Clinical trial NCT03988608: Study Assessed the Safety and Efficacy of Eltrombopag in Chinese Refractory or Relapsed Severe Aplastic Anemia (SAA) Subjects.
Official title: A Non-randomized, Open-label, Multi-center, Phase II Study to Assess the Safety and Efficacy of Eltrombopag in Chinese Subjects With Refractory or Relapsed Severe Aplastic Anemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Aplastic Anemia
Keywords: Severe Aplastic Anemia
Eltrombopag
ETB115
Chinese subject
Chinese refractory or relapsed SAA subjects
refractory severe aplastic anemia
relapsed severe aplastic anemia
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2019-06-17
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This was a non-randomized, open-label, phase II study to assess the efficacy and safety of eltrombopag in Chinese subjects with refractory or relapsed severe aplastic anemia (SAA). Treatment with eltrombopag was started at 25 mg/day and increased by 25 mg/day every 2 weeks according to the platelet count up to 150 mg/day. The hematological response rate was assessed at 3, 6 months and 1 year after starting the study treatment (Week 13, 26 and 52).

Detailed description: This was a bridging study to support China registration. An estimation strategy rather than a formal hypothesis testing was pursued. Twenty subjects were enrolled into the study.

Treatment with eltrombopag started at 25 mg/day and increased by 25 mg/day every 2 weeks according to the platelet count, up to 150 mg/day. Hematological response rate was assessed at 3, 6 months and 1 year (Week 13, 26 and 52) after starting the study treatment. Subjects in whom the treatment was found to be effective at 6 months continued to receive the treatment. Eltrombopag was discontinued if the treatment was ineffective at 6 months. Subjects discontinued eltrombopag before 6 months if any of the treatment discontinuation criteria was met.

Analysis set for the primary endpoint was Full Analysis Set (FAS) and subjects who discontinue from the study before Week 26 were treated as non-responders in the response analysis. Eltrombopag treatment was provided to subjects who were considered to require continued treatment at Week 26. After Week 26, if all of the hematologic response criteria (i.e., platelet count \> 50×109/L, hemoglobin level \> 100 g/L without transfusion, and neutrophil count \> 1.0×109/L) remained fulfilled for more than 8 weeks, the dose of eltrombopag was decreased by half. If the response continued for further 8 weeks even at the decreased dose, the treatment was discontinued. If a decrease in any of the hematologic values (i.e., platelet count \< 30×109/L, hemoglobin \< 90 g/L, or neutrophil count \< 0.5×109/L) was found after dose reduction, the dose was increased to the previous level. Furthermore, after treatment interruption, the treatment was restarted if any of the hematologic values decreased to the above-mentioned levels. The response assessment and safety evaluation were performed at Week 52.

The Extension part of this study started 1 year (Week 52) after the initiation of study treatment. This part was included in the study with an ethical consideration for subjects who required continued treatment. The continued treatment was provided up to the launch of eltrombopag after approval. Follow-up visit was performed 30 days after the discontinuation of eltrombopag treatment.

To better understand the pharmacokinetics (PK) characteristics of eltrombopag in Chinese severe aplastic anemia (SAA) patient population, intensive PK blood samples were collected only in the initial 12 Chinese subjects receiving 25 mg/day dose after reaching steady-state, to provide evaluable full PK profiles. Steady-state trough concentrations were collected at other dose levels and in other subjects.

Eligibility criteria: Inclusion Criteria:

* Chinese patients aged greater than or equal to 18 years old.
* Patient with a previous diagnosis of severe aplastic anemia and had insufficient response following at least one treatment course in the period time of \> 6 months of immunosuppression with a regimen containing anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG), and/or cyclophosphamide, or alemtuzumab.
* Platelet count ≤ 30 × 10\^9/L at screening.
* Patient must not currently have the option of stem cell transplantation.
* Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
* Patient with QTcF (Fridericia's QT correction formula) at screening \<450 msec, or \<480 msec with bundle branch block, as determined via the mean of a triplicate ECG and assessed at site.

