A Randomized Double-Blind Placebo-Controlled Trial of Ganciclovir/Valganciclovir for Prevention of Cytomegalovirus Reactivation in Acute Injury of the Lung and Respiratory Failure (The GRAIL Study)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 160
- 试验地点
- 14
- 主要终点
- Serum IL-6 Level
研究概览
简要总结
To evaluate whether administration of ganciclovir reduces serum IL-6 levels (i.e. reduction between baseline and 14 days post-randomization) in immunocompetent adults with severe sepsis or trauma associated respiratory failure.
Primary Hypotheses:
- In CMV seropositive adults with severe sepsis or trauma , pulmonary and systemic CMV reactivation amplifies and perpetuates both lung and systemic inflammation mediated through specific cytokines, and contributes to pulmonary injury and multiorgan system failure,
AND
- Prevention of CMV reactivation with ganciclovir decreases pulmonary and systemic inflammatory cytokines that are important in the pathogenesis of sepsis and trauma related complications.
详细描述
Critical illness due to severe sepsis and trauma are major causes of morbidity and mortality, and a substantial economic burden in the United States and worldwide. Despite advances in clinical care, patients with sepsis and trauma-associated respiratory failure represent specific populations with high rates of adverse outcomes. The etiology of respiratory failure in patients with severe sepsis and trauma is multifactorial, but acute lung injury (ALI) is one of the leading causes, and is associated with prolonged ICU and hospital stays, mortality, and long-term sequelae. Other than general supportive care, few specific interventions other than lung protective ventilation have been shown to improve outcomes in such patients. New approaches for understanding the pathogenesis and developing better therapies are urgently needed.
Acute Lung Injury (ALI) is a syndrome consisting of acute hypoxemic respiratory failure with bilateral pulmonary infiltrates that is associated with both pulmonary and nonpulmonary risk factors (eg. sepsis, trauma) and that is not due primarily to left atrial hypertension. Although a distinction between ALI and a more severe subtype (termed acute respiratory distress syndrome (ARDS) has been made, the pathogenesis, risk factors, and outcomes appear to be similar and for the purposes of this protocol, the term acute lung injury [ALI] will be used to encompass both entities. Accepted consensus definitions of ALI have been introduced and are now widely used for laboratory and clinical investigations of ALI. Acute Lung Injury (ALI) is defined as:
- PaO2/FiO2 <300
- Bilateral pulmonary infiltrates on chest x-ray
- Pulmonary Capillary Wedge Pressure <18mmHg or no clinical evidence of increased left atrial pressure Although a broad range of risk factors for ALI have been described, those that account for the majority of cases include: sepsis, pneumonia, trauma, and aspiration. It is well established that severe trauma is recognized as a precipitating cause of ALI. Recent studies have demonstrated that the incidence of acute lung injury (ALI) is much higher than previously thought, with an estimated age-adjusted incidence of 86 per 100,000 persons per year, resulting in an estimated ~190,000 cases annually in the US. The clinical and health care system impact of ALI is substantial, with an estimated 2,154,000 intensive care unit (ICU) days, 3,622,000 hospital days, and 75,000 deaths in 2000, and is expected to grow significantly given the marked age-related incidence and the aging population. Although general improvements in ICU care over the last 2 decades have led to a trend towards lower mortality due to certain ALI-associated risk factors (trauma, aspiration), the most common causes of ALI, sepsis and pneumonia, remain associated with high mortality rates of ~25-35%. Mortality in ALI is most commonly due to secondary infections/sepsis and multiorgan system failure rather than primary respiratory failure due to hypoxemia, highlighting the systemic nature of ALI. Even among initial survivors of ALI, substantial pulmonary and nonpulmonary functional impairment remains for months to years. Specifically, a proportion of those who survive the initial insult are at risk for prolonged mechanical ventilation and ICU/hospital stay, and the risk factors remain poorly defined. It has been hypothesized that a "2nd hit" may predispose certain patients to greater morbidity in this setting. Despite intensive basic and clinical investigation, only a single intervention (low-tidal volume ["lung protective"] ventilation) is generally accepted to decrease mortality in ALI, while multiple other strategies have failed to improve survival either in early clinical studies or definitive efficacy trials. Thus, given the high incidence and continued substantial clinical impact of ALI despite improvements in general medical/ICU care, and limited proven options other than lung-protective ventilation, new approaches to understanding the pathophysiology and identifying novel targets for intervention in ALI are a high priority.
