Clinical trial • Phase II • Infectious Disease

PIVMECILLINAM HYDROCHLORIDE for Febrile urinary tract infection (E. coli)

Phase II trial of PIVMECILLINAM HYDROCHLORIDE for Febrile urinary tract infection (E. coli).

Overview

Trial Therapeutic Area
Infectious Disease
Trial Disease
Febrile urinary tract infection (E. coli)
Trial Stage
Phase II
Drug Modality
Small molecule

Key dates

Initial CTIS Submission Date
23-06-2025
First CTIS Authorization Date
06-10-2025

Trial design

Randomised, multiple standard-of-care comparator antibiotic regimens are permitted and are listed as comparator arms: amoxicillin and beta-lactamase inhibitor (amoxicillin sodium + clavulanic acid) – max daily dose 3.38 g, oral; ceftriaxone (ceftriaxone sodium) – max daily dose 2 g, infusion; cefuroxime axetil – max daily dose 4.5 g, infusion; tobramycin – max daily dose 7 mg/kg, infusion; aztreonam – max daily dose 8 g, infusion; amikacin sulfate – max daily dose 30 mg/kg, infusion; fosfomycin calcium – max daily dose 24 g, infusion; meropenem – max daily dose 3 g, infusion; imipenem and cilastatin – max daily dose 4 g, infusion; ertapenem – max daily dose 1 g, infusion; ampicillin – max daily dose 12 g, infusion; amoxicillin – max daily dose 3 g, oral; piperacillin and beta-lactamase inhibitor – max daily dose 18 g, infusion; gentamicin – max daily dose 7 mg/kg, infusion; sulfamethoxazole and trimethoprim – max daily dose 2.88 g, oral; cefotaxime – max daily dose 12 g, infusion; ciprofloxacin – max daily dose 1.5 g, oral. test (interventional) treatment: pivmecillinam (pivmecillinam hydrochloride) – 400 mg qid (400 mg four times daily), oral; max daily dose 1.6 g.-controlled Phase II trial in Sweden, Norway.

Randomised
Yes
Comparator
Multiple standard-of-care comparator antibiotic regimens are permitted and are listed as comparator arms: Amoxicillin and beta-lactamase inhibitor (amoxicillin sodium + clavulanic acid) – max daily dose 3.38 g, oral; Ceftriaxone (ceftriaxone sodium) – max daily dose 2 g, infusion; Cefuroxime axetil – max daily dose 4.5 g, infusion; Tobramycin – max daily dose 7 mg/kg, infusion; Aztreonam – max daily dose 8 g, infusion; Amikacin sulfate – max daily dose 30 mg/kg, infusion; Fosfomycin calcium – max daily dose 24 g, infusion; Meropenem – max daily dose 3 g, infusion; Imipenem and cilastatin – max daily dose 4 g, infusion; Ertapenem – max daily dose 1 g, infusion; Ampicillin – max daily dose 12 g, infusion; Amoxicillin – max daily dose 3 g, oral; Piperacillin and beta-lactamase inhibitor – max daily dose 18 g, infusion; Gentamicin – max daily dose 7 mg/kg, infusion; Sulfamethoxazole and trimethoprim – max daily dose 2.88 g, oral; Cefotaxime – max daily dose 12 g, infusion; Ciprofloxacin – max daily dose 1.5 g, oral. Test (interventional) treatment: Pivmecillinam (pivmecillinam hydrochloride) – 400 mg QID (400 mg four times daily), oral; max daily dose 1.6 g.
Target Sample Size
560
Trial Duration For Participant
36

Eligibility

Recruits 560 No vulnerable populations selected. Participants must be ≥18 years of age and provide signed informed consent. Separate subject information and consent forms are available for the main study and for substudies (microbiota and PK). Subject information/consent documents are available in English, Swedish and Norwegian..

Pregnancy Exclusion
Pregnancy or breastfeeding.
Vulnerable Population
No vulnerable populations selected. Participants must be ≥18 years of age and provide signed informed consent. Separate subject information and consent forms are available for the main study and for substudies (microbiota and PK). Subject information/consent documents are available in English, Swedish and Norwegian.

