<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02998645</url>
  </required_header>
  <id_info>
    <org_study_id>CETB115E2403</org_study_id>
    <secondary_id>2016-002814-29</secondary_id>
    <nct_id>NCT02998645</nct_id>
  </id_info>
  <brief_title>Eltrombopag Combined With Cyclosporine as First Line Therapy in Patients With Severe Acquired Aplastic Anemia</brief_title>
  <acronym>SOAR</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Novartis</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This interventional Phase II, single-arm, multicenter, open-label study will investigate the&#xD;
      efficacy and safety of a combination regimen of 6 months eltrombopag and cyclosporine&#xD;
      treatment in adult patients with severe aplastic anemia (SAA) as first line therapy, with an&#xD;
      additional 18 months follow-up for cyclosporine tapering and duration of response until&#xD;
      relapse or 24 months whichever is earlier (responders only who do not relapse prior to 6&#xD;
      months).&#xD;
&#xD;
      The usage of eltrombopag and cyclosporine combines two therapies with different modes of&#xD;
      action. Cyclosporine acts as an immunosuppressant and eltrombopag acts as a stimulator of&#xD;
      bone marrow progenitor cells. Given that SAA is currently viewed as having an autoimmune&#xD;
      pathogenesis resulting in bone marrow progenitor cell destruction, the combination of&#xD;
      eltrombopag and cyclosporine is attractive. Preliminary experience with their combined use&#xD;
      appears favorable, with no untoward toxicity observed to date.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 11, 2017</start_date>
  <completion_date type="Actual">May 2, 2022</completion_date>
  <primary_completion_date type="Actual">November 3, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall hematologic response (CR + PR) rate - 6 month</measure>
    <time_frame>by 6 months</time_frame>
    <description>Overall hematologic response = patients with complete response (CR) + patients with partial response (PR).&#xD;
Partial response is defined as any two of the following parameters at two consecutive measurements at least 7 days apart during the study:&#xD;
Absolute neutrophil count (ANC) &gt;500/μL&#xD;
Platelet count &gt;20 000/μL&#xD;
Reticulocyte count &gt;60 000/μL&#xD;
Complete response is defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart during the study:&#xD;
Absolute neutrophil count (ANC) &gt; 1 000/μL&#xD;
Platelet count &gt;100 000/μL&#xD;
Hemoglobin &gt;10 g/L</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall hematologic response (CR + PR) rate - 3, 12 and 24 month</measure>
    <time_frame>by 3 months (all patients) and at 12 and 24 months (responders only)</time_frame>
    <description>Overall hematologic response = patients with complete response (CR) + patients with partial response (PR).&#xD;
Partial response is defined as any two of the following parameters at two consecutive measurements at least 7 days apart during the study:&#xD;
Absolute neutrophil count (ANC) &gt;500/μL&#xD;
Platelet count &gt;20 000/μL&#xD;
Reticulocyte count &gt;60 000/μL&#xD;
Complete response is defined as all three parameters meet the following criteria at two consecutive measurements at least 7 days apart during the study:&#xD;
Absolute neutrophil count (ANC) &gt; 1 000/μL&#xD;
Platelet count &gt;100 000/μL&#xD;
Hemoglobin &gt;10 g/L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of hematologic response</measure>
    <time_frame>by 6 months (all patients) and 24 months (responders only)</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients who relapse</measure>
    <time_frame>by 6 months (all patients) and 24 months (responders only)</time_frame>
    <description>Percentage of patients who relapse. Relapse is defined as no longer meeting the definition of PR (and not CR).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of patients with clonal evolution to myelodysplasia, paroxysmal nocturnal hemoglobinuria (PNH), and leukemia</measure>
    <time_frame>by 6 months (all patients) and 24 months (responders only)</time_frame>
    <description>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 &lt; 10% that rose to greater than 50% on study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of patients who are red blood cells (RBC) transfusion independent</measure>
    <time_frame>by 6 months (all patients) and 24 months (responders only)</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of patients who are platelet transfusion independence</measure>
    <time_frame>by 6 months (all patients) and 24 months (responders only)</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Longest interval without platelet or RBC transfusion</measure>
    <time_frame>by 6 months (all patients) and 24 months (responders only)</time_frame>
    <description>Duration of longest interval without a platelet or RBC transfusion by 6 months and by 24 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in scores of FACIT-Fatigue Patient Reported Outcome</measure>
    <time_frame>Baseline and by 6 months (all patients) and 24 months (responders only)</time_frame>
    <description>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 &quot;not at all&quot; and a 4 rating being &quot;very much&quot;.&#xD;
Total score ranges from 0 to 52. High scores represent less fatigue.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in scores of FACT-TH18 Patient Reported Outcome</measure>
