Efficacy and Safety of Eltrombopag + CSA in Patients With Moderate Aplastic Anemia (EMAA)

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Brief Title

Efficacy and Safety of Eltrombopag + CSA in Patients With Moderate Aplastic Anemia (EMAA)

Official Title

Efficacy and Safety of Thrombopoetin-Receptor Agonist Eltrombopag in in Combination With Ciclosporin A in Moderate Aplastic Anemia (EMAA): Prospective Randomized Multicenter Study

Brief Summary

      The aim of this study is to improve treatment of Moderate Aplastic Anemia (MAA) by evaluating
      the safety and efficiency of Eltrombopag as a new treatment option in patients with therapy
      requiring MAA.
    

Detailed Description

      After enrollment (see detailed inclusion and exclusion criteria below) the patients are
      randomized either to the Placebo or Eltrombopag arm. The randomization is double blinded.
      Randomization will take in account patient's age and disease severity by stratifying into 4
      block combinations to ensure homogeneity between treatment arms. All patients receive
      background therapy with CSA, regardless of randomisation group, to treat MAA according to
      current standard of care.

      Eltrombopag (or Placebo) is given at a daily starting dose of 150 mg orally as 75 mg tablets
      once daily (2 tablets Eltrombopag or placebo per day), (Olnes et al NEJM 2012).

      In Asian patients Eltrombopag (or Placebo) is given at a daily starting dose of 75 mg orally
      (1 tablet Eltrombopag or placebo per day). In Asian-Caucasian patients no dose reduction of
      the starting dose is carried out, but cautious observation of the liver function due to the
      possibility of altered Eltrombopag metabolism is recommended.

      Dose reduction:

      In patients without history of thromboembolism or known risk factors for thrombembolism dose
      reduction (the possibility of an alternating dose schedule is given) is recommended if the
      platelet count is increasing > 150 G/L.

        -  Dosage should be decreased to achieve a platelet count between 100 and 150 G/L after
           reaching a sufficient erythrocyte and granulocyte response (see 10.1).

        -  If the platelet count decreases below 100 G/L the Eltrombopag dose should be escalated
           again.

        -  Eltrombopag should be discontinued if the platelet count exceeds 450 G/L and could be
           restarted with a lower dose after decrease of the platelet count below 150 G/L.

      In patients with history of thromboembolism or known risk factors for thromboembolism (e. g.
      Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, PNH with GPI-deficient
      granulocyte population > 50 %, prolonged periods of immobilization, contraceptives and
      hormone replacement therapy or surgery) dose reduction is recommended if the platelet count
      is increasing > 100 G/L

        -  The target platelet count will be 70-120 G/L after reaching a sufficient erythrocyte and
           granulocyte response (see 10.1).

        -  If the platelet count decreases below 70 G/L the Eltrombopag dose should be escalated
           again.

        -  Eltrombopag should be discontinued in patients with history of and risk factors for
           thromboembolism if the platelet count exceeds 150 G/L.

      Duration of follow up: Last Follow up 24 months after end of study treatment. Patients will
      receive Eltrombopag or placebo within the study for a minimum of 6 months. Exceptions are
      patients with disease progression in Severe or Very Severe AA or patients with inacceptable
      adverse events within the first 6 months.

      Eltrombopag will be administered for a maximum period of 12 months within the protocol.
      Recent data show that the response of hematopoiesis in refractory severe aplastic anemia can
      be sustained on discontinuation of Eltrombopag25.

      As long-term effects of investigational treatments are an objective of the study, the
      follow-up of patients will cover 24 months after the end of the study treatment according to
      the protocol
    

Study Phase

Phase 2/Phase 3

Study Type

Interventional


Primary Outcome

Trilineage hematologic response rate (CR + PR)

Secondary Outcome

 Trilineage hematological response rate (CR and PR, detailed definition => primary endpoint) at 3, 12 and 18

Condition

Anemia, Aplastic

Intervention

Eltrombopag

Study Arms / Comparison Groups

 Eltrombopag + Ciclosporin A
Description:  Eltrombopag, 75 mg film tablets, starting dose: 2 tablets (150 mg per day), daily, per os
+ According to European guidelines CSA is administered orally with an initial daily dose of 5 mg/kg/day divided into two doses. Then dosage should be adjusted with the aim of a trough CSA blood level of 200-400 ng/mL (using a polyclonal assay) or 150-250 ng/mL (using a monoclonal assay).

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

116

Start Date

January 27, 2015

Completion Date

September 30, 2023

Primary Completion Date

September 30, 2022

Eligibility Criteria

        Inclusion Criteria:

          1. Current diagnosis of a Moderate Aplastic Anemia requiring standard treatment with CSA
             without prior specific therapy.

