Trial in Non-cystic Fibrosis Bronchiectasis Patients With Chronic Lung Infections Treated With Colistimethate Sodium.

Non Cystic Fibrosis Bronchiectasis Clinical Trial

— PROMIS-II  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03460704
• Other study ID #: Z7224L02
• Secondary ID: 2016-004558-13
• Status: Terminated
• Phase: Phase 3
• Start date: January 29, 2018
• Est. completion date: March 15, 2022

Study information

• Verified date: December 2023
• Source: Zambon SpA
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 287
• Est. completion date: March 15, 2022
• Est. primary completion date: March 15, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Bronchiectasis
• Fibrosis
• Non Cystic Fibrosis Bronchiectasis

Intervention

Drug:
• 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.

Other:
• 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.

Locations

Country	Name	City	State
Argentina	Zambon Investigative Site	Buenos Aires
Argentina	Zambon Investigative Site	Buenos Aires
Argentina	Zambon Investigative Site	Buenos Aires
Argentina	Zambon Investigative Site	Buenos Aires
Argentina	Zambon Investigative Site	Buenos Aires
Argentina	Zambon investigative site	Buenos Aires
Argentina	Zambon Investigative Site	Ciudad Autónoma de Buenos Aires
Argentina	Zambon Investigative Site	Ciudad Autónoma de Buenos Aires
Argentina	Zambon Investigative Site	Quilmes
Argentina	Zambon Investigative Site	Santa Fe
Argentina	Zambon Investigative Site	Tucumán
Australia	Zambon Investigative Site	Adelaide
Australia	Zambon investigative site	Concord
Australia	Zambon investigative site	Greenslopes
Australia	Zambon Investigative Site	Kent Town
Australia	Zambon Investigative Site	South Brisbane
Australia	Zambon investigative site	Spearwood
Canada	Zambon investigative Site	Burlington
Canada	Zambon investigative site	Kelowna
Canada	Zambon Investigative Site	London
Canada	Zambon Investigative Site	Montréal
Canada	Zambon Investigative Site	Ottawa
Canada	Zambon Investigative Site	Quebec City
Canada	Zambon Investigative Site	Winnipeg
France	Zambon Investigative Site	Amiens
France	Zambon investigative site	Brest
France	Zambon Investigative Site	Créteil
France	Zambon investigative site	La Tronche
France	Zambon investigative site	Lyon
France	Zambon Investigative Site	Montpellier
France	Zambon investigative site	Nice
France	Zambon Investigative Site	Pessac
France	Zambon investigative site	Reims
France	Zambon Investigative Site	Toulouse
Germany	Zambon Investigative Site	Frankfurt
Germany	Zambon Investigative Site	Hanover
Greece	Zambon Investigative Site	Athens
Israel	Zambon Investigative Site	Haifa
Israel	Zambon Investigative Site	Jerusalem
Israel	Zambon Investigative Site	Kfar Saba
Italy	Zambon Investigative Site	Milano
Italy	Zambon Investigative Site	Monza
New Zealand	Zambon Investigative Site	Christchurch
New Zealand	Zambon Investigative Site	Havelock North
New Zealand	Zambon Investigative Site	Mount Cook
New Zealand	Zambon Investigative Site	Tauranga
Poland	Zambon Investigative Site	Bialystok
Poland	Zambon Investigative Site	Bielsko-Biala
Poland	Zambon Investigative Site	Cracovia
Poland	Zambon Investigative Site	Grudziadz
Poland	Zambon Investigative Site	Legnica
Poland	Zambon Investigative Site	Lódz
Poland	Zambon Investigative Site	Lublin
Poland	Zambon Investigative Site	Ostrowiec Swietokrzyski
Poland	Zambon Investigative Site	Piaseczno
Poland	Zambon Investigative Site	Proszowice
Poland	Zambon Investigative Site	Rzeszów
Poland	Zambon Investigative Site	Sosnowiec
Poland	Zambon Investigative Site	Warszawa
Poland	Zambon Investigative Site	Wroclaw
Portugal	Zambon Investigative Site	Guimarães
Portugal	Zambon Investigative Site	Lisboa
United States	ZambonInvestigative Site	Abingdon	Virginia
United States	Zambon Investigative Site	Centennial	Colorado
United States	Zambon investigative site	Chapel Hill	North Carolina
United States	Zambon Investigative Site	Chesterfield	Missouri
United States	Zambon Investigative Site	Chicago	Illinois
United States	Zambon Investigative Site	Durham	North Carolina
United States	Zambon Investigative Site	Jacksonville	Florida
United States	Zambon Investigative Site	Kissimmee	Florida
United States	Zambon Investigative Site	Lebanon	New Hampshire
United States	Zambon Investigative Site	Louisville	Kentucky
United States	Zambon Investigative Site	Michigan City	Indiana
United States	Zambon Investigative Site	New York	New York
United States	Zambon Investigative Site	Newport Beach	California
United States	Zambon Investigative Site	Northwest	Washington
United States	Zambon Investigative Site	Orlando	Florida
United States	Zambon Investigative Site	Palm Springs	California
United States	Zambon Investigative Site	Portland	Oregon
United States	Zambon Investigative Site	Reseda	California
United States	Zambon investigative site	Richmond	Virginia
United States	Zambon Investigative Site	Rochester	Minnesota
United States	Zambon investigative Site	Saint Petersburg	Florida
United States	Zambon Investigative Site	Saint Petersburg	Florida
United States	Zambon Investgative Site	San Diego	California
United States	Zambon investigative site	San Diego	California
United States	Zambon Investigative Site	Tyler	Texas
United States	Zambon Investigative Site	Weston	Florida
United States	Zambon investigative site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Zambon SpA

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Canada,  France,  Germany,  Greece,  Israel,  Italy,  New Zealand,  Poland,  Portugal, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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)	12 months