Short course antibiotic treatment of Gram-negative bacteremia: A multicenter, randomized, non-blinded, non-inferiority interventional study

Start 25 Jul 2024 · Status Ongoing, recruiting · 1 EU/EEA countries · 7 sites · Protocol 2019-003282-17

Overview

Sponsor-declared trial summary

Phase Therapeutic use (Phase IV)

Status Ongoing, recruiting

Participants planned 380

Countries 1

Sites 7

Gram-negative Bacteremia

The aim of this study is to assess efficacy and safety of shortened antibiotic duration (5 days) in treatment of Gram-negative bacteremia with a urinary tract source of infection in hospitalized immunocompetent adults compared to 7 days or more of antibiotic treatment

Key facts

Sponsor: Region Hovedstaden
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: 25 Jul 2024 → ongoing
Decision date (initial): 2024-07-25
Transition trial: Yes
Low-intervention: Yes
Rare-disease indication: No
Vulnerable population: No

External identifiers

EU CT number: 2024-514900-16-00
EudraCT number: 2019-003282-17
ClinicalTrials.gov: NCT04291768

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

Conditions and MedDRA coding

Gram-negative Bacteremia

Version	Level	Code	Term	System organ class
20.1	LLT	10054227	Gram-negative bacteraemia	10021881
20.0	SOC	10021881	Infections and infestations	1
20.0	HLT	10046577	Urinary tract infections	10021881

Study design 1 period

#	Title	Allocation	Blinding	Roles blinded	Arms
1	5 days vs. 7 days or more Patients are randomized either to 5 days of treatment or minimum of 7 days	Randomised Controlled	None		Intervention group: 5 days of antibiotic treatment Control group: minimum of 7 days or more of antibiotic treatment

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

Age >18 years
Blood culture positive for Gram-negative bacteria
Evidence of urinary tract source of infection (positive urine culture or at least one clinical symptom compatible with urinary tract infection)
Antibiotic treatment with antimicrobial activity to Gram-negative bacteria administrated within 12 hours of first blood culture
Temperature <37.8°C at randomization
Clinically stabile at randomization (systolic blood pressure > 90 mm Hg, heart rate <100 beats/min., respiratory rate <24/minute, peripheral oxygen saturation > 90 %)
Oral and written informed consent

Exclusion criteria 7

Antibiotic treatment (>2 day) with antimicrobial activity to Gram-negative bacteria within 14 days of inclusion
Gram-negative bacteremia within 30 days of blood culture
Immunosuppression (Untreated HIV-infection, Neutropenia (absolute neutrophil count < 1.0 x 109/l), Untreated terminal cancer, Receiving immunosuppressive agents (ATC-code L04A), Corticosteroid treatment (≥20 mg/day prednisone or the equivalent for >14 days) within the last 30 days, Chemotherapy within the last 30 days, Immunosuppressed after solid organ transplantation, Asplenia)
Polymicrobial growth in blood culture
Bacteremia with non-fermenting Gram-negative bacteria (Acinetobacter spp, Burkholderia spp, Pseudomonas spp), Brucella spp, or Fusobacterium spp
Failure to remove source of infection within 72 hours of first blood culture (e.g. change of catheter á demeure)
Pregnancy or breastfeeding

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

90-day survival without clinical or microbiological failure to treatment

Secondary endpoints 12

Mortality (timeframe 14, 30 and 90 days)
Total duration of antibiotic treatment (timeframe 90 days)
Type of antibiotic treatment (timeframe 90 days)
Duration of antibiotic treatment (timeframe 90 days)
Total length of hospital stay (timeframe 90 days)
Hospital re-admission
Antibiotic adverse events (timeframe 30 and 90 days)
Use of antimicrobials after discharge (timeframe 90 days)
Severe adverse events (timeframe 90 days)
Acute kidney injury (timeframe 90 days)
Clostridioides difficile infection - Number of participants with Clostridioides difficile infection (timeframe 90 days)
Multidrug-resistance organism: Multidrug-resistance organism defined as identification of resistant bacteria in a clinical specimen obtained only from a clinical infection. (timeframe 90 days)

Investigational products

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

Test 22

Sulfametizol ”Alternova”, tabletter

PRD447627 · Product

Active substance: Sulfamethizole
Pharmaceutical form: TABLET
Route of administration: ORAL
Max daily dose: 2000 mg milligram(s)
Max total dose: 14000 mg milligram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01EB02 — SULFAMETHIZOLE
Marketing authorisation: 16510
MA holder: ALTERNOVA A/S
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Ceftazidim "Fresenius Kabi", pulver til injektionsvæske, opløsning

PRD1962874 · Product

Active substance: Ceftazidime
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: SOLUTION FOR INJECTION
Max daily dose: 3 g gram(s)
Max total dose: 21 g gram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01DD02 — -
Marketing authorisation: 42731
MA holder: FRESENIUS KABI AB
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Bioclavid, filmovertrukne tabletter

PRD769154 · Product

Active substance: Amoxicillin
Substance synonyms: AMOXICILLINE, AMOXICILLINUM
Pharmaceutical form: FILM-COATED TABLET
Route of administration: ORAL
Max daily dose: 1500 mg milligram(s)
Max total dose: 10500 mg milligram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01CR02 — AMOXICILLIN AND ENZYME INHIBITOR
Marketing authorisation: 18925
MA holder: SANDOZ GMBH
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Meropenem ”Stada”, pulver til injektions- og infusionsvæske, opløsning

PRD1864081 · Product

Active substance: Meropenem Anhydrous
Pharmaceutical form: SOLUTION FOR INJECTION/INFUSION
Route of administration: SOLUTION FOR INJECTION OR INFUSION
Max daily dose: 1500 mg milligram(s)
Max total dose: 10500 mg milligram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01DH02 — MEROPENEM
Marketing authorisation: 48869
MA holder: STADA ARZNEIMITTEL AG
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Meropenem ”Stada”, pulver til injektions- og infusionsvæske, opløsning

PRD1864074 · Product

Active substance: Meropenem Anhydrous
Pharmaceutical form: SOLUTION FOR INJECTION/INFUSION
Route of administration: SOLUTION FOR INJECTION OR INFUSION
Max daily dose: 3 g gram(s)
Max total dose: 21 g gram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01DH02 — MEROPENEM
Marketing authorisation: 48870
MA holder: STADA ARZNEIMITTEL AG
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Trimopan, filmovertrukne tabletter

PRD620953 · Product

Active substance: Trimethoprim
Pharmaceutical form: FILM-COATED TABLET
Route of administration: ORAL
Max daily dose: 400 mg milligram(s)
Max total dose: 2800 mg milligram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01EA01 — TRIMETHOPRIM
Marketing authorisation: 09204
MA holder: ORION CORPORATION
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Ampicillin "PCD", pulver til injektionsvæske, opløsning

PRD6006656 · Product

Active substance: Ampicillin
Pharmaceutical form: POWDER FOR SOLUTION FOR INJECTION
Route of administration: SOLUTION FOR INJECTION
Max daily dose: 8 g gram(s)
Max total dose: 56 g gram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01CA01 — AMPICILLIN
Marketing authorisation: 06940
MA holder: STADA NORDIC APS
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Ampicillin "PCD", pulver til injektionsvæske, opløsning

PRD6006657 · Product

Active substance: Ampicillin
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: SOLUTION FOR INJECTION
Max daily dose: 8 g gram(s)
Max total dose: 56 g gram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01CA01 — AMPICILLIN
Marketing authorisation: 06941
MA holder: STADA NORDIC APS
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Hexamycin, injektionsvæske, opløsning

PRD769248 · Product

Active substance: Gentamicin
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: SOLUTION FOR INJECTION
Max daily dose: 5 mg/Kg milligram(s)/kilogram
Max total dose: 5 mg/Kg milligram(s)/kilogram
Max treatment duration: 3 Day(s)
Authorisation status: Authorised
ATC code: J01GB03 — GENTAMICIN
Marketing authorisation: 11812
MA holder: SANDOZ A/S
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Ertapenem Fresenius Kabi

PRD5082241 · Product

Active substance: Ertapenem Sodium
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: SOLUTION FOR INFUSION
Max daily dose: 1 g gram(s)
Max total dose: 7 g gram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01DH03 — -
Marketing authorisation: 57307
MA holder: FRESENIUS KABI AB
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Piperacillin/Tazobactam "Stragen", pulver til infusionsvæske, opløsning

PRD417104 · Product

Active substance: Piperacillin
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: SOLUTION FOR INFUSION
Max daily dose: 8 g gram(s)
Max total dose: 56 g gram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01CR05 — PIPERACILLIN AND ENZYME INHIBITOR
Marketing authorisation: 40525
MA holder: STRAGEN NORDIC A/S
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Piperacillin/Tazobactam "Stragen", pulver til infusionsvæske, opløsning

