N3O·HCl·H2O M.W. 310.56. 
Anagrelide is approved by the FDA for the treatment of patients with thrombocythemia, 
secondary to MPNs, to reduce the elevated platelet count and the risk of thrombosis and to 
ameliorate associated symptoms including thrombo-hemorrhagic events.   
The mechanism by which anagrelide reduces blood platelet count is still under investigation.  
Studies in subjects support a hypothesis of dose-related reduction in platelet production resulting 
from a decrease in megakaryocyte hypermaturation.  In blood withdrawn from normal volunteers 
treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte 
development and a reduction in megakaryocyte size and ploidy.  At therapeutic doses, anagrelide 
does not produce significant changes in white cell counts or coagulation parameters and may 
have a small, but clinically insignificant, effect on red cell parameters.  Anagrelide inhibits cyclic 
adenosine monophosphate (AMP) phosphodiesterase III.  Phosphodiesterase III inhibitors can 
also inhibit platelet aggregation.  However, significant inhibition of platelet aggregation is 
observed only at doses of anagrelide higher than those required to reduce platelet count. 
Anagrelide is metabolized at least in part by CYP1A2.  It is known that CYP1A2 is inhibited by 
several medicinal products, including fluvoxamine, and that such medicinal products could 
theoretically adversely influence the clearance of anagrelide.  Anagrelide demonstrates some 
limited inhibitory activity towards CYP1A2, which may present a theoretical potential for 
interaction with other coadministered medicinal products sharing that clearance mechanism (eg, 
theophylline). 
Anagrelide is an inhibitor of cyclic AMP PDEIII.  The effects of medicinal products with similar 
properties such as inotropes milrinone, enoximone, amrinone, olprinone, and cilostazol may be 
exacerbated by anagrelide. 
At fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3 hours.  The available 
plasma concentration time data at steady state in subjects showed that anagrelide does not 
accumulate in plasma after repeated administration.  Food has no clinically significant effect on 
the bioavailability of anagrelide. 
Two major metabolites have been identified (RL603 and 3-hydroxy anagrelide).  
Refer to the anagrelide label for complete detailed information on the product (Agrylin 2013). 
 
1.4. 
Study Rationale 
Essential thrombocythemia is a chronic MPN, which may result in a reduced life expectancy in 
subjects compared with the normal population.  Multiple risk factors impacting overall survival 
of individuals with ET have been described (Tefferi et al 2014a, Tefferi et al 2014b).  Subjects at 
increased risk for thrombosis or bleeding, particularly those with a history of thrombosis, and 
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high platelet and WBC counts, are treated with cytoreductive therapies.  Hydroxyurea is 
effective and tolerated in most subjects with ET, but many require alternative cytoreductive 
therapy because of inadequate efficacy or poor tolerability of HU.  Anagrelide is an FDA 
approved standard of care for ET but is associated with intolerable short- and long-term side 
effects.  In addition, anagrelide has minimal effect on WBCs, which may also be an important 
mediator of thrombotic risk and does not appear to stop the progression of bone marrow fibrosis 
and hypercellularity in ET or PV. 
Ruxolitinib may represent an effective, better-tolerated treatment than anagrelide, and the present 
study is proposing to compare ruxolitinib with anagrelide therapy in subjects with ET who are 
candidates for anagrelide therapy.  
1.4.1. 
Essential Thrombocythemia Symptoms and Treatment 
Essential thrombocythemia patients with specific characteristics such as age ≥ 60 years, extreme 
thrombocytosis, leukocytosis, or previous thrombo-hemorrhagic complications are treated with 
cytoreductive therapy, with the goal of normalizing platelet counts to reduce the risk of 
complications.   
Anagrelide is approved by the FDA for the treatment of patients with thrombocythemia, 
secondary to MPNs, to reduce the elevated platelet count and the risk of thrombosis and to 
ameliorate associated symptoms, including thrombo-hemorrhagic events.   
Essential thrombocythemia patients who are candidates for cytoreductive therapy as described 
above are eligible for anagrelide therapy.  In general, the drug is capable of reducing the platelet 
count to less than 600 × 109/L in more than 80% of subjects.  Anagrelide would be an 
appropriate comparator. 
1.4.2. 
Rationale for Study Design and Treatment and Dose Selection 
In order to optimize the benefit-risk for patients, a dose titration approach is necessary.  In 
Study INCB 18424-256, ruxolitinib treatment at doses of 10 to 25 mg BID resulted in 
improvements in platelet and WBC count and disease-related symptoms in subjects with ET who 
were hydroxyurea-refractory/intolerant, with no unexpected safety signals compared with 
treatment in subjects with MF.  However, subjects who received starting doses of 25 mg Bid or 
50 mg QD commonly required dose reduction for anemia, supporting 10 mg BID as a starting 
dose of ruxolitinib. 
In the currently approved US label for Agrylin® capsules, dose modification guidelines 
recommend that the starting dose should be 0.5 mg 4 times daily or 1 mg BID and maintained for 
at least 1 week. 
• The starting dose in Treatment Group A is ruxolitinib 10 mg BID and 
anagrelide-placebo capsules BID.  
• The starting dose in Treatment Group B is anagrelide 1 mg BID orally and 
ruxolitinib-placebo. 
This study is proposed to establish clinical benefit using a composite primary endpoint of durable 
control of platelet and WBC counts.  Secondary 
 endpoints were chosen to 
systematically evaluate and compare safety and tolerability to anagrelide.  Symptom 
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amelioration will also be assessed in subjects who have symptoms related to ET at baseline, such 
as pruritus, which presents in approximately 34% to 70% of ET patients (Mesa et al 2007, 
Tefferi et al 2001, Fenaux et al 1990).  The rate of thrombo-hemorrhagic events will also be 
assessed. 
1.4.2.1. 
Double-Dummy Design 
Patients and investigators in open-label clinical studies are aware of treatment assignment, and 
therefore this approach is not suitable for clinical studies investigating efficacy of a compound 
with a reference treatment and the relief of symptoms using PRO instruments.  This is because 
patients and their healthcare providers who know that they are on a particular therapy may 
overestimate the symptom benefit.  To avoid this, a double-blinded clinical study is necessary 
that includes a placebo and an active drug in each group.  Therefore the patient-reported 
symptoms are collected without the influence of the knowledge of study treatment assignment by 
the subjects and their health care providers.  This study is designed as a double-blind, 
double-dummy, randomized study in which the blind is maintained until the subjects have 
reached Week 52, marking the timepoint for comparative analyses of the primary and secondary 
endpoints.  Therefore, 1-way crossover to ruxolitinib for individual subjects originally 
randomized to anagrelide is allowed after Week 52 according to investigator's decision after 
consultation with the sponsor.  Subjects initially assigned to Group A (ruxolitinib) receiving 
benefit from therapy will be assessed for durability of their responses in the open-label portion of 
the study. 
However, unblinding for medical emergency purposes may be performed at any time during a 
subject's participation in the study. 
1.4.2.2. 
Prior Anagrelide Use 
While the original study design excluded subjects who have previously used even a limited 
course of anagrelide, Amendment 2 allows for participation of these subjects provided that 
anagrelide was not discontinued as a result of an AE.   Prohibiting prior anagrelide use severely 
limited the number of subjects who needed alternative therapies permitted to participate in this 
study.  This revision is intended to be more inclusive and allow for a greater number of subjects 
to participate.  To avoid bias, subjects will be stratified based on prior anagrelide use. 
1.5. 
Potential Risks and Benefits of the Treatment Regimen 
1.5.1. 
Risks Related to Ruxolitinib 
No specific findings in nonclinical repeat-dose toxicity studies identify clinical risks other than 
noting that consequences of immunosuppression may occur.  Hypotension and increases in heart 
rate were noted at a high dose in a cardiovascular preclinical study.  However, these findings 
have not been recapitulated in a clinical setting at doses up to 25 mg BID. 
The primary clinical risks with ruxolitinib treatment are the potential sequelae of decreased 
hematopoietic proliferation secondary to the inhibition of growth factor pathways with JAK2 
inhibition.  Dose-dependent, reversible thrombocytopenia has been observed in the ongoing 
study of subjects with MF.  Anemia and, less frequently, neutropenia have also been observed in 
the ongoing study of MF subjects.  Increased rates of infection and anemia are potential risks of 
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myelosuppression, and there are multiple sequelae of anemia, including the burden and risks of 
transfusion.  In healthy volunteers, rheumatoid arthritis patients, and hormone-refractory prostate 
cancer patients with greater bone marrow reserve, the effects on hematopoietic proliferation 
appear to be less pronounced.  
Long-term ruxolitinib treatment was well-tolerated in subjects with ET (ongoing Study 
INCB 18424-256, cutoff date 22 FEB 2016).  The majority of treatment-emergent AEs (TEAEs) 
were mild or moderate.  Three subjects (7.6%) with ET died during the study (SAE of unrelated 
cardiac failure after 3 years of treatment; SAE of unrelated osteolytic lesions from vulva Paget's 
disease after 6 years of treatment; and SAE of unrelated multiorgan failure after 4 years).  Fifteen 
subjects (38.4%) had at least 1 SAE.  The most frequently reported TEAE was anemia and the 
most frequently reported nonhematologic TEAE were cough and increased weight.  One case of 
unrelated basal cell carcinoma and 1 case of possibly related Kaposi's sarcoma were reported 
after 7 years of treatment.  Headache, leukopenia, and pain in extremity were also reported in 
this study.  There were no patterns among clinical hematology or chemistry parameters that were 
indicative of new safety concerns during long-term treatment with ruxolitinib in subjects with 
ET.  Refer to the IB for full details. 
1.5.2. 
Risks Related to Anagrelide 
Anagrelide therapy requires close clinical supervision of the patient.  While the platelet count is 
being lowered (usually during the first 2 weeks of treatment), blood counts (hemoglobin, 
WBCs), and renal function (serum creatinine, blood urea nitrogen) should be monitored.  Cases 
of clinically significant hepatotoxicity (including symptomatic ALT and AST elevations and 
elevations > 3 × upper limit of normal [ULN]) have been reported in postmarketing surveillance.  
Liver function tests (ALT, AST) should be performed before initiating anagrelide treatment and 
during therapy. 
Refer to the anagrelide label for complete detailed information on the product (Agrylin 2013). 
1.5.3. 
Potential Benefits of Ruxolitinib 
The clinical efficacy results of ruxolitinib that have emerged from the ongoing studies and 
Phase 3 studies are notable, including marked reduction in splenomegaly, improvement in 
symptoms, performance status and activity level, and reduction in plasma levels of 
inflammatory, prothrombotic, and angiogenic cytokines.  In those subjects with prolonged 
exposure to ruxolitinib (median of 5 years therapy), these positive effects have been maintained, 
given the closely related pathophysiology of MPNs. 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
• To compare efficacy of ruxolitinib versus anagrelide as measured by the proportion of 
subjects demonstrating platelet and WBC control. 
2.1.2. 
Secondary Objectives 
• To evaluate the safety and tolerability of ruxolitinib compared with anagrelide in 
subjects with ET. 
• To compare complete remission (CR) and partial remission (PR) rates of ruxolitinib 
and anagrelide in subjects with ET. 
• To evaluate the duration of response. 
• To evaluate the proportion of subjects demonstrating platelets control. 
• To evaluate the proportion of subjects demonstrating WBC control. 
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2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoint 
• Proportion of subjects who achieve a simultaneous reduction of platelet counts to 
< 600 × 109/L with a reduction of WBC counts to < 10 × 109/L for at least 80% of 
biweekly measurements for a consecutive 12-week period between Weeks 32 and 52. 
2.2.2. 
Secondary Endpoints 
• Safety and tolerability of ruxolitinib measured by AEs and laboratory values. 
• Proportion of subjects who discontinue study treatment because of AEs.  
• Time to treatment discontinuation. 
• Proportion of subjects who achieve CR or PR at Week 32 based on European 
LeukemiaNet (ELN) 2013 response criteria. 
− Analyses completed for subjects achieving CR plus PR. 
− Analyses completed for subjects achieving CR. 
− Analyses completed for subjects achieving PR. 
• Duration of response as measured from the onset of response to the loss of response 
for responders.  Response is defined the same as in the primary endpoint. 
• Proportion of subjects who achieve reduction of platelet counts to < 600 × 109/L for 
at least 80% of biweekly measurements for a consecutive 12-week period between 
Weeks 32 and 52. 
• Proportion of subjects who achieve a reduction of WBC counts to < 10 × 109/L for at 
least 80% of biweekly measurements for a consecutive 12-week period between 
Weeks 32 and 52. 
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3. 
SUBJECT ELIGIBILITY 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or subject safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential. 
3.1. 
Subject Inclusion Criteria 
A subject who meets all of the following criteria may be included in the study: 
1. Men and women, aged 18 or older. 
2. Subjects diagnosed with ET according to revised WHO 2016 criteria (Appendix A; 
Arber et al 2016). 
3. Subjects who are resistant to or intolerant of HU (Appendix B), that is, fulfilling at least 
1 of the following criteria: 
a. Platelet count > 600× 109/L after 3 months of at least 2 g/day of HU (2.5 g/day in 
subjects with a body weight over 80 kg) OR at the subject's maximally tolerated dose 
if that dose is < 2 g/day.  
b. Platelet count > 400 × 109/L and WBC count < 2.5 × 109/L or hemoglobin (Hgb) 
< 10 g/dl at any dose of HU. 
c. Presence of leg ulcers or other unacceptable muco-cutaneous manifestations at any 
dose of HU. 
d. HU-related fever. 
4. Platelet count ≥ 650 × 109/L at screening. 
5. WBC ≥ 11.0 × 109/L at screening.  
6. ECOG performance status 0 to 2. 
7. Known status of JAKV617F mutation. 
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8. Willingness to avoid pregnancy or fathering children based on the following criteria 
(Appendix G): 
a. Woman of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or 
bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age). 
b. Woman of childbearing potential who has a negative serum pregnancy test at 
screening and negative urinary test before the first dose on Day 1 and who agrees to 
take appropriate precautions to avoid pregnancy (with at least 99% certainty) from 
screening through safety follow-up.  Permitted methods that are at least 99% effective 
in preventing pregnancy should be communicated to the subject and their 
understanding confirmed. 
c. Man who agrees to take appropriate precautions to avoid fathering children (with at 
least 99% certainty) from screening through safety follow-up.  Permitted methods that 
are at least 99% effective in preventing pregnancy should be communicated to the 
subject and their understanding confirmed. 
3.2. 
Subject Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Subjects who have previously been treated with JAK inhibitors. 
2. Subjects being treated concurrently with anagrelide or HU. 
a. Prior anagrelide use is allowed provided the reason for discontinuation is not 
AE-related and anagrelide is stopped at least 28 days before the start of study 
medications (ie, Day 1). 
b. Treatment with HU can be stopped at any time once one of the inclusion criteria for 
HU refractoriness or resistance have been met, and up to the day before the first dose 
of study treatment (ie, Day 1). 
3.  Subjects with inadequate liver function at screening and Day 1 (before drug 
administration) as demonstrated by the following:  
a. Total bilirubin > 1.5 × ULN. 
b. AST or ALT > 1.5 × ULN. 
c. Hepatocellular disease (eg, cirrhosis). 
4. Subjects with inadequate renal function at screening as demonstrated by creatinine 
clearance < 40 mL/min calculated by Cockcroft-Gault equation. 
5. Subjects with clinically significant cardiovascular disease, including uncontrolled cardiac 
disease, including unstable angina; acute myocardial infarction within 6 months from 
Day 1 of study drug administration; New York Heart Association Class III or IV 
congestive heart failure; and arrhythmia requiring therapy unless approved by medical 
monitor/sponsor.   
6. History or presence of an abnormal ECG that, in the investigator's opinion, is clinically 
meaningful. 
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7. Subjects with impairment of gastrointestinal (GI) function or active GI disease that may 
significantly alter absorption of ruxolitinib or anagrelide (eg, active ulcerative diseases, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, and small bowel 
obstruction). 
8. Inability to swallow and retain oral medication. 
9. Subjects with clinically significant bacterial, fungal, parasitic, or viral infection that 
requires therapy:  
a. Subjects with acute bacterial infections requiring antibiotic therapy should delay 
screening/enrollment until the course of antibiotic therapy has been completed.  
b. Subjects on chronic antibiotics for prophylaxis are allowed. 
10. Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or risk of 
reactivation:  HBV DNA and HCV RNA must be undetectable.  Subjects cannot be 
positive for hepatitis B surface antigen or anti–hepatitis B core antibodies.  Subjects who 
have positive anti-HBs as the only evidence of prior exposure may participate in the 
study provided that there is both 1) no known history of HBV infection and 2) verified 
receipt of hepatitis B vaccine.  
11. Known human immunodeficiency virus infection. 
12. Subjects with diagnosed primary immunodeficiency syndromes, such as X-linked 
gammaglobulinemia and common variable immune deficiency. 
13. Subjects with peripheral blood blast count of > 0% at screening.  
14. Subjects with an active malignancy over the previous 2 years except treated cervical 
intraepithelial neoplasia, basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or completely resected papillary thyroid and follicular thyroid cancers. 
15. Pregnant or breastfeeding women.  
16. Use of any potent CYP3A4 inhibitors or inducers or CYP1A2 inhibitors within 14 days 
or 5 half-lives (whichever is longer) before the first dose of ruxolitinib or anagrelide or 
their anticipated use during the study (does not apply to topical ketoconazole). 
17. Use of concomitant treatment of fluconazole at a dose > 200 mg. 
18. Subjects being treated concurrently with any prohibited medications.  
19. Subjects being treated concurrently with any medications that may prolong QTc interval 
of the ECG (see Appendix J). 
20. Subjects being treated concurrently with any investigational agent or who have 
previously participated in an investigational study within 30 days before to the first dose 
of study drug or within 5 half-lives of the previous investigational product, whichever is 
longer. 
21. Subjects who are unable to comprehend or are unwilling to sign an informed consent 
form (ICF).  
22. Subjects who are unwilling or incapable of complying with the requirements of the study. 
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23. Subjects with active alcohol or drug addiction that would interfere with their ability to 
comply with the study requirements. 
24. Any condition that would, in the investigator's judgment, interfere with full participation 
in the study, including administration of study drug and attending required study visits; 
pose a significant risk to the subject; or interfere with interpretation of study data. 
3.3. 
Subjects Who Fail to Meet Screening Criteria 
A subject who has a laboratory test result, vital sign assessment, or ECG finding that does not 
satisfy the entrance criteria may have the tests repeated once.  These tests may be repeated as 
soon as the investigator believes that the retest result is likely to be within the acceptable range to 
satisfy the entrance criteria, but they must be completed within the 4-week screening period 
(Days -35 to  -8).  In this case, the subject will not be required to sign another ICF, and the 
original subject identification number will be used.  If the laboratory tests cannot be performed 
within the screening period, if the retests do not meet the entrance criteria, or if the subject's 
medical condition has changed significantly during the screening period such that 
inclusion/exclusion criteria are no longer met, then the subject is considered a screen failure and 
must be withdrawn from the study.  Therefore, sites should consider the testing schedule 
carefully so that any potential retests are accomplished within the 4-week timeframe.  If the 
subject and investigator agree to rescreening, then the subject must sign a new ICF, a new 
subject identification number will be assigned, and all required screening activities must be 
performed when the subject is rescreened for participation in the study (except bone marrow 
biopsy if already performed at screening).  An individual subject may only rescreen once for the 
study. 
If all screening activities cannot be completed during the screening period because of an event 
unrelated to a laboratory finding, ECG finding, or medical history finding, including scheduling 
difficulties at the clinic site, then the subject may retain the original subject number and complete 
the remaining screening activities as soon as possible, within a maximum of 42 days (6 weeks) 
from the original screening visit date.  A blood draw for hematology and serum chemistry must 
be taken at the time that the subject returns for completion of screening activities and will be 
used to determine eligibility. 
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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is a Phase 2, randomized, double-blind, double-dummy study in subjects with ET who are 
resistant to or intolerant of HU (according to modified ELN criteria) with a screening platelet 
count ≥ 650 × 109/L and WBC count ≥ 11.0 × 109/L.  Subjects will be randomized in a 1:1 ratio, 
stratified by JAKV617 mutation status (positive vs negative), platelet count at screening (≥ 1000 
× 109/L or < 1000 × 109/L), and prior anagrelide use (yes vs no) to the following 2 treatment 
groups: 
• Group A:  ruxolitinib at a dose of 10 mg BID orally and anagrelide-placebo. 
• Group B:  anagrelide at a dose of 1 mg BID orally and ruxolitinib-placebo. 
The study will enroll approximately 120 subjects.  Due to block randomization and stratification, 
the 2 treatment groups may not each contain exactly the targeted number of subjects (n = 60). 
Subjects will receive blinded study treatment for 52 weeks.  Options for the open-label treatment 
phase are detailed in Section 4.1.1.  All subjects will be followed for safety (eg, reporting of AEs 
and SAEs) 30 to 37 days after the last dose of blinded study treatment or open-label study 
treatment.  The overall study design is shown in Figure 1. 
Figure 1: 
Study Design 
 
