Clinical Trials Register

Summary
EudraCT Number:	2015-002743-33
Sponsor's Protocol Code Number:	Z7224L01
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2016-12-13
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

UK - MHRA

A.2

EudraCT number

2015-002743-33

A.3

Full title of the trial

A double-blind, placebo controlled, multi-centre, clinical trial to investigate the efficacy and safety of 12 months of therapy with inhaled colistimethate sodium in the treatment of subjects with non-cystic fibrosis bronchiectasis chronically infected with Pseudomonas aeruginosa (P. aeruginosa)

A.3.1

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

A double-blind, placebo controlled, multicentre, clinical trial to investigate the efficacy and safety of 12 months of therapy with inhaled colistimethate sodium in the treatment of subjects with non-cystic fibrosis bronchiectasis chronically infected with Pseudomonas aeruginosa (P. aeruginosa)

A.3.2

Name or abbreviated title of the trial where available

PROMIS I

A.4.1

Sponsor's protocol code number

Z7224L01

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	Zambon S.p.A.
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Zambon SpA
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Zambon S.p.A.
B.5.2	Functional name of contact point	Medical Lead Clinical Development
B.5.3	Address:
B.5.3.1	Street Address	Via Lillo del Duca, 10
B.5.3.2	Town/ city	Milan
B.5.3.3	Post code	20091
B.5.3.4	Country	Italy
B.5.4	Telephone number	+441243859016
B.5.6	E-mail	clinicaltrials@zambongroup.com

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	Promixin/Tadim
D.2.1.1.2	Name of the Marketing Authorisation holder	Zambon S.p.A
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Colistimethate sodium
D.3.4	Pharmaceutical form	Powder for nebuliser solution
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.3.9.3	Other descriptive name	Colistimethate Sodium
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	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	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	Nebuliser solution
D.8.4	Route of administration of the placebo	Inhalation use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Non-cystic fibrosis bronchiectasis chronically infected with Pseudomonas aeruginosa

E.1.1.1

Medical condition in easily understood language

Non-cystic fibrosis bronchiectasis chronically infected with Pseudomonas aeruginosa

E.1.1.2

Therapeutic area

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

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10006445
E.1.2	Term	Bronchiectasis
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

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 objective of the trial is to investigate the effect of the use of inhaled colistimethate sodium, administered twice daily via the I-neb for 12 months, compared to placebo in subjects with NCFB chronically infected with P. aeruginosa on the frequency of pulmonary exacerbations

E.2.2

Secondary objectives of the trial

The secondary objectives of the trial are to investigate the effect of the use of inhaled colistimethate sodium, administered twice daily via the I-neb for 12 months, compared to placebo in subjects with NCFB chronically infected with P. aeruginosa on:

• the time to the first NCFB pulmonary exacerbation;
• the number of exacerbation-free days;
• number of severe NCFB pulmonary exacerbations, defined as those requiring intravenous antibiotics and/or hospitalisation;
• the time to the first NFCB severe pulmonary exacerbation;
• Quality of Life;
• pharmaco-economic evaluation;
• P. aeruginosa density and susceptibility and the emergence of other bacterial colonies and any developing resistance to colistin;
• Overall safety and tolerability.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects can be included in the trial if they meet all the inclusion criteria listed below:
1) are able and willing to give informed consent, following a detailed explanation of participation in the protocol and signed consent obtained;
2) are aged 18 years or older of either gender;
3) are diagnosed with NCFB by computerised tomography (CT) or high resolution CT (HRCT) as recorded in the subject’s notes and this is their predominant condition being treated;
4) had at least 2 NCFB pulmonary exacerbations requiring oral or inhaled antibiotics or 1 NCFB pulmonary exacerbation requiring intravenous antibiotics in the 12 months preceding the Screening Visit (Visit 1) and had no NCFB pulmonary exacerbation with or without treatment during the period between Visit 1 and Visit 2;
5) have a documented history of P. aeruginosa infection;
6) are clinically stable and have not required a change in pulmonary treatment for at least 30 days before the Screening Visit (Visit 1);
7) have pre-bronchodilator FEV1 ≥25% of predicted;
8) had a positive sputum culture for P. aeruginosa from an adequate sample taken at the Screening Visit (Visit 1) or during the screening period.

