Clinical Trials Register

Summary
EudraCT Number:	2021-003814-37
Sponsor's Protocol Code Number:	AKF-400
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-08-18
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

Denmark - DHMA

A.2

EudraCT number

2021-003814-37

A.3

Full title of the trial

The effect of dicloxacillin on oral absorption of drugs

Dicloxacillins effekt på optagelsen af lægemidler fra tarmen

A.3.1

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

Dicloxacillins effect on the oral absorption of drugs from the intestine

Dicloxacillins effekt på optagelsen af lægemidler fra tarmen

A.4.1

Sponsor's protocol code number

AKF-400

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	Odense University Hosipital
B.1.3.4	Country	Denmark
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	The Novo Nordisk Foundation
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	The Faculty of Health Sciences, University of SOuthern Denmark
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Clinical Pharmacology, Pharmacy and Environmental Medicine, Institure of Publich Health, University of Southern Denmark
B.5.2	Functional name of contact point	Clinical Pharmacology and Pharmacy
B.5.3	Address:
B.5.3.1	Street Address	J.B. Winsløws Vej 19, 2. floor
B.5.3.2	Town/ city	Odense
B.5.3.3	Post code	5000
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+4565502352
B.5.6	E-mail	dbiversen@health.sdu.dk

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	Dicillin
D.2.1.1.2	Name of the Marketing Authorisation holder	Sandoz A/S
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DICLOXACILLIN
D.3.9.1	CAS number	3116-76-5
D.3.9.4	EV Substance Code	SUB07099MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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

Healthy volunteers. (Dicloxacillin is used against infections caused by beta-lactamase-producing organisms)
Testing for drug-drug interactions caused by dicloxacillin.

Raske frivillige. (Dicloxacillin bruges mod infektioner forårsaget af beta-laktamase producerende organismer).
Tester for lægemiddelinteraktioner forårsaget af dicloxacillin.

E.1.1.1

Medical condition in easily understood language

Healthy volunteers.
(Dicloxacillin is used against bacterial infections)
Investigating if dicloxacillin causes drug-drug interactions when it is administered for a longer period of time.

Raske frivillige.

(Dicloxacillin bruges mod bakterielle infektioner)
Tester for om dicloxacillin forårsager lægemiddelinteraktioner når det gives i en længere periode.

E.1.1.2

Therapeutic area

Not possible to specify

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10004035
E.1.2	Term	Bacterial infection due to staphylococcus aureus
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary aim of this study is to investigate if treatment with dicloxacillin can lead to drug-drug interactions through induction of the efflux transporter P-glycoprotein (P-gp).

Hovedformålet med studiet er at undersøge om behandling med dicloxacillin fører til lægemiddelinteraktioner gennem induktion af efflux transporteren P-glycoprotein (P-gp).

E.2.2

Secondary objectives of the trial

It will be investigated whether or not dicloxacillin induces its own metabolism.

Det vil blive undersøgt om dicloxacillin inducerer sin egen metabolisme.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age 18-55 years
- The following data must be in the normal range or only clinical insignificantly different from this: eGFR, ALAT, bilirubin, HbA1c, hemoglobin
- BMI >18.5 and < 30 kg/m2
- Bodyweight ≥ 50 kg
- Non-smoker (abstained from smoking minimum 2 weeks before the first study day and during the trial)
- Generally healthy
- Willing to give informed consent

- Alder 18-55 år
- Nyrefunktion (eGFR), leverfunktion (ALAT, bilirubin), langtidsblodsukker (HbA1c) og blodmængde (hæmoglobin) i det normale interval eller uden væsentlig klinisk afvigelse herfra
- Body Mass Index (BMI) >18,5 og < 30 kg/m
- Ikke-ryger (har ikke røget i minimum 14 dage inden første forsøgsdag og gennem hele forsøgsperioden)
- Godt helbred
- Kropsvægt ≥ 50 kg
- Villig til at afgive informeret samtykke

E.4

Principal exclusion criteria

- Known sensitivity to any of the used drugs or any excipients listed in section 6.1 in the Summary of Product Characteristics (SmPC).
- Intake of any significant prescription drugs, over-the-counter drugs, herbal drugs, or dietary supplements*.
Contraindicated drugs include:
Anticoagulants, antiplatelet aggregation medicinal products, ticagrelor, clopidogrel, acetylsalicylic acid, chronic NSAIDs use, amiodarone, verapamil, systemic ketoconazole, clarithromycin, cyclosporin, itraconazole, tacrolimus, posaconazole, dronedarone, glecaprevir/pibrentasvir, quinidine, ritonavir, digoxin, selective serotonin reuptake inhibitors (SSRIs), selective serotonin norephinephrine reuptake inhibitors (SNRIs), pantoprazole, ranitidine, previous use of dicloxacillin or other P-gp or CYP450 inhibitors/inducers within 4 weeks prior to the start of treatment, probenecid, tetracycline, methotrexate
- Alcohol abuse or if the Danish Health Authority recommendation regarding alcohol intake has been exceeded 2 weeks before the first study day (men 14 units alcohol/week, women 7 unites alcohol/week)
- Participating in any other intervention trials
- A positive pregnancy test at inclusion screening or any of the study days
- Known penicillin allergy or reactions against cephalosporins, cephamycin, 1-oxa-ß-lactamer, or carbapenems
- Women who are breastfeeding
- Diagnosis of any of the following diseases (current or previous):
Mechanical heart valve, congenital or acquired coagulation disorders, thrombocytopenia or functional platelet defects, biopsy within 4 weeks, major trauma, bacterial endocarditis, esophagitis, gastritis, gastroesophageal reflux, active meningitis, encephalitis, intracranial abscess, undergoing surgery, liver disease, history of thrombosis or diagnosed with antiphospholipid syndrome, active cancer

