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Ease of Use and Microbial Contamination of Tobramycin Inhalation Powder (TIP) Versus Nebulised Tobramycin Inhalation Solution (TIS) and Nebulised Colistimethate (COLI)

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ClinicalTrials.gov Identifier: NCT01844778
Recruitment Status : Completed
First Posted : May 1, 2013
Results First Posted : May 24, 2016
Last Update Posted : July 27, 2016
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE April 29, 2013
First Posted Date  ICMJE May 1, 2013
Results First Submitted Date  ICMJE April 15, 2016
Results First Posted Date  ICMJE May 24, 2016
Last Update Posted Date July 27, 2016
Study Start Date  ICMJE August 2013
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 15, 2016)
Mean Total Administration Time [ Time Frame: days 22 through 28 (cycle 1), days 78 through 84 (cycle 2) ]
The mean total time for administration of TIP via T-326 inhaler versus the total time for administration of COLI or TIS was assessed from information entered by participants into an ediary during the last 7 days prior to the last dose of a cycle. The total time included the setup, preparation, administration and cleaning/disinfection time.
Original Primary Outcome Measures  ICMJE
 (submitted: April 29, 2013)
Total time for administration of TIP with the Podhaler compared to the total time for administration of TIS or colistimethate with nebulisers [ Time Frame: 7 days ]
The total time for administration of Tobramycin Inhalation Powder (TIP) via Podhaler vs the total time for administration of colistimethate or Tobramycin Inhalation Solution (TIS) will be assessed from information entered by participants into an ediary, with a built in timer, during the last 7 days of each active treatment period. The total and combined time includes the setup, preparation, administration and cleaning/disinfection time for all devices.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 15, 2016)
  • Change in P. Aeruginosa Sputum Density [ Time Frame: days 1, 28 (cycle 1); 57, 84, 112 (cycle 2) ]
    Sputum samples were sent to a central laboratory at the start and end of 2 treatment periods. The absolute change in the number of colony forming units (CFU) of Pseudomonas aeruginosa in sputum = the value of end of on/off treatment period of the cycle minus the pre-dose value at the start of that cycle. A negative change from baseline indicates improvement.
  • Number of Participants With Any Contaminated Delivery Device [ Time Frame: days (d) 1, 28, 57, 84 ]
    Devices used to administer the drugs (the T-326 inhaler and nebulisers) were swabbed for contamination testing at the start and end of each treatment cycle (or discontinuation visit if the participant withdrew). No assessments were required from the T-326 inhaler when participants started the treatment period (days 1 and 57). Microbial contamination was measured according to device type and the frequency of organism growth (light/ moderate/ heavy). All nebulisers (neb) used by the participants were analyzed, including those for inhaling other medications, like mucolytics.
  • Minimum Inhibitory Concentration (MIC) - MIC50 and MIC90 Tobramycin Values [ Time Frame: days 1, 28, 57, 84, 112 ]
    MIC50/90 is the lowest concentration required to inhibit 50%/90% of the isolates tested. The MIC50/90 of a range of antibiotics for P.aeruginosa was determined at the start and end of each treatment cycle, and at the end of the off-treatment period of the second cycle.
  • Number of Participants With Post-inhalation Bronchospasm [ Time Frame: days 1, 28, 57, 84 ]
    Bronchospasm was defined as the relative decrease of 20% or more in forced expiratory volume in 1 second (FEV1) percent predicted from pre-dose to 15 to 45 minutes post-dose.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 29, 2013)
  • Number of P. aeruginosa Colony Forming Units [ Time Frame: 28 days post-treatment ]
    Sputum samples will be sent to a central laboratory at the start and end of 2 treatment periods. The change in the number of Colony Forming Units (CFU) of Pseudomonas aeruginosa in sputum at the end of each treatment period, compared to the start, will be determined.
  • Frequency of microbial contamination of the T-326 Inhaler (Podhaler) compared with the contamination of the nebulizer used for the patient's usual nebulised antibiotic [ Time Frame: 28 days post-treatment ]
    Devices used to administer the drugs (the Podhaler and nebulisers) will be swabbed for contamination testing at the start and end of each treatment cycle. The Podhaler is replaced after 7 days, hence the frequency of growth (low/ medium/ high) of organisms contaminating the device at the start and end of this period will be reported, and compared with the frequency of organisms contaminating the nebulisers at the start and end of the treatment period.
  • Adverse event (AE) rates after each treatment cycle [ Time Frame: 168 days ]
    Comparison of the rates of adverse events (AEs) for treatment via Podhaler vs nebulized treatments after each treatment cycle.
  • Change in the minimum inhibitory concentration of the relevant antibiotic for P. aeruginosa [ Time Frame: 28 days post treatment ]
    The Minimum Inhibitory Concentration (MIC) of a range of antibiotics for P. aeruginosa in sputum and in swabs taken off inhaler devices (nebulizers and Podhalers) will be determined at the start and end of each treatment cycle.
  • Clinical laboratory abnormalities for Tobramycin Inhalation Powder vs Tobramycin Inhalation Solution and colistimethate after upto 28 days of treatment [ Time Frame: 28 days post treatment ]
    All abnormalities in clinical chemistry, hematology and urinalysis data will be recorded and reported.
  • Type of microbial contamination of the T-326 Inhaler (Podhaler) compared with the contamination of the nebulizer used for the patient's usual nebulised antibiotic after upto 28 days of treatment in each treatment period [ Time Frame: 28 days post-treatment ]
    Devices used to administer the drugs (the Podhaler and nebulisers) will be swabbed for contamination testing at the start and end of each treatment cycle. The Podhaler is replaced after 7 days, hence the type of organisms contaminating the device at the start and end of this period will be reported, and compared with the types of organisms contaminating the nebulisers at the start and end of the treatment period.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ease of Use and Microbial Contamination of Tobramycin Inhalation Powder (TIP) Versus Nebulised Tobramycin Inhalation Solution (TIS) and Nebulised Colistimethate (COLI)
Official Title  ICMJE An Open-label, Crossover, Interventional Phase IV Study to Compare the Ease of Use of TIP With Nebulized TIS and Nebulized COLI for the Treatment of Pulmonary Pseudomonas Aeruginosa (P.a) in Patients With Cystic Fibrosis
Brief Summary