    <time_frame>Baseline and by 6 months (all patients) and 24 months (responders only)</time_frame>
    <description>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.&#xD;
FACT-TH18 is comprised of FACT-G and a thrombocytopenia specific questionnaire.&#xD;
FACT-G consists of 27-items divided into 4 QOL domains (physical well-being, social/Family well-being, emotional and functional well-being).&#xD;
FACT-TH18 has 18-items which asks the patient to rate degree of thrombocytopenia.&#xD;
All items of the FACT-TH18 use a 5 point scale ranging from 0 to 4 with a 0 rating being &quot;not at all&quot; and a 4 rating being &quot;very much&quot;.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency and severity of AEs and serious AEs (SAEs)</measure>
    <time_frame>by 6 months (all patients) and 24 months (responders only)</time_frame>
    <description>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)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameter- Cmax of eltrombopag when combined with cyclosporine</measure>
    <time_frame>Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0</time_frame>
    <description>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.&#xD;
Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameter-AUClast of eltrombopag when combined with cyclosporine</measure>
    <time_frame>Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0</time_frame>
    <description>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.&#xD;
Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameter- AUCtau of eltrombopag when combined with cyclosporine</measure>
    <time_frame>Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0</time_frame>
    <description>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.&#xD;
Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameter- Ctrough of eltrombopag when combined with cyclosporine</measure>
    <time_frame>Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0</time_frame>
    <description>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.&#xD;
Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameter- Tmax of eltrombopag when combined with cyclosporine</measure>
    <time_frame>Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0</time_frame>
    <description>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.&#xD;
Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameter- CLss/F of eltrombopag when combined with cyclosporine</measure>
    <time_frame>Week 2:hour 0,2,4,6,8 Week 4,8,12,26: hour 0</time_frame>
    <description>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.&#xD;
Concentration values below the LLOQ will be reported as zero, and missing samples will be labeled accordingly</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">54</enrollment>
  <condition>Severe Aplastic Anemia</condition>
  <arm_group>
    <arm_group_label>Eltrombopag + cyclosporine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Planned duration of treatment with eltrombopag &amp; cyclosporine is 6 months (for all patients); the planned duration of treatment with cyclosporine (cyclosporine tapering) is 18 months (for responder patients only).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>eltrombopag</intervention_name>
    <description>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)</description>
    <arm_group_label>Eltrombopag + cyclosporine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclosporine</intervention_name>
    <description>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:&#xD;
6-9 months: at the 6 months visit, the dose must be reduced by 25% for 3 months&#xD;
9-12 months: at the 9 months visit, the dose must be further reduced by 25% for another 3 months&#xD;
12-24 months: maintain dose</description>
    <arm_group_label>Eltrombopag + cyclosporine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patient has signed the Informed Consent (ICF) prior to any screening procedures being&#xD;
             performed.&#xD;
&#xD;
          2. Patient is male/female ≥18 years old at the time of informed consent and able to&#xD;
             swallow a tablet.&#xD;
&#xD;
          3. Patient has SAA characterized by:&#xD;
&#xD;
               1. Bone marrow cellularity &lt;30% (excluding lymphocytes) and&#xD;
&#xD;
               2. At least two of the following (peripheral blood):&#xD;
&#xD;
                    -  Absolute neutrophil count &lt;500/µL&#xD;
&#xD;
                    -  Platelet count &lt;20,000/µL&#xD;
&#xD;
                    -  Absolute reticulocyte count &lt;60,000/µL&#xD;
&#xD;
          4. Normal ECG defined as the following as determined via the mean of a triplicate ECG&#xD;
&#xD;
               -  Resting heart rate: 50-90 bpm&#xD;
&#xD;
               -  QTcF at screening &lt;450 msec (for male patients), ≤460 msec (for female patients)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Diagnosis of Fanconi anemia.&#xD;
&#xD;
          2. Evidence of a clonal hematologic bone marrow disorder on cytogenetics by central&#xD;
             review&#xD;
&#xD;
          3. Prior immunosuppressive therapy with cyclosporine, alemtuzumab, rabbit or horse ATG&#xD;
             and thrombopoietin receptor (TPO-R) agonists.&#xD;
&#xD;
          4. a. Hypersensitivity to eltrombopag or cyclosporine or their components. b.&#xD;
             Contraindications to cyclospsorine.&#xD;
&#xD;
          5. AST or ALT &gt;3 x ULN.&#xD;
&#xD;
