Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Combination of Eltrombopag With Immunosuppressive Therapy in East-Asian Patients With Severe Aplastic Anemia (REACTS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04328727
Recruitment Status : Recruiting
First Posted : March 31, 2020
Last Update Posted : April 19, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This study is designed to evaluate the efficacy and safety of eltrombopag when added to r-ATG and CsA in treatment naive East-Asian adult and pediatric patients with SAA.

Condition or disease Intervention/treatment Phase
Severe Aplastic Anemia (SAA) Drug: eltrombopag Drug: rabbit anti-thymocyte globulin (r-ATG) Drug: cyclosporine A (CsA) Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Non-randomized, Open Label, Multi-center, Phase II Study to Assess the Safety and Efficacy of Eltrombopag in Combination With Rabbit Anti-thymocyte Globulin (r-ATG) and Cyclosporine A (CsA) in East-Asian Patients With Treatment Naive Severe Aplastic Anemia (REACTS)
Actual Study Start Date : November 4, 2020
Estimated Primary Completion Date : January 18, 2022
Estimated Study Completion Date : July 22, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: eltrombopag
Participants will receive eltrombopag in combination with r-ATG and CsA.
Drug: eltrombopag
Tablet 25mg and 12.5mg
Other Name: ETB115

Drug: rabbit anti-thymocyte globulin (r-ATG)
r-ATG 25 mg sterile lyophilized powder in 10 mL vials for IV use
Other Name: r-ATG

Drug: cyclosporine A (CsA)
CsA 25mg Capsule or CsA 5.0g/50mL solution for oral use
Other Name: CsA




Primary Outcome Measures :
  1. Complete response (CR) rate [ Time Frame: Week 26 (6 months after starting study treatment) ]

    A CR will be defined as (all 3 must be met):

    • Absolute neutrophil count > 1.0 x10^9/L
    • Platelet count > 100 x10^9/L
    • Hemoglobin > 100 g/L

  2. PK Outcome: The AUC calculated to the end of a dosing interval (tau) at steady-state (AUCtau) [ Time Frame: Day 14 to 15 after the initial dose of eltrombopag: pre-day 14 dose (trough), and 2, 4, 6, 8, and 24 hours post-day 14 dose ]
    AUCtau will be calculated by the trapezoidal rule


Secondary Outcome Measures :
  1. CR rate [ Time Frame: Week 13 (3 months), Week 52 (12 months) and yearly after until end of study up to approx. 3 years ]

    A CR will be defined as (all 3 must be met):

    • Absolute neutrophil count > 1.0 x10^9/L
    • Platelet count > 100 x10^9/L
    • Hemoglobin > 100 g/L

  2. Overall response (ORR) rate [ Time Frame: Week 13 (3 months), 26 weeks (6 months), 52 weeks, yearly after until end of study up to approx. 3 years ]

    Overall response rate is patients achieving complete response (CR) or partial response (PR).

    A partial response (PR) will be defined as blood counts that do not meet criteria for SAA but are not sufficient for a CR.


  3. Time from the date of the start of response to the date of relapse or death, which ever occurs first at any time during the study. [ Time Frame: from the date of the start of response to the date of relapse or death, whichever occurs first at any time during the study up to 3 years ]

    Relapse: Clinical relapse is considered as the occurrence of any of the following event in a subject who had achieved a hematological response (CR or PR) but has subsequently lost response (not explained by any other independent concomitant medical conditions):

    • meeting again the criteria for SAA
    • requirement for transfusion again for subjects who had been transfusion independent
    • decrease in any of the peripheral blood counts to: absolute neutrophil count < 0.5 x10^9/L or platelets < 20 x10^9/L.

  4. Time from the date of first dose of study treatment to the date of death [ Time Frame: from date of first dose to date of death up to approx. 3 years ]
    Overall Survival (OS) is defined as the time from the date of the first dose of study treatment to the date of death due to any cause. If a subject is not known to have died, survival will be censored at the date of last contact. The distribution function of OS will be estimated using the Kaplan- Meier method and will be plotted.

  5. Overall survival (OS) rate [ Time Frame: Week 26, Wee 52 & yearly after up to 3 years ]
    Overall Survival is defined as the time from the date of the first dose of study treatment to the date of death due to any cause. If a subject is not known to have died, survival will be censored at the date of last contact. The distribution function of OS will be estimated using the Kaplan- Meier method and will be plotted.

