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

NCT03093974 | Completed Phase 3 Results

• 2 other identifiers: Z7224L012015-002743-33
• Study Type: interventional
• Target: 377
• Locations: 12 countries
• Sites: 85

Brief 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.

Conditions

Non Cystic Fibrosis Bronchiectasis

Keywords

Colistimethate Sodium; CMS

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (2)

CMS (Colimesthate sodium)

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

Saline solution inhaled twice daily, provided and administered at the same way of the IMP.

Other: Placebo

Interventions

CMS DRUG

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.

Also known as: Colistimethate Sodium

CMS (Colimesthate sodium)

Placebo OTHER

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.

Also known as: Saline Solution

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• are able and willing to give informed consent, following a detailed explanation of participation in the protocol and signed consent obtained;
• aged 18 years or older of either gender;
• 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;
• 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;
• have a documented history of P. aeruginosa infection ;
• are clinically stable and have not required a change in pulmonary treatment for at least 30 days before the Screening Visit (Visit 1);
• have pre-bronchodilator FEV1 ≥25% of predicted;
• had a positive sputum culture for P. aeruginosa from an adequate sample taken at the Screening Visit (Visit 1) or during the screening period.

You may not qualify if:

• known bronchiectasis as a consequence of cystic fibrosis (CF);
• known history of hypogammaglobulinaemia requiring treatment with immunoglobulin, unless fully replaced and considered immuno-competent by the Investigator;
• myasthenia gravis or porphyria;
• 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;
• had major surgery in the 3 months prior to Screening Visit (Visit 1) or planned inpatient major surgery during the study period;
• receiving treatment for allergic bronchopulmonary aspergillosis (ABPA);
• 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;
• respiratory failure that would compromise patient safety or confound the evaluation of safety or efficacy of the study in the opinion of the Investigator;
• current active malignancy, except for basal cell carcinoma or squamous cell carcinoma of the skin without metastases;
• 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);
• known history of human immunodeficiency virus (HIV);
• current treatment for non-tuberculous mycobacterial (NTM) lung disease or tuberculosis;
• 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;
• 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)
• 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;

Sponsors & Collaborators

• Zambon SpA: lead

Study Sites (85)