PRD417103 · Product

Active substance: Piperacillin
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: SOLUTION FOR INFUSION
Max daily dose: 16 g gram(s)
Max total dose: 112 g gram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01CR05 — PIPERACILLIN AND ENZYME INHIBITOR
Marketing authorisation: 40526
MA holder: STRAGEN NORDIC A/S
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Ciprofloxacin "HEXAL", filmovertrukne tabletter

PRD743012 · Product

Active substance: Ciprofloxacin
Pharmaceutical form: FILM-COATED TABLET
Route of administration: ORAL
Max daily dose: 1000 mg milligram(s)
Max total dose: 7000 mg milligram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01MA02 — CIPROFLOXACIN
Marketing authorisation: 33094
MA holder: HEXAL A/S
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Ciprofloxacin "HEXAL", filmovertrukne tabletter

PRD743017 · Product

Active substance: Ciprofloxacin
Pharmaceutical form: FILM-COATED TABLET
Route of administration: ORAL
Max daily dose: 1500 mg milligram(s)
Max total dose: 10500 mg milligram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01MA02 — CIPROFLOXACIN
Marketing authorisation: 33096
MA holder: HEXAL A/S
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Ciprofloxacin "HEXAL", filmovertrukne tabletter

PRD799080 · Product

Active substance: Ciprofloxacin
Pharmaceutical form: FILM-COATED TABLET
Route of administration: ORAL
Max daily dose: 1000 mg milligram(s)
Max total dose: 7000 mg milligram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01MA02 — CIPROFLOXACIN
Marketing authorisation: 33095
MA holder: HEXAL A/S
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Nebcina, injektionsvæske, opløsning

PRD324371 · Product

Active substance: Tobramycin
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: IV INJECTION, IV INFUSION
Max daily dose: 5 mg/Kg milligram(s)/kilogram
Max total dose: 15 mg/Kg milligram(s)/kilogram
Max treatment duration: 3 Day(s)
Authorisation status: Authorised
ATC code: J01GB01 — TOBRAMYCIN
Marketing authorisation: 06331
MA holder: EUROCEPT INTERNATIONAL BV
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Nitrofurantoin "EQL Pharma", tabletter

PRD11011401 · Product

Active substance: Nitrofurantoin
Pharmaceutical form: TABLET
Route of administration: ORAL
Max daily dose: 400 mg milligram(s)
Max total dose: 2800 mg milligram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01XE01 — NITROFURANTOIN
Marketing authorisation: 7397
MA holder: EQL PHARMA AB
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Selexid

PRD7897897 · Product

Active substance: Mecillinam
Substance synonyms: AMDINOCILLIN
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: SOLUTION FOR INJECTION
Max daily dose: 3 g gram(s)
Max total dose: 21 g gram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01CA11 — MECILLINAM
Marketing authorisation: 13525
MA holder: KARO PHARMA AB
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Selexid

PRD7180854 · Product

Active substance: Pivmecillinam Hydrochloride
Pharmaceutical form: FILM-COATED TABLET
Route of administration: ORAL
Max daily dose: 2400 mg milligram(s)
Max total dose: 16800 mg milligram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01CA08 — PIVMECILLINAM
Marketing authorisation: 45237
MA holder: KARO PHARMA AB
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Selexid

PRD7180798 · Product

Active substance: Pivmecillinam Hydrochloride
Pharmaceutical form: FILM-COATED TABLET
Route of administration: ORAL
Max daily dose: 1200 mg milligram(s)
Max total dose: 8400 mg milligram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01CA08 — PIVMECILLINAM
Marketing authorisation: 09131
MA holder: KARO PHARMA AB
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Ciprofloxacin Fresenius Kabi

PRD408961 · Product

Active substance: Ciprofloxacin
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: IV INJECTION, IV INFUSION
Max daily dose: 800 mg milligram(s)
Max total dose: 5600 mg milligram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01MA02 — CIPROFLOXACIN
Marketing authorisation: 38748
MA holder: FRESENIUS KABI AB
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Sulfametoxazol med trimetoprim SAD, tabletter

PRD351283 · Product

Active substance: Sulfamethoxazole
Pharmaceutical form: TABLET
Route of administration: ORAL
Max daily dose: 1920 mg milligram(s)
Max total dose: 13440 mg milligram(s)
Max treatment duration: 7 Day(s)
Authorisation status: Authorised
ATC code: J01EE01 — SULFAMETHOXAZOLE AND TRIMETHOPRIM
Marketing authorisation: 16511
MA holder: AMGROS I/S
MA country: Denmark
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Region Hovedstaden

