- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05199324
Early Oral Step-down Antibiotic Therapy for Uncomplicated Gram-negative Bacteraemia
June 27, 2022 updated by: Tan Tock Seng Hospital
Early Oral Step-down Antibiotic Therapy Versus Continuing Intravenous Therapy for Uncomplicated Gram-negative Bacteraemia (the INVEST Trial)
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.
Study Overview
Status
Recruiting
Conditions
Detailed Description
This is an international, multicentre, randomised controlled, open-label, phase III, 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 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 minimum treatment duration should be 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.
Study Type
Interventional
Enrollment (Anticipated)
720
Phase
- Phase 3
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Contact
- Name: David Lye, MBBS
- Phone Number: 63577457
- Email: David_Lye@ncid.sg
Study Contact Backup
- Name: Russel Lee, PhD
- Phone Number: 65115060
- Email: ivor_russel_mc_lee@ncid.sg
Study Locations
-
-
-
Singapore, Singapore, 308433
- Recruiting
- Tan Tock Seng Hospital
-
Contact:
- David Lye, MBBS
- Phone Number: 63577457
- Email: david_lye@ttsh.com.sg
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 99 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- One or more set(s) of blood cultures positive for Gram-negative bacteria (GNB) associated with evidence of infection
- Able to be randomised within 72 hours of index blood culture collection
- Age ≥18 years (≥21 in Singapore)
- Latest Pitt bacteraemia score <4
- Patient or legal representative is able to provide informed consent
Exclusion Criteria:
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 computed tomography scan prior to enrolment)
- Undrained moderate-to-severe hydronephrosis
Complicated infections, including but not limited to:
- Necrotising fasciitis
- Empyema
- Central nervous system infections and meningitis
- Endocarditis / endovascular infections
- Sepsis as defined by infection with consequent acute organ dysfunction or septic shock as defined by systolic blood pressure <90 or mean arterial pressure <70 mmHg despite adequate fluid resuscitation
- Polymicrobial bacteraemia involving Gram-positive pathogens or anaerobes (defined as either growth of 2 different microorganism species in the same blood culture, or growth of different species in 2 separate blood cultures within the same episode [<48 hours] and with clinical or microbiological evidence of the same source)
- Bacteraemia is due to a vascular catheter or intravascular materials (e.g. pacing wire, vascular graft) that cannot be removed
- Specific Gram-negative pathogens that cannot be effectively treated with fluoroquinolones or trimethoprim-sulfamethoxazole, including but not limited to, Burkholderia spp. and Brucella spp.
- Index GNB with resistance to fluoroquinolones AND trimethoprim-sulfamethoxazole
- Hypersensitivity to fluoroquinolones AND sulphur drugs as defined by history of rash, urticaria, angiodema, bronchospasm, circulatory collapse or significant adverse reaction following prior administration
- Unable to consume or absorb oral medications for any reason or unsuitable for ongoing intravenous therapy (e.g. no intravenous access)
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
- Current radiation therapy
- 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
- Women who are known to be pregnant or breast-feeding
- Treatment is not with intent to cure the infection (i.e. palliative care)
- Unable to collect patient's follow-up data for at least 30 days post-randomisation for any reason
- Treating doctor deems enrolment into the trial is not in the best interest of the patient
- Previous enrolment in this trial
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Early step-down to oral antibiotic therapy
The oral antibiotic options are fluoroquinolones (most commonly, ciprofloxacin) or trimethoprim-sulfamethoxazole.
The recommended doses for patients with normal renal function would be ciprofloxacin 750 mg twice daily (if body weight ≥70 kg) or ciprofloxacin 500 mg twice daily (if body weight <70 kg) or trimethoprim-sulfamethoxazole 5 mg/kg (for trimethoprim component) every 12 hourly or trimethoprim-sulfamethoxazole (160 mg / 800 mg; double strength) two tablets twice daily.
Doses may be adjusted in the setting of renal dysfunction.
The minimum treatment duration should be 7 days of active antibiotics (including empiric therapy), although treatment regimen may be longer than 7 days due to regimen extension or requirement for prolonged regimen as clinically indicated.
|
Clinically stable / non-critically ill inpatients with uncomplicated Gram-negative bacteraemia randomised to the intervention arm will be switched early to oral antibiotics (within 72 hours from index blood culture collection)
Other Names:
|
Active Comparator: Continuing intravenous antibiotic therapy
The intravenous antibiotic(s) to be administered will be determined by the treating doctor according to what would be considered standard of care in the hospital site.
