Clinical Trials Register

Summary
EudraCT Number:	2016-001528-69
Sponsor's Protocol Code Number:	EmergencyMedicineTrial001
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-08-10
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

Ireland - HPRA

A.2

EudraCT number

2016-001528-69

A.3

Full title of the trial

PENICILLIN FOR THE EMERGENCY DEPARTMENT-DIRECTED OUTPATIENT TREATMENT OF CELLULITIS (PEDOCELL) STUDY: A NON-INFERIORITY ADAPTIVE RANDOMISED CONTROLLED TRIAL.

A.3.1

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

Clinical trial of one antibiotic (flucloxacillin) versus two antibiotics (flucloxacillin and phenoxymethylpenicillin) for the Emergency department treatment of skin infections

A.4.1

Sponsor's protocol code number

EmergencyMedicineTrial001

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	Royal College of Surgeons in Ireland
B.1.3.4	Country	Ireland
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	Health Research Board
B.4.2	Country	Ireland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Royal College of Surgeons in Ireland
B.5.2	Functional name of contact point	Quality & Regulatory Affairs Manage
B.5.3	Address:
B.5.3.1	Street Address	RCSI Smurfit Building
B.5.3.2	Town/ city	Dublin
B.5.3.3	Post code	Dublin 9
B.5.3.4	Country	Ireland
B.5.4	Telephone number	00353018093863
B.5.5	Fax number	00353018093809
B.5.6	E-mail	mandyjackson@rcsi.com

D. IMP Identification
D.IMP: 1
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	Floxapen
D.2.1.1.2	Name of the Marketing Authorisation holder	Actavis Group PTC
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
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.3.1	Product name	Flucloxacillin
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	FLUCLOXACILLIN
D.3.9.1	CAS number	5250-39-5
D.3.9.4	EV Substance Code	SUB07673MIG
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	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	Penicillin VK
D.2.1.1.2	Name of the Marketing Authorisation holder	Sandoz GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
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.3.1	Product name	Phenoxymethylpenicillin
D.3.4	Pharmaceutical form	Film-coated tablet
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	PHENOXYMETHYLPENICILLIN POTASSIUM
D.3.9.1	CAS number	132-98-9
D.3.9.4	EV Substance Code	SUB03766MIG
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Skin Infection

E.1.1.1

Medical condition in easily understood language

Acute Bacterial Skin Infection (ABSSSI)

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 determine the non-inferiority of oral flucloxacillin alone (monotherapy) compared with a combination of oral flucloxacillin and phenoxymethylpenicillin (dual therapy) for the ED- directed outpatient treatment of cellulitis.

E.2.2

Secondary objectives of the trial

To measure adherence and persistence of trial patients with outpatient antibiotic therapy measured by self-report and counting the number of unused study medications at the end of treatment visit. In addition, to describe adherence and persistence in a sub-study using an electronic medication event monitoring system (MEMS®)
II. To perform a within-trial evaluation of the cost per QALY gained from the use of oral flucloxacillin compared with combination therapy over a one-month time horizon from the perspective of the health-care payer (direct costs). In a secondary analysis the perspective will be extended to consider costs related to the intervention falling on the patient and government.
III. To externally validate the ESTI-score, a HRQL questionnaire designed to quantify the impact of cellulitis on patient HRQL in clinical trials.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

The study design includes a sub-study to evaluate both adherence to therapy using an electronic monitoring system (MEMS) and persistence to therapy within the trial. The purpose of this is to both describe these parameters in the understudied area of short course outpatient antibiotic treatment as well as providing evidence for any adjustments in analysis based on medication taking behaviour. The objectives of the sub-study is to measure adherence and persistence of trial patients with outpatients antibiotic therapy measure by self report and counting the number of unused study medication at the end of treatment visit. In addition, to describe adherence and persistence in a sub-study using electronic medication event monitoring system (MEMS)

E.3

Principal inclusion criteria

1. Clinically diagnosed cellulitis, wound infection & abscess affecting any body part, excluding the perineum, and having any two of the following signs:
•Erythema
•Warmth
•Tenderness / Pain of affected area
•Oedema / Induration
•Regional lymphadenopathy
•Purulent drainage
2. Cellulitis, wound infection & abscess deemed treatable with oral antibiotics on an outpatient basis
3. Patients with cellulitis, wound infection & abscess who have no signs of systemic toxicity and have no uncontrolled co-morbidities.
4. Written informed consent obtained.
5. 16 years of age or older.
6. Fluency in written and spoken English.
7. Willing to return for study follow-up or to have the research nurse or clinical project coordinator visit them.
8. Willing to receive a telephone call from a study investigator.

