Efficacy and Safety of Avatrombopag in the Treatment of Thrombocytopenia After Haplo-HSCT (Haplo-HSCT)

Efficacy and Safety of Avatrombopag in the Treatment of Thrombocytopenia After Haploidentical Hematopoietic Stem Cell Transplantation: Prospective, Multi-center, Double-blinded, Randomized Placebo-controlled Study

In this study, investigators aim to evaluate the efficacy of avatrombopag in thrombocytopenic patients after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) through a prospective, multi-center, double-blinded, randomized placebo-controlled clinical trial.

Study Overview

• Status: Not yet recruiting
• Conditions: Thrombocytopenia; Stem Cell Transplant Complications
• Intervention / Treatment: Drug: avatrombopag; Drug: Placebo

Detailed Description

Thrombocytopenia is a common and severe complication after haplo-HSCT, including primary isolated thrombocytopenia (PIT) and secondary failure of platelet recovery (SFPR), which may cause bleeding and infection, and thus influence the OS, DFS, and NRM of the patients. Avatrombopag has been proved effective and safe in patients with chronic liver disease(CLD) and immune thrombocytopenia (ITP) and have been approved for CLD-associated thrombocytopenia undergoing elective invasive procedure (FDA&NMPA) and ITP(FDA). Chinese consensus has recommended avatrombopag and some other thrombopoietin receptor agonists (TPO-RAs) to treat thrombocytopenia after haplo-HSCT. However, it lacks prospective studies to support that.Investigators aim to evaluate the efficacy of avatrombopag in thrombocytopenic patients after haplo-HSCT through a prospective, multi-center, double-blinded, randomized placebo-controlled clinical trial.

The patients with PLT<20×10^9/L or transfusion dependent on the 7th day (+D7) after haplo-HSCT are included and assigned in a 1:1 randomization schedule to the avatrombopag group (receiving avatrombopag, n=71）and the placebo group (receiving placebo, n=71). The primary endpoint is the proportion of participants whose PLT≥50×10^9/L on +D60 after haplo-HSCT without the need for PLT transfusion for 7 consecutive days or above. Second endpoints includ the proportion of participants whose PLT≥100×10^9/L on +D60 after haplo-HSCT without the need for PLT transfusion for 7 consecutive days or above, the proportion of participants whose PLT≥20×10^9/L and whose PLT≥50×10^9/L on +D30 after haplo-HSCT without the need for PLT transfusion for 7 consecutive days or above, the proportion of participants whose PLT≥50×10^9/L and whose PLT≥100×10^9/L on +D90 after haplo-HSCT without the need for PLT transfusion for 7 consecutive days or above, the first day to achieve PLT≥20×10^9/L and PLT≥50×10^9/L and PLT≥100×10^9/L without the need for PLT transfusion for consecutive 7 days and above within +D60 after haplo-HSCT, the percentage of participants who need PLT transfusion and the average count of PLT from +D7 to + D60 after haplo-HSCT, the first day and the percentage of participants to achieve absolute neutrophil≥500/μL for consecutive 3 days within +D30 after haplo-HSCT, the graft-versus-host disease(GVHD), infection, the overall survival(OS),the disease free survival(DFS) and the non-relapse mortality(NRM) rates of participants within the first year after haplo-HSCT.

• Study Type: Interventional
• Enrollment (Estimated): 142
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Haixia Fu; Phone Number: 13581830157; Email: fuhaixia_210@163.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100044
      • Peking University People's Hospital
      • Contact: Xiaohui Zhang, MD; Email: zhangxiaohui@bjmu.edu.cn
      • Contact: Haixia Fu, MD; Phone Number: 13581830157; Email: fuhaixia_210@163.com
  • Heilongjiang
    • Harbin, Heilongjiang, China
      • The First Affiliated Hospital, Harbin Medical University
      • Contact: Shengjin Fan
  • Henan
    • Zhengzhou, Henan, China
      • The First Affiliated Hospital of Zhengzhou University
      • Contact: Dingming Wan
  • Hunan
    • Changsha, Hunan, China, 410008
      • Xiangya Hospital, Central South University
      • Contact: Yajing Xu
  • Jiangxi
    • Nanchang, Jiangxi, China
      • The First Affiliated Hospital of Nanchang University
      • Contact: Fei Li
  • Shanxi
    • Taiyuan, Shanxi, China, 030032
      • Shanxi Bethune Hospital,Shanxi Academy of Medical Sciences
      • Contact: Liangming Ma
    • Xi'an, Shanxi, China
      • Tangdu Hospital, PLA Air Force Military Medical University
      • Contact: Li Liu
  • Sichuan
    • Chengdu, Sichuan, China
      • Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China
      • Contact: Xiaobing Huang
  • Xinjiang
    • Urumqi, Xinjiang, China, 830054
      • The First Affiliated Hospital of Xinjiang Medical University
      • Contact: Hailong Yuan
  • Yunnan
    • Kunming, Yunnan, China, 650100
      • 920th Hospital of Joint Logistics Support Force of People's Liberation Army of China

