Clinical trial NCT03460704: Trial in Non-cystic Fibrosis Bronchiectasis Patients With Chronic Lung Infections Treated With Colistimethate Sodium.
Official title: Efficacy and Safety of 12 Months of Therapy With Inhaled Colistimethate Sodium in Subjects With Non-cystic Fibrosis Bronchiectasis Chronically Infected With P. Aeruginosa
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Non Cystic Fibrosis Bronchiectasis
Keywords: NCFB
NCFB pulmonary exacerbation
Bronchiectasis
Lead sponsor: Zambon SpA
Sponsor class: INDUSTRY
First posted: 2018-03-09
Enrollment: 287
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The primary objective of the trial was to investigate the effect of the use of inhaled colistimethate sodium (CMS), administered twice a day (b.i.d.) via a specific nebulizer for 12 months, compared to placebo in subjects with non-cystic fibrosis bronchiectasis (NCFB) chronically infected with P. aeruginosa on the annualised frequency of pulmonary exacerbations.

Detailed description: This was a randomised, multi-centre, double-blind, placebo-controlled, parallel-group interventional trial in subjects with NCFB chronic P. aeruginosa infection. Subjects were randomised to CMS or placebo in a 1:1 ratio. The study consisted of 7 clinic visits with a follow-up phone call 12.5 month after randomisation or 2 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.

Every effort was made to have all planned and unscheduled visits at the study site. Mandatory on-site visits were Screening Visit (Visit 1) and Randomisation (Visit 2). However, if one of the visits after Visit 2 could not be performed at site due to COVID-19, remote visits (e.g., by telephone) were permitted. If the final visit (Visit 7) had to be conducted remotely, the subjects were asked to return to the clinic for on-site assessments at the earliest opportunity.

After consulting with the US Food and Drug Administration, the study was brought to an early close primarily due to the difficulty of recruiting subjects in the context of the COVID pandemic, but also due to the potential for loss of scientific equipoise and the ethical implications of continuing to expose subjects to placebo given the positive results from PROMIS I. Recruitment to PROMIS II was stopped as of 27 October 2021, with the study terminated as of 15 March 2022. The study was not stopped prematurely due to any safety or futility concerns and the accrued data were fully analysed and are presented.

Eligibility criteria: Inclusion Criteria:

1. are able and willing to give informed consent, following a detailed explanation of partecipation 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 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 the Screening Visit (Visit 1) or planned inpatient major surgery during the study period;
6. receiving treatment for allergic bronchopulmonary aspergillosis (ABPA);
7. 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 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) started 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 two years 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.

