Multicenter, Randomized Controlled Clinical Study on Early Application of Realgar-Indigo Naturalis Formula (RIF) for Treatment of Acute Promyelocytic Leukemia (APL)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 224
- 试验地点
- 1
- 主要终点
- Early Death Rate
研究概览
简要总结
Study Title:
Multicenter, Randomized Controlled Clinical Study on Early Application of Realgar-Indigo Naturalis Formula (RIF) for Treatment of Acute Promyelocytic Leukemia (APL)
Sponsor:
Xi'an Jiaotong University First Affiliated Hospital
Principal Investigator:
Wang Huaiyu
Study Description:
This multicenter, randomized controlled trial evaluates whether early induction treatment with oral Realgar-Indigo Naturalis Formula (RIF) combined with all-trans retinoic acid (ATRA) reduces early death rates in patients with acute promyelocytic leukemia (APL). APL is a subtype of acute myeloid leukemia characterized by a high risk of early death, largely due to coagulopathy and bleeding events, especially in high-risk patients with elevated white blood cell counts.
Traditional treatment with ATRA and arsenic trioxide (ATO) has improved outcomes but early mortality remains a major challenge. RIF, an oral arsenic compound Chinese patent medicine, has demonstrated efficacy comparable to ATO with advantages in safety and oral administration convenience. Previous smaller studies suggested RIF may accelerate recovery of coagulation parameters and reduce early death.
Patients clinically suspected of APL will be randomized into two groups:
Experimental group: oral ATRA + RIF before molecular diagnosis confirmation
Control group: oral ATRA only before confirmation
After molecular or genetic diagnosis confirmation:
Experimental group receives 1 week of ATRA + RIF induction (days 0-7), then switches to 3 weeks ATRA + ATO (days 8-28)
Control group receives 4 weeks ATRA + ATO (days 0-28)
Both groups then receive identical consolidation therapy with ATRA + ATO for 6 cycles (2 weeks treatment + 2 weeks off per cycle) following molecular complete remission.
Primary Objective:
To evaluate whether early induction with ATRA + RIF reduces early death rate (within 30 days of diagnosis) in APL patients.
Secondary Objectives:
To explore if early ATRA + RIF (prior to molecular confirmation) is non-inferior to ATRA alone in reducing coagulopathy and early death in suspected APL patients. Secondary endpoints include 2-year event-free survival (EFS) and overall survival (OS).
Study Design:
Type: Multicenter, randomized, open-label controlled clinical trial
Population: Adults aged 18-80 years with newly diagnosed acute myeloid leukemia highly suspected as APL
Randomization: Central randomization assigns participants to experimental (ATRA + RIF) or control (ATRA only) groups
Blinding: Open-label (no blinding)
Inclusion Criteria:
Age 18-80
Newly diagnosed AML with strong clinical suspicion of APL based on bone marrow morphology and immunophenotyping
Exclusion Criteria:
Negative for PML-RARα fusion by cytogenetics or RT-PCR
Severe organ dysfunction not related to APL (renal, hepatic, cardiac)
QTc >480 ms before treatment
Other malignancies
Pregnant or breastfeeding women
Treatment Regimen:
Induction: Experimental group receives oral ATRA 25 mg/m²/day + RIF 60 mg/kg/day for 7 days, then ATRA + intravenous ATO 0.15 mg/kg/day for 3 weeks; Control group receives ATRA + ATO for 4 weeks.
Consolidation:During the consolidation phase, intermediate- and low-risk patients receive either intravenous ATO or oral RIF, while high-risk patients receive intravenous ATO together with intravenous mannitol infusion. Routine lumbar puncture and intrathecal chemotherapy are not performed.
Supportive care includes hydroxyurea and venetoclax for elevated WBC, transfusions for coagulopathy, and dexamethasone for differentiation syndrome.
Endpoints:
Primary endpoint: Early death rate (death within 30 days of diagnosis)
Secondary endpoints: 2-year event-free survival (EFS), 2-year overall survival (OS)
Sample Size:
Approximately 224 patients (112 per group), calculated to detect a reduction in early death rate from 12% (historical) to 3% (experimental), with 80% power and 5% significance level.