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female, aged between 18-65 years;
2. PLT<20×10^9/L or transfusion dependent on +D7 after haplo-HSCT;
3. Agree to receive the treatment of avatrombopag after Haplo-HSCT and sign the informed consent form.

Exclusion Criteria:

1. With active infection;
2. ALT or AST>3ULN, or total Bil>2ULN
3. Ccr<50 mL/min;
4. With the history of arteriovenous thrombosis;
5. With history of cardiovascular disease (such as NYHA Class III/IV congestive heart failure, arrhythmia that increases the risk of thromboembolic events [such as atrial fibrillation] and angina), and subjects who have undergone coronary stent implantation, angioplasty, or coronary artery bypass grafting;
6. With treatment of drugs to promote platelet production two weekes before enrollment, including but not limited to rhTPO and TPO-RA;
7. HBsAg or anti-HCV or anti-HIV positive;
8. Known to be allergic to avatrombopag and any of its excipients;
9. With secondary or multiple HSCT;
10. Females who were pregnant or breastfeeding or who had fertile ability but refuse to take effective contraceptive measures during and one month after this trial;
11. With any other clinical trial of investigational product or device within 30 days prior to the baseline visit, except for observational study;
12. Deemed unsuitable for enrollment by the investigator for any history of or concomitant medical condition.
13. Concomitant medication:The rhIL-11, rhTPO or TPO-RA(such as eltrombopag, hetrombopag and romiplostim) and desitabine, etc. were not allowed for use during this trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: avatrombopag; Avatrombopag 20 mg/d will be taken orally from +D7 after haplo-HSCT until reaching the adjustment indication or to +D60 after haplo-HSCT. Routine treatment is allowed. Adjustment indication: When PLT<50×10^9/L or PLT transfusion dependent on the +D30 after haplo-HSCT, increase the dosage to 40 mg/d; When the dosage has been increased to 40 mg/d, and PLT≥80×10^9/L excluding the factor of PLT transfusion, decrease the dosage to 20 mg/d; When PLT≥80×10^9/L for 7 consecutive days excluding the factor of PLT transfusion, or PLT≥300×10^9/L excluding the factor of PLT transfusion, stop administration; When PLT<50×10^9/L or become PLT transfusion dependent after stopping administration, initiate administration again at the dosage 40 mg/d. PLT transfusion Indication: When PLT<20×10^9/L, and/or with the symptom or risk of bleeding.	Drug: avatrombopag; The avatrombopag 20mg/d will be orally taken from +D7 after haplo-HSCT until meeting the adjustment indication or to +D60 after haplo-HSCT; When PLT<50×10^9/L or PLT transfusion-dependent on the +D30 after haplo-HSCT, increase avatrombopag dosage to 40 mg/d; When PLT≥80×10^9/L and without PLT transfusion within avatrombopag dosage at 40 mg/d, decrease avatrombopag dosage to 20 mg/d; When PLT≥80×10^9/L for 7 consecutive days or PLT≥300×10^9/L and without PLT transfusion, stop avatrombopag; When PLT<50×10^9/L or PLT transfusion-dependent after stopping avatrombopag , reuse avatrombopag at 40 mg/d.; Other Names: Doptelet
Placebo Comparator: Placebo; Placebo 20 mg/d will be taken orally from +D7 after haplo-HSCT until reaching the adjustment indication or to +D60 after haplo-HSCT. Routine treatment is allowed. Adjustment indication: When PLT<50×10^9/L or PLT transfusion dependent on the +D30 after haplo-HSCT, increase the dosage to 40 mg/d; When the dosage has been increased to 40 mg/d, and PLT≥80×10^9/L excluding the factor of PLT transfusion, decrease the dosage to 20 mg/d; When PLT≥80×10^9/L for 7 consecutive days excluding the factor of PLT transfusion, or PLT≥300×10^9/L excluding the factor of PLT transfusion, stop administration; When PLT<50×10^9/L or become PLT transfusion dependent after stopping administration, initiate administration again at the dosage 40 mg/d. PLT transfusion Indication: When PLT<20×10^9/L, and/or with the symptom or risk of bleeding.	