Primary outcomes:
measure: Mean Annual Non-cystic Fibrosis Bronchiectasis (NCFB) Pulmonary Exacerbation Rate
timeFrame: 12 months
Secondary outcomes:
Other outcomes:
Locations:
city: Newport Beach
country: United States
facility: Zambon Investigative Site
state: California
city: Palm Springs
country: United States
facility: Zambon Investigative Site
state: California
city: Reseda
country: United States
facility: Zambon Investigative Site
state: California
city: San Diego
country: United States
facility: Zambon investigative site
state: California
city: San Diego
country: United States
facility: Zambon Investgative Site
state: California
city: Centennial
country: United States
facility: Zambon Investigative Site
state: Colorado
city: Jacksonville
country: United States
facility: Zambon Investigative Site
state: Florida
city: Kissimmee
country: United States
facility: Zambon Investigative Site
state: Florida
city: Orlando
country: United States
facility: Zambon Investigative Site
state: Florida
city: Saint Petersburg
country: United States
facility: Zambon investigative Site
state: Florida
city: Saint Petersburg
country: United States
facility: Zambon Investigative Site
state: Florida
city: Weston
country: United States
facility: Zambon Investigative Site
state: Florida
city: Chicago
country: United States
facility: Zambon Investigative Site
state: Illinois
city: Michigan City
country: United States
facility: Zambon Investigative Site
state: Indiana
city: Louisville
country: United States
facility: Zambon Investigative Site
state: Kentucky
city: Rochester
country: United States
facility: Zambon Investigative Site
state: Minnesota
city: Chesterfield
country: United States
facility: Zambon Investigative Site
state: Missouri
city: Lebanon
country: United States
facility: Zambon Investigative Site
state: New Hampshire
city: New York
country: United States
facility: Zambon Investigative Site
state: New York
city: Chapel Hill
country: United States
facility: Zambon investigative site
state: North Carolina
city: Durham
country: United States
facility: Zambon Investigative Site
state: North Carolina
city: Winston-Salem
country: United States
facility: Zambon investigative site
state: North Carolina
city: Portland
country: United States
facility: Zambon Investigative Site
state: Oregon
city: Tyler
country: United States
facility: Zambon Investigative Site
state: Texas
city: Abingdon
country: United States
facility: ZambonInvestigative Site
state: Virginia
city: Richmond
country: United States
facility: Zambon investigative site
state: Virginia
city: Northwest
country: United States
facility: Zambon Investigative Site
state: Washington
city: Buenos Aires
country: Argentina
facility: Zambon Investigative Site
city: Buenos Aires
country: Argentina
facility: Zambon Investigative Site
city: Buenos Aires
country: Argentina
facility: Zambon Investigative Site
city: Buenos Aires
country: Argentina
facility: Zambon Investigative Site
city: Buenos Aires
country: Argentina
facility: Zambon Investigative Site
city: Buenos Aires
country: Argentina
facility: Zambon investigative site
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: Zambon Investigative Site
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: Zambon Investigative Site
city: Quilmes
country: Argentina
facility: Zambon Investigative Site
city: Santa Fe
country: Argentina
facility: Zambon Investigative Site
city: Tucumán
country: Argentina
facility: Zambon Investigative Site
city: Adelaide
country: Australia
facility: Zambon Investigative Site
city: Concord
country: Australia
facility: Zambon investigative site
city: Greenslopes
country: Australia
facility: Zambon investigative site
city: Kent Town
country: Australia
facility: Zambon Investigative Site
city: South Brisbane
country: Australia
facility: Zambon Investigative Site
city: Spearwood
country: Australia
facility: Zambon investigative site
city: Burlington
country: Canada
facility: Zambon investigative Site
city: Kelowna
country: Canada
facility: Zambon investigative site
city: London
country: Canada
facility: Zambon Investigative Site
city: Montréal
country: Canada
facility: Zambon Investigative Site
city: Ottawa
country: Canada
facility: Zambon Investigative Site
city: Quebec City
country: Canada
facility: Zambon Investigative Site
city: Winnipeg
country: Canada
facility: Zambon Investigative Site
city: Amiens
country: France
facility: Zambon Investigative Site
city: Brest
country: France
facility: Zambon investigative site
city: Créteil
country: France
facility: Zambon Investigative Site
city: La Tronche
country: France
facility: Zambon investigative site
city: Lyon
country: France
facility: Zambon investigative site
city: Montpellier
country: France
facility: Zambon Investigative Site
city: Nice
country: France
facility: Zambon investigative site
city: Pessac
country: France
facility: Zambon Investigative Site
city: Reims
country: France
facility: Zambon investigative site
city: Toulouse
country: France
facility: Zambon Investigative Site
city: Frankfurt
country: Germany
facility: Zambon Investigative Site
city: Hanover
country: Germany
facility: Zambon Investigative Site
city: Athens
country: Greece
facility: Zambon Investigative Site
city: Haifa
country: Israel
facility: Zambon Investigative Site
city: Jerusalem
country: Israel
facility: Zambon Investigative Site
city: Kfar Saba
country: Israel
facility: Zambon Investigative Site
city: Milano
country: Italy
facility: Zambon Investigative Site
city: Monza
country: Italy
facility: Zambon Investigative Site
city: Christchurch
country: New Zealand
facility: Zambon Investigative Site
city: Havelock North
country: New Zealand
facility: Zambon Investigative Site
city: Mount Cook
country: New Zealand
facility: Zambon Investigative Site
city: Tauranga
country: New Zealand
facility: Zambon Investigative Site
city: Białystok
country: Poland
facility: Zambon Investigative Site
city: Bielsko-Biala
country: Poland
facility: Zambon Investigative Site
city: Cracovia
country: Poland
facility: Zambon Investigative Site
city: Grudziądz
country: Poland
facility: Zambon Investigative Site
city: Legnica
country: Poland
facility: Zambon Investigative Site
city: Lublin
country: Poland
facility: Zambon Investigative Site
city: Ostrowiec Świętokrzyski
country: Poland
facility: Zambon Investigative Site
city: Piaseczno
country: Poland
facility: Zambon Investigative Site
city: Proszowice
country: Poland
facility: Zambon Investigative Site
city: Rzeszów
country: Poland
facility: Zambon Investigative Site
city: Sosnowiec
country: Poland
facility: Zambon Investigative Site
city: Warszawa
country: Poland
facility: Zambon Investigative Site
city: Wrocław
country: Poland
facility: Zambon Investigative Site
city: Łódź
country: Poland
facility: Zambon Investigative Site
city: Guimarães
country: Portugal
facility: Zambon Investigative Site
city: Lisboa
country: Portugal
facility: Zambon Investigative Site
Study officials:
affiliation: Zambon S.p.A.
name: Paola Castellani, MD
role: PRINCIPAL_INVESTIGATOR
References: