Overview

This trial is active, not recruiting.

Condition cytopaenia
Treatments eltrombopag, rabbit atg, csa
Phase phase 2
Sponsor Novartis Pharmaceuticals
Start date May 2015
End date July 2016
Trial size 11 participants
Trial identifier NCT02404025, 201793

Summary

This is an open label, non-randomized, phase II study of eltrombopag in combination with rabbit ATG/CsA in subjects with moderate or more severe AA who have not received prior ATG/ALG-based immunosuppressive therapy. The objective is to assess additive effects of eltorombopag on overall response rate (ORR) at 6 months (Week 26) of treatment with ATG/CsA. Subjects will be assessed at least weekly for safety during the period from the start of ATG/CsA to 4 weeks after the start of administration of eltrombopag. After that, subjects will visit every 2 weeks until Week 26. Subjects in whom the treatment is assessed as effective at Week 26 may continue treatment with eltrombopag after 6 months when clinically indicated at the discretion of the investigator. There are five follow-up visits: at discontinuation of the treatment of eltrombopag, and Weeks 1, 2, 3, 4 and 26 after treatment discontinuation. As this study is the first Japanese phase II study in which this product is administered in combination with ATG/CsA to subjects with naive moderate or more severe AA, the subject number of this study is determined to be 10 based on the feasibility survey.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Masking open label
Primary purpose treatment
Arm
(Experimental)
Subjects will receive rabbit ATG diluted by 500 mL of saline or 5% glucose injection at a dose of 2.5 to 3.75 mg per kilogram (kg) per day for 5 days as a slow intravenous infusion over 6 hours. CsA will be administered at a dose of 3 mg per kg twice a day from day 0. The dose level will be adjusted based on the monitoring of blood level or renal function. Eltrombopag will be initiated on day 14 and it can be delayed up to 2 weeks if the subject has infection, serum sickness, or other adverse events. Eltrombopag will be administered orally once a day at fasting at an initial dose of 75 mg, and adjust the dose every 2 weeks according to the platelet count. Eltrombopag and CsA are continued until Week 26.After Week 26, eligible subjects will receive eltrombopag; and CsA will be tapered or maintained as per the investigator's discretion.
eltrombopag
Eltrombopag is provided as white round film-coated tablets containing 12.5 mg or 25 mg of eltrombopag free acid (SB-497115-GR, eltrombopag).
rabbit atg
Rabbit ATG, as an intravenous drip infusion, diluted by 500 mL of saline or 5% glucose injection will be administered at a dose of 2.5 to 3.75 mg per kg per day as a slow intravenous infusion over 6 hours.
csa
CsA as capsules, oral solution, or fine granule, will be administered at a dose of 3 mg per kg twice a day.

Primary Outcomes

Measure
ORR at 6 months
time frame: Week 26

Secondary Outcomes

Measure
ORR at 3 months
time frame: Week 14
Complete Response (CR), and Partial Response (PR) rate at 3 months and 6 months
time frame: Week 14 and Week 26
CR rate based on the criteria used in NIH 12-H-0150 study at 6 months
time frame: Week 26
Changes in hematology parameters in the absence of platelet transfusion
time frame: Week 26 and up to approval (100 weeks)
Frequency of platelet and red blood cells (RBC) transfusions
time frame: Week 26 and up to approval (100 weeks)
Volume of platelet and RBC transfusions
time frame: Week 26 and up to approval (100 weeks)
The proportion of subjects whose transfusion unit (or volume) are decreased or who became transfusion (platelet, RBC) independent
time frame: Week 26 and up to approval (100 weeks)
Duration of hospitalization
time frame: Up to Week 26 follow-up visit
Time to onset of CR and PR
time frame: Week 26 and up to approval (100 weeks)
Duration of CR or PR
time frame: Week 26 and up to approval (100 weeks)
Degree of exposure to eltrombopag
time frame: Week 26 and up to approval (100 weeks)
Number of participants with adverse events
time frame: Week 26 and up to approval (100 weeks)
Composite of laboratory parameters assessment as a safety measure.
time frame: Week 26 and up to approval (100 weeks)
Vital signs as a measure of safety and tolerability
time frame: Week 26 and up to approval (100 weeks)
12-lead electrocardiogram (ECG) as measure of safety and tolerability
time frame: Week 26 and up to approval (100 weeks)
The trough concentrations of eltrombopag following repeat doses of at 75 mg, 50 mg and 25 mg
time frame: Week 4 to Week 26
The concentration after 4 hours of dose of eltrombopag 75 mg
time frame: Week 4 to Week 6

Eligibility Criteria

Male or female participants from 18 years up to 75 years old.

