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Trial record 1 of 1 for:    CETB115E2403
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Eltrombopag Combined With Cyclosporine as First Line Therapy in Patients With Severe Acquired Aplastic Anemia (SOAR)

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ClinicalTrials.gov Identifier: NCT02998645
Recruitment Status : Recruiting
First Posted : December 20, 2016
Last Update Posted : February 5, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:

This is a two-part study, interventional Phase II, single-arm, multicenter, open-label study to investigate the efficacy and safety of a combination regimen of eltrombopag and cyclosporine in patients with severe aplastic anemia (SAA) as first line therapy and an extension with up to 60-months follow-up. All patients will receive eltrombopag for 6 months with cyclosporine. Patients who respond (who had overall hematologic response by 6 months) will continue tapering down cyclosporine for up to 30 months and will be followed up for a post-treatment follow-up up to 60 months by regular clinic visits. Patients who do not have an overall hematologic response (non-responders) by the end of 6 month time point will be discontinued from the treatment and will be followed up for non-responder post-treatment follow-up up to 60 months.

The usage of eltrombopag and cyclosporine combines two therapies with different modes of action. Cyclosporine acts as an immunosuppressant and eltrombopag acts as a stimulator of bone marrow progenitor cells. Given that SAA is currently viewed as having an autoimmune pathogenesis resulting in bone marrow progenitor cell destruction, the combination of eltrombopag and cyclosporine is attractive. Preliminary experience with their combined use appears favorable, with no untoward toxicity observed to date.


Condition or disease Intervention/treatment Phase
Severe Aplastic Anemia Drug: eltrombopag Drug: Cyclosporine Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: SOAR Trial, A Two-part Study: Interventional Phase II Single-arm Trial to Assess Efficacy and Safety of Eltrombopag Combined With Cyclosporine as First Line Therapy in Patients With Severe Acquired Aplastic Anemia, and an Extension With up to 60-months Follow-up
Actual Study Start Date : May 11, 2017
Estimated Primary Completion Date : July 21, 2020
Estimated Study Completion Date : January 21, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Eltrombopag + cyclosporine
Planned duration of treatment with eltrombopag is 6 months (for all patients); the planned duration of treatment with cyclosporine is 30 months (for responder patients).
Drug: eltrombopag
Film-coated tablets (12.5 mg, 25 mg, 50 mg and 75 mg) administered orally, once daily. Dosing is done according to age and ethnicity (East Asian)

Drug: Cyclosporine
Supplied in oral soft gel capsules or oral solution and dosage is based on body weight and administered every 12 hours. Dosing is titrated individually according to therapeutic trough level for 6 months.




Primary Outcome Measures :
  1. Overall hematologic response (CR + PR)* rate - 6 month [ Time Frame: by 6 months ]

    Overall hematologic response = patients with complete response (CR) + patients with partial response (PR)

    1. Partial response is defined as any two of the following parameters at two consecutive measurements at least 7 days apart during the study:

      • Absolute neutrophil count (ANC) >500/μL
      • Platelet count >20 000/μL
      • Reticulocyte count >60 000/μL
    2. Complete response is defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart during the study:

      • Absolute neutrophil count (ANC) > 1 000/μL
      • Platelet count >100 000/μL
      • Hemoglobin >10 g/L


Secondary Outcome Measures :
  1. Overall hematologic response (CR + PR)* rate - 3 and 12 month [ Time Frame: by 3 months (all patients) and 12 months (responders only, except OS) ]

    Overall hematologic response = patients with complete response (CR) + patients with partial response (PR)

    1. Partial response is defined as any two of the following parameters at two consecutive measurements at least 7 days apart during the study:

      • Absolute neutrophil count (ANC) >500/μL
      • Platelet count >20 000/μL
      • Reticulocyte count >60 000/μL
    2. Complete response is defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart during the study:

      • Absolute neutrophil count (ANC) > 1 000/μL
      • Platelet count >100 000/μL
      • Hemoglobin >10 g/L

  2. Duration of hematologic response [ Time Frame: by 6 months (all patients), at 30 and 60 months (responders only, except OS) ]
    Time from the date of the start of the first response to the date of first relapse defined as again meeting criteria for severe aplastic anemia (absolute neutrophil count <500/μL; platelet counts <20 000/μL; reticulocytes <20 000/μL) and/or becoming transfusion dependent

  3. Percentage of patients treated with immunosuppressive therapy (IST) [ Time Frame: by 3 months (all patients) and 12 months (responders only, except OS) ]
    Percentage of patients who required immunosuppressive therapy due to relapse defined as again meeting criteria for severe aplastic anemia (absolute neutrophil count <500/μL; platelet counts <20 000/μL; reticulocytes <20 000/μL) and/or becoming transfusion dependent

  4. Percentage of patients with clonal evolution to myelodysplasia, PNH, acute leukemia [ Time Frame: by 3 months (all patients) and 12 months (responders only, except OS) ]
    Clonal evolution to myelodysplasia is defined as a new marrow cytogenic abnormality with or without characteristic dysplastic marrow findings. Evolution to leukemia is defined as greater than 20% peripheral blood and/or marrow blasts. Evolution to paroxysmal nocturnal hemoglobinuria (PNH) is defined as a clone at baseline < 10% that rose to greater than 50% on study.