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4.1.1. 
Options for the Open-Label Treatment Phase 
Subjects originally randomized to ruxolitinib with anagrelide placebo (Group A) who are 
receiving benefit from therapy can 1) continue receiving open-label ruxolitinib until the study is 
concluded or they meet discontinuation criteria, or 2) choose to discontinue therapy. 
Subjects originally randomized to receive anagrelide plus ruxolitinib placebo (Group B) have 
3 options:  1) they may cross over to begin receiving ruxolitinib if they meet eligibility criteria 
after consultation with the sponsor and may then continue until the study is concluded or they 
meet discontinuation criteria; 2) they may continue receiving anagrelide until the study is 
concluded or they meet discontinuation criteria; or 3) they can choose to discontinue therapy.  
Note that subjects originally randomized to Group B may cross over to receive ruxolitinib at any 
time during the open-label part of the study. 
Subjects who will continue with the same active agent to which they were randomized will have 
a study visit at Week 56, at which time study drugs will switch over to open-label supplies 
(ruxolitinib or anagrelide) and then study visits every 12 weeks (Week 68, 80, etc).  Subjects 
who were originally randomized to anagrelide (Group B) and who cross over to ruxolitinib will 
begin receiving ruxolitinib at the Week 56 visit.  These subjects will have study visits at 
Weeks 1, 2, 3, 4, and every 4 weeks up to 52 weeks, then every 12 weeks thereafter.  Subjects 
who initially remain on anagrelide after unblinding but choose to cross over to receive ruxolitinib 
at a later time will have study visits at Weeks 1, 2, 3, 4, and every 4 weeks up to 52 weeks, then 
every 12 weeks thereafter. 
4.2. 
Measures Taken to Avoid Bias 
This is a randomized, double-blind, placebo-controlled study with a composite primary endpoint, 
defined as the proportion of subjects who complete at least 52 weeks of treatments and who 
achieve a simultaneous reduction of platelet count to < 600 × 109/L and of WBC count to 
< 10 × 109/L for at least 80% of biweekly measurements for 12 consecutive weeks between 
Weeks 32 and 52.  Subjects will receive blinded study drug (ruxolitinib + anagrelide placebo or 
anagrelide + ruxolitinib placebo). 
Centralized randomization numbers within each stratum will be created for treatment 
assignment.  Subjects will be stratified by presence/absence of the JAK2 V617F mutation, 
screening platelet count, and prior anagrelide use.  Subjects will be assigned to study treatment in 
accordance with the randomization schedule.  Subjects, investigators, and the study team will be 
blinded to treatment assignment.  A sponsor statistician who is not part of the study team will be 
unblinded and may provide summary-aggregated data by treatment group to the sponsor and/or 
the Data Monitoring Committee (DMC), but individual subject data will remain blinded. 
4.3. 
Number of Subjects 
Approximately 120 subjects will be randomized in a 1:1 ratio to 1 of 2 treatment groups 
(approximately 60 subjects per group). 
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4.4. 
Duration of Treatment and Subject Participation 
After signing the ICF, subject study participation is estimated to average approximately 24 to 
36 months per individual subject:  
Screening (Day -35 to Day -8):  Up to 28 days. 
Baseline (pretreatment) period (Day -7 to Day -1):  7 days before the first dose of treatment 
(required for all eligible subjects to complete the daily symptom diary for 7 days before the first 
dose of study medication). 
Blinded Treatment Phase (Day 1 through Week 52):  Begins with first dose of either 
ruxolitinib plus anagrelide-placebo or anagrelide plus ruxolitinib-placebo (Day 1).  The efficacy 
assessment period will be defined by collection of blood samples every 2 weeks between Weeks 
32 and 52. 
Open-Label Treatment Phase (Crossover and Extension Period):  After each individual 
subjects reach the Week 52 study visit (and all data through the Week 52 visit have been entered 
to the eCRF and the data verified), crossover to an open-label extension may occur.  Once 
Week 52 data completion has been confirmed, the study subject and the investigator will be 
unblinded to study treatment assignment.  The subjects will be brought into the study clinic for 
the unblinding crossover visit, which is designated as Week 56 in the schedules of assessments 
(Table 3 and Table 5). 
Subjects originally randomized to anagrelide (Group B) will be evaluated for eligibility to cross 
over to open-label ruxolitinib according to investigator's decision and if subjects meet safety 
criteria (eg, they do not now meet any exclusion criteria that would have precluded their 
participation in the study), after consultation with the sponsor.  Subjects originally randomized to 
ruxolitinib (Group A) who are receiving benefit from therapy will continue receiving open-label 
ruxolitinib until the study is concluded.  All subjects will be followed for safety (eg, reporting of 
AEs and SAEs) 30 to 37 days after last dose of blinded study treatment or open-label study 
treatment. 
Follow-up period:  30 to 37 days after the last dose of blinded study treatment or open-label 
ruxolitinib. 
4.5. 
Overall Study Duration 
The study begins when the first subject signs the ICF.  The blinded treatment phase is complete 
and study data analysis can occur for the primary endpoint when all subjects have completed 
Week 52 or discontinued, and all study data through the Week 52 visit have been entered and the 
data cleaned and verified.  The database will be frozen at this time for the initial data analysis to 
occur. 
The study is completed when the last subject has reached Week 156 (approximately 3 years of 
treatment).  Individual subject participation is expected to average 24 to 36 months. 
4.6. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the institutional review board 
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(IRB)/independent ethics committee (IEC) in writing of the study's completion or early 
termination, send a copy of the notification to the sponsor or sponsor's designee, and retain 
1 copy for the site study regulatory file. 
The sponsor may terminate the study electively, if required by regulatory decision, or upon 
advice of the DMC.  If the study is terminated prematurely, then the sponsor will notify the 
investigators, the IRBs and IECs, and regulatory bodies of the decision and reason for 
termination of the study. 
5. 
TREATMENT 
5.1. 
Treatment Assignment 
5.1.1. 
Subject Numbering and Treatment Assignment 
Each subject will be identified in the study by a subject ID number, which is a combination of 
the site ID and subject number (see Section 7.2). 
Enrollment will be controlled by an interactive voice/web response system (IXRS).   
Study sites will enter subject demographic and baseline data into the IXRS in order to receive a 
subject number and treatment allocation. 
All subject numbers will be 6 digits; the first 3 digits will be the site number, and the last 3 digits 
will be the subject's number.  This subject number will be maintained throughout the study and 
will not be reassigned.  Subjects who withdraw consent or discontinue from the study after being 
assigned a subject number will retain their initial number. 
Site staff will contact the IXRS to allocate the subject to treatment assignment and obtain the 
initial study drug assignment.  The investigator or designee will select the assigned units of study 
drug from their stock that correspond to the number provided by the IXRS and dispense the 
study drug to the subject.  All subsequent dispensing of study drug should follow this process.  
Refer to the IXRS manual for detailed information. 
If a subject is mistakenly given a bottle of study drug that is not the bottle assigned by the IXRS, 
then the IXRS help desk must be notified immediately.  The reason for the misallocation of the 
study drug must be documented by the study site and reported to the IRB/IEC. 
For subjects who signed an ICF but are not allocated and for subjects who are allocated but were 
not treated, refer to the electronic case report form (eCRF) Completion Guidelines for instruction 
on which eCRFs to complete. 
5.1.2. 
Randomization and Blinding 
Subjects will be randomly assigned to either Group A or Group B through central randomization 
by the IXRS.  Full details will be provided in the IXRS manual. 
Subjects, investigators, and the sponsor will remain blinded to each subject's treatment 
assignment throughout the study.  Emergency unblinding will occur if an AE requires the 
investigator to be made aware of the subject's treatment assignment. 
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5.1.2.1. 
Blinding and Unblinding 
Treatment assignment should remain blinded to the investigators, subjects, and sponsor as long 
as the blinded treatment period continues for that subject.  Unblinding of treatment assignment 
may occur in 2 different circumstances:  emergency unblinding and scheduled unblinding for 
individual subjects after Week 52. 
5.1.2.1.1. Emergency Unblinding 
The investigator will, whenever possible, discuss options with the sponsor's medical monitor 
before initiating the emergency unblinding procedure.  If the investigator is unable to contact the 
sponsor before unblinding, then the investigator must notify the sponsor as soon as possible after 
the unblinding incident.  In addition, the investigator will record the date and reason for 
revealing the blinded treatment assignment for that subject.  Refer to the IXRS manual for 
detailed emergency unblinding procedures. 
If an SAE (as defined in Section 8.3) is reported to the sponsor, then the sponsor may choose to 
unblind the treatment assignment for the individual subject.  If an expedited regulatory report to 
1 or more regulatory agencies is required, then the report will identify the subject's treatment 
assignment.  When applicable, a copy of the regulatory report may be sent to investigators in 
accordance with relevant regulations, the sponsor's policy, or both. 
Generally, emergency unblinding will occur only in the case of a serious medical event for which 
knowledge of the treatment assignment is critical for the acute medical management of the 
subject's condition.  Subjects experiencing this type of event will be withdrawn from study 
participation for safety reasons. 
5.1.2.1.2. Scheduled Unblinding 
After each individual subject completes the Week 52 visit, and when all data for each subject 
have been entered into the eCRFs and cleaned and verified, unblinding for an individual subject 
can occur.  Subjects will be brought to the study clinic for the unblinding/crossover visit, which 
is designated Week 56 in the schedules of assessments (Table 3 and Table 5).  Subjects who will 
continue receiving the study drug to which they were originally randomized will have 
subsequent visits every 12 weeks (Week 68, 80, etc). 
Subjects who are unblinded and cross over to start ruxolitinib for the first time will have study 
visits at Weeks 1, 2, 3, 4, and every 4 weeks up to 52 weeks, then every 12 weeks thereafter. 
The unblinding of study treatment before Week 52 will only occur for medical emergency 
purposes (SAE for which unblinding is necessary for medical management) and will result in 
withdrawal from the study.  
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5.2. 
Study Drug  
5.2.1. 
Ruxolitinib 
5.2.1.1. 
Description and Administration  
Ruxolitinib or matching placebo will be provided as 5 mg tablets packaged in high-density 
polyethylene (HDPE) bottles.  Ruxolitinib or matching placebo will be self-administered as a 
BID oral treatment. 
Doses of ruxolitinib or matching placebo should be self-administered with approximately 
12 hours apart without regards to food. 
Note that subjects must be instructed to withhold the morning dose of ruxolitinib or matching 
placebo until reaching the clinic for each study visit where dose administration will occur.  The 
dose must be reduced or interrupted for declining platelet count, hemoglobin, or ANC as 
described in Section 5.4 and will be increased or restarted with recovery of hematologic 
parameters. 
5.2.1.2. 
Supply, Packaging, and Labeling 
The study drugs will be dispensed in a kit form in which paired bottles of study drugs will be 
dispensed to the subject, with instructions of how to self-administer the study drugs. 
All Incyte investigational product labels will be in the local language and will comply with the 
legal requirements of each country. 
5.2.1.3. 
Storage 
The bottles of tablets should be stored at room temperature, 15°C to 30°C (59°F to 86°F). 
5.2.2. 
Anagrelide  (Non-Incyte Product) 
5.2.2.1. 
Description and Administration 
Anagrelide hydrochloride or matching placebo will be provided as 0.5 mg capsules packaged in 
HDPE bottles.  
Anagrelide or matching placebo will be self-administered as a BID oral treatment using the dose 
designated at the time of the screening visit for each subject. 
Doses of anagrelide or matching placebo should be self-administered approximately 12 hours 
apart without regards to food.  
Note that subjects must be instructed to withhold the morning dose of anagrelide or matching 
placebo until reaching the clinic for each study visit where dose administration will occur.  The 
dose must be reduced or interrupted for declining platelet count or ANC as described in 
Section 5.4 and will be increased or restarted with recovery of hematologic parameters. 
For patient-specific counseling information, refer to the anagrelide label (Agrylin 2013). 
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5.2.2.2. 
Supply, Packaging, and Labeling  
The study drugs will be dispensed in a kit form in which paired bottles of study drugs will be 
dispensed to the subject, with instructions of how to self-administer the study drugs. 
Anagrelide or matching placebo reference therapies with marketing authorisation must be used in 
accordance with the storage conditions and shelf life in the manufacturer's approved label. 
5.2.2.3. 
Storage 
The bottles of anagrelide or matching placebo capsules should be stored at room temperature, 
15°C to 30°C (59°F to 86°F).  Stability studies will be conducted on clinical batches to support 
the clinical study. 
5.2.3. 
Instruction to Subjects for Handling Study Drug Ruxolitinib and Anagrelide  
and Their Matching Placebo 
The subject must be instructed in the handling of study drugs as follows: 
• To store study drugs at room temperature. 
• To only remove from the bottle of ruxolitinib and/or anagrelide or matching placebo 
the number of tablets needed at the time of administration. 
• Not to remove doses in advance of the next scheduled administration. 
• To make every effort to take doses of ruxolitinib and/or anagrelide or matching 
placebo on schedule. 
• To report any missed doses at the next study visit.  
• If the subject vomits after taking study drug(s), then the subject should not take 
another dose. 
• If a dose of study drug is missed by more than 4 hours, then that dose should be 
skipped, and the next scheduled dose taken at the usual time. 
• To keep study drug in a safe place and out of reach of children. 
• To bring all used and unused study drug kits to the site at each visit. 
5.3. 
Treatment Compliance 
Compliance with all study-related treatments should be emphasized to the subject by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study.  
Compliance with ruxolitinib and/or anagrelide or matching placebo will be calculated by the 
sponsor based on the drug accountability documented by the site staff and monitored by the 
sponsor/designee (tablet counts).  Subjects will be instructed to bring all study drugs with them 
to the study visits in order for site personnel to conduct tablet counts to assess study drug 
accountability.  The drug accountability documentation will be used by the sponsor to calculate 
treatment compliance.  
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5.4. 
Treatment Modifications:  Increases, Interruptions, and 
Adjustments 
Subjects randomized to either study group will be receiving both an active drug and a placebo 
(dummy drug).  Neither the investigator nor the subject will know which is the active drug and 
which is the placebo.  Thus, in order to maintain the blind, when dose modification is required, 
both of the study drugs will be titrated together.  
5.4.1. 
Dose Increases for Inadequate Efficacy 
Dose increases will be permitted for inadequate efficacy.  Dose increases for subjects meeting 
prespecified criteria for inadequate efficacy will be permitted after 2 weeks of therapy, and dose 
decreases for safety are allowed at any time.  Doses of both study drugs will be titrated 
simultaneously using different dose levels as shown in Table 2.  Anagrelide or anagrelide 
placebo and ruxolitinib or ruxolitinib placebo increases are permitted per investigator discretion 
and taking into account the manufacturer's instructions, labeling, and subject's medical condition.  
Each dose escalation must be at least 1 week apart, and subjects must meet all of the following 
criteria: 
1. Platelet count ≥ 150 × 109/L 
2. Hemoglobin ≥ 9 g/dL. 
3. ANC ≥ 1500 × 109/L. 
4. One or more of the following:  
a. Platelet count > 600 × 109/L. 
b. WBC count > 10 × 109/L. 
c. Minimal improvement, no change, or worsening of vasomotor symptoms including 
headache, lightheadedness, syncope, atypical chest pain, acral paresthesia, livedo 
reticularis, erythromelalgia, and transient visual disturbances (eg, amaurosis fugax, 
scintillating scotomata, ophthalmic migraine).  
Additionally, it is recommended that safety hematology be performed within 14 days of a 
dose increase to confirm that a safe dose has not been exceeded.  Doses may be increased 
by 5 mg BID for ruxolitinib or ruxolitinib-placebo.  These are per investigator discretion and 
taking into account the manufacturer's instructions, labeling, and subject's medical condition.  
The dose of ruxolitinib or ruxolitinib-placebo will never exceed 25 mg BID. 
Doses of anagrelide or anagrelide placebo may not be increased by more than 0.5 mg/day per 
week from the previous dose or to a dose that was not previously tolerated by the subject.  The 
dose of anagrelide or anagrelide placebo should not exceed 2.5 mg BID (and 2.5 mg in a single 
dose).  The maximum dose of anagrelide is 2.5 mg BID (5 mg total per day), which corresponds 
to a high maintenance dose used in practice. 
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5.4.2. 
Dose Interruptions or Decreases for Toxicity 
5.4.2.1. 
Hematologic Toxicities 
The following changes in hematologic values will be considered sufficient reason for dose 
interruption according to the guidelines in Table 1. 
Table 1: 
Dose Interruptions for Hematologic Toxicities 
Parameter 
Dose Reduction by 
1 Dose Level If: 
Hold If 
Reinstitute Drug at 
1 Dose Level Lower 
When Recovered to 
Hematocrit (%) 
< 35% 
< 30% 
≥ 35% 
ANC (× 109/L) 
< 1.5 × 109/L 
< 1.0 × 109/L 
≥ 1.25 × 109/L 
Platelet count (× 109/L) 
< 150× 109/L 
< 100× 109/L 
≥ 125 × 109/L 
5.4.2.2. 
Nonhematologic Toxicities 
Treatment with study drug should also be withheld for any ≥ Grade 3 nonhematologic toxicity 
possibly, probably, or definitely related to treatment and only resumed after the toxicity returns 
to baseline. 
Hematological and nonhematological toxicities should be reviewed by the investigator with the 
subject in person, by telephone, or by e-mail at least weekly.  Drug may be withheld up to 
4 weeks at a time up to a maximum of 8 weeks, but if hematology parameters do not return to the 
level for reinstituting drug by that time, or if another nonhematological form of toxicity does not 
return to baseline grade, then the subject will be discontinued from the study.  Erythropoietin is 
not allowed during the study.  
 
