Clinical Trials Register

Summary
EudraCT Number:	2015-003662-87
Sponsor's Protocol Code Number:	Pseud-0708-MLJ
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-09-22
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

2015-003662-87

A.3

Full title of the trial

Pseudomonas Aeruginosa - Inhalation treatment, biomarkers and quality of life

Pseudomonas Aeruginosa - Inhalationsbehandling, biomarkører og livskvalitet

A.3.1

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

Pseudomonas Aeruginosa - Inhalation treatment, biomarkers and quality of life

Pseudomonas Aeruginosa - Inhalationsbehandling, biomarkører og livskvalitet

A.3.2

Name or abbreviated title of the trial where available

Pseudomonas, Tazocin or Colistin

Pseudomonas, Tazocin eller Colistin

A.4.1

Sponsor's protocol code number

Pseud-0708-MLJ

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	Aarhus University Hospital, Department of Respiratory Medicine
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	Danish Lung Association
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	Aarhus University Hospital
B.5.2	Functional name of contact point	Department of Respiratory Medicine
B.5.3	Address:
B.5.3.1	Street Address	Noerrrebrogade 44
B.5.3.2	Town/ city	Aarhus C
B.5.3.3	Post code	8000
B.5.3.4	Country	Denmark
B.5.4	Telephone number	78 45 00 00 +45
B.5.6	E-mail	madjesen@rm.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	colistimethate sodium (promixin)
D.2.1.1.2	Name of the Marketing Authorisation holder	Orifarm 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	Inhalation vapour, powder
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	COLISTIMETHATE SODIUM
D.3.9.1	CAS number	8068-28-8
D.3.9.4	EV Substance Code	SUB06801MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000000
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	Piperacillin with Tazobactam (tazocin)
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer APS
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	Powder and solvent for solution for 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	PIPERACILLIN
D.3.9.3	Other descriptive name	PIPERACILLIN
D.3.9.4	EV Substance Code	SUB09867MIG
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TAZOBACTAM
D.3.9.3	Other descriptive name	TAZOBACTAM
D.3.9.4	EV Substance Code	SUB10849MIG
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

Chronic pulmonary disease patients, except cystic fibrosis patients, with confirmed pulmonary infection by sputum sample positive for Pseudomonas Aeruginosa.

Kronisk lungesyge, fraset cystisk fibrose patienter, med verificeret Pseudomonas Aeruginosa pneumoni verificeret ved sputum dyrkning.

E.1.1.1

Medical condition in easily understood language

Chronic pulmonary disease patients, except cystic fibrosis patients, with confirmed pulmonary infection by sputum sample positive for Pseudomonas Aeruginosa.

Kronisk lungesyge, fraset cystisk fibrose patienter, med verificeret Pseudomonas Aeruginosa pneumoni verificeret ved dyrkning af sekret fra luftvejene.

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10051190
E.1.2	Term	Pneumonia Pseudomonas aeruginosa
E.1.2	System Organ Class	100000004862

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10050700
E.1.2	Term	Chronic respiratory disease NOS
E.1.2	System Organ Class	100000004855

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Chronic pulmonary disease patients often gets bacterial pneumonia with the bacteria Pseudomonas Aeruginosa, often with severe morbidity and mortality as a result. It is well examined for patients with cystic fibrosis, but for non-cystic fibrosis chronic pulmonary disease patients our knowledge is sparse. The standard treatment at the moment is 14 days of a combination of intravenously and oral antibiotic. We will examine whether we can more effectively clear the infection with inhaled colistimethate and oral ciprofloxacin. Furthermore we will follow the patient with pulmonary function tests, sputum samples for relapse infections and clinical assessments.

Kronisk lungesyge bliver ofte pulmonalt inficeret med bakterien Pseudomonas Aeruginosa, ofte med øget morbiditet og mortalitet som resultat. Pneumonien er velkendt og velundersøgt for patienter med cystisk fibrose, men for andre kronisk lungesyge er der kun sparsom viden omhandlende dette. Standart behandlingen er 14 dages intravenøs og oral antibiotisk behandling. Vi vil undersøge om vi mere effektivt kan behandle infektionen med inhaleret colistin og oral ciprofloxacin. Yderligere vil vi følge patienterne med lungefunktioner, sputum dyrkninger for evt recidiv og generel kliniske vurderinger.

E.2.2

Secondary objectives of the trial

Secondary end points is to examine the current and future immune status of the infected patient and to examine their experience of “quality of life” between the control and intervention group during 1 year of follow up. Further more we will examine whether we can make an assessment of the risk for the patient when they debut with their infection by means of biomarkers.

Secondære end-points er at undersøge den aktive og fremtidige immunstatus på vores inficerede patient samt undersøge deres vurdering af livskvalitet i forhold til interventions og kontrolgruppen gennem vores 1års follow-up periode. Yderligere vil vi undersøge om vi kan lave risikostratificering for den inficerede patient vha. forskellige biomarkører.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

In order to be eligible to participate in this study, the patient must meet all of the following criteria:
· Signed informed consent to participate in the study in accordance with local
regulations
· Diagnosed with a chronic pulmonary disease by lung functions test or CT
· Diagnosed with one positive sputum sample with PA during the last year
· Age 18 - 85 years inclusive
· Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study
procedures specified in the protocol.

