Combination Letermovir and Standard of Care Antiviral for Enhanced Antiviral Response in Cytomegalovirus Infection in Lung Transplant Recipients: A Pilot Trial
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Proportion of patients achieving clearance of CMV viremia by week 3, as measured by quantitative PCR.
研究概览
简要总结
The primary objective of the CLEAR-CMV trial is to evaluate the efficacy of letermovir therapy plus standard of care (SOC) antiviral compared to SOC plus placebo in achieving clearance of CMV viremia by week 3 in lung transplant recipients with active CMV infection.
详细描述
Lung transplant recipients are particularly susceptible to CMV infection due to intensive immunosuppressive regimens required to prevent graft rejection. CMV viremia is associated with increased morbidity, including CMV pneumonitis, and may contribute to chronic lung allograft dysfunction (CLAD).Approximately 30-50% of lung transplant recipients develop CMV infection within the first year post-transplant, with higher rates in CMV-seronegative recipients receiving organs from seropositive donors (D+/R-).
Current standard treatment for CMV infection in transplant recipients involves ganciclovir or its oral prodrug, valganciclovir, which inhibit CMV DNA polymerase. While effective, prolonged use is associated with toxicities, including myelosuppression, and the emergence of resistant strains in some cases. Letermovir, a novel antiviral targeting the CMV terminase complex, has shown efficacy in CMV prophylaxis in hematopoietic stem cell transplant recipients, and in kidney transplant recipients. It has now been extensively studied for use in prophylaxis but there are limited data in treatment. It is an attractive drug in transplant recipients because it has an excellent safety profile and requires no dose adjustment for renal dysfunction. However, data on the use of letermovir for treatment (as opposed to prophylaxis) are more limited. A multicenter study of letermovir use for treatment showed reasonable response rates especially in patients with low viral loads. The use of combination therapy for CMV treatment represents an attractive option, as there is extensive experience with other viruses (e.g. HIV , HCV) to show that this strategy leads to improved response rates and lessens the emergence of antiviral resistance. The use of ganciclovir plus letermovir is attractive because they target two different viral enzymes and both have oral options facilitating outpatient treatment. The most recently published international CMV consensus guidelines reports that the use of combination antiviral therapy is a key research need.
The investigators plan to conduct a pilot trial to determine the efficacy of letermovir plus standard of care (SOC) antiviral therapy in clearing CMV infection. The trial will be conducted in compliance with the protocol, Good Clinical Practices (GCP) and the applicable regulatory requirements.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Recipient of a lung transplant.
- •Has confirmed CMV viremia with a viral load ≥ 1000 IU/mL and will receive or has just started SOC antiviral treatment in the past 72h as per the decision of the treating physician.
排除标准
- •Renal failure with Creatinine clearance <15 mL/min or requiring dialysis
- •Severe hepatic impairment (Child-Pugh Class C)
- •Participating in another interventional clinical trial
- •Combined transplant (e.g heart-lung, lung-liver)
- •Known allergy or contraindication to any of the antiviral medications
- •Known antiviral resistance.
- •Patient receiving cyclosporin, pimozide or ergot alkaloids (due to significant drug interaction with letermovir).
- •Patient receiving or expected to receive CMV immunoglobulin or IVIG during the initial three week treatment phase
研究组 & 干预措施
SOC antiviral plus placebo
Patients will receive the standard of care (SOC) antiviral therapy along with a placebo drug. The placebo drug will be administered for three weeks, while the SOC antiviral duration and dosage will be at the discretion of the treating physician.
干预措施: Placebo (Drug)
SOC antiviral plus placebo
Patients will receive the standard of care (SOC) antiviral therapy along with a placebo drug. The placebo drug will be administered for three weeks, while the SOC antiviral duration and dosage will be at the discretion of the treating physician.
干预措施: Valganciclovir/Ganciclovir (Drug)
SOC antiviral plus letermovir active drug
Patients will receive the standard of care (SOC) antiviral therapy in combination with letermovir. The letermovir active drug will be administered for three weeks, while the SOC antiviral treatment duration and dosage will be at the discretion of the treating physician.
干预措施: Letermovir (Drug)
SOC antiviral plus letermovir active drug
Patients will receive the standard of care (SOC) antiviral therapy in combination with letermovir. The letermovir active drug will be administered for three weeks, while the SOC antiviral treatment duration and dosage will be at the discretion of the treating physician.
干预措施: Valganciclovir/Ganciclovir (Drug)
结局指标
主要结局
Proportion of patients achieving clearance of CMV viremia by week 3, as measured by quantitative PCR.
时间窗: From time of enrollment until 3 weeks after enrolment
Viral clearance is described by a plasma CMV viral load \< 200 IU/mL, the UHN clinically used threshold
次要结局
- Time to clearance of CMV viremia(From enrolment until clearance of CMV viremia, up to 6 months after enrolment)
- Time to resolution of symptoms if present(From enrolment until clearance of symptoms, up to 6 months after enrolment)
- Development of antiviral resistance(From enrolment until up to 6 months after enrolment)
- Monthly enrollment rate as a measure of recruitment feasibility(From start of enrollment until up to 6 months after the final patient is enrolled)
- Proportion of patients achieving CMV viral load <137 IU/mL (lower limit of quantification of the assay)(At week 3 from enrolment and at 6 months)
- Proportion of patients achieving an undetectable viral load(At week 3 and by month 6 after enrolment)
- Incidence of adverse events(From enrolment until up to 6 months after enrolment)
- Proportion of patients with clinically significant CMV recurrence within 6months, as determined by quantitative PCR or symptomatic CMV disease(From enrollment until 6 months.)