Early Oral Step-down Antibiotic Therapy for Uncomplicated Gram-negative Bacteraemia

NCT ID: NCT05199324

Last Updated: 2023-11-24

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 720 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-04-01
• Study Completion Date: 2025-06-01

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.

Conditions

Gram-negative Bacteraemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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 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 due to regimen extension or requirement for prolonged regimen as clinically indicated.

Group Type: EXPERIMENTAL

Oral fluoroquinolones (most commonly, ciprofloxacin) or oral trimethoprim-sulfamethoxazole

Intervention Type: DRUG

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)

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 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 due to regimen extension or requirement for prolonged regimen as clinically indicated.

Group Type: ACTIVE_COMPARATOR

Standard of care intravenous antibiotics (e.g. ceftriaxone, cefazolin)

Intervention Type: DRUG

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 24 hours post-randomisation before clinical re-assessment and decision making by the treating doctor

Interventions

Oral fluoroquinolones (most commonly, ciprofloxacin) or oral trimethoprim-sulfamethoxazole

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

Standard of care intravenous antibiotics (e.g. ceftriaxone, cefazolin)

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 24 hours post-randomisation before clinical re-assessment and decision making by the treating doctor

Intervention Type: DRUG

Other Intervention Names

Fluoroquinolones (most commonly, cipro); Bactrim; Rocephin; Kefzol

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Singapore Clinical Research Institute, Singapore

UNKNOWN

Sponsor Role: collaborator

National University Hospital, Singapore

OTHER

Sponsor Role: collaborator

Singapore General Hospital

OTHER

Sponsor Role: collaborator

Changi General Hospital

OTHER

Sponsor Role: collaborator

Ng Teng Fong General Hospital, Singapore

UNKNOWN

Sponsor Role: collaborator

Sengkang General Hospital, Singapore

UNKNOWN

Sponsor Role: collaborator

Royal Brisbane and Women's Hospital, Australia

UNKNOWN

Sponsor Role: collaborator

Royal Melbourne Hospital, Australia

UNKNOWN

Sponsor Role: collaborator

University Malaya Medical Centre, Malaysia

UNKNOWN

Sponsor Role: collaborator

Samsung Medical Center, South Korea

UNKNOWN

Sponsor Role: collaborator

Princess Alexandra Hospital, Australia

UNKNOWN

Sponsor Role: collaborator

Gold Coast University Hospital, Australia

UNKNOWN

Sponsor Role: collaborator

Ampang Hospital, Malaysia

UNKNOWN

Sponsor Role: collaborator

Sungai Buloh Hospital, Malaysia

UNKNOWN

Sponsor Role: collaborator

Universiti Kebangsaan Medical Centre, Malaysia

UNKNOWN

Sponsor Role: collaborator

Medipol Mega University Hospital, Turkey

UNKNOWN

Sponsor Role: collaborator

Rambam Hospital, Israel

UNKNOWN

Sponsor Role: collaborator

Sheba Medical Centre, Israel

UNKNOWN

Sponsor Role: collaborator

IRCCS Policlinico di Sant'Orsola, University Alma Mater Studiorum of Bologna, Italy

UNKNOWN

Sponsor Role: collaborator

Monaldi Hospital, Italy

UNKNOWN

Sponsor Role: collaborator

University Hospital of Pisa, Italy

UNKNOWN

Sponsor Role: collaborator

IRCCS San Raffaele

OTHER

Sponsor Role: collaborator

University General Hospital of Patras, Greece

UNKNOWN

Sponsor Role: collaborator

Hospital del Mar, Parc de Salut MAR, Spain

UNKNOWN

Sponsor Role: collaborator

American University of Beirut Medical Center

OTHER

Sponsor Role: collaborator

Tan Tock Seng Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David Lye, MBBS

Role: PRINCIPAL_INVESTIGATOR

Tan Tock Seng Hospital

Locations

Tan Tock Seng Hospital

Singapore, , Singapore

Site Status: RECRUITING

Countries

Singapore

Central Contacts

David Lye, MBBS

Role: CONTACT

David_Lye@ncid.sg

63577457

Russel Lee, PhD

Role: CONTACT

ivor_russel_mc_lee@ncid.sg

65115060

Facility Contacts

David Lye, MBBS

Role: primary

david_lye@ttsh.com.sg

63577457

References

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.

Reference Type: DERIVED

PMID: 35854360 (View on PubMed)

Other Identifiers

DSRB 2021/00764

Identifier Type: -

Identifier Source: org_study_id