E.4

Principal exclusion criteria

Subjects are not eligible for the trial if they meet one or more of the exclusion criteria listed below:
1) known bronchiectasis as a consequence of cystic fibrosis (CF);
2) known history of hypogammaglobulinaemia requiring treatment with immunoglobulin, unless fully replaced and considered immuno-competent by the Investigator;
3) myasthenia gravis or porphyria;
4) severe cardiovascular disease such as severe uncontrolled hypertension, ischaemic heart disease or cardiac arrhythmia and any other conditions that would confound the evaluation of safety, in the opinion of the Investigator;
5) had major surgery in the 3 months prior to the Screening Visit (Visit 1) or planned inpatient major surgery during the study period;
6) receiving treatment for allergic bronchopulmonary aspergillosis (ABPA);
7) had massive haemoptysis (greater than or equal to 300 mL or requiring blood transfusion) in the preceding 4 weeks before the Screening Visit (Visit 1) or between Visit 1 and Visit 2;
8) respiratory failure that would compromise patient safety or confound the evaluation of safety or efficacy of the study in the opinion of the Investigator;
9) current active malignancy, except for basal cell carcinoma or squamous cell carcinoma of the skin without metastases;
10) taking immunosuppressive medications (such as azathioprine, cyclosporine, tacrolimus, sirolimus, mycophenolate, rituximab), and/or anti-cytokine medications (such as anti-IL-6 and anti-tumour alpha necrosis factor products) in the preceding year before the Screening Visit (Visit 1);
11) known history of human immunodeficiency virus (HIV);
12) current treatment for non-tuberculous mycobacterium (NTM) lung disease or tuberculosis.
13) known or suspected to be allergic or unable to tolerate colistimethate sodium (intravenous or inhaled) or other polymixins, including previous evidence of bronchial hyper-reactivity following inhaled colistimethate sodium;
14) treatment with long term (≥ 30 days) prednisone at a dose greater than 15 mg a day (or equivalent dose of any other corticosteroid) within six months of the Screening Visit (Visit 1);
15) new maintenance treatment with any oral macrolides (e.g. azithromycin/erythromycin/clarithromycin) started within 30 days of the Screening Visit (Visit 1) and between Visit 1 and Visit 2;
16) use of any intravenous or intramuscular or oral or inhaled anti-pseudomonal antibiotic (except chronic oral macrolide treatment with a stable dose) within 30 days prior to the Screening Visit (Visit 1) and between Visit 1 and Visit 2;
17) pregnant or breast feeding or plan to become pregnant over the next year or of child-bearing potential and unwilling to use a reliable method of contraception for at least one month before randomisation and throughout their involvement in the trial;
18) significant abnormality in clinical evaluations and/or laboratory tests (physical examination, vital signs, haematology, clinical chemistry, clinically relevant impaired renal function, defined as serum creatinine levels ≥2.0x upper limit of normal, ECG) endangering the safe participation of the patient in the study at the Screening Visit (Visit 1) and during the study;
19) participated in another investigational, interventional trial within 30 days prior to the Screening Visit (Visit 1);
20) in the opinion of the Investigator not suitable for inclusion for whatever reason.

E.5 End points

E.5.1

Primary end point(s)

Primary Efficacy Variable:
· Mean annual pulmonary exacerbation rate

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

E.5.2

Secondary end point(s)

Secondary Efficacy Variables:
· the time (in days) from the first dose of IMP until the first pulmonary exacerbation;
· annualised number of pulmonary exacerbation-free days;
· number of severe pulmonary exacerbations, defined as those requiring intravenous antibiotics and/or hospitalisation;
· the time (in days) from the first dose of IMP until the first severe pulmonary exacerbation;
· quality of life (QoL) as measured by the total score of the Saint George's Respiratory Questionnaire (SGRQ) and Quality of Life – Bronchiectasis (QOL B) questionnaire as well as changes in SGRQ and QOL-B from baseline to each post-baseline visit;
· number of days of work absence due to pulmonary exacerbations;
· P. aeruginosa density as determined by the mean change in log10 colony forming units (CFU)/g sputum from baseline (Visit 2) to Day 28 of treatment (Visit 3) as well as to Visits 5 and 7, inclusive.
Safety Variables:
· incidence of treatment emergent adverse events (TEAEs);
· absolute changes in percent-predicted FEV1 from baseline (Visit 2) to end of treatment (Visit 7);
· number of subjects experiencing bronchospasm clinically or spirometrically determined following IMP administration at the end of treatment;
· P. aeruginosa resistance to colistin sulphate as determined by in-vitro susceptibility testing on sputum from Screening (Visit 1) to end of treatment (Visit 7) as well as on sputum from Exacerbation Visits and clinic visits due to pneumonia;
· emergence of other bacterial colonies and any developing resistance in sputum from Screening (Visit 1) to End of Treatment (Visit 7);
· haematology, clinical chemistry and renal function tests;
· physical examination and vital signs data;
· 12-lead electrocardiogram.

E.5.2.1

Timepoint(s) of evaluation of this end point

For time points, please refer protocol Section 18.2 Study Variables and Protocol Appendix 1

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

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)

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

E.8.2.2

Placebo

Yes

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Belgium

France

Germany

Greece

Israel

Italy

Netherlands

New Zealand

Portugal

Spain

Switzerland

United Kingdom

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 years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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:

210

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

210

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

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.4.2

For a multinational trial

F.4.2.1

In the EEA

410

F.4.2.2

In the whole clinical trial

420

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)

After the end of the study the patient will return to standard treatment

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

2017-01-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-21

P. End of Trial
P.	End of Trial Status	GB - no longer in EU/EEA

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