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Dose Ranging Study of the Salmeterol Component of Fluticasone /Salmeterol Spiromax Compared to Fluticasone Spiromax and Advair Diskus in Asthma Subjects

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products, R&D Inc. )
ClinicalTrials.gov Identifier:
NCT01772368
First received: January 17, 2013
Last updated: May 10, 2017
Last verified: May 2017
  Purpose
The primary objective of this study is to evaluate the dose response, efficacy, and safety of 4 different doses of salmeterol Spiromax (6.25, 12.5, 25, and 50 mcg) each combined with a fixed dose of fluticasone propionate (100 mcg) delivered as Fluticasone/Salmeterol Spiromax® Inhalation Powder (FS Spiromax) when administered as a single dose in subjects 12 years of age and older with persistent asthma.

Condition Intervention Phase
Asthma Drug: Fp MDPI Drug: FS MDPI Drug: Advair Diskus Drug: Albuterol Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Six-Period Crossover, Dose-Ranging Study to Evaluate the Efficacy and Safety of Four Doses of FS Spiromax (Fluticasone Propionate/Salmeterol Xinafoate Inhalation Powder) Administered as Single Doses Compared With Single Doses of Fluticasone Propionate Spiromax and Open Label Advair Diskus in Adult and Adolescent Subjects With Persistent Asthma

Resource links provided by NLM:


Further study details as provided by Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products, R&D Inc. ):

Primary Outcome Measures:
  • Standardized Baseline-Adjusted Area Under the Curve For Forced Expiratory Volume In 1 Second Over 12 Hours Post-dose (FEV1 AUC0-12) [ Time Frame: Pre-dose: 30 minutes prior, within 5 minutes of dose. Post-dose: 0.5, 1, 2, 3, 4, 5, 6, 9, 12 hours ]
    Standardized baseline-adjusted FEV1 AUC0-12 was defined as the area under the curve for baseline-adjusted FEV1 measurements from the predose to 12 hours postdose time points using the trapezoidal rule based on actual (not scheduled) time of measurement and was standardized by dividing the actual time of last non-missing FEV1 measurement. Baseline-adjusted FEV1 was calculated as postdose FEV1 after subtracting period-specific baseline FEV1. The period-specific baseline FEV1 was measured at predose within 5 minutes of AM dose administration at each treatment visit. If that value was missing, then FEV1 measured at 30 minutes predose was used as the period-specific baseline.


Secondary Outcome Measures:
  • Change From Baseline at 12 Hours Post-Dose in Forced Expiratory Volume in One Second (FEV1) By Treatment [ Time Frame: Pre-dose: 30 minutes prior, within 5 minutes of dose. Post-dose: 12 hours ]

    The secondary efficacy variable was the change from period-specific baseline in FEV1 at 12 hours, calculated as FEV1 measured at 12 hours postdose after subtracting period-specific baseline FEV1 at each treatment period.

    The period-specific baseline FEV1 was measured at predose within 5 minutes of AM dose administration at each treatment visit. If that value was missing, then FEV1 measured at 30 minutes predose was used as the period-specific baseline.


  • Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC0-t) of Salmeterol [ Time Frame: Predose (0), and at 5, 10, 15 and 30 minutes, 1, 1.5, 2, 3, 4, 8, and 12 hours postdose ]
    Blood samples for measurement of plasma SAL concentrations were obtained during each treatment visit (subjects 18 years of age and older only) and pharmacokinetic parameters were derived. The primary pharmacokinetic parameters were AUC0-t and Cmax for Salmeterol.

  • Maximum Observed Plasma Concentration (Cmax) of Salmeterol [ Time Frame: Predose (0), and at 5, 10, 15 and 30 minutes, 1, 1.5, 2, 3, 4, 8, and 12 hours postdose ]
    Blood samples for measurement of plasma SAL concentrations were obtained during each treatment visit (subjects 18 years of age and older only) and pharmacokinetic parameters were derived. The primary pharmacokinetic parameters were AUC0-t and Cmax for Salmeterol.

  • Time of Maximum Observed Plasma Concentration (Tmax) of Salmeterol [ Time Frame: Predose (0), and at 5, 10, 15 and 30 minutes, 1, 1.5, 2, 3, 4, 8, and 12 hours postdose ]
    Blood samples for measurement of plasma SAL concentrations were obtained during each treatment visit (subjects 18 years of age and older only) and pharmacokinetic parameters were derived.

  • Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period [ Time Frame: Day 1 up to Day 35 ]

    TEAEs were recorded during each double-blind treatment. In addition, at the end of each treatment, patients continued to use 2 inhalations of Fp MDPI 50 mcg (100 mcg total dose) twice daily, so adverse events during this treatment were assigned to Fp MDPI 50 mcg.

