A Study of Tobramycin Inhalation Powder From a Modified Manufacturing Process Versus Placebo (EDIT)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00918957
First received: June 4, 2009
Last updated: October 1, 2012
Last verified: October 2012
  Purpose

This study is designed to show how well tobramycin inhalation powder works and how safe it is when produced by a modified manufacturing process


Condition Intervention Phase
Cystic Fibrosis
Drug: Tobramycin Inhalation Powder
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase III Study in Cystic Fibrosis (CF) Subjects to Assess Efficacy, Safety and Pharmacokinetics of Tobramycin Inhalation Powder From a Modified Manufacturing Process (TIPnew).

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) [ Time Frame: Baseline, Day 29 ] [ Designated as safety issue: No ]

    Relative change in percentage predicted FEV1 in the Intent-to-treat (ITT), modified ITT (mITT) and Observed cases in the ITT populations were calculated from an adjusted analysis ANOVA model.

    ITT Patients with missing or unacceptable Day 29 spirometry measurements had their primary endpoint data imputed with zero.

    BSL = Baseline, defined as the latest measurement prior to the first dosing of study medication

    - Relative change = 100 * (value - baseline) / baseline There were 3 patients who had no screening nor baseline values (due to inadequate spirometry) and so were excluded from all change from baseline analyses.


  • Pre-planned Sensitivity Analysis: Absolute Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent (%) Predicted to End of Dosing (Day 29) [ Time Frame: Baseline, Day 29 ] [ Designated as safety issue: No ]

    Absolute change in percentage predicted FEV1 in the Intent-to-treat (ITT), modified ITT (mITT) and Observed cases in the ITT populations were calculated from an adjusted analysis ANOVA model.

    In the adjusted analysis model: response = treatment + screening FEV1 % predicted (<50 and >=50) + age (<13 and >=13) + error.

    Significance for the FEV1 % predicted is reached for p-values <= 0.05. There were 3 patients who had no screening nor baseline values (due to inadequate spirometry) and so were excluded from all change from baseline analyses.


  • Post-hoc: Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) Without Outlier [ Time Frame: Baseline, Day 29 ] [ Designated as safety issue: No ]
    Relative change in percentage predicted FEV1 without outlier (outliers with respect to FEV1 values and PK data), in the Intent-to-treat (ITT), modified ITT (mITT) and Observed cases in the ITT populations were calculated from an adjusted analysis ANOVA model.


Secondary Outcome Measures:
  • Change From Baseline of Forced Vital Capacity (FVC) Percent Predicted to End of Dosing (Day 29) and to the End of Off-cycle Period (Day 57) [ Time Frame: Baseline, Day 29, Day 57 ] [ Designated as safety issue: No ]

    Results of statistical analysis were calculated from an ANOVA model. Baseline is defined as the latest measurement prior to the first dosing of study medication.

    Response (percentage change) = treatment + Screening FEV1 percentage predicted (<50 and >=50) + age (<13 and >=13) + error


  • Change From Baseline of Forced Expiratory Flow Rate Over 25 and 75 Percent. (FEF25-75%) Predicted to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) [ Time Frame: Baseline, Day 29, Day 57 ] [ Designated as safety issue: No ]

    FEF25-75: Forced expiratory flow rate over 25% to 75% of vital capacity

    For FEF25-75 percentage predicted the relative change is analyzed. If screening FEV1 percentage predicted is missing, it will be imputed by the baseline value.


  • Absolute Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) in Sputum Pseudomonas Aeruginosa Density (log10 Colony Forming Units(CFU) Per Gram Sputum) [ Time Frame: Baseline, Day 29, Day 57 ] [ Designated as safety issue: No ]

    P. aeruginosa sputum density refers to overall density, defined as the sum of biotypes (mucoid, dry and small colony variant).

    If sub-isolates exist for CFU biotype mucoid or dry, then the sum of sub-isolates is analyzed.


  • Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) of Pseudomonas Aeruginosa Minimum Inhibitory Concentration (MIC) [ Time Frame: Baseline, Day 29, Day 57 ] [ Designated as safety issue: No ]
    Maximum MIC values from all biotypes were used. Absolute values and changes in tobramycin MIC for P. aeruginosa from baseline are summarized by biotype. Overall, a high variability of MIC was observed within each treatment group. For the maximum of all biotypes, large differences in mean changes from baseline at Day 29 were observed between the TIP group and the placebo group.

  • Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal [ Time Frame: Baseline, Study completion ] [ Designated as safety issue: No ]

    Hematology values shift from baseline to above upper/below lower limit of normal at any time post-baseline.