Exclusion Criteria:

* Treatment with ATG/ALG, cyclophosphamide or alemtuzumab in the past 6 months.
* Congenital aplastic anemia
* AST or ALT ≥3 times the upper limit of normal.
* Creatinine, total bilirubin, and alkaline phosphatase (ALP) ≥ 1.5× local ULN (total bilirubin ≥ 2.5 × local ULN with Gilbert's Syndrome).
* Paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size determined by flow cytometry ≥ 50%.
* Presence of chromosomal aberration (-7/7q- detected by fluorescence in situ hybridization (FISH), or other aberrations detected by G-band staining).
* Evidence of a clonal hematologic bone marrow disorder on cytogenetics.
* Past medical history of thromboembolism within 6 months or current use of anticoagulants.
* Have any concomitant malignancies and must be fully recovered from treatment for any other malignancy and have been disease-free for 5 years.
* Patient with clinically significant (of such severity that it would preclude the patient's ability to consent, be compliant with study procedures, tolerate protocol therapy) bacterial, fungal, mycobacterial, parasitic or viral infection (Patient with acute bacterial infections requiring antibiotic use should delay Screening/enrollment until the course of antibiotic therapy has been completed).
* Patient with known hepatocellular disease
* Presences of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening.
* Cardiac disorder (NYHA) functional classification Grade II/III/IV
* Past medical history of immediate or delayed hypersensitivity to compounds chemically similar to eltrombopag or their excipients.
* Treatment with another investigational product within 30 days.
* Prior treatment with eltrombopag, romiplostim, or any other TPO (thrombopoietin) receptor agonist.
* Positive result for HIV (Human Immunodeficiency Virus) antibody test.
* Pregnant or nursing (lactating) woman.
* Woman of child-bearing potential.

Primary outcomes:
measure: Hematologic Response Rate at 6 Months (Week 26) by Investigator
timeFrame: 6 months (Week 26)
Secondary outcomes:
measure: Hematologic Response Rate by Investigator
timeFrame: Week (Wk) 13, Week 52
measure: Change From Baseline in Platelet Count
timeFrame: Baseline, Week 13, Week 26, Week 52
measure: Change From Baseline in Hemoglobin Levels
timeFrame: Baseline, Week 13, Week 26 and Week 52
measure: Change From Baseline in Neutrophil Count
timeFrame: Baseline, Week 13, Week 26 and Week 52
measure: Time to Hematologic Response by Investigator
timeFrame: Baseline to Week 26
measure: Duration of Hematologic Response by Investigator
timeFrame: up to approx. 3.5 years
measure: Frequency of Platelets Transfusion
timeFrame: Baseline, Week 13, Week 26 and Week 52
measure: Amount of Platelets Transfusion
timeFrame: Baseline, Week 13, Week 26 and Week 52
measure: Frequency of Red Blood Cells (RBC) Transfusion
timeFrame: Baseline, Week 13, Week 26 and Week 52
measure: Amount of Red Blood Cells (RBC) Transfusion
timeFrame: Baseline, Week 13, Week 26 and Week 52
measure: Plasma PK Parameters of Eltrombopag: Cmax
timeFrame: pre-dose, and 1, 2, 4, 6, 8 and 24 hours post-dose on Day 14
measure: Plasma PK Parameters of Eltrombopag: Tmax
timeFrame: pre-dose, and 1, 2, 4, 6, 8 and 24 hours post-dose on Day 14
measure: Plasma PK Parameters of Eltrombopag: AUCtau & AUClast
timeFrame: pre-dose, and 1, 2, 4, 6, 8 and 24 hours post-dose on Day 14
measure: Plasma PK Parameters of Eltrombopag: CLss/F
timeFrame: pre-dose, and 1, 2, 4, 6, 8 and 24 hours post-dose on Day 14
measure: Plasma Trough Concentration of Eltrombopag
timeFrame: Pre-dose sample on the 15th day after each new dose level was started
measure: Number of Participants With Clonal Evolution
timeFrame: From Baseline up to approx. 2.9 years
Other outcomes:
Locations:
city: Nanjing
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Nanchang
country: China
facility: Novartis Investigative Site
state: Jiangxi
city: Chengdu
country: China
facility: Novartis Investigative Site
state: Sichuan
city: Tianjin
country: China
facility: Novartis Investigative Site
city: Tianjin
country: China
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: