A Study Comparing the Efficacy and Tolerability of Tobrineb®/Actitob®/Bramitob® Versus TOBI®

Study Overview
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Brief Summary
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The objectives of the study are to demonstrate that Tobrineb®/Actitob®/Bramitob® is non-inferior to TOBI® in the primary efficacy variable, forced expiratory volume in one second (FEV1) percent of predicted normal, and to compare the safety in participants with cystic fibrosis and chronic infection of the lungs with Pseudomonas aeruginosa.

Official Title
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A Multicentre, Multinational, Open-Label, Randomised, Parallel Group Clinical Trial of Tobrineb®/Actitob®/Bramitob® (Tobramycin Solution for Nebulisation, 300mg Twice Daily in 4mL Unit Dose Vials) Compared to TOBI® in the Treatment of Patients With Cystic Fibrosis and Chronic Infection With Pseudomonas Aeruginosa

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: tobramycin / Bramitob
* Drug: tobramycin / TOBI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients of either sex aged ≥ 6; Clinical diagnosis of cystic fibrosis defined as: (1)Patients preferably registered in the National Registry of CF (or other documents depending on country legislation); (2) Evidence of two or more typical pulmonary clinical features observed in CF, e.g., persistent colonization/infection with typical CF pathogens, chronic cough and sputum production, persistent chest radiography abnormalities, airway obstruction, nasal polyps and/or digital clubbing; Positive response in the standard sweat test (sweat chloride concentration ≥ 60 mmol/l for the standard method or ≥ 80 mmol/L for a microduct technique) documented in the clinical records and/or gene mutation documented in the clinical records; Chronic colonization of P. aeruginosa: presence in a sputum or throat culture of a minimum of 2 positive samples for P. aeruginosa over the previous 12 months and/or presence of more than two precipitating antibodies against P. aeruginosa; Sputum containing P. aeruginosa susceptible to tobramycin (defined as a zone diameter ≥ 16 mm after testing with 10 µg tobramycin disk or as a minimal inhibition concentration based on microdilution testing system) as identified by local laboratory at screening visit; Forced expiratory volume in 1 sec (FEV₁) ≥ 40% and ≤ 80% of the predicted normal value; Written informed consent obtained by parents/legal representative according to local regulations) and by the patient (when appropriate). Exclusion Criteria: Administration of antipseudomonal antibiotic therapy by any route in the previous 4 weeks; Evidence of impaired renal function (serum creatinine level ≥ 1.5 mg/dl); Evidence of impaired auditory function (auditory threshold in either ear above 20 dB at frequencies between 250 and 8000Hz); Sputum culture containing Burkholderia cepacia; Patients with end-stage lung disease, candidates for heart-lung transplantation; History of other clinically significant cardiac, renal, neurological, gastrointestinal, hepatic or endocrine disease related to cystic fibrosis, whose sequelae and/or treatment can interfere with the results of the present study; Female subjects: pregnant or with active desire to be pregnant, lactating mother or lack of efficient contraception in a subject with child-bearing potential (i.e., contraceptive methods other than rod containing a hormone that prevents user from getting pregnant and that will be placed under the skin, syringes that contain a contraceptive hormone, combined birth control pill, i.e., such that contains two hormones, some intrauterine devices (IUDs) and sexual abstinence). A pregnancy test in urine is to be carried out in women of a fertile age at screening and at the last clinic visit; Known hypersensitivity to aminoglycosides; Patients with evidence of alcohol or drug abuse, likely to be not compliant with the study protocol or likely to be not compliant with the study treatments; Participation in another clinical trial with an investigational drug in the four weeks preceding the screening visit.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bramitob<br>tobramycin / Bramitob administered 300mg twice a day for 4 weeks | Drug: tobramycin / Bramitob<br>* 300mg/4ml solution, via a nebuliser, over a 4-week treatment in a twice-daily regimen<br>* Other names: Bethkis;|
| Active Comparator: TOBI<br>tobramycin / TOBI administered 300mg twice a day for 4 weeks | Drug: tobramycin / TOBI<br>* 300mg/5ml solution administered via nebuliser, over a 4-week treatment in a twice-daily regimen<br>* Other names: TOBI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to End of the Treatment Period of Forced Expiratory Volume in 1 Second (FEV1), Expressed as Percentage of Predicted Normal | Pulmonary function measurements were performed by using a self-calibrated computer-operated pneumotochographic spirometer at all clinic visits. Because this study included both adults and children and lung volume is an age-dependent variable, reference normal FEV1 values for children were different than the reference normal values used with adult participants. Three measurements were collected and the greatest FEV1 value was recorded. | Day 0 (baseline), Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Volume in 1 Second (FEV1), Expressed as Percentage of Predicted Normal | Pulmonary function measurements were performed by using a self-calibrated computer-operated pneumotochographic spirometer at all clinic visits. Because this study included both adults and children and lung volume is an age-dependent variable, reference normal FEV1 values for children were different than the reference normal values used with adult participants. Three measurements were collected and the greatest FEV1 value was recorded. Observed values are summarized (without last observation carry forward). | Day 0 (baseline), Week 2, Week 4, Week 8 | 
| Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Expiratory Volume in 1 Second (FEV1) | Pulmonary function measurements were performed by using a self-calibrated computer-operated pneumotochographic spirometer at all clinic visits. Three measurements were collected and the greatest FEV1 value was recorded. Observed values are summarized (without last observation carry forward). | Day 0 (baseline), Week 2, Week 4, Week 8 | 