          6. Serum creatinine, total bilirubin, or alkaline phosphatase &gt;1.5 x ULN.&#xD;
&#xD;
          7. Patient with liver cirrhosis.&#xD;
&#xD;
          8. a. Infection not adequately controlled with appropriate therapy. b. Patients who are&#xD;
             human immune deficiency virus (HIV), hepatitis C virus or hepatitis B surface antigen&#xD;
             (HBsAg) positive. HCV-RNA negative patients are allowed to be enrolled.&#xD;
&#xD;
          9. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary,&#xD;
             infectious, or metabolic disease of such severity that it would preclude the patient's&#xD;
             ability to consent, be compliant with study procedures, tolerate protocol therapy, or&#xD;
             that death within 30 days is likely.&#xD;
&#xD;
         10. Patients with cancer who are not considered cure, are on active chemotherapeutic&#xD;
             treatment or who take drugs with hematological effects.&#xD;
&#xD;
         11. Administration of an investigational drug within 30 days or 5 half-lives, whichever is&#xD;
             longer, preceding the first dose of study treatment.&#xD;
&#xD;
         12. Pregnancy statements and contraception requirements:&#xD;
&#xD;
             Pregnancy or nursing (lactating) women Women of child-bearing potential, defined as&#xD;
             all women physiologically capable of becoming pregnant (or female partners of male&#xD;
             patients), unless they are using highly effective methods of contraception during&#xD;
             dosing and for 3 months after stopping medication.&#xD;
&#xD;
         13. Not able to understand the investigation nature of the study or to give informed&#xD;
             consent.&#xD;
&#xD;
         14. Clinically significant ECG abnormality including cardiac arrhythmias (e. g.&#xD;
             ventricular tachycardia) complete left bundle branch block, high grade&#xD;
             atrioventricular block, or inability to determine the QTcF interval on the ECG.&#xD;
&#xD;
         15. Presence of cardiac disease, or family history of idiopathic sudden death or&#xD;
             congenital long QT syndrome.&#xD;
&#xD;
         16. Risk factors for Torsades de Pointe including uncorrected hypokalemia or&#xD;
             hypomagnesemia, or use of concomitant medication(s) with a known risk to prolong the&#xD;
             QT interval that cannot be discontinued or replaced by safe alternative medication per&#xD;
             www.qtdrugs.org.&#xD;
&#xD;
         17. ECOG performance status of ≥2.&#xD;
&#xD;
         18. Patients under the age of 40 must be referred for consideration of allogeneic bone&#xD;
             marrow transplantation (HSCT) if (human leukocyte antigen) HLA matching has been done&#xD;
             and a suitable matched sibling donor is available and the patient is willing to&#xD;
             undergo transplantation (i.e. patients who do not have a HLA match or are not&#xD;
             medically fit, not willing or unable to undergo transplantation will be considered for&#xD;
             enrollment).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Novartis Pharmaceuticals</last_name>
    <role>Study Director</role>
    <affiliation>Novartis Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ribeirao Preto</city>
        <state>SP</state>
        <zip>14048-900</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>São Paulo</city>
        <state>SP</state>
        <zip>01323-900</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Hong Kong</city>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Hyderabad</city>
        <state>Telangana</state>
        <zip>500082</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Vellore</city>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bologna</city>
        <state>BO</state>
        <zip>40138</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Brescia</city>
        <state>BR</state>
        <zip>25123</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Milano</city>
        <state>MI</state>
        <zip>20122</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Seoul</city>
        <zip>03722</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Seoul</city>
        <zip>06351</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Mexico D F</city>
        <state>Ciudad De Mexico</state>
        <zip>06726</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Monterrey</city>
        <state>Nuevo Leon</state>
        <zip>64460</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Puebla</city>
        <zip>72000</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>San Sebastian</city>
        <state>Pais Vasco</state>
        <zip>20080</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Madrid</city>
        <zip>28041</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bangkok</city>
        <zip>10330</zip>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bangkok</city>
        <zip>10700</zip>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Chiang Mai</city>
        <zip>50200</zip>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Istanbul</city>
        <zip>34890</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Samsun</city>
        <zip>55139</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
    <country>Hong Kong</country>
    <country>India</country>
    <country>Italy</country>
    <country>Korea, Republic of</country>
    <country>Mexico</country>
    <country>Spain</country>