Inclusion Criteria: - Japanese subjects aged >=18 and <71 years at the time of informed consent. Note: subjects aged >=71 and <75 may be eligible when clinically indicated at the discretion of the investigator by mutual agreement with GSK medical monitor. - Diagnosed with moderate or more severe AA according to the diagnostic criteria of AA. The severity classification is: Stage I - Mild - Other than the stages below; Stage II - Moderate - At least two of the following conditions are met: Reticulocyte <60,000/microliter, Neutrophil <1,000/microliter, Platelet <50,000/microliter; Stage III - Moderately severe - At least two of the following conditions are met and regular red blood cell transfusion (a need for transfusion of >=2 units per month) is required: Reticulocyte <60,000/microliter, Neutrophil <1,000/microliter, Platelet <50,000/microliter; Stage IV - Severe - At least two of the following conditions are met: Reticulocyte <20,000/microliter, Neutrophil <500/microliter, Platelet <20,000/microliter; Stage V - Very severe - At least one of the following conditions is met in addition to neutrophil <200/microliter: Reticulocyte <20,000/microliter, Platelet <20,000/microliter. - Subjects who are considered an indication for the treatment with rabbit ATG and CsA. - Adequate baseline organ function defined by the following criteria: Alanine aminotransferase (ALT), aspartate aminotransferase (AST)<=3 × local upper limit of normal (ULN) Creatinine, total bilirubin, and alkaline phosphatase (ALP) <1.5 × local ULN (total bilirubin <2.5 × local ULN with Gilbert's Syndrome) - Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): 0 or 1 - Subjects with QTcF<450 millisecond (msec) or QTcF<480 msec with branch block: QTc is QT interval corrected by Fridericia formula (QTcF), machine ,or manual overread. QTcF is based on single or averaged QTc value of triplicate ECG. - Subjects are able to understand and comply with protocol requirements and instructions. - Subjects have signed and dated informed consent. - Subjects who meet one of the following conditions: Male subjects who have a female partner of childbearing potential must either have a prior vasectomy or agree to use an acceptable method of contraception from time of enrollment in the study until 16 weeks after the last dose of eltrombopag (based upon the lifecycle of sperm). Female subjects of non-childbearing potential (who are physiologically unable to become pregnant) defined as: Premenopausal women with documented bilateral oophorectomy, bilateral tubal ligation, or hysterectomy; or postmenopausal women after at least 12 months of natural amenorrhea [if uncertain, postmenopausal state should be confirmed by hematology result of follicle stimulating hormone (FSH) >40 milli-international units (mIU)/milliliter (mL) or estradiol <40 picogram (pg)/mL (<140 picomoles (pmol)/L)]. Female subjects of childbearing potential: Defined as those not meeting the definition of non-childbearing potential. Female subjects of childbearing potential must have a negative serum human chorionic gonadotropin (hCG) or urine pregnancy test within 7 days prior to the first dose of ATG/CsA. It is recommended that the pregnancy test should be performed as close as possible to the first dose of ATG/CsA. Female subjects with a positive pregnancy test must be excluded from the study. Subjects with a negative pregnancy test must use acceptable contraception including abstinence after the pregnancy test. Subjects must agree to use the acceptable contraception including abstinence from 14 days prior to the first dose of ATG/CsA until 28 days after the last dose of eltrombopag. Exclusion Criteria: - Diagnosis of congenital AA (e.g. Fanconi anemia or Dyskeratosis congenital). - Subjects who have a sibling donor with matched human leukocyte antigen (HLA) or who underwent hematopoietic stem cell transplantation (HSCT) previously. However, such subjects may be enrolled if HSCT is not indicated, or the subject does not want to undergo HSCT. - Subjects with abnormal chromosome (monosomy 7 detected by fluorescence in situ hybridization (FISH), or other aberrations detected by G-band staining). Note: Subjects with abnormal chromosome which is not adopted into the clone definition of An International System for Human Cytogenetic Nomenclature (ISCN) may be enrolled after consulting with medical monitor. - Previous ATG/ALG-based immunosuppressive therapy or steroid pulse therapy for AA. - Treatment with CsA within 6 months before administration of ATG. - Subjects with a paroxysmal nocturnal hemoglobinuria (PNH) clone size in granulocytes of >50% by flow cytometric analysis. - Pre-existing cardiac disease (congestive heart failure New York Heart Association (NYHA) Grade II/III/IV), or arrhythmias known to involve the risk of thromboembolic events (e.g. atrial fibrillation) - Past history of thromboembolic event (including anti-phospholipid antibody syndrome) and current use of anticoagulants. - Subjects with past or current malignancy. Note : Subjects who have a history of completely resected malignant tumor and have been disease-free for 5 years are eligible. - Subjects who test positive for hepatitis B surface (HBs) antigen, hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) antibody at screening. - Infection not adequately responding to appropriate therapy. - Subject with liver cirrhosis - Subjects with any clinically significant severe cardiac, renal, or hepatic medical condition. - Pregnant women (a positive serum or urine pregnancy test within 7 days prior to the first dose of ATG/CsA or lactating women) Note: Female subjects who are lactating are eligible to participate if they discontinue nursing prior to the first dose of ATG/CsA and refrain from nursing until 5 days after the completion of treatment with eltrombopag. - Known hypersensitivity, intolerance or allergy to rabbit ATG, cyclosporine A, eltrombopag or any of their excipients. - Current alcohol or drug abuse. - Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) proceeding the first dose of ATG/CsA. - Subjects who is not candidates for ATG. - Subjects who is not candidates for CsA. - History of treatment with eltrombopag, romiplostim or other thrombopoietin-receptor (TPO-R) agonists.

Additional Information

Official title A Non-randomized, Phase II Study of Eltrombopag in Combination With Rabbit Anti-thymocyte Globulin/Cyclosporine A (ATG/CsA) in Subjects With Moderate or More Severe Aplastic Anemia Who Have Not Received Prior ATG/Anti-lymphocyte Globulin (ALG)-Based Immunosuppressive Therapy
Trial information was received from ClinicalTrials.gov and was last updated in September 2016.
Information provided to ClinicalTrials.gov by Novartis.