    An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical in



Enrollment: 72
Study Start Date: January 2013
Study Completion Date: June 2013
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: FS MDPI 100/6.25 mcg
Subjects inhaled a single dose of 100 mcg fluticasone propionate and 6.25 mcg salmeterol xinafoate.
Drug: FS MDPI
FS MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate and salmeterol xinafoate dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. The fluticasone propionate component was a fixed dose of 100 mcg. The salmeterol xinofoate dosage varied: 6.25, 12.5, 25 or 50 mcg.
Other Names:
  • fluticasone propionate
  • inhaled corticosteroid
  • Salmeterol xinafoate
  • β2 adrenoceptor agonist
  • FS Spiromax
Drug: Albuterol
Albuterol (Pro-Air) hydrofluoroalkane (HFA) metered dose inhaler (MDI), was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject's current rescue medication).
Other Names:
  • Pro-Air
  • short-acting β2-adrenergic agonists
Experimental: FS MDPI 100/12.5mcg
Subjects inhaled a single dose of 100 mcg fluticasone propionate and 12.5 mcg salmeterol xinafoate.
Drug: FS MDPI
FS MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate and salmeterol xinafoate dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. The fluticasone propionate component was a fixed dose of 100 mcg. The salmeterol xinofoate dosage varied: 6.25, 12.5, 25 or 50 mcg.
Other Names:
  • fluticasone propionate
  • inhaled corticosteroid
  • Salmeterol xinafoate
  • β2 adrenoceptor agonist
  • FS Spiromax
Drug: Albuterol
Albuterol (Pro-Air) hydrofluoroalkane (HFA) metered dose inhaler (MDI), was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject's current rescue medication).
Other Names:
  • Pro-Air
  • short-acting β2-adrenergic agonists
Experimental: FS MDPI 100/25
Subjects inhaled a single dose of 100 mcg fluticasone propionate and 25 mcg salmeterol xinafoate.
Drug: FS MDPI
FS MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate and salmeterol xinafoate dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. The fluticasone propionate component was a fixed dose of 100 mcg. The salmeterol xinofoate dosage varied: 6.25, 12.5, 25 or 50 mcg.
Other Names:
  • fluticasone propionate
  • inhaled corticosteroid
  • Salmeterol xinafoate
  • β2 adrenoceptor agonist
  • FS Spiromax
Drug: Albuterol
Albuterol (Pro-Air) hydrofluoroalkane (HFA) metered dose inhaler (MDI), was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject's current rescue medication).
Other Names:
  • Pro-Air
  • short-acting β2-adrenergic agonists
Experimental: FS MDPI 100/50
Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate.
Drug: FS MDPI
FS MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate and salmeterol xinafoate dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. The fluticasone propionate component was a fixed dose of 100 mcg. The salmeterol xinofoate dosage varied: 6.25, 12.5, 25 or 50 mcg.
Other Names:
  • fluticasone propionate
  • inhaled corticosteroid
  • Salmeterol xinafoate
  • β2 adrenoceptor agonist
  • FS Spiromax
Drug: Albuterol
Albuterol (Pro-Air) hydrofluoroalkane (HFA) metered dose inhaler (MDI), was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject's current rescue medication).
Other Names:
  • Pro-Air
  • short-acting β2-adrenergic agonists
Active Comparator: Fp MDPI 100 mcg
Subjects inhaled a single dose of 100 mcg fluticasone propionate.
Drug: Fp MDPI

Fp MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened.

Fp at 100 mcg was an active comparator (single dose). Further, participants were instructed to administer two inhalations of Fp MDPI 50 mcg twice daily (100 mcg total dose) during the Run-in (to replace the participant's current inhaled corticosteroid) and Washout Periods between treatments.

Other Names:
  • fluticasone propionate
  • inhaled corticosteroid
  • Fp Spiromax
Drug: Albuterol
Albuterol (Pro-Air) hydrofluoroalkane (HFA) metered dose inhaler (MDI), was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject's current rescue medication).
Other Names:
  • Pro-Air
  • short-acting β2-adrenergic agonists
Active Comparator: Advair Diskus 100/50 mcg
Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate. This arm is the only arm which is open-label because the inhaler device was different than the MDPI used in the other treatment arms.
Drug: Advair Diskus
ADVAIR DISKUS (100/50 mcg fluticasone propionate/salmeterol xinafoate) consists of a dry powder formulation of fluticasone propionate and salmeterol xinafoate in a lactose excipient. The dry powder is contained within individual blisters on a double foil strip within the device. Activation of the device opens a single blister of medication which is then dispersed into the air-stream by patient inhalation.
Other Names:
  • fluticasone propionate
  • inhaled corticosteroid
  • salmeterol xinafoate
  • β2 adrenoceptor agonist
Drug: Albuterol
Albuterol (Pro-Air) hydrofluoroalkane (HFA) metered dose inhaler (MDI), was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject's current rescue medication).
Other Names:
  • Pro-Air
  • short-acting β2-adrenergic agonists

Detailed Description:

This was a multicenter, randomized, double-blind and open-label active-controlled, single-dose, 6 period crossover, dose-ranging study conducted in male and female subjects ages 12 years and older with persistent asthma.

