Phase 2 N=160 Randomized Double-blind Prevention

Ganciclovir/Valganciclovir for Prevention of CMV Reactivation in Acute Injury of the Lung and Respiratory Failure

Acute Lung Injury · Acute Respiratory Distress Syndrome · Respiratory Failure

Bottom Line

View on ClinicalTrials.gov: NCT01335932 ↗

Enrolled (actual)

160

Serious AEs

0.0%

Results posted

Sep 2017

Primary outcome: Primary: Serum IL-6 Level — -0.79; -0.79 pg/mL

Study Design & Population

Study type: Interventional
Phase: Phase 2
Interventions: IV Ganciclovir (Drug); Placebo (Drug)
Age: Adult, Older Adult · 18+ yrs
Sex: All
Sponsor: Fred Hutchinson Cancer Center
Primary completion: Jun 2016

Outcome Measures

Outcome	Result	p-value
PRIMARY Serum IL-6 Level	-0.79; -0.79	—
SECONDARY Number of Participants With CMV Reactivation at 28 Days in Plasma	3; 23; 74; 44	.0001 sig
SECONDARY BAL Levels of IL-6	1.01; 1.66	0.31
SECONDARY Number of Participants With Organ System Failure at 14 Days	0; 2; 84; 70	—
SECONDARY Number of Days Alive and Not in the ICU	10.02; 10.97	—
SECONDARY CMV Disease	0; 0; 84; 72	—
SECONDARY Grade 3 AEs or Higher	11; 10; 73; 62	—
SECONDARY SF-36 Health Survey	36.37; 35	—
SECONDARY Incidence of CMV Reactivation >1,000 IU Per mL at Day 28 in Plasma	0; 5; 77; 62	0.006 sig
SECONDARY Incidence of CMV Reactivation at Any Level at 28 Days in Throat	2; 6; 78; 61	0.14
SECONDARY Incidence of CMV Reactivation >1,000 IU Per mL at 28 Days in Throat	0; 1; 80; 66	0.10
SECONDARY CMV AUC in Blood	0.11; 0.39	0.002 sig
SECONDARY CMV AUC in Throat	0.03; 0.17	0.03 sig
SECONDARY CMV Peak Viral Load in Blood	0.24; 0.89	<0.0001 sig
SECONDARY BAL Levels of IL-8	2.21; 2.61	0.73
SECONDARY BAL Levels of TNFa	0.18; 0.46	0.33
SECONDARY Plasma Levels of IL-6	0.35; 0.59	0.12
SECONDARY Plasma Levels of IL-8	1.09; 1.27	0.13
SECONDARY Plasma Levels of TNF a	-0.06; -0.11	0.51
SECONDARY Plasma Levels of TNF a	-0.06; -0.11	0.51
SECONDARY Plasma Levels of IL-6	0.35; 0.59	0.12
SECONDARY Plasma Levels of IL-8	1.09; 1.27	0.13
SECONDARY Plasma Levels of Soluble ICAM-1	5.43; 5.45	0.64
SECONDARY Plasma Levels of Soluble ICAM-1	5.43; 5.45	0.64
SECONDARY Peak Plasma Levels of Soluble ICAM-1	5.52; 5.57	0.24
SECONDARY Peak Plasma Levels of TNF-a	0.16; 0.17	0.76
SECONDARY Peak Plasma Levels of IL-10	0.88; 0.82	0.45
SECONDARY Peak Plasma Levels of IL-8	1.67; 1.66	0.92
SECONDARY Peak Plasma Levels of IL-6	1.57; 1.56	0.94
SECONDARY AUC Plasma Levels of IL-6	0.68; 0.75	0.37
SECONDARY AUC Plasma Levels of IL-8	1.15; 1.13	0.80
SECONDARY AUC Plasma Levels of IL-10	0.36; 0.35	0.93
SECONDARY AUC Plasma Levels of TNF-a	-0.14; -0.14	0.93
SECONDARY AUC Plasma Levels of Soluble ICAM-1	4.78; 4.65	0.45
SECONDARY Length of Stay	9.96; 8.72	—
SECONDARY Length of Stay	9.96; 8.72	—
SECONDARY Organ System Failure at 28 Days	0; 2; 84; 70	—
SECONDARY Duration of Mechanical Ventilation as Assessed by Ventilator Free Days	18.71; 15.97	—
SECONDARY Duration of Mechanical Ventilation as Assessed by Ventilator Days	6.95; 8.5	—
SECONDARY Bacteremia and/or Fungemia	15; 11; 69; 61	—
SECONDARY Mortality	13; 12; 71; 60	—
SECONDARY Mortality at 180 Days	18; 19; 66; 53	—
SECONDARY SF-36 Functional Assessment Physical Component	35.51; 38.17	—
SECONDARY SF-36 Functional Assessment Mental Component	45.55; 44.08	—
SECONDARY SF-36 Functional Assessment Mental Component on Day 1	43.83; 42.73	—
SECONDARY Patients With Serious Adverse Events	0; 0; 84; 72	—
SECONDARY Time to Neutropenia	0; 0	—
SECONDARY Use of Granulocyte-colony Stimulating Factor	0; 0; 84; 72	—
SECONDARY Renal Insufficiency	36; 41; 48; 31	—
SECONDARY Red Blood Cell Transfusions Required Per Patients	2; 1	—
SECONDARY Platelet Transfusions	1; 1	—
SECONDARY Clinical Outcomes	42; 49; 42; 23	—
SECONDARY Bacteremia and Fungemia Outcomes	15; 9; 67; 55	—
SECONDARY Bacteremia and Fungemia Outcomes in Mechanically Ventilated Subjets	6; 9; 24; 24	—
SECONDARY Overall Mortality	16; 11; 66; 53	—
SECONDARY Number of Mechanical Ventilated Days	7.05; 9.05	—
SECONDARY Number of Ventilator-free Days	19.17; 17.97	—
SECONDARY Number of Days in the ICU	10.20; 11.83	—
SECONDARY Number of ICU-free Days	15.38; 13.89	—
SECONDARY Number of Days in the Hospital	6.21; 5.53	—
SECONDARY Number of Hospital-free Days	10.22; 9.87	—
SECONDARY Mortality Among Subjects Mechanically Ventilated From Day 7 to 14	9; 6; 21; 27	—
SECONDARY Number of Mechanically Ventilated Days Among Subjects by Day 28	13.4; 14.42	—
SECONDARY Number of Ventilator-free Days Among Subjects by Day 28	11.4; 12.45	—
SECONDARY Number of Days in ICU Amongst Subjects by Day 28	16.73; 17.79	—
SECONDARY Number of ICU-free Days Amongst Subjects by Day 28	7.73; 8.15	—
SECONDARY Number of Hospital-free Days Among Subjects by Day 28	3.54; 4.59	—

Summary

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.

Eligibility Criteria

Inclusion Criteria

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

Exclusion Criteria

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 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

View full record on ClinicalTrials.gov →

Data sourced from ClinicalTrials.gov (NCT01335932). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.