For at være inklusionskandidat må patient have følgende kriterier:
- Informeret samtykke
- Kronisk lungesygdom diagnosticeret via lungefunktionstest eller CT
- Have en positiv sputum prøve med Pseudomonas
- Være mellem 18-85år
- Villig til at medvirke til aftalte kontroller m.m.

E.4

Principal exclusion criteria

A potential subject who meets any of the following criteria will be excluded from participation in this study:
· Prophylactic treatment with any other antibiotic
· Allergy to tazocin, ciprofloxacin or colistimethate-sodium
· Patients who are pregnant or planning a pregnancy
· Patients with any solid organ transplant
· Patients with cystic fibrosis
· Patients on assisted ventilation
· Bronchiectasis as a consequence of cystic fibrosis or focal endobronchial
lesion or otherwise curable causes (e.g. foreign body aspiration)
· Be considered "terminally ill" or listed for transplantation
· Actively treated Mycobacterium tuberculosis or other mycobacteria
· Patients in a condition or in a situation, which in the investigator's opinion
may put the subject at significant risk, may confound results or may interfere
significantly with the patient's participation in the study

- Profylaktisk antibiotisk behandling
- Allergi overfor forsøgsstofferne
- Gravide eller planlagt gravide
- Organtransplanterede
- Cystisk fibrose
- Patienter på assisteret ventilation
- Bronchiectasier med årsag i cystisk fibrose eller fokal endobronchial skade
- Terminal syg eller på transplantationsliste
- Aktiv behandlet mycobakterieinfektion
- Vurderes generelt ikke egnet til at gennemføre kontrolforløbet

E.5 End points

E.5.1

Primary end point(s)

1: Number of positive Pseudomonas (PA) sputum cultures after treatment and 12, 26 and 52 weeks after end of treatment. If possible PCR for PA oprf gene.

2: Number of specific immune deficiencies and their relation to baseline clinical status and clinical outcome.

3: Number of precipitating antibodies during intervention and follow-up, measured 26 and 52 weeks after treatment.

1: Antal positive PA sputum dyrkninger efter endt behandling samt efter 12, 26 og 52 uger. Hvis muligt undersøgelse for PA oprf genet.

2: Antal specifikke immun defekter og deres korrelation til baseline klinisk status og clinical outcome.

3: Antal precipiterende antistoffer under intervention og follow-up, målt 26 og 52 uger efter endt behandling.

E.5.1.1

Timepoint(s) of evaluation of this end point

Each patient will be followed for a year. The trial will run for 2-3 years.

Hver patient følges i 1 år. Selve forsøget løber over 2-3 år.

E.5.2

Secondary end point(s)

1: Relative change from baseline of FVC (% predicted), FEV1 (% predicted), DLCO and 6minuttes walking test (6MWT) at follow-up.
2: Subjective change in dyspnea, cough and quality of life after treatment and at follow-up.
3: Numbers of exacerbations and hospital admissions after treatment
4: Assess whether immune deficiencies can be used as a prognostic factor
5: Changes in immunoglobulins, interferon gamma and lymphocytes during follow-up
6: Number of pre-treatment precipitating antibodies and their relation to the number of cleared PA infections, change in lung function and dyspnea score at 12, 26 and 52 weeks after treatment.
7: Correlation between detected exotoxins, exoenzymes and TNFR75 on clinical outcome determined by the numbers of exacerbations, number of sputum eradications of PA, time to sputum eradication of PA, time to stabilization of pulmonary function, 6MWT and survival.
8: Correlation between detected plasma elastase and alkaline protease on clinical outcome determined by the numbers of exacerbations, number of sputum eradications of PA, time to sputum eradication of PA, time to stabilization of pulmonary function, 6MWT and survival.

1: Relative ændringer fra baseline af FVC, FEV1, DLCO og 6MWT ved follow-up.
2: Subjektive ændringer i dyspnø, hoste og livskvalitet efter endt behandling og ved follow-up.
3: Antal exacerbationer og indlæggelser i follow-up perioden
4: Undersøge om immundefekter kan være en prognostisk faktor
5: Ændringer i immonoglobuliner, interferon gamma og lymfocytter ved follow-up
6: Antal precipiterende antistoffer før behandling og deres relation til antallet af clearede PA infektioner, ændring i lungefunktion og dyspnøscore efter 12, 26 og 52 uger efter endt behandling.
7: Sammenhæng med detekterede exotoksiner, exoenzymer og TNFR75 på klinisk outcome bestemt ved antal exacerbationer, antal sputum eradikationer af PA, tid til eradikation, tid til stabilisering af lungefunktion, 6MWT og overlevelse.
8: Sammenhæng med detekteret plasma elastase/alkalisk protease på klinisk outcome bestemt ved antal exacerbationer, antal sputum eradikationer af PA, tid til eradikation, tid til stabiliseret lungefunktion, 6MWT og overlevelse.

E.5.2.1

Timepoint(s) of evaluation of this end point

Each patient will be followed for a year. The trial will run for 2-3 years.

Hver patient følges i 1 år. Selve forsøget løber over 2-3 år.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

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

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

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

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

Each patient will be followed for a year. The trial will run for 2-3 years.

Hver patient følges i 1 år. Selve forsøget løber over 2-3 år.

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)

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

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

110

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

Ingen

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

2015-11-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-10-20

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2017-08-18

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