Inclusion criteria

  • {"criterion_text":"- ≥18 years of age.\n- Diagnosis of fUTI, defined as i) fever ≥ 38°C measured in a healthcare institution and ii) at least one of the following: flank pain or pelvic pain, nausea or vomiting, dysuria, urinary frequency or urgency, and costovertebral angle tenderness on physical examination.\n- Growth of E. coli in urine with antimicrobial susceptibility to mecillinam.\n- Adequate intravenous antibiotic treatment for fUTI (defined below) for >=2 days to which the isolated E. coli is determined susceptible.\n- Defervescence and hemodynamic stability for at least 24 hours, according to the responsible physician.\n- Signed informed consent."}

Exclusion criteria

  • {"criterion_text":"- Adequate intravenous antibiotic treatment for > 4 days prior to randomization or other adequate (microbiologically active) oral antibiotic treatment for the same fUTI episode prior to recruitment.\n- Other intravenous or oral antibiotic treatment; ongoing or planned during the follow-up period (i.e. until 28 days after EOT for fUTI).\n- Severe renal impairment (eGFR < 20 mL/min) at randomization.\n- Morbid obesity (BMI > 40 kg/m2).\n- Pregnancy or breastfeeding.\n- Unlikely to follow instructions or the study protocol.\n- Previous participation in the study.\n- If consenting to microbiome analysis: i) contraindication for ciprofloxacin (e.g. allergy), ii) unlikely to be able to provide fecal samples per protocol, iii) treatment with antibiotics in the past 3 months before the current fUTI episode, iv) chronic intestinal disease or previous surgery in the gastrointestinal tract.\n- If consenting to pharmacokinetic analysis: expected difficulties in taking blood and urine samples per protocol.\n- Growth of other bacterial species than E. coli, or fungi, in urine.\n- Contraindication for pivmecillinam (e.g. allergy).\n- Clinical suspicion of bacterial prostatitis.\n- Renal abscess.\n- Kidney transplant.\n- Myelosuppressive disorder with neutrophil count < 0.5 x 10^9/L at randomization.\n- Planned antibiotic treatment for fUTI > 14 days.\n- Likely to be prescribed antibiotic prophylaxis after treatment."}

Endpoints

Primary endpoints

  • {"endpoint_text":"- Clinical response: i) no new healthcare contacts or antibiotic treatments for suspected or proven UTI, ii) sustained defervescence (< 38°C), and iii) patient-documented resolution of fUTI symptoms that were present and recorded in the eCRF at trial entry (and no new fUTI symptoms) at test of cure (TOC), which will be performed 7 (+/-2) days after EOT.","definition_or_measurement_approach":"Clinical response assessed at test of cure (TOC) performed 7 (+/-2) days after end of treatment (EOT); requires i) no new healthcare contacts or antibiotic treatments for suspected/proven UTI, ii) sustained defervescence (<38°C), iii) patient-documented resolution of baseline fUTI symptoms recorded in eCRF (and no new fUTI symptoms)."}

Secondary endpoints

  • {"endpoint_text":"- Sustained clinical response: i) no new healthcare contacts or antibiotic treatments for suspected or proven UTI, ii) no recurrent fever (≥ 38°C), and iii) no recurrent UTI symptoms after completion of the initial therapy and until 28 (+/- 2) days after EOT.","definition_or_measurement_approach":"Sustained clinical response assessed up to 28 (+/-2) days after EOT using healthcare contact records, antibiotic prescriptions, fever recordings and patient symptom reports."}
  • {"endpoint_text":"- Microbiological response: no detectable growth of E. coli in urine sampled at TOC, 7 (+/-2) days after EOT.","definition_or_measurement_approach":"Urine culture at TOC (7 +/-2 days after EOT) showing no detectable growth of E. coli."}
  • {"endpoint_text":"- Sustained microbiological response; no detectable growth of E. coli in urine sampled at the second follow-up 28 (+/- 2) days after EOT.","definition_or_measurement_approach":"Urine culture at second follow-up (28 +/-2 days after EOT) with no detectable growth of E. coli."}
  • {"endpoint_text":"- Occurrence and severity of AEs from start of study treatment until TOC: recorded by the participating patients in a diary, documented in the medical records, or reported at the TOC follow-up.","definition_or_measurement_approach":"Adverse events collected via patient diary, medical records, and reports at TOC; severity graded per study protocol (not further specified in JSON)."}
  • {"endpoint_text":"- Disturbances in the intestinal microbiome: analysed by repeated collection of fecal samples from 30 patients treated with pivmecillinam or ciprofloxacin, respectively.","definition_or_measurement_approach":"Microbiome analysis on repeated fecal samples from 30 patients per treatment group (pivmecillinam vs ciprofloxacin); specific analysis methods not specified in JSON."}
  • {"endpoint_text":"- Pharmacokinetics of mecillinam in plasma and urine and PK/PD target attainment; assessed by blood and urine sampling from 30 patients treated with pivmecillinam.","definition_or_measurement_approach":"PK assessed via blood and urine sampling in 30 patients on pivmecillinam; PK/PD target attainment evaluated per protocol (methods not detailed in JSON)."}
  • {"endpoint_text":"- Cost-effectiveness of pivmecillinam as compared with standard of care.","definition_or_measurement_approach":"Health economic analysis comparing pivmecillinam with standard of care (methods not detailed in JSON)."}

Recruitment

Planned Sample Size
560
Recruitment Window Months
42
Consent Approach
Participants (≥18 years) must provide signed informed consent. Separate subject information and consent forms exist for the main study and for substudies (microbiota and PK). Subject information/consent documents are available in English, Swedish and Norwegian. No assent process described.

Geography

Total Number Of Sites
13
Total Number Of Participants
560

Sweden

Earliest CTIS Part Ii Submission Date
02-07-2025
Latest Decision Or Authorization Date
06-10-2025
Processing Time Days
96
Number Of Sites
11
Number Of Participants
510

Sites

Site Name
Region Vaesterbotten
Department Name
Norrlands Universitetssjukhus, Infektionskliniken
Principal Investigator Name
Urban Johansson Kostenniemi
Contact Person Name
Urban Johansson Kostenniemi
Site Name
Sahlgrenska University Hospital-Vaestra Goetalandsregionen
Department Name
Verksamhet Infektion
Principal Investigator Name
Erik Sörstedt
Principal Investigator Email
erik.sorstedt@vgregion.se
Contact Person Name
Erik Sörstedt
Contact Person Email
erik.sorstedt@vgregion.se
Site Name
Malarsjukhuset Eskilstuna
Department Name
Infektionskliniken
Principal Investigator Name
Joakim Lundvik
Principal Investigator Email
joakim.lundvik@regionsormland.se
Contact Person Name
Joakim Lundvik
Site Name
Region Vaesternorrland
Department Name
Länssjukhuset Sundsvall-Härnösand, Infektionskliniken
Principal Investigator Name
Björn Diedrichs
Principal Investigator Email
bjorn.diedrichs@rvn.se
Contact Person Name
Björn Diedrichs
Contact Person Email
bjorn.diedrichs@rvn.se
Site Name
Soedra Aelvsborg Hospital Vaestra Goetalandsregionen
Department Name
Infektionskliniken
Principal Investigator Name
Anders Lundqvist
Principal Investigator Email
anders.lundqvist@vgregion.se
Contact Person Name
Anders Lundqvist
Contact Person Email
anders.lundqvist@vgregion.se
Site Name
Region Blekinge
Department Name
Blekingesjukhuset, Infektionskliniken
Principal Investigator Name
Eva Lindqvist
Principal Investigator Email
eva.lindqvist@regionblekinge.se
Contact Person Name
Eva Lindqvist
Site Name
Region Skane Skanes Universitetssjukhus
Department Name
Infektionsklinken
Principal Investigator Name
Christian Kampmann
Principal Investigator Email
christian.kampmann@skane.se
Contact Person Name
Christian Kampmann
Contact Person Email
christian.kampmann@skane.se
Site Name
Region Oerebro Laen
Department Name
Universitetssjukhuset Örebro, VO Infektion
Principal Investigator Name
Edvin Ingberg
Principal Investigator Email
edvin.ingberg@regionorebrolan.se
Contact Person Name
Edvin Ingberg
Site Name
Region Kronoberg
Department Name
Centrallasarettet Växjö, Infektionskliniken
Principal Investigator Name
Olov Elvstam
Principal Investigator Email
f.elvstam@kronoberg.se
Contact Person Name
Olov Elvstam
Contact Person Email
f.elvstam@kronoberg.se
Site Name
Karolinska University Hospital
Department Name
Medicinska Enheten för infektionssjukdomar
Principal Investigator Name
Pontus Naucler
Principal Investigator Email
pontus.naucler@ki.se
Contact Person Name
Pontus Naucler
Contact Person Email
pontus.naucler@ki.se
Site Name
Uppsala University Hospital
Department Name
Infektionskliniken
Principal Investigator Name
Thomas Tängdén
Principal Investigator Email
thomas.tangden@medsci.uu.se
Contact Person Name
Thomas Tängdén
Contact Person Email
thomas.tangden@medsci.uu.se

Norway

Earliest CTIS Part Ii Submission Date
08-09-2025
Latest Decision Or Authorization Date
08-10-2025
Processing Time Days
30
Number Of Sites
2
Number Of Participants
50

Sites

Site Name
Oslo University Hospital HF
Department Name
Dept. of Infectious Diseases
Principal Investigator Name
Kristian Tonby
Principal Investigator Email
post@ous-hf.no
Contact Person Name
Kristian Tonby
Contact Person Email
post@ous-hf.no
Site Name
Helse Bergen HF
Department Name
Dept. of Infectious Diseases
Principal Investigator Name
Eivind Rath
Principal Investigator Email
postmottak@helse-bergen.no
Contact Person Name
Eivind Rath
Contact Person Email
postmottak@helse-bergen.no

