Study of the Effects of Ciclesonide Hydrofluoroalkane (HFA) Nasal Aerosol on Hypothalamic-Pituitary-Adrenal (HPA) Axis

Sumitomo Pharma America, Inc.310 enrolled

Overview

To demonstrate the effects of ciclesonide applied as a nasal aerosol and ciclesonide aqueous (AQ) nasal spray on hypothalamic-pituitary-adrenal axis.

This is a multicenter, randomized, double-blind, placebo-controlled, parallel group, safety and efficacy study of the effects of ciclesonide HFA nasal aerosol and ciclesonide AQ nasal spray on the HPA axis, when administered once daily to male and female subjects 12 years or older diagnosed with Perennial Allergic Rhinitis (PAR). The study consists of a screening period, a single blind run in period, a 6 week double blind treatment period including an active control segment, and a follow up period. Placebo was used as the control during the double-blind treatment period for both delivery methods (HFA nasal aerosol and aqueous nasal spray)and for the study outcome analyses. There was also a positive control administered to a subset of these placebo subjects during the last 4 days of Week 6 (dexamethasone placebo or dexamethasone 6 mg). The active control was utilized to validate the assay sensitivity (ie, distinguish an effective from an ineffective drug) of this study, as dexamethasone is a known HPA axis suppressant, therefore this subset of placebo subjects was not included in the study outcome analyses. This study was previously posted by Sepracor Inc. In October 2009, Sepracor Inc. was acquired by Dainippon Sumitomo Pharma., and in October 2010, Sepracor Inc's name was changed to Sunovion Pharmaceuticals Inc.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

310

Conditions

Perennial Allergic Rhinitis

Interventions

Ciclesonide HFA Nasal Aerosol 320 mcgDRUG

Ciclesonide HFA Nasal Aerosol 320 μg once daily

Ciclesonide HFA Nasal Aerosol 160 mcgDRUG

Ciclesonide HFA Nasal Aerosol 160 μg once daily

HFA Nasal Aerosol placeboDRUG

HFA Nasal Aerosol placebo once daily

Eligibility

Sex: ALLMin age: 12 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Give written informed consent and assent, including privacy authorization as well as adherence to concomitant medication withholding periods, prior to participation. * Subject must be in general good health (defined as the absence of any clinically relevant abnormalities as determined by the Investigator) based on screening physical examination, medical history, and clinical laboratory values (Hematology, Chemistries and Urinalysis). * If any of the screening Hematology, Chemistries, or Urinalysis are not within the clinical laboratory's reference range, then the subject can be included only if the Investigator judges the deviations to be not clinically significant. * A history of PAR to a relevant perennial allergen (house dust mites, cockroach, molds, animal dander) for a minimum of two years immediately preceding the study Screening visit. The PAR must have been of sufficient severity to have required treatment (either continuous or intermittent) in the past and require treatment throughout the entire study period. * A demonstrated sensitivity to at least one allergen known to induce PAR (house dust mite, animal dander, cockroach, and molds) based on a documented result with a standard skin-prick test either within 90 days prior to screening or performed at the Screening visit. A positive test is defined as a wheal diameter at least 3 mm larger than the negative control wheal for the skin prick test. The subject's positive allergen test must be consistent with the medical history of PAR and must be present in the subject's environment throughout the study. * Subject, if female, must have a negative serum pregnancy test at screening. Females of childbearing potential must be instructed to and agree to avoid pregnancy during the study and must use an acceptable method of birth control. 1. An oral contraceptive, an intrauterine device (IUD), implantable contraceptive, transdermal or injectable contraceptive for at least 1 month prior to entering the study with continued use throughout the study and for thirty days following study participation. 2. Barrier method of contraception, eg, condom and/or diaphragm with spermicide while participating in the study. 3. Abstinence. Exclusion Criteria: * Female subject who is pregnant or lactating. * History of physical findings of nasal pathology, including nasal polyps or other clinically significant respiratory tract malformations; recent nasal biopsy; nasal trauma; or nasal ulcers or perforations. Surgery and atrophic rhinitis or rhinitis medicamentosa are not permitted within the last 120 days prior to the Screening visit. * Subject is, in the investigator's judgement, having a seasonal exacerbation at the time of screening. * Participation in any investigational drug trial within the 30 days preceding the Screening visit or planned participation in another investigational drug trial at any time during this trial. * A known hypersensitivity to any corticosteroid or any of the excipients in the formulation of ciclesonide. * History of a respiratory infection or disorder \[including, but not limited to bronchitis, pneumonia, influenza, severe acute respiratory syndrome (SARS)\] within the 14 days preceding the Screening visit. * History of alcohol or drug abuse within 2 years preceding the Screening visit. * History of a positive test for HIV, hepatitis B or hepatitis C. * Active asthma requiring treatment with inhaled or systemic corticosteroids and/or routine use of beta agonists and any controller drugs (eg, theophylline, leukotriene antagonists, etc.); intermittent use (less than or equal to 3 uses per week) of inhaled short acting beta-agonists is acceptable. Use of short acting beta-agonists for exercise-induced bronchospasm will be allowed. * Expected use of any disallowed concomitant medications during the treatment period. * Initiation of immunotherapy during the study period or dose escalation during the study period. However, initiation of immunotherapy 90 days or more prior to the Screening Visit and use of a stable (maintenance) dose (30 days or more) may be considered for inclusion. * Previous randomization in an intranasal ciclesonide HFA nasal aerosol study. * Non-vaccinated exposure to or active infection with, chickenpox or measles within the 21 days preceding the Screening Visit. * Initiation of pimecrolimus cream 1% or greater or tacrolimus ointment 0.03% or greater during the study period or planned dose escalation during the study period. However, initiation of these creams/ointments 30 days or more prior to screening and use of a stable (maintenance) dose during the study period may be considered for inclusion. * Study participation by clinical investigator site employees and/or their immediate relatives who reside in the same household. * Study participation by more than one subject from the same household. * Have any of the following conditions that are judged by the investigator to be clinically significant and/or affect the subject's ability to participate in the clinical trial: impaired hepatic function including alcohol related liver disease or cirrhosis; history of ocular disturbances, eg, glaucoma or posterior subcapsular cataracts; any systemic infection hematological, hepatic, renal, endocrine (except for controlled diabetes mellitus or postmenopausal symptoms or hypothyroidism; gastrointestinal disease; malignancy (excluding basal cell carcinoma); current neuropsychological condition with or without drug therapy * Any condition that, in the judgment of the investigator, would preclude the subject from completing the protocol with capture of the assessments as written.

