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

University Hospital Tuebingen

Status and phase: Completed; Phase 3

Conditions: Cystic Fibrosis With Pulmonary Manifestations

Treatments: Drug: Tobramycin Powder; Drug: Colistin

Study type: Interventional

Funder types: Other

Identifiers

NCT03341741

Coto V3.0

Details and patient eligibility

About

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.

Full 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.

Enrollment: 26 patients

Sex: All

Ages: 12+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

26 participants in 2 patient groups

Tobramycin powder / Colistin

Experimental group

Description:

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

Treatment:

Drug: Colistin

Drug: Tobramycin Powder

Colistin

Active Comparator group

Description:

Colistin solution 2 x daily 1 Mega continuously for at least 30 days

Treatment:

Drug: Colistin