Sponsor

Primary sponsor

Full Name
Uppsala Universitet
Organisation Type
Educational Institution
Country Of Registered Address
Sweden

Investigational products

Investigational Product Name
PIVMECILLINAM
Active Substance
PIVMECILLINAM HYDROCHLORIDE
Modality
Small molecule
Routes Of Administration
ORAL USE
Route
ORAL USE
Starting Dose
400 mg QID
Frequency
QID
Maximum Dose
1.6 g
Investigational Product Name
AMOXICILLIN AND BETA-LACTAMASE INHIBITOR
Active Substance
AMOXICILLIN SODIUM, CLAVULANIC ACID
Modality
Small molecule
Routes Of Administration
ORAL USE
Route
ORAL USE
Maximum Dose
3.38 g
Investigational Product Name
CEFTRIAXONE
Active Substance
CEFTRIAXONE SODIUM, LIDOCAINE HYDROCHLORIDE
Modality
Small molecule
Routes Of Administration
INFUSION
Route
INFUSION
Maximum Dose
2 g
Investigational Product Name
CEFUROXIME
Active Substance
CEFUROXIME AXETIL
Modality
Small molecule
Routes Of Administration
INFUSION
Route
INFUSION
Maximum Dose
4.5 g
Investigational Product Name
TOBRAMYCIN
Modality
Small molecule
Routes Of Administration
INFUSION
Route
INFUSION
Maximum Dose
7 mg/kg
Investigational Product Name
AZTREONAM
Active Substance
AZTREONAM
Modality
Small molecule
Routes Of Administration
INFUSION
Route
INFUSION
Maximum Dose
8 g
Investigational Product Name
AMIKACIN
Active Substance
AMIKACIN SULFATE
Modality
Small molecule
Routes Of Administration
INFUSION
Route
INFUSION
Maximum Dose
30 mg/kg
Investigational Product Name
FOSFOMYCIN
Active Substance
FOSFOMYCIN CALCIUM
Modality
Small molecule
Routes Of Administration
INFUSION
Route
INFUSION
Maximum Dose
24 g
Investigational Product Name
MEROPENEM
Active Substance
LINEZOLID
Modality
Small molecule
Routes Of Administration
INFUSION
Route
INFUSION
Maximum Dose
3 g
Investigational Product Name
IMIPENEM AND CILASTATIN
Active Substance
CILASTATIN SODIUM, IMIPENEM
Modality
Small molecule
Routes Of Administration
INFUSION
Route
INFUSION
Maximum Dose
4 g
Investigational Product Name
ERTAPENEM
Active Substance
ERTAPENEM SODIUM
Modality
Small molecule
Routes Of Administration
INFUSION
Route
INFUSION
Maximum Dose
1 g
Investigational Product Name
AMPICILLIN
Active Substance
AMPICILLIN SODIUM
Modality
Small molecule
Routes Of Administration
INFUSION
Route
INFUSION
Maximum Dose
12 g
Investigational Product Name
AMOXICILLIN
Active Substance
AMOXICILLIN SODIUM
Modality
Small molecule
Routes Of Administration
ORAL USE
Route
ORAL USE
Maximum Dose
3 g
Investigational Product Name
PIPERACILLIN AND BETA-LACTAMASE INHIBITOR
Active Substance
PIPERACILLIN SODIUM, TAZOBACTAM SODIUM
Modality
Small molecule
Routes Of Administration
INFUSION
Route
INFUSION
Maximum Dose
18 g
Investigational Product Name
GENTAMICIN
Active Substance
BETAMETHASONE VALERATE, GENTAMICIN SULFATE
Modality
Small molecule
Routes Of Administration
INFUSION
Route
INFUSION
Maximum Dose
7 mg/kg
Investigational Product Name
SULFAMETHOXAZOLE AND TRIMETHOPRIM
Active Substance
BROMHEXINE HYDROCHLORIDE, SULFAMETHOXAZOLE, TRIMETHOPRIM
Modality
Small molecule
Routes Of Administration
ORAL USE
Route
ORAL USE
Maximum Dose
2.88 g
Investigational Product Name
CEFOTAXIME
Active Substance
CEFOTAXIME, LIDOCAINE
Modality
Small molecule
Routes Of Administration
INFUSION
Route
INFUSION
Maximum Dose
12 g
Investigational Product Name
CIPROFLOXACIN
Active Substance
CIPROFLOXACIN HYDROCHLORIDE, CIPROFLOXACIN
Modality
Small molecule
Routes Of Administration
ORAL USE
Route
ORAL USE
Maximum Dose
1.5 g

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