Clinical Trials Register

Summary
EudraCT Number:	2015-003898-15
Sponsor's Protocol Code Number:	FoHM/UVI2015
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-10-01
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Sweden - MPA

A.2

EudraCT number

2015-003898-15

A.3

Full title of the trial

A randomized, controlled, multicentre trial of collateral damage on the intestinal microbiota inferred by cefotaxime versus temocillin in patients receiving empirical treatment for febrile urinary tract infections

Påverkan på tarmens mikrobiota av temocillin- jämfört med cefotaximbehandling vid febril urinvägsinfektion – en kontrollerad randomiserad multicenterstudie

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Comparison of temocillin and cefotaxim against urinary tract infection with fever (pyelonephritis) - clinical effect and effect on the intestinal microbiota

Jämförelse av temocillin och cefotaxim mot urinvägsinfektion med feber (njurbäckeninflammation) – klinisk effekt och påverkan på tarmfloran

A.4.1

Sponsor's protocol code number

FoHM/UVI2015

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Public Health Agency of Sweden
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Public Health Agency of Sweden
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Public Health Agency of Sweden
B.5.2	Functional name of contact point	Antibiotics and Infection Control
B.5.3	Address:
B.5.3.1	Street Address	Nobels väg 18
B.5.3.2	Town/ city	Solna
B.5.3.3	Post code	17182
B.5.3.4	Country	Sweden
B.5.4	Telephone number	46102052000

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Negaban
D.2.1.1.2	Name of the Marketing Authorisation holder	Eumedica
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TEMOCILLIN
D.3.9.1	CAS number	66148-78-5
D.3.9.4	EV Substance Code	SUB10886MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Claforan, cefotaxim
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CEFOTAXIME
D.3.9.1	CAS number	63527-52-6
D.3.9.4	EV Substance Code	SUB07405MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Febrile urinary tract infection

Febril urinvägsinfektion

E.1.1.1

Medical condition in easily understood language

Urinary tract infection with fever

Urinvägsinfektion med feber (njurbäckeninflammation)

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the ecological impact on the intestinal microbiota of temocillin compared to cefotaxime, in empiric treatment of febrile UTI.

Att studera ekologisk påverkan på tarmens mikrobiota, av temocillin (2 g x 2) respektive cefotaxim (1 g x 3) vid empirisk behandling av febril urinvägsinfektion.

E.2.2

Secondary objectives of the trial

To compare the safety and efficacy of temocillin compared to cefotaxime in empiric treatment of febrile UTI.

Att studera säkerhet och effekt av temocillin (2 g x 2) respektive cefotaxim (1 g x 3) vid empirisk behandling av febril urinvägsinfektion.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Males and females ≥ 18 years of age with suspected or confirmed febrile UTI, fulfilling at least one of the following signs and symptoms:
- Flank pain or suprapubic pain
- Tenderness over the kidney on physical examination
- Urinary symptoms such as dysuria, urinary frequency or urinary urgency
2. Fever ≥ 38.0°C (highest temperature recorded at home or at the hospital)
3. Positive urinalysis tests (U-Nitrit and/or U-LPK)
4. Have a pre-treatment baseline urinary culture obtained
5. Require iv antibacterial treatment of the presumed infection
6. Fertile women: Agree to practice highly effective anti-contraceptive methods from study-start to TOC
7. Signed informed consent

1. Kvinnor och män ≥ 18 år som har misstänkt eller konstaterad febril urinvägsinfektion (komplicerad eller okomplicerad) med minst ett av följande symtom:
-Flanksmärta.
-Ömhet över njurlogerna.
-Miktionsbesvär som dysuri, urinträngningar och frekvent blåstömning.
2. Feber ≥ 38.0°C (högsta temperatur uppmätt hemma eller på sjukhus).
3. Positiv urinsticka (U-Nitrit och/eller U-LPK).
4. Urinprov för odling taget innan behandlingsstart.
5. Bedöms behöva parenteral antibiotikabehandling mot aktuell infektion
6. Kvinnor i fertil ålder: Samtycka till att praktisera effektiv antikonceptionsmetod från studiestart t.o.m. Kontroll 4.
7. Signerat samtycke.