  
Doses of both study drugs are titrated simultaneously following the guidelines in Table 2. 
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Table 2: 
Dose Levels for Ruxolitinib and Anagrelide and Dose Reduction/Restart 
Guidelines 
Dose Level  
Ruxolitinib 
Dose Level  
Anagrelide 
Week 
Dose (mg) 
Total Daily 
Dose (mg) 
Week  
Dose (mg) 
Total Daily 
Dose (mg)  
AM 
PM 
AM 
PM 
DL 4 
W 2 
25 
25 
50 
DL 4 
W 2 
2.5 
2.5 
5 
W 1 
25 
25 
50 
W 1 
2 
2.5 
4.5 
DL 3 
W 2 
20 
20 
40 
DL 3 
W 2 
2 
2 
4 
W 1 
20 
20 
40 
W 1 
1.5 
2 
3.5 
DL 2 
W 2 
15 
15 
30 
DL 2 
W 2 
1.5 
1.5 
3 
W 1 
15 
15 
30 
W 1 
1 
1.5 
2.5 
DL 1 - STARTING DOSE 
10 
10 
20 
DL 1 - STARTING DOSE 
1 
1 
2 
DL -1 
W 1 
10 
5 
15 
DL -1 
W 1 
1 
0.5 
1.5 
W 2 
10 
5 
15 
W 2 
1 
0.5 
1.5 
DL -2 
W 1 
5 
5 
10 
DL -2 
W 1 
0.5 
0.5 
1 
W 2 
5 
5 
10 
W 2 
0.5 
0.5 
1 
DL -3 
W 1 
5 
0 
5 
DL -3 
W 1 
0.5 
0 
0.5 
W 2 
5 
0 
5 
W 2 
0.5 
0 
0.5 
5.4.2.3. 
Dose Reductions With Concomitant Cytochrome P450 Inhibitors 
5.4.2.3.1. Cytochrome P450 3A4 Inhibitors 
Ruxolitinib is metabolized in the liver by the CYP-metabolizing enzyme system, predominantly 
by the 3A4 isozyme.  With concomitant treatment of potent CYP3A4 inhibitors such as systemic 
ketoconazole (see Appendix H), plasma exposure of ruxolitinib increases by approximately 
2-fold.  Thus, a dose reduction of approximately 50% for study treatment is appropriate for 
subjects who take systemic ketoconazole or other potent CYP3A4 inhibitors systemically as 
concomitant medication.  This dose reduction should be accomplished by reducing doses of 
ruxolitinib or ruxolitinib-placebo from BID to QD. 
Potent inhibitors of CYP3A4 include systemic ketoconazole, posaconazole, voriconazole, 
clarithromycin, itraconazole, nefazodone, and telithromycin (see Appendix H).  Dose reductions 
are not required for topical ketoconazole. 
NOTE:  Once the course of therapy using a CYP3A4 inhibitor has been completed, the subject 
may resume his/her previous BID dose regimen of study treatment beginning the next day. 
5.4.2.3.2. Cytochrome P450 1A2 Inhibitors 
Anagrelide is metabolized at least in part by CYP1A2.  Anagrelide is an inhibitor of cyclic AMP 
PDEIII.  Thus, a dose reduction of approximately 50% for study treatment is appropriate for 
subjects who take potent CYP1A2 inhibitors systemically as concomitant medication (see 
Appendix H).  This dose reduction should be accomplished by reducing doses of anagrelide or 
anagrelide-placebo from BID to QD. 
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NOTE:  Once the course of therapy using a CYP1A2 inhibitor has been completed, the subject 
may resume his/her previous BID dose regimen of study treatment beginning the next day. 
Investigators may refer to anagrelide label for further detailed information of potential 
interactions. 
5.4.3. 
Dose Discontinuation of Ruxolitinib or Ruxolitinib Placebo/Anagrelide or 
Anagrelide Placebo 
5.4.3.1. 
Discontinuation of Study Drugs for Hematologic Toxicity 
Study drug (ruxolitinib, anagrelide, or matching placebos) MUST be permanently discontinued if 
any 1 of the following Grade 3 or 4 hematologic toxicities (National Cancer Institute [NCI] 
CTCAE v 4.03) fails to resolve to ≤ Grade 2 within 8 weeks of study drug interruption or if a 
lower restart dose or administration schedule subsequent to any of the following recurrent 
Grade 3 hematologic toxicities is either not available or likely to be clinically ineffective:  
• Hgb < 8.0 g/dL (Grade 3). 
• Platelet count < 25 × 109/L (Grade 4). 
• ANC < 0.5 × 109/L (Grade 4). 
5.4.3.2. 
Discontinuation of Study Drug for Nonhematologic Toxicity 
Study drug (ruxolitinib, anagrelide, or matching placebos) MUST be permanently discontinued if 
any 1 of the following AEs fails to resolve to ≤ Grade 2 within 8 weeks of study drug 
interruption or if a lower restart dose or administration schedule subsequent to any of the 
following nonhematologic toxicities is either not available or likely to be clinically ineffective:  
• The occurrence of a Grade 4 laboratory or nonlaboratory abnormality attributable to 
study treatment (ruxolitinib, anagrelide, or matching placebo). 
• The occurrence of a Grade 3 laboratory or nonlaboratory abnormality attributable to 
study treatments (ruxolitinib, anagrelide, or matching placebo) that remains at 
Grade 3 or worse for > 7 days duration and, for laboratory abnormalities, is deemed 
clinically significant in the judgment of the investigator. 
5.4.3.3. 
Dose Reduction Tapering Strategy (Optional) 
Following discontinuation of study drugs, symptoms from MPNs may return to pretreatment 
levels over a period of approximately 1 week. 
When discontinuing or interrupting therapy for reasons other than thrombocytopenia or 
neutropenia, consider tapering the dose of study drugs gradually rather than discontinuing 
abruptly.  A dose-tapering strategy may be considered, based on evaluation of the condition of 
the subject, current dosing regimen, and the clinical judgment of the investigator. 
5.4.4. 
Dose Modifications for Subjects Receiving Open-Label Treatment 
The dose increase, decrease, and discontinuation rules described in Sections 5.4.1, 5.4.2, and 
5.4.3 will be followed for subjects receiving open-label anagrelide or open-label ruxolitinib.  
Table 2 should be used to identify dose levels for the individual study medications.  
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5.5. 
Withdrawal of Subjects From Study Treatment 
In the event that any subject permanently discontinues the study treatment, regardless of reason, 
reasonable efforts should be made to have the subject return to have the end-of-treatment (EOT) 
and follow-up evaluations completed as described in Section 6.6. 
The date that the subject discontinued the study treatment and the specific reason for withdrawal 
will be recorded in the eCRF.  This information will be used to summarize the reasons for study 
withdrawal. 
5.5.1. 
Withdrawal Criteria 
Subjects must be withdrawn from study treatment for the following reasons: 
• Toxicities occur as noted in Section 5.4.3. 
• Treatment is interrupted for ≥ 8 weeks, unless approved by medical monitor. 
• Subject is unblinded before Week 52 for safety reasons. 
• The subject becomes pregnant (positive urine pregnancy test, confirmed by positive 
serum pregnancy [serum human chorionic gonadotropin] test results). 
• Consent is withdrawn.   
• Further participation would be injurious to the subject's health or well-being, in the 
investigator's medical judgment. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A subject may be discontinued from study treatment as follows: 
• Subjects may choose to withdraw from the study at any time without penalty of 
jeopardizing their health care or loss of benefits to which the subject is otherwise 
entitled.  Every reasonable effort should be made to determine the reason that a 
subject withdraws prematurely, and this information should be recorded in the eCRF. 
• If, during the course of the study, a subject is found not to have met eligibility 
criteria, then the medical monitor, in collaboration with the investigator, will 
determine whether the subject should be withdrawn from the study (see Section 10.5, 
Protocol Adherence). 
• A subject may be withdrawn from the study if, in the investigator's expert medical 
judgment, the subject is noncompliant with the study requirements.  The sponsor 
should be consulted for instruction on handling the subject.  Subjects may be 
withdrawn at the discretion of the FDA or the investigator. 
5.5.2. 
Withdrawal Procedures 
In the event that the decision is made to permanently discontinue the study treatment, the subject 
will be withdrawn from the study and the end-of-treatment visit should be conducted.  
Reasonable efforts should be made to have the subject return for a follow-up visit.  These visits 
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are described in Section 6.  The last date of the last dose of study treatment and the reason for 
subject withdrawal will be recorded in the eCRF. 
If a subject is withdrawn from the study treatments: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal must be documented in the subject's medical record and 
in the eCRF. 
• The EOT visit should be performed, including diary completion. 
• The date of the EOT visit should be recorded in the IXRS. 
• In the event that a decision is made to permanently discontinue the study treatment 
and the subject is withdrawn from the study, reasonable efforts should be made to 
have the subjects return for a follow-up visit for safety until the time of the follow-up 
visit or until study treatment–related toxicities resolve, return to baseline, or are 
deemed irreversible, whichever is longest. 
If the subject discontinues study treatment and actively withdraws consent for collection of 
follow-up data (safety follow-up or disease assessment), then no additional data collection 
should occur; however, subjects will have the option of withdrawing consent for study treatment 
but continuing in the follow-up period of the study for safety/efficacy assessments. 
5.6. 
Concomitant Medications 
5.6.1. 
Permitted Medications 
All concomitant medications and treatments must be recorded in the eCRF.  Any prior 
medication received up to 30 days before randomization will be recorded in the eCRF.  
Concomitant treatments or procedures that are required to manage a subject's medical condition 
during the study will also be recorded in the eCRF.  
 
 
Antibiotic prophylaxis for chronic treatment is permitted; subjects requiring acute antibiotic 
treatment at the time of screening must delay screening/enrollment until the course of antibiotic 
therapy is completed.  
All randomized subjects should receive low dose aspirin (75 mg to 125 mg daily) unless 
medically contraindicated.  In this case, other prophylactic antithrombotic agents may be used. 
The subject needs to notify the investigational site about any new medications he/she takes after 
the start of the study drug.  All medications (other than study drug) and significant nondrug 
therapies (including physical therapy and blood transfusions) administered after the subject starts 
treatment with study drug must be listed on the Concomitant Medications/Significant Nondrug 
Therapies After Start of Study Drug eCRF.   
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5.6.2. 
Restricted Medications 
The following medications are restricted during the study: 
1. Aspirin in doses exceeding 125 mg per day is not permitted.  Low-dose aspirin is 
permitted.  Acetaminophen and nonsteroidal anti-inflammatory agents (eg, ibuprofen, 
NSAIDs) may be used at over-the-counter doses.  Subjects receiving over-the-counter 
NSAIDs should not exceed the recommended dose and should be encouraged to use 
gastroprotective agents (antacids, H2 antagonists, or proton pump inhibitors).   
2. Inducers of CYP3A4 (Appendix H) may be used with caution, and investigators should 
seek other options if available. 
3. Moderate CYP3A4 inhibitors (Appendix H) may be used with caution.  Differences in 
individual sensitivity and variation in potency of inhibition of various CYP enzymes may 
result in the need for a reduced dose of ruxolitinib during a period of concomitant 
medication use.  If required for safety, the study drug dose may be reduced from BID to 
QD in these circumstances.  The sponsor's medical monitor may be consulted for advice 
when using these agents. 
4. Use of potent inhibitors of CYP3A4 and CYP1A2 should be avoided where possible.  
See Section 5.4.2.3 for required dose reductions and Appendix H for included CYP 
inhibitors.  
5. If concomitant administration of an anticoagulant/antiplatelet medication is indicated, 
then caution and enhanced monitoring is required.  History of thrombocytopenia and any 
concurrent ruxolitinib-related thrombocytopenia should be a factor in the choice of 
anticoagulant and dose.   
5.6.3. 
Prohibited Medications 
The following medications are prohibited during the study: 
1. Any prior or concomitant use of another JAK inhibitor. 
2. Concurrent use of anagrelide or HU. 
a. Prior anagrelide use is allowed provided the reason for discontinuation is not 
AE-related and anagrelide is stopped at least 28 days before the start of study 
medications (ie, Day 1). 
b. Treatment with HU can be stopped at any time once one of the inclusion criteria for 
HU refractoriness or resistance have been met, and up to the day before the first dose 
of study treatment (ie, Day 1). 
3. Any investigational medication (other than ruxolitinib) that is not approved for any 
indication.   
a. Use of such medications within 30 days or 5 half-lives, whichever is longer, before 
the first dose of study drug and during the study through the safety follow-up visit is 
prohibited. 
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4. Steroid doses greater than the equivalent of 10 mg prednisone per day.  During study 
participation, if a subject requires steroids for a comorbid condition, then continuation in 
the study will be considered on an individual basis by the sponsor and the investigator 
(unless part of study treatment dose-tapering strategy).  
5. Use of busulfan, interferon alpha, pegylated interferon, or any investigational medication 
used to treat ET is not permitted at any time beginning on Day -30 up until the time that 
ruxolitinib therapy is permanently discontinued.  Use of androgens to treat anemia is 
permitted. 
 
 
7. Erythropoietin is not allowed during the study. 
8. Romiplostim or eltrombopag are not permitted beginning with the baseline visit (Day -7) 
through the final dose of ruxolitinib.   
9. St John's Wort and rifampin are not permitted at any time during participation in the 
study. 
10. Any medications that may prolong QTc interval of the ECG.  
See Appendix H  for a list of CYP inhibitors and inducers. 
See Appendix J for a list of drugs that may cause prolongation of QT interval.  
6. 
STUDY ASSESSMENTS 
All study assessments will be performed as indicated in the schedule of assessments (Table 3), 
and all laboratory assessments will be performed as indicated in Table 4.  The schedule of 
assessments and laboratory assessments for subjects in Group B (anagrelide) who cross over to 
open-label ruxolitinib after Week 52 are provided in Table 5 and Table 6.  Table 7 presents a 
summary of clinical laboratory analytes to be assessed.  The order of assessments is suggested by 
the order of mention within the schedule.  See Section 7 for instructions on each assessment.  
Further details of study procedures and assessments can be found in the study reference manual.
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Table 3: 
Schedule of Assessments 
 
Section 
Screening Baseline 
Blinded Treatment (All Subjects) 
Open-Label Treatment 
EOT 
Safety 
Follow-Up 
30-37d 
After Last 
Dose 
Notes 
Subjects 
Who Do Not 
Cross Over 
Subjects 
Who 
Cross Over 
W1-W3 
W4-W52 
q4w 
W34-W50 
q4w (lab only) W56 + q12w W56+ q12w 
Days -35 
to -8 
Days -7 
to -1 
D1 
D8 
(±2d) 
D15 
(±2d) 
D22 
(± 2d) 
D7 
(± 3d) 
D7 (± 3d) 
D7 (± 7d) 
 
Informed consent 
7.1  
X 
 
 
 
 
 
 
 
 
See Table 5 
 
 
 
Contact IXRS 
7.2  
X 
 
X 
 
 
 
X 
 
X 
X 
 
 
Review inclusion 
and exclusion 
criteria 
7.5.1  
X 
 
X 
 
 
 
 
 
 
 
 
 
Demography, 
medical history 
7.3  
X 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
7.4  
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Vital signs 
7.5.4  
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Vital signs collected after 
5 min rest in recumbent, 
semirecumbent, or sitting 
position. 
Physical 
examination,  
body weight, 
height 
7.5.3  
X* 
 
X 
X 
X 
X 
X 
 
X 
X* 
X 
* Comprehensive 
examination at screening and 
EOT visits, targeted physical 
examination at all other 
indicated visits. 
Height at screening only. 
ECOG status 
7.7.1  
X* 
 
X* 
 
 
 
X 
 
X 
X 
 
* Performance status must be 
0, 1, or 2 at baseline. 
/liver 
palpation 
7.6.3   
X 
X 
 
 
 
 
X 
 
X 
X 
X 
Using flexible ruler provided 
for study. 
Complete MPN-
SAF 
questionnaire 
7.7.4 
 
X 
 
 
 
 
X* 
 
 
X* 
 
*Weeks 32 and 52 and/or 
EOT visits. 
Overall response 
assessment 
7.6.2 
 
 
 
 
 
 
X* 
 
 
X* 
 
* Weeks 32 and 52 and/or 
EOT visits. 
12-lead ECG 
7.5.5  
X 
 
 
 
 
 
X* 
 
 
X 
 
* Week 52. 
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Table 3: 
Schedule of Assessments (Continued) 
 
Section 
Screening Baseline 
Blinded Treatment (All Subjects) 
Open-Label Treatment 
EOT 
Safety 
Follow-Up 
30-37d 
After Last 
Dose 
Notes 
Subjects 
Who Do Not 
Cross Over  
Subjects 
Who 
Cross Over 
W1-W3 
W4-W52 
q4w 
W34-W50 
q4w (lab only) W56 + q12w W56+ q12w 
Days -35 
to -8 
Days -7 
to -1 
D1 
D8 
(±2d) 
D15 
(±2d) 
D22 
(± 2d) 
D7 
(± 3d) 
D7 (± 3d) 
D7 (± 7d) 
D7 (± 7d) 
Laboratory tests 
7.5.6  
X 
X 
X 
X 
X 
X 
X* 
X* 
X 
See Table 5 
X 
X 
* Weeks 32-52 are 
evaluation period for primary 
endpoint.  Should ALL be 
carefully monitored by sites. 
Review AEs 
7.5.2  
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Transfusion 
history/status 
7.4  
X 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
Drug dispensed 
7.10.2  
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
Drug 
accountability 
7.10.3  
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
MPN-SAF = Myeloproliferative Neoplasm–Symptom Assessment Form (paper/pencil format). 
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Table 4: 
Schedule of Laboratory Assessments 
 
Section 
Screening Baseline 
 Blinded Treatment (All Subjects) 
Open-Label Treatment 
EOT 
Safety 
Follow-Up 
30-37d 
After Last 
Dose 
Notes 
Subjects 
Who Do Not 
Cross Over  
Subjects 
Who 
Cross Over 
W1-W3 
W4-
W52 
q4w 
W34-W50 
q4w 
(lab only) W56+ q12w W56+ q12w 
Days -35 to 
-8 
Days -7 
to -1 
D1 
D8 
(±2d) 
D15 
(± 2d) 
D22 
(± 2d) 
D7 
(± 3d) 
D7 
(± 3d) 
D7 
(± 7d) 
D7 
(± 7d) 
Local 
laboratory 
assessments 
 
