OPTIFLU: Early Oseltamivir Carboxylate Low Plasma Concentration in Patients Admitted to Intensive Care for Severe Influenza
Study Details
Study Description
Brief Summary
Introduction
Pandemic and seasonal influenza epidemics can be associated with a high degree of morbidity and mortality, especially in patients developing severe influenza pneumonitis with the acute respiratory distress syndrome (ARDS) or the less frequent fulminant myocarditis. Early administration (i.e. in the first 48 hours) of the neuraminidase inhibitor oseltamivir is associated with reduced mortality in patients hospitalized for severe influenza. Early oseltamivir administration, which can only be given orally (or through a nasogastric tube), is thus recommended by the World Health Organization in patients hospitalized for severe influenza, including those requiring intensive care (ICU) admission. However, enteric absorption may be compromised in critically ill patients due to impaired gut function.
Hypothesis/Objective
The hypothese is that, in patients admitted for severe influenza, early (i.e., measured at the 48th hour of treatment initiation) oseltamivir carboxylate (OC) low plasma concentration would be: 1) associated with a poor prognosis; and 2) detectable by carrying out a paracetamol absorption test (PAT).
The main objective of the study is to determine the prognostic impact of early OC low plasma concentration in patients admitted to the intensive care unit (ICU) for severe influenza.
Primary outcome measure: Number of live ventilator-free days at 28-day in patients with versus without OC low plasma concentration.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Detailed Description
Methods
Prospective cohort study conducted in 21 French intensive care units. Adult patients admitted to the ICU for severe influenza requiring invasive mechanical ventilation and treated with oseltamivir through a gastric tube for less than 24 hours will be included. Non-inclusion criteria are pregnancy, breastfeeding, zanamivir treatment, other respiratory virus infection (including SARS CoV-2), contraindication to esophageal tube insertion, Child-Pugh C cirrhosis or severe liver insufficiency, paracetamol allergy, prisoners or patients under legal protection.
After inclusion, oseltamivir treatment will be continued through a gastric tube (75mg x 2 /day). After the 4th administration, plasma peak concentration of oseltamivir phosphate (OP) will be dosed at 60 minutes (CmaxOP) and plasma residual concentration of OC will be dosed at 12 hours (just before the 5th dose) (CresOC). A paracetamol absorption test will also be performed at the same time (consisting in the measurement of plasma paracetamol concentration 60 minutes after enteral loading with 1000 mg of paracetamol). CmaxOP and CresOC will also be measured at day 3 and 5 in order to realize pharmacokinetic analysis. Nasal swabs will be performed at inclusion (day 1) and day 5 for viral load quantification and viral strain sequencing (detection of the H275Y mutation). Clinical and biological variables will be collected from day 1 to day 90.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Paracetamol absorption test
|
Other: Absorption test
Paracetamol's administration (1 gram) - 48 hours after oseltamivir administration.
|
Outcome Measures
Primary Outcome Measures
- Live ventilator-free days (VFDs) [Day 28]
VFDs = 0 if subject dies within 28 days of mechanical ventilation. VFDs = 28 - x if successfully liberated from ventilation x days after initiation. VFDs = 0 if the subject is mechanically ventilated for > 28 days.
Secondary Outcome Measures
- Diagnostic performance of the paracetamol absorption test (PAT) [48 hours]
Sensitivity = ability of PAT to correctly classify a patient as "having a low oseltamivir carboxylate (OC) concentration" = (true positive) / (true positive + false negative) Specificity = ability of PAT to correctly classify a patient as "not having a low oseltamivir carboxylate (OC) concentration" = (true negative) / (true negative + false positive) Positive predictive value (PPV) = percentage of patients with negative PAT who actually are "having a low oseltamivir carboxylate (OC) concentration"= (true positive) / (true positive + false positive) Negative predictive value (NPV) = percentage of patients with positive PAT who actually are not ""having a low oseltamivir carboxylate (OC) concentration" = (true negative) / (false negative + true negative) Positive Likelihood Ratio = Sensitivity / (1 - Specificity) Negative Likelihood Ratio = (1 - Sensitivity) / Specificity
- Prevalence of patients with low plasma OC concentration [48 hours]
- Independent variables present on admission associated with low plasma OC concentration [48 hours]
- Prevalence of acquisition of the oseltamivir resistance mutation (H275Y) in patients with versus without low plasma OC concentration. [Day 5]
- Maximum oseltamivir carboxylate concentrations measurement [Days 2, 3 and 5]
- Maximum oseltamivir phosphate concentrations measurement [Days 2, 3 and 5]
- Residual oseltamivir carboxylate concentrations measurement [Days 2, 3 and 5]
- Residual oseltamivir phosphate concentrations measurement [Days 2, 3 and 5]
- Mortality [Days 28 and 90]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Adult patients
-
Severe influenza requiring mechanical ventilation
-
Oseltamivir treatment administered through a gastric tube initiated since less than 24 hours
-
Affiliation to a social security system
-
Written consent obtained
Exclusion Criteria:
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Pregnancy or breastfeeding
-
Zanamivir or other antiviral effective treatment received for more than 24 hours
-
Other respiratory virus infection (including SARS-CoV-2)
-
Contra-indication to esophageal tube insertion or use
-
Child-Pugh C cirrhosis or severe liver insufficiency
-
Paracetamol allergy
-
Prisoners
-
Patients under legal protection
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Anne-Fleur Haudebourg | Créteil | France | 94010 |
Sponsors and Collaborators
- Assistance Publique - Hôpitaux de Paris
Investigators
- Study Director: Anne-Fleur Haudebourg, M.D, Assistance Publique Hôpitaux de Paris - CHU Henri Mondor
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- APHP210090