Commonly used intravenous antibiotics (and doses) for treatment of Gram-negative bacteraemia include ceftriaxone 2 g daily or cefazolin 2 g three times daily.
The minimum treatment duration should be 7 days of active antibiotics (including empiric therapy), although treatment regimen may be longer than 7 days due to regimen extension or requirement for prolonged regimen as clinically indicated.
|
Clinically stable / non-critically ill inpatients with uncomplicated Gram-negative bacteraemia randomised to the standard arm will continue to receive an active intravenous antibiotic therapy for at least another 48 hours post-randomisation before clinical re-assessment and decision making by the treating doctor
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
30-day mortality
Time Frame: 30 days
|
All-cause mortality at day 30 post-randomisation
|
30 days
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
14-day and 90-day mortality
Time Frame: 90 days
|
All-cause mortality at days 14 and 90 from the time of randomisation
|
90 days
|
Duration of survival by day 90
Time Frame: 90 days
|
Duration of survival (in days) from the time of randomisation until day 90
|
90 days
|
Number of days on IV antibiotic therapy in the total index hospitalisation
Time Frame: 90 days
|
Number of days on IV antibiotic therapy in the total index hospitalisation (including outpatient parenteral antibiotic therapy [OPAT]) for surviving participants from the time of randomisation until i. hospital discharge and ii.
day 90
|
90 days
|
Number of days alive and free of antibiotics by day 90
Time Frame: 90 days
|
Number of days alive and free of antibiotics (i. for all antibiotics and ii. for IV antibiotics) between the time of randomisation and day 90
|
90 days
|
Adverse events from the time of randomisation until day 90
Time Frame: 90 days
|
Solicited adverse events include Clostridioides difficile-associated diarrhoea, peripherally inserted central catheter and other central venous catheter complications (such as catheter-related bloodstream infection, catheter-related superficial or deep venous thrombosis/thrombophlebitis, catheter blockage, and exit site infection) requiring line removal during index hospitalisation (including OPAT) from the time of randomisation, and liver function test abnormalities or acute kidney injury
|
90 days
|
Change in treatment strategy between the time of randomisation and day 30
Time Frame: 30 days
|
Change in treatment strategy (e.g.
switch to IV antibiotics from allocated oral antibiotics or vice versa) between the time of randomisation and day 30 due to: (i) an adverse event deemed by the treating doctor to be of sufficient severity to change treatment strategy, or (ii) presumed lack of efficacy of treatment strategy according to the judgement of treating doctor
|
30 days
|
Time to being discharged alive from the total index hospitalisation between the time of randomisation and day 90
Time Frame: 90 days
|
Time to being discharged alive from the total index hospitalisation (including OPAT and hospital in the home) between the time of randomisation and day 90 (note: any death occurrence within 90 days will be considered '90 days')
|
90 days
|
Number of days alive and not in hospital by day 90
Time Frame: 90 days
|
Number of days alive and not in hospital (including OPAT) between the time of randomisation and day 90
|
90 days
|
Readmission or extended hospitalisation by day 90.
Time Frame: 90 days
|
Readmission is defined as a new hospitalisation for any cause occurring after discharge from the index hospitalisation.
Extended hospitalisation is defined as >14 days of hospital LOS starting from the day of randomisation.
