Efficacy and safety of Eltrombopag in patients with acquired moderate aplastic anemia treated with Ciclosporin A (EMAA)
Zusammenfassung der Studie
In this study, the Eltrombopag + Ciclosporin therapy is compared with the placebo + Ciclosporin therapy in patients with moderate aplastic anemia without prior treatment. Due to the manifestation of aplastic anemia, there is a need for immunosuppressive therapy with Ciclosporin. This therapy is independent of study participation. Ciclosporin is a mild immunosuppressive therapy that is very commonly used in aplastic anemia. Within the study, all patients receive this therapy. In addition, patients receive either the study drug Eltrombopag or a so-called placebo. The placebo does not differ externally from the drug being tested, but contains no active ingredients and is intended to keep external influences on the results as low as possible. Neither you nor the treating physician on site know whether you have received the active substance or the placebo. After 6 months, the treatment is unmasked. This means that you and your attending physicians will find out whether you received Eltrombopag or placebo. Additionally, it will be checked how you responded to the therapy. The results will determine the further course of action.
(BASEC)
Untersuchte Intervention
• a bone marrow puncture to assess changes in the bone marrow with an additional examination of specific genes that are often associated with another bone marrow disease (myelodysplastic syndrome) to safely exclude these
• a differentiated examination of the blood count (white and red blood cells, platelets and "young" red blood cells (reticulocytes) from the blood
• Clinical chemistry tests (especially regarding kidney and liver function) from the blood
• Coagulation tests (with the question of a tendency to bleeding or clumping of blood cells) from the blood
• a test to exclude an HIV infection, as you would otherwise not be able to participate in the study. This test is also performed from the blood.
• an examination of various markers, e.g., GPI-anchored proteins and telomeres (which have provided indications of therapeutic response in other therapies for aplastic anemia), to clarify whether these could also be markers for response to Eltrombopag therapy. These examinations are performed from the blood
• an ophthalmological examination to exclude the presence of a change (especially cataract) that could be worsened by treatment with Eltrombopag
• an electrocardiogram (ECG) to exclude the presence of concerning changes.
• Quality of life assessments with various quality of life questionnaires (FACIT-F SCALE/EORTC QLQ-C30 and QLQ-AA/PNH) to clarify whether the therapy can lead to an improvement in your quality of life
• For a portion of the patients, after separate information and consent, additional examinations of drug levels from the blood will be performed.
(BASEC)
Untersuchte Krankheit(en)
Patients with moderate aplastic anemia (MAA) without specific prior treatment can participate in this study, who now require specific treatment. Since MAA is a very rare disease, this study is conducted in centers in 6 different countries, and your treating clinic is the only center in Switzerland participating in this study. Moderate aplastic anemia (MAA) is a blood formation disorder that, although not malignant by definition, can become life-threatening. In aplastic anemia, a failure of the bone marrow (site of blood formation) leads to insufficient production of blood cells. This reduction in cell counts (cytopenia) can lead to relevant complaints. A decrease in white blood cells (leukopenia or granulocytopenia or neutropenia) can lead to an increase in infections and inflammations. A decrease in platelets (thrombocytopenia) can result in an increased tendency to bleed. The decrease in red blood cells (anemia) can lead to complaints such as fatigue, weakness, shortness of breath, and similar symptoms. When the need for therapy arises, the standard therapy consists of suppressing the body's immune system (immunosuppressive therapy). Unfortunately, some patients do not respond to this therapy or cannot be treated with such immunosuppressive therapy due to possible side effects and contraindications. In these situations, there are unfortunately too few effective therapeutic options. Currently, the treatment of these patients often relies on symptom-oriented and supportive therapeutic measures, such as the regular administration of blood products. Therefore, there is an urgent need for patients with moderate aplastic anemia for further effective therapeutic options with a low rate of side effects, particularly to reduce the life-threatening risk of infections and bleeding and to improve quality of life. The study drug Eltrombopag is a thrombopoietin receptor agonist. This means it activates the same signaling pathways in stem cells and precursor cells in the bone marrow as the body's own hormone thrombopoietin (TPO). Stem cells and precursor cells are essential components of blood formation, as all other blood cells develop from them. For this, these cells need the right signals, such as those provided by thrombopoietin. A recent study shows that patients with severe and very severe aplastic anemia (SAA and VSAA) who did not respond to immunosuppressive therapy had a significant therapeutic response to Eltrombopag.
