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

Non Cystic Fibrosis Bronchiectasis Clinical Trial

— PROMIS-I  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03093974
• Other study ID #: Z7224L01
• Secondary ID: 2015-002743-33
• Status: Completed
• Phase: Phase 3
• Start date: June 6, 2017
• Est. completion date: April 9, 2021

Study information

• Verified date: January 2023
• Source: Zambon SpA
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 377
• Est. completion date: April 9, 2021
• Est. primary completion date: April 9, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Bronchiectasis
• Fibrosis
• Non Cystic Fibrosis Bronchiectasis

Intervention

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:
• 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.

Locations

Country	Name	City	State
Australia	Zambon Investigative Site	Adelaide
Australia	Zambon Investigative Site	Adelaide
Australia	Zambon Investigative Site	Chermside
Australia	Zambon Investigative Site	Concord
Australia	Zambon Investigative Site	Frankston
Australia	Zambon Investigative Site	Greenslopes
Australia	Zambon Investigative Site	Melbourne
Australia	Zambon Investigative Site	Nedlands
Australia	Zambon Investigative Site	New Lambton Heights
Australia	Zambon Investigative Site	South Brisbane
Australia	Zambon Investigative Site	Spearwood
Australia	Zambon Investigative Site	Westmead
Belgium	Zambon Investigative Site	Gent
Belgium	Zambon Investigative Site	Roeselare
Germany	Zambon Investigative Site	Berlin
Germany	Zambon Investigative Site	Berlin
Germany	Zambon Investigative Site	Essen
Germany	Zambon Investigative Site	Frankfurt am Main
Germany	Zambon Investigative Site	Frankfurt am Main
Germany	Zambon Investigative Site	Hamburg
Germany	Zambon Investigative Site	Hannover
Germany	Zambon Investigative Site	Lübeck
Germany	Zambon Investigative Site	Muenchen
Germany	Zambon Investigative Site	München
Germany	Zambon Investigative Site	Münster
Greece	Zambon Investigative Site	Athens
Israel	Zambon Investigative Site	Haifa
Israel	Zambon Investigative Site	Jerusalem
Israel	Zambon Investigative Site	Kfar Saba
Israel	Zambon Investigative Site	Petah Tikva
Israel	Zambon Investigative Site	Re?ovot
Israel	Zambon Investigative Site	Tsrifin
Italy	Zambon Investigative Site	Bari
Italy	Zambon Investigative Site	Brescia
Italy	Zambon Investigative Site	Foggia
Italy	Zambon Investigative Site	Milano
Italy	Zambon Investigative Site	Monza
Italy	Zambon Investigative Site	Orbassano	TO
Italy	Zambon Investigative Site	Palermo
Italy	Zambon Investigative Site	Palermo
Italy	Zambon Investigative Site	Pavia
Italy	Zambon Investigative Site	Pisa
Italy	Zambon Investigative Site	Roma
Netherlands	Zambon Investigative Site	Groningen
New Zealand	Zambon Investigative Site	Auckland
New Zealand	Zambon Investigative Site	Auckland
New Zealand	Zambon Investigative Site	Christchurch
New Zealand	Zambon Investigative Site	Dunedin
New Zealand	Zambon Investigative Site	Hamilton West
Portugal	Zambon Investigative Site	Aveiro
Portugal	Zambon Investigative Site	Braga
Portugal	ZambonInvestigative Site	Coimbra
Portugal	Zambon Investigative Site	Guimarães
Portugal	Zambon Investigative site	Lisboa
Portugal	Zambon Investigative Site	Loures
Portugal	Zambon Investigative Site	Porto
Portugal	Zambon Investigative Site	Porto
Portugal	Zambon Investigative Site	Vila Nova De Gaia
Spain	Zambon Investigative Site	A Coruña
Spain	Zambon Investigative Site	Barcelona
Spain	Zambon Investigative Site	Barcelona
Spain	Zambon Investigative Site	Barcelona
Spain	Zambon Investigative Site	Lleida
Spain	Zambon Investigative Site	Madrid
Spain	Zambon Investigative Site	Madrid
Spain	Zambon Investigative Site	Santander
Spain	Zambon Investigative Site	Sevilla
Spain	Zambon Investigative Site	Torrejón de Ardoz
Spain	Zambon Investigative Site	Usansolo
Spain	Zambon Investigative Site	Valencia
Spain	Zambon Investigative Site	Valencia
Switzerland	Zambon Investigative Site	Saint Gallen
United Kingdom	Zambon Investigative Site	Cambridge
United Kingdom	Zambon Investigative Site	Cardiff
United Kingdom	Zambon Investigative site	Dundee
United Kingdom	Zambon Investigative Site	Edinburgh
United Kingdom	Zambon Investigative Site	Gillingham
United Kingdom	Zambon Investigative Site	Glasgow
United Kingdom	Zambon Investigative Site	Kirkcaldy
United Kingdom	Zambon Investigational site	Liverpool
United Kingdom	Zambon Investigative Site	Llanelli
United Kingdom	Zambon Investigative Site	London
United Kingdom	Zambon investigative Site	Manchester
United Kingdom	Zambon Investigative Site	Newcastle upon Tyne
United Kingdom	Zambon Investigative Site	Worcester

Sponsors (1)

Lead Sponsor	Collaborator
Zambon SpA

Countries where clinical trial is conducted

Australia,  Belgium,  Germany,  Greece,  Israel,  Italy,  Netherlands,  New Zealand,  Portugal,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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