 
 
 
 
 
 
 
 
 
See Table 6  
 
 
 
Hematology  
7.5.6  
X 
X* 
X* 
X 
X 
X 
X** 
X** 
X 
X 
X 
* Should be taken as close as possible 
to Day 1 but may be drawn up to 
3 days before first dose.  Only 1 
sample for baseline/Day 1 is required. 
** Weeks 32-52 are evaluation period 
for primary endpoint:  Should ALL be 
carefully monitored by sites. 
Ferritin level 
7.5.6 
 
X 
 
 
 
 
 
 
 
 
 
 
Coagulation 
panel 
7.5.6  
X 
X* 
X* 
 
 
 
 
 
 
X 
 
* Should be taken as close as possible 
to Day 1 but may be drawn up to 
3 days before first dose.  Only 
1 sample for baseline/Day 1 is 
required. 
Serum 
chemistries 
7.5.6   
X 
X* 
X* 
X 
X 
X 
X 
 
X 
X 
X 
* Should be taken as close as possible 
to Day 1 but may be drawn up to 
3 days before first dose.  Only 1 
sample for baseline/Day 1 is required. 
Urine 
pregnancy test 
7.5.6.1 
 
 
X 
 
 
 
X 
 
X 
 
 
Females of childbearing potential.  
Test should be repeated if required by 
local regulations. 
Not needed if FSH elevated or 
amenorrheic > 1 year. 
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Table 4: 
Schedule of Laboratory Assessments (Continued) 
 
Section 
Screening Baseline 
 Blinded Treatment (All Subjects) 
Open-Label Treatment 
EOT 
Safety 
Follow-Up 
30-37d 
After Last 
Dose 
Notes 
Subjects 
Who Do Not 
Cross Over  
Subjects 
Who 
Cross Over 
W1-W3 
W4-
W52 
q4w 
W34-W50 
q4w 
(lab only) W56+ q12w W56+ q12w 
Days -35 to 
-8 
Days -7 
to -1 
D1 
D8 
(±2d) 
D15 
(± 2d) 
D22 
(± 2d) 
D7 
(± 3d) 
D7 
(± 3d) 
D7 
(± 7d) 
D7 
(± 7d) 
Bone marrow 
biopsy and 
analysis 
7.6.4 
X* 
 
 
 
 
 
X** 
 
X*** 
See Table 6 
X 
 
Local laboratory evaluation and 
pathology report. 
* Predose biopsy not required if 
previous biopsy and report from 
2 months before screening are 
available. 
** Weeks 32 and 52 only. 
*** Optional at Week 104 and 152 for 
ruxolitinib-treated subjects only. 
Central 
laboratory 
samples 
 
 
 
 
 
 
 
 
 
 
 
 
The central laboratory is the sponsor 
or designee. 
Bone marrow 
biopsy and 
analysis 
7.6.4   
X* 
 
 
 
 
 
X** 
 
X*** 
X 
 
Samples sent for banking to central 
laboratory.  See notes for local 
laboratory collections above. 
Lipid panel 
7.5.6  
X 
 
X* 
X 
X 
X 
X 
 
X 
X 
X 
* Should be taken as close as possible 
to Day 1 but may be drawn up to 3 
days before first dose.  Only 1 sample 
for baseline/Day 1 is required. 
Serology 
hepatitis A, B, 
and C 
7.5.6  
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
7.5.6  
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
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Table 4: 
Schedule of Laboratory Assessments (Continued) 
 
Section 
Screening Baseline 
 Blinded Treatment (All Subjects) 
Open-Label Treatment 
EOT 
Safety 
Follow-Up 
30-37d 
After Last 
Dose 
Notes 
Subjects 
Who Do Not 
Cross Over  
Subjects 
Who 
Cross Over 
W1-W3 
W4-
W52 
q4w 
W34-W50 
q4w 
(lab only) W56+ q12w W56+ q12w 
Days -35 
to -8 
Days -7 
to -1 
D1 
D8 
(±2d) 
D15 
(± 2d) 
D22 
(± 2d) 
D7 
(± 3d) 
D7 
(± 3d) 
D7 
(± 7d) 
D7 
(± 7d) 
Serum 
pregnancy 
7.5.6.1  
X 
 
 
 
 
 
 
 
 
See Table 6  
X 
 
Not needed if FSH elevated or 
amenorrheic > 1 year.  Test should be 
repeated if required by local 
regulations. 
FSH 
7.5.6.1  
X 
 
 
 
 
 
 
 
 
 
 
To document hormonal menopause. 
FSH = follicle-stimulating hormone 
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Table 5: 
Schedule of Assessments for Subjects From Group B Who Cross Over to Open-Label Ruxolitinib 
 
Section 
Crossover 
Eligibility 
Visit  
Crossover Treatment Phase 
Notes 
W1-W3  
After Crossover  
W4-W52 q4w 
After Crossover 
W56+ q12w  
After Crossover 
Day  
 -1 
D1 
D8 
(± 2d) 
D15 
(± 7d) 
D22 
(± 2d) 
D7 (± 3d) 
D7 (± 7d) 
Contact IXRS 
7.2  
X 
 
 
 
 
X 
X 
 
Review inclusion and 
exclusion criteria 
7.5.1  
X 
 
 
 
 
 
 
To determine eligibility for crossover. 
Prior/concomitant 
medications 
7.4  
X 
 
X 
X 
X 
X 
X 
 
Vital signs 
7.5.4  
X 
 
X 
X 
X 
X 
X 
Vital signs collected after 5 min rest in 
recumbent, semirecumbent, or sitting 
position. 
Physical examination,  
body weight 
7.5.3  
X 
 
X 
X 
X 
X 
X 
Comprehensive examination at the 
crossover eligibility visit and EOT; 
targeted examination at all other visits. 
ECOG status 
7.7.1  
X* 
 
 
X 
 
X 
X 
* Must be 0, 1, or 2 to start ruxolitinib. 
/liver palpation 
7.6.3   
X 
 
 
X 
 
X 
X 
Using flexible ruler provided for study. 
12-lead ECG 
7.5.5  
X 
 
 
 
 
X* 
 
* Week 52 
Laboratory tests 
7.5.6  
X 
 
X 
X 
X 
X 
X 
See Table 6 and Table 7. 
Review AEs 
7.5.2  
X 
 
X 
X 
X 
X 
X 
 
Transfusion history/status 
7.4  
X 
 
 
 
 
 
 
 
Open-label ruxolitinib 
dispensed 
7.10.2  
X* 
 
 
 
 
X 
X 
* Open-label ruxolitinib may be 
dispensed at the crossover eligibility 
visit. 
Record first day of open-
label ruxolitinib dosing 
7.10.1 
X 
 
 
 
 
 
 
 
Drug accountability 
7.10.3  
 
 
 
 
 
X 
X 
 
 
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Table 6: 
Schedule of Laboratory Assessments for Subjects From Group B Who Cross Over to Open-Label Ruxolitinib 
 
Section 
Crossover 
Eligibility 
Visit  
Crossover Treatment Phase 
Notes 
W1-W3 after Cross Over 
W4-52 q4w 
After Crossover 
W56 + q12w 
After Crossover 
Day -1 
D1 
D8 
(± 2d) 
D15 
(± 2d) 
D22 
(± 2d) 
D7 (± 3d) 
D7 (± 3d) 
Local laboratory 
assessments 
 
 
 
 
 
 
 
 
 
Hematology  
7.5.6  
X 
 
X 
X 
X 
X 
X 
 
Coagulation panel 
7.5.6  
X 
 
 
 
 
 
 
 
Serum chemistries 
7.5.6   
X 
 
X 
X 
X 
X 
 
 
Urine pregnancy test 
7.5.6.1 
X 
 
 
 
 
X 
X 
Females of childbearing potential if 
required by local regulations.  Test 
should be repeated if required by local 
regulations. 
Central laboratory 
samples* 
 
 
 
 
 
 
 
 
* The central laboratory is the sponsor or 
designee. 
Lipid panel 
7.5.6  
X 
 
 
 
 
X 
X 
 
Urinalysis 
7.5.6  
X 
 
 
 
 
X 
X 
 
 
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Table 7: 
Laboratory Tests:  Required Analytes 
Serum Chemistry 
Hematology 
Urinalysis With 
Microscopic Examination 
Hepatitis Screening 
Coagulation 
Albumin 
Alkaline phosphatase 
ALT 
AST  
Bicarbonate 
Blood urea nitrogen  
Calcium 
Chloride  
Creatinine 
Ferritin 
Glucose 
Lactate dehydrogenase 
Phosphate 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin (if total bilirubin is 
elevated above ULN) 
Total protein 
Uric acid 
Complete blood count, 
including reporting of % 
blasts: 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
WBC count 
 
Differential count, including: 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
 
Absolute values must be 
provided for:  
WBC differential laboratory 
results: 
Lymphocytes 
Neutrophils 
 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Urobilinogen 
Hepatitis B surface antigen 
Hepatitis  B surface antigen 
antibody 
Hepatitis A, B core antibody 
HBV-DNA 
HCV antibody 
HCV-RNA 
PT 
aPTT 
INR 
Lipid Panel 
Pregnancy Testing 
Total cholesterol 
Triglycerides 
Low density lipoprotein  
High density lipoprotein  
Female subjects of 
childbearing potential 
only require a serum test 
at screening and EOT and 
a urine pregnancy test at 
each study visit when the 
test is requested. 
Pregnancy tests (serum or 
urine) should be repeated 
if required by local 
regulations. 
FSH 
Note:  Additional tests may be required, as agreed by investigator and sponsor, based on emerging safety data. 
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6.1. 
Screening 
Screening is the interval between signing the ICF and the day that the subject is randomized in 
the study (Cycle 1 Day 1).  Informed consent must be obtained, in writing, before performing 
any study-specific procedures.  Screening may not exceed 28 days (from Day -35 to Day -8).  
Assessments that are required to demonstrate eligibility may be performed over the course of 
1 or more days during the screening process.  Procedures conducted as part of the subject's 
routine clinical management (eg, blood count, bone marrow biopsy) and obtained before signing 
of informed consent may be used for screening purposes provided that the procedure meets the 
Protocol-defined criteria and has been performed in the timeframe of the study (ie, within 
35 days of Cycle 1 Day 1).  All information associated with eligibility requirements must be 
entered into the appropriate eCRF pages. 
Results from the screening visit evaluations will be reviewed to confirm subject eligibility before 
randomization.  Tests with results that fail eligibility requirements may be repeated once during 
screening if the investigator believes the results to be in error.  Additionally, a subject who fails 
screening may repeat the screening process (to include repeating the informed consent process) if 
the investigator believes that there has been a change in eligibility status (eg, after recovery from 
an infection).  For screening assessments that are repeated, the most recent available result before 
randomization will be used to determine subject eligibility. 
6.2. 
Baseline 
Subjects who meet all eligibility criteria may begin the baseline period of this study (7 days 
before Day 1 study start).  During the baseline period, all eligible subjects will be issued a 
handheld device (eDiary) on which to record symptoms of ET in the 
 diary (see 
Appendix E).  Subjects will receive training on the device by study site staff before leaving the 
site.  The investigative site staff must ensure that the diary is completed each night beginning on 
at least Day -7 in order to provide 1 complete week of data entries before the Day 1 visit.  
Subjects will bring the device along to the Day 1 visit to confirm that at least 4 of 7 diary entries 
have been completed.  The subjects will also bring the device along to every study visit to verify 
the device charging and download accumulated data.  The device will then be returned to the 
subject upon visit completion for continued use each night.  Subjects will return the device and 
its docking station for the final time at the EOT visit so that all data can be archived.  
NOTE:  The diary may be distributed as early as the screening visit in order to accommodate 
subject visit schedules during the baseline period. 
6.3. 
Blinded Treatment 
The blinded treatment period begins on the day that the subject receives the first dose of study 
treatment (Day 1of treatment) – and normally also the day of randomization – through the 
Week 52 visit or an earlier point at which the investigator determines that the subject will be 
permanently discontinued from study treatment.  Day 1 of treatment must be no more than 
35 days after the subject has signed the ICF and no more than 7 days after the date of 
randomization.  Dates for subsequent study visits will be determined based on this day and 
should occur within ± 2 or 3 days of the scheduled date unless delayed for safety reasons.  On 
Day 1 of treatment, results from screening visit evaluations should be reviewed to determine 
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whether the subject continues to meet the eligibility requirements, as specified in the Protocol, 
excepting platelet and WBC counts if they differ from screening evaluation. 
Study treatment will be given continuously.   
After 2 weeks of treatment, subjects may have the dose of ruxolitinib/ruxolitinib-placebo or 
anagrelide/anagrelide-placebo increased because of inadequate efficacy.  At this visit or any time 
during the study, the dose may be adjusted for hematologic safety, following the guidelines 
described in Section 5.4.  The individual study visit descriptions describe activities that must 
occur to support and document these dose changes. 
This study schedule is designed to closely monitor symptom response to ruxolitinib or 
ruxolitinib-placebo and anagrelide/anagrelide-placebo.  In addition, the doses of study treatment 
will need modifications for hematologic parameters.  Every effort must be made to ensure that 
the visit assessment data as well the hematology data are obtained at each scheduled study visit 
and laboratory-only visit, and repeat laboratory assessments should be conducted if WBC counts 
and/or platelet count data are not obtained from the initial blood collection conducted as part of 
the visit procedures.  If at any time during the study a subject experiences unexpected signs or 
symptoms, additional safety evaluations should be conducted at a regular study visit or 
unscheduled visit. 
Study visits during the blinded treatment period will be conducted on the following days:  
• Day 1; Day 8 (± 2 days); Day 15 (± 2 days); Day 22 (± 2 days). 
• Day 7 every 4 weeks beginning with Week 4 and ending with Week 52 (± 3 days). 
Laboratory-only visits during the blinded treatment period will be conducted every 4 weeks 
beginning with Week 34 and ending at Week 50. 
Note:  Assessment period from Weeks 32 through Week 52 will be closely monitored to ensure 
that requested laboratory assessments for evaluation have been completed. 
6.3.1. 
Transition Period Before Open-Label Period 
Upon completion of the Week 52 study visit for each individual subject, a period of 
approximately 2 to 4 weeks will be used to perform eCRF entry and cleaning of clinical data up 
to and including the Week 52 visit.  During this period, the subject should continue on blinded 
study treatment (unless interrupted for safety reasons).  When the data cleaning process is 
complete (procedure to be detailed in the Study Manual), the sponsor will authorize the 
unblinding of the subject's treatment assignment via the IXRS system (see Section 5.1.2.1) and 
perform the following actions: 
• Contact the IXRS for treatment management. 
• Schedule subject to return to clinic to begin the open-label treatment period or EOT 
visit. 
• Conduct an unscheduled visit if necessary to perform safety assessments for 
determining eligibility to begin open-label treatment. 
This period will end when the subject either begins receiving open-label treatment or is 
withdrawn from the study.  It may be necessary to delay initiating the open-label treatment 
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period treatment once reaching Week 52 of the blinded treatment in order for the subject to meet 
these eligibility criteria (see Section 3).  A delay of up to 4 weeks is permitted for this purpose.  
Additional study visits will be scheduled for all subjects the first 4 weeks after open-label 
ruxolitinib is initiated to permit safety evaluations and dose modification.  Afterward, the regular 
study schedule will be resumed for the patients initially treated with ruxolitinib.  Subjects 
initially treated in the anagrelide arm will follow a specific crossover study schedule (see Table 5 
and Table 6).  Subjects not willing or eligible to continue in the open-label treatment period will 
be withdrawn from the study. 
6.4. 
Open-Label Treatment 
Subjects randomized to either Group A (ruxolitinib and anagrelide-placebo) or Group B 
(anagrelide and ruxolitinib-placebo) will return to the clinic to turn in study treatment dispensed 
during the blinded treatment period and receive new study treatment (see Section 4.1.1).  
Subjects from Group A (ruxolitinib and anagrelide-placebo) will continue on the same dose used 
during the blinded treatment period. 
Subjects not willing or not eligible to continue will be scheduled for the EOT visit and follow-up 
evaluations and will discuss further therapeutic options with their treating physician. 
6.4.1. 
Visits After Week 52 
Subjects who continue with the same active agent to which they were randomized will have a 
study visit at Week 56, at which time study drugs will switch over to open label supplies 
(ruxolitinib or anagrelide) and then study visits every 12 weeks (Week 68, 80, etc).  Subjects 
who were originally randomized to anagrelide (Group B) and who cross over to ruxolitinib will 
begin receiving ruxolitinib at the Week 56 visit.  These subjects will have study visits at 
Weeks 1, 2, 3, 4, and every 4 weeks up to 52 weeks, then every 12 weeks thereafter.  Subjects 
who initially remain on anagrelide after unblinding but choose to cross over to receive ruxolitinib 
at a later time will have study visits at Weeks 1, 2, 3, 4, and every 4 weeks up to 52 weeks, then 
every 12 weeks thereafter. 
6.5. 
End of Treatment 
If a decision is made that the subject will withdraw from study participation, then an EOT visit 
should be conducted within 7 days after the last dose of study treatment.  If the EOT visit 
coincides with a regular study visit, then the EOT evaluations will supersede those of that 
scheduled visit, and the data should be entered in the EOT visit in the eCRF.  The subject should 
be encouraged to return for the follow-up visit.   
If a study withdrawal occurs, or if the subject fails to return for visits, then the investigator must 
determine the primary reason for a subject's premature withdrawal from the study and record this 
information in the eCRF. 
The investigator must contact the IXRS system to register the subject's discontinuation. 
6.6. 
Safety Follow-Up 
The safety follow-up period is the interval between the EOT visit and the scheduled follow-up 
visit, which should occur 30 to 37 days after the EOT visit (or after the last dose of study 
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treatment if the EOT visit was not performed).  Adverse events and SAEs must be reported up 
until 30 days after the last dose of study treatment, the date of the follow-up visit, or until study 
treatment–related toxicities resolve, return to baseline, or are deemed irreversible, whichever is 
longer.  Reasonable efforts should be made to have the subject return for the follow-up visit and 
report any AEs that may occur during this period.  If the subject cannot return to the site for the 
safety follow-up visit (eg, lives far away), then the subject should be contacted by telephone for 
assessing AEs and SAEs.  Sites should be instructed to document this contact in the source. 
6.7. 
Unscheduled Visits 
Unscheduled study visits may occur at any time if medically warranted.  Any assessments 
performed (eg, laboratory or clinical assessments) at those visits should be recorded in the eCRF. 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
Prospective participants will be scheduled for a screening visit by site staff.  A subject number 
will be assigned by an IXRS.  All procedures for screening and baseline must be completed 
within the 28-day screening + 7-day baseline period, except as noted in Section 6.1.  The 
procedures in this section will be performed. 
7.1. 
Administration of Informed Consent Form 
Valid informed consent must be obtained from the study subject before conducting any 
study-specific procedures using an ICF approved by the local IRB/IEC that contains all elements 
required by ICH E6, and describes the nature, scope, and possible consequences of the study in a 
form understandable to the study subject.  Local and institutional guidelines for ICF content and 
administration must be followed; the original signed ICF must be retained by the investigator, 
and a copy of the signed ICF must be provided to the study subject.  The informed consent 
process for each subject must be documented in writing within the subject source documentation. 
7.2. 
Interactive Response Technology Procedure 
The IXRS will be contacted to obtain a subject ID number when a subject enters screening 
period.  Upon determining that the subject is eligible for randomization, the IXRS will be 
contacted to obtain the treatment assignment.  Additionally, the IXRS will be contacted at each 
regular study visit to update the study treatment supply and at the EOT visit to record subject 
discontinuation from the study treatment (see Section 5.1.1). 
7.3. 
Demography and Medical History 
Demographic data and a complete medical and medication history will be collected at screening.  
The subject's date of birth, race, ethnicity, medical and surgical history, and concurrent illnesses 
assessed using CTCAE v4.03 (NCI 2010) will be recorded.  Documentation of disease history, 
including details of ET diagnosis, prior therapies, and phlebotomy history, will also be collected. 
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7.4. 
Prior and Concomitant Medications and Procedures 
Prior and concomitant medications and procedures will be reviewed to determine subject 
eligibility.  All concomitant medications and measures must be recorded in the eCRF, and any 
medication received or procedure performed within 30 days before randomization and up to the 
end of study will be recorded in the eCRF.  The medication record will be maintained after 
signing the ICF to document concomitant medications, including any changes to the dose or 
regimen.  Concomitant medications include any prescription, over-the-counter, or natural/herbal 
preparations taken or administered during the study period.  Concomitant treatments and/or 
procedures that are required to manage a subject's medical condition during the study will also be 
recorded in the eCRF.  Transfusions of packed red blood cells, platelets, or other blood product 
must be recorded in the eCRF.   
7.5. 
Safety Assessments 
Safety examinations must be performed by a suitably trained, medically qualified individual such 
as a licensed physician, Physician's Assistant, or an advanced Registered Nurse Practitioner, as 
local law permits. 
7.5.1. 
Review Inclusion and Exclusion Criteria 
All safety data and other eligibility assessments must be reviewed during the screening period to 
confirm the subject's eligibility. 
7.5.2. 
Adverse Events 
Adverse events will be monitored from the time the subject signs the ICF.  Subjects will be 
instructed to report all AEs during the study and will be assessed for the occurrence of AEs 
throughout the study.  In order to avoid bias in eliciting AEs, subjects will be asked general, 
nonleading questions such as "How are you feeling?"  All AEs (serious and nonserious) must be 
recorded on the source documents and eCRFs regardless of the assumption of a causal 
relationship with the study treatment.  The definition, reporting, and recording requirements for 
AEs are described in Section 8. 
7.5.3. 
Physical Examinations 
7.5.3.1. 
Comprehensive and Targeted Physical Examinations 
The comprehensive physical examination will include height (at screening) and body weight, and 
assessment(s) of the following organ or body systems:  skin; head, eyes, ears, nose, and throat; 
thyroid; lungs; cardiovascular system; abdomen (liver, spleen); extremities; and lymph nodes; as 
well as a brief neurological examination. 
A targeted physical examination will be performed as indicated in Table 3 and Table 5 will 
always include liver and spleen.  In addition, it will include body systems as indicated by subject 
symptoms. 
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7.5.4. 
Vital Signs 
Vital sign measurements include blood pressure, pulse, respiratory rate, and body temperature.  
Blood pressure and pulse will be taken with the subject in the recumbent, semirecumbent, or 
sitting position after 5 minutes of rest.  Clinically notable abnormalities that are considered 
clinically significant in the judgment of the investigator are to be reported as AEs. 
7.5.5. 
Electrocardiograms 
All 12-lead ECGs will be performed with the subject in a recumbent or semirecumbent position 
after 5 minutes of rest. 
The 12-lead ECGs will be interpreted by the investigator at the site to be used for immediate 
subject management.  The decision to include or exclude a subject or withdraw a subject from 
the study based on an ECG flagged as "Abnormal, Clinically Significant" is the responsibility of 
the investigator, in consultation with the sponsor's medical monitor, as appropriate.  Clinically 
notable abnormalities that are considered clinically significant in the judgment of the investigator 
are to be reported as AEs. 
7.5.6. 
Laboratory Assessments 
All hematology laboratory assessments, serum chemistries, and coagulation parameters will be 
analyzed by local laboratories.  Serology, urinalysis, and lipid panel will be analyzed by a central 
laboratory.  Samples for hematology, serum chemistry, serology, coagulation tests, pregnancy, 
and FSH tests and urinalysis will be prepared using standard procedures.  A complete list of 
laboratory assessments is shown in Table 4 and Table 6.  Refer to the Laboratory Manual for 
further details and specifications for sample handling, processing, and shipping.  Additional 
laboratory assessments may be conducted at investigator's discretion to understand safety 
findings or to support dose modifications. 
7.5.6.1. 
Pregnancy Testing 
A serum pregnancy test will be required for all women of childbearing potential at screening and 
at the EOT visit.  An FSH test will be performed on females who have been amenorrheic for 
> 1 year.  If FSH levels are elevated to postmenopausal range, no pregnancy testing is required 
for these female subjects.  Urine pregnancy tests will be conducted as outlined in Table 4 and 
Table 6, as medically indicated, or per country-specific requirement.  Urine pregnancy tests will 
be performed locally. 
If a urine pregnancy test is positive, then the results should be confirmed with a serum pregnancy 
test.  If the serum pregnancy test is negative after a urine test was positive, then the investigator 
will assess the potential benefit/risk to the subject and determine whether it is in the subject's 
best interest to resume study treatment and continue participation in the study. 
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7.6. 
Efficacy Assessments 
7.6.1. 
Measurement of Platelet and White Blood Cell Control Between Weeks 32 
and 52 
Platelet and WBC control will be measured by the performance of blood collection for 
hematologic assessment (complete blood count) every 2 weeks between Weeks 32 and 52.  
Subjects will be closely monitored by their treating physicians and reminded (diary with 
appointments) to perform these assessments in a timely manner.  A window of ± 3 days is 
allowed for the performance of the test.  Subjects should closely follow the schedule of blood 
test assessments and provide copies of local laboratory hematological results at each clinical 
study visit. 
Sites should closely follow-up with subjects by phone call to ensure that those tests are 
performed in a timely manner and to provide subjects support if appropriate, as subjects should 
not miss blood testing in this timeframe.  A detailed description of the procedures for the 
collection of hematologic blood tests is provided in the Study Reference Manual. 
7.6.2. 
Overall Response Assessment 
Overall response assessment (Appendix C) will be assessed at Weeks 32 and 52.    
 