E.4

Principal exclusion criteria

1. Penicillin allergy (self-reported or confirmed).
2. Any cellulitis wound infection & abscess that treating clinicians deem treatable with intravenous (IV) antibiotics.
3.
3. Patients that may have a significant systemic upset such as acute confusion, tachycardia, tachypnoea, hypotension or may have unstable co-morbidities that may interfere with a response to therapy or have a limb threatening infection due to vascular compromise.
4. Patients who may have a severe life threatening infection such as necrotizing fasciitis.
5. Any cellulitis wound infection & abscess of the perineal region.
6. Patients who have received more than 24 hours of effective antibiotics for the current episode of acute cellulitis, wound infection & abscess
7. Any medical condition, based on clinical judgment that may interfere with the interpretation of the primary outcome measures (e.g. a chronic skin condition at the site of the cellulitis wound infection or abscess).
8. Immunodeficiency from primary or secondary causes (e.g. corticosteroids, chemotherapeutic agents).
9. Previous history of renal dysfunction or known chronic kidney disease under the care of a nephrologist.  
10. Previous history of liver dysfunction defined as chronically deranged liver function tests elicited from the medical notes or history.
11. Suspected or confirmed septic arthritis.
12. Suspected or confirmed osteomyelitis.
13. Infection involving prosthetic material.
14. Pregnant or lactating women.
15. Patients with a previous history of flucloxacillin-associated jaundice/hepatic dysfunction
16. Patients with a previous history of methicillin-resistant staphylococcus aureus (MRSA) colonisation/infection.
17. Patients with lactose intolerance diagnosed by a medical professional.
18. Patients currently taking probenecid, neomycin, chloramphenicol, erythromycin , tetracyclines sulfinpyrazone, methotrexate, guar gum or an oral anticoagulant.

E.5 End points

E.5.1

Primary end point(s)

i. A suitably trained member of the study team will determine clinical cure at the TOC visit. This is a clinically-determined response to treatment based on the judgment of a suitably trained member of the study team.
ii. Definition of clinical cure:
a. No treatment failure at any previous visit
b. Resolution or minimal presence of the following signs and symptoms from the baseline assessment based on the study investigators clinical assessment
i. Erythema
ii. Swelling
iii. Tenderness
iv. Induration

E.5.1.1

Timepoint(s) of evaluation of this end point

14- 21

E.5.2

Secondary end point(s)

The principle secondary outcome measure is a ≥ 20% reduction in lesion surface area on day 2-3 after enrolment compared to the baseline visit. In addition, the following secondary outcome measures will be assessed:
1. Clinical treatment failure at each follow-up visit
2. Adherence and persistence of trial patients with outpatient antibiotic therapy at EOT (day 8-10 post enrolment).
3. HRQL assessments at each follow-up visit.
4. A pharmaco-economic assessment of cost per QALY.

ECR measured on day 2-3 is defined as
i. ≥20% reduction in the lesion surface area from that which was measured at enrolment.
ii. Objective measurement of lesion size is the US-FDA recommended outcome measure of choice. In order to enhance the validity of the study findings, an objective measure of the percentage decrease in the diameter of infection at day 2-3 will be utilized as a secondary outcome measure.
iii. Surface area measurement will be achieved by multiplying the vertical and horizontal measurements of the lesion.

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 2-3 post enrolment
Day 8-10 Post enrolment and Day 14-21 Post enrolment

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

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

Yes

E.6.13

Others

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

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

Yes

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

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

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)

Yes

F.1.3.1

Number of subjects for this age range:

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

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

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

2016-10-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-09-23

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-04-07

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