Clinical trial NCT05199324: Early Oral Step-down Antibiotic Therapy for Uncomplicated Gram-negative Bacteraemia
Official title: Early Oral Step-down Antibiotic Therapy Versus Continuing Intravenous Therapy for Uncomplicated Gram-negative Bacteraemia (the INVEST Trial)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Gram-negative Bacteraemia
Keywords: Gram-negative bacteraemia
Early stepdown to oral antibiotics
Oral fluoroquinolones
Oral trimethoprim-sulfamethoxazole
Continuing intravenous antibiotics
Health economic evaluation
Lead sponsor: Tan Tock Seng Hospital
Sponsor class: OTHER
Collaborators: name: Singapore Clinical Research Institute, Singapore
name: National University Hospital, Singapore
name: Singapore General Hospital
name: Changi General Hospital
name: Ng Teng Fong General Hospital, Singapore
name: Sengkang General Hospital, Singapore
name: Royal Brisbane and Women's Hospital, Australia
name: Royal Melbourne Hospital, Australia
name: University Malaya Medical Centre, Malaysia
name: Samsung Medical Center, South Korea
name: Princess Alexandra Hospital, Australia
name: Gold Coast University Hospital, Australia
name: Ampang Hospital, Malaysia
name: Sungai Buloh Hospital, Malaysia
name: Universiti Kebangsaan Medical Centre, Malaysia
name: Medipol Mega University Hospital, Turkey
name: Rambam Hospital, Israel
name: Sheba Medical Centre, Israel
name: IRCCS Policlinico di Sant'Orsola, University Alma Mater Studiorum of Bologna, Italy
name: Monaldi Hospital, Italy
name: University Hospital of Pisa, Italy
name: IRCCS San Raffaele
name: University General Hospital of Patras, Greece
name: Hospital del Mar, Parc de Salut MAR, Spain
name: American University of Beirut Medical Center
First posted: 2022-01-20
Enrollment: 720
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Current management of uncomplicated Gram-negative bacteraemia entails prolong intravenous (IV) antibiotic therapy with limited evidence to guide oral conversion. This trial aim to evaluate the clinical efficacy and economic impact of early step-down to oral antibiotics (within 72 hours from index blood culture collection) versus continuing standard of care IV therapy (for at least another 24 hours post-randomisation) for clinically stable / non-critically ill inpatients with uncomplicated Gram-negative bacteraemia.

Detailed description: This is an international, multicentre, randomised controlled, open-label, phase IV, non-inferiority trial with a non-inferiority margin of 6%. Eligible participants must be clinically stable / non-critically ill inpatients over the age of 18 years old (in Singapore, 21 years and above) with uncomplicated Gram-negative bacteraemia. Randomisation into the intervention or standard arms will be performed with 1:1 allocation ratio according to a randomisation list prepared in advance using a secure online randomisation system. Randomisation will be stratified by country and random sequence will be generated using random permuted blocks of unequal length. Participants randomised to the intervention arm (within 72 hours from index blood culture collection) will be immediately converted to oral fluoroquinolones (most commonly, ciprofloxacin) or oral trimethoprim-sulfamethoxazole. In the event of microbiological or clinical failure of the oral antibiotic treatment, escalation to IV antibiotics may be initiated at any time point post-randomisation. Participants randomised to the standard arm should continue to receive an active IV therapy for at least another 24 hours post-randomisation before clinical re-assessment and decision making by the treating doctor. All the study drugs (and dosage) would be routinely used in clinical practice and will be ordered/dispensed from the hospital pharmacy as per site institutional practice. The recommended treatment duration by the study team is 7 days of active antibiotics (including empiric therapy), although treatment regimen may be longer than 7 days if clinically indicated. Participants may be discharged home or to OPAT at any time post-randomisation.

