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

Cystic Fibrosis Clinical Trial

— CT03 Core  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00885365
• Other study ID #: CMA-0631-PR-0010 Core
• Status: Completed
• Phase: Phase 3
• Start date: April 2009
• Est. completion date: May 2010

Study information

• Verified date: April 2018
• Source: Chiesi Farmaceutici S.p.A.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 324
• Est. completion date: May 2010
• Est. primary completion date: April 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Drug:
• tobramycin / Bramitob
300mg/4ml solution, via a nebuliser, over a 4-week treatment in a twice-daily regimen
• tobramycin / TOBI
300mg/5ml solution administered via nebuliser, over a 4-week treatment in a twice-daily regimen

Locations

Country	Name	City	State
Czechia	Centrum pro cystickou fibrosu, Pediatricka klinika UK 2.LF, Fakultní nemocnice v Motole	Praha
France	CHR Clemenceau	Caen
France	Hopital Arnaud de Villeneuve, Clinique des maladies respiratoires	Montpellier
France	Hopital Necker	Paris
Germany	Pädiatrische Pneumologie und Allergologie, Mukovizidose-Zentrum, Zentrum für Kinderheilkunde und Jugendmedizin	GieBen
Germany	HELIOS Klinikum Krefeld, Zentrum für Kinder- und Jugendmedizin	Krefeld
Hungary	Fovárosi Önkormányzat Heim Pál	Budapest
Hungary	Kaposi Mór Oktatókórház	Mosdos
Hungary	Szegedi Tudományegyetem Szent-Györgyi Albert Orvos- és Gyógyszerésztudományi Centrum	Szeged
Poland	Specjalistyczny ZOZ nad Matka i Dzieckiem, Poradnia Leczenia Mukowiscydozy	Gdansk
Poland	I Oddzial Chorob Dzieciecych, Wojewodzki Specjalistyczny Szpital Dzieciecy	Kielce
Poland	Oddzial Kliniczny Interny Dzieciecej i Alergologii, Wojewodzki Szpital Specjalistyczny	Lodz
Poland	Dzieciecy Szpital Kliniczny Akademii Medycznej, Klinika Chorob Pluc I Reumatologii	Lublin
Poland	Klinika Pneumonologii, Alergologii Dzieciecej i Immunologii Klinicznej Szpital Kliniczny Uniwersytetu Medycznego w Poznaniu	Poznan
Poland	Klinika Pneumonologii i Mukowiscydozy, Instytut Gruzlicy i Chorob Pluc w Rabce Zdroj	Rabka Zdroj
Poland	Poradnia Mukowiscydozy Wojewodzkiej, Przychodni Specjalistycznej dla Dzieci, Szpitala Wojewodzkiego Nr 2	Rzeszow
Poland	Klinika Pediatrii Instytut Matki I Dziecka	Warszawa
Russian Federation	State Medical Institution: Republican Childrens Clinical Hospital under the Ministry of Health of the Republic of Tatarstan	Kazan
Russian Federation	Federal State Institution: Scientific Research Pulmonology Institute under the Roszdrav	Moscow
Russian Federation	State Medical Institution: Filatov Chidren's City Clinical Hospital #13	Moscow
Russian Federation	Federal State Institution "Nizhegorodskiy Research Institute of Children's Gastroenterology of Russian Medical Technologies"	Nizhniy Novgorod
Russian Federation	State Medical Institution: Regional Children's Hospital Pulmonology Department	Rostov-on-Don
Russian Federation	Regional State Medical Institution: Smolensk Regional Children's Clinical Hospital	Smolensk
Russian Federation	Saint-Petersburg State Medical Institution: City Children's Hospital of Saint Olga	St. Petersburg
Russian Federation	State Higher Educational Institution: Bashkir State Medical University under the Roszdrav	Ufa
Russian Federation	State Higher Educational Institution: Burdenko Voronezh State Medical Academy under the Roszdrav	Voronezh
Russian Federation	Minicipal Medical Institution: Children's Clinical Hospital #1	Yaroslavl
Spain	Complejo Hospitalario Universitario A Coruña	A Coruña
Spain	Complejo Hospitalario Universitario A Coruña (Hospital Materno-Infantil Teresa Herrera)	A Coruña
Spain	Hospital Universitario La Paz	Madrid
Spain	Corporació Sanitaria Parc Tauli	Sabadell
Spain	Hospital Universitario Ntra Sra. De la Candelaria	Santa Cruz de Tenerife
Spain	Hospital Universitario La Fe	Valencia
Spain	Hospital Universitario Miguel Servet (Children)	Zaragoza
Ukraine	Dnipropetrovsk City Children Clinical Hospital # 2	Dnipropetrovsk
Ukraine	Donetsk Regional Children Clinical Hospital	Donetsk
Ukraine	Kriviy Rig City Clinical Hospital # 8	Kriviy Rig
Ukraine	Institute of Pediatrics, Obstetrics and Gynecology of the Academy of Medical Science of Ukraine	Kyiv
Ukraine	Institute of Phthysiology and Pulmonology n.a., F.G.Yanovskiy of the Academy of Medical Science of Ukraine	Kyiv
Ukraine	Lviv Regional Children Specialized Clinical Hospital	Lviv
Ukraine	Odesa Regional Children Clinical Hospital	Odesa
Ukraine	Simferopol Central District Clinical Hospital	Simferopol
Ukraine	Zaporizhya Regional Clinical Children Hospital	Zaporizhya

Sponsors (1)

Lead Sponsor	Collaborator
Chiesi Farmaceutici S.p.A.

Countries where clinical trial is conducted

Czechia,  France,  Germany,  Hungary,  Poland,  Russian Federation,  Spain,  Ukraine, 

References & Publications (1)

Mazurek H, Chiron R, Kucerova T, Geidel C, Bolbas K, Chuchalin A, Blanco-Aparicio M, Santoro D, Varoli G, Zibellini M, Cicirello HG, Antipkin YG. Long-term efficacy and safety of aerosolized tobramycin 300 mg/4 ml in cystic fibrosis. Pediatr Pulmonol. 201 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change From Baseline to End of Weeks 2, 4 and 8 in Body Mass Index (BMI)		Day 0 (baseline), Weeks 2, 4 and 8
Secondary	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
Secondary	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

External Links

•   Study Record on EU Clinical Trials Register including results