Overly intense, persistent and dysregulated pulmonary and systemic inflammation has emerged as the leading hypothesis for the pathogenesis of ALI and its complications, but the contributory factors and mechanisms are incompletely defined. Several carefully-conducted prospective human studies have shown an association between specific inflammatory biomarkers in blood and BALF (both the initial levels at onset and changes over time) and important clinical outcomes in ALI. [Animal models have also demonstrated an association between inflammatory cytokines and non-pulmonary organ injury and dysfunction] In addition, one of the most important interventions (low-tidal volume ["lung protective"] ventilation) shown to decrease mortality in ALI is associated with reductions in inflammatory cytokines (IL-6, IL-8) in blood and bronchoalveolar lavage fluid [BALF].
Cytomegalovirus (CMV) is a ubiquitous virus in humans worldwide, and has been linked to adverse clinical outcomes including prolongation of mechanical ventilation, increased length of stay, and mortality in multiple studies of critically-ill, apparently immunocompetent, seropositive adults.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Double (Participant, Investigator)
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
- •Subject/next of kin informed consent
- •Age >= 18 years
- •CMV IgG seropositive. The following tests are acceptable:
- •FDA licensed test in a local lab approved by the coordinating center (FHCRC, Seattle, WA).
- •Test in central study lab (ARUP, Salt Lake City, UT)
- •A report that patient has previously been tested and found to be CMV seropositive at any time (a credible next of kin report is acceptable; confirmatory test will be done but results are not required for randomization)
- •Intubated and requiring mechanical positive pressure ventilation (including Acute Lung Injury/ARDS (EA Consensus Definition))
- •Meets criteria for either:
- •Severe sepsis criteria (as defined in appendix G) within a 24-hour time period within the 120 hour window
- •Trauma with respiratory failure and an ISS score > 15 within a 24 hour time period, and within the 120 hour window (where mechanical ventilation is not due solely to a head injury)
- •On the day of randomization (by local criteria):
- •Not eligible for SBT (use of sedation and/or vasopressor does not specifically contraindicate SBT),or
- •Failed SBT
排除标准
- •BMI > 60 (1st weight during hospital admission)
- •Known or suspected immunosuppression, including:
- •HIV+ (i.e. prior positive test or clinical signs of suspicion of HIV/AIDS; a negative HIV test is not required for enrollment)
- •stem cell transplantation:
- •within 6 months after autologous transplantation or
- •within 1 years after allogeneic transplantation (regardless of immunosuppression)
- •greater than 1 year of allogeneic transplantation if still taking systemic immunosuppression or prophylactic antibiotics (e.g. for chronic graft versus host disease)
- •Note: if details of stem cell transplantation are unknown, patients who do not take systemic immunosuppression and do not take anti-infective prophylaxis are acceptable for enrollment and randomization.
- •solid organ transplantation with receipt of systemic immunosuppression (any time).
- •cytotoxic anti-cancer chemotherapy within the past three months (Note: next-of-kin estimate is acceptable).
- •congenital immunodeficiency requiring antimicrobial prophylaxis (e.g. TMP-SMX, dapsone, antifungal drugs, intravenous immunoglobulin).
- •receipt of one or more of the following in the indicated time period:
- •within 6 months: alemtuzumab, antithymocyte/antilymphocyte antibodies
- •within 3 months: immunomodulator therapy (TNF-alpha antagonist, rituximab, tocilizumab, IL1 receptor antagonist and other biologics)
- •within 30 days:
- •corticosteroids > 10 mg/day (chronic administration, daily average over the time period)
- •topical steroids are permissible
- •use of hydrocortisone in "stress doses" up to 100 mg four times a day (400mg/daily) for up to 4 days prior to randomization is permissible
- •use of temporary short-term (up to 2 weeks) increased doses of systemic steroids (up tp 1 mg/kg) for exacerbation of chronic conditions are permissible.
- •methotrexate (> 10.0 mg/week)
- •azathioprine (> 75 mg/day)
- •Note: if no information on these agents is available in the history and no direct or indirect evidence exists from the history that any condition exists that requires treatment with these agents (based on the investigator's assessment), the subject may be enrolled. For all drug information, next-of-kin estimates are acceptable. See Appendix D for commonly prescribed immunosuppressive agents.
- •Expected to survive < 72 hours (in the opinion of the investigator)
- •Has been hospitalized for > 120 hours (subjects who are transferred from a chronic care ward, such as a rehabilitation unit, with an acute event are acceptable).
- •Pregnant or breastfeeding (either currently or expected within one month).
- •Note: for women of childbearing age (18-60 years, unless documentation of surgical sterilization [hysterectomy, tubal ligation, oophorectomy]), if a pregnancy test has not been done as part of initial ICU admission work-up, it will be ordered stat and documented to be negative before randomization. Both urine and blood tests are acceptable.
- •Absolute neutrophil count < 1,000/mm3 (if no ANC value is available, the WBC must be > 2500/mm3)
- •Use of cidofovir within seven (7) days of patient randomization. The use of the following antivirals is permitted under the following conditions:
- •Ganciclovir, foscarnet, high-dose acyclovir, or valacyclovir until the day of randomization
- •Acyclovir as empiric therapy for central nervous system HSV or VZV infection until the diagnosis can be excluded
- •For enrolled patients during the active study drug phase, acyclovir, famciclovir, valacyclovir for treatment of HSV or VZV infection as clinically indicated.
- •Currently enrolled in an interventional trial of an investigational therapeutic agent known or suspected to have anti-CMV activity, or to be associated with significant known hematologic toxicity (Note: confirm eligibility with one of the study medical directors at the coordinating site).
- •At baseline patients who have both a tracheostomy, and have been on continuous 24-hour chronic mechanical ventilation.
- •Patients with Child Class C Cirrhosis.
- •Patients with pre-existing interstitial lung disease.
研究组 & 干预措施
IV Ganciclovir
5mg/kg IV twice daily for 5 days, then followed by either IV ganciclovir or oral valganciclovir once daily until hospital discharge
干预措施: IV Ganciclovir (Drug)
Placebo
normal saline IV twice daily for 5 days, then followed by either IV normal saline or oral placebo once daily until hospital discharge
干预措施: Placebo (Drug)
结局指标
主要结局
Serum IL-6 Level
时间窗: Baseline and Day 14
Change between baseline and 14 days post-randomization between placebo \& ganciclovir groups
次要结局
- CMV AUC in Blood(Day 0 to 28 days post-randomization)
- Number of Participants With CMV Reactivation at 28 Days in Plasma(at 28 days post-randomization)
- BAL Levels of IL-6(at 7 days post-randomization)
- Number of Participants With Organ System Failure at 14 Days(at 14 days post-randomization)