    <country>Thailand</country>
    <country>Turkey</country>
  </location_countries>
  <removed_countries>
    <country>Hungary</country>
    <country>Netherlands</country>
  </removed_countries>
  <verification_date>June 2022</verification_date>
  <study_first_submitted>November 4, 2016</study_first_submitted>
  <study_first_submitted_qc>December 16, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 20, 2016</study_first_posted>
  <last_update_submitted>June 29, 2022</last_update_submitted>
  <last_update_submitted_qc>June 29, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">June 30, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>severe acquired aplastic anemia</keyword>
  <keyword>SAA</keyword>
  <keyword>first line</keyword>
  <keyword>eltrombopag</keyword>
  <keyword>cyclosporine</keyword>
  <keyword>h-ATG</keyword>
  <keyword>severe aplastic anemia</keyword>
  <keyword>aplastic anemia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia</mesh_term>
    <mesh_term>Anemia, Aplastic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclosporine</mesh_term>
    <mesh_term>Cyclosporins</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>February 24, 2023</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02998645
org study id: CETB115E2403
secondary id: 2016-002814-29
nct id: NCT02998645
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall hematologic response (CR + PR) rate - 6 month
time frame: by 6 months
description: Overall hematologic response = patients with complete response (CR) + patients with partial response (PR).
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
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
measure: 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)
description: Overall hematologic response = patients with complete response (CR) + patients with partial response (PR).
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
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
measure: Duration of hematologic response
time frame: by 6 months (all patients) and 24 months (responders only)
description: 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)
measure: Proportion of patients who relapse
time frame: by 6 months (all patients) and 24 months (responders only)
description: Percentage of patients who relapse. Relapse is defined as no longer meeting the definition of PR (and not CR).
measure: 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)
description: 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.
measure: Percentage of patients who are red blood cells (RBC) transfusion independent
time frame: by 6 months (all patients) and 24 months (responders only)
description: 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.
measure: Percentage of patients who are platelet transfusion independence
time frame: by 6 months (all patients) and 24 months (responders only)
description: 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.
measure: Longest interval without platelet or RBC transfusion
time frame: by 6 months (all patients) and 24 months (responders only)
description: Duration of longest interval without a platelet or RBC transfusion by 6 months and by 24 months.
measure: 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)
description: 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.
measure: 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)
description: 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".
measure: Frequency and severity of AEs and serious AEs (SAEs)
time frame: by 6 months (all patients) and 24 months (responders only)
description: 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)
measure: 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
description: 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
measure: 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
description: 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
measure: 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
description: 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
measure: 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
description: 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
measure: 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
description: 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
measure: 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
description: 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
arm group label: Eltrombopag + cyclosporine
arm group type: Experimental
description: 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).
intervention type: Drug
intervention name: eltrombopag
description: 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)
arm group label: Eltrombopag + cyclosporine
intervention type: Drug
intervention name: Cyclosporine
description: 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
arm group label: Eltrombopag + cyclosporine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Novartis Pharmaceuticals
role: Study Director
affiliation: Novartis Pharmaceuticals
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country: Brazil
country: Hong Kong
country: India
country: Italy
country: Korea, Republic of
country: Mexico
country: Spain
country: Thailand
country: Turkey
country: Hungary
country: Netherlands
responsible party type: Sponsor
mesh term: Anemia
mesh term: Anemia, Aplastic
mesh term: Cyclosporine
mesh term: Cyclosporins
sharing ipd: No
submitted: February 24, 2023