             MAA is defined as Aplastic Anemia fulfilling the following criteria:

               -  no evidence for other disease causing marrow failure

               -  hypocellular bone marrow for age

               -  depression of at least two out of three peripheral blood counts below the normal
                  values:

                    -  absolute neutrophil count (ANC) < 1.2 G/L and > 0.5 G/l

                    -  platelet count < 70 G/L

                    -  absolute reticulocyte count < 60 G/L

             without fulfilling the criteria for SAA (hypocellularity of bone marrow 25 % and
             depression of two of the three peripheral counts: ANC < 0.5 G/L, platelet count < 20
             G/L, reticulocyte count < 20 G/L)

          2. In this study need for treatment with CSA is defined as:

        2a) transfusion-independent MAA and:

          -  ANC < 1.0 G/L

          -  or hemoglobin < 8.5 g/dl and reticulocyte count < 60 G/L

          -  or platelet count < 30 G/L

          -  or significant clinical symptoms (infections, bleeding, anemia)

             2b) transfusion-dependent moderate aplastic anemia

          -  Platelet transfusion dependency is defined as prophylactic transfusion (platelet
             counts < 10 G/L with no bleeding) or therapeutic transfusion in the 12 weeks prior to
             study entry

          -  Red cell transfusion dependency is defined as transfusion of at least 4 units of
             packed red blood cell concentrates (PRBC) in the 12 weeks prior to study entry

             3) A signed and dated informed consent is necessary before the conduct of any
             study-specific procedure.

        Exclusion Criteria:

          1. Age < 18 years

          2. Severe or Very Severe Aplastic Anemia (hypocellularity of bone marrow 25 % and
             depression of two of the three peripheral counts: ANC < 0.5 G/L, platelet count < 20
             G/L, reticulocyte count < 20 G/L)

          3. Constitutional aplastic anemia (Fanconi anemia or Dyskeratosis congenita)

          4. Clonal myeloid disorders based on cytogenetic findings performed within 12 weeks of
             study entry. Especially, patients with cytogenetic abnormalities which are recurrent
             in MDS are not eligible for the study.

          5. Bone marrow reticulin fibrosis of grade 3 or greater

          6. Severe concurrent diseases precluding the patient's ability to tolerate protocol
             therapy

          7. ALT > 3 times the upper limit of normal if this elevation is progressive, or
             persistent for 4 weeks, or accompanied by increased direct bilirubin, or accompanied
             by clinical symptoms of liver injury or evidence for hepatic decompensation

          8. Infection not adequately responding to appropriate therapy

          9. HIV-positivity (patients with Hepatitis B or Hepatits C-positivity are only in
             combination with hepatic failure (see criteria 7) excluded)

         10. Moribund status with a likely death within 3 months

         11. History of malignancy other than localized tumors diagnosed more than one year
             previously and treated surgically with curative intent (for instance squamous cell or
             other skin cancers, stage 1, breast cancer in situ, cervical carcinoma in situ...).

         12. Prior specific treatment of Aplastic Anemia with immunosuppression or androgens or
             interleukin2-receptor-antibodies. The use of these drugs in context of other disorders
             before diagnosis of aplastic anemia is not an exclusion criteria if these treatments
             were finished longer than 6 months before study entry.

         13. Treatment with other hematological effective drugs (including erythropoetin) within 3
             months before study entry as well as treatment with corticosteroids and G-CSF within 3
             weeks before enrollment

         14. Known hypersensitivity to Eltrombopag or its components

         15. Known hypersensitivity to Ciclosporin

         16. Current nursing, pregnancy, or unwillingness to take oral contraceptives or use a
             barrier method of birth control to refrain from pregnancy as well as a missing or
             positive pregnancy test within the last 14 days before inclusion for women with
             childbearing potential during the course of this study.

         17. Inability to understand the investigational nature of the study or to give informed
             consent.

         18. Renal failure with creatinine > 2× upper limit of normal.

         19. Uncontrolled hypertension

         20. Participation in any study using an investigational drug or treatment with an
             investigational drug within 30 days preceding the first dose of study medication
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Britta Höchsmann, MD, , [email protected]

Location Countries

Germany

Location Countries

Germany

Administrative Informations


NCT ID

NCT02773225

Organization ID

9345


Responsible Party

Sponsor-Investigator

Study Sponsor

B. Höchsmann


Study Sponsor

Britta Höchsmann, MD, Principal Investigator, Sponsor GmbH


Verification Date

February 2018