Long Term Safety of Tobramycin Inhalation Powder in Patients With Cystic Fibrosis

A Single Arm, Open-label, Multicenter, Phase IV Trial to Assess Long Term Safety of Tobramycin Inhalation Powder (TIP) in Patients With Cystic Fibrosis

This study assessed the long term safety data for the use of tobramycin inhalation powder in patients suffering from cystic fibrosis who have a chronic pulmonary infection with Pseudomonas aeruginosa.

Study Overview

• Status: Completed
• Conditions: Pulmonary Infections; Pseudomonas Aeruginosa in Cystic Fibrosis
• Intervention / Treatment: Drug: TBM100

• Study Type: Interventional
• Enrollment (Actual): 157
• Phase: Phase 4

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1425DTG
      • Novartis Investigative Site
    • Capital Federal, Buenos Aires, Argentina, C1425EFD
      • Novartis Investigative Site
  • Cordoba
    • Córdoba, Cordoba, Argentina, X5014AKN
      • Novartis Investigative Site
  • Entre Rios
    • Paraná, Entre Rios, Argentina, E3100FKA
      • Novartis Investigative Site
• Australia
  • New South Wales
    • New Lambton Heights, New South Wales, Australia, 2305
      • Novartis Investigative Site
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Novartis Investigative Site
    • Parkville, Victoria, Australia, 3052
      • Novartis Investigative Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N1
      • Novartis Investigative Site
    • Edmonton, Alberta, Canada, T6G 2B7
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H3T1C5
      • Novartis Investigative Site
• France
  • Giens Cedex, France, 83406
    • Novartis Investigative Site
  • Montpellier, France, 34059
    • Novartis Investigative Site
  • Paris, France, 75006
    • Novartis Investigative Site
  • Reims, France, 51092
    • Novartis Investigative Site
  • Roscoff, France, 29684
    • Novartis Investigative Site
• Germany
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Frankfurt, Germany, 60590
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1121
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • Palermo, Italy, 90100
    • Novartis Investigative Site
  • Roma, Italy, 00161
    • Novartis Investigative Site
  • FI
    • Firenze, FI, Italy, 50139
      • Novartis Investigative Site
  • GE
    • Genova, GE, Italy, 16147
      • Novartis Investigative Site
  • ME
    • Messina, ME, Italy, 98125
      • Novartis Investigative Site
  • VR
    • Verona, VR, Italy, 37126
      • Novartis Investigative Site
• Mexico
  • Distrito Federal
    • Mexico, Distrito Federal, Mexico, 06720
      • Novartis Investigative Site
  • Nuevo León
    • Monterrey, Nuevo León, Mexico, 64460
      • Novartis Investigative Site
• Spain
  • Cataluña
    • Barcelona, Cataluña, Spain
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46026
      • Novartis Investigative Site
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Novartis Investigative Site
  • Colorado
    • Denver, Colorado, United States, 80206
      • Novartis Investigative Site
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Novartis Investigative Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Novartis Investigative Site
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Novartis Investigative Site
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • Novartis Investigative Site
  • Nevada
    • Las Vegas, Nevada, United States, 89107
      • Novartis Investigative Site
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • Novartis Investigative Site
  • Ohio
    • Akron, Ohio, United States, 44308
      • Novartis Investigative Site
    • Cleveland, Ohio, United States, 44106
      • Novartis Investigative Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Novartis Investigative Site
    • Oklahoma City, Oklahoma, United States, 73112
      • Novartis Investigative Site
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Novartis Investigative Site
  • Texas
    • Dallas, Texas, United States, 75230
      • Novartis Investigative Site
    • Fort Worth, Texas, United States, 76104
      • Novartis Investigative Site
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78212
      • Novartis Investigative Site
  • Washington
    • Tacoma, Washington, United States, 98405
      • Novartis Investigative Site
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-1615
      • Novartis Investigative Site
    • Milwaukee, Wisconsin, United States, 53226
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Confirmed diagnosis of Cystic Fibrosis
• FEV1 at screening must be between 25 and 75 percent of normal predicted values for age, sex and height based on the Knudson equation
• Pseudomonas aeruginosa must be present in a sputum / deep cough throat swab culture or bronchoalveolar lavage within 6 months prior to screening and in the sputum/deep-throat cough swab culture at screening

