Back to resultsEarly Oral Step-down Antibiotic Therapy for Uncomplicated Gram-negative Bacteraemia
Primary Purpose
Gram-negative Bacteraemia
Status
Recruiting
Phase
Phase 3
Locations
Singapore
Study Type
Interventional
Intervention
Oral fluoroquinolones (most commonly, ciprofloxacin) or oral trimethoprim-sulfamethoxazole
Standard of care intravenous antibiotics (e.g. ceftriaxone, cefazolin)
Sponsored by
About this trial
This is an interventional treatment trial for Gram-negative Bacteraemia focused on measuring Gram-negative bacteraemia, Early step-down to oral antibiotics, Oral fluoroquinolones, Oral trimethoprim-sulfamethoxazole, Continuing intravenous antibiotics, Health economics evaluation
Eligibility Criteria
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
Sites / Locations
- Tan Tock Seng HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Early step-down to oral antibiotic therapy
Continuing intravenous antibiotic therapy
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
30-day mortality
All-cause mortality at day 30 post-randomisation
Secondary Outcome Measures
14-day and 90-day mortality
All-cause mortality at days 14 and 90 from the time of randomisation
Duration of survival by day 90
Duration of survival (in days) from the time of randomisation until day 90
Number of days on IV antibiotic therapy in the total index hospitalisation
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
Number of days alive and free of antibiotics by day 90
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
Adverse events from the time of randomisation until day 90
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
Change in treatment strategy between the time of randomisation and day 30
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
Time to being discharged alive from the total index hospitalisation between the time of randomisation and day 90
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')
Number of days alive and not in hospital by day 90
Number of days alive and not in hospital (including OPAT) between the time of randomisation and day 90
Readmission or extended hospitalisation by day 90.
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.
Health economics evaluation
Health economics evaluation includes calculation of estimated total healthcare cost (from healthcare system and patient perspective) by day 90
Assessment of patient's quality of life
Assessment of patient's quality of life via EQ-5D or WHOQoL-BREF on screening day, end of treatment day, and day 90
Full Information
NCT ID
NCT05199324
First Posted
December 21, 2021
Last Updated
June 27, 2022
Sponsor
Tan Tock Seng Hospital
Collaborators
Singapore Clinical Research Institute, National University Hospital, Singapore, Singapore General Hospital, Changi General Hospital, Ng Teng Fong General Hospital, Sengkang General Hospital, Royal Brisbane and Women's Hospital, John Hunter Hospital, Melbourne Health, Imperial College Healthcare NHS Trust, University of Malaya, Samsung Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT05199324
Brief Title
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
2. Study Status
Record Verification Date
June 2022
Overall Recruitment Status
Recruiting
Study Start Date
April 1, 2022 (Actual)
Primary Completion Date
January 1, 2025 (Anticipated)
Study Completion Date
March 1, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Tan Tock Seng Hospital
Collaborators
Singapore Clinical Research Institute, National University Hospital, Singapore, Singapore General Hospital, Changi General Hospital, Ng Teng Fong General Hospital, Sengkang General Hospital, Royal Brisbane and Women's Hospital, John Hunter Hospital, Melbourne Health, Imperial College Healthcare NHS Trust, University of Malaya, Samsung Medical Center
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Gram-negative Bacteraemia
Keywords
Gram-negative bacteraemia, Early step-down to oral antibiotics, Oral fluoroquinolones, Oral trimethoprim-sulfamethoxazole, Continuing intravenous antibiotics, Health economics evaluation
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
720 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Early step-down to oral antibiotic therapy
Arm Type
Experimental
Arm Description
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.
Arm Title
Continuing intravenous antibiotic therapy
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Oral fluoroquinolones (most commonly, ciprofloxacin) or oral trimethoprim-sulfamethoxazole
Other Intervention Name(s)
Fluoroquinolones (most commonly, cipro), Bactrim
Intervention Description
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)
Intervention Type
Drug
Intervention Name(s)
Standard of care intravenous antibiotics (e.g. ceftriaxone, cefazolin)
Other Intervention Name(s)
Rocephin, Kefzol
Intervention Description
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
Primary Outcome Measure Information:
Title
30-day mortality
Description
All-cause mortality at day 30 post-randomisation
Time Frame
30 days
Secondary Outcome Measure Information:
Title
14-day and 90-day mortality
Description
All-cause mortality at days 14 and 90 from the time of randomisation
Time Frame
90 days
Title
Duration of survival by day 90
Description
Duration of survival (in days) from the time of randomisation until day 90
Time Frame
90 days
Title
Number of days on IV antibiotic therapy in the total index hospitalisation
Description
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
Time Frame
90 days
Title
Number of days alive and free of antibiotics by day 90
Description
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
Time Frame
90 days
Title
Adverse events from the time of randomisation until day 90
Description
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
Time Frame
90 days
Title
Change in treatment strategy between the time of randomisation and day 30
Description
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
Time Frame
30 days
Title
Time to being discharged alive from the total index hospitalisation between the time of randomisation and day 90
Description
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')
Time Frame
90 days
Title
Number of days alive and not in hospital by day 90
Description
Number of days alive and not in hospital (including OPAT) between the time of randomisation and day 90
Time Frame
90 days
Title
Readmission or extended hospitalisation by day 90.
Description
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.
Time Frame
90 days
Title
Health economics evaluation
Description
Health economics evaluation includes calculation of estimated total healthcare cost (from healthcare system and patient perspective) by day 90
Time Frame
90 days
Title
Assessment of patient's quality of life
Description
Assessment of patient's quality of life via EQ-5D or WHOQoL-BREF on screening day, end of treatment day, and day 90
Time Frame
90 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
David Lye, MBBS
Phone
63577457
Email
David_Lye@ncid.sg
First Name & Middle Initial & Last Name or Official Title & Degree
Russel Lee, PhD
Phone
65115060
Email
ivor_russel_mc_lee@ncid.sg
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Lye, MBBS
Organizational Affiliation
Tan Tock Seng Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Tan Tock Seng Hospital
City
Singapore
ZIP/Postal Code
308433
Country
Singapore
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
David Lye, MBBS
Phone
63577457
Email
david_lye@ttsh.com.sg
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
35854360
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.
Results Reference
derived
Learn more about this trial
Early Oral Step-down Antibiotic Therapy for Uncomplicated Gram-negative Bacteraemia
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