Thursday, November 21, 2024 11/21/2024

1/2 Ganciclovir to Prevent Reactivation of Cytomegalovirus in Patients with Acute Respiratory Failure and Sepsis

Award Number: UH3HL147011
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Sepsis-associated acute respiratory failure is a leading cause of morbidity, mortality and health care expenditure world-wide, and is increasing in incidence. Despite intensive investigation, there are few pharmacologic interventions, and care is largely supportive. Cytomegalovirus (CMV) is a human herpesvirus that infects 50- 80% of healthy adults and establishes lifelong latency in the lung, generally causing overt disease only in severely immunosuppressed patients. CMV reactivation (viral replication) from latency occurs in ~40% of CMV seropositive, otherwise immunocompetent persons during critical illness and is associated with worse clinical outcomes including increased mortality, prolonged mechanical ventilation, and increased ICU length of stay. Compelling evidence implicating CMV reactivation as a causal contributor to morbidity and mortality in sepsis- associated respiratory failure comes from animal models and our recently completed NHLBI-funded phase 2 randomized placebo-controlled trial (RCT) of ganciclovir prophylaxis. In this trial, among CMV seropositive adults with sepsis-associated respiratory failure, ganciclovir effectively suppressed CMV replication, had an acceptable safety profile, and was associated with improved clinical outcomes, including increased ventilator-free days (VFD), shorter duration of mechanical ventilation among survivors, shorter ICU length of stay, and improved PaO2/FiO2 ratio in day-7 survivors. We hypothesize that IV ganciclovir administered early in critical illness will effectively suppress CMV reactivation in CMV seropositive adults with sepsis-associated acute respiratory failure, thereby reducing lung damage, accelerating recovery, and leading to improved clinical outcomes. We propose to conduct a phase 3 RCT to determine whether the antiviral drug ganciclovir given as prophylaxis improves VFDs and other clinically relevant outcomes when administered within 5 days of ICU admission to CMV seropositive immunocompetent adults with sepsis-associated acute respiratory failure. We will measure the effect of the study intervention on the primary trial outcome (VFDs) and secondary outcomes (mortality at 28 days, duration of mechanical ventilation in survivors, oxygenation, static respiratory system compliance, CMV plasma and lung reactivation, and a core set of longer-term outcomes at 6 months). In exploratory analyses, we will assess baseline factors as predictors for CMV reactivation, and characterize the relationship of CMV viral load kinetics with VFDs and other clinical outcomes. Our interdisciplinary team has unique experience in successfully coordinating multi-site multi-PI ICU-based RCTs. We have established a network of 19 clinical sites in the US, all of which have robust infrastructure for ICU clinical trials and proven ability to recruit patients into RCTs. If it is effective, this inexpensive and feasible intervention has the potential to significantly improve care of patients with sepsis-associated respiratory failure, substantially change clinical practice, and offer new insights into the sepsis-CMV reactivation relationship.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $2,170,027 )
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Lung Diseases Research	002	6	9/9/2024	NON-COMPETING CONTINUATION	$2,170,027
2024	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Lung Diseases Research	001	3	12/12/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,064,614
2024	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Lung Diseases Research	000	2	12/12/2023	EXTENSION WITH OR WITHOUT FUNDS	-$1,064,614
														Subtotal = $2,170,027

Issue Date FY: 2023 ( Subtotal = $2,120,121 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Lung Diseases Research	001	5	8/30/2023	NON-COMPETING CONTINUATION	$2,120,121
2023	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Lung Diseases Research	000	2	11/21/2022	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $2,120,121

Issue Date FY: 2022 ( Subtotal = $3,281,372 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Lung Diseases Research	003	4	9/9/2022	NON-COMPETING CONTINUATION	$2,216,758
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Lung Diseases Research	000	2	4/7/2022	EXTENSION WITH OR WITHOUT FUNDS	$1,064,614
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Lung Diseases Research	002	3	6/30/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,503,461
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Lung Diseases Research	001	2	6/28/2022	EXTENSION WITH OR WITHOUT FUNDS	-$1,503,461
														Subtotal = $3,281,372

Issue Date FY: 2021 ( Subtotal = $2,216,945 )
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Lung Diseases Research	000	2	9/13/2021	EXTENSION WITH OR WITHOUT FUNDS	$2,216,945
														Subtotal = $2,216,945

Grand Total All Awards = $9,788,465

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1/2 Ganciclovir to Prevent Reactivation of Cytomegalovirus in Patients with Acute Respiratory Failure and Sepsis

Award Number: UH3HL147011

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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