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)

• Register: EUCTR
• Last refreshed on: 14 March 2022
• Main ID: EUCTR2016-004558-13-PL
• Date of registration: 30/06/2017
• Prospective Registration: Yes
• Primary sponsor: Zambon S.p.A.
• Public title: 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)
• Scientific title: 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) - PROMIS II
• Date of first enrolment: 14/08/2017
• Target sample size: 420
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-004558-13
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Canada, France, Germany, Greece, Israel, Italy, New Zealand, Poland, Portugal, United States

Contacts

• Name: Dearbhla Hull
• Affiliation: Zambon S.p.A.

• Name: Dearbhla Hull
• Affiliation: Zambon S.p.A.

Key inclusion & exclusion criteria

Inclusion criteria:
Subjects can be included in the trial if they meet all 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 genders;
3. Are diagnosed with NFCB by CT (or high resolution CT) 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.
Are the trial subjects under 18? no
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 210
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 210

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 immunocompetent 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 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, cyclosporin, tacrolimus, sirolimus, mycophenolate, anticytokine medications, rituximab) and/or
anti-cytokine medications (such asanti-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 mycobacterial (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 evidence of bronchial hyper-reactivity following inhaled
colistimethate sodium;
14. treatment with long term (= 30 days) prednisone at a dose of 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) within 30 days of the Screening Visit (Visit 1) or started between Visit 1 and Visit 2;
16. use of any intravenous or intramuscular or oral or inhaled anti-pseudomonal
antibiotic (except chronic macrolides 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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Non-cystic fibrosis bronchiectasis chronically infected with Pseudomonas aeruginosa
MedDRA version: 21.0 Level: PT Classification code 10006445 Term: Bronchiectasis System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

Intervention(s)

Trade Name: Promixin, 1 million International Units (IU) Powder for Nebuliser Solution
Product Name: Colistimethate sodium
Pharmaceutical Form: Powder for nebuliser solution
INN or Proposed INN: COLISTIMETHATE SODIUM
CAS Number: 8068-28-8
Other descriptive name: Colistimethate Sodium
Concentration unit: IU international unit(s)
Concentration type: equal
Concentration number: 1000000-
Pharmaceutical form of the placebo: Powder for nebuliser solution
Route of administration of the placebo: Inhalation use

Primary Outcome(s)

Main Objective: 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

Primary end point(s): Primary Efficacy Variable
The primary variable for this trial is the mean annual NCFB pulmonary exacerbation rate.

Secondary Objective: The secondary objectives of the trial are to investigate the effect of the use of inhaled colistimethate sodium, administered twice daily via the Ineb for 12 months in subjects with NCFB chronically infected with P. aeruginosa on:
• the time to the first pulmonary exacerbation compared to placebo;
• the number of exacerbation-free days compared to placebo;
• the severity of pulmonary exacerbations compared to placebo;
• the time to the first severe pulmonary exacerbation compared to placebo;
• the Quality of Life compared to placebo;
• to evaluate the pharmaco-economic effect of the use of inhaled colistimethate sodium, administered twice daily via the I-neb for 12 months, compared to placebo;
• the density and susceptibility of P. aeruginosa compared to placebo and to investigate the emergence of other bacterial colonies and any developing resistance;
• to characterize the safety and tolerability of inhaled colistimethate sodium compared to placebo.

Timepoint(s) of evaluation of this end point: 12 months

Secondary Outcome(s)

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.

Safety Variables:
• incidence of treatment emergent adverse events (TEAEs);
• absolute changes in percent-predicted FEV1 from baseline to each post-baseline visit;
• number of subjects experiencing bronchospasm clinically or spirometrically determined following IMP administration;
• P. aeruginosa resistance to colistin sulphate as determined by in-vitro susceptibility testing on sputum from Screening/Randomisation (Visit 1/Visit 2) to Visits 3, 5 and 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.

Timepoint(s) of evaluation of this end point: For timepoints, please refer protocol Section 19.2 Study Variables and Protocol Appendix 1

Secondary ID(s)

2016-004558-13-FR

Z7224L02

Source(s) of Monetary Support

Zambon SpA

Ethics review

Status: Approved
Approval date: 06/07/2017
Contact: