Clinical Trials Register

Summary
EudraCT Number:	2015-005772-16
Sponsor's Protocol Code Number:	HEH-SF-01
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:	2016-02-19
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

2015-005772-16

A.3

Full title of the trial

The safety and pharmacokinetics of intraperitoneal administration of granulocyte-macrophage colony-stimulating factor, fosfomycin, and metronidazole in patients undergoing appendectomy for uncomplicated appendicitis

A.3.1

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

The safety and blood concentration measurements of antibiotics after treatment with antibiotics and a drug, which stimulates the immune response, administrated in the abdominal cavity in patients undergoing appendectomy for appendicitis without perforation

Sikkerhed ved behandling med og måling af antibiotikakoncentrationen i blodet ved behandling med antibiotika og et lægemiddel, der stimulerer immunforsvaret, indgivet i bughulen under operation for blindtarmsbetændelse

A.4.1

Sponsor's protocol code number

HEH-SF-01

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	Department of Surgery, Herlev Hospital
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	Reponex Pharmaceuticals ApS
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	Department of Surgery
B.5.2	Functional name of contact point	CPO office
B.5.3	Address:
B.5.3.1	Street Address	Herlev Ringvej 75
B.5.3.2	Town/ city	Herlev
B.5.3.3	Post code	2730
B.5.3.4	Country	Denmark
B.5.4	Telephone number	004538683414
B.5.5	Fax number	004538683602
B.5.6	E-mail	siv.fonnes@regionh.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	No
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	Repomol
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraperitoneal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Fosfomycin disodium salt
D.3.9.1	CAS number	26016-99-9
D.3.9.3	Other descriptive name	FOSFOMYCIN
D.3.9.4	EV Substance Code	SUB127116
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	4000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
D.3.11.13.1	Other medicinal product type	Repomol (molgramostim/rhGM-CSF) is produced under GMP rules in a strain of E. coli bearing a genetically engineered plasmid which contains a human GM-CSF gene, and purified.
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	Metronidazol "B. Braun"
D.2.1.1.2	Name of the Marketing Authorisation holder	B. Braun
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraperitoneal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METRONIDAZOLE
D.3.9.1	CAS number	443-48-1
D.3.9.3	Other descriptive name	METRONIDAZOLE
D.3.9.4	EV Substance Code	SUB08922MIG
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	1000
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: 3
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	Infectofos
D.2.1.1.2	Name of the Marketing Authorisation holder	Infectopharm
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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 infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraperitoneal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	rhGM-CSF
D.3.9.1	CAS number	8000048-22-8
D.3.9.3	Other descriptive name	GRANULOCYTE MACROPHAGE COLONY STIM FACTOR
D.3.9.4	EV Substance Code	SUB14019MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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

We intend to investigate the safety of treating secondary infectious peritonitis due to uncomplicated appendicitis with intraperitoneally administered fosfomycin, metronidazole and GM-CSF.

Vi ønsker at undersøge sikkerheden ved behandling af sekundær, infektiøs peritonitis grundet ukompliceret appendicitis acuta med fosfomycin, metronidazol og GM-CSF indgivet intraperitonealt.

E.1.1.1

Medical condition in easily understood language

We intend to investigate the safety of treating appendicitis without perforation with antibiotics and a drug, which stimulates the immune response, administered into the abdominal cavity.

Vi ønsker at undersøge sikkerheden ved behandling af blindtarmsbetændelse uden perforation med antibiotika og et lægemiddel, der stimmulerer immunforsvaret, indgivet ind i bughulen.

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10000677
E.1.2	Term	Acute appendicitis
E.1.2	System Organ Class	100000004862

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10053349
E.1.2	Term	Pharmacokinetic study
E.1.2	System Organ Class	100000004848

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 safety of intraperitoneal administration is evaluated through the white blood cell counts 4 hours postoperatively. A toxic effect is defined by a drop below the lower reference range.

E.2.2

Secondary objectives of the trial

Repeated biochemical markers (including a white blood cell differential count, inflammation marker C-reactive protein (CRP), kidney function tests, liver function tests, and electrolytes), vital signs (blood pressure, pulse, frequency of respiration, peripheral saturation (SAT), and temperature), length of stay, side effects, and adverse events until 30 days after surgery.

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

Full title of the sub-trial: The pharmacokinetics of fosfomycin and metronidazole after intraperitoneal administration of granulocyte-macrophage colony-stimulating factor, fosfomycin, and metronidazole in patients undergoing appendectomy for uncomplicated appendicitis.
Short title of the sub-trial: Pharmacokinetics.
Date: 15.02.2016.
Version: 1.7.
Number of participants: 8 patients.

Main objective: Investigation of the plasma concentrations of fosfomycin over time are measured with high-performance liquid chromatography mass spectrometry (HPLC-MS).

Time-points for main objective: Blood samples will be collected at ½, 1, 2, 4, 8, 12, and 24 hours after the trial treatment. The blood sample at ½, 1, and 2 hours will be collected with a leeway of ±15 minutes. The blood sample at 4, 8, and 12 hours will be collected with a leeway of ±30 minutes. The blood sample at 24 hours after surgery will be collected with a leeway of ±4 hours.

