A pHase III cluster randomIsed controlled, cross-over, non-inferiority Trial of a short course, High dose AntimicRobials vs conventional dose and Duration in critically ill patients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitair Ziekenhuis Gent

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

1 Jul 2025 → ongoing

Decision date (initial)

2025-04-18

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

UNIVERSITY HOSPITAL GHENT · BELGIAN HEALTH CARE KNOWLEDGE CENTRE (“KCE”) · ZONMW

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To determine the non-inferiority of a short course, high dose antimicrobial therapy in critically ill patients with pneumonia, intra-abdominal infection (IAI) or bloodstream infection (BSI) for all cause 90-day mortality.
Our primary hypothesis is that a short course, high dose antimicrobial therapy results in similar outcomes compared to conventional duration and dose, while it results in a lower exposure to antimicrobials.

Secondary objectives 5

1. • To determine, in critically ill patients with pneumonia, intra-abdominal infection (IAI) or bloodstream infection (BSI), if short course, high dose antimicrobial therapy is superior to conventional duration and dose, for total quantity antimicrobial use, DOTs, clinical cure, number of organ support free days, and ICU length of stay.
2. • To compare all-cause hospital/ICU mortality, DDDs, recurrence of infection, emergence of antimicrobial resistance during and after ICU admission in critically ill patients with pneumonia, intra-abdominal infection (IAI) or bloodstream infection (BSI) between participants with a high dose antimicrobial therapy to conventional duration and dose. Antimicrobial resistance will be evaluated at day 28 based on available data obtained via routine laboratory tests and MDR pathogens identified.To assess the safety of short course, high dose antimicrobial therapy in critically ill patients with pneumonia, IAI, or BSI.
3. • To assess the safety of short course, high dose antimicrobial therapy in critically ill patients with pneumonia, IAI, or BSI.
4. • To estimate the incremental cost-effectiveness of a short course, high dose antimicrobial therapy compared to conventional dose and duration from a medical perspective.
5. • To gain further insight into antibiotic exposure and inter-patient variability following higher doses of beta-lactam antibiotics and the possible relation between exposure and toxicity.

Conditions and MedDRA coding

Bacterial infections and mycoses

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Age ≥18 years.
2. Patient with (suspicion of) community acquired pneumonia (CAP) or hospital acquired pneumonia (HAP) or ventilator acquired pneumonia (VAP) or intra- abdominal infection (IAI) or bloodstream infection (BSI) for which one of the following antimicrobials has been prescribed or has been commenced: ceftriaxone, cefotaxime, cefuroxime, piperacillin- tazobactam or meropenem. To note: The beta lactam antimicrobial is considered the pivotal antibiotic in a multidrug strategy: co-administration of other – non-study – antibiotics in standard dosage, e.g. to expand the spectrum of the empirical therapy (e.g. vancomycin, aminoglycosides), or because they are recommended in guidelines (e.g. macrolides) is allowed; these antimicrobials will be dosed as per local practice, and data will be collected.
3. Treatment may be empirical or targeted (I.e. based on culture results)
4. Patients must be admitted to the ICU and have to be expected to be hospitalized in the ICU until at least the day after tomorrow.
5. Administering study related antimicrobials using either a short course, high dose treatment or conventional dose and duration treatment, are considered appropriate for the patient. To note: Patients with infections that require a (according to prevailing guidelines) higher than standard dose, or require a longer duration, e.g. endocarditis, Staphylococcus aureus bacteraemia or prosthetic joint infection, osteomyelitis... (non-limitative list) are therefore not to be included. Also patients in who(m) source control is evidently not achieved, cannot be included. Of course, some patients may be included but then need to ‘drop out’ because one of the above-mentioned diagnoses becomes apparent during the course of therapy e.g. S. aureus is cultured from blood in a patient with CAP. This will lead to secondary exclusion of the patient (“drop out”).
6. One or more organ dysfunction criteria in the previous 24 hours and ongoing: - MAP < 60mmHg for at least 1 hours. - Vasopressor required for > 4 hours. - Respiratory support using supplemental high flow nasal oxygen, continuous positive airway pressure, bilevel positive airway pressure or invasive mechanical ventilation for at least 1 hour. - Serum creatinine concentration > 220µmol/L or >2.49 mg/dL.

Exclusion criteria 8

1. Patient is known or suspected to be pregnant.
2. Patient has received the study related antimicrobial for more than 12 hours prior to inclusion in the study.
3. Patient has a proven severe allergy for one of the study antibiotics. To note:In case of a documented non-severe (suspected) allergy for one of the study antibiotics: choice of antibiotic according to local protocol, on discretion of the treating physician.
4. The attending physician or patient or legal representative is not committed to full active treatment. To note: Limitation of cardiopulmonary resuscitation (CPR) only is not an exclusion criterium.
5. The patient is treated for an infection that requires a higher than standard dose or longer than the CONTROL strategy. To note: Patients with infections that require a (according to prevailing guidelines) higher than standard dose, or require a longer duration, e.g. endocarditis, Staphylococcus aureus bacteraemia or prosthetic joint infection, osteomyelitis... (non-limitative list) are therefore not to be included. Also patients in who(m) source control is evidently not achieved, cannot be included. Of course, some patients may be included but then need to ‘drop out’ because one of the above-mentioned diagnoses becomes apparent during the course of therapy e.g. S. aureus is cultured from blood in a patient with CAP. This will lead to secondary exclusion of the patient (“drop out”).
6. The patient has previously been enrolled in the HIT-HARD study.
7. Use of the study related antimicrobial as prophylactic therapy administered as the IV component of SDD strategy, without proven infection. Oral / enteral components of SDD may be used in patients included in the HITHARD study, as long as the pivotal study antibiotic is administered because of an infection as per the inclusion criteria.
8. Patient is requiring renal replacement therapy at the time of randomisation, including renal replacement therapy for chronic kidney disease.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. All-cause mortality within 90 days after inclusion.

Secondary endpoints 13

1. All-cause ICU mortality.
2. All-cause hospital mortality.
3. New colonization or infection with a multi-resistant organism (MRSA, VRE, MDR P. aeruginosa, CRE, ESBL Enterobacterales, Acinetobacter baumannii) or C. difficile diarrhea/infection up to 28 days post inclusion.
4. Antimicrobial free days.
5. Recurrence of infection.
6. Toxicity.
7. Health related quality of life (EQ-5D-5L measured at D90).
8. Exposure.
9. Clinical cure
10. 10. ICU length of stay
11. 11. Hospital length of stay
12. 12. Organ support free days
13. 13. DDDs and DOTs

Investigational products

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

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitair Ziekenhuis Gent

Sponsor organisation

Universitair Ziekenhuis Gent

Address

Corneel Heymanslaan 10

City

Gent

Postcode

9000

Country

Belgium

Scientific contact point

Organisation

Universitair Ziekenhuis Gent

Contact name

Prof. dr. Jan De Waele

Public contact point

Organisation

Universitair Ziekenhuis Gent

Contact name

Prof. dr. Jan De Waele

Locations

2 EU/EEA countries · 14 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 35 files

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

Application history

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