Drug: Placebo; The placebo 20mg/d will be orally taken from +D7 after haplo-HSCT until meeting the adjustment indication or to +D60 after haplo-HSCT; When PLT<50×10^9/L or PLT transfusion-dependent on the +D30 after haplo-HSCT, increase placebo dosage to 40 mg/d; When PLT≥80×10^9/L and without PLT transfusion within placebo dosage at 40 mg/d, decrease placebo dosage to 20 mg/d; When PLT≥80×10^9/L for 7 consecutive days or PLT≥300×10^9/L and without PLT transfusion, stop placebo; When PLT<50×10^9/L or PLT transfusion-dependent after stopping placebo, reuse placebo at 40 mg/d.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the proportion of complete response(CR) on day 60 after haplo-HSCT	the proportion of participants whose PLT≥50×10^9/L on day 60 after haplo-HSCT independent of PLT transfusion for 7 consecutive days or above	from randomization to day 60 after haplo-HSCT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the proportion of resonse(R)/remission on day 60 after haplo-HSCT	the proportion of participants whose PLT≥20×10^9/L or PLT≥100×10^9/L on day 60 after haplo-HSCT independent of PLT transfusion for 7 consecutive days or above	from randomization to day 60 after haplo-HSCT
the proportion of R/CR on day 30 after haplo-HSCT	the proportion of participants whose PLT≥20×10^9/L or PLT≥50×10^9/L on day 30 after haplo-HSCT independent of PLT transfusion for 7 consecutive days or above,respectively	from randomization to day 30 after haplo-HSCT
the proportion of CR/remission on day 90 after haplo-HSCT	the proportion of participants whose PLT≥50×10^9/L or PLT≥100×10^9/L on day 90 after haplo-HSCT independent of PLT transfusion for 7 consecutive days or above	from randomization to day 90 after haplo-HSCT
Time to R/CR/remission	the first day of the time to achieve PLT≥20×10^9/L and PLT≥50×10^9/L or PLT≥100×10^9/L independent of PLT transfusion for consecutive 7 days and above within 60 days after haplo-HSCT,respectively	from randomization to day 60 after haplo-HSCT
PLT transfusion dependence	the percentage of participants who need PLT transfusion and the average volume of transfused PLT from day 7 to day 60 after haplo-HSCT	from randomization to day 60 after haplo-HSCT
neutrophil engraftment	the first day and the percentage of participants to achieve absolute neutrophil≥500/μL for consecutive 3 days within 30 days after haplo-HSCT	from randomization to day 30 after haplo-HSCT
GVHD	the incidece of graft versus host disease(GVHD)	from randomization to 1 year after haplo-HSCT
overall survival(OS)	the 1-year OS of participants	from randomization to 1 year after haplo-HSCT
disease free survival(DFS)	the 1-year DFS of participants	from randomization to 1 year after haplo-HSCT
non-relapse mortality(NRM)	the 1-year NRM of participants	from randomization to 1 year after haplo-HSCT

Collaborators and Investigators

• Sponsor: Peking University People's Hospital
• Collaborators: The First Affiliated Hospital of Nanchang University; Xiangya Hospital of Central South University; The First Affiliated Hospital of Zhengzhou University; 920th Hospital of Joint Logistics Support Force of People's Liberation Army of China; Tang-Du Hospital; First Affiliated Hospital of Xinjiang Medical University; Sichuan Provincial People's Hospital; First Affiliated Hospital of Harbin Medical University; Shanxi Bethune Hospital
• Investigators: Principal Investigator: Xiaohui Zhang, Peking University People's Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): January 15, 2024
• Primary Completion (Estimated): October 30, 2024
• Study Completion (Estimated): October 30, 2025

Study Registration Dates

• First Submitted: December 14, 2023
• First Submitted That Met QC Criteria: January 1, 2024
• First Posted (Estimated): January 11, 2024

Study Record Updates

• Last Update Posted (Estimated): January 11, 2024
• Last Update Submitted That Met QC Criteria: January 1, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: hematopoietic stem cell transplantation; Thrombocytopenia; haploidentical
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Platelet Disorders; Thrombocytopenia
• Other Study ID Numbers: 2023PHD009-001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No