Non Cystic Fibrosis Bronchiectasis
Conditions
Keywords
NCFB, NCFB pulmonary exacerbation, Bronchiectasis
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.
Interventions
DRUGCMS
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.
OTHERPlacebo
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.
Sponsors
Zambon SpA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Annual Non-cystic Fibrosis Bronchiectasis (NCFB) Pulmonary Exacerbation Rate | 12 months | 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 and * 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) |
Countries
Argentina, Australia, Canada, France, Germany, Greece, Israel, Italy, New Zealand, Poland, Portugal, United States
Participant flow
Recruitment details
Recruitment was halted with 287 subjects randomised.
Participants by arm
| Arm | Count |
|---|---|
| CMS (Colistimethate 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 Internation Organization for Standardization (ISO) glass vials.
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 (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. | 152 |
| Placebo Saline solution inhaled twice daily, provided and administered at the same way of the IMP.
Placebo: 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. | 135 |
| Total | 287 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 5 |
| Overall Study | Death | 3 | 2 |
| Overall Study | Non-Compliance with Study Drug | 3 | 0 |
| Overall Study | Other | 2 | 1 |
| Overall Study | Protocol-Specified Withdrawal Criterion Met | 0 | 5 |
| Overall Study | Study terminated by the Sponsor | 29 | 19 |
| Overall Study | Withdrawal by Subject | 11 | 14 |
Baseline characteristics
| Characteristic | CMS (Colistimethate Sodium) | Total | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 67 Participants | 129 Participants | 62 Participants |
| Age, Categorical Between 18 and 65 years | 85 Participants | 158 Participants | 73 Participants |
| Age, Continuous | 59.9 years STANDARD_DEVIATION 15.19 | 59.7 years STANDARD_DEVIATION 14.95 | 59.6 years STANDARD_DEVIATION 14.73 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 146 Participants | 276 Participants | 130 Participants |
| Region of Enrollment Argentina | 56 participants | 108 participants | 52 participants |
| Region of Enrollment Australia | 7 participants | 13 participants | 6 participants |
| Region of Enrollment Canada | 9 participants | 19 participants | 10 participants |
| Region of Enrollment France | 18 participants | 30 participants | 12 participants |
| Region of Enrollment Germany | 1 participants | 3 participants | 2 participants |
| Region of Enrollment Greece | 2 participants | 3 participants | 1 participants |
| Region of Enrollment Israel | 1 participants | 4 participants | 3 participants |
| Region of Enrollment Italy | 1 participants | 1 participants | 0 participants |
| Region of Enrollment New Zealand | 4 participants | 6 participants | 2 participants |
| Region of Enrollment Poland | 22 participants | 48 participants | 26 participants |
| Region of Enrollment Portugal | 1 participants | 2 participants | 1 participants |
| Region of Enrollment United States | 30 participants | 50 participants | 20 participants |
| Sex: Female, Male Female | 104 Participants | 198 Participants | 94 Participants |
| Sex: Female, Male Male | 48 Participants | 89 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 152 | 2 / 135 |
| other Total, other adverse events | 123 / 152 | 104 / 135 |
| serious Total, serious adverse events | 27 / 152 | 17 / 135 |
Outcome results
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 and * 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)
Time frame: 12 months
Population: The modified Intention-To-Treat (mITT) Population is the Full Analysis Set and comprised all subjects who provided informed consent, were randomised and received at least 1 dose or partial dose of the IMP.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| CMS (Colistimethate Sodium) | Mean Annual Non-cystic Fibrosis Bronchiectasis (NCFB) Pulmonary Exacerbation Rate | 0.889 Number of Pulmonary Exacerbations |
| Placebo | Mean Annual Non-cystic Fibrosis Bronchiectasis (NCFB) Pulmonary Exacerbation Rate | 0.885 Number of Pulmonary Exacerbations |
Comparison: The number of NCFB pulmonary exacerbations was compared between treatment groups using a negative binomial model including treatment, country, and baseline use of stable concomitant therapy with oral macrolides as fixed effects and log-exposure time on treatment as an offset.p-value: 0.9788995% CI: [0.747, 1.349]negative binomial model