- Kendt overfølsomhed over for de anvendte lægemidler eller nogle af de hjælpestoffer, der er nævnt i produktresumeet sektion 6.1 for lægemidlerne
- Indtag af receptlægemidler, håndkøbslægemidler, naturlægemidler eller kosttilskud, der kan ændre effekten af lægemidler anvendt i forsøget*.
Kontraindicerede lægemidler inkluderer:
Antikoagulantia, blodpladehæmmende lægemidler, ticagrelor, clopidogrel, acetylsalicylsyre, kronisk anvendelse af NSAID’er, amiodaron, verapamil, quinidin, systemisk ketoconazol, clarithromycin, cyclosporin, itraconazol, tacrolimus, posaconazol, dronedaron, glecaprevir/pibrentasvir, ritonavir, digoxin, selektive serotonin-genoptagshæmmere (SSRI), selektive serotonin norephinephrine-genoptagshæmmere (SNRI), pantoprazol, ranitidin, probenicid, tetracyclin, methotrexat, tidligere brug af dicloxacillin eller andre P-gp eller CYP450 hæmmere/inducere indenfor de sidste 4 uger før forsøgsstart
- Alkoholmisbrug eller hvis sundhedsmyndighedernes anbefalinger overskrides 14 dage inden forsøgsdagene (mænd 14 genstande/uge, kvinder 7 genstande/uge)
- Deltagelse i et andet interventionsstudie
- Positiv graviditetstest inden forsøgets start eller på de pågældende forsøgsdage
- Kendt penicillin allergi eller overfølsomhed overfor cephalosporiner, cephamycin, 1-oxa-ß-lactamer eller carbapenemer
- Kvinder der ammer
- Diagnose af en af følgende sygdomme (nuværende eller tidligere): mekanisk hjerteklap, medfødt eller erhvervede koagulationsforstyrrelser, trombocytopeni eller blodpladefejl, biopsi 4 uger inden forsøgsstart, større traumer, bakteriel endokarditis, esophagitis, gastritis, gastroesophagael reflux, aktiv menigitis, encephalitis, intrakraniel abscess, gennemgår operation, leversygdom, fortid med blodprop eller diagnosticeret med antiphospholipidsyndrom, aktiv kræft

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the change in AUC of the P-gp substrate dabigatran after 28 days of dicloxacillin treatment compared to baseline.

Det primære endepunkt er ændring i AUC for P-gp substratet dabigatran efter 28 dages behandling med dicloxacillin sammenlignet med baseline.

E.5.1.1

Timepoint(s) of evaluation of this end point

After the drug analysis is completed

Nå lægemiddelanalysen er afsluttet

E.5.2

Secondary end point(s)

Changes in the full pharmacokinetics of the P-gp substrate dabigatran etexilate and all relevant metabolites after 10 and 28 days of dicloxacillin treatment compared to baseline. The concentrations will be determined from plasma and urine samples.

Changes in the full pharmacokinetics of dicloxacillin and its metabolites after 9 and 27 days of dicloxacillin treatment compared to baseline. This will be measured as concentrations in plasma and urine samples.

Changes in biomarkers of DMET after 10 and 28 days of dicloxacillin treatment compared to baseline.

Changes in exosome-derived biomarkers after 10 and 28 days of dicloxacillin treatment compared to baseline.

Ændringer i farmakokinetikken for P-gp substratet dabigatran etexilate og alle dets relevante metabolitter efter 10 og 28 dages dicloxacillin behandling sammenlignet med baseline. Koncentrationen bliver målt i plasma og urinprøver.

Ændringer i farmakokinetikken af dicloxacillin og dets metabolitter efter 9 og 27 dages behandling med dicloxacillin sammenlignet med baseline. Koncentrationen bliver målt i plasma og urinprøver.

Ændring i biomarkører for DMET efter 10 of 28 dages dicloxacillin behandling sammenlignet med baseline.

Ændring i exosome-biomarkører efter 10 og 28 dages behandling med dicloxacillin sammenlignet med baseline

E.5.2.1

Timepoint(s) of evaluation of this end point

After the drug analysis is completed

Når lægemiddelanalysen er afsluttet

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

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Pharmacokinetic trial

Farmakokinetisk forsøg

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

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

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Selv-kontrolleret

Self-controlled

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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. LVLS is defined as the day for the phone call 2 weeks after the last visit from the last trial subject.

LVLS.
LVLS er defineret som dagen for opringningen, 2 uger efter det sidste besøg fra den sidste forsøgsdeltager.

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:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

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)

In 3 weeks after the last visit the subjects need to use the following contraceptives to be sure of optimal protection, condom and/or diaphragm with spermicide or intrauterine device (copper or hormone).
Subjects will be contacted 2 weeks after the last visit and asked about any potential adverse events.

I 3 uger efter sidste besøg skal forsøgsdeltagerne benytte sig af følgende prævention for at være sikker på at opnå optimal beskyttelse, spiral (kobber- eller hormonspiral) eller kondom og/eller pessar med sæddræbende creme.
Forsøgsdeltagere vil desuden blive kontaktet 2 uger efter det sidste besøg og blive spurgt ind til om de har oplevet nogle bivirkninger.

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

2021-09-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-11-29

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-06-21

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