(BASEC)
1. Diagnosis of moderate aplastic anemia (MAA) without specific prior treatment and indication for CSA treatment. MAA is an aplastic anemia defined as follows: - no evidence of other bone marrow diseases - age-appropriate hypocellular bone marrow - drop of at least two of the following three peripheral blood values below normal values: absolute neutrophil count (ANC) <1.2 G/L, platelet count < 70 G/L, absolute reticulocyte count < 60 G/L, without meeting the criteria for SAA 2. The need for treatment with CSA is defined in this study as: EMAA study / EudraCT No. 2014-000174-19 6 a) MAA and transfusion dependence, when: 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) b) MAA and transfusion dependence Platelet transfusion dependence is defined as prophylactic transfusion (platelet count < 10 G/L without bleeding) or therapeutic transfusion Erythrocyte transfusion dependence is defined as transfusion of at least 4 units of packed red blood cell concentrates (PRBC) within 12 weeks prior to inclusion. 3. Signed patient information and consent form. (BASEC)
Ausschlusskriterien
1. Adult age 2. Severe or very severe aplastic anemia (hypocellularity of the bone marrow of 25% and drop of at least two of the following three peripheral blood values: ANC < 0.5 G/L, platelet count < 20 G/L, reticulocyte count < 20 G/L) 3. Diagnosis of Fanconi anemia 4. Clonal myeloid disorder based on cytogenetic examinations performed within 12 weeks prior to planned inclusion In particular, patients with cytogenetic abnormalities showing recurrent MDS are not suitable for this study. 5. Bone marrow fibrosis with increased reticulin of grade 3 or higher 6. Other serious illnesses preventing the patient from tolerating the protocol therapy 7. ALT > 3 times normal level if this increase is progressive or persistent for four weeks or accompanied by elevated bilirubin levels or associated with clinical symptoms of liver damage or a demonstration of hepatic decompensation 8. An infection that does not adequately respond to appropriate therapy 9. HIV positivity, hepatitis B or C infection 10. Moribund patients of a severity that makes the death of the patient within the next 3 months appear possible. 11. History of other malignancies other than localized tumors diagnosed more than a year ago and surgically treated with curative intent (e.g., squamous cells or other skin cancers in stage 1, breast cancer, in situ cervical cancer...). 12. Previous specific treatment of aplastic anemia with immunosuppressants or androgens or interleukin 2 receptor antibodies. The use of these medications in the context of other diseases is not an exclusion criterion if the use occurred more than six months before inclusion. 13. Treatment with other hematologically active substances (including growth factors) within three months prior to inclusion as well as Treatment with corticosteroids within three weeks prior to inclusion. 14. Known hypersensitivity to Eltrombopag or its components 15. Known hypersensitivity to Ciclosporin 16. Current breastfeeding, pregnancy or refusal to take contraceptives or use other methods to prevent pregnancy in women of childbearing age during this study 17. Inability of participants to understand the investigational nature of the study or to consent to participation / to provide informed consent 18. Renal impairment with creatinine > 2x normal. 19. Uncontrolled hypertension 20. Participation in another clinical study involving treatment with a clinical trial drug, with a washout period of 30 days prior to inclusion. (BASEC)
Studienstandort
Basel
(BASEC)
Sponsor
University Hospital Ulm (Germany) Universitätsspital Basel
(BASEC)
Kontakt für weitere Auskünfte zur Studie
Kontaktperson Schweiz
Dr. Carsta Köhler
+49 (0) 351 25933 190
carsta.koehler@clutterg-wt.deGWT-TUD GmbH
(BASEC)
Wissenschaftliche Auskünfte
Sponsor GmbH,
Kathrin.kiok@gwtonline.de; hoechsmann@blutspende.de(ICTRP)
Name der bewilligenden Ethikkommission (bei multizentrischen Studien nur die Leitkommission)
Ethikkommission Nordwest- und Zentralschweiz EKNZ
(BASEC)
Datum der Bewilligung durch die Ethikkommission
14.03.2016
(BASEC)
ICTRP Studien-ID
NCT02773225 (ICTRP)
Offizieller Titel (Genehmigt von der Ethikkommission)
Efficacy and Safety of Eltrombopag in Patients with Acquired Moderate Aplastic Anemia (EMAA) who are treated with Ciclosporin A Prospective Randomized Multicenter Study comparing Thrombopoetin-Receptor agonist Eltrombopag with Placebo in Patients with Acquired Moderate Aplastic Anemia who are treated with Ciclosporin A (BASEC)
Wissenschaftlicher Titel
Efficacy and Safety of Thrombopoetin-Receptor Agonist Eltrombopag in in Combination With Ciclosporin A in Moderate Aplastic Anemia (EMAA): Prospective Randomized Multicenter Study (ICTRP)
Öffentlicher Titel
Efficacy and Safety of Eltrombopag + CSA in Patients With Moderate Aplastic Anemia (EMAA) (ICTRP)
Untersuchte Krankheit(en)
Anemia, Aplastic (ICTRP)
Untersuchte Intervention
Drug: Eltrombopag;Drug: Placebo (for Eltrombopag) (ICTRP)
Studientyp
Interventional (ICTRP)
Studiendesign
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor). (ICTRP)
Ein-/Ausschlusskriterien
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
(ICTRP)
nicht verfügbar
Primäre und sekundäre Endpunkte
Trilineage hematologic response rate (CR + PR) (ICTRP)
Comparison of number of SAEs between the two arms (CSA + Placebo versus CSA + Eltrombopag;cumulative incidence of response;single hematological response rate (CR and PR, detailed definition => primary endpoint) at 3, 12 and 18;Trilineage hematological response rate (CR and PR, detailed definition => primary endpoint) at 3, 12 and 18 (ICTRP)
Registrierungsdatum
29.02.2016 (ICTRP)
Einschluss des ersten Teilnehmers
27.01.2015 (ICTRP)
Sekundäre Sponsoren
nicht verfügbar
Weitere Kontakte
Britta Höchsmann, MD;Kiok Kathrin, Dr rer nat;Britta Höchsmann, MD, Kathrin.kiok@gwtonline.de; hoechsmann@blutspende.de, Sponsor GmbH, (ICTRP)
Sekundäre IDs
9345 (ICTRP)
Angaben zur Verfügbarkeit von individuellen Teilnehmerdaten
Yes (ICTRP)
Weitere Informationen zur Studie
https://clinicaltrials.gov/show/NCT02773225 (ICTRP)
Ergebnisse der Studie
Zusammenfassung der Ergebnisse
nicht verfügbar
Link zu den Ergebnissen im Primärregister
nicht verfügbar