Locations (6)

Clinical Research Atlanta

Stockbridge, Georgia, United States

Northeast Medical Research Associates

North Dartmouth, Massachusetts, United States

Clinical Research Institute

Minneappolis, Minnesota, United States

Princeton Center for Clinical Research

Skillman, New Jersey, United States

Outcomes

Primary Outcomes

Serum Cortisol Area Under the Concentration-time Curve (AUC)(0-24h) at Baseline

AUC(0-24h) will be computed using the linear trapezoidal rule based on the actual time of serum cortisol drawing. AUC(0-24) is then approximated by the sum of the areas of trapezoids. The trapezoid for each time interval is based on the actual times of non-missing cortisol values, and is defined by the actual time interval as the base, the line connecting the two cortisol values, and the two vertical sides at the two time points. Raw data is presented for baseline values (i.e. mean/SD), while inferential statistics are presented for week 6 values (i.e. LS mean/SE).

Time frame: Baseline

The Change in Serum Cortisol Area Under the Concentration-time Curve (AUC)(0-24h) From Baseline to Week 6 of the Double Blind Treatment Period

Change is calculated as week 6 minus baseline. AUC(0-24h) will be computed using the linear trapezoidal rule based on the actual time of serum cortisol drawing. AUC(0-24) is then approximated by the sum of the areas of trapezoids. The trapezoid for each time interval is based on the actual times of non-missing cortisol values, and is defined by the actual time interval as the base, the line connecting the two cortisol values, and the two vertical sides at the two time points. Raw data is presented for baseline values (i.e. mean/SD), while inferential statistics are presented for week 6 values (i.e. LS mean/SE).

Time frame: week 6

Secondary Outcomes

Number of Subjects Experiencing Adverse Events (AEs)

Time frame: Weeks 0-6

Percentage of Subjects Experiencing Adverse Events (AEs)

Time frame: Weeks 0-6

Number of Subjects Experiencing Serious Adverse Events (SAEs).

Time frame: Weeks 0-6

Percentage of Subjects Experiencing Serious Adverse Events (SAEs).

Data from ClinicalTrials.gov

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Ciclesonide Aqueous Nasal Spray 200 mcg once daily

AQ Nasal Spray PlaceboDRUG

AQ Nasal Spray Placebo once daily

Placebo plus Dexamethasone HFADRUG

Dexamethasone capsules 6 mg once daily

Placebo AQ plus Dexamethasone 6 mgDRUG

Placebo AQ plus Dexamethasone 6 mcg capsules once daily

Central Texas Health Research

New Braunfels, Texas, United States

Sylvana Research

San Antonio, Texas, United States

Time frame: Weeks 0-6

Number of Subjects Who Discontinue Due to AEs

Time frame: Weeks 0-6

Percentage of Subjects Who Discontinue Due to AEs

Time frame: Weeks 0-6

Number of Subjects Experiencing Local Nasal AEs

Local Nasal adverse events are defined as adverse events occurring in the middle ear, nose, throat, and upper respiratory tract down to the larynx, anatomic regions.

Time frame: Weeks 0-6

Percentage of Subjects Experiencing Local Nasal AEs

Local Nasal adverse events are defined as adverse events occurring in the middle ear, nose, throat, and upper respiratory tract down to the larynx, anatomic regions.

Time frame: Weeks 0-6

Serum Cortisol Area Under the Concentration-time Curve (AUC)(0-12h) at Baseline

Time frame: Baseline

Change in Serum Cortisol Area Under the Concentration-time Curve (AUC)(0-12h) From Baseline After 6 Weeks of Treatment

Time frame: Weeks 0-6

Serum Cortisol Area Under the Concentration-time Curve (AUC)(12-24h) at Baseline

Time frame: Baseline

Change in Serum Cortisol Area Under the Concentration-time Curve (AUC)(12-24h) From Baseline After 6 Weeks of Treatment

Time frame: Weeks 0-6

Baseline Daily Subject-reported AM Reflective TNSS

TNSS is the sum of individual symptoms of runny nose, sneezing, itchy nose, and nasal congestions. Subjects assess each individual symptom on a scale of 0-3 where: 0 = absent 1. = mild 2. = moderate 3. = severe Therefore, rTNSS values range from 0-12 (with 0 representing an absence of symptoms and higher scores reflecting more severe symptoms). Reflective TNSS measures these symptoms over the previous 12-hour time interval. Difference was calculated as the six week treatment average - baseline. Greater reductions in the change from baseline score indicate greater improvement.

Time frame: Baseline

Change From Baseline in Daily Subject-reported AM Reflective TNSS Averaged Over the 6 Weeks of Double-blind Treatment

Time frame: Weeks 0-6

Baseline Daily Subject-reported PM Reflective TNSS

Time frame: Baseline

Change From Baseline in Daily Subject-reported PM Reflective TNSS Averaged Over the 6 Weeks of Double-blind Treatment

Time frame: Weeks 0-6

Baseline Daily Subject-reported AM Instantaneous TNSS

TNSS is the sum of individual symptoms of runny nose, sneezing, itchy nose, and nasal congestions. Subjects assess each individual symptom on a scale of 0-3 where: 0 = absent 1. = mild 2. = moderate 3. = severe Therefore, iTNSS values range from 0-12 (with 0 representing an absence of symptoms and higher scores reflecting more severe symptoms). Instantaneous TNSS measures these symptoms over the previous 10 minute time interval. Difference was calculated as the six week treatment average - baseline. Greater reductions in the change from baseline score indicate greater improvement.

Time frame: Baseline

Change From Baseline in Daily Subject-reported AM Instantaneous TNSS Averaged Over the 6 Weeks of Double-blind Treatment

TNSS is the sum of individual symptoms of runny nose, sneezing, itchy nose, and nasal congestions. Subjects assess each individual symptom on a scale of 0-3 where: 0 = absent 1. = mild 2. = moderate 3. = severe Therefore, iTNSS values range from 0-12 (with 0 representing an absence of symptoms and higher scores reflecting more severe symptoms). Instantaneous TNSS measures these symptoms over the previous 10 minute time interval. Difference was calculated as the six week treatment average - baseline. Greater reductions in the change from baseline score indicate greater improvement.

