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

• 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: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis	Drug: Tobramycin Inhalation Powder; Drug: Tobramycin inhalation solution; Drug: Colistimethate	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 60 participants
• Allocation: Non-Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: August 2013
• Actual Primary Completion Date: October 2015
• Actual Study Completion Date: October 2015

Arms and Interventions

Arm	Intervention/treatment
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.	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
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.	Drug: Tobramycin Inhalation Powder; Tobramycin Inhalation Powder was administered via TOBI® Podhaler (T-326 inhaler).; Other Name: TIP; Drug: Colistimethate; Colistimethate was administered via nebuliser.; Other Name: COLI
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.	Drug: Tobramycin Inhalation Powder; Tobramycin Inhalation Powder was administered via TOBI® Podhaler (T-326 inhaler).; Other Name: TIP

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.

Eligibility Criteria

• Ages Eligible for Study: 6 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Germany

Novartis Investigative Site

Berlin, Germany, 13353

Novartis Investigative Site

Essen, Germany, 45147

Novartis Investigative Site

München, Germany, 81241

Novartis Investigative Site

Tübingen, Germany, 72076

Ireland

Novartis Investigative Site

Galway, Ireland

Spain

Novartis Investigative Site

Sevilla, Andalucia, Spain, 41013

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08035

Novartis Investigative Site

Valencia, Comunidad Valenciana, Spain, 46026

Novartis Investigative Site

Palma De Mallorca, Islas Baleares, Spain, 07120

Novartis Investigative Site

Madrid, Spain, 28046

Switzerland

Novartis Investigative Site

Basel, Switzerland, 4031

Novartis Investigative Site

St. Gallen, Switzerland, 9007

Novartis Investigative Site

Zürich, Switzerland, 8032

United Kingdom

Novartis Investigative Site

Southampton, Hampshire, United Kingdom, SO16 6YD

Novartis Investigative Site

Penarth, Vale of Glamorgan, United Kingdom, CF64 2XX

Novartis Investigative Site

Birmingham, West Midlands, United Kingdom, b9 5ss

Novartis Investigative Site

Bristol, United Kingdom, BS1 3NU

Novartis Investigative Site

East Yorkshire, United Kingdom, HU16 5JQ

Novartis Investigative Site

Exeter, United Kingdom, EX2 5DW

Novartis Investigative Site

Liverpool, United Kingdom, L14 3PE

Novartis Investigative Site

Newcastle upon Tyne, United Kingdom, NE1 4LP

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01844778
• Other Study ID Numbers: CTBM100C2403; 2012-001565-33 ( EudraCT Number )
• First Posted: May 1, 2013
• Results First Posted: May 24, 2016
• Last Update Posted: July 27, 2016
• Last Verified: July 2016

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Cystic Fibrosis, Pseudomonas aeruginosa, FEV1, tobramycin inhalation powder, TOBI,; colistimethate; Cystic Fibrosis, Pseudomonas aeruginosa, FEV1, tobramycin inhalation powder, TOBI, colistimethate

Additional relevant MeSH terms:

Cystic Fibrosis; Fibrosis; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Tobramycin; Anti-Bacterial Agents; Anti-Infective Agents