Exclusion Criteria:

• History of sputum culture or deep cough throat swab culture yielding Burkholderia cenocepacia complex within 2 years prior to screening and /or sputum culture yielding Burkholderia cenocepacia at screening
• Hemoptysis more than 60mL at any time within 30 days prior to study drug administration
• History of hearing loss or chronic tinnitus deemed clinically significant
• Serum creatinine 2mg/dl or more, BUN 40mg/dl or more, or an abnormal urinalysis defined as 2+ or greater proteinuria at screening
• Known local or systemic hypersensitivity to aminoglycosides or inhaled antibiotics
• Patients who are regularly receiving more than 1 class of inhaled anti-pseudomonal antibiotic
• Any use of inhaled or systemic anti-pseudomonal antibiotic within 28 days prior to study drug administration
• Use of loop diuretics within 7 days prior to study drug administration

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Tobramycin Inhalation Powder (TIP); Eligible patients were assigned to four capsules of TIP at 28mg dosage strength, inhaled b.i.d. in the morning and in the evening via the T-326 inhaler, for 28 days (on treatment), followed by 28 days of no study treatment (off treatment). Each treatment therefore consisted of 112mg tobramycin (4 capsules of 28mg each) with the total daily dose = 224mg tobramycin (112mg b.i.d.). These 56 days represented 1 cycle of therapy.

