Trial in Non-cystic Fibrosis Bronchiectasis Patients With Chronic Lung Infections Treated With Colistimethate Sodium.
Condition: Non Cystic Fibrosis Bronchiectasis
MeSH terms: Bronchiectasis; Fibrosis
Intervention: CMS; Placebo
Intervention description: 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 (11 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 aperiod of 12 month.
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.; 1 mL saline solution 0.45%. The placebo was made up of identical empty glass vials to which the same saline solution 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 mantain the blind.
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 287.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: NCFB; NCFB pulmonary exacerbation; Bronchiectasis

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.
    

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.