The primary objectives of the trial are to investigate the effect of the use of inhaled colistimethate sodium, administered twice daily via the I-Neb for 12 months, compared to placebo in subjects with non*cystic fibrosis bronchiectasis (NCFB)…
ID
Source
Brief title
Condition
- Other condition
- Bacterial infectious disorders
Synonym
Health condition
subjects with non-cystic fibrosis bronchiectasis chronically infected with Pseudomonas aeruginosa
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Variable:
Mean annual pulmonary exacerbation rate.
Secondary outcome
Secondary Efficacy Variables:
* the time (in days) from the first dose of IMP until the first pulmonary
exacerbation;
* annualised number of pulmonary exacerbation-free days;
* number of severe pulmonary exacerbations, defined as those requiring
intravenous antibiotics and/or hospitalisation;
* the time (in days) from the first dose of IMP until the first severe
pulmonary exacerbation;
* quality of life (QoL) as measured by the total score of the Saint George*s
Respiratory Questionnaire (SGRQ) and Quality of Life * Bronchiectasis (QOL B)
questionnaire as well as changes in SGRQ and QOL-B from baseline to each
post-baseline visit;
* number of days of work absence due to pulmonary exacerbations;
* P. aeruginosa density as determined by the mean change in log10 colony
forming units (CFU)/g sputum from baseline (Visit 2) to Day 28 of treatment
(Visit 3) as well as to Visits 5 and 7.
Background summary
Colistimethate sodium is an antibacterial cationic cyclic polypeptide belonging
to the polymyxin group; it is currently approved in the US for i.v.
administration and in Europe for both i.v. and inhaled administration.
The approved injectable forms of CMS in the US are indicated for the treatment
of acute or chronic infections due to sensitive strains of certain
Gram-negative bacilli and are particularly indicated when the infection is
caused by sensitive strains of P. aeruginosa.
In Europe, CMS has been extensively used in clinical practice for over 30 years
via the inhaled administration route, for the treatment of colonization and
infections of the lung by susceptible P. aeruginosa in patients with Cystic
Fibrosis (CF).
In conclusion, CMS is an established medicinal product which is widely approved
in the EU and has been used for over 30 years to treat CF patients with P.
aeruginosa infection. It is also used off-label extensively in NCFB patients in
Europe in accordance with national and international society guidelines for the
treatment of NCFB. Extensive real-life clinical use data show that long-term
use of inhaled CMS is effective and has good safety and tolerability in
children and adults.
(For more information see IB capture 2: Summary)
Study objective
The primary objectives of the trial are to investigate the effect of the use of
inhaled colistimethate sodium, administered twice daily via the I-Neb for 12
months, compared to placebo in subjects with non*cystic fibrosis bronchiectasis
(NCFB) chronically infected with P. aeruginosa on the frequency of pulmonary
exacerbations.
Key secondary objectives are: time to first pulmonary exacerbation, number of
exacerbation-free days, health-related patient reported outcomes, microbiology
assessments, pharmaco-economic evaluations as well as safety and tolerability.
Study design
Randomised, multicentre, double-blind, placebo-controlled, parallel group trial.
Subjects will be randomized to active or placebo in a 1:1 ratio.
The study will consist of a total of 7 clinic visits with a follow-up call two
weeks after discontinuation of treatment. Additional clinic visits, where
feasible, and weekly calls will be conducted following pulmonary exacerbations
until resolution.
Intervention
Subjects will administer the investigational medicinal product (IMP) twice
daily (morning and evening) via the I-neb Adaptive Aerosol Delivery (AAD)
System.
The content of the vial is reconstituted with 1 mL of 0.45% sodium chloride
(saline) solution and 1 mL of the medication placed in the I-neb device to fill
the 0.3 mL nebulisation chamber to give a delivered dose of 10 mg colistin base
activity (CBA).
Study burden and risks
In terms of safety profile, the use of Promixin in the previous trial (phase
II) was not associated with the development of resistance to colistimethate
sodium by P. aeruginosa and no overgrowth of other bacteria occurred. The
safety profile of Promixin in patients with non-CF bronchiectasis was similar
to the safety profile established for patients with CF bronchiectasis. There
were no safety concerns, no significant changes in FEV1 and the incidence of
adverse events was similar in both groups.
According to SmPC; approximately 10% of patients experience coughing and
bronchospasm with the first administration by inhalation. So in the present
study, a bronchodilator (salbutamol) is provided to prevent bronchospasm by
administration about 15 minutes before inhalation of study drug. Spirometry
tests are also performed 30 minutes after study drug administration to check
any bronchoconstriction. In case a bronchospasm is observed even at the first
administration at the study site or in the following visits, patients are to be
withdrawn from the study.
Other common side effects include chest tightness and bronchoconstriction, sore
throat and sore mouth,
which may be due to hypersensitivity or candidiasis, hypersensitivity reactions
including skin rash,
neurotoxicity and nephrotoxicity.
Via Lillo del Duca 10 Via Lillo del Duca 10
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Milan 20091 Bresso
IT
Listed location countries
Age
Inclusion criteria
Subjects can be included in the trial if they meet all the inclusion criteria
listed below:, 1. are able and willing to give informed consent following a
detailed explanation of participation in the protocol and signed consent
obtained;
2. are 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;
4. had at least 2 NCFB pulmonary exacerbations requiring oral 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 *30% of predicted;
8. had a positive sputum culture for P. aeruginosa from an adequate sample
taken at the Screening Visit (Visit 1).
Exclusion criteria
Subjects are not eligible for the trial if they meet one or more of the
exclusion criteria listed below:, 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, porphyria or myeloproliferative disease;
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. had massive haemoptysis (greater than or equal to 300 mL or requiring blood
transfusion) in the preceding 4 weeks before the Screening Visit (Visit 1) or
between Visit 1 and Visit 2;
8. predominant lung condition being chronic obstructive pulmonary disease
(COPD), asthma or interstitial lung disease in the opinion of the Investigator;
9. respiratory failure requiring long-term domiciliary oxygen therapy or
non-invasive ventilation;
10. current active malignancy, except for basal cell carcinoma of the skin
without metastases;
11. taking immunosuppressive medications (such as azathioprine, methotrexate,
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);
12. known history of human immunodeficiency virus (HIV);
13. current diagnosis or current treatment for non-tuberculous mycobacterial
(NTM) pulmonary disease or Mycobacterium tuberculosis infection;
14. known to be intolerant to inhaled beta-2 agonists (bronchodilators);
15. 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;
16. treatment with long term (* 30 days) prednisone at a dose greater than 15
mg a day (or equivalent dose of any other corticosteroid) within 6 months of
the Screening Visit 1 (Visit 1);
17. new maintenance treatment with oral macrolides (e.g.
azithromycin/erythromycin/clarithromycin) started within 30 days of the
Screening Visit (Visit 1) or started between Visit 1 and Visit 2;
18. use of any intravenous or intramuscular or oral or inhaled anti-pseudomonal
antibiotic (except chronic oral macrolide treatment with a stable dose) within
30 days prior to the Screening Visit (Visit 1) and between Visit 1 and Visit 2;
19. 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;
20. 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;
21. participated in another investigational, interventional trial within 30
days prior to the Screening Visit (Visit 1).
22. in the opinion of the Investigator not suitable for inclusion for whatever
reason.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-002743-33-NL |
| CCMO | NL66006.042.18 |