Drug: TBM100; Tobramycin inhalation powder was assigned as four capsules at 28mg dosage strength. It was inhaled b.i.d in the morning and in the evening via the T-326 Inhaler.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treatment Emergent Adverse Events, Serious Adverse Events (SAEs) and Deaths	Adverse events were deemed treatment-emergent if the onset date/time was on or after the date and time of first study drug. All adverse events were included after this time during both on and off-treatment periods.	337 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Percent Predicted	Spirometry was performed at each visit. FEV1, FVC, and FEF25-75 were recorded at all visits according to American Thoracic Society (ATS) guidelines. FEV1 = the volume of air expired in 1 second. FEV1 % predicted is a normalized value of FEV1 calculated using the Knudsen equation, based upon participant's age, gender and height. FVC (forced vital capacity) = the maximal volume of air exhaled with maximally forced effort from a position of maximal inspiration. FEF25-75 = forced expiratory flow from 25% to 75% of the FVC. Relative change in FEV1 % predicted from baseline to pre-dose day X = ((pre-dose day X FEV1 % predicted - baseline FEV1 % predicted) / baseline FEV1 % predicted) • 100.	Baseline, day 29, day 85, day 141, day 197, day 253, day 309, day 337. All study visits except baseline and day 337 occurred at the end of a 28-day on-treatment period of a cycle. Day 337 was the end of the final 28-day off treatment period.
Relative Change From Baseline in FVC Percent Predicted	Spirometry was performed at each visit. FEV1, FVC, and FEF25-75 were recorded at all visits according to American Thoracic Society (ATS) guidelines. FEV1 = the volume of air expired in 1 second. FEV1 % predicted is a normalized value of FEV1 calculated using the Knudsen equation, based upon participant's age, gender and height. FVC (forced vital capacity) = the maximal volume of air exhaled with maximally forced effort from a position of maximal inspiration. FEF25-75 = forced expiratory flow from 25% to 75% of the FVC. Relative change in FVC % predicted from baseline to pre-dose day X = ((pre-dose day X FVC % predicted - baseline FVC % predicted) / baseline FVC % predicted) • 100.	Baseline, day 29, day 85, day 141, day 197, day 253, day 309, day 337. All study visits except baseline and day 337 occurred at the end of a 28-day on-treatment period of a cycle. Day 337 was the end of the final 28-day off treatment period.
Relative Change From Baseline in FEF Rate Over 25 to 75 Percent of Vital Capacity Predicted	Spirometry was performed at each visit. FEV1, FVC, and FEF25-75 were recored at all visits according to American Thoracic Society (ATS) guidelines. FEV1 = the volume of air expired in 1 second. FEV1 % predicted is a normalized value of FEV1 calculated using the Knudsen equation, based upon participant's age, gender and height. FVC (forced vital capacity) = the maximal volume of air exhaled with maximally forced effort from a position of maximal inspiration. FEF25-75 = forced expiratory flow from 25% to 75% of the FVC. Relative change in FEEF25-75 from baseline to pre-dose day X = ((pre-dose day X FEF25-75 - baseline FEF25-75) / baseline FEF25-75) • 100.	Baseline, day 29, day 85, day 141, day 197, day 253, day 309, day 337. All study visits except baseline and day 337 occurred at the end of a 28-day on-treatment period of a cycle. Day 337 was the end of the final 28-day off treatment period.
Change From Baseline in Pseudomonas Aeruginosa Colony Forming Units in Sputum	Sputum was collected in sterile containers and cultured for Pseudomonas aeruginosa (Pa.) (quantitative test) and other typical Cystic Fibrosis respiratory pathogens. The Pa. biotypes measured were mucoid, dry and small colony variant. Results are presented for the sum of all biotypes of Pa, with data transformed using a base 10 logarithm.	Baseline, day 1, day 29, day 85, day 141, day 197, day 253, day 309, day 337
Tobramycin MIC 50 and MIC 90 Values Over All Isolates for the Sum of All Biotypes (Mucoid, Dry and Small Colony Variant) of Pseudomonas Aeruginosa	Tobramycin MIC 50 and MIC 90 values were defined as the lowest concentration of tobramycin required to inhibit 50% and 90%, respectively, of the P. aeruginosa strains tested.	Baseline, day 29, day 85, day 141, day 197, day 253, day 309, day 337
Percentage of Participants Hospitalized Due to Serious Respiratory-related Adverse Events		Day 337
Number of Hospitalization Days Due to Serious Respiratory-related Adverse Events	The total number of hospitalization days due to serious respiratory-related adverse events was analyzed.	Day 337
Time to First Hospitalization Due to Serious Respiratory-related Adverse Events	The day of first hospitalization due to serious respiratory-related adverse events was analyzed.	Day 337
Percentage of Participants Who Used New Anti-pseudomonal Antibiotics		Day 337
Number of Days of New Anti-pseudomonal Antibiotic Use	The total number of days of new anti-pseudomonal antibiotic use was analyzed.	Day 337
Time to Use of New Anti-pseudomonal Antibiotic	Time to first use of new anti-pseudomonal antibiotic was analyzed.	Day 337

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Sommerwerck U, Virella-Lowell I, Angyalosi G, Viegas A, Cao W, Debonnett L. Long-term safety of tobramycin inhalation powder in patients with cystic fibrosis: phase IV (ETOILES) study. Curr Med Res Opin. 2016 Nov;32(11):1789-1795. doi: 10.1080/03007995.2016.1211516. Epub 2016 Sep 9.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (ACTUAL): January 1, 2014
• Study Completion (ACTUAL): January 1, 2014

Study Registration Dates

• First Submitted: January 24, 2012
• First Submitted That Met QC Criteria: January 26, 2012
• First Posted (ESTIMATE): January 27, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): February 10, 2015
• Last Update Submitted That Met QC Criteria: February 8, 2015
• Last Verified: February 1, 2015

More Information

Terms related to this study

• Keywords: Cystic fibrosis; Anti-bacterial agents; Lung disease; Tobramycin Inhalation powder
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Respiratory Aspiration; Cystic Fibrosis
• Other Study ID Numbers: CTBM100C2401; 2011-002000-32 (EUDRACT_NUMBER)