Fluticasone propionate multidose dry powder inhaler (Fp MDPI) 50 mcg was provided (to replace the subject's current inhaled corticosteroid (ICS)) throughout the 14 day run-in period and each of the washout periods between treatments. Subjects were instructed to administer 2 inhalations of Fp MDPI 50 mcg (100 mcg total dose) twice daily during the run-in and washout periods. All other medications for the treatment of asthma were discontinued at or prior to the screening visit.

A short-acting β2-adrenergic agonist (SABA), salbuterol HFA, MDI, was provided (to replace the subject's current rescue medication) for symptomatic relief of asthma symptoms in each the run-in, treatment, and washout periods.

Treatment period lasted 5 weeks with a 5 to 7 day washout between each of the six single dose treatments:

  • fluticasone propionate/salmeterol xinafoate multidose dry powder inhaler (FS MDPI) given in doses of 6.25, 12.5, 25, or 50 mcg of salmeterol xinafoate in blinded fashion.
  • fluticasone propionate multidose dry powder inhaler (Fp MDPI) 100 mcg in blinded fashion
  • ADVAIR DISKUS, 100/50 mcg in open-label fashion
  Eligibility

Ages Eligible for Study:   12 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent/assent
  • General good health
  • Diagnosis of asthma as defined by the National Institutes of Health (NIH)
  • A best FEV1 of 40%-85% of the predicted normal value during the screening visit (SV)
  • Subjects need to demonstrate a ≥ 15% reversibility of FEV1 within 30 minutes following 4 inhalations of albuterol inhalation aerosol (if required, spacers are permitted for reversibility testing) at the SV.
  • Other inclusion criteria apply

Exclusion Criteria:

  • History of life-threatening asthma that is defined for this protocol as an asthma episode that required intubation.
  • Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear that is not resolved within 2 weeks prior to the SV.
  • Any asthma exacerbation requiring oral corticosteroids within 3 months of the SV. A subject must not have had any hospitalization for asthma within 6 months prior to the SV.
  • Taking long-acting β-agonists within 2 weeks of the SV
  • Other exclusion criteria 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: NCT01772368

Locations
United States, Colorado
Teva Investigational Site 10453
Denver, Colorado, United States
United States, Massachusetts
Teva Investigational Site 10452
North Dartmouth, Massachusetts, United States
United States, Missouri
Teva Investigational Site 10455
Saint Louis, Missouri, United States
United States, New Jersey
Teva Investigational Site 10454
Skillman, New Jersey, United States
United States, North Carolina
Teva Investigational Site 10448
Raleigh, North Carolina, United States
United States, Oregon
Teva Investigational Site 10451
Medford, Oregon, United States
Teva Investigational Site 10449
Portland, Oregon, United States
United States, Texas
Teva Investigational Site 10457
El Paso, Texas, United States
Teva Investigational Site 10450
New Braunfels, Texas, United States
Teva Investigational Site 10456
San Antonio, Texas, United States
Sponsors and Collaborators
Teva Branded Pharmaceutical Products, R&D Inc.
  More Information

Responsible Party: Teva Branded Pharmaceutical Products, R&D Inc.
ClinicalTrials.gov Identifier: NCT01772368     History of Changes
Other Study ID Numbers: FSS-AS-201
Study First Received: January 17, 2013
Results First Received: February 28, 2017
Last Updated: May 10, 2017

Keywords provided by Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products, R&D Inc. ):
Asthma
dry powder inhaler
long-acting beta2-agonist
bronchodilation
bronchodilator
metered dose inhaler
inhaled corticosteroid

Additional relevant MeSH terms:
Asthma
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Fluticasone
Salmeterol Xinafoate
Albuterol
Fluticasone Propionate, Salmeterol Xinafoate Drug Combination
Adrenergic Agonists
Anti-Inflammatory Agents
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Dermatologic Agents
Anti-Allergic Agents
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Tocolytic Agents
Reproductive Control Agents

ClinicalTrials.gov processed this record on September 21, 2017