Zambon Investigative Site

Adelaide, 5000, Australia

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Zambon Investigative Site

Adelaide, 5042, Australia

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Zambon Investigative Site

Chermside, 4032, Australia

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Zambon Investigative Site

Concord, NSW 2134, Australia

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Zambon Investigative Site

Frankston, VIC 3199, Australia

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Zambon Investigative Site

Greenslopes, 4120, Australia

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Zambon Investigative Site

Melbourne, 3004, Australia

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Zambon Investigative Site

Nedlands, WA 6009, Australia

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Zambon Investigative Site

New Lambton Heights, 2305, Australia

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Zambon Investigative Site

South Brisbane, 4101, Australia

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Zambon Investigative Site

Spearwood, 6163, Australia

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Zambon Investigative Site

Westmead, NSW 2145, Australia

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Zambon Investigative Site

Ghent, 9000, Belgium

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Zambon Investigative Site

Roeselare, 8800, Belgium

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Zambon Investigative Site

Berlin, 10717, Germany

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Zambon Investigative Site

Berlin, 14059, Germany

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Zambon Investigative Site

Essen, 45239, Germany

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Zambon Investigative Site

Frankfurt am Main, 60590, Germany

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Zambon Investigative Site

Frankfurt am Main, 60596, Germany

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Zambon Investigative Site

Hamburg, 22767, Germany

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Zambon Investigative Site

Hanover, 30625, Germany

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Zambon Investigative Site

Lübeck, 23538, Germany

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Zambon Investigative Site

München, 80336, Germany

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Zambon Investigative Site

München, 81241, Germany

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Zambon Investigative Site

Münster, 48149, Germany

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Zambon Investigative Site

Athens, 11527, Greece

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Zambon Investigative Site

Haifa, 3436212, Israel

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Zambon Investigative Site

Jerusalem, 9103, Israel

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Zambon Investigative Site

Kfar Saba, 4428164, Israel

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Zambon Investigative Site

Petah Tikva, 49100, Israel

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Zambon Investigative Site

Rehovot, 76100, Israel

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Zambon Investigative Site

Ẕerifin, 70300, Israel

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Zambon Investigative Site

Orbassano, TO, 10043, Italy

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Zambon Investigative Site

Bari, 70124, Italy

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Zambon Investigative Site

Brescia, 25100, Italy

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Zambon Investigative Site

Foggia, 71100, Italy

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Zambon Investigative Site

Milan, 20122, Italy

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Zambon Investigative Site

Monza, 20900, Italy

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Zambon Investigative Site

Palermo, 90127, Italy

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Zambon Investigative Site

Palermo, 90147, Italy

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Zambon Investigative Site

Pavia, 27100, Italy

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Zambon Investigative Site

Pisa, 56124, Italy

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Zambon Investigative Site

Roma, 00161, Italy

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Zambon Investigative Site

Groningen, 9713 GZ, Netherlands

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Zambon Investigative Site

Auckland, 1051, New Zealand

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Zambon Investigative Site

Auckland, 2025, New Zealand

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Zambon Investigative Site

Christchurch, 8011, New Zealand

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Zambon Investigative Site

Dunedin, 9016, New Zealand

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Zambon Investigative Site

Hamilton West, 3204, New Zealand

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Zambon Investigative Site

Aveiro, 3814-501, Portugal

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Zambon Investigative Site

Braga, 4710-243, Portugal

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ZambonInvestigative Site

Coimbra, 3000-075, Portugal

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Zambon Investigative Site

Guimarães, 4835-044, Portugal

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Zambon Investigative site

Lisbon, 1649-035, Portugal

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Zambon Investigative Site

Loures, 2674-514, Portugal

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Zambon Investigative Site

Porto, 4099-001, Portugal

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Zambon Investigative Site

Porto, 4200-319, Portugal

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Zambon Investigative Site

Vila Nova de Gaia, 4435-502, Portugal

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Zambon Investigative Site

A Coruña, 15006, Spain

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Zambon Investigative Site

Barcelona, 08035, Spain

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Zambon Investigative Site

Barcelona, 08036, Spain

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Zambon Investigative Site

Barcelona, 08041, Spain

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Zambon Investigative Site

Lleida, 25198, Spain

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Zambon Investigative Site

Madrid, 28006, Spain

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Zambon Investigative Site

Madrid, 28046, Spain

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Zambon Investigative Site

Santander, 39008, Spain

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Zambon Investigative Site

Seville, 41071, Spain

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Zambon Investigative Site

Torrejón de Ardoz, 28850, Spain

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Zambon Investigative Site

Usansolo, 48960, Spain

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Zambon Investigative Site

Valencia, 46014, Spain

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Zambon Investigative Site

Valencia, 46026, Spain

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Zambon Investigative Site

Sankt Gallen, CH-9007, Switzerland

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Zambon Investigative Site

Cambridge, CB23 3RE, United Kingdom

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Zambon Investigative Site

Cardiff, CF64 2XX, United Kingdom

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Zambon Investigative site

Dundee, DD1 9SY, United Kingdom

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Zambon Investigative Site

Edinburgh, EAH16 4SA, United Kingdom

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Zambon Investigative Site

Gillingham, ME7 5NY, United Kingdom

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Zambon Investigative Site

Glasgow, G31 2ER, United Kingdom

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Zambon Investigative Site

Kirkcaldy, KY2 5AH, United Kingdom

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Zambon Investigational site

Liverpool, L14 3PE, United Kingdom

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Zambon Investigative Site

Llanelli, SA14 8QF, United Kingdom

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Zambon Investigative Site

London, SW36NP, United Kingdom

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Zambon investigative Site

Manchester, M23 9LT, United Kingdom

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Zambon Investigative Site

Newcastle upon Tyne, NE7 7DN, United Kingdom

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Zambon Investigative Site

Worcester, WR5 1DD, United Kingdom

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MeSH Terms

Interventions

colistinmethanesulfonic acid; Saline Solution

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Results Point of Contact

• Title: Michela Meroni - Clinical Trial Manager
• Organization: Zambon S.p.A.

clincaltrials@zambongroup.com

+39 02 665241

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 9, 2017
• First Posted: March 28, 2017
• Study Start: June 6, 2017
• Primary Completion: April 9, 2021
• Study Completion: April 9, 2021
• Last Updated: November 15, 2023
• Results First Posted: November 15, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

DE (11); AU (12); NZ (5); GB (13); IL (6); ES (13); IT (11); NL (1); PT (9); GR (1); BE (2); CH (1)