| Change From Baseline at End of Weeks 2, 4, and 8 of Forced Vital Capacity (FVC) Expressed as Percentage of Predicted Normal | FVC is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. It is measured via spirometry. Because this study included both adults and children and lung volume is an age-dependent variable, reference normal FVC values for children were different than the reference normal values used with adult participants. | Day 0 (baseline), Week 2, Week 4, Week 8 | 
| Change From Baseline to End of Weeks 2, 4, and 8 of Absolute Forced Vital Capacity (FVC) | FVC is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. It is measured via spirometry. | Day 0 (baseline), Week 2, Week 4, Week 8 | 
| Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%), Expressed as Percentage of Predicted Normal | Difference in the forced expiratory flow rate in mid-exhalation as a percent of predicted to standard values measured from baseline to weeks 2 (treated), 4 (treated), and 8 (untreated). Because this study included both adults and children and lung volume is an age-dependent variable, reference normal FEF 25-75% values for children were different than the reference normal values used with adult participants. | Day 0 (baseline), Week 2, Week 4, Week 8 | 
| Change From Baseline to End of Weeks 2, 4, and 8 of Forced Expiratory Flow at 25-75% of Vital Capacity (FEF 25-75%) | Difference in the forced expiratory flow rate in mid-exhalation measured from baseline to weeks 2 (treated), 4 (treated), and 8 (untreated). | Day 0 (baseline), Week 2, Week 4, Week 8 | 
| Change From Baseline to End of Weeks 4 and 8 in Pseudomonas Aeruginosa Log10 Bacterial Load in Sputum | If a participant had more than one Pseudomonas aeruginosa (PA) morphotype at a given visit, and therefore more than one bacterial load value, then the bacterial load value corresponding to the highest tobramycin minimal inhibitory concentration (MIC) value regardless of the PA morphotype was used. If the tobramycin MIC value was the same for different PA morphotypes, then the bacterial load value corresponding to morphotype 1 (mucoid colony) was used. If morphotype 1 was not available, bacterial load value corresponding to morphotype 2 (dry colony) was used. | Day -10 to -1 (baseline), Week 4, Week 8 | 
| Minimal Inhibitory Concentration Inhibiting Growth of 50% (MIC50) of Pseudomonas Aeruginosa | MIC50 is the concentration of tobramycin required to inhibit 50% of Pseudomonas aeruginosa. MIC values were calculated for three different Pseudomonas aeruginosa (PA) strains: Morphotype 1: mucoid Morphotype 2: dry Morphotype 3: variant Overall MIC50 values are reported. If a participant has more than one PA morphotype at a given visit, then the highest tobramycin MIC value was used, regardless of PA morphotype. If a participant has more than one available result for each morphotype then the highest tobramycin MIC value was used. If the tobramycin MIC values are equal then the MIC value for the isolate with the highest bacterial load value was used. | Week 4, Week 8 | 
| Minimal Inhibitory Concentration Inhibiting Growth of 90% (MIC90) of Pseudomonas Aeruginosa | MIC90 is the concentration of tobramycin required to inhibit 90% of Pseudomonas aeruginosa. MIC values were calculated for three different Pseudomonas aeruginosa (PA) strains: Morphotype 1: mucoid Morphotype 2: dry Morphotype 3: variant Overall MIC90 values are reported. If a participant has more than one PA morphotype at a given visit, then the highest tobramycin MIC value was used, regardless of PA morphotype. If a participant has more than one available result for each morphotype then the highest tobramycin MIC value was used. If the tobramycin MIC values are equal then the MIC value for the isolate with the highest bacterial load value was used. | Week 4, Week 8 | 
| Microbiological Outcome Summary by Visit | Microbiological outcomes are derived considering all P. aeruginosa (PA) morphotypes together. Week 4 and Week 8 microbiological outcomes: Eradication = elimination of PA Persistence = persistence of PA detected at previous visit Superinfection = appearance of a pathogen (other than PA) not detected at previous visit Re-infection (week 8 only) = re-appearance of PA detected at Screening and eradicated at Week 4 Superinfection supersedes eradication. Persistence for P. aeruginosa supersedes superinfection. Re-infection for P. aeruginosa supersedes superinfection. | Day -10 to -1 (screening), Weeks 4 and 8 | 
| Change From Baseline to End of Weeks 2, 4 and 8 in Body Weight | Body weight was measured at all study visits as part of the physical examination. | Day 0 (baseline), Weeks 2, 4 and 8 | 
| Change From Baseline to End of Weeks 2, 4 and 8 in Body Mass Index (BMI) |  | Day 0 (baseline), Weeks 2, 4 and 8 | 
| Count of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-Emergent Adverse Events defined as adverse events occurring after the first intake of study treatment (or the same day). The investigator assessed relation to study treatment as a binary question: Reasonable possibility of relatedness or no reasonable possibility of relatedness. The expression reasonable possibility of relatedness is meant to convey in general that there are facts (evidence) or arguments meant to suggest a causal relationship. A serious AE results in death, is life-threatening, requires hospitalization or prolongation of existing inpatient hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or an important medical event. The investigator rates the severity of the AE based on a three point scale: mild, moderate or severe. A severe event prevents any usual routine activity of the participant and causes severe discomfort. | Day 0 to Week 8 | 
| Participants With a Hearing Threshold >20 Decibel in at Least One Ear | The potential ototoxic effects (hearing loss) of tobramycin were investigated by performing audiometric tests. Participants with a loss of auditory acuity greater than the 20 decibels auditory threshold are reported. | Day -10 to -1 (screening), Weeks 4 and 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cystic fibrosis, P. aeruginosa, tobramycin