Secondary objectives: Investigations of the plasma concentrations of metronidazole over time are measured with HPLC-MS and microbiological investigations of specimens from appendices and/or abdominal fluid removed during surgery with regard to microbiological flora and susceptibility.

Time-points for secondary objectives:
Blood samples will be collected at ½, 1, 2, 4, 8, 12, and 24 hours after the trial treatment. The blood sample at ½, 1, and 2 hours will be collected with a leeway of ±15 minutes. The blood sample at 4, 8, and 12 hours will be collected with a leeway of ±30 minutes. The blood sample at 24 hours after surgery will be collected with a leeway of ±4 hours.
Microbiological specimens will be collected peroperatively.

E.3

Principal inclusion criteria

Men ≥18 years old
Suspicion of acute appendicitis and planned for diagnostic laparoscopy and eventual appendectomy
Written informed consent after written and verbal information

Mand ≥18 år
Mistænkt syg af en blindtarmsbetændelse og planlagt til en diagnostisk kikkertoperation med henblik på at fjerne blindtarmen.
Skriftligt, informeret samtykke efter mundtlig og skriftlig information

E.4

Principal exclusion criteria

Cannot understand, read or speak Danish
Previous allergic reaction to fosfomycin, metronidazole, or GM-CSF
Perforated appendicitis (diagnosed either during surgery or at a preoperative computer tomography (CT) scan)
Diagnostic laparoscopy revealing normal appendix not requiring an appendectomy
Other intra-abdominal pathology requiring surgical intervention (diagnosed either during surgery or at a preoperative CT-scan)
Known renal or hepatic disease or biochemical evidence at the time of admission
Known autoimmune disease or other chronic inflammation
Known hematologic disease or cancer
Previous abdominal surgery (either laparoscopic or open surgery)
Daily use or use of medication one week prior to or during the trial period apart from painkillers such as paracetamol, ibuprofen, tramadol, and morphine as well as drugs needed for anaesthesia, thrombosis prophylaxis, and nausea. Limitations for antibiotics are defined below
Use of other antimicrobial agents than the trial treatment one month before until 24 hours after the trial treatment
Participant in another drug trial one month prior to the date of the surgery
Body mass index ≥35 kg/m2
Weekly intake of alcohol >14 units, where one unit corresponds to 12 g alcohol

Ikke i stand til at forstå, læse eller tale dansk
Tidligere allergisk reaktion overfor fosfomycin, metronidazol eller granulocyt-makrofag koloni-stimulerende faktor
Blindtarmsbetændelse med synligt hul (diagnosticeret enten under operation eller ved en CT-skanning inden operationen)
Ikke nødvenligt at fjerne blindtarmen under kikkertoperationen
Anden operationskrævende sygdom i bughulen (diagnosticeret enten under operationen eller ved en CT-scanning inden operationen)
Kendt med nyre- eller leversygdom
Kendt med autoimmun sygdom eller kronisk betændelsestilstand
Kendt med blodsygdom eller kræft
Tidligere opereret i maven (enten ved kikkertoperation eller åben operation)
Dagligt medicinindtag eller indtag af medicin en uge forud for eller under forsøgsperioden fraset smertestillende så som paracetamol, ibuprofen, tramadol eller morfin samt de lægemidler, der er nødvendige for bedøvelse, forebyggelse af blodpropper og kvalmestillende. Begrænsninger med hensyn til antibiotika er beskrevet nedenfor
Infusion af eller tabletbehandling med andre antibiotika end forsøgslægemidlerne en måned før indtil 24 timer efter indgivelse af forsøgslægemidlerne
Deltager i et andet lægemiddelstudie en måned forud for operationsdatoen
Body mass index (BMI)≥ 35 kg/m2
Ugentligt alkoholindtag >14 genstande, hvor en genstand svarer til 12 g alkohol

E.5 End points

E.5.1

Primary end point(s)

Compare preoperative (baseline) with postoperative white blood cell counts. A toxic effect defined by a drop below the reference range.

E.5.1.1

Timepoint(s) of evaluation of this end point

Preoperatively (baseline) and 4 hours ± 30 minutes postoperatively.

E.5.2

Secondary end point(s)

Compare preoperative (baseline) with postoperative standard panel of blood samples.
Vital signs: Pulse, blood pressure, temperature, frequency of respiration, and SAT.
Length of stay in hours postoperatively.
Side effects: Evaluated through an objective examination and questions about changes.
Adverse events: Registered from the surgery until 30 days postoperatively through medical records and contact with the participant by telephone.

E.5.2.1

Timepoint(s) of evaluation of this end point

Blood samples: Preoperatively (baseline) and 4 hours ± 30 minutes postoperatively.
Vital values: Measured perioperatively at: Baseline, 5 minutes, 10 minutes and 15 minutes after the trial treatment has been administered and postoperatively at: 4 and 12 hours ± 30 minutes after the trial treatment has been administered.
Length of stay: After discharge.
Side effects: 12 hours ± 30 minutes and 10 days postoperatively ± 1 day.
Adverse events: 30 days postoperatively.

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

E.6.6

Pharmacokinetic

Yes

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

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)

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

E.8.1.1

Randomised

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

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

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

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

E.8.9.2

In all countries concerned by the trial months

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)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

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

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

2016-06-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-04-14

P. End of Trial
P.	End of Trial Status	Completed

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