Time frame: Weeks 0-6

Baseline Daily Subject-reported AM and PM Reflective TNSS

Time frame: Baseline

Change From Baseline in Daily Subject-reported AM and PM Reflective TNSS Averaged Over Each Week, and Averaged Over the 6 Weeks of Double-blind Treatment

Time frame: Weeks 0-6

Baseline Daily Subject-reported PM Instantaneous TNSS

TNSS is the sum of individual symptoms of runny nose, sneezing, itchy nose, and nasal congestions. Subjects assess each individual symptom on a scale of 0-3 where: 0 = absent 1. = mild 2. = moderate 3. = severe Therefore, iTNSS values range from 0-12 (with 0 representing an absence of symptoms and higher scores reflecting more severe symptoms). Instantaneous TNSS measures these symptoms over the previous 10 minute time interval. Difference was calculated as the six week treatment average - baseline. Greater reductions in the change from baseline score indicate greater improvement.

Time frame: Baseline

Change From Baseline in Daily Subject-reported PM Instantaneous TNSS Averaged Over the 6 Weeks of Double-blind Treatment

TNSS is the sum of individual symptoms of runny nose, sneezing, itchy nose, and nasal congestions. Subjects assess each individual symptom on a scale of 0-3 where: 0 = absent 1. = mild 2. = moderate 3. = severe Therefore, iTNSS values range from 0-12 (with 0 representing an absence of symptoms and higher scores reflecting more severe symptoms). Instantaneous TNSS measures these symptoms over the previous 10 minute time interval. Difference was calculated as the six week treatment average - baseline. Greater reductions in the change from baseline score indicate greater improvement.

Time frame: Weeks 0-6

Baseline Daily Subject-reported AM and PM Instantaneous TNSS

TNSS is the sum of individual symptoms of runny nose, sneezing, itchy nose, and nasal congestions. Subjects assess each individual symptom on a scale of 0-3 where: 0 = absent 1. = mild 2. = moderate 3. = severe Therefore, iTNSS values range from 0-12 (with 0 representing an absence of symptoms and higher scores reflecting more severe symptoms). Instantaneous TNSS measures these symptoms over the previous 10 minute time interval. Difference was calculated as the six week treatment average - baseline. Greater reductions in the change from baseline score indicate greater improvement.

Time frame: Baseline

Change From Baseline in Daily Subject-reported AM and PM Instantaneous TNSS Averaged Over the 6 Weeks of Double-blind Treatment

TNSS is the sum of individual symptoms of runny nose, sneezing, itchy nose, and nasal congestions. Subjects assess each individual symptom on a scale of 0-3 where: 0 = absent 1. = mild 2. = moderate 3. = severe Therefore, iTNSS values range from 0-12 (with 0 representing an absence of symptoms and higher scores reflecting more severe symptoms). Instantaneous TNSS measures these symptoms over the previous 10 minute time interval. Difference was calculated as the six week treatment average - baseline. Greater reductions in the change from baseline score indicate greater improvement.

Time frame: Weeks 0-6

Baseline Daily Subject-reported Individual AM Reflective NSS

NSS is the assessment of the individual symptoms of runny nose, sneezing, itchy nose, and nasal congestions. Subjects assess each individual symptoms on a scale of 0-3 where: 0 = absent (no sign/symptom evident); 1. = mild 2. = moderate 3. = severe Reflective NSS measures these symptoms over the previous 12-hour time interval. Difference was calculated by subtracting baseline value from the 6-week DB average. Greater reductions in the change from baseline score indicate greater improvement.

Time frame: Baseline

Change From Baseline in Daily Subject-reported Individual AM Reflective NSS Averaged Over the 6 Weeks of Double-blind Treatment Period

Time frame: Weeks 0-6

Baseline Daily Subject-reported Individual PM Reflective NSS

Time frame: Baseline

Change From Baseline in Daily Subject-reported Individual PM Reflective NSS Averaged Over the 6 Weeks of Double-blind Treatment Period

Time frame: Weeks 0-6

Baseline Daily Subject-reported Individual AM and PM Reflective NSS

Time frame: Baseline

Change From Baseline in Daily Subject-reported Individual AM and PM Reflective NSS Averaged Over the 6 Weeks of Double-blind Treatment Period

Time frame: Weeks 0-6

Baseline Daily Subject-reported Individual AM Instantaneous NSS

NSS is the assessment of the individual symptoms of runny nose, sneezing, itchy nose, and nasal congestions. Subjects assess each individual symptoms on a scale of 0-3 where: 0 = absent (no sign/symptom evident); 1. = mild 2. = moderate 3. = severe Instantaneous NSS measures these symptoms over the previous 10 minute time interval. Difference was calculated by subtracting baseline value from the 6-week DB average. Greater reductions in the change from baseline score indicate greater improvement.

Time frame: Baseline

Change From Baseline in Daily Subject-reported Individual AM Instantaneous NSS Averaged Over the 6 Weeks of Double-blind Treatment

NSS is the assessment of the individual symptoms of runny nose, sneezing, itchy nose, and nasal congestions. Subjects assess each individual symptoms on a scale of 0-3 where: 0 = absent (no sign/symptom evident); 1. = mild 2. = moderate 3. = severe Instantaneous NSS measures these symptoms over the previous 10 minute time interval. Difference was calculated by subtracting baseline value from the 6-week DB average. Greater reductions in the change from baseline score indicate greater improvement.

Time frame: Weeks 0-6

Baseline Daily Subject-reported Individual PM Instantaneous NSS

NSS is the assessment of the individual symptoms of runny nose, sneezing, itchy nose, and nasal congestions. Subjects assess each individual symptoms on a scale of 0-3 where: 0 = absent (no sign/symptom evident); 1. = mild 2. = moderate 3. = severe Instantaneous NSS measures these symptoms over the previous 10 minute time interval. Difference was calculated by subtracting baseline value from the 6-week DB average. Greater reductions in the change from baseline score indicate greater improvement.

Time frame: Baseline

Change From Baseline in Daily Subject-reported Individual PM Instantaneous NSS Averaged Over the 6 Weeks of Double-blind Treatment

NSS is the assessment of the individual symptoms of runny nose, sneezing, itchy nose, and nasal congestions. Subjects assess each individual symptoms on a scale of 0-3 where: 0 = absent (no sign/symptom evident); 1. = mild 2. = moderate 3. = severe Instantaneous NSS measures these symptoms over the previous 10 minute time interval. Difference was calculated by subtracting baseline value from the 6-week DB average. Greater reductions in the change from baseline score indicate greater improvement.

Time frame: Weeks 0-6

Baseline Daily Subject-reported Individual AM and PM Instantaneous NSS

NSS is the assessment of the individual symptoms of runny nose, sneezing, itchy nose, and nasal congestions. Subjects assess each individual symptoms on a scale of 0-3 where: 0 = absent (no sign/symptom evident); 1. = mild 2. = moderate 3. = severe Instantaneous NSS measures these symptoms over the previous 10 minute time interval. Difference was calculated by subtracting baseline value from the 6-week DB average. Greater reductions in the change from baseline score indicate greater improvement.

Time frame: Baseline

Change From Baseline in Daily Subject-reported Individual AM and PM Instantaneous NSS Averaged Over the 6 Weeks of Double-blind Treatment

NSS is the assessment of the individual symptoms of runny nose, sneezing, itchy nose, and nasal congestions. Subjects assess each individual symptoms on a scale of 0-3 where: 0 = absent (no sign/symptom evident); 1. = mild 2. = moderate 3. = severe Instantaneous NSS measures these symptoms over the previous 10 minute time interval. Difference was calculated by subtracting baseline value from the 6-week DB average. Greater reductions in the change from baseline score indicate greater improvement.

Time frame: Weeks 0-6

Time to Maximal Effect Over 6 Weeks of Double-blind Treatment.

The time to maximal effect is defined as the number of days until the first treatment day on which the estimated difference between each active treatment group and corresponding placebo is at least 90% of the largest estimated difference. This is based on the analyses of change from baseline in the average of AM and PM reflective TNSS scores for each day. The evaluation is made separately for each dose level of Ciclesonide HFA compared to placebo. Difference is calculated as placebo - ciclesonide. Analysis of HFA data and AQ data were conducted separately.

Time frame: Weeks 0-6

Ratio (Percentage) of Correct Advances of the Dose Indicator Out of Expected Advances.

Ratio of correct advance is defined as the (number of doses actuated/number of dose reported).

Time frame: Weeks 1-2, 2-4

Number of Devices With Actuation Consistency

Actuation consistency is defined as a dose indicator count within ±20% of the subject self report of study medication administration.

Time frame: Weeks 1-4

Percentage of Devices With Actuation Consistency

Actuation consistency is defined as a dose indicator count within ±20% of the subject self report of study medication administration.

Time frame: Weeks 1-4

Number of Devices With Major Discrepancies

A major discrepancy is defined as a discrepancy of \>20 actuations between the dose indicator and subject self report of study medication administration.

Time frame: Week 6

Percentage of Devices With Major Discrepancies

A major discrepancy is defined as a discrepancy of \>20 actuations between the dose indicator and subject self report of study medication administration.

Time frame: Week 6