 
 
 
 
7.6.4. 
Bone Marrow Biopsy 
A bone marrow biopsy should be obtained as outlined in Table 4.  The local site 
laboratory/pathology laboratory will be responsible for obtaining and analyzing the biopsy and 
collecting samples of tissue and aspirate.  The marrow should be evaluated for histomorphologic 
abnormalities as well as the presence of cytogenetic abnormalities and mutations associated with 
ET.  A quantitative evaluation for the JAK2V617F mutation is recommended.  If the marrow 
has been evaluated in the 2 months before screening, then the pretreatment examination 
does not need to be repeated.  Biopsy samples at Weeks 32 and 52 (and baseline with the 
caveat above) are required; biopsy samples at Weeks 104 and 152 are optional only, and only for 
subjects receiving open-label ruxolitinib (they may provide additional data regarding changes in 
bone marrow parameters while on treatment).  Samples of the bone marrow biopsy materials will 
be sent to the central laboratory for archiving and retrospective analyses by the sponsor or its 
designee. 
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7.7. 
Performance and Quality-of-Life Assessments 
7.7.1. 
Eastern Cooperative Oncology Group Performance Status 
The ECOG performance status will be assessed as shown in Table 3 and Table 5 (Appendix D). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.7.4. 
MPN-SAF Questionnaire 
 
The MPN-SAF questionnaire (see Appendix I) will be completed at baseline, Week 32 and 
Week 52, and/or the EOT visits so that the overall response assessment can be determined and 
reported.  This questionnaire will be on a paper/pencil format. 
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7.10. 
Other Study Procedures 
7.10.1. 
Administration of Study Treatment 
Subjects will take their dose of ruxolitinib or ruxolitinib-placebo in the morning and in the 
evening, approximately 12 hours apart, without regard to food.   
Anagrelide or anagrelide-placebo will be administered orally as directed by the local prescribing 
information.  In the United States, updated information can be found at 
http://dailymed.nlm.nih.gov/dailymed/about.cfm. 
7.10.2. 
Dispensing of Study Treatment 
Site staff will contact the IXRS to obtain the initial subject study treatment assignment, as well 
as for subsequent dispensing of study treatment.  Kits containing paired bottles of ruxolitinib or 
ruxolitinib-placebo plus anagrelide or anagrelide-placebo will be used during the blinded 
treatment period, and bottles of ruxolitinib will be used during the open-label treatment period.  
The investigator or designee will select the assigned study drug kits or bottles from their stock 
that correspond with the number provided by IXRS and dispense the medication.  The 
investigator will enter the kit numbers in the eCRF.  Full details will be provided in the IXRS 
Manual. 
7.10.3. 
Assessment of Compliance With Study Drug 
Compliance will be calculated by the sponsor based on the drug accountability documented by 
the site staff and monitored by the sponsor/designee (tablet counts).  The objective is 100% 
compliance, and investigators and their staff should evaluate compliance at each visit and take 
appropriate steps to optimize compliance. 
7.10.4. 
Distribution of Subject Reminder Cards 
Subjects will be provided with reminder cards at each visit.  The subject reminder cards will 
indicate the date/time of the next visit and include any special instructions for that visit.  This 
card will have an area for the subject to record the date and time of the last dose taken before the 
study visit and the time of their last meal 
 as well as an area indicating 
laboratory assessments scheduled for the period of evaluation between Weeks 32 and 52 of 
treatment. 
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8. 
SAFETY MONITORING AND REPORTING 
8.1. 
Adverse Events 
8.1.1. 
Definitions 
For the purposes of this Protocol, an adverse event (AE) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related, 
that occurs after a subject provides informed consent.  Abnormal laboratory values or test results 
occurring after informed consent constitute AEs only if they induce clinical signs or symptoms, 
are considered clinically meaningful, require therapy (eg, hematologic abnormality that requires 
transfusion), or require changes in the study drug(s). 
8.1.2. 
Reporting 
Adverse events that begin or worsen after informed consent should be recorded on the Adverse 
Events form of the eCRF.  Conditions that were already present at the time of informed consent 
should be recorded on the Medical History form in the eCRF.  Monitoring for the occurrence of 
new AEs should be continued for at least 30 days after the last dose of study drug  Adverse 
events (including laboratory abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible rather than by individual underlying signs and symptoms.  When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate AE. 
The term "disease progression" should be recorded as an AE/SAE only if there are no other 
identifiable AEs/SAEs associated with the disease progression at the time of reporting.  For 
events associated with disease progression, the relevant signs and symptoms should be reported 
using a diagnosis whenever possible rather than individual underlying signs and symptoms.  
When a clear diagnosis cannot be identified, each sign or symptom should be reported as a 
separate AE.  If the events resulting from disease progression meet the criteria for an SAE (eg, 
resulted in hospitalization, a life-threatening event, or death), the specific event(s) should be 
reported as an SAE(s) as described in Section 8.3.2.  In both cases (ie, AEs or SAEs related to 
disease progression), it should be indicated that each event (reported as a diagnosis or as signs 
and symptoms) is related to disease progression on the Adverse Events form of the eCRF. 
The severity of AEs will be assessed using CTCAE v4.03 Grades 1 through 5.  If an event is not 
classified by CTCAE, the severity of the AE will be graded according to the scale below to 
estimate the grade of severity: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate activities of daily living. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of 
daily living. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death due to AE 
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The occurrence of AEs should be sought by nondirective questioning of the subject during the 
screening process after signing the ICF and at each visit during the study.  Adverse events may 
also be detected when they are volunteered by the subject during the screening process or 
between visits, or through physical examination, laboratory test, or other assessments.  To the 
extent possible, each AE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 4). 
• Whether there is at least a reasonable possibility that the AE is related to the study 
treatment:  suspected (yes) or not suspected (no). 
• The start and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study drug. 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, 
recovering/resolving, recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per serious adverse event (SAE) definition provided in 
Section 8.3.1. 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements (see Section 8.3.2). 
All AEs should be treated appropriately.  If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on Adverse Event form and the treatment should 
be specified on the Prior/Concomitant Medications or Procedures and Non-Drug Therapy form 
in the eCRF. 
Once an AE is detected, it should be followed until it has resolved or until it is judged to be 
permanent; assessment should be made at each visit (or more frequently if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to 
treat the event, and the outcome. 
When the severity of an AE changes over time for a reporting period (eg, between visits), each 
change in severity will be reported as a separate AE until the event resolves.  For example, 
2 separate AEs will be reported if a subject has Grade 1 diarrhea, meeting the definition of an 
AE, that lasts for 3 days before worsening to a Grade 3 severity.  The Grade 1 event will be 
reported as an AE with a start date equal to the day the event met the Grade 1 AE definition and 
a stop date equal to the day that the event increased in severity from Grade 1 to Grade 3.  The 
Grade 3 event will also be reported as an AE, with the start date equal to the day the event 
changed in intensity from Grade 1 to Grade 3 and a stop date equal to the day that the event 
either changed severity again or resolved. 
8.2. 
Laboratory Test Abnormalities 
Laboratory abnormalities that constitute an AE in their own right (considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study drug) should be recorded on the Adverse Event form in the eCRF.  Whenever possible, a 
diagnosis rather than a symptom should be provided (eg, "anemia" instead of "low hemoglobin").  
Laboratory abnormalities that meet the criteria for AEs should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found.  When an abnormal 
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laboratory test result corresponds to a sign or symptom of a previously reported AE, it is not 
necessary to separately record the laboratory test result as an additional event. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs.  
A Grade 3 or 4 AE does not automatically indicate an SAE unless it meets the definition of 
serious, as defined in Section 8.3.1.  A dose modification for the laboratory abnormality may be 
required (see Section 5.4) and should not contribute to the designation of a laboratory test 
abnormality as an SAE. 
8.3. 
Serious Adverse Events 
8.3.1. 
Definitions 
An SAE is defined as an event that meets at least 1 of the following criteria: 
• Is fatal or life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
− A routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition. 
− An elective surgery or preplanned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since signing the 
ICF. 
− A treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE and not resulting in hospital admission. 
− Any social reasons and respite care, in the absence of any deterioration in the 
subject's general condition. 
• Results in persistent or significant disability, incapacity, or a substantial disruption of 
a person's ability to conduct normal life functions. 
• Constitutes a congenital anomaly or birth defect. 
• Is considered to be an important medical event or a medically significant event that 
may not result in death, be immediately life-threatening, or require hospitalization but 
may be considered serious when, based on appropriate medical judgment, the event 
may jeopardize the subject or may require medical or surgical intervention to prevent 
1 of the outcomes listed above. 
8.3.2. 
Reporting 
Every SAE, regardless of suspected causality (eg, relationship to study drug(s) or study 
procedure or disease progression), occurring after the subject has signed the ICF through the last 
study visit (or 30 days after the last dose of study drug, whichever is later) must be reported to 
the sponsor (or designee) within 24 hours of learning of its occurrence, unless otherwise 
specified by the Protocol.  Any SAEs occurring more than 30 days after the last dose of study 
drug should be reported to the sponsor or its designee only if the investigator suspects a causal 
relationship to the study drug.   
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Information about all SAEs is collected and recorded on the Adverse Event form of the eCRF.  
The investigator must assess and record the causal relationship of each SAE to the study 
treatment.  
The investigator must also complete the Incyte Serious Adverse Event Report Form, in English, 
and send the completed and signed form to the sponsor or designee within 24 hours of becoming 
aware of the SAE.  The investigator must provide a causality assessment, that is, assess whether 
there is at least a reasonable possibility that the SAE is related to the study treatment:  suspected 
(yes) or not suspected (no).  Refer to the Incyte Reference Guide for Completing the Serious 
Adverse Event Report Form. 
The contact information of the sponsor's study-specific representatives is listed in the 
investigator manual provided to each site.  The original copy of the SAE Report Form and the 
confirmation sheet must be kept at the study site. 
Investigational site personnel must report any new information regarding the SAE within 
24 hours of becoming aware of the information in the same manner that the initial SAE Report 
Form was sent.  Follow-up information is recorded on an amended or new SAE Report Form, 
with an indication that it is follow-up to the previously reported SAE and the date of the original 
report.  The follow-up report should include information that was not provided on the previous 
SAE Report Form, such as the outcome of the event (eg, resolved or ongoing), treatment 
provided, action taken with study drug because of the SAE (eg, dose reduced, interrupted, or 
discontinued), or subject disposition (eg, continued or withdrew from study participation).  Each 
recurrence, complication, or progression of the original event should be reported as follow-up to 
that event, regardless of when it occurs. 
If the SAE is not documented in the IB for the study drug (new occurrence) and is thought to be 
related to the sponsor's study drug, the sponsor or its designee may urgently require further 
information from the investigator for reporting to health authorities.  The sponsor or its designee 
may need to issue an Investigator Notification (IN) to inform all investigators involved in any 
study with the same drug that this SAE has been reported.  Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC, or as per national 
regulatory requirements in participating countries. 
8.4. 
Emergency Unblinding of Treatment Assignment 
The procedure for emergency unblinding is provided in the study reference manual.  This option 
may be used ONLY if the subject's well-being requires the investigator to be aware of the 
subject's treatment assignment. 
The investigator should make every effort to contact the sponsor's (or its designee's) clinical 
research physician or medical monitor before unblinding a subject's treatment assignment; 
however, this is not mandatory.  If a subject's treatment assignment is unblinded, the sponsor or 
its designee must be notified immediately by telephone. 
If an investigator, site personnel performing assessments, or subject is unblinded, the subject 
must be withdrawn from the study treatment.  In cases where there are ethical reasons to have the 
subject remain in the study, the investigator must obtain specific approval from the sponsor's (or 
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its designee's) clinical research physician or medical monitor for the subject to continue in the 
study. 
8.5. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a subject during maternal or paternal exposure to study drug, 
the following procedures should be followed in order to ensure subject safety: 
• The study drug must be discontinued immediately (female subjects only; see 
Section 5.5.1 for the maximum permitted duration of study drug interruption). 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug safety 
evaluation.  Follow-up should be conducted for each pregnancy to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications, by following 
until the first well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy form 
and reported by the investigator to the sponsor or its designee.  Pregnancy follow-up information 
should be recorded on the same form and should include an assessment of the possible causal 
relationship to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the 
first well-baby visit or the duration specified in local regulations, whichever is later.  Refer to the 
Incyte Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy must be recorded on the SAE report form and 
submitted to the sponsor or designee. 
8.6. 
Warnings and Precautions 
Special warnings or precautions for the study drug, derived from safety information collected by 
the sponsor or its designee, are presented in the Investigator's Brochure (IB).  Additional safety 
information collected between IB updates will be communicated in the form of Investigator 
Notifications (INs).  Any important new safety information should be discussed with the subject 
during the study, as necessary.  If new significant risks are identified, they will be added to the 
ICF. 
8.7. 
Data Monitoring Committee 
An independent DMC will be formed.  The DMC will consist of qualified individuals who are 
not involved with the conduct of the study.  The establishment, composition, roles, duties, and 
responsibilities of the DMC are addressed in the approved DMC charter. 
8.8. 
Adverse Events of Special Interest 
All reported AEs will be collected.  
 