Statistical Analysis:
Descriptive statistics for baseline characteristics and adverse events
Kaplan-Meier survival analysis for EFS and OS
Significance threshold p < 0.05
Safety Monitoring:
Daily blood count and coagulation tests during induction
Monitoring and management of adverse events including severe coagulation disorders, differentiation syndrome, arsenic toxicity, infection, and bone marrow suppression
Adverse events graded with CTCAE criteria and reported accordingly
Data Handling:
Electronic data capture system compliant with ICH-GCP and CDISC standards
Confidential storage at Xi'an Jiaotong University First Affiliated Hospital
Data anonymized for reporting
Ethics:
Conducted in accordance with the Declaration of Helsinki and Chinese clinical research regulations
Protocol approved by local ethics committee
Written informed consent required before study enrollment
Study Timeline:
Planned start: June 2025
Planned completion: June 2028
详细描述
Background and Rationale Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) characterized by the t(15;17) translocation, resulting in the PML-RARα fusion gene. The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has transformed APL into a highly curable disease. However, early death (ED), defined as mortality within 30 days of diagnosis, remains a significant challenge, particularly in high-risk patients (initial white blood cell [WBC] count >10×10⁹/L). The predominant cause of ED is hemorrhagic complications, often intracranial hemorrhage, driven by a severe coagulopathy resembling disseminated intravascular coagulation (DIC). Real-world data indicate an ED rate of approximately 12% overall, increasing to 17.6% in the high-risk subset. Thus, interventions that can rapidly stabilize coagulopathy and mitigate bleeding risk during the initial days of therapy are critical to improving overall outcomes.
Realgar-Indigo Naturalis Formula (RIF) is an oral arsenic-containing Chinese patent medicine. Preclinical and clinical studies suggest that RIF has a pharmacodynamic profile distinct from intravenous ATO, potentially offering a more rapid correction of coagulation parameters. Prior pivotal trials have established its non-inferiority to intravenous ATO for consolidation therapy in low-to-intermediate risk APL, with the added advantages of oral administration and a favorable safety profile suitable for outpatient management. Furthermore, a small randomized study reported zero early deaths among patients receiving ATRA plus RIF during induction, with observations suggesting faster recovery of platelet counts and fibrinogen levels compared to ATO in patients with subclinical DIC. These findings provide the rationale for evaluating whether the early introduction of RIF during the critical pre-diagnosis and initial induction period can reduce the incidence of early fatal events.
Study Design and Rationale This is a multicenter, randomized, open-label, controlled trial designed to evaluate the impact of early RIF administration on early death in patients with newly diagnosed AML highly suspected to be APL. The open-label design is necessitated by the distinct nature of the interventions (oral RIF vs. no RIF), and the primary endpoint (early death) is an objective, hard endpoint not subject to assessment bias.
The study employs a pragmatic, response-adaptive treatment framework. Patients are randomized prior to molecular confirmation of APL to reflect a real-world clinical scenario where prompt initiation of targeted therapy is critical. The initial 7-day window (Days 0-7) is the focus of the intervention, aiming to test the hypothesis that early RIF combined with ATRA yields superior early mortality outcomes compared to ATRA alone. Upon confirmation of PML-RARα positivity, patients in the experimental group transition to a standard ATRA + ATO regimen, while control patients initiate ATRA + ATO from Day 0. This design ensures that all confirmed APL patients ultimately receive guideline-directed therapy with ATRA and ATO, isolating the variable of early RIF exposure. Patients who are found to be PML-RARα-negative are withdrawn from the study and managed according to standard clinical practice for non-APL AML.
Treatment Regimen and Supportive Care Details The induction phase is protocolized with specific supportive care measures to manage APL-related complications.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age between 18 and 80 years.
- •Diagnosed with acute myeloid leukemia confirmed by bone marrow morphology and immunophenotyping, with a high clinical suspicion of acute promyelocytic leukemia (APL).
排除标准
- •Confirmed non-APL (M3 type) acute myeloid leukemia through cytogenetic and RT-PCR testing (PML-RARα fusion gene negative).
- •Severe liver or kidney dysfunction unrelated to APL (e.g., serum creatinine > 2.5 times the upper limit of normal, total bilirubin ≥ 2 times the upper limit, ALT and AST > 3 times the upper limit), or heart failure (e.g., EF < 40%).
- •Presence of other malignancies.
- •Pregnant or breastfeeding women.
结局指标
主要结局
Early Death Rate
时间窗: within 30 days from the date of diagnosis
Early death rate
时间窗: 4 Years
次要结局
未报告次要终点