Eltrombopag in Combination With Rabbit Anti-thymocyte Globulin/Cyclosporine A in Naive Aplastic Anemia (AA) Subjects

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02404025
• Date of registration: 26/02/2015
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharmaceuticals
• Public title: Eltrombopag in Combination With Rabbit Anti-thymocyte Globulin/Cyclosporine A in Naive Aplastic Anemia (AA) Subjects
• Scientific 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
• Date of first enrolment: May 12, 2015
• Target sample size: 10
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02404025
• Study type: Interventional
• Study design: Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 2

Countries of recruitment

Japan

Contacts

• Name: Novartis Pharmaceuticals
• Affiliation: Novartis Pharmaceuticals

Key inclusion & exclusion 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.



Age minimum: 18 Years
Age maximum: 75 Years
Gender: All

Health Condition(s) or Problem(s) studied

Aplastic Anemia

Intervention(s)

Drug: Rabbit ATG

Drug: CsA

Drug: Eltrombopag

Primary Outcome(s)

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 [Time Frame: Week 26]

Secondary Outcome(s)

Composite of Laboratory Parameters Assessment as a Safety Measure (Lymphocytes and Neutrophils). [Time Frame: Baseline, Week 26]

CR Rate Based on the Criteria Used in NIH 12-H-0150 Study at 6 Months [Time Frame: Week 26]

Duration of Hospitalization [Time Frame: Week 26]

Changes in Hematology Parameters (Haemoglobin) in the Absence of Platelet Transfusion [Time Frame: Week 26 and week 104]

Degree of Exposure to Eltrombopag : Cumulative Dose [Time Frame: Week 104]

Frequency of Platelet and Red Blood Cells (RBC) Transfusions [Time Frame: Baseline, Week 26]

Composite of Laboratory Parameters Assessment as a Safety Measure (Haemoglobin and Albumin). [Time Frame: Baseline, Week 26]

12-lead Electrocardiogram (ECG) as Measure of Safety and Tolerability [Time Frame: Baseline, Week 26]

Complete Response (CR), and Partial Response (PR) Rate at 3 Months [Time Frame: Week 14]

Composite of Laboratory Parameters Assessment as a Safety Measure (Alcaline Phosphatase and Aspartate Amino Transferase) . [Time Frame: Baseline, Week 26]

The Concentration After 4 Hours of Dose of Eltrombopag 75 mg [Time Frame: day 15]

Time to Onset of CR and PR [Time Frame: Week 26]

Degree of Exposure to Eltrombopag : Average Daily Dose [Time Frame: Week 104]

Degree of Exposure to Eltrombopag : Days on Study [Time Frame: Week 104]

Duration of CR or PR [Time Frame: Week 104]

Number of Participants With Adverse Events [Time Frame: though study completion , approximately 2 years]

ORR at 3 Months [Time Frame: Week 14]

Volume of Platelet and RBC Transfusions [Time Frame: Baseline, Week 26]

Vital Signs (Temperature) as a Measure of Safety and Tolerability [Time Frame: baseline and Week 26]

Changes in Hematology Parameters in the Absence of Platelet Transfusion [Time Frame: Week 26 and week 104]

Composite of Laboratory Parameters Assessment as a Safety Measure. [Time Frame: Baseline, Week 26]

The Proportion of Subjects Whose Transfusion Unit (or Volume) Are Decreased or Who Became Transfusion (Platelet, RBC) Independent [Time Frame: Week 26]

The Trough Concentrations of Eltrombopag Following Repeat Doses of at 75 mg, 50 mg and 25 mg [Time Frame: day 15]

Vital Signs (Blood Pressure) as a Measure of Safety and Tolerability [Time Frame: baseline and Week 26]

Vital Signs (Pulse Rate) as a Measure of Safety and Tolerability [Time Frame: baseline and Week 26]

Secondary ID(s)

201793

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 26/07/2019
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02404025