Efficacy and Safety of Inhaled CMS in Bronchiectasis Subjects With Chronic P. Aeruginosa Infection. (PROMIS-I) (PROMIS-I)

Double-blind, Placebo-controlled, Clinical Trial on Efficacy and Safety of 12-months Therapy With Inhaled Colistimethate Sodium in the Treatment of Subjects With Non-cystic Fibrosis Bronchiectasis Chronically Infected With P. Aeruginosa

The objective of the trial was to investigate the effect of the use of inhaled CMS, administered b.i.d. via a specific nebuliser for 12 months, compared to placebo in subjects with NCFB chronically infected with P. aeruginosa on the annualised frequency of pulmonary exacerbations.

Study Overview

• Status: Completed
• Conditions: Non Cystic Fibrosis Bronchiectasis
• Intervention / Treatment: Drug: CMS; Other: Placebo

Detailed Description

This was a randomised, multi-centre, double-blind, placebo-controlled, parallel group interventional trial in subjects with NCFB and chronic P. aeruginosa infection. Subjects were randomised to CMS or placebo in a 1:1 ratio. The study consisted of seven clinic visits over one year with a follow-up phone call two weeks after discontinuation of treatment. Additional clinic visits, where feasible,and weekly phone calls were conducted during or after pulmonary exacerbations (or any episodes of pneumonia) until resolution.

All planned and unscheduled visits were preferably performed at sites, whenever possible. If on site visits after Visit 2 could not be performed at site due to COVID-19, remote visits (e.g., by telephone) were permitted. Mandatory on site visits were kept for Screening Visit (Visit 1) and Randomisation (Visit 2). If the final visit (Visit 7) had to be conducted remotely, then subjects were asked to return to the clinic for on-site assessments at the earliest opportunity.

• Study Type: Interventional
• Enrollment (Actual): 377
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, 5000
    • Zambon Investigative Site
  • Adelaide, Australia, 5042
    • Zambon Investigative Site
  • Chermside, Australia, 4032
    • Zambon Investigative Site
  • Concord, Australia, NSW 2134
    • Zambon Investigative Site
  • Frankston, Australia, VIC 3199
    • Zambon Investigative Site
  • Greenslopes, Australia, 4120
    • Zambon Investigative Site
  • Melbourne, Australia, 3004
    • Zambon Investigative Site
  • Nedlands, Australia, WA 6009
    • Zambon Investigative Site
  • New Lambton Heights, Australia, 2305
    • Zambon Investigative Site
  • South Brisbane, Australia, 4101
    • Zambon Investigative Site
  • Spearwood, Australia, 6163
    • Zambon Investigative Site
  • Westmead, Australia, NSW 2145
    • Zambon Investigative Site
• Belgium
  • Gent, Belgium, 9000
    • Zambon Investigative Site
  • Roeselare, Belgium, 8800
    • Zambon Investigative Site
• Germany
  • Berlin, Germany, 10717
    • Zambon Investigative Site
  • Berlin, Germany, 14059
    • Zambon Investigative Site
  • Essen, Germany, 45239
    • Zambon Investigative Site
  • Frankfurt am Main, Germany, 60590
    • Zambon Investigative Site
  • Frankfurt am Main, Germany, 60596
    • Zambon Investigative Site
  • Hamburg, Germany, 22767
    • Zambon Investigative Site
  • Hannover, Germany, 30625
    • Zambon Investigative Site
  • Lübeck, Germany, 23538
    • Zambon Investigative Site
  • Muenchen, Germany, 80336
    • Zambon Investigative Site
  • München, Germany, 81241
    • Zambon Investigative Site
  • Münster, Germany, 48149
    • Zambon Investigative Site
• Greece
  • Athens, Greece, 11527
    • Zambon Investigative Site
• Israel
  • Haifa, Israel, 3436212
    • Zambon Investigative Site
  • Jerusalem, Israel, 9103
    • Zambon Investigative Site
  • Kfar Saba, Israel, 4428164
    • Zambon Investigative Site
  • Petah Tikva, Israel, 49100
    • Zambon Investigative Site
  • Reẖovot, Israel, 76100
    • Zambon Investigative Site
  • Tsrifin, Israel, 70300
    • Zambon Investigative Site
• Italy
  • Bari, Italy, 70124
    • Zambon Investigative Site
  • Brescia, Italy, 25100
    • Zambon Investigative Site
  • Foggia, Italy, 71100
    • Zambon Investigative Site
  • Milano, Italy, 20122
    • Zambon Investigative Site
  • Monza, Italy, 20900
    • Zambon Investigative Site
  • Palermo, Italy, 90127
    • Zambon Investigative Site
  • Palermo, Italy, 90147
    • Zambon Investigative Site
  • Pavia, Italy, 27100
    • Zambon Investigative Site
  • Pisa, Italy, 56124
    • Zambon Investigative Site
  • Roma, Italy, 00161
    • Zambon Investigative Site
  • TO
    • Orbassano, TO, Italy, 10043
      • Zambon Investigative Site
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Zambon Investigative Site
• New Zealand
  • Auckland, New Zealand, 1051
    • Zambon Investigative Site
  • Auckland, New Zealand, 2025
    • Zambon Investigative Site
  • Christchurch, New Zealand, 8011
    • Zambon Investigative Site
  • Dunedin, New Zealand, 9016
    • Zambon Investigative Site
  • Hamilton West, New Zealand, 3204
    • Zambon Investigative Site
• Portugal
  • Aveiro, Portugal, 3814-501
    • Zambon Investigative Site
  • Braga, Portugal, 4710-243
    • Zambon Investigative Site
  • Coimbra, Portugal, 3000-075
    • ZambonInvestigative Site
  • Guimarães, Portugal, 4835-044
    • Zambon Investigative Site
  • Lisboa, Portugal, 1649-035
    • Zambon Investigative Site
  • Loures, Portugal, 2674-514
    • Zambon Investigative Site
  • Porto, Portugal, 4099-001
    • Zambon Investigative Site
  • Porto, Portugal, 4200-319
    • Zambon Investigative Site
  • Vila Nova De Gaia, Portugal, 4435-502
    • Zambon Investigative Site
• Spain
  • A Coruña, Spain, 15006
    • Zambon Investigative Site
  • Barcelona, Spain, 08035
    • Zambon Investigative Site
  • Barcelona, Spain, 08036
    • Zambon Investigative Site
  • Barcelona, Spain, 08041
    • Zambon Investigative Site
  • Lleida, Spain, 25198
    • Zambon Investigative Site
  • Madrid, Spain, 28006
    • Zambon Investigative Site
  • Madrid, Spain, 28046
    • Zambon Investigative Site
  • Santander, Spain, 39008
    • Zambon Investigative Site
  • Sevilla, Spain, 41071
    • Zambon Investigative Site
  • Torrejón de Ardoz, Spain, 28850
    • Zambon Investigative Site
  • Usansolo, Spain, 48960
    • Zambon Investigative Site
  • Valencia, Spain, 46014
    • Zambon Investigative Site
  • Valencia, Spain, 46026
    • Zambon Investigative Site
• Switzerland
  • Saint Gallen, Switzerland, CH-9007
    • Zambon Investigative Site
• United Kingdom
  • Cambridge, United Kingdom, CB23 3RE
    • Zambon Investigative Site
  • Cardiff, United Kingdom, CF64 2XX
    • Zambon Investigative Site
  • Dundee, United Kingdom, DD1 9SY
    • Zambon Investigative Site
  • Edinburgh, United Kingdom, EAH16 4SA
    • Zambon Investigative Site
  • Gillingham, United Kingdom, ME7 5NY
    • Zambon Investigative Site
  • Glasgow, United Kingdom, G31 2ER
    • Zambon Investigative Site
  • Kirkcaldy, United Kingdom, KY2 5AH
    • Zambon Investigative Site
  • Liverpool, United Kingdom, L14 3PE
    • Zambon Investigational site
  • Llanelli, United Kingdom, SA14 8QF
    • Zambon Investigative Site
  • London, United Kingdom, SW36NP
    • Zambon Investigative Site
  • Manchester, United Kingdom, M23 9LT
    • Zambon Investigative Site
  • Newcastle upon Tyne, United Kingdom, NE7 7DN
    • Zambon Investigative Site
  • Worcester, United Kingdom, WR5 1DD
    • Zambon Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. are able and willing to give informed consent, following a detailed explanation of participation in the protocol and signed consent obtained;
2. aged 18 years or older of either gender;
3. 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.

