Combined Dry Powder Tobramycin and Nebulized Colistin Inhalation in CF Patients (CotoCFII)

To assess whether the inhalative combination of Tobramycin/Colistin is more effective in reducing Pseudomonas colony forming units (CFUs) and improvement of lung function than Colistin in mono-therapy.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis With Pulmonary Manifestations
• Intervention / Treatment: Drug: Tobramycin Powder; Drug: Colistin

Detailed Description

Cystic fibrosis (CF), the most common autosomal recessive disorder in Western countries, is caused by mutations of the cystic fibrosis transmembrane conductance regulator molecule (CFTR) and affects approximately 40.000 patients in Europe. The majority of CF patients develop chronic pulmonary infections with Pseudomonas aeruginosa. These are normally treated with single antibiotics, administered orally, intravenously or inhalatively. Once the infection becomes chronic, eradication of the pathogen is not any more possible due to biofilm formation of the pathogen and increasing resistance. However, inhalative antibiotic combination therapy might be more efficient than single antibiotic therapy in chronically infected CF patients. This notion is supported by previous in vitro and animal studies using Tobramycin/Colistin combination therapy. Importantly, a pilot study in five CF patients who inhaled consecutively Colistin and Tobramycin solutions for 4 week, revealed a decrease of log10 2.52 ± 2.5 cfu of P. aeruginosa in sputum specimens during the course of the treatment compared to baseline values (p=0.027). The treatment was shown to be safe and well tolerated. However, forced expiratory volume in 1 sec (FEV1) did not differ significantly.

Taking advantage of the new development of dry powder inhalation (DPI) antibiotics, specifically TOBI© Podhaler, a larger randomised trial has been performed in which the combined TOBI© Podhaler and Colistin treatment is compared to the monotherapy with Colistin.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Cystic Fibrosis is verified;
2. Patient is 12 years or older;
3. FEV1 is higher than 25% and lower than 100%;
4. The patients' lung is colonised with P. aeruginosa chronically (≥6 months);
5. P. aeruginosa must be sensitive for Tobramycin or Colistin;
6. Pretreated with Colistin >2 months;
7. Last i.v. antibiotic treatment ≥2 weeks;
8. Informed consent is given by patients/legal representatives

Exclusion Criteria:

1. Clinical deterioration is present (exacerbation symptoms);
2. Last Tobramycin inhalation treatment ≤ 2 weeks;
3. Renal dysfunction (creatinine <1.5 fold of normal, glomerular filtration rate (GFR) <80%) at baseline
4. auditoria or vestibular dysfunction, hearing loss
5. Intolerances against Tobramycin, Colistin or Polymyxin B
6. Myasthenia gravis
7. Porphyria
8. Pregnancy and nursing

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tobramycin powder / Colistin; TOBI®Podhaler 2 x 112 mg daily for 2 x 28 days (on/off); and Colistin solution 2 x daily 1 Mega continuously for 112 days	Drug: Tobramycin Powder; TOBI®Podhaler 2 x 112 mg daily for 2 x 28 days (on/off); Other Names: TOBI®Podhaler; Drug: Colistin; Colistin solution 2 x daily 1 Mega continuously; Other Names: Colistin solution
Active Comparator: Colistin; Colistin solution 2 x daily 1 Mega continuously for at least 30 days	Drug: Colistin; Colistin solution 2 x daily 1 Mega continuously; Other Names: Colistin solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amount of P. aeruginosa in sputum	The primary endpoint will be the difference of P. aeruginosa cfu/ml in sputum with combined therapy with Tobramycin/Colistin compared to colistin mono-therapy. The analysis will be adjusted for baseline values of each cycle and parametric (paired t-Test) or non-parametric (sign test) methods will be used as appropriate.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Course of P.aeruginosa amount in sputum	Course of P. aeruginosa in sputum measured as cfu/ml during the study	112 days
Course of forced vital capacity (FVC) absolute amount	Course of FVC absolute in litres during the study	112 days
Course of FVC relative amount	Course of FVC relative (percent of expected amount for given body height and gender) during the study	112 days
Course of FEV1 absolute amount	Course of FEV1 absolute in litres during the study	112 days
Course of FEV1 relative amount	Course of FEV1 relative (percent of expected amount for given body height and gender) during the study	112 days
Course of MEF25-75 absolute amount	Course of MEF25-75 absolute in litres during the study	112 days
Course of MEF25-75 relative amount	Course of MEF25-75 relative (percent of expected amount for given body height and gender) during the study	112 days
Course of proinflammatory cytokine IL1ß amount	Course of proinflammatory cytokine IL1ß amount in sputum [pg/ml] during the study	112 days
Course of proinflammatory cytokine IL6 amount	Course of proinflammatory cytokine IL6 amount in sputum [pg/ml] during the study	112 days
Course of proinflammatory cytokine IL8 amount	Course of proinflammatory cytokine IL8 amount in sputum [pg/ml] during the study	112 days
Course of antiinflammatory cytokine IL10 amount	Course of antiinflammatory cytokine IL10 amount in sputum [pg/ml] during the study	112 days
Course of proinflammatory cytokine TNFa amount	Course of proinflammatory cytokine TNFa amount in sputum [pg/ml] during the study	112 days
Course of proinflammatory cytokine GM-CSF amount	Course of proinflammatory cytokine GM-CSF amount in sputum [pg/ml] during the study	112 days
Course of DNA amount in sputum	Course of DNA amount {pg/ml] in sputum during the study	112 days
Course of leukocyte amount in sputum	Course of leukocyte amount [pg/ml] in sputum during the study	112 days
Exacerbation	Number of exacerbations during the study	112 days
Antibiotics	Use of antibiotics during the study	112 days

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2014
• Primary Completion (Actual): December 19, 2015
• Study Completion (Actual): November 25, 2016

Study Registration Dates

• First Submitted: November 3, 2017
• First Submitted That Met QC Criteria: November 8, 2017
• First Posted (Actual): November 14, 2017

Study Record Updates

• Last Update Posted (Actual): November 14, 2017
• Last Update Submitted That Met QC Criteria: November 8, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: chronic pulmonary infection
• Additional Relevant MeSH Terms: Digestive System Diseases; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Cystic Fibrosis; Anti-Infective Agents; Anti-Bacterial Agents; Tobramycin; Colistin
• Other Study ID Numbers: Coto V3.0

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No