The purpose of this study is to determine the efficacy, safety and tolerability, of AKR-501 (avatrombopag) tablets, as compared to placebo, in the treatment of participants with chronic Idiopathic Thrombocytopenic Purpura (ITP).

This is a Phase 2, multi-center, double-blind, randomized, placebo-controlled, dose-ranging, parallel-group study. The pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) relationship of avatrombopag will also be studied. Approximately 65 eligible participants will be randomized in a 3:3:3:3:1 ratio in a double-blinded fashion into one of five parallel treatment groups to receive daily doses of either avatrombopag 2.5, 5, 10 or 20 mg or placebo for 28 days, respectively. Each avatrombopag dosing group will consist of 15 participants while the placebo group will consist of 5 participants. All study participants will be evaluated weekly (Days 3, 5, 7, 14, 21 and 28) for safety, efficacy, and (Days 7, 14, 21, and 28) avatrombopag PK while receiving study treatment with a final assessment for safety and effectiveness to be done 2 weeks after the last study dose (Day 42).

At the completion of Visit Day 28±1, participants who complete 28±1 days of study dosing will be assessed for eligibility to enroll into the rollover Study 501-CL-004 (NCT00625443) based on this visit.

Inclusion Criteria:

1. Men and women ≥ 18 years of age.

2. Confirmed diagnosis of ITP according to American Society of Hematology (ASH) Guidelines ≥ 3 months prior to Day 1.

3. If ≥ 60 years old, must have had either a bone marrow biopsy consistent with ITP within past 3 years or a good response (platelet count > 100,000/mm^3) to a previous ITP treatment.

4. Are refractory or relapsed after at least one prior ITP therapy (patients who are refractory and failed to achieve a platelet count ≥ 50,000/mm^3 despite steroids or ≥ 30,000/mm^3 to other prior ITP therapies, such as splenectomy, danazol, or immunosuppressive drugs. For patients who are relapsed, the platelet counts must be below 50,000/mm^3 if using steroids or 30,000/mm^3 if not prescribed steroids.)

5. Patients receiving maintenance corticosteroids may be enrolled, as long as the corticosteroids have been administered at a stable dose (same milligram amount ± 10%) for ≥ 2 weeks prior to Screening Visit A and the investigator does not foresee the need to change the steroid dose during study participation. Patients should remain on this stable corticosteroid dose during study participation.

6. Patients receiving stable dosages of cyclosporine A, mycophenolate mofetil, azathioprine or danazol may also be enrolled. The dosages of all these medications must be stable for at least 3 months prior to AKR-501 administration.

7. Platelet count:

   • Patients not receiving steroids (no steroid treatment for > 2 weeks prior to the Screening Visit A): platelets < 30,000/mm^3 at Screening Visit A and within 96 hours prior to Day 1 (Screening Visit B)
   • Patients receiving steroids: platelets < 50,000/mm^3 at Screening Visit A and within 96 hours prior to Day 1 (Screening Visit B).

8. Women of child-bearing potential must have a negative pregnancy test at Screening Visit A and Screening Visit B. (Childbearing potential is defined as any woman who has not been surgically sterilized and is premenopausal or peri-menopausal i.e., any menstrual flow within 12 months of Screening Visit A).

9. Women of child-bearing potential and all men must agree to practice a medically approved form of contraception (one of the following must be used: condoms (male or female) with a spermicidal agent, diaphragm, or cervical cap with a spermicidal agent, IUD, hormonal contraception, abstinence).

10. Willing and able to provide written informed consent before any study-related procedure.

Exclusion Criteria:

1. Women who are pregnant and/or lactating.

2. Splenectomy procedure performed 4 weeks prior to AKR-501 administration.

3. Use of the following drugs or treatments prior to Day 1:

   • Within 3 months - Rituximab;
   • Within 2 weeks - Aspirin or Aspirin-containing compounds, Salicylates, Anticoagulants, clopidogrel, ticlopidine, Rh0(D) Immune Globulin (WinRho®), or intravenous immunoglobulin (IVIG).

4. Participation in a clinical trial involving any investigational agent within 4 weeks of Day 1.

5. Exposure to eltrombopag or AMG -531.

6. Significant medical conditions or diseases as determined by the Investigator (e.g., clinically active systemic lupus erythematosus; known or suspected HIV infection; acute hepatitis or clinically active chronic hepatitis; lymphoproliferative disease; congestive heart failure).

7. History of cardiovascular disease (e.g., angina, unstable angina, myocardial infraction, coronary artery stent placement, angioplasty, coronary artery bypass grafting).

8. History of thromboembolic disease (e.g., transient ischemic attack [TIA], stroke [CVA], pulmonary embolism [PE]).

9. History of deep venous thrombosis (DVT).

10. History of lupus anticoagulant or anticardiolipin antibody syndrome or positive anti b2 glycoprotein antibody.

11. History of any medical condition where systemic anticoagulation was required for more than 6 months.

12. Laboratory abnormalities:

    • Hemoglobin < 12.5 g/dL for men and < 11.5 g/dL for women. If anemia is clearly related to ITP, for example excessive blood loss, then that patient may be enrolled without the need for a waiver after discussion with the Sponsor's medical monitor
    • White blood cell count (WBC) < lower limit of normal
    • Absolute neutrophil count (ANC) < 1000/mm^3
    • Prothrombin time (PT) > 1.25 x upper limit of normal
    • Partial thromboplastin time (PTT) > 1.25 x upper limit of normal
    • Total bilirubin > 3 x upper normal limit
    • Alanine transaminase (ALT) > 3 x upper normal limit
    • Aspartate transaminase (AST) > 3 x upper normal limit
    • Creatinine > 1.5x upper normal limit
    • Blood urea nitrogen (BUN) > 1.5 x upper normal limit
    • HIV positive
    • IgM HAV positive, Hepatitis B surface antigen (HBsAg) or hepatitis C antibody (HCV) positive.

13. History of, or current alcohol or drug abuse likely to interfere with ability to comply with protocol.

    requirements or give informed consent, as determined by the Investigator.

14. History of, or current psychiatric illness likely to interfere with ability to comply with protocol requirements or give informed consent, as determined by the Investigator.

15. Currently taking any of the following medications: Rituximab, Aspirin or Aspirin-containing compounds, Salicylates, Anticoagulants, clopidogrel, ticlopidine, Rh0(D) Immune Globulin (WinRho®), or intravenous immunoglobulin (IVIG).