An Efficacy and Safety Study of Fedratinib Compared to Best Available Therapy in Subjects With DIPSS-intermediate or High-risk Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, or Post-essential Thrombocythemia Myelofibrosis and Previously Treated With Ruxolitinib

Inclusion Criteria: 1. Subject is at least 18 years of age at the time of signing the informed consent form (ICF) 2. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) of 0, 1 or 2 3. Subject has diagnosis of primary myelofibrosis (PMF) according to the 2016 World Health Organization (WHO) criteria, or diagnosis of post-ET or post-PV myelofibrosis according to the IWG-MRT 2007 criteria, confirmed by the most recent local pathology report 4. Subject has a DIPSS Risk score of Intermediate-2 or High 5. Subject has a measurable splenomegaly during the screening period as demonstrated by spleen volume of ≥ 450 cm3 by MRI or CT-scan and by palpable spleen measuring ≥ 5 cm below the left costal margin 6. Subject has a measurable total symptoms score (≥ 1) as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) 7. Subject has been previously exposed to ruxolitinib, and must meet at least one of the following criteria (a and/or b) 1. Treatment with ruxolitinib for ≥ 3 months with inadequate efficacy response (refractory) defined as \< 10% spleen volume reduction by MRI or \< 30% decrease from baseline in spleen size by palpation or regrowth (relapsed) to these parameters following an initial response 2. Treatment with ruxolitinib for ≥ 28 days complicated by any of the following (intolerant): * Development of a red blood cell transfusion requirement (at least 2 units/month for 2 months) or * Grade ≥ 3 AEs of thrombocytopenia, anemia, hematoma, and/or hemorrhage while on treatment with ruxolitinib 8. Subject must have treatment-related toxicities from prior therapy resolved to Grade 1 or pretreatment baseline before start of last therapy prior to randomization 9. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted 10. Subject is willing and able to adhere to the study visit schedule and other protocol requirements 11. A female of childbearing potential (FCBP) must: 1. Have 2 negative pregnancy tests as verified by the Investigator during screening prior to starting study treatment. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact. 2. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use and be able to comply with highly effective contraception without interruption, -14 days prior to starting investigational product, during the study treatment (including dose interruptions), and for 30 days after discontinuation of study treatment. Note: A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). 12. A male subject must: Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 30 days following investigational product discontinuation, or longer if required for each compound and/or by local regulations, even if he has undergone a successful vasectomy Exclusion Criteria: 1. Any of the following laboratory abnormalities: 1. Platelets \< 50 x 109/L 2. Absolute neutrophil count (ANC) \< 1.0 x 109/L 3. White blood count (WBC) \> 100 x 109/L 4. Myeloblasts ≥ 5 % in peripheral blood 5. Estimated glomerular filtration rate \< 30 mL/min/1.73 m2 (as per the Modification of Diet in Renal Disease \[MDRD\] formula) 6. Serum amylase or lipase \> 1.5 x upper limit of normal (ULN) 7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3 x upper limit of normal (ULN) 8. Total bilirubin \> 1.5 x ULN, subject's total bilirubin between 1.5 - 3.0 x ULN are eligible if the direct bilirubin fraction is \< 25% of the total bilirubin 2. Subject is pregnant or lactating female 3. Subject with previous splenectomy 4. Subject with previous or planned hematopoietic cell transplant 5. Subject with prior history of encephalopathy, including Wernicke's (WE) 6. Subject with signs or symptoms of encephalopathy, including WE (eg, severe ataxia, ocular paralysis or cerebellar signs) 7. Subject with thiamine deficiency, defined as thiamine levels in whole blood below normal range according to the central laboratory and not demonstrated to be corrected prior to randomization 8. Subject with concomitant treatment with or use of pharmaceutical, herbal agents or food known to be strong or moderate inducers of Cytochrome P450 3A4 (CYP3A4), or dual CYP2C19 and CYP3A4 inhibitors 9. Subject on any chemotherapy, immunomodulatory drug therapy (eg, thalidomide, interferon-alpha), anagrelide, immunosuppressive therapy, systemic corticosteroids \> 10 mg/day prednisone or equivalent. Subjects who have had prior exposure to hydroxyurea (eg, Hydrea) in the past may be enrolled into the study as long as it has not been administered within 14 days prior to randomization 10. Subject has received ruxolitinib within 14 days prior to randomization 11. Subject with previous exposure to Janus kinase (JAK) inhibitor(s) other than ruxolitinib treatment 12. Subject on treatment with aspirin with doses \> 150 mg daily 13. Subject with major surgery within 28 days prior to randomization 14. Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis) 15. Subject with prior malignancy other than the disease under study unless the subject has not required treatment for the malignancy for at least 3 years prior to randomization. However, subject with the following history/concurrent conditions provided successfully treated may enroll: non-invasive skin cancer, in situ cervical cancer, carcinoma in situ of the breast, incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis \[TNM\] clinical staging system), or is free of disease and on hormonal treatment only 16. Subject with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4) 17. Subject with known human immunodeficiency virus (HIV), known active infectious Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC) 18. Subject with serious active infection 19. Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication 20. Subject is unable to swallow capsule 21. Subject with any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study 22. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study 23. Subject has any condition that confounds the ability to interpret data from the study 24. Subject with participation in any study of an investigational agent (drug, biologic, device) within 30 days prior to randomization 25. Subject with a life expectancy of less than 6 months