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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02998645
Recruitment Status : Active, not recruiting
First Posted : December 20, 2016
Last Update Posted : October 20, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:

This interventional Phase II, single-arm, multicenter, open-label study will investigate the efficacy and safety of a combination regimen of 6 months eltrombopag and cyclosporine treatment in adult patients with severe aplastic anemia (SAA) as first line therapy, with an additional 18 months follow-up for cyclosporine tapering and duration of response until relapse or 24 months whichever is earlier (responders only who do not relapse prior to 6 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)
Actual Enrollment : 54 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: SOAR, Interventional Phase II Single-arm Study to Assess Efficacy and Safety of Eltrombopag Combined With Cyclosporine as First Line Therapy in Adult Patients With Severe Acquired Aplastic Anemia
Actual Study Start Date : May 11, 2017
Estimated Primary Completion Date : November 19, 2020
Estimated Study Completion Date : June 22, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Eltrombopag + cyclosporine
Planned duration of treatment with eltrombopag & cyclosporine is 6 months (for all patients); the planned duration of treatment with cyclosporine (cyclosporine tapering) is 18 months (for responder patients only).
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. After 6 months (for responders), tapering of cyclosporine must be done as follows:

  • 6-9 months: at the 6 months visit, the dose must be reduced by 25% for 3 months
  • 9-12 months: at the 9 months visit, the dose must be further reduced by 25% for another 3 months
  • 12-24 months: maintain dose




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, 12 and 24 month [ Time Frame: by 3 months (all patients) and at 12 and 24 months (responders only) ]

    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) and 24 months (responders only) ]
    Time from the date of the start of first response to the date of first relapse (defined as no longer meeting definition of PR (and not CR)

  3. Proportion of patients who relapse [ Time Frame: by 6 months (all patients) and 24 months (responders only) ]
    Percentage of patients who relapse. Relapse is defined as no longer meeting the definition of PR (and not CR).

  4. Percentage of patients with clonal evolution to myelodysplasia, paroxysmal nocturnal hemoglobinuria (PNH), and leukemia [ Time Frame: by 6 months (all patients) and 24 months (responders only) ]
    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 are red blood cells (RBC) transfusion independent [ Time Frame: by 6 months (all patients) and 24 months (responders only) ]
    Percentage of patients who are RBC transfusion independent at least once by 6 months and by 24 months. Independence defined as no RBC transfusion for at least 56 days.

  6. Percentage of patients who are platelet transfusion independence [ Time Frame: by 6 months (all patients) and 24 months (responders only) ]
    Percentage of patients who are platelet transfusion independent at least once by 6 months and by 24 months. Independence defined as no platelet transfusion for at least 28 days.

  7. Longest interval without platelet or RBC transfusion [ Time Frame: by 6 months (all patients) and 24 months (responders only) ]
    Duration of longest interval without a platelet or RBC transfusion by 6 months and by 24 months.

  8. Change from baseline in scores of FACIT-Fatigue Patient Reported Outcome [ Time Frame: Baseline and by 6 months (all patients) and 24 months (responders only) ]

    FACIT-Fatigue responses will be generated in accordance with the respective scoring manual. 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.


  9. Change from baseline in scores of FACT-TH18 Patient Reported Outcome [ Time Frame: Baseline and by 6 months (all patients) and 24 months (responders only) ]

    FACT-TH18 responses will be generated in accordance with the respective scoring manual. 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.

    FACT-TH18 is comprised of FACT-G and a thrombocytopenia specific questionnaire.

    FACT-G consists of 27-items divided into 4 QOL domains (physical well-being, social/Family well-being, emotional and functional well-being).

    FACT-TH18 has 18-items which asks the patient to rate degree of thrombocytopenia.

    All items of the FACT-TH18 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".


  10. Frequency and severity of AEs and serious AEs (SAEs) [ Time Frame: by 6 months (all patients) and 24 months (responders only) ]
    Safety will be assessed by frequency and severity of AEs, serious AEs (SAEs) based on the CTCAE version 4. 03, and AEs leading to discontinuation, and evaluating changes in laboratory values within 6 months and within 24 months (responders only)

  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). 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). 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. 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. 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:   18 Years and older   (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 ≥18 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: 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 by central review
  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. a. Infection not adequately controlled with appropriate therapy. b. Patients who are human immune deficiency virus (HIV), hepatitis C virus or hepatitis B surface antigen (HBsAg) positive. HCV-RNA negative patients are allowed to be enrolled.
  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.
  17. ECOG performance status of ≥2.
  18. Patients under the age of 40 must be referred for consideration of allogeneic bone marrow transplantation (HSCT) if (human leukocyte antigen) HLA matching has been done and a suitable matched sibling donor is available and the patient is willing to undergo transplantation (i.e. patients who do not have a HLA match or are not medically fit, not willing or unable to undergo transplantation will be considered for enrollment).

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


Locations
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Brazil
Novartis Investigative Site
Ribeirao Preto, SP, Brazil, 14048-900
Novartis Investigative Site
São Paulo, SP, Brazil, 01323-900
Hong Kong
Novartis Investigative Site
Hong Kong, Hong Kong
India
Novartis Investigative Site
Hyderabad, Telangana, India, 500082
Novartis Investigative Site
Vellore, India
Italy
Novartis Investigative Site
Bologna, BO, Italy, 40138
Novartis Investigative Site
Brescia, BR, Italy, 25123
Novartis Investigative Site
Milano, MI, Italy, 20122
Korea, Republic of
Novartis Investigative Site
Seoul, Korea, Republic of, 03722
Novartis Investigative Site
Seoul, Korea, Republic of, 06351
Mexico
Novartis Investigative Site
Mexico D F, Ciudad De Mexico, Mexico, 06726
Novartis Investigative Site
Monterrey, Nuevo Leon, Mexico, 64460
Novartis Investigative Site
Puebla, Mexico, 72000
Spain
Novartis Investigative Site
San Sebastian, Pais Vasco, Spain, 20080
Novartis Investigative Site
Madrid, Spain, 28041
Thailand
Novartis Investigative Site
Bangkok, Thailand, 10330
Novartis Investigative Site
Bangkok, Thailand, 10700
Novartis Investigative Site
Chiang Mai, Thailand, 50200
Turkey
Novartis Investigative Site
Istanbul, Turkey, 34890
Novartis Investigative Site
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    
Other Study ID Numbers: CETB115E2403
First Posted: December 20, 2016    Key Record Dates
Last Update Posted: October 20, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Cyclosporine
Cyclosporins
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