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

NCT00918957 | Completed Phase 3 Results

• 2 other identifiers: CTBM100C23032008-002318-22
• Study Type: interventional
• Target: 62
• Locations: 9 countries
• Sites: 24

Brief 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

Conditions

Cystic Fibrosis

Keywords

Tobramycin Inhalation Powder; Cystic fibrosis; Lung diseases; Anti-Bacterial Agents; Treatment of infections with P. aeruginosa in cystic fibrosis subjects

Outcome Measures

Primary Outcomes (3)

• 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

• 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

• 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

Secondary Outcomes (9)

• 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)

  Baseline, Day 29, Day 57

• 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)

  Baseline, Day 29, Day 57

• 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)

  Baseline, Day 29, Day 57

• Change From Baseline to End of Dosing (Day 29) and End of Off-cycle Period (Day 57) of Pseudomonas Aeruginosa Minimum Inhibitory Concentration (MIC)

  Baseline, Day 29, Day 57

• Shift From Baseline in Laboratory Parameters to Above Upper/Lower Limit of Normal

  Baseline, Study completion

Study Arms (2)

TIP (Tobramycin Inhalation Powder)

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Tobramycin Inhalation Powder DRUG

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.

TIP (Tobramycin Inhalation Powder)

Placebo DRUG

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.

Placebo

Eligibility Criteria

• Age: 6 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (24)

Novartis Investigative Site

Pleven, Bulgaria

Location

Novartis Investigative Site

Plovdiv, Bulgaria

Location

Novartis Investigative Site

Sofia, Bulgaria

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Novartis Investigative Site

Varna, Bulgaria

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Novartis Investigative Site

Alexandria, Egypt

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Novartis Investigative Site

Giza, Egypt

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Novartis Investigative Site

Tallinn, Estonia

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Novartis Investigative Site

Tartu, Estonia

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Novartis Investigative Site

Chandigarh, India

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Novartis Investigative Site

Hyderabad, India

Location

Novartis Investigative Site

New Delhi, India

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Novartis Investigative Site

Vellore, India

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Novartis Investigative Site

Riga, Latvia

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Novartis Investigative Site

Kaunas, Lithuania

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Novartis Investigative Site

Vilnius, Lithuania

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Novartis Investigative Site

Bucharest, Romania

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Novartis Investigative Site

Timișoara, Romania

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Novartis Investigative Site

Kazan', Russia

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Novartis Investigative Site

Moscow, Russia

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Novartis Investigative Site

Saint Petersburg, Russia

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Novartis Investigative Site

Samara, Russia

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Novartis Investigative Site

Voronezh, Russia

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Novartis Investigator Site

Yaroslavi, Russia

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Novartis Investigative Site

Durban, South Africa

Location

Related Publications (1)

• Galeva I, Konstan MW, Higgins M, Angyalosi G, Brockhaus F, Piggott S, Thomas K, Chuchalin AG. Tobramycin inhalation powder manufactured by improved process in cystic fibrosis: the randomized EDIT trial. Curr Med Res Opin. 2013 Aug;29(8):947-56. doi: 10.1185/03007995.2013.805122. Epub 2013 Jun 5.

  PMID: 23672633 DERIVED

MeSH Terms

Conditions

Cystic Fibrosis; Lung Diseases

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Results Point of Contact

• Title: Clinical Disclosure Office
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 4, 2009
• First Posted: June 11, 2009
• Study Start: June 1, 2009
• Primary Completion: May 1, 2011
• Study Completion: May 1, 2011
• Last Updated: October 3, 2012
• Results First Posted: October 3, 2012

Record last verified: 2012-10

Locations

RO (2); ES (2); ZA (1); EG (2); IN (4); BU (4); RU (6); LA (1); LI (2)