  6. Time from the most recent transfusion to week 13 and week 26 [ Time Frame: week 13, 26 ]
    Transfusion of packed RBC (Red blood cell(s)) units and platelet units

  7. Percentage of participants who become (platelet/RBC) transfusion independent [ Time Frame: From date of first dose to approx. 3 years ]

    Transfusion independence at each assessment point is defined as follows:

    • Platelet transfusion independence: The subjects who are transfusion dependent at baseline become transfusion free for a period of at least last 4 weeks.
    • RBC transfusion independence: The subjects who are transfusion dependent at baseline become transfusion free for a period of at least last 8 weeks

  8. Time from the date of first dose of investigational treatment to the date of first occurrence of any clonal evolution events [ Time Frame: Week 13, Week 26, Week 52 and yearly after, and when clinically indicated till approximately 3 years ]
    Cytogenetic abnormalities will be assessed by karyotyping (G-banding) and FISH (Fluorescence in situ hybridization) targeting abnormalities including, but not restricted to chromosome 3q del,5q del, monosomy 7, trisomy 8 and those associated with SAA (Severe aplastic anemia), MDS (Myelodysplastic syndrome), AML (Acute myeloid leukemia) etc

  9. Pharmacokinetics (PK) parameters: Area under the concentration-time curve from time zero to the last measurable concentration sampling time (AUClast) [ Time Frame: Day 14 to 15 after the initial dose of eltrombopag: pre-day 14 dose (trough), and 2, 4, 6, 8, and 24 hours post-day 14 dose ]
    Blood samples (2 mL/sample) for eltrombopag PK evaluation will be collected. Full PK profile will be collected in a subset of patients. The plasma eltrombopag concentrations was determined using a validated LC-MS/MS approach. This PK parameter will be calculated by non-compartmental analysis. AUClast will be calculated by the trapezoidal rule

  10. Plasma trough concentration of eltrombopag [ Time Frame: Baseline to week 26 ]
    Blood samples (2 mL/sample) for eltrombopag PK evaluation will be collected. The plasma samples will be assayed for eltrombopag concentrations using a validated liquid chromatography - tandem mass spectrometry assay (LC-MS/MS). 15th day of initial dose and each new dose has started

  11. PK Outcome: Observed maximum plasma concentration following administration (Cmax) [ Time Frame: Day 14 to 15 after the initial dose of eltrombopag: pre-day 14 dose (trough), and 2, 4, 6, 8, and 24 hours post-day 14 dose ]
    Full PK profile will be collected in a subset of patients. The plasma eltrombopag concentrations was determined using a validated LC-MS/MS approach. This PK parameter will be calculated by non-compartmental analysis. Cmax will be obtained directly from the concentration-time curve

  12. PK Outcome: The time to reach peak or maximum concentration (Tmax) [ Time Frame: Day 14 to 15 after the initial dose of eltrombopag: pre-day 14 dose (trough), and 2, 4, 6, 8, and 24 hours post-day 14 dose ]
    Full PK profile will be collected in a subset of patients. The plasma eltrombopag concentrations was determined using a validated LC-MS/MS approach. This PK parameter will be calculated by non-compartmental analysis. Tmax will be obtained directly from the concentration-time curve

  13. PK Outcome:Apparent systemic (or total body) clearance at steady state from plasma (CLss/F) [ Time Frame: Day 14 to 15 after the initial dose of eltrombopag: pre-day 14 dose (trough), and 2, 4, 6, 8, and 24 hours post-day 14 dose ]
    Full PK profile will be collected in a subset of patients. The plasma eltrombopag concentrations was determined using a validated LC-MS/MS approach. This PK parameter will be calculated by non-compartmental analysis. CLss/F will be calculated by dose/AUCtau



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   6 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written study informed consent and (where applicable) assent from the subject, parent, or guardian must be obtained prior to participation in the study.
  • Subjects of East Asian ethnicity aged ≥ 6 years old at the time of written informed consent and assent form (if applicable).

SAA characterized by:

  • Bone marrow cellularity < 25%, or 25-50% with < 30% residual hematopoietic cells and pancytopenia, with at least two of the following parameters in peripheral blood:
  • Absolute neutrophil count < 0.5×109/L
  • Platelet count < 20×109/L
  • Absolute reticulocyte count < 20×109/L
  • HSCT is not suitable or available as a treatment option (determined as per local practices or national guidelines), or has been refused by subject.

Exclusion Criteria:

  • Prior IST with any ATG/ALG , alemtuzumab, high dose cyclophosphamide (≥ 45 mg/kg/day), CsA within 6 months, or prior thrombopoietin receptor agonists.
  • Eastern Cooperative Oncology Group (ECOG) performance status (age ≥ 16 years) >2, or Lansky performance status (age < 16 years) <50.
  • Prior and/or active medical history of:
  • Known underlying congenital/inherited bone marrow failure or aplastic anemia (e.g.,such as but not limited to Fanconi anemia, congenital dyskeratosis, congenital amegakaryocytic thrombocytopenia, or Shwachman-Diamond Syndrome)
  • Symptomatic paroxysmal nocturnal hemoglobinuria (PNH) and/or PNH clones >50% of polymorphonuclear neutrophil (PMN) or RBC at time of enrollment Myelodysplastic syndrome (MDS)
  • Any cytogenetic abnormalities on karyotyping or FISH within 30 days of study enrollment (an evaluable karyotyping with at least 10 metaphases is mandatory for eligibility)
  • Other known or suspected underlying primary immunodeficiency
  • Any concomitant malignancies that have not fully recovered from treatment or have not been disease-free for 5 years
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN).
  • Creatinine ≥ 2.5×local ULN
  • Past medical history of thromboembolism within 6 months, and/or prior or current antiphospholipid antibody syndrome (APS).
  • Presence of clinically active uncontrolled significant (of such severity that it would preclude the subject's ability to consent, be compliant with study procedures, tolerate protocol therapy) infection, including bacterial, fungal, mycobacterial, parasitic or viral infection, or any concurrent condition that, in the Investigator's opinion, would jeopardize the safety of the subject or compliance with the protocol
  • Any severe and/or uncontrolled medical conditions which could cause unacceptable safety risks or compromise compliance with the protocol, such as:
  • Known hepatocellular disease (e.g. active hepatitis or cirrhosis)
  • Impairment of gastrointestinal (GI) function or gastrointestinal disease that may significantly alter the absorption of study treatment (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
  • Active skin, mucosa, ocular or GI disorders of Grade > 1
  • Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening. A positive serology for Hepatitis B (HB) is considered as a positive test for HBsAg. In addition, if serology is negative for HBsAg but hepatitis B core antibody (HBcAb) is positive (regardless of hepatitis B surface antibody (HBsAb) status), a hepatitis B virus (HBV) DNA test will be performed and if positive the patient will be excluded.
  • Cardiac disorder (subjects with congestive heart disease of New York Heart Association (NYHA) functional classification Grade II/III/IV (for pediatric subjects, refer to the Grade II/III/IV of Modified ross heart failure classification for Children) should not be enrolled; subjects with NYHA Grade II due to cardiac disorder should not be enrolled but those with NYHA Grade II due to aplastic anemia (AA) may be enrolled.), arrhythmia with a risk of thrombosis (e.g. atrial fibrillation), pulmonary hypertension, or uncontrolled hypertension (>180/100 mmHg).

Other protocol-defined Inclusion/Exclusion may apply.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04328727


Contacts
Layout table for location contacts
Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +81337978748

Locations
Layout table for location information
China, Henan
Novartis Investigative Site Recruiting
Zhengzhou, Henan, China, 450052
China, Jiangsu
Novartis Investigative Site Recruiting
Nanjing, Jiangsu, China
Novartis Investigative Site Recruiting
Xuzhou, Jiangsu, China, 221003
China, Jiangxi
Novartis Investigative Site Recruiting
Nanchang, Jiangxi, China, 330006
China, Jilin
Novartis Investigative Site Recruiting
Chang Chun, Jilin, China, 130021
China, Tianjin
Novartis Investigative Site Recruiting
Tianjin, Tianjin, China, 300020
China
Novartis Investigative Site Recruiting
Guangzhou, China, 510180
Novartis Investigative Site Recruiting
Tianjin, China, 300052
Japan
Novartis Investigative Site Recruiting
Nagoya, Aichi, Japan, 466 8560
Novartis Investigative Site Recruiting
Chuo ku, Tokyo, Japan, 104-8560
Korea, Republic of
Novartis Investigative Site Recruiting
Seoul, Korea, Republic of, 03080
Novartis Investigative Site Recruiting
Seoul, Korea, Republic of, 06351
Taiwan
Novartis Investigative Site Recruiting
Kaohsiung City, Taiwan, 83301
Novartis Investigative Site Recruiting
Taoyuan, Taiwan, 333
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Layout table for investigator information
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Layout table for additonal information
Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04328727    
Other Study ID Numbers: CETB115G2201
First Posted: March 31, 2020    Key Record Dates
Last Update Posted: April 19, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

URL: https://www.clinicalstudydatarequest.com

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Treatment naïve severe aplastic anemia
SAA
eltrombopag
ETB115
immunosuppressive therapy
rabbit anti-thymocyte globulin
r-ATG
cyclosporine A
CsA
East-Asian patients
Additional relevant MeSH terms:
Layout table for MeSH terms
Anemia
Anemia, Aplastic
Hematologic Diseases
Bone Marrow Diseases
Cyclosporine
Cyclosporins
Antilymphocyte Serum
Thymoglobulin
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents
Calcineurin Inhibitors