 
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8.9. 
Product Complaints 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor.  All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information.  Any AE associated with a product 
complaint should be reported as described in Section 8.1.2 of this Protocol. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 
9. 
STATISTICS 
9.1. 
Study Populations 
The intent-to-treat (ITT) population will include subjects randomized in the study.  Treatment 
groups for this population will be defined according to the treatment assignment at 
randomization. 
The per protocol population will include those ITT subjects who are considered to be sufficiently 
compliant with the Protocol.  The criteria will be detailed in the SAP, and this population is 
defined for use in supportive sensitivity analyses for the primary efficacy endpoint. 
The safety evaluable population will include randomized subjects who received at least 1 dose of 
study drug. 
 
 
 
 
 
9.2. 
Selection of Sample Size 
Based on a literature search and the Incyte Phase 2 study (INCB 18424-256) and a difference in 
response rate of 25% (30% vs 5%), a total of approximately 120 subjects (60 subjects per group) 
would provide approximately 90% power to detect a treatment difference of 25% in the primary 
endpoint at 2-sided chi-square test with an alpha level of 0.05. 
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9.3. 
Level of Significance 
The level of significance for the primary endpoint is 2-sided 0.05. 
The family wise alpha level will be controlled at 0.05 and will be controlled using a fixed 
sequential testing procedure.  The proportion of subjects who achieve CR or PR at Week 32, as 
defined by the ELN 2013 response criteria, will only be formally tested if the hypothesis for the 
primary endpoint is rejected.  
The duration of response for responders in both treatments will be estimated with 95% 
confidence intervals without comparison.  No alpha adjustment will be applied for the remaining 
endpoints. 
9.4. 
Statistical Analyses 
When the last subject reaches Week 52 or discontinues, the database will be cleaned and locked, 
and the final analyses will be conducted. 
9.4.1. 
Efficacy Analyses 
9.4.1.1. 
Primary Efficacy Analyses 
The primary efficacy endpoint is the proportion of subjects who achieve a simultaneous 
reduction of platelet counts to < 600 × 109/L with a reduction of WBCs to < 10 ×109/L for at 
least 80% of biweekly assessments for 12 consecutive weeks between Week 32 and Week 52.  
This analysis will be based on the ITT population according to the treatment assigned at 
randomization.  The proportion of subjects who meet the response criteria will be estimated with 
a 95% confidence interval.  The Cochran-Mantel-Haenszel (CMH) test stratified by JAK2V617F 
mutation status (positive or negative), screening platelet count  (≥ 1000 × 109/L or 
< 1000 × 109/L), and prior anagrelide use (yes vs no) will be applied to compare the 2 treatment 
groups.  The test will be 2-sided at 5% significant level.  The overall stratum-adjusted odds ratio, 
along with its 95% confidence interval, will be presented. 
In the analysis of the primary efficacy endpoint, subjects who discontinue study treatment 
without meeting the response criteria will be considered as nonresponders.  Subjects who meet 
the primary endpoint criteria of a response but discontinue treatment before Week 52 will be 
considered as responders. 
The primary endpoint will also be analyzed based on per protocol population as sensitivity 
analysis. 
9.4.1.2. 
Secondary Efficacy Analyses 
Secondary efficacy analyses will be conducted for the ITT population. 
• Proportion of subjects who achieve CR or PR at Week 32, as defined by ELN 2013 
response criteria, will be estimated with a 95% confidence interval.  The CMH test 
stratified by JAK2V617F mutation status (positive or negative), screening platelet 
count (≥ 1000 × 109/L or < 1000 × 109/L), and prior anagrelide use (yes vs no) will be 
applied to compare the 2 treatment groups.  The overall stratum-adjusted odds ratio 
along with its 95% confidence interval will be presented. 
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• Proportion of subjects who achieve CR or those who achieve PR (separate analyses) 
at Week 32, as defined by ELN 2013 response criteria, will be estimated with a 
95% confidence interval.  The CMH test stratified by JAK2V617F mutation status 
(positive or negative), screening platelet count (≥ 1000 × 109/L or < 1000 × 109/L), 
and prior anagrelide use (yes vs no) will be applied to compare the 2 treatment 
groups.  The overall stratum-adjusted odds ratio along with its 95% confidence 
interval will be presented. 
• Duration of responses for subjects who achieve primary response as defined in the 
primary efficacy endpoint is defined as the time from the start of response until the 
end of response.  The start of a response will be the first visit where both platelet 
control (defined as a reduction to < 600 × 109/L) and WBC control (defined as a 
reduction to < 10 × 109/L) are achieved.  Loss of response will be defined as 
2 consecutive visits where either platelet count is ≥ 600 × 109/L or WBC is 
≥ 10 × 109/L.  The earlier of the 2 consecutive visits will be used as the end of 
response time.  Duration of response will be estimated using the Kaplan-Meier 
method. 
• Proportion of subjects who achieve reduction of platelet count to < 600 × 109/L for at 
least 80% of biweekly assessments for a consecutive 12-week period between 
Weeks 32 and 52 will be summarized along with their 95% confidence interval. 
• Proportion of subjects who achieve reduction of WBC counts to < 10 × 109/L for at 
least 80% of biweekly assessments for a consecutive 12 weeks period between 
Weeks 32 and 52 will be summarized along with their 95% confidence interval. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
9.4.2. 
Safety Analyses 
The safety analyses will be conducted for the safety evaluable population.  Safety data collected 
after crossover will be summarized separately. 
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9.4.2.1. 
Adverse Events 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first dose of study drug.  Analysis of AEs will be limited to TEAEs, but data listings will include 
all AEs regardless of their timing to study drug administration.  Adverse events will be tabulated 
by the MedDRA preferred term and system organ class.  Severity of AEs will be based on the 
NCI CTCAE v4.03 using Grades 1 through 5. 
The subset of AEs considered by the investigator to have a relationship to study drug will be 
considered to be treatment-related AEs.  If the investigator does not specify the relationship of 
the AE to study drug, then the AE will be considered treatment-related.  The incidence of AEs 
and treatment-related AEs will be tabulated. 
 
 
9.4.2.2. 
Clinical Laboratory Tests 
Laboratory test values outside the normal range will be assessed for severity based on the normal 
ranges for the clinical reference laboratory.  The incidence of abnormal laboratory values and 
shift tables relative to baseline will be tabulated. 
Laboratory data will be classified into Grades 1 through 5 using CTCAE v4.03.  The following 
summaries will be produced for the laboratory data: 
• Number and percentage of subjects with worst postbaseline CTCAE grade (regardless 
of baseline value).  Each subject will be counted only for the worst grade observed 
postbaseline. 
• Shift tables from baseline to the worst postbaseline value using CTCAE grade. 
• For laboratory parameters where CTCAE grades are not defined, shift tables to the 
worst postbaseline value using the low/normal/high classifications based on 
laboratory reference ranges. 
9.4.2.3. 
Vital Signs 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, pulse, respiratory rate, and body temperature) at each assessment time.  Vital sign 
results will be reviewed for clinically notable abnormalities (see Table 9), and subjects exhibiting 
clinically notable vital sign abnormalities will be listed.  A value will be considered an "alert" 
value if it is outside the established range and shows a > 25% change from baseline. 
Table 9: 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 40 bpm 
Temperature 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 24/min 
< 8/min 
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9.5. 
Analyses for the Data Monitoring Committee  
Preplanned analyses of safety will be provided to an independent DMC as specified in the DMC 
charter.  The DMC will review safety data of the ongoing study at close, regular intervals as 
specified in the DMC charter.  Such safety will be summarized by treatment group.  The process 
by which the DMC will make recommendations and decisions will be documented in the DMC 
charter. 
9.6. 
Interim Analysis 
No interim analysis for efficacy is planned. 
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10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
10.1. 
Investigator Responsibilities 
This study will be performed in accordance with ethical principles that originate in the 
Declaration of Helsinki and conducted in adherence to the study Protocol; GCPs as defined in 
Title 21 of the US CFR Parts 11, 50, 54, 56, and 312; ICH E6 GCP consolidated guidelines; and 
local regulatory requirements as applicable to the study locations. 
The investigator will be responsible for: 
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring:  Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan.  The 
investigator must allow the study monitors to review any study materials and 
subject records at each monitoring visit. 
− Auditing:  Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct.  The 
investigator must allow the auditors to review original source records and study 
documentation for all subjects. 
− Regulatory inspection:  Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product.  The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study-related documents.  The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
• Obtaining informed consent and ensuring that the study subjects' questions have been 
answered and the subjects fully understand study procedures: 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
− Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the subject.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF template.  The ICF must 
include a statement that the sponsor or its designee and regulatory authorities have 
direct access to subject records. 
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• Obtaining approval from the IRB/IEC before the start of the study and for any 
changes to the clinical study Protocol, important Protocol deviations, routine updates, 
and safety information in accordance with institutional requirements and local law. 
− The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements 
and with the policies and procedures established by the IRB/IEC. 
• Adhering to the Protocol as described in this document and agreeing that changes to 
the Protocol procedures, with the exception of medical emergencies, must be 
discussed and approved, first, by the sponsor or its designee and, second, by the 
IRB/IEC.  Each investigator is responsible for enrolling subjects who have met the 
specified eligibility criteria. 
The IRB/IEC that granted original approval, or the IRB/IEC currently responsible for 
overseeing the conduct of the study must be notified of all changes in and deviations 
from the protocol that may increase risk to the subject, and/or that may adversely 
affect the rights of the subject or validity of the investigation.  The investigator must 
send a copy of the approval letter from the IRB/IEC to the sponsor or CRO and retain 
the original in the site study regulatory file. 
Major eligibility deviations must be reported to the IRB/IEC in accordance with the 
IRB/IEC requirements.  During the course of the study, the monitor must notify the 
sponsor of subjects found not to have met eligibility criteria.  The medical monitor, in 
collaboration with the investigator, will determine if the subject should be withdrawn 
from the study. 
• Retaining records in accordance with all local, national, and regulatory laws, but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure that the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study without 
receiving approval from the sponsor.  The investigator must notify the sponsor or 
its designee in the event of accidental loss or destruction of any study records.  If 
the investigator leaves the institution where the study was conducted, the sponsor 
or its designee must be contacted to arrange alternative record storage options. 
− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations.  
The sponsor will retain the original eCRF data and audit trail. 
10.2. 
Accountability, Handling, and Disposal of Study Drug 
The investigator is responsible for drug accountability at the study site; however, the investigator 
may assign some of the drug accountability duties to an appropriate pharmacist or designee.  
Inventory and accountability records must be maintained and readily available for inspection by 
the study monitor and are open to inspection at any time by any applicable regulatory authorities. 
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The investigator or designee will be expected to collect and retain all used, unused, and partially 
used containers of study drug until the end of the study.  The investigator or designee must 
maintain records that document: 
• Investigational product delivery to the study site 
• The inventory at the site 
• Use by each subject including pill/unit counts from each supply dispensed 
• Return to the investigator or designee 
These records should include dates, quantities, batch/serial numbers (if available), and the unique 
code numbers (if available) assigned to the investigational product and study subjects. 
The investigational product must be used only in accordance with the protocol.  The investigator 
will also maintain records adequately documenting that the subjects were provided the correct 
study drug specified. 
Completed accountability records will be archived by the site.  At the completion of the study, 
the investigator or designee will oversee shipment of any remaining study drug back to the 
sponsor or sponsor's designee for destruction according to institutional standard operating 
procedures.  If local procedures mandate site destruction of investigational supply, prior written 
approval must be obtained from the sponsor. 
10.3. 
Data Management 
10.3.1. 
Data Collection 
The investigator will be provided with an eCRF for each subject.  Entries made in the eCRF must 
be verifiable against source documents; any discrepancies should be explained and documented.  
The investigator will be responsible for reviewing all data and eCRF entries and will sign and 
date the designated pages in each subject's eCRF, verifying that the information is true and 
correct.  The investigator is responsible for the review and approval of all responses.   
10.3.2. 
Data Management 
Data management will be performed in a validated database via an Electronic Data Capture 
(EDC) system.  All data entry, verification, and validation will be performed in accordance with 
the current standard operating procedures of the Data Management Department at the sponsor or 
its designee.  The database will be authorized for lock once all defined procedures are completed. 
10.4. 
Study Monitoring 
Qualified representatives of the sponsor or sponsor designees, "study monitors," will monitor the 
study according to a predetermined monitoring plan.  Monitoring visits provide the sponsor with 
the opportunity to: 
• Evaluate the progress of the study  
• Verify the accuracy and completeness of eCRFs 
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• Assure that all protocol requirements, applicable laws and/or regulations, and 
investigator's obligations are being fulfilled 
• Resolve any inconsistencies in the study records. 
The investigator must allow the study monitors to periodically review, at mutually convenient 
times, during the study and after the study has been completed, all eCRFs and office, hospital, 
and laboratory records supporting the participation of each subject in the study.  The eCRFs and 
other documentation supporting the study must be kept up-to-date by the investigator and the 
research staff at the investigative site.  These study materials must be available for review by the 
study monitor, and/or other qualified representatives of the sponsor, at each monitoring visit. 
The study monitor will review the various records of the study (eCRFs, subject medical and 
laboratory records, and other pertinent data).  The study monitor will verify the eCRF data 
against original source documentation for accuracy and completeness.  The study monitor will 
identify data discrepancies and collaborate with the investigator and research staff to resolve the 
discrepancies in a timely manner.  Protocol deviations will also be identified and recorded on a 
"Protocol Deviation Log."  The study monitor will follow an "Issue Escalation" plan in order to 
ensure that each issue identified during a monitoring visit is appropriately documented, reported, 
and resolved in a timely manner in accordance with the plan's requirements. 
10.5. 
Protocol Adherence 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the subject ICF and recruitment 
materials must be maintained by the investigator and made available for inspection. 
Each investigator must adhere to the protocol as described in this document and agree that 
changes to the protocol, with the exception of medical emergencies, must be discussed and 
approved, firstly, by the sponsor and, secondly, by the IRB/IEC.  Each investigator is responsible 
for enrolling subjects who have met the protocol inclusion and exclusion criteria.  The IRB/IEC 
that granted original approval, or the IRB/IEC currently responsible for overseeing the conduct 
of the study must be notified of all changes in and deviations from the protocol that may increase 
risk to the subject, and/or that may adversely affect the rights of the subject or validity of the 
investigation.  The investigator must send a copy of the approval letter from the IRB/IEC to the 
sponsor or CRO and retain the original in the site study regulatory file. 
Major eligibility deviations must be reported to the IRB/IEC in accordance with the IRB/IEC 
requirements.  During the course of the study, the monitor must notify the sponsor of subjects 
found not to have met eligibility criteria.  The medical monitor, in collaboration with the 
investigator, will determine if the subject should be withdrawn from the study. 
10.6. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor or its designee are responsible for ensuring that 
sensitive information is handled in accordance with local requirements (eg, HIPAA).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 
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Subject names will not be supplied to the sponsor or its designee, if applicable.  Only the subject 
number and subject's initials (subject's initials will only be recorded if allowable by local 
regulations) will be recorded in the eCRF, where permitted; if the subject's name appears on any 
other document (eg, laboratory report), it must be obliterated on the copy of the document to be 
supplied to the sponsor or its designee.  Study findings stored on a computer will be stored in 
accordance with local data protection laws.  The subjects will be informed that representatives of 
the sponsor or its designee, IRB or IEC, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
10.7. 
Financial Disclosure 
All clinical investigators participating in clinical studies subject to FDA Regulation Title 21 
Code of Federal Regulations (CFR) Part 54 – Financial Disclosure by Clinical Investigators, are 
required prior to study initiation to submit a completed Clinical Investigator Financial Disclosure 
Request Form that sufficiently details any financial interests and arrangements that apply.  For 
the purpose of this regulation, clinical investigator is defined as any investigator or 
subinvestigator who is directly involved in the treatment or evaluation of research subjects, 
including the spouse and each dependent child of the clinical investigator.  These requirements 
apply to both US and foreign clinical investigators conducting covered clinical studies. 
Any new investigators or sub-investigators added to the covered clinical study during its conduct 
must also submit a completed Clinical Investigator Financial Disclosure Request Form.  During a 
covered clinical study, any changes to the financial information previously reported by a clinical 
investigator must be reported to the sponsor/designee.  At the conclusion of the covered clinical 
study, the clinical investigators will be reminded of their obligation to report to the 
sponsor/designee any changes to the financial information previously reported.  The clinical 
investigators will also be reminded that they must report any changes in their financial 
information for a period of 1 year after completion of the covered clinical study. 
10.8. 
Quality Control and Quality Assurance 
10.8.1. 
Sponsor Audits 
At some point during the study, individuals from the sponsor's Quality Assurance department 
and/or their authorized representative may visit the investigator's site to conduct an audit of the 
study.  The purpose of this visit will be to determine the investigator's adherence to the protocol, 
applicable regulations, and the sponsor's procedures, in addition to assessing the accuracy of the 
study data.  Before initiating this audit, the investigator will be contacted by the sponsor to 
arrange a convenient time for this visit.  The investigator and staff are expected to cooperate with 
the auditors and allow access to all subject records supporting the eCRFs and other study-related 
documents. 
10.8.2. 
Inspection by Regulatory Authorities 
At some point during the investigational product's development program, a regulatory authority 
may visit the investigator to conduct an inspection of the study and the site.  The investigator and 
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staff are expected to cooperate with the inspectors and allow access to all source documents 
supporting the eCRFs and other study-related documents.  The investigator must immediately 
notify the sponsor when contacted by any regulatory authority for purposes of conducting an 
inspection. 
10.9. 
Data Handling and Recordkeeping 
10.9.1. 
Inspection of Records 
The sponsor will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study.  The investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. 
The investigator must ensure that all records pertaining to the conduct of the clinical study (as 
listed above) are adequately maintained for a period of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal termination of 
clinical development of the investigational product. 
10.9.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved, 2 years after the 
termination of the test article for investigation.  If it becomes necessary for the sponsor or the 
Regulatory Authority to review any documentation relating to the study, the investigator must 
permit access to such records. 
The investigator must not destroy any records associated with the study without receiving 
approval from the sponsor.  The investigator must notify the sponsor in the event of accidental 
loss or destruction of any study records.  If the investigator leaves the institution where the study 
was conducted, the sponsor must be contacted to arrange alternative record storage options. 
Whenever possible, an original recording of an observation must be retained as the source 
document.  However, a photocopy of a record is acceptable, provided it is legible and is a 
verified copy of the original document. 
All eCRF data entered by the site (including audit trail), as well as computer hardware and 
software (for accessing the data), will be maintained or made available at the site in compliance 
with applicable record retention regulations.  The sponsor will retain the original eCRF data and 
audit trail. 
10.9.3. 
Confidentiality 
Subject names will not be supplied to the sponsor.  Only the subject number and subject initials 
will be recorded in the eCRF, and if the subject name appears on any other document (eg, 
laboratory report), it must be obliterated on the copy of the document to be supplied to the 
sponsor.  Study findings stored on a computer will be stored in accordance with local data 
protection laws.  The subjects will be informed that representatives of the sponsor, IRB/IEC, or 
regulatory authorities may inspect their medical records to verify the information collected, and 
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that all personal information made available for inspection will be handled in strictest confidence 
and in accordance with local data protection laws. 
10.10. 
Publication Policy 
By signing the study Protocol, the investigator and his or her institution agree that the results of 
the study may be used by the sponsor, Incyte Corporation (Incyte), for the purposes of national 
and international registration, publication, and information for medical and pharmaceutical 
professionals.  Study results will be published in accordance with applicable local and national 
regulations.  If necessary, the authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement.  The terms regarding the publication of study results 
are contained in the agreement signed with the sponsor or its designee.  A signed agreement will 
be retained by the sponsor or its designee. 
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11. 
REFERENCES 
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Amabile CM, Spencer AP. Keeping your patient with heart failure safe: a review of potentially 
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Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization 
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Balduini CL, Bertolino G, Noris P, Ascari E. Effect of anagrelide on platelet count and function 
in patients with thrombocytosis and myeloproliferative disorders. Haematologica 1992;77:40-43. 
Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative 
neoplasms: critical concepts and management recommendations from European LeukemiaNet. 
J Clin Oncol 2011a; 29:761-770. 
Barbui T, Finazzi G. When and how to treat essential thrombocythemia. N Engl J Med 
2005;353:85-86. 
Barbui T, Thiele J, Passamonti F, et al. Survival and disease progression in essential 
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APPENDIX A. REVISED WHO 2016 CRITERIA FOR ESSENTIAL 
THROMBOCYTHEMIA 
Diagnosis of essential thrombocythemia requires meeting all 4 major criteria or the first 3 major 
criteria and the minor criterion: 
Major criteria 
1.  Platelet count ≥ 450 × 109/L. 
2.  Bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased 
numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei.  No significant increase or 
left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (Grade 1) increase in 
reticulin fibers. 
3.  Not meeting WHO criteria for BCR-ABL1+ CML, PV, PMF, myelodysplastic syndromes, or other 
myeloid neoplasms. 
4.  Presence of JAK2, CALR, or MPL mutation. 
Minor criterion 
Presence of a clonal marker or absence of evidence for reactive thrombocytosis. 
CALR = calreticulin; CML = chronic myeloid leukemia; JAK2 = Janus kinase 2; PMF = primary myelofibrosis; 
PV = polycythemia vera. 
Source:  Arber et al 2016. 
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APPENDIX B. DEFINITION OF MODIFIED CLINICAL RESISTANCE 
OR INTOLERANCE TO HYDROXYUREA 
Hydroxyurea (HU)-resistant or HU-intolerant subjects should demonstrate at least 1 of the 
following criteria:  
• Platelet count greater than 600 × 109/L after 3 months of at least 2 g/day of HU 
(2.5 g/day in subjects with a body weight over 80 kg); OR at the subject's maximally 
tolerated dose if that dose is less than 2 g/day; 
• Platelet count greater than 400 × 109/L and white blood cell count less than 
2.5 × 109/L or hemoglobin less than 10 g/dl, at any dose of HU;  
• Presence of leg ulcers or other unacceptable muco-cutaneous manifestations at any 
dose of HU;  
• HU-related fever. 
Source:  Barosi et al 2007, Verstovsek et al 2014a, Verstovsek et al 2014b. 
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APPENDIX C. RESPONSE CRITERIA FOR ESSENTIAL 
THROMBOCYTHEMIA 
 
Criteria 
Complete remission 
A 
Durable
a resolution of disease-related signs including palpable hepatosplenomegaly, 
large symptoms improvement,
b AND 
B 
Durablea peripheral blood count remission, defined as platelet count ≤ 400 × 109/L, 
WBC count < 10 × 109/L, and absence of leukoerythroblastosis, AND 
C 
Without signs of progressive disease and absence of any hemorrhagic or thrombotic 
events, AND 
D 
Bone marrow histological remission defined as disappearance of megakaryocyte 
hyperplasia and absence of > Grade 1 reticulin fibrosis. 
Partial remission 
A 
Durablea resolution of disease-related signs including palpable hepatosplenomegaly, 
and large symptoms improvement,b AND 
B 
Durablea peripheral blood count remission, defined as platelet count ≤ 400 × 109/L, 
WBC count < 10 × 109/L, absence of leukoerythroblastosis, AND 
C 
Without signs of progressive disease, and absence of any hemorrhagic or thrombotic 
events, AND 
D 
Without bone marrow histological remission, defined as the persistence of 
megakaryocyte hyperplasia. 
No response 
Any response that does not satisfy partial remission. 
Progressive 
disease 
Transformation into PV, post-ET myelofibrosis, myelodysplastic syndrome, or acute 
leukemia.
c 
ET = essential thrombocythemia; IWG-MRT = International Working Group-Myeloproliferative Neoplasms 
Research and Treatment; MPN-SAF TSS = Myeloproliferative Neoplasm–Symptom Assessment Form Total 
Symptom Score; PV = polycythemia vera; WBC = white blood cell. 
Note:  Molecular response is not required for assignment as complete response or partial response.  Molecular 
response evaluation requires analysis in peripheral blood granulocytes.  Complete response is defined as 
eradication of a pre-existing abnormality.  Partial response applies only to subjects with at least 20% mutant allele 
burden at baseline.  Partial response is defined as ≥ 50% decrease in allele burden. 
a Lasting at least 12 weeks. 
b Large symptom improvement (≥ 10-point decrease) in MPN-SAF TSS. 
c For the diagnosis of PV, see the WHO 2016 criteria 13; for the diagnosis of post-ET myelofibrosis, see the IWG 
MRT criteria12; for the diagnosis of myelodysplastic syndrome and acute leukemia, see the WHO criteria. 
Source:  Barosi et al 2013. 
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APPENDIX D. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
Grade 
Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, 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. 
Source:  Oken et al 1982. 
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APPENDIX G. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For Subjects Participating in the Study: 
The following methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective birth control methods.  
Such methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation1 
− oral 
− injectable 
− implantable2 
• Intrauterine device (IUD)2 
• Intrauterine hormone-releasing system (IUS)2 
• Bilateral tubal occlusion2 
• Vasectomised partner2,3 
• Sexual abstinence4 
 
1  Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2  Contraception methods that in the context of this guidance are considered to have low user dependency. 
3  Vasectomised partner is a highly effective method provided of avoiding pregnancy that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the 
surgical success.  
4  In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
Source:  CTFG 2014. 
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APPENDIX H. CYTOCHROME P450 INHIBITORS AND INDUCERS 
CYP 3A4 Inhibitors 
Inhibitor 
Therapeutic Class 
Potent CYP3A Inhibitors  
VIEKIRA PAK 
Antivirals 
Indinavir /RIT 
Protease inhibitors 
Tipranavir/RIT 
Protease inhibitors 
Ritonavir 
Protease inhibitors 
Cobicistat (GS-9350) 
None 
Ketoconazole 
Antifungals 
Indinavir 
Protease inhibitors 
Troleandomycin 
Antibiotics 
Telaprevir 
Antivirals 
Danoprevir/RIT 
Antivirals 
Elvitegravir/RIT 
Treatments of AIDS 
Saquinavir/RIT 
Protease inhibitors 
Lopinavir/RIT 
Protease inhibitors 
Itraconazole 
Antifungals 
Voriconazole 
Antifungals 
Mibefradil 
Calcium channel blockers 
LCL161 
Cancer treatments 
Clarithromycin 
Antibiotics 
Posaconazole 
Antifungals 
Telithromycin 
Antibiotics 
Grapefruit juice DS 
Food products 
Conivaptan 
Diuretics 
Nefazodone 
Antidepressants 
Nelfinavir 
Protease inhibitors 
Saquinavir 
Protease inhibitors 
Ribociclib 
Kinase inhibitors 
Idelalisib 
Kinase inhibitors 
Boceprevir 
Antivirals 
 
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Inhibitor 
Therapeutic Class 
Moderate CYP3A Inhibitors  
Erythromycin 
Antibiotics 
Fluconazole 
Antifungals 
Atazanavir/RIT 
Protease inhibitors 
Darunavir 
Protease inhibitors 
Diltiazem 
Calcium channel blockers 
Darunavir/RIT 
Protease inhibitors 
Dronedarone 
Antiarrhythmics 
Crizotinib 
Kinase inhibitors 
Atazanavir 
Protease inhibitors 
Letermovir 
Antivirals 
GSK2647544 
Alzheimer's disease & dementia treatments 
Aprepitant 
Antiemetics 
Casopitant 
Antiemetics  
Amprenavir 
Protease inhibitors 
Faldaprevir 
Antivirals 
Imatinib 
Antineoplastic agents 
Verapamil 
Calcium channel blockers 
Netupitant 
Antiemetics 
Nilotinib 
Kinase inhibitors 
Grapefruit juice 
Food products 
Tofisopam 
Benzodiazepines 
Cyclosporine 
Immunosuppressants 
ACT-178882 
Renin inhibitors 
Ciprofloxacin 
Antibiotics 
Magnolia vine (Schisandra sphenanthera) 
Herbal medications 
Isavuconazole 
Antifungals 
Cimetidine 
H-2 receptor antagonists 
FK1706 
Central nervous system agents 
 
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Inhibitor 
Therapeutic Class 
Weak CYP3A Inhibitors 
Tabimorelin 
Hormone replacement 
Amlodipine 
Calcium channel blockers 
Ranolazine 
Cardiovascular drugs 
Breviscapine 
Herbal medications 
Lomitapide 
Other antilipemics 
Fosaprepitant (IV) 
Antiemetics 
Seville orange (Citrus aurantium) juice 
Food products 
Amiodarone 
Antiarrhythmics 
Diosmin 
Herbal medications 
Chlorzoxazone 
Muscle relaxants 
M100240 
Antihypertensive agents 
Fluvoxamine 
Antidepressants 
Ranitidine 
H-2 receptor antagonists 
Goldenseal 
Herbal medications  
Clotrimazole 
Antifungals 
Tacrolimus 
Immunosuppressants 
Palbociclib 
Kinase inhibitors 
Cilostazol 
Antiplatelets 
Ticagrelor 
Antiplatelets 
Peppermint oil 
Food products 
Ivacaftor 
Cystic fibrosis treatments 
GSK2248761 
Transcriptase inhibitors 
Guan Mai Ning 
Herbal medications 
Osilodrostat 
Adrenal steroidogenesis inhibitors 
AZD2327 
Depression treatments 
Piperine 
Food products 
Resveratrol 
Food products 
Roxithromycin 
Antibiotics 
Suvorexant 
Hypnotics - sedatives 
Propiverine 
Anticholinergics 
Isoniazid 
Antibiotics 
Berberine 
Herbal medications 
Oral contraceptives 
Oral contraceptives 
Delavirdine 
NNRTIs 
Daclatasvir 
Antivirals 
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Inhibitor 
Therapeutic Class 
Weak CYP3A Inhibitors 
Simeprevir 
Protease inhibitors 
Atorvastatin 
HMG CoA reductase inhibitors (statins) 
Tolvaptan 
Vasopressin antagonists 
Almorexant 
Hypnotics - sedatives 
GSK1292263 
Other antilipemics 
Evacetrapid 
CETP inhibitors 
Linagliptin 
Dipeptidyl peptidase 4 inhibitors 
Grazoprevir (ingredient of Zepatier) 
Antivirals 
Lacidipine 
Calcium channel blockers 
Cranberry juice 
Food products 
Pazopanib 
Kinase inhibitors 
Fostamatinib 
Other 
Everolimus 
Immunosuppressants 
Blueberry juice 
Food products 
Flibanserin 
Central nervous system agents 
Lapatinib 
Kinase Inhibitors 
Brodalumab 
Immunomodulators biologics 
AMD070 
Fusion inhibitors  
Alprazolam 
Benzodiazepines 
Tong Xin Luo 
Herbal medications 
Glecaprevir and pibrentasvir 
Antivirals 
Bicalutamide 
Antiandrogens 
Sitaxentan 
Endothelin receptor antagonists 
Azithromycin 
Antibiotics 
Obeticholic acid 
Miscellaneous agents 
Ginkgo 
Herbal medications 
Teriflunomide 
Other immunomodulators 
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CYP 3A4 Inducers 
Inducers 
Therapeutic class 
Potent CYP3A Inducers  
Rifampin 
Antibiotics  
Mitotane 
Other Antineoplastics  
Avasimibe 
Other Antilipemics  
Rifapentine 
Antibiotics  
Apalutamide 
Antiandrogens  
Phenytoin 
Anticonvulsants 
Carbamazepine 
Anticonvulsants 
Enzalutamide 
Antiandrogens 
St John's Wort extract 
Herbal medications 
Lumacaftor 
Cystic fibrosis treatments 
Rifabutin 
Antibiotics 
Phenobarbital 
Anticonvulsants 
Moderate CYP3A Inducers  
Ritonavir and St. Johns wort 
None 
Semagacestat 
Alzheimer's treatments 
Efavirenz 
NNRTIs 
Tipranavir and ritonavir 
Protease inhibitors 
Dabrafenib 
Kinase inhibitors 
Lesinurad 
Antigout and uricosuric agents 
Bosentan 
Endothelin receptor antagonists 
Genistein 
Food products 
Thioridazine 
Antipsychotics 
Nafcillin 
Antibiotics 
Talviraline 
NNRTIs 
Lopinavir 
Protease inhibitors 
Modafinil 
Psychostimulants 
Pf-06282999 
Myeloperoxidase inactivators 
Etravirine 
NNRTIs 
Lersivirine 
NNRTIs 
Telotristat ethyl 
Antidiarrheals 
 
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Inducers 
Therapeutic class 
Weak CYP3A Inducers 
Eslicarbazepine 
Anticonvulsants 
Telaprevir 
Antivirals 
Daclatasvir and asunaprevir and beclabuvir 
Antivirals 
Amenamevir 
Antivirals 
Garlic 
Food products 
Bexarotene 
Other antineoplastics 
Sarilumab 
Immunomodulators biologics 
Artesunate and mefloquine 
Antimalarials 
Amprenavir (fosamprenavir) 
Protease inhibitors 
Raltegravir 
HIV-integrase strand transfer inhibitors 
Vemurafenib 
Kinase inhibitors 
Troglitazone 
Thiazolidinediones 
Dicloxacillin 
Antibiotics 
Sorafenib 
Kinase inhibitors 
Rufinamide 
Anticonvulsants 
Sirukumab 
Immunomodulators biologics 
Pleconaril 
Antivirals 
Ginseng 
Herbal medications 
Boceprevir 
Antivirals 
Sulfinpyrazone 
Antigout and uricosuric agents 
Ginkgo 
Herbal medications 
Vinblastine 
Vinca alkaloids 
Nevirapine 
NNRTIs 
Armodafinil (R-modafinil) 
Psychostimulants 
Ticagrelor 
Anticoagulants and antiplatelets  
LCL161 
Cancer treatments 
Vicriviroc and ritonavir 
Treatments of AIDS 
Ritonavir 
Protease inhibitors  
Prednisone 
Corticosteroids  
Oxcarbazepine 
Anticonvulsants  
Danshen 
Herbal medications 
Clobazam 
Benzodiazepines 
Echinacea 
Herbal medications 
Ticlopidine 
Anticoagulants and antiplatelets 
Isavuconazole 
Antifungals 
Brivaracetam 
Anticonvulsants 
Stribild 
Treatments of AIDS 
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Inducers 
Therapeutic class 
Weak CYP3A Inducers 
Pioglitazone 
Thiazolidinediones 
VIEKIRA PAK 
Antivirals  
Dexamethasone 
Corticosteroids  
Terbinafine 
Antifungals  
Quercetin 
Food products 
Glycyrrhizin 
Herbal medications  
Aprepitant 
Neurokinin-1 receptor antagonists 
Pretomanib (PA-824) 
Antibiotics  
Safinamide 
MAO-B inhibitors 
Oritavancin 
Antibiotics  
AZD 7325 
Anxiolytics 
Methylprednisolone 
Corticosteroids  
Topiramate 
Anticonvulsants  
CYP1A2 Inhibitors 
Inhibitor 
Therapeutic Class 
Strong CYP1A2 Inhibitors 
Ciprofloxacin 
Antibiotics 
Cinafloxacin 
Antibiotics 
Enoxacin 
Antibiotics 
Fluvoxamine 
Serotonin reuptake inhibitor 
Oltiprza 
Cancer chemotherapy 
Rofecoxib 
NSAID 
Zafirlukast 
Anti-asthmatic 
Angelica root – Bai Zhi 
Herbal medication 
Moderate CYP1A2 Inhibitors 
Etintidine 
H=2 Receptor antagonist 
Genistein 
Food product 
Idrocilamide 
Muscle relaxant 
Methoxsalen 
Anti-psoriasis 
Mexiletine 
Anti-arrhythmic 
Osilodrostat 
Adrenal steroidogenesis inhibitor 
Oral contraceptives 
Oral contraceptives 
Phenylpropaholamine 
Vasoconstrictor 
Pipemidic acid 
Antibiotics 
Propafenone 
Anti-arrhythmic 
Propranolol 
Beta adrenergic blocker 
Troleandomcin 
Antibiotics 
Vemurafenib 
Kinase inhibitors 
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Inhibitor 
Therapeutic Class 
Weak CYP1A2 Inhibitors 
Acyclovir 
Antivirals 
Antofloxacin 
Antibiotics 
Artemisinin 
Antimalerials 
Caffeine 
Methylxanthines 
Cimetidine 
H-2 Receptor antagonists 
Curcumin 
Food product 
Deferasirox 
Miscellaneous 
Disulfiram 
Alcohol deterrent 
Echinacea 
Herbal medicine 
Famotidine 
H-2 Receptor antagonist 
Glecaprevir and pibrentasvir 
Antivirals 
Grapefruit juice 
Food product 
Grepafloxacin 
Antibiotics 
Hormone replacement therapy 
Hormone replacement therapy 
Interferon alpha 
Immunomodulator 
Interferon beta 
Immunomodulator 
Norfloxacin 
Antibiotics 
Obeticholic acid 
Other 
Pefloxacin 
Antibiotics 
Peg interferon alpha 2a 
Immunomodulator 
Peperine 
Food product 
Safinamide 
MAO-B inhibitor 
Simeprevir 
Antivirals 
Sirukumab 
Immunomodulator 
Terbinafine 
Antifungals 
Thiabendazole 
Antiparasitics 
Ticlopidine 
Anticoagulants and Antiplatelets 
Verapamil 
Calcium Channel Blocker 
Viloxazine 
Other antidepressants 
Zileuton 
Anti-asthmatics 
 
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APPENDIX I. MYELOPROLIFERATIVE NEOPLASMS SYMPTOM 
ASSESSMENT FORM (MPN-SAF) 
Subject 
Number  
 
 
 
 
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 
WORST level of fatigue during the past 24 hours. 
0 (Absent)   1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Circle the one number that describes, during the past week, how much difficulty you had with each 
of the following symptoms 
Night sweats 
0 (Absent)   1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Itching (pruritus) 
0 (Absent)   1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Bone pain (diffuse, not joint pain or arthritis) 
0 (Absent)   1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Fever (> 100°F) 
0 (Absent)   1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Unintentional weight loss in the last 6 months 
0 (Absent)   1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Filling up quickly when you eat (early satiety) 
0 (Absent)   1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Abdominal discomfort 
0 (Absent)   1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Inactivity 
0 (Absent)   1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
Problems with concentration - 
 compared to prior to my MPD 
0 (Absent)   1  2  3  4  5  6  7  8  9     10 (Worst Imaginable) 
 
 
 
 
 
TSS:    ____________________ 
 
MD Signature/Date 
Per IWG-MRT 2013 Criteria: TSS to include fatigue, 
concentration, early satiety, inactivity, night sweats, itching, 
bone pain, abdominal discomfort, weight loss, and fevers. 
 
Staff Signature/Date 
 
 
 
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APPENDIX J. DRUGS THAT MAY PROLONG QT INTERVAL 
NOTE:  This list is not complete; investigators should review all concomitant medications for 
possible QT effects. 
Psychiatric Medications 
Thioridazine 
Haloperidol 
Chlorpromazine 
Pimozide 
Aiprasidone 
Iloperidone 
Quetiapine 
Citalopram 
Escitalopram 
Amitryptyline 
Imipramine 
Maprotiline 
Nortriptyline 
Despipramine 
Clomipramine 
Trimipramine 
Ventafaxine 
Mirtazapine 
Risperidone 
Doxepin 
Lithium 
Antihistamines 
Diphenhydramine 
Astemizole 
Loratidine 
Terfanadine 
Azelastine 
Clemastine 
 
Anti-infectives 
Amantadine 
Clarithromycin 
Chloroquine 
Foscarnet 
Halofantrine 
Hydroxychloroquine 
Quinine 
Mefloquine 
Erythromycin 
Azithromycin 
Mofloxacin 
Sparfloxacin 
Ciprofloxacin 
Pentamidine 
Trimethoprim-sulfamethoxazole 
Ketoconazole 
Cardiovascular Agents 
Quinidine 
Procainamide 
Disopyramide 
Flecainide 
Encainide 
Sotalol 
Amiodarone 
Bepridil 
Nicardipine 
Israpidine 
Indapamide 
Moesipril/HCTZ 
 
Other 
Cisapride 
Salmeterol 
Zolmitriptan 
Naratriptan 
Sumatriptan 
Tizanidine 
Fosphenytoin 
Felbamate 
Sources:   
1. Dietle A. QTc Prolongation with Antidepressants and Antipsychotics. US Pharm 2015;40:HS34-HS40. 
2. FDA. Drug-induced QT prolongation and Torsades de Pointes. 
https://www.fda.gov/ohrms/dockets/ac/01/slides/3746s_01_ruskin.ppt. 
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APPENDIX K. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment (Version) 1: 
21 DEC 2016 
Amendment (Version) 2: 
02 AUG 2019 
Amendment 2 (02 AUG 2019) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to revise the prior medication restrictions.  Under 
Amendment 2, prior anagrelide will be allowed, provided it was not discontinued because of 
adverse events.  Any prior anagrelide must be discontinued no later than 28 days before the 
anticipated start of study medications.  This revision is intended to allow for a greater number of 
subjects to participate in the study without making significant changes to the previous SPA 
agreement by allowing prior anagrelide use; the requirement for high WBC and high platelet 
counts severely limited possible enrollees, and prohibiting prior anagrelide use further restricted 
the number of subjects allowed to participate. 
Additional changes to the Protocol that had been communicated to the study sites via previous 
administrative change letters were also incorporated.  These include multiple 
clarifications/corrections of typographical errors to the schedules of assessments, addition of an 
appendix listing drugs that may prolong the QT interval, clarifying the options available for 
crossover for subjects completing 52 weeks of treatment, and options for discontinuing HU. 
1. Synopsis; Section 3.1, Subject Inclusion Criteria; Section 4.1, Overall Study Design 
Description of change:  Changed required WBC and platelet count from > 650 × 109/L 
and > 11.0 × 109/L to ≥ 650 × 109/L and ≥ 11.0 × 109/L, respectively. 
Rationale for change:  Correct typographical error in original Protocol. 
2. Synopsis; Section 1.4.2.2, Prior Anagrelide Use; Section 3.2, Subject Exclusion 
Criteria; Section 5.6, Concomitant Medications 
Description of change:  Revised to allow prior anagrelide use provided the reason for 
discontinuation is not AE-related.  Added language to indicate that anagrelide must be 
stopped at least 28 days before the first dose of study treatment.  
Rationale for change:  To increase the available pool of potential participants in the 
study, while avoiding enrolling subjects who might be more susceptible to AEs related to 
anagrelide based on prior experience with the drug. 
3. Synopsis; Section 1.4.2.2, Prior Anagrelide Use;  Section 4.1, Overall Study Design; 
Section 4.3, Measures Taken to Avoid Bias, Section 9.4.1, Efficacy Analysis 
Description of change:  Addition of wording to indicate that subjects will be stratified 
by prior anagrelide use. 
Rationale for change:  To ensure equivalent enrollment of subjects with prior anagrelide 
use into both treatment groups to decrease potential bias. 
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4. Synopsis;  Section 2.2.2, Secondary Endpoints, Section 9.4.1.2, Secondary Efficacy 
Analysis 
Description of change:  Reworded endpoint to allow for analysis of CR and PR both 
together and separately. 
Rationale for change:  FDA request. 
5. Appendix H, Cytochrome P450 Inhibitors and Inducers 
Description of change:  Replaced appendix with updated version. 
Rationale for change:  To provide updated information. 
The following changes are from Administrative Change 3 (dated 09 NOV 2017): 
6. Synopsis; Section 3.2, Exclusion Criteria; Section 5.6, Concomitant Medications 
Description of change: Clarified that HU can be discontinued once one of the criteria for 
HU refractoriness or resistance have been met (as described in inclusion criterion 3) and 
up to the day before the first dose of study treatments. 
Rationale for change:  To clarify when HU can be stopped before the start of the study. 
7. Section 3.2, Subject Exclusion Criteria; Section 5.6.3, Prohibited Medications; 
Appendix J, Drugs That Prolong QT Interval  
Description of change:  Exclusion criterion 19 and Section 5.6.3 revised to include a 
cross-reference to the new Appendix J, which lists QT-prolonging drugs that are 
prohibited. 
Rationale for change:  To provide guidance on concomitant medications. 
The following changes are from Administrative Change 2 (dated 29 AUG 2017): 
8. Section 6, Study Assessments (Table 5, Schedule of Assessments for Subjects From 
Group B Who Cross Over to Open-Label Ruxolitinib) 
Description of change:  Assessments were added for the visits beginning 56 weeks after 
crossover and continuing every 12 weeks.   
Rationale for changes:  Addition of missing assessments. 
The following changes are from Administrative Change 1 (dated 07 APR 2017): 
9. Synopsis; Section 4.1.1, Options for the Open-Label Treatment Phase; Section 4.4, 
Duration of Treatment and Subject Participation; Section 5.1.2.1.2, Scheduled 
Unblinding; Section 6, Study Assessments (Table 3, Schedule of Assessments; Table 
4, Schedule of Laboratory Assessments; Table 5, Schedule of Assessments for 
Subjects From Group B Who Cross Over to Open-Label Ruxolitinib); Section 6.4, 
Open-Label Treatment 
Description of change:  Treatment options were added for the open-label crossover 
period. 
Rationale for change:  To clarify treatment options after unblinding. 
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10. Synopsis, Section 3.2, Subject Exclusion Criteria 
Description of change:  In Synopsis and Section 3.2, Criterion 16 was revised to include 
CYP1A2 inhibitors.  In Section 3.2, criteria 19 and 20 are the same, and criteria 24 and 
25 are the same.  The duplicate criteria were deleted. 
Rationale for change:  Correction of typographical errors and to be consist with 
Section 5.4.2.3.2 (Cytochrome P450 1A2 Inhibitors). 
11. Section 5.4.4, Dose Modifications for Subjects Receiving Open-Label Treatment 
Description of change:  A subsection was added to indicate that subjects receiving 
open-label ruxolitinib or open-label anagrelide will follow the same rules for dose 
modifications as described in Sections 5.4.1, 5.4.2, and 5.4.3. 
Rationale for change:  To clarify treatment modification options after unblinding. 
12. Section 5.6.1, Permitted Medications; Section 5.6.2, Restricted Medications 
Description of change:  The maximum allowed dose of aspirin was changed to 125 mg 
per day (instead of 150 mg per day). 
Rationale for change:  Correction of a typographical error. 
13. Section 6, Study Assessments (Table 4, Schedule of Laboratory Assessments) 
a. Description of change:  The time frame for Screening was changed to Days -35 to -8 
(instead of Days -28 to -8). 
Rationale for change:  Correction of typographical error. 
b. Description of change:  JAK2V617F assessment:  the X was moved from the 
baseline column to the screening column. 
Rationale for change:  Correction of a typographical error.  The status of 
JAK2V617F must be known at screening per inclusion criteria and will be used for 
stratification (not an additional laboratory assessment). 
 
   
d. Description of change:  Urinalysis assessment:  an X was added at W56 + q12w in 
the open-label treatment column for subjects who do not cross over. 
Rationale for change:  Correction of a typographical error.  
e. Description of change:  FSH testing and blood sample for mutations testing:  the X 
in the baseline column was moved to the screening column. 
Rationale for change:  Correction of a typographical error.   
14. Section 6, Study Assessments (Table 4, Schedule of Laboratory Assessments); 
Section 7.6.4, Bone Marrow Biopsy 
Description of change:  In Table 4 under central laboratory samples, the third note for 
bone marrow biopsy and analyses (***) was revised to indicate Week 152 instead of 
Week 156 and to specify only subjects treated with open-label ruxolitinib.  In addition, 
bone marrow biopsy and analyses was added under local laboratory assessments (for 
local laboratory evaluation and pathology report) in addition to central laboratory 
assessments (central samples for banking).  Section 7.6.4 was revised to specify that 
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samples of tissue/aspirate will be initially analyzed at the site's local laboratory and stored 
at a central vendor for potential future central pathology reading. 
Rationale for change:  To allow the bone marrow biopsy to be performed during a 
subject's visit every 12 weeks and to specify ruxolitinib subjects only as the table now 
includes anagrelide- and ruxolitinib-treated subjects, and clarification of sample 
management specifications. 
15. Section 6, Study Assessments (Table 7, Laboratory Tests:  Required Analytes) 
Description of change:  Under Hematology, "including reporting of % blasts" was added 
after the complete blood count.  Under Coagulation, PTT was replaced with aPTT.  
Pregnancy testing was revised to indicate a serum test at both screening and EOT and a 
urine pregnancy test at each study site visit if the test is requested. 
Rationale for change:  The % of blasts is already part of the complete hematology blood 
count and has been specified in writing, aPTT is the generic term for this assessment, and 
the pregnancy testing information was updated to be consistent with Table 4 and Table 6.   
 
 
 
 
 
17. Section 8.1.2, Reporting; Section 8.2, Laboratory Test Abnormalities; 
Section 9.4.2.1, Adverse Events 
Description of change:  In Sections 8.1.2 and 9.4.2.1, the severity of adverse events 
assessed using CTCAE v4.03 was updated to include up to Grade 5 (death due to AE).  In 
Section 8.2, the parenthetical "severe" after Grade 4 was deleted. 
Rationale for change:  To align with sponsor safety reporting process update. 
18. Appendix E, Essential Thrombocythemia Symptom Assessments Diary 
Description of change:  A column has been added to increment the numbering of the 
questions from 1 to 18, and the title of the last subsection was corrected to "modified BPI 
item" instead of "Physical weakness item." 
Rationale for change:  To facilitate readability of the questions for the subjects in the 
electronic device and correct a typographical error. 
19. Incorporation of other administrative changes.  Other minor, administrative changes 
have been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 
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Amendment 1 (21 DEC 2016) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to update the Protocol based on feedback from FDA.  
Updates include but are not limited to adding a rationale for the ruxolitinib 10 mg twice daily 
(BID) starting dose, updating the dose modification guidelines for anagrelide, and updating and 
laboratory guidelines for absolute neutrophil count (ANC) and white blood cell (WBC) count.  
This amendment includes the changes to Protocol INCB 18424-272 (22 JUL 2016) summarized 
below.  A redline version of the amendment depicting updated and previous text is also provided. 
1. Synopsis; Section 2.1.2, Secondary Objectives
 Section 2.2.2, Secondary Endpoints
 Section 9.4.1.2, Secondary Efficacy Analysis; Section 9.4.1.3, Other 
Analyses 
 
 
 
 
 
 
 
 
 
 
2. Synopsis; 
 
Section 5.6.1, Permitted Medications; Section 9.4.2.1, Adverse Events 
 
 
  
 
 
3. Synopsis; Section 4.1, Overall Study Design; Section 1.2.3.2, Clinical Safety Data; 
Section 1.4.2, Rationale for Study Design and Treatment and Dose Selection 
Description of change:  The starting dose for ruxolitinib has been revised from 20 mg 
BID to 10 mg BID, and the rationale for this change has been added. 
Rationale for change:  Revision to the starting dose was made based on FDA feedback 
in response to question 2a in the SPA No Agreement response dated September 8, 2016.  
FDA agreement with the 10 mg BID starting dose was indicated in the Meeting 
Preliminary Comments dated December 15, 2016. 
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4. Synopsis; Section 1.4.3, Double-Dummy Design; Section 4.1, Overall Study Design; 
Section 4.4, Duration of Treatment and Subject Participation; Section 5.1.2.1.2, 
Scheduled Unblinding; Section 6, Study Assessments (Table 5, Schedule of 
Assessments for Crossover Subjects From Group B; Table 6, Schedule of 
Laboratory Assessments for Crossover Subjects From Group B); Section 6.3.1, 
Transition Period Before Open-Label Period; Section 6.4, Open-Label Treatment; 
Section 9.4.1.3, Other Analyses; Section 9.4.2, Safety Analyses 
Description of change:  A crossover open-label extension has been added after the 
Week 52 visit and will allow subjects originally randomized to anagrelide to be evaluated 
for eligibility to cross over to the open-label treatment phase according to investigator's 
decision, after consultation with the sponsor.  For Group A, study assessments during the 
open-label phase will be every 12 weeks instead of 8 weeks.  Specific schedules of 
assessments for Group B during the open-label phase have been added.  All other 
relevant sections have been updated accordingly. 
Rationale for change:  Crossover was added to address an additional comment from 
FDA (in Clinical section of additional comments on the meeting minutes dated May 9, 
2016, and feedback from investigators.  FDA agreement on crossover was indicated in 
the Meeting Preliminary Comments dated December 15, 2016. 
5. Synopsis; Section 3.2, Subject Exclusion Criteria; Section 5.6.3, Prohibited 
Medications 
Description of change:  A new exclusion criterion #18 was added to exclude subjects 
being treated concurrently with any medications that may prolong QTc interval of the 
electrocardiogram.  Section 5.6.3 was updated to prohibit medications that may prolong 
QTc interval of the electrocardiogram. 
Rationale for change:  Exclusion criterion was added to address a clinical comment 
from FDA in clinical comments 2 on SPA No Agreement response dated September 8, 
2016, and agreed upon by FDA in the Meeting Preliminary Comments dated 
December 15, 2016. 
6. Synopsis; Section 5.4, Treatment Modifications:  Increases, Interruptions, and 
Adjustments; Section 6.3, Blinded Treatment 
Description of change:  The guidelines and criteria for dose modification for anagrelide, 
for dose increases for inadequate efficacy and for hematologic/nonhematologic toxicities 
have been updated.  Table 1 (Dose Interruptions for Hematologic Toxicities) has been 
updated with revised ANC and platelet count criteria, and Tables 2 and 3 (Dose Levels 
for Ruxolitinib and Anagrelide, respectively) have been replaced with a new Table 2 
(Dose Levels for Ruxolitinib and Anagrelide and Dose Reduction/Restart Guidelines). 
Rationale for change:  These changes address the response to question 2b from SPA 
letter, dated September 8, 2016:  the anagrelide dose modification has been adjusted to 
reflect the Agrylin® Prescribing Information (2b/c); ANC and platelet count criteria have 
been updated to include FDA suggestions of counts cutoff for lack of efficacy/symptoms 
improvement (2b/a; b).  Changes were indicated as generally acceptable in the Meeting 
Preliminary Comments dated December 15, 2016. 
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7. Synopsis; Section 6, Study Assessments (Table 4, Schedule of Laboratory 
Assessments); Section 7.6.4 Bone Marrow Biopsy  
Description of change:   Optional additional bone marrow biopsies will be requested at 
Week 104 and Week 156. 
Rationale for change:  These samples have been added as optional only as they may 
provide additional data regarding changes in bone marrow parameters while on treatment. 
8. Synopsis; Section 6, Study Assessments (Table 4, Schedule of Assessments); 
 
 
 
 
 
 
 
 
 
 
 
10. Synopsis; Section 9.4.1.1, Primary Efficacy Analyses 
Description of change:  The definition of nonresponders for the primary efficacy 
endpoint was revised to subjects who discontinue treatment without meeting the response 
criteria. 
Rationale for change:  To address the question 4b on SPA no agreement response dated 
September 8, 2016, to clarify the definition of nonresponder subjects. 
11. Section 4.5, Overall Study Duration; Section 6.3, Blinded Treatment 
Description of change:  Timing for the blinded treatment phase and study completion 
has been updated. 
Rationale for change:  To clarify the overall study duration. 
12. Section 5.1.2.1.2, Scheduled Unblinding; Section 5.5.1, Withdrawal Criteria 
Description of change:  Updated to indicate that subjects who are unblinded before 
Week 52 will be withdrawn from the study. 
Rationale for change:  To clarify subjects accounted for the primary analysis if not 
reaching Week 52 timepoint interval used for primary endpoint and address FDA 
comment 2 on statistics on SPA No Agreement response dated September 8, 2016. 
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13. Section 5.2, Study Drug 
Description of change:  The tablet and capsule counts per bottle for ruxolitinib and 
anagrelide, respectively, have been deleted. 
Rationale for change:  The count per bottle has been removed as it has not been defined 
yet for the blinded kits logistics preparation. 
 
 
 
 
 
 
15. Incorporation of administrative changes.  Other minor, administrative changes, 
including rewording for clarity, have been incorporated throughout the Protocol and are 
noted in the redline version of the amendment. 
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