Sponsor organisation: Region Hovedstaden
Address: Kettegaard Alle 30
City: Hvidovre
Postcode: 2650
Country: Denmark

Scientific contact point

Organisation: Hvidovre Hospital
Contact name: Thomas

Public contact point

Organisation: Hvidovre Hospital
Contact name: Thomas

Third parties 1

Organisation	City, country	Duties
Frederiksberg Hospital ORG-100028217	Frederiksberg, Denmark	On site monitoring

Locations

1 EU/EEA country · 7 investigational sites

By country

Country	MS status	Planned subjects	Sites
Denmark	Ongoing, recruiting	380	7
Rest of world	—	0	—

Investigational sites

Denmark

7 sites · Ongoing, recruiting

Gentofte Hospital

Infectious Diseases, Gentofte Hospitalsvej 1, 2900, Hellerup

Aalborg University Hospital

Infectious Diseases, Hobrovej 18-22, 9000, Aalborg

Odense University Hospital

Infectious Diseases, J B Winsloews Vej 4, 5000, Odense C

Nordsjællands Hospital

Infectious Diseases, Dyrehavevej 29, 3400, Hillerød

Hvidovre Hospital

Infectious Diseases, Kettegaard Alle 30, 2650, Hvidovre

Bispebjerg Hospital

Infectious Diseases, Bispebjerg Hospital, Bispebjerg Bakke, Copenhagen

Herlev og Gentofte Hospital

Infectious Diseases, Borgmester Ib Juuls Vej 1, 2730, Herlev

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Country	Trial start	Trial end	Recruitment start	Recruitment end	Early termination
Denmark	2024-07-25		2024-07-29

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 23 files

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

Type	Title	Version
Protocol (for publication)	D1_Protocol 2024-514900-16-00 - CLEAN	7
Protocol (for publication)	D1_Protocol 2024-514900-16-00 - TRACKED	7
Protocol (for publication)	Summary of Changes to protocol_2024-514900-16-00	7
Recruitment arrangements (for publication)	Recruitment arrangements	1
Subject information and informed consent form (for publication)	GNB5 Samtykkeerklring AHH	3
Subject information and informed consent form (for publication)	GNB5 Skriftlig deltagerinformation AHH	3
Summary of Product Characteristics (SmPC) (for publication)	SmPC Ampicillin	1
Summary of Product Characteristics (SmPC) (for publication)	SmPC Bioclavid	1
Summary of Product Characteristics (SmPC) (for publication)	SmPC Ceftazidim	1
Summary of Product Characteristics (SmPC) (for publication)	SmPC Cipofloxacin infusion	1
Summary of Product Characteristics (SmPC) (for publication)	SmPC Ciprofloxacin tabl	1
Summary of Product Characteristics (SmPC) (for publication)	SmPC Ertapenem	1
Summary of Product Characteristics (SmPC) (for publication)	SmPC Hexamycin	1
Summary of Product Characteristics (SmPC) (for publication)	SmPC Meropenem	1
Summary of Product Characteristics (SmPC) (for publication)	SmPC Nebcina	1
Summary of Product Characteristics (SmPC) (for publication)	SmPC Nitrofurantoin	1
Summary of Product Characteristics (SmPC) (for publication)	SmPC PiperacillinTazobactam	1
Summary of Product Characteristics (SmPC) (for publication)	SmPC Selexid inj	1
Summary of Product Characteristics (SmPC) (for publication)	SmPC Selexid tabl	1
Summary of Product Characteristics (SmPC) (for publication)	SmPC Sulfametizol	1
Summary of Product Characteristics (SmPC) (for publication)	SmPC Sulfametoxazol med trimetoprim	1
Summary of Product Characteristics (SmPC) (for publication)	SmPC Trimopan	1
Synopsis of the protocol (for publication)	Protocol synopsis_ENG 2019-003282-17	1

Application history

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

#	Type	Code	Submitted	Reference MS	Conclusion	Decision date
1	INITIAL	IN	2024-07-01	Denmark	Acceptable 2024-07-19	2024-07-25
2	SUBSTANTIAL MODIFICATION	SM-4	2025-02-25	Denmark	Acceptable 2025-04-14	2025-04-15
3	SUBSTANTIAL MODIFICATION	SM-5	2025-09-10	Denmark	Acceptable 2025-09-11	2025-09-12