  5. Percentage of patients who received RBC transfusion [ Time Frame: by 3 months (all patients) and 12 months (responders only, except OS) ]
    Transfusions red blood cells may be given during study participation as medically necessary. Packed RBCs should be administered for hemoglobin <8 g/dL, or when patients are symptomatic

  6. Percentage of patients who received platelet transfusion [ Time Frame: by 3 months (all patients) and 12 months (responders only, except OS) ]
    Transfusions with platelets may be given during study participation as medically necessary. In general, platelet transfusions should be administered when the platelet count <10 x 109/L or when significant bleeding occurs

  7. Duration of platelet and RBC transfusion independence [ Time Frame: by 3 months (all patients) and 12 months (responders only, except OS) ]
    Transfusion independency is defined when blood and platelet transfusions are not required in a consecutive 8-week period. Transfusion dependency will be defined as at least 2 units of red blood cells or five units of random platelets or equivalent apheresis per month for a period of 8 weeks. The duration of platelet and blood transfusion independence will be evaluated separately.

  8. Overall survival of participants [ Time Frame: by 3 months (all patients) and 12 months (responders only, except OS) ]
    Overall survival is defined as the time from the date of the first dose of study treatment (eltrombopag + cyclosporine) to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the data of last contact. Median OS time and its two-sided 95% confidence interval will be reported using Kaplan-Meier method

  9. Change in scores of FACIT-Fatigue Patient Reported Outcome [ Time Frame: by 3 months (all patients) and 12 months (responders only, except OS) ]

    FACIT-Fatigue responses will be generated in accordance with the respective scoring manual. Descriptive statistics will be used to summarize the raw and absolute change from baseline to each assessment visit. Patients with an evaluable baseline score and at least one evaluable post baseline score during the treatment period will be included in the change from baseline analyses. The FACT- Fatigue is a 13-item fatigue subscale that asks the patient to rate their degree of tiredness, weakness and fatigue. All items of the FACT-Fatigue use a 5 point scale ranging from 0 to 4 with a 0 rating being "not at all" and a 4 rating being "very much".

    Total score ranges from 0 to 52. High scores represent less fatigue.


  10. Change in scores of FACT-TH18 Patient Reported Outcome [ Time Frame: by 3 months (all patients) and 12 months (responders only, except OS) ]
    FACT-TH18 responses will be generated in accordance with the respective scoring manual. Descriptive statistics will be used to summarize the raw and absolute change from baseline to each assessment visit. Patients with an evaluable baseline score and at least one evaluable post baseline score during the treatment period will be included in the change from baseline analyses. The FACT- TH is an 18-item fatigue subscale that asks the patient to rate their degree of thrombocytopenia All items of the FACT-Fatigue use a 5 point scale ranging from 0 to 4 with a 0 rating being "not at all" and a 4 rating being "very much".

  11. Pharmacokinetic parameter- Cmax of eltrombopag when combined with cyclosporine [ Time Frame: Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0 ]

    Cmax=Observed maximum plasma concentration following administration (mass/volume). The plasma samples from all patients will be assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) will be 100 ng/mL.

    Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly


  12. Pharmacokinetic parameter-AUClast of eltrombopag when combined with cyclosporine [ Time Frame: Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0 ]

    AUClast=Area under the curve calculated to the last quantifiable concentration point (Tlast) (mass*time/volume). The plasma samples from all patients will be assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) will be 100 ng/mL.

    Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly


  13. Pharmacokinetic parameter- AUCtau of eltrombopag when combined with cyclosporine [ Time Frame: Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0 ]

    AUCtau=Area under the curve calculated to the end of the dosing interval ( tau) (mass*time/volume). The plasma samples from all patients will be assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) will be 100 ng/mL.

    Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly


  14. Pharmacokinetic parameter- Ctrough of eltrombopag when combined with cyclosporine [ Time Frame: Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0 ]

    Ctrough=Pre-dose plasma concentration (mass/volume). Observed maximum plasma concentration following administration (mass/volume). The plasma samples from all patients will be assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) will be 100 ng/mL.

    Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly


  15. Pharmacokinetic parameter- Tmax of eltrombopag when combined with cyclosporine [ Time Frame: Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0 ]

    Tmax=The time to reach peak or maximum concentration (time). The plasma samples from all patients will be assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) will be 100 ng/mL.

    Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly


  16. Pharmacokinetic parameter- CLss/F of eltrombopag when combined with cyclosporine [ Time Frame: Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0 ]

    CLss/F=Apparent systemic (or total body) clearance at steady state from plasma (volume/time). The plasma samples from all patients will be assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). The lower limit of quantitation (LLOQ) will be 100 ng/mL.

    Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patient has signed the Informed Consent (ICF) prior to any screening procedures being performed.
  2. Patient is male/female ≥6 years old at the time of informed consent and able to swallow a tablet.
  3. Patient has SAA characterized by:

    1. Bone marrow cellularity <30% (excluding lymphocytes) and
    2. At least two of the following (peripheral blood):

      • Absolute neutrophil count <500/µL
      • Platelet count <20,000/µL
      • Absolute reticulocyte count <60,000/µL
  4. Normal ECG defined as the following as determined via the mean of a triplicate ECG

    • Resting heart rate 6-<12 years: 60-130 bpm 12-<18 years: 60-120 bpm

      ≥18 years: 50-90 bpm

    • QTcF at screening <450 msec (for male patients), ≤460 msec (for female patients)

Exclusion Criteria:

  1. Diagnosis of Fanconi anemia.
  2. Evidence of a clonal hematologic bone marrow disorder on cytogenetics. Patients with very severe neutropenia (ANC < 200/μL) will not be excluded initially if cytogenetics are not available or pending. If a clonal disorder is identified, the patient will be excluded.
  3. Prior immunosuppressive therapy with cyclosporine, alemtuzumab, rabbit or horse ATG and thrombopoietin receptor (TPO-R) agonists.
  4. a. Hypersensitivity to eltrombopag or cyclosporine or their components. b. Contraindications to cyclospsorine.
  5. AST or ALT >3 x ULN.
  6. Serum creatinine, total bilirubin, or alkaline phosphatase >1.5 x ULN.
  7. Patient with liver cirrhosis.
  8. Infection not adequately controlled with appropriate therapy.
  9. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient's ability to consent, be compliant with study procedures, tolerate protocol therapy, or that death within 30 days is likely.
  10. Patients with cancer who are not considered cure, are on active chemotherapeutic treatment or who take drugs with hematological effects.
  11. Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment.
  12. Pregnancy statements and contraception requirements:

    Pregnancy or nursing (lactating) women Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant (or female partners of male patients), unless they are using highly effective methods of contraception during dosing and for 3 months after stopping medication.

  13. Not able to understand the investigation nature of the study or to give informed consent.
  14. Clinically significant ECG abnormality including cardiac arrhythmias (e. g. ventricular tachycardia) complete left bundle branch block, high grade atrioventricular block, or inability to determine the QTcF interval on the ECG.
  15. Presence of cardiac disease, or family history of idiopathic sudden death or congenital long QT syndrome.
  16. Risk factors for Torsades de Pointe including uncorrected hypokalemia or hypomagnesemia, or use of concomitant medication(s) with a known risk to prolong the QT interval that cannot be discontinued or replaced by safe alternative medication per www.qtdrugs.org.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02998645


Contacts
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Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals

Locations
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Brazil
Novartis Investigative Site Recruiting
Ribeirao Preto, SP, Brazil, 14048-900
Novartis Investigative Site Recruiting
São Paulo, SP, Brazil, 01323-900
Hong Kong
Novartis Investigative Site Recruiting
Hong Kong, Hong Kong
Hungary
Novartis Investigative Site Recruiting
Debrecen, Hungary, 4032
India
Novartis Investigative Site Recruiting
Vellore, India
Italy
Novartis Investigative Site Recruiting
Bologna, BO, Italy, 40138
Novartis Investigative Site Recruiting
Brescia, BR, Italy, 25123
Novartis Investigative Site Recruiting
Milano, MI, Italy, 20122
Korea, Republic of
Novartis Investigative Site Recruiting
Seoul, Korea, Republic of, 03722
Novartis Investigative Site Recruiting
Seoul, Korea, Republic of, 06351
Netherlands
Novartis Investigative Site Recruiting
Leiden, Netherlands, 2300 RC
Spain
Novartis Investigative Site Recruiting
San Sebastian, Pais Vasco, Spain, 20080
Novartis Investigative Site Recruiting
Madrid, Spain, 28041
Novartis Investigative Site Recruiting
Madrid, Spain, 28222
Thailand
Novartis Investigative Site Recruiting
Bangkok, Thailand, 10330
Novartis Investigative Site Recruiting
Bangkok, Thailand, 10700
Novartis Investigative Site Recruiting
Chiang Mai, Thailand, 50200
Turkey
Novartis Investigative Site Recruiting
Istanbul, Turkey, 34890
Novartis Investigative Site Recruiting
Samsun, Turkey, 55139
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02998645     History of Changes
Other Study ID Numbers: CETB115E2403
First Posted: December 20, 2016    Key Record Dates
Last Update Posted: February 5, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
severe acquired aplastic anemia
SAA
first line
eltrombopag
cyclosporine
h-ATG
severe aplastic anemia
aplastic anemia

Additional relevant MeSH terms:
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Anemia
Anemia, Aplastic
Hematologic Diseases
Bone Marrow Diseases
Cyclosporins
Cyclosporine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents
Calcineurin Inhibitors