The purpose of this interventional Phase IV study was to explore the ease of use of TIP and prevalence of microbial contamination of the T-326 Inhaler compared with TIS and colistimethate administered via nebuliser for the treatment of Cystic Fibrosis (CF) patients chronically infected with P. aeruginosa.

It was anticipated that the data from this study would provide clinicians with further guidance on the relative differences between the speed and ease of use of these treatments as well as useful information on the prevalence of microbial contamination of the inhalation devices in "real world" use.

Detailed Description Patients who were on colistimethate (COLI), Tobramycin Inhalation Powder (TIP) or Tobramycin Inhalation Solution (TIS) were recruited for the study. They went through one treatment cycle on their usual inhaled antibiotic treatment, and were all transferred to TIP for the second treatment cycle. The primary endpoint was the total administration time of TIP vs TIS vs colistimethate, defined as the total time taken to prepare the delivery device and drug, administer the drug, and clean and disinfect the delivery device.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cystic Fibrosis
Intervention  ICMJE
  • Drug: Tobramycin Inhalation Powder
    Tobramycin Inhalation Powder was administered via TOBI® Podhaler (T-326 inhaler).
    Other Name: TIP
  • Drug: Tobramycin inhalation solution
    Tobramycin inhalation solution was administered via nebuliser
    Other Name: TIS
  • Drug: Colistimethate
    Colistimethate was administered via nebuliser.
    Other Name: COLI
Study Arms  ICMJE
  • Active Comparator: TIS/TIP
    During the first cycle of treatment, participants received nebulized TIS, 300 mg twice per day for 28 days followed by 28 days off-treatment. During the second cycle, participants received 112 mg (four 28 mg capsules) twice per day for 28 days followed by 28 days off-treatment.
    Interventions:
    • Drug: Tobramycin Inhalation Powder
    • Drug: Tobramycin inhalation solution
  • Active Comparator: COLI/TIP
    During the first cycle, participants received nebulized COLI, 1 million or 2 million units twice or thrice per day (or the participant's usual dose and regimen) for 56 days (no off-treatment period) or 28 days on-treatment followed by 28 days off-treatment (cycling regimen), depending on local treatment guidelines. During the second cycle, participants received TIP, 112 mg (four 28 mg capsules) twice per day for 28 days followed by 28 days off-treatment.
    Interventions:
    • Drug: Tobramycin Inhalation Powder
    • Drug: Colistimethate
  • Active Comparator: TIP/TIP
    During the first and second cycles, participants received TIP, 112 mg (four 28 mg capsules) twice per day for 28 days followed by 28 days off-treatment.
    Intervention: Drug: Tobramycin Inhalation Powder
Publications * Greenwood J, Schwarz C, Sommerwerck U, Nash EF, Tamm M, Cao W, Mastoridis P, Debonnett L, Hamed K. Ease of use of tobramycin inhalation powder compared with nebulized tobramycin and colistimethate sodium: a crossover study in cystic fibrosis patients with pulmonary Pseudomonas aeruginosa infection. Ther Adv Respir Dis. 2017 Jul;11(7):249-260. doi: 10.1177/1753465817710596.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 26, 2016)
60
Original Estimated Enrollment  ICMJE
 (submitted: April 29, 2013)
67
Actual Study Completion Date  ICMJE October 2015
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

  • Provide written informed consent, HIPAA authorization, and assent (as appropriate for minors) prior to the performance of any study-related procedure
  • Confirmed diagnosis of Cystic Fibrosis (CF)
  • Male and female patients 6 years of age or older at screening
  • Forced Expiratory Volume in 1 second (FEV1) at screening (Visit 1) must be at least 25% and less than or equal to 90% of normal predicted values for age, sex, and height based on the NHANES III values (Hankinson, 1999) for patients 18 years of age or greater, and based on values from Wang (Wang 1993) for patients less than 18 years of age.
  • Documented use of any of the nebulized antibiotics based on local practice:
  • Tobramycin Inhalation Solution, colistimethate, or Tobramycin Inhalation Powder for at least 1 cycle within the last 6 months or
  • Colistimethate continuous use for at least 8 weeks within the last 6 months This cycle of treatment (or continuous colistimethate treatment period) is in addition to the treatment cycle during which the subject is being screened.
  • P. aeruginosa must be present in a sputum or deep cough throat swab culture or bronchoalveolar lavage (BAL) (only for BAL a threshold level of 10^3 CFU/mL is required) within 6 months prior to screening, and in the sputum or deep cough throat swab culture at screening or rescreening (Visit 1);

Key Exclusion Criteria:

  • History of sputum culture or deep cough throat swab (or BAL) culture yielding Burkholderia cenocepacia complex within 2 years prior to prescreening or sputum culture yielding B. cenocepacia complex at screening (Visit 1)
  • History of hearing loss or chronic tinnitus deemed clinically significant by the investigator
  • Serum creatinine 176.8 μmol/L (2 mg/dL) or greater, blood urea nitrogen (BUN) 14.28 mmol/L (40 mg/dL) or greater, or an abnormal urinalysis defined as 2+ or greater proteinuria at screening
  • Known local or systemic hypersensitivity to aminoglycosides
  • Regularly receiving more than 1 class of inhaled antipseudomonal antibiotic
  • Use of any investigational drug within 30 days or 5 half-lives, whichever is longer, prior to screening
  • Signs and symptoms of acute pulmonary disease, e.g., pneumonia, pneumothorax
  • Body mass index less than 12 kg/m2
  • History of malignancy of any organ system, treated or untreated
  • Clinically significant laboratory abnormalities (not associated with the study indication) at screening (Visit 1)
  • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test
  • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during study treatment.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany,   Ireland,   Spain,   Switzerland,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01844778
Other Study ID Numbers  ICMJE CTBM100C2403
2012-001565-33 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date July 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP