Early Oseltamivir Carboxylate Low Plasma Concentration in Patients Admitted to Intensive Care for Severe Influenza.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

18 Dec 2023 → ongoing

Decision date (initial)

2024-10-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

French Ministry of Health PHRC Interrégional 2020

External identifiers

EU CT number

2024-516058-23-00

EudraCT number

2022-002377-28

ClinicalTrials.gov

NCT05375864

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Pharmacokinetic, Pharmacodynamic

To determine the prognostic impact of early plasma underdosing (measured at 48 hours of treatment) of oseltamivir carboxylate (OC) on early morbidity and mortality in patients hospitalized in the ICU for severe influenza infection.

Secondary objectives 7

1. To determine the diagnostic performance of the paracetamol absorption test for the early diagnosis (H48) of plasma OC underdosing.
2. Determine the prevalence of early (H48) plasma OC underdosing
3. Identify factors associated with early plasma OC underdosing
4. Determine the relationship between early OC concentration and viral clearance
5. Determine the relationship between early OC concentration and the acquisition of a variant carrying the oseltamivir resistance mutation (H275Y) in the subgroup of patients with influenza A(H1N1)pdm2009 infection.
6. Study of oseltamivir plasma pharmacokinetics and determination of the prevalence of OC overdosage
7. To determine the prognostic impact of early plasma oseltamivir carboxylate underdosing on mortality at D28 and D90 of patients hospitalized in the ICU for severe influenza infection.

Conditions and MedDRA coding

Adult patients admitted to the ICU for management of severe influenza infection requiring orotracheal intubation for invasive mechanical ventilation

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Patients over 18 years of age
2. Confirmed severe influenza infection requiring intensive care with tracheal intubation for invasive mechanical ventilation (influenza ARDS with or without bacterial co-infection, cardiorespiratory decompensation of influenza origin, influenza myocarditis)
3. Oseltamivir treatment administered through a gastric tube initiated since less than 24 hours (i.e. maximum two doses administered)
4. Affiliation to a social security scheme, beneficiary or beneficiary entitled (excluding AME)
5. Patient or, by default, a trusted support person or, by default, an informed family member who has given written consent or patient who has been included in emergency procedures.

Exclusion criteria 9

1. Pregnant or breastfeeding woman
2. Patient deprived of liberty or under legal protection (guardianship or curatorship)
3. For patients not included in emergency situations: Inability, according to the investigator, to understand or refusal to sign the informed consent to participate in the study (non-French-speaking patient).
4. Weight less than 40 kg
5. Previous treatment with Zanamivir or other antiviral treatment active against influenza virus for more than 24 hours
6. Co-infection with another respiratory virus (including SARS CoV-2)
7. Administration of medication via nasogastric tube impossible
8. Current participation in a therapeutic interventional trial or be in the exclusion period at the end of a clinical trial (drugs that may interact with paracetamol or oseltamivir)
9. Patient benefiting from AME (Aide Médicale d'Etat)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is the number of days alive without invasive mechanical ventilation at D28.

Secondary endpoints 7

1. Diagnostic performance of the paracetamol absorption test (sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios) performed at H48 for the diagnosis of plasma oseltamivir underdosing.
2. Prevalence of patients with low plasma OC concentration
3. Plasma OC underdosage at H48 (dependent variable); the independent variables are the clinical and biological data present on admission, which will be studied as prognostic factors for OC underdosage using univariate and multivariate logistic regression models.
4. Viral clearance, calculated from nasopharyngeal viral load measurements taken on D1 (initial influenza diagnostic test) and D5. The association between viral clearance and plasma OC concentration at H48 will be assessed.
5. Prevalence of acquisition of the H275Y oseltamivir resistance mutation (investigated by PCR and high-throughput sequencing).
6. Measurements of Cmax and Residual OC and oseltamivir phosphate (OP, inactive prodrug) at D2, D3 and D5
7. Mortality at D28 and D90 in patients under-dosed in OC at 48h of treatment initiation and in patients not under-dosed

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Coordinating investigator - Dr Anne-Fleur Haudebourg

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Coordinating investigator - Dr Anne-Fleur Haudebourg

Locations

1 EU/EEA country · 28 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications