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

Cystic Fibrosis Clinical Trial

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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).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00918957
• Other study ID #: CTBM100C2303
• Secondary ID: 2008-002318-22
• Status: Completed
• Phase: Phase 3
• First received: June 4, 2009
• Last updated: October 1, 2012
• Start date: June 2009
• Est. completion date: May 2011

Study information

• Verified date: October 2012
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: Bulgaria: Ministry of HealthChile: Instituto de Salud Pública de ChileEgypt: Ministry of Health and PopulationEstonia: The State Agency of MedicineEuropean Union: European Medicines AgencyIreland: Ministry of HealthIndia: Ministry of HealthLatvia: State Agency of MedicinesLithuania: State Medicine Control Agency - Ministry of HealthRomania: Ministry of Public HealthRussia: Ministry of Health of the Russian FederationSouth Africa: Department of HealthUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 62
• Est. completion date: May 2011
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Years to 21 Years

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

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
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.

Locations

Country	Name	City	State
Bulgaria	Novartis Investigative Site	Pleven
Bulgaria	Novartis Investigative Site	Plovdiv
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Varna
Egypt	Novartis Investigative Site	Alexandria
Egypt	Novartis Investigative Site	Giza
Estonia	Novartis Investigative Site	Tallin
Estonia	Novartis Investigative Site	Tartu
India	Novartis Investigative Site	Chandigarh
India	Novartis Investigative Site	Hyderabad
India	Novartis Investigative Site	New Delhi
India	Novartis Investigative Site	Vellore
Latvia	Novartis Investigative Site	Riga
Lithuania	Novartis Investigative Site	Kaunas
Lithuania	Novartis Investigative Site	Vilnius
Romania	Novartis Investigative Site	Bucuresti
Romania	Novartis Investigative Site	Timisoara
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
South Africa	Novartis Investigative Site	Durban

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Bulgaria,  Egypt,  Estonia,  India,  Latvia,  Lithuania,  Romania,  Russian Federation,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29)	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.	Baseline, Day 29	No
Primary	Pre-planned Sensitivity Analysis: Absolute Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent (%) Predicted to End of Dosing (Day 29)	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.	Baseline, Day 29	No
Primary	Post-hoc: Relative Change From Baseline of Forced Expiratory Volume in One Second (FEV1) Percent Predicted to End of Dosing (Day 29) Without Outlier	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.	Baseline, Day 29	No
Secondary	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)	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	Baseline, Day 29, Day 57	No
Secondary	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)	?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.	Baseline, Day 29, Day 57	No
Secondary	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)	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.	Baseline, Day 29, Day 57	No
Secondary	Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) of Pseudomonas Aeruginosa Minimum Inhibitory Concentration (MIC)	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.	Baseline, Day 29, Day 57	No
Secondary	Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal	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.	Baseline, Study completion	No
Secondary	Percentage of Participants With Adverse Events (AEs)	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.	First administration of study drug, study completion	Yes
Secondary	Percentage of Participants With Serious Adverse Events (SAEs)	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.	Time of consent, 4 weeks after study completion	Yes
Secondary	Acute Change in Airways Reactivity (FEV1 Percent Predicted) From Pre-dose to 30 Minutes After Completion of First Dose of Study Drug	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.	Day 1, Day 29	No
Secondary	Tobramycin Serum Concentration	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.	Pre-dose, 0 - 1 hour post-dose, 1 -2 hours post-dose, 2 - 6 hours post-dose	No