E.4

Principal exclusion criteria

1. Have a documented history of hypersensitivity or allergic reaction to any beta-lactam
2. Pregnant or nursing women
3. Receipt of any prior potentially therapeutic antibacterial agent within 1 month before randomisation and sampling for urine and faecal cultures. Exceptions will be ≤ 72 hours prior treatment with pivmecillinam or nitrofurantoin, which will be recorded in the CRF.
4. Known chronic renal insufficiency (creatinine clearance < 10 mL/min at screening as estimated by Cockcroft-Gault), or receiving intermittent haemodialysis or peritoneal dialysis
5. Known ESBL carriage
6. Any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the subject or the quality of study data.

1. Känd överkänslighet mot betalaktamantibiotika.
2. Graviditet eller pågående amning.
3. Behandlats med antibiotika inom en månad före randomisering och provtagning. Undantag är behandling med pivmecillinam eller nitrofurantoin för aktuell infektion.
4. Patient med känd kronisk njurinsufficiens (estimerat kreatinin clearance < 10 ml/min skattat enligt Cockcroft-Gault), eller som erhåller intermittent hemodialys/peritoneal dialys.
5. Känt ESBL-bärarskap
6. Annan orsak som, enligt läkarens bedömning, gör det olämpligt för patienten att delta i studien.

E.5 End points

E.5.1

Primary end point(s)

Emergence of any of the two following events (see suggested definitions below):
Colonisation or infection with C. difficile, and/or colonisation or infection with Enterobacteriaceae resistant to extended-spectrum cephalosporins (cefotaxime and/or ceftazidime).

Förekomst av minst en av följande två händelser i tarmens mikrobiota efter avslutad intravenös behandling av studieläkemedlet:
• Kolonisation eller infektion med Clostridium difficile.
• Kolonisation med Enterobacteriaceae resistent mot cefalosporiner med utvidgat spektrum.

E.5.1.1

Timepoint(s) of evaluation of this end point

After the last dose of study drug, prior to any de-escalation therapy (Sample 2).

Efter avslutad behandling med studieläkemedel (prov 2).

E.5.2

Secondary end point(s)

Clinical endpoints:
• Clinical efficacy of temocillin compared to cefotaxime in the treatment of febrile UTI, 7-10 days after discontinuation of antibiotic treatment (parenteral and oral).
• Bacteriological cure per patient and per pathogen.
• Early clinical response, Day 4.
• Rate of patients with diarrhea (≥ 3 loose stools per day) during treatment and up to 7-10 days after discontinuation of antibiotic treatment (parenteral and oral).
• Frequency adverse events during the study period.

Microbiological endpoints:
• Difference between treatment groups in each of the two separate endpoints comprising the composite primary endpoint above.
• Decreased susceptibility among intestinal Enterobacteriaceae to of the study drugs over time.
• Difference between treatment groups in each of:
- Shift of dominating Enterobacteriaceae from E. coli to non-E. coli (e.g. Klebsiella, Enterobacter, Citrobacter spp.)
- Overgrowth (increased relative frequency of) of Candida spp,
- Overgrowth (increased relative frequency of) of Enterococcus spp.
- Change in diversity of the faecal microbiome by 16S rDNA sequencing of the total faecal microbiome.

Kliniska utfallsmått:
• Klinisk effekt 7-10 dagar efter avslutad behandling (parenteral och peroral)
• Bakteriologisk utläkning per patient och per patogen 7-10 dagar efter avslutad behandling (parenteral och peroral).
• Tidigt kliniskt svar, dag 4.
• Frekvens diarréer (≥ 3 lösa avföringar per dygn) under behandlingen och 7-10 dagar efter avslutad antibiotikabehandling.
• Frekvens incidenser (adverse events) under studieperioden.

Mikrobiologiska utfallsmått, jämförelse mellan behandlingsgrupperna efter avslutad behandling med studieläkemedlet:
• Skillnad avseende var och en av de två primära utfallsmåtten.
• Skillnad avseende:
- Förändring i känslighet över tid hos gramnegativa tarmbakterier mot respektive studieläkemedel.
- Skift bland dominerande Enterobacteriaceae från E. coli till non-E. coli (t. ex. Citrobacter, Enterobacter, Klebsiella spp.).
- Överväxt av svamp (Candida spp.)
- Överväxt av enterokocker.
- Förändringar i faecala mikrobiomets diversitet.

E.5.2.1

Timepoint(s) of evaluation of this end point

Clinical efficacy 7-10 days after discontinuation of antibiotic administration.

Klinisk effekt 7-10 dagar efter avslutad antibiotikabehandilng.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Ecological impact on the intestinal microbiota.

Ekologisk påverkan på tarmens mikrobiota.

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

132

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

200

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Information not present in EudraCT

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

332

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

Inga

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-12-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-10-22

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-08-20

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