Brief Title
Eltrombopag in Combination With Rabbit Anti-thymocyte Globulin/Cyclosporine A in Naive Aplastic Anemia (AA) Subjects
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
Brief Summary
This was 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 did not received prior
ATG/ALG-based immunosuppressive therapy. The objective was to assess additive effects of
eltorombopag on overall response rate (ORR) at 6 months (Week 26) of treatment with ATG/CsA.
Subjects were 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 had visits
every 2 weeks until Week 26. Subjects in whom the treatment was assessed as effective at Week
26 could continued treatment with eltrombopag after 6 months when clinically indicated at the
discretion of the investigator. There were 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 was the first Japanese phase II study in which this product was administered in
combination with ATG/CsA to subjects with naive moderate or more severe AA, the subject
number of this study was determined to be 10 based on the feasibility survey.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
ORR at 6 Months: Overall Response Rate (ORR) Defined as the Number of Participants Who Met the Criteria of Either Complete Response (CR) or Partial Response (PR) at Week 26
Secondary Outcome
ORR at 3 Months
Condition
Aplastic Anemia
Intervention
Eltrombopag
Study Arms / Comparison Groups
Eltrombopag+rabbit ATG/CsA arm
Description: Subjects received 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 was administered at a dose of 3 mg per kg twice a day from day 0. The dose level was adjusted based on the monitoring of blood level or renal function. Eltrombopag was initiated on day 14 and it could be delayed up to 2 weeks if the subject had infection, serum sickness, or other adverse events. Eltrombopag wasadministered orally once a day at fasting at an initial dose of 75 mg, and the dose adjusted every 2 weeks according to the platelet count. Eltrombopag and CsA were continued until Week 26.After Week 26, eligible subjects received eltrombopag; and CsA was tapered or maintained as per the investigator's discretion.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
10
Start Date
May 12, 2015
Completion Date
September 6, 2017
Primary Completion Date
July 5, 2016
Eligibility Criteria
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 Novartis medical advisor.
- 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.
Gender
All
Ages
18 Years - 75 Years
Accepts Healthy Volunteers
No
Contacts
Novartis Pharmaceuticals, ,
Location Countries
Japan
Location Countries
Japan
Administrative Informations
NCT ID
NCT02404025
Organization ID
201793
Responsible Party
Sponsor
Study Sponsor
Novartis Pharmaceuticals
Study Sponsor
Novartis Pharmaceuticals, Study Director, Novartis Pharmaceuticals
Verification Date
May 2019