|
90 days
|
Health economics evaluation
Time Frame: 90 days
|
Health economics evaluation includes calculation of estimated total healthcare cost (from healthcare system and patient perspective) by day 90
|
90 days
|
Assessment of patient's quality of life
Time Frame: 90 days
|
Assessment of patient's quality of life via EQ-5D or WHOQoL-BREF on screening day, end of treatment day, and day 90
|
90 days
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Principal Investigator: David Lye, MBBS, Tan Tock Seng Hospital
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
April 1, 2022
Primary Completion (Anticipated)
January 1, 2025
Study Completion (Anticipated)
March 1, 2025
Study Registration Dates
First Submitted
December 21, 2021
First Submitted That Met QC Criteria
January 16, 2022
First Posted (Actual)
January 20, 2022
Study Record Updates
Last Update Posted (Actual)
July 1, 2022
Last Update Submitted That Met QC Criteria
June 27, 2022
Last Verified
June 1, 2022
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Infections
- Systemic Inflammatory Response Syndrome
- Inflammation
- Bacterial Infections
- Bacterial Infections and Mycoses
- Sepsis
- Bacteremia
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Antineoplastic Agents
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Cytochrome P-450 Enzyme Inhibitors
- Antiprotozoal Agents
- Antiparasitic Agents
- Antimalarials
- Folic Acid Antagonists
- Cytochrome P-450 CYP1A2 Inhibitors
- Anti-Dyskinesia Agents
- Anti-Infective Agents, Urinary
- Renal Agents
- Cytochrome P-450 CYP2C8 Inhibitors
- Ceftriaxone
- Anti-Bacterial Agents
- Ciprofloxacin
- Cefazolin
- Fluoroquinolones
- Trimethoprim
- Sulfamethoxazole
- Trimethoprim, Sulfamethoxazole Drug Combination
Other Study ID Numbers
- DSRB 2021/00764
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
NO
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
No
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Gram-negative Bacteraemia
-
Hamad Medical CorporationCompletedEscherichia Coli Bacteremia | Klebsiella Bacteraemia | Enterobacter Bacteraemia | Serratia Bacteraemia | Citrobacter Bacteraemia | Proteus BacteraemiaQatar, Turkey, Bahrain, Kuwait
-
University of Geneva, SwitzerlandCentre Hospitalier Universitaire Vaudois; Cantonal Hospital of St. GallenCompletedBacteraemia Caused by Gram-Negative BacteriaSwitzerland
-
University of PittsburghCompletedGram Negative OrganismUnited States
-
Seoul National University HospitalCompletedMultidrug-resistant Gram-negative Bacteria InfectionKorea, Republic of
-
Poitiers University HospitalCompletedGram-negative BacteriaFrance
-
Assistance Publique - Hôpitaux de ParisCompletedOropharyngeal Gram-negative Bacilli ColonizationFrance
-
Assistance Publique - Hôpitaux de ParisCompletedOropharyngeal Gram-negative Bacilli ColonizationFrance
-
University of PittsburghMerck Sharp & Dohme LLCWithdrawnSurveillance Study - Incidence of Antibiotic Resistance in Serial Gram-negative Bloodstream IsolatesGram-negative Bacterial InfectionsUnited States
-
Hoffmann-La RocheCompletedGram-negative Bacterial InfectionsUnited States
-
University of PittsburghCelgene CorporationCompletedGram-negative Bacterial InfectionsUnited States
Clinical Trials on Oral fluoroquinolones (most commonly, ciprofloxacin) or oral trimethoprim-sulfamethoxazole
-
PfizerForest LaboratoriesCompletedComplicated Urinary Tract Infection (cUTI) Including Acute PyelonephritisCroatia, Brazil, Bulgaria, Korea, Republic of, Russian Federation, Hungary, Poland, Romania, Ukraine, Argentina, Israel, Portugal, Greece, Taiwan, Japan, Slovakia, Serbia, United States, Mexico, Germany, Turkey, Czechia
-
PfizerForest LaboratoriesCompletedComplicated Urinary Tract Infection (cUTI) Including Acute PyelonephritisCroatia, Bulgaria, Korea, Republic of, Mexico, Peru, Poland, Russian Federation, Spain, Romania, Ukraine, United States, Argentina, Czechia, Israel, Taiwan, Germany, Italy
-
University of MonastirCompletedSepsis | Chronic Obstructive Pulmonary Disease | Antibiotics
-
Fundacion Clinic per a la Recerca BiomédicaNot yet recruitingEndocarditis InfectiveSpain
-
Instituto Nacional de Ciencias Medicas y Nutricion...National Council of Science and Technology, MexicoUnknownLupus Erythematosus, SystemicMexico
-
Johns Hopkins UniversityWithdrawnBacteriuria | Antibiotic Resistant Infection | Microtia | UTI | Antibiotics Causing Adverse Effects in Therapeutic Use
-
Array Biopharma, now a wholly owned subsidiary...CompletedFallopian Tube Cancer | Epithelial Ovarian Cancer | Peritoneal CancerUnited States
-
Baylor College of MedicineCompleted
-
St. Joseph's Hospital and Medical Center, PhoenixThe Cleveland Clinic; Thomas Jefferson UniversityRecruitingPituitary Adenoma | AntibioticsUnited States
-
University College, LondonNational Institute for Health Research, United KingdomActive, not recruitingSpontaneous Bacterial PeritonitisUnited Kingdom