Eligibility criteria: Inclusion Criteria:

1. One or more set(s) of blood cultures positive for Gram-negative bacteria (GNB) associated with evidence of infection
2. Able to be randomised within 72 hours of index blood culture collection
3. Age ≥18 years (≥21 in Singapore)
4. Latest Pitt bacteraemia score \<4
5. Patient or legal representative is able to provide informed consent

Exclusion Criteria:

1. Established uncontrolled focus of infection, including but not limited to:

   * Undrained abdominal abscess, deep seated intra-abdominal infection and other unresolved abdominal sources requiring surgical intervention
   * Central nervous system abscess (patients with focal neurology should have cranial CT prior to enrolment)
   * Undrained moderate-to-severe hydronephrosis
2. Complicated infections, including but not limited to:

   * Necrotising fasciitis
   * Empyema
   * Central nervous system infections and meningitis
   * Endocarditis / endovascular infections
3. Septic shock as defined by systolic blood pressure \<90 or mean arterial pressure \<70 mmHg despite adequate fluid resuscitation or need for inotropic/vasopressor support
4. Polymicrobial bacteraemia involving Gram-positive pathogens or anaerobes (defined as either growth of 2 or more different microorganism species in the same blood culture, or growth of different species in 2 or more separate blood cultures within the same episode \[\<48 hours\] and with clinical or microbiological evidence of the same source)
5. Bacteraemia is due to a vascular catheter or intravascular materials (e.g. pacing wire, vascular graft) that cannot be removed
6. Specific Gram-negative pathogens that cannot be effectively treated with fluoroquinolones or trimethoprim-sulfamethoxazole, including but not limited to, Burkholderia spp. and Brucella spp.
7. Index GNB with resistance to fluoroquinolones AND trimethoprim-sulfamethoxazole
8. Hypersensitivity to fluoroquinolones AND sulphur drugs as defined by history of rash, urticaria, angioedema, bronchospasm, circulatory collapse or significant adverse reaction following prior administration
9. Unable to consume or absorb oral medications for any reason or unsuitable for ongoing IV therapy (e.g. no intravenous access)
10. Severely immunocompromised in the opinion of the treating doctor, including but not limited to, medical conditions such as:

    * Active leukaemia or lymphoma
    * Aplastic anaemia
    * Bone marrow transplant within two years of transplantation or transplants of longer duration still on immunosuppressive drugs or with graft-versus-host disease
    * Congenital immunodeficiency
    * HIV/AIDS with CD4 lymphocyte count \<200
    * Neutropenia or expected post-chemotherapy neutropenia within 14 days from the time of screening, defined as absolute neutrophil count \< 500 cells/μL
11. Women who are known to be pregnant or breast-feeding
12. Treatment is not with intent to cure the infection (i.e. palliative care)
13. Unable to collect patient's follow-up data for at least 30 days post-randomisation for any reason
14. Treating doctor deems enrolment into the trial is not in the best interest of the patient
15. Previous enrolment in this trial

Primary outcomes:
measure: 30-day mortality
timeFrame: 30 days
Secondary outcomes:
measure: 14-day and 90-day mortality
timeFrame: 90 days
measure: Duration of survival by day 90
timeFrame: 90 days
measure: Number of days on IV antibiotic therapy in the total index hospitalisation
timeFrame: 90 days
measure: Number of days alive and free of antibiotics by day 90
timeFrame: 90 days
measure: Adverse events from the time of randomisation until day 90
timeFrame: 90 days
measure: Change in treatment strategy between the time of randomisation and day 30
timeFrame: 30 days
measure: Time to being discharged alive from the total index hospitalisation between the time of randomisation and day 90
timeFrame: 90 days
measure: Number of days alive and not in hospital by day 90
timeFrame: 90 days
measure: Readmission or extended hospitalisation by day 90.
timeFrame: 90 days
measure: Health economic evaluation
timeFrame: 90 days
measure: Assessment of patient's quality of life
timeFrame: 90 days
Other outcomes:
Locations:
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
Study officials:
affiliation: Tan Tock Seng Hospital
name: David Lye, MBBS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lee IR, Tong SYC, Davis JS, Paterson DL, Syed-Omar SF, Peck KR, Chung DR, Cooke GS, Libau EA, Rahman SBA, Gandhi MP, Shi L, Zheng S, Chaung J, Tan SY, Kalimuddin S, Archuleta S, Lye DC. Early oral stepdown antibiotic therapy versus continuing intravenous therapy for uncomplicated Gram-negative bacteraemia (the INVEST trial): study protocol for a multicentre, randomised controlled, open-label, phase III, non-inferiority trial. Trials. 2022 Jul 19;23(1):572. doi: 10.1186/s13063-022-06495-3.