Safety Study of the Potential Inhibitory Effects of Ciclesonide Nasal Aerosol on the Hypothalamic-Pituitary-Adrenal Axis in Subjects 6-11 Years With Perennial Allergic Rhinitis

Study Overview
=================
Brief Summary
-----------------
This is a multicenter, randomized, double-blind, placebo-controlled, parallel group, safety study of the effects of ciclesonide nasal aerosol (74 mcg) on the HPA axis when administered once daily to male and premenarchal female subjects 6 to 11 years of age with a diagnosis of PAR.

Detailed Description
-----------------
This is a multicenter, randomized, double-blind, placebo-controlled, parallel group, safety study of the effects of ciclesonide nasal aerosol (74 mcg) on the HPA axis when administered once daily to male and premenarchal female subjects 6 to 11 years of age with a diagnosis of PAR. The study requires that subjects be domiciled during two 24- to 36-hour time periods for sample collection for serum and urinary free cortisol measurements, as well as PK evaluations (single [predose] time point during the first domiciled period, and 24-hour sampling during the second domiciled period).

Official Title
-----------------
A 6-Week Randomized, Double-blind, Placebo-controlled, Parallel Group, Safety Study of the Potential Inhibitory Effects of Ciclesonide Nasal Aerosol on the Hypothalamic-Pituitary-Adrenal (HPA) Axis in Subjects 6-11 Years With Perennial Allergic Rhinitis (PAR)

Conditions
-----------------
Perennial Allergic Rhinitis, PAR

Intervention / Treatment
-----------------
* Drug: ciclesonide nasal aerosol
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Gives written informed consent (parent/legal guardian) and assent (when appropriate, from the child), including privacy authorization as well as adherence to concomitant medication withholding periods, prior to participation. Is a male or premenarchal female 6 to 11 years old and ≥ 20 kg at the screening visit. Is in general good health (defined as the absence of any clinically relevant abnormalities as determined by the investigator) based on screening physical examination and medical history. Has a history of PAR to a relevant perennial allergen (house dust mites, cockroaches, molds, animal dander) for a minimum of one year 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. Has a demonstrated sensitivity to at least one allergen known to induce PAR (house dust mites, cockroaches, molds, and animal dander) based on a documented result with a standard skin-prick test either within one year prior to the screening visit 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 of PAR, and the allergen must be present in the subject's environment throughout the study. Exclusion Criteria: Has a 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 120 days prior to the screening visit. Has evidence of infection, significant anatomic abnormality, ulceration of the mucosa, blood in the nose, or any other clinically relevant finding on nasal examination at the screening visit. Has nasal jewelry. Has participated in any investigational drug trial within the 30 days preceding the screening visit or is planning participation in another investigational drug trial at any time during this trial. Has a known hypersensitivity to any corticosteroid or any of the excipients in the formulation of ciclesonide. Has a history of a respiratory infection or disorder, including but not limited to bronchitis, pneumonia, influenza, and severe acute respiratory syndrome (SARS), within the 14 days preceding the screening visit. Has a history of adrenal insufficiency. Has active asthma requiring treatment with inhaled or systemic corticosteroids and/or routine use of beta-agonists and any controller drugs (eg, theophylline, leukotriene antagonists); intermittent use (≤ 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. Is expecting to use any disallowed concomitant medications during the treatment period. Is, in the investigator's judgment, having a seasonal exacerbation at the time of the screening visit. Is planning 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. Has nonvaccinated exposure to or active infection with chickenpox or measles within the 21 days preceding the screening visit. Initiates pimecrolimus cream 1% or greater or tacrolimus ointment 0.03% or greater during the study period or plans a 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. Has experienced significant blood loss within 60 days or loss of plasma within 72 hours prior to the screening visit or intends to undergo elective surgery within 30 days following end of study. Is a child or immediate relative of any clinical investigator or site personnel, even those who are not directly involved in this study. Resides in the same household as another subject who is participating in this study at the same time. Has any of the following conditions that are judged by the investigator to be clinically significant and/or to affect the subject's ability to participate in the clinical trial: impaired hepatic function history of ocular disturbances, eg, glaucoma or posterior subcapsular cataracts or herpes simplex any systemic infection hematological (including anemia), hepatic, renal, endocrine disease gastrointestinal disease malignancy (excluding basal cell carcinoma) current neuropsychological condition with or without drug therapy. Any behavioral condition that could affect subject's ability to accurately report symptoms to the caregiver such as developmental delay, attention deficit disorder, and autism. Has any condition that, in the judgment of the investigator, would preclude the subject from completing the protocol with capture of the assessments as written.

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 11 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ciclesonide nasal aerosol<br>ciclesonide nasal aerosol (74 mcg) | Drug: ciclesonide nasal aerosol<br>* ciclesonide nasal aerosol (74 mcg)<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Change in Serum Cortisol Area Under the Curve (AUC) From Time 0 to 24 Hours (0-24), Calculated Using a Trapezoidal Rule, From Baseline to the End of the 6 Week Treatment Period | Area under the concentration-time curve from time 0 to 24 hours [AUC(0-24h)]. Timepoints at which data were collected: 0, 2, 4, 8, 12, 16, and 24 at week 0 and 6. | Week 0 and 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Urinary Free Cortisol-Corrected for Urine Creatinine |  | weeks 0-6 | 
| Change From