A Study of Eltrombopag or Placebo in Combination With Azacitidine in Subjects With International Prognostic Scoring System (IPSS) Intermediate-1, Intermediate-2 or High-risk Myelodysplastic Syndromes (MDS)
Condition: Thrombocytopaenia
MeSH terms: Preleukemia; Myelodysplastic Syndromes; Thrombocytopenia; Syndrome
Intervention: Eltrombopag; Azacitidine; Placebo; Placebo
Intervention description: Eltrombopag will be round film-coated tablets containing eltrombopag equivalent to 50 mg (white to off-white), 200 mg and 300 mg (green) of eltrombopag free acid; Subcutaneous Injection (IV if local standard); Eltrombopag matching placebo tablets; Eltrombopag matching placebo tablets will be supplied
Intervention MeSH terms: Azacitidine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 356.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: thrombocytopenia; myelodysplastic syndromes; MDS; thrombopoietin; azacitidine; Eltrombopag; myelodysplastic syndromes (MDS)

Summary:

      Eltrombopag olamine (SB-497115-GR) is an orally bioavailable, small molecule thrombopoietin
      receptor agonist that may be beneficial in medical disorders associated with
      thrombocytopenia. Eltrombopag has been shown to increase platelet counts in patients with
      thrombocytopenia from various etiologies (Idiopathic thrombocytopenic purpura [ITP], liver
      disease, aplastic anemia and chemotherapy induced thrombocytopenia). Approximately 350
      subjects will be randomized in a 1:1 ratio (175 into the eltrombopag arm and 175 into the
      placebo arm). Approximately 55 subjects will be enrolled into the azacitidine. Subjects with
      intermediate-1, intermediate-2 or high risk MDS by IPSS, and baseline platelet count of <75
      Giga (10^9) per liter (Gi/L) will only be enrolled. This is a randomized, double-blind,
      parallel group, placebo-controlled study designed to explore the platelet supportive care
      effects of eltrombopag versus placebo in combination with the standard of care
      hypomethylating agent, azacitidine. The primary objective of this study is to determine the
      effect of eltrombopag versus placebo on the proportion of subjects who are platelet
      transfusion free during the first 4 cycles of azacitidine therapy. Key secondary endpoints
      include overall survival, disease response, and disease progression.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age >=18 years (For subjects in Taiwan, Age >= 20 years)

          -  MDS by World Health Organization (WHO) or French-American-British (FAB) classification

          -  Intermediate 1, intermediate 2 or high risk MDS by IPSS

          -  At least one platelet count < 75 Gi/L

          -  Eastern Cooperative Oncology Group (ECOG) Status 0-2

          -  Adequate baseline organ function defined by the criteria below: total bilirubin =<
             1.5x the upper limit of normal (ULN) except for Gilbert's syndrome or cases clearly
             not indicative of inadequate liver function (i.e. elevation of indirect [haemolytic]
             bilirubin in the absence of alanine aminotransferase [ALT] abnormality); ALT =<
             2.5xULN; creatinine =< 2.5xULN

          -  Subjects with a corrected QT interval (QTc) <450 milliseconds (msec) or <480msec for
             subjects with bundle branch block. The QTc is the QT interval corrected for heart rate
             according to Fridericia's formula (QTcF), machine or manual overread. For subject
             eligibility and withdrawal, QTcF will be used. For purposes of data analysis, QTcF
             will be used. The QTc should be based on single or averaged QTc values of triplicate
             electrocardiograms (ECGs) obtained over a brief recording period

          -  Subject is able to understand and comply with protocol requirements and instructions

          -  Subject has signed and dated informed consent

          -  Women must be either of non-child bearing potential, or women with child-bearing
             potential and men with reproductive potential must be willing to practice acceptable
             methods of birth control during the study

          -  Women of childbearing potential must have a negative serum or urine pregnancy test
             within 7 days of first dose of study treatment and agree to use effective
             contraception during the study and for 3 months following the last dose of study
             treatment

          -  Men with a female partner of childbearing potential must have either had a prior
             vasectomy or agree to use effective contraception from time of randomization until 16
             weeks after the last dose of study treatment

          -  French subjects: In France, a subject will be eligible for inclusion in this study
             only if either affiliated to or a beneficiary of a social security category

        Exclusion Criteria:

          -  Previous treatment with hypomethylating agent or induction chemotherapy for MDS

          -  Proliferative type chronic myelomonocytic leukemia with white blood cell count >12
             Gi/L at any time during the 28 days before Day 1

          -  History of treatment with eltrombopag, romiplostim or other thrombopoietin receptor
             (TPO-R) agonists

          -  Previous allogeneic stem-cell transplantation

          -  Known thrombophilic risk factors. Exception: Subjects for whom the potential benefits
             of participating in the study outweigh the potential risks of thromboembolic events,
             as determined by the investigator

          -  Treatment with an investigational drug within 30 days or 5 half-lives (whichever is
             longer) preceding the first dose of investigational product (eltrombopag/placebo)

          -  Active and uncontrolled infections, including hepatitis B or C

          -  Human Immunodeficiency Virus (HIV) infection

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to eltrombopag or its excipient, or azacitidine, that
             contraindicates the subjects' participation

          -  Pregnant or lactating female

          -  Any serious and/or unstable pre-existing medical condition (including any advanced
             malignancy other than the disease under study), psychiatric disorder, or other
             conditions that could interfere with subject's safety, obtaining informed consent or
             compliance with the study procedures

          -  French subjects: the French subject has participated in any study using an
             investigational drug during the previous 30 days