Exclusion Criteria:

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 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 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 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 previous evidence of bronchial hyperreactivity 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 antipseudomonal antibiotic (except chronic oral macrolide treatment with a stable dose) within 30 days prior to 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CMS (Colimesthate sodium); Inhaled colistimethate sodium twice daily. The active pharmaceutical ingredient consisting of pure CMS one million international units (MIU) / 80 mg of CMS / 33 mg colistin base activity (CBA) was provided as a powder for nebuliser solution in 10R International Organization for Standardization (ISO) glass vials.	Drug: CMS; 1 MIU equivalent to 80 mg colistimethate sodium diluted in 1 mL saline solution 0.45%. Investigational Medicinal Product (IMP) glass vials were shrink wrapped in opaque white plastic and provided in boxes of 30 vials (two weeks of b.i.d dosing). The 1 MIU/mL CMS/0.45% saline solution was transferred from the glass vial into a specific nebuliser system fitted with a 0.3 mL medication chamber, for administration by inhalation. This delivered a nominal dose of 0.3 MIU/24 mg CMS (~10 mg CBA) from the device. The first dose of the IMP was administered at the site under the supervision of the site staff and subjects were instructed how to prepare and self-administer the IMP at home via a specific nebuliser system, b.i.d (morning and evening) over a period of 12 months. At least 10 minutes (min) before each administration, an inhaled short-acting bronchodilator (e.g., salbutamol /albuterol), supplied by the Sponsor, could be taken to improve tolerability.; Other Names: Colistimethate Sodium
Placebo Comparator: Placebo; Saline solution inhaled twice daily, provided and administered at the same way of the IMP.	Other: Placebo; 1 ml saline solution 0.45%. the placebo was made up of identical empty glass vials to which the same saline diluent was added in exactly the same way as the reconstitution of the active treatment by injecting the diluent through the rubber stopper. The glass vials were shrink wrapped with opaque white plastic to maintain the blind.; Other Names: Saline Solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Annual Non-cystic Fibrosis Bronchiectasis (NCFB) Pulmonary Exacerbation Rate	The primary efficacy assessment for an individual subject was the frequency of pulmonary exacerbations (exacerbation rate). A pulmonary exacerbation was defined as the presence concurrently of at least three of the following eight symptoms/signs for at least 24 hours: increased cough;; increased sputum volume and/or consistency;; increased sputum purulence;; new or increased haemoptysis;; increased wheezing;; increased dyspnoea;; increased fatigue/malaise;; episodes of fever (temperature ≥38°C). AND It was clinically determined that the subject required and was prescribed systemic antibiotic therapy. AND The episode of exacerbation lasted for at least 24 hours. The overall episode of exacerbation needs to last at least 24 hours, but individual symptoms/signs can last less than 24 hours (e.g, a temperature). AND in the opinion of the Investigator, the subject required and started treatment with systemic antibiotics.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first pulmonary exacerbation	Time (in days) from the first dose of IMP until the first pulmonary exacerbation;	12 months
Annualised number of pulmonary exacerbation-free days	Number of exacerbation-free days	12 months
Time to first severe pulmonary exacerbation	Time (in days) from first dose of IMP until the first severe pulmonary exacerbation	12 months
Days of work absence	Number of days of work absence due to NCFB pulmonary exacerbations	12 months
Number of severe NCFB pulmonary exacerbations,	Severe NCFB pulmonary exacerbations are defined as those requiring intravenous antibiotics and/or hospitalisation;	12 months
Quality of life (SGRQ)	Quality of life (QoL) as measured by the total score of the Saint George's Respiratory Questionnaire (SGRQ)	12 months
Quality of Life (QOL-B)	change from baseline in total score Quality of Life - Bronchiectasis (QOL B) questionnaire	12 months
P. aeruginosa density	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 (6 months) to 7 (12 months), inclusive	12 months

Collaborators and Investigators

• Sponsor: Zambon SpA
• Investigators: Study Director: Dearbhla Hull, MD, Zambon SpA

Study record dates

Study Major Dates

• Study Start (Actual): June 6, 2017
• Primary Completion (Actual): April 9, 2021
• Study Completion (Actual): April 9, 2021

Study Registration Dates

• First Submitted: March 9, 2017
• First Submitted That Met QC Criteria: March 22, 2017
• First Posted (Actual): March 28, 2017

Study Record Updates

• Last Update Posted (Actual): November 15, 2023
• Last Update Submitted That Met QC Criteria: November 14, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: CMS; Colistimethate Sodium
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Bronchial Diseases; Fibrosis; Bronchiectasis
• Other Study ID Numbers: Z7224L01; 2015-002743-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No