    Biochemistry values shift from baseline to above upper/below lower limit of normal at any time post-baseline.


  • Percentage of Participants With Adverse Events (AEs) [ Time Frame: First administration of study drug, study completion ] [ Designated as safety issue: Yes ]

    Adverse Events (AEs) (on and off treatment) regardless of study relationship by primary system organ and treatment group.

    Primary system organ classes are sorted in descending order of frequency in the TIP treatment group.

    A patient with more than one AE within a primary system organ class is counted only once for that class.


  • Percentage of Participants With Serious Adverse Events (SAEs) [ Time Frame: Time of consent, 4 weeks after study completion ] [ Designated as safety issue: Yes ]

    Serious Adverse Events (on and off treatment) by preferred term and treatment group.

    Preferred terms are sorted in descending order of frequency in the TIP treatment group.

    A patient with multiple occurrences of the same preferred term is counted only once in the preferred term.


  • Acute Change in Airways Reactivity (FEV1 Percent Predicted) From Pre-dose to 30 Minutes After Completion of First Dose of Study Drug [ Time Frame: Day 1, Day 29 ] [ Designated as safety issue: No ]

    Relative change = 100 * (30-m-post-dose - pre-dose)/pre-dose assessed by the number and percentage of patients with a decrease of ≥20 % in FEV1 % predicted from pre dose to 30 minutes post dose.

    Day 1 is the scheduled visit of first study drug administration.


  • Tobramycin Serum Concentration [ Time Frame: Pre-dose, 0 - 1 hour post-dose, 1 -2 hours post-dose, 2 - 6 hours post-dose ] [ Designated as safety issue: No ]

    Descriptive statistics of serum and sputum concentrations per scheduled sampling time.

    Detectable concentration values at pre-dose on Day 1 were excluded from the analysis.



Enrollment: 62
Study Start Date: June 2009
Study Completion Date: May 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: TIP (Tobramycin Inhalation Powder)
Tobramycin 28 mg powder. The TIP dose of 112 mg twice a day (bis in diem = b.i.d.), given in a cycle of 28 days on treatment followed by 28 days off treatment.
Drug: Tobramycin Inhalation Powder
Tobramycin Inhalation Powder as produced by a modified manufacturing process TIP. TIP was provided in hard capsules each containing 28 mg active ingredient (tobramycin); Capsules were packaged in blister cards and administered by the T-326 Inhaler.
Placebo Comparator: Placebo
Placebo 20 mg powder capsules. The dose regimen for the reference product was inhaling the contents of four capsules twice a day (bis in diem = b.i.d.), in the morning and in the evening for 28 days (on treatment), followed by 28 days of no study treatment (off treatment).
Drug: Placebo
Placebo inhalation powder consisting of the excipients used for TIP. Placebo was provided in hard capsules, containing 20 mg placebo powder, which were packaged in blister cards, matching in appearance to TIP. Capsules were administered by the T-326 Inhaler.

  Eligibility

Ages Eligible for Study:   6 Years to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent given by adults or by the parents/legal guardian in combination with the patient's assent, if capable of assenting, before any assessment was performed
  • Confirmed diagnosis of Cystic Fibrosis (CF) by the presence of one or more clinical features of CF in addition to:

    • a quantitative pilocarpine iontophoresis sweat chloride test of >60 mEq/L; or
    • identification of well-characterized disease-causing mutations in each CFTR gene; or
    • an abnormal nasal transepithelial potential difference characteristic of CF.
  • Forced Expiratory Volume in one second (FEV1) at screening must have been ≥25% and ≤80% of normal predicted values for age, sex, and height based on Knudson criteria
  • P. aeruginosa must have been present in a sputum/deep-throat cough swab culture (or bronchoalveolar lavage [BAL]) within 6 months prior to screening and in the sputum/deep-throat cough swab culture at the screening visit
  • Able to expectorate a sputum sample or provide a deep throat cough swab at screening
  • Able to comply with all protocol requirements
  • Use of an effective means of contraception in females of childbearing potential
  • Clinically stable in the opinion of the investigator to be treated according to this protocol

Exclusion Criteria:

  • FEV1 at baseline (Visit 2) <25% or >80% of normal predicted values for age, sex, and height based on Knudson criteria, and/or FEV1 at baseline (Visit 2) deviated by ≥10% from the FEV1 measured at screening (Visit 1)
  • Any use of inhaled anti-pseudomonal antibiotics within 4 months prior to screening
  • Any use of systemic anti-pseudomonal antibiotics within 28 days prior to study drug administration
  • Serum creatinine 2 mg/dL or above, blood urea nitrogen (BUN) 40 mg/dL or above, or an abnormal urinalysis defined as 2+ or greater proteinuria
  • Known local or systemic hypersensitivity to aminoglycosides or inhaled antibiotics
  • Signs and symptoms of acute pulmonary disease, e.g. pneumonia, pneumothorax
  • Administration of any investigational drug within 30 days prior to enrollment
  • Any previous exposure to tobramycin dry powder for inhalation (TIP)
  • Administration of loop diuretics within 7 days prior to study drug administration
  • Initiation of treatment with chronic macrolide therapy within 28 days prior to study drug administration
  • Initiation of treatment with dornase alfa within 28 days prior to study drug administration
  • Initiation of treatment with inhaled steroids (or increased dose) within 28 days prior to study drug administration
  • Initiation of treatment with inhaled hypertonic saline (HS) within 28 days prior to study drug administration
  • Personal history of abnormal hearing or family history of abnormal hearing other than typical hearing loss associated with the aging process
  • Known abnormal result from any audiology testing (defined as either a unilateral puretone audiometry test showing a threshold elevation >20 dB at any frequency across the frequency range 0.25 kHz to 8 kHz or the absence of emission at the evoked otoacoustic emission test)
  • History of sputum culture or throat swab (or BAL) culture yielding Burkholderia cepacia (B. cepacia) within 2 years prior to screening and/or sputum culture yielding B. cepacia at screening
  • Hemoptysis of more than 60 mL at any time within 30 days prior to study drug administration
  • History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of evidence of local recurrence or metastases
  • Patients with clinically significant laboratory abnormalities (not associated with the study indication) at screening
  • Patients or caregivers with a history of noncompliance to medical regimens and patients or caregivers who are considered potentially unreliable
  • Pregnant or nursing (lactating) women
  • Women of child-bearing potential unless they used two reliable birth control methods

Other protocol-defined inclusion/exclusion criteria may apply

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00918957

Locations
Bulgaria
Novartis Investigative Site
Pleven, Bulgaria
Novartis Investigative Site
Plovdiv, Bulgaria
Novartis Investigative Site
Sofia, Bulgaria
Novartis Investigative Site
Varna, Bulgaria
Egypt
Novartis Investigative Site
Alexandria, Egypt
Novartis Investigative Site
Giza, Egypt
Estonia
Novartis Investigative Site
Tallin, Estonia
Novartis Investigative Site
Tartu, Estonia
India
Novartis Investigative Site
Chandigarh, India
Novartis Investigative Site
Hyderabad, India
Novartis Investigative Site
New Delhi, India
Novartis Investigative Site
Vellore, India
Latvia
Novartis Investigative Site
Riga, Latvia
Lithuania
Novartis Investigative Site
Kaunas, Lithuania
Novartis Investigative Site
Vilnius, Lithuania
Romania
Novartis Investigative Site
Bucuresti, Romania
Novartis Investigative Site
Timisoara, Romania
Russian Federation
Novartis Investigative Site
Kazan, Russian Federation
Novartis Investigative Site
Moscow, Russian Federation
Novartis Investigative Site
Saint Petersburg, Russian Federation
Novartis Investigative Site
Samara, Russian Federation
Novartis Investigative Site
Voronezh, Russian Federation
Novartis Investigator Site
Yaroslavi, Russian Federation
South Africa
Novartis Investigative Site
Durban, South Africa
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided by Novartis

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00918957     History of Changes
Other Study ID Numbers: CTBM100C2303, 2008-002318-22
Study First Received: June 4, 2009
Results First Received: May 5, 2012
Last Updated: October 1, 2012
Health Authority: Bulgaria: Ministry of Health
Chile: Instituto de Salud Pública de Chile
Egypt: Ministry of Health and Population
Estonia: The State Agency of Medicine
European Union: European Medicines Agency
Ireland: Ministry of Health
India: Ministry of Health
Latvia: State Agency of Medicines
Lithuania: State Medicine Control Agency - Ministry of Health
Romania: Ministry of Public Health
Russia: Ministry of Health of the Russian Federation
South Africa: Department of Health
United States: Food and Drug Administration

Keywords provided by Novartis:
Tobramycin Inhalation Powder
Cystic fibrosis
Lung diseases
Anti-Bacterial Agents
Treatment of infections with P. aeruginosa in cystic fibrosis subjects

Additional relevant MeSH terms:
Cystic Fibrosis
Fibrosis
Respiratory Aspiration
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Pathologic Processes
Respiration Disorders
Tobramycin
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 16, 2014