Dexamethasone for treating severe hospital-acquired pneumonia in critically ill patients with a proinflammatory phenotype, an international phase III, double-blind, placebo-controlled, randomized trial - the HAP-DEX study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Nantes

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

Trial duration

26 Mar 2024 → ongoing

Decision date (initial)

2025-06-23

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

European Commission

External identifiers

EU CT number

2023-508153-12-00

ClinicalTrials.gov

NCT06269900

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The primary objective of this randomized trial is to determine the efficacy of dexamethasone plus standard of care (SOC) as compared to placebo plus SOC for the treatment of severe hospital-acquired pneumonia in patients with a pro-inflammatory profile.

Secondary objectives 6

1. To demonstrate the efficacy of dexamethasone on pneumonia-associated morbidity and mortality reduction
2. To describe the safety of dexamethasone.
3. To assess the economic efficiency of dexamethasone.
4. To assess the suitability and acceptability of dexamethasone from the patients’ perspectives.
5. To develop biomarkers for the stratification of patients into responders and non-responders to dexamethasone.
6. To create a biobank of blood and respiratory samples collected from humans with hospital-acquired pneumonia. Increasing the number of available samples is required to increase the statistical power of studies which use high-throughput analyses to develop biomarkers for HAP predictions and improve knowledge about HAP pathophysiology. Indeed, omics produce millions of information in each sample, so many samples and patients are needed to control statistical risks.

Conditions and MedDRA coding

Hospital-acquired pneumonia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Adult patients (18yr to 85yr)
2. Hospital-acquired pneumonia (HAP) according to European guidelines (Torres et al. Eur Respir J 2017): Association of two criteria among (body temperature > 38°C,leukocytosis>12000 cells per mL, leucopenia <4000 cells per mL and purulent pulmonary secretions), appearance of a new infiltrate or change in an existing infiltrate on chest radiography, and respiratory sample (Sputum, AET, BAL, mini–BAL or blind BAL) collected for bacteriological diagnosis (results can be pending at inclusion). The diagnosis of HAP can have been made outside of ICU. Diagnosis is done at least 48 hours after hospital admission.
3. HAP severity defined as a PaO2/FiO2 ratio < 300 under mechanical ventilation.
4. Biological systemic inflammatory response defined as CPR≥ 150 mg/L (15 mg/dL)
5. Receiving curative antimicrobial therapy for the current episode of HAP pneumonia for less than 48 hours.
6. Informed consent from a legal representative, or emergency procedure (when possible, according to national regulation, see below). If it is not possible to obtain the patient consent prior the inclusion (comatose patients), patient consent for the study continuation will be obtained as soon as deemed possible.
7. Person insured under a health insurance scheme.
8. Female of childbearing age who agree and who are able to comply with effective contraception for the 28 first days of the study: sexual abstinence, use of a condom with spermicide, contraceptive sponge, uterine diaphragm, hormonal contraception, or intrauterine contraceptive device

Exclusion criteria 10

1. Pregnant women (serum or urine test), breastfeeding women.
2. Patients not expected to survive for more than 48 hours
3. Severe septic shock (norepinephrine > 0.4 microg/kg/min and serum lactate level greater than 2 mmol/L) at the time of randomisation
4. Patient under legal protection (incl. under guardianship or trusteeship).
5. Hypersensitivity to dexamethasone and hypersensitivity to all of its excipients
6. Ongoing administration of glucocorticoid at the time of randomisation.
7. Prolonged use of corticosteroids at a mean minimum dose of 0.3 mg/kg/day of prednisone equivalent for >3 weeks in the past 60 days
8. Uncontrolled viral (hepatitis, zona,herpes, varicella) or systemic fungal infection
9. Immunosuppression pre existing to hospitalisation (severe lymphopenia < 500 lymphocytes/mm3, hematologic cancer, aplasia, chemotherapy/radiotherapy for cancer within 3 months prior to the inclusion, or anti-graft rejection drug).
10. Uncontrolled psychotic disorder (acute or chronical)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The co-primary hierarchic endpoints to demonstrate the efficacy of dexamethasone plus SOC compared to placebo plus SOC for the treatment of hospital-acquired pneumonia will be a clinical cure at the test-of-cure (TOC) visit and all-cause mortality at Day 28.

Secondary endpoints 18

1. In case of a non-significant difference in the rate of clinical cure, the co-primary outcome (all-cause mortality at Day 28) will be presented as a secondary outcome.
2. All-cause mortality at Month 3 and Month 6.
3. Rate of pleural empyema at Day 28.
4. Rate of microbiological failure (defined as a positive respiratory culture at the ToC visit).
5. Rate of pneumonia relapse (defined as a second episode of HAP with one or more identical pathogens), rate of pneumonia recurrence (defined as a second episode of HAP with different pathogens) at Day 28.
6. Time course of body temperature, cardiac pulse rate, oxygen saturation, PaO2/FiO2, type of mechanical ventilation support (invasive, noninvasive, none) (daily evaluation at 8.00 am and 8.00 pm), and leukocyte counts (every 48 hours) for 10 days.
7. Rates of non-respiratory hospital-acquired infection at day 28: urinary tract infection, surgical site infection, invasive candidiasis, septicemia.
8. Antibiotic-free days at Day 28 (the number of antibiotic-free days is defined as the number of days between Day 1 and Day 28 for which living patients do not receive antibiotics. Dead patients will be ascribed 0 antibiotic-free days).
9. Duration of invasive mechanical ventilation and invasive mechanical ventilation-free days at Month 6 (defined as the number of days between Day 1 and Month 6 for which living patients breathe spontaneously. Dead patients will be ascribed 0 mechanical ventilation-free days).
10. Duration of hospitalization and hospital-free days at Month 6 (the number of hospital-free days is defined as the number of days between Day 1 and Month 6 for which living patients are outside of a hospital. Dead patients will be ascribed 0 hospital-free days).
11. Rate of serious adverse reactions and suspected unexpected serious adverse reaction (SUSAR) at Day 28.
12. Rate of metabolic adverse events during the 5-7-day treatment period (number of days with a blood level of potassium < 3.5 mmol/l, number of days with of sodium < 135 mmol/l, daily dose of insulin).
13. Rate of gastric ulcer.
14. Economic endpoints at 6 months: Incremental cost-effectiveness ratio (ICER)
15. Changes in health-related quality of life (HRQoL) from three (M3) to six months (M6) after randomization measured with the Short Form (SF)-36 scale validated in French
16. Changes in anxiety and depression from M3 to M6 were measured with the HADS scale validated in French
17. Changes in subjective well-being from M3 to M6 measured with the Satisfaction With Life Scale (SWLS) validated in French
18. Rates of major cardiovascular events at Day 28: subsegmental pulmonary embolism, stroke, myocardial infarction (positive ST segment).

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Nantes

Sponsor organisation

Centre Hospitalier Universitaire De Nantes

Address

5 Allee De L Ile Gloriette, Cs 69301 Cs 69301

City

Nantes Cedex 1

Postcode

44093

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Nantes

Contact name

Antoine Roquilly

Public contact point

Organisation

Centre Hospitalier Universitaire De Nantes

Contact name

Antoine Roquilly

Third parties 1

Locations

4 EU/EEA countries · 40 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 47 files

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

Application history

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