Comparison of Two Strategies for Monitoring HCMV Breakthrough Infections During Letermovir Prophylaxis. a Multicenter, Randomized, Open-label Trial
试验速览
- 阶段
- 不适用
- 发起方
- 入组人数
- 140
- 试验地点
- 10
- 主要终点
- - Proportion of patients with positive HCMV DNAemia developing antiviral drug-related toxicity.
研究概览
简要总结
The goal of this clinical trial is to compare two strategies to monitor human cytomegalovirus (HCMV) infections in transplanted patients receiving letermovir (LTV) as anti-HCMV prophylaxis.
HCMV infection after transplantation is diagnosed by detection of HCMV DNA in blood. However, due to the peculiar mechanism of action of LTV, most episodes of HCMV DNA detection are caused by release in the blood stream of non-infectious HCMV DNA.
In true episodes of productive infection, HCMV DNA in blood is present inside the virion and therefore is resistant to DNAse digestion. Conversely, when non-infectious free-floating HCMV DNA is released in the bloodstream, it will be degraded after treatment of plasma with DNAse and will not be detectable by real-time PCR assays.
Researchers will compare determination of HCMV DNA in blood with or without previous digestion of non-infectious free-floating DNA with DNAse.
In patients of the Control group HCMV DNA will be tested without DNAse digestion. If HCMV DNA is positive, patients will stop LTV prophylaxis and receive antiviral therapy with another drug.
In patients of the Study group HCMV DNA will be tested after DNAse digestion. Only if HCMV DNA is positive after DNAse digestion, patients will stop LTV prophylaxis and receive antiviral therapy with another drug.
The main aim of the study is to demonstrate that, by avoiding inappropriate antiviral therapy during LTV prophylaxis, transplant patients will suffer of lower antiviral-drug-related toxicity. A monitoring strategy able to identify true episodes of HCMV productive infection during LTV prophylaxis will lead to a lower rate of inappropriate antiviral therapy and drug-related toxicity without an increased risk of HCMV disease.
详细描述
Patients will be enrolled at the start of conditioning regimen, and all patients of both arms will receive LTV prophylaxis after transplantation until day 100, according to standard procedures. Patients will be randomized (1:1) in two arms in case of positive HCMV DNAemia and will follow two different diagnostic strategies to assess HCMV refractivity to LTV prophylaxis.
- In the Control arm, patients will stop LTV shifting to GCV/VGCV/FOS pre-emptive therapy in case of positive HCMV DNAemia confirmed in two consecutive samples.
- In the Study arm, patients will stop LTV shifting to GCV/VGCV/FOS pre-emptive therapy in case of positive HCMV DNA and subsequent confirmation of productive infection by detection of DNAse-resistant HCMV plasma DNAemia. However, for safety reasons, patients of the Study arm will stop LTV and shift to pre-emptive therapy in case of HCMV DNAemia >10,000 copies/ml whole blood in two consecutive samples, even if DNAse-resistant HCMV plasma DNAemia is negative.
GCV/VGCV/FOS pre-emptive therapy will be stopped in all cases after detection of a negative HCMV DNAemia (i.e. below detection level of the assay adopted) in two consecutive samples.
After the end of LTV prophylaxis, HCMV infection will be treated with pre-emptive therapy according to current procedures of each center.
The hypothesis is that in the Study arm, due to the lower use of antiviral drugs as preemptive therapy, a significant reduction of neutropenia, renal failure and/or alteration in plasma electrolytes will be observed without an increase of HCMV diseases.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age>18 years.
- •Allogeneic hematopoietic stem cell transplant.
- •HCMV IgG seropositivity before transplant
- •Written informed consent.
- •LTV prophylaxis administration
排除标准
- •Age <18 years.
- •Inability to comply with the requirements of the protocol.
结局指标
主要结局
- Proportion of patients with positive HCMV DNAemia developing antiviral drug-related toxicity.
时间窗: Day 100
Antiviral drug-related toxicity will be considered as neutrophil impairment or kidney injury. Patients who exit before day 100 for death, underlying disease relapse, or transplant rejection after detection of HCMV-positive DNAemia will be considered as failures and counted along with antiviral drug-related toxicities for the analysis of the primary end-point occurring at least 5 days after start of preemptive antiviral therapy
次要结局
- Proportion of patients developing HCMV DNAemia during LTV prophylaxis.(Day 100)
- Proportion of patients developing HCMV disease within day 100 and between day 100 and 360 from transplant (key secondary endpoint)(Day 100 and day 360)
- Proportion of patients stopping LTV prophylaxis and shifting to GCV/VGCV/FOS therapy.(Day 100)
- Proportion of patients developing neutropenia between day 100 and 360.(Day 360)
- Proportion of patients developing HCMV-specific T-cell response at day 100, 180, and 360.(Day 100, day 180 and day 360)
- Proportion of patients requiring GCV/VGCV/FOS therapy between day 100 and 360.(Day 360)
- Cumulative incidence of acute or chronic GvHD.(Day 100 and day 360)
- Proportion of patients with persisting HCMV DNAemia.(Day 360)
- Proportion of patients developing LTV-resistant HCMV strains.(Day 100)
- Transplant related mortality (TRM), underlying disease relapse, and 1-year survival.(Day 360)
研究者
Daniele Lilleri
Medical staff
Fondazione IRCCS Policlinico San Matteo di Pavia