- Number of Days Alive and Not in the ICU(by 28 days post-randomization)
- CMV Disease(by 180 days post-randomization)
- Grade 3 AEs or Higher(by 35 days post-randomization)
- SF-36 Health Survey(at 1 day post-randomization)
- Incidence of CMV Reactivation >1,000 IU Per mL at Day 28 in Plasma(at 28 days post-randomization)
- Incidence of CMV Reactivation at Any Level at 28 Days in Throat(at 28 days post-randomization)
- Incidence of CMV Reactivation >1,000 IU Per mL at 28 Days in Throat(at 28 days post-randomization)
- CMV AUC in Throat(Day 0 to 28 days post-randomization)
- CMV Peak Viral Load in Blood(at 28 days post-randomization)
- BAL Levels of IL-8(at 7 days post-randomization)
- BAL Levels of TNFa(at 7 days post-randomization)
- Plasma Levels of IL-6(at 28 days post-randomization)
- Plasma Levels of IL-8(at 28 days post-randomization)
- Plasma Levels of TNF a(Day 0 to 28 days post-randomization)
- Plasma Levels of Soluble ICAM-1(at 7 days post-randomization)
- Peak Plasma Levels of Soluble ICAM-1(Day 0 to 28 days post-randomization)
- Peak Plasma Levels of TNF-a(at 28 days post-randomization)
- Peak Plasma Levels of IL-10(at 28 days post-randomization)
- Peak Plasma Levels of IL-6(at 28 days post-randomization)
- AUC Plasma Levels of IL-6(Day 0 to 28 days post-randomization)
- AUC Plasma Levels of IL-8(Day 0 to 28 days post-randomization)
- AUC Plasma Levels of IL-10(at 28 days post-randomization)
- Peak Plasma Levels of IL-8(at 28 days post-randomization)
- AUC Plasma Levels of TNF-a(at 28 days post-randomization)
- AUC Plasma Levels of Soluble ICAM-1(at 28 days post-randomization)
- Length of Stay(by 28 days post-randomization)
- Organ System Failure at 28 Days(at 28 days post-randomization)
- Duration of Mechanical Ventilation as Assessed by Ventilator Free Days(at 28 days post-randomization)
- Duration of Mechanical Ventilation as Assessed by Ventilator Days(at 28 days post-randomization)
- Bacteremia and/or Fungemia(at 28 days post-randomization)
- Mortality(at 60 days post-randomization)
- Mortality at 180 Days(at 180 days post-randomization)
- SF-36 Functional Assessment Physical Component(at 180 days post-randomization)
- SF-36 Functional Assessment Mental Component(at 180 days post-randomization)
- SF-36 Functional Assessment Mental Component on Day 1(at 1 day post-randomization)
- Patients With Serious Adverse Events(by 35 days post-randomization)
- Time to Neutropenia(by 35 days post-randomization)
- Renal Insufficiency(by 35 days post-randomization)
- Use of Granulocyte-colony Stimulating Factor(by 35 days post-randomization)
- Red Blood Cell Transfusions Required Per Patients(by 35 days post-randomization)
- Platelet Transfusions(by 35 days post-randomization)
- Clinical Outcomes(at 14 days post-randomization)
- Bacteremia and Fungemia Outcomes(at 7 days post-randomization)
- Bacteremia and Fungemia Outcomes in Mechanically Ventilated Subjets(at 7 through 14 days post-randomization)
- Overall Mortality(at 7 days post-randomization)
- Number of Mechanical Ventilated Days(at 7 days post-randomization)
- Number of Ventilator-free Days(at 7 days post-randomization)
- Number of Days in the ICU(at 7 days post-randomization)
- Number of ICU-free Days(at 7 days post-randomization)
- Number of Days in the Hospital(at 7 days post-randomization)
- Number of Hospital-free Days(at 7 days post-randomization)
- Mortality Among Subjects Mechanically Ventilated From Day 7 to 14(28 days)
- Number of Mechanically Ventilated Days Among Subjects by Day 28(28 days)
- Number of Ventilator-free Days Among Subjects by Day 28(28 days)
- Number of Days in ICU Amongst Subjects by Day 28(28 days)
- Number of ICU-free Days Amongst Subjects by Day 28(28 days)
- Number of Hospital-free Days Among Subjects by Day 28(28 days)
研究者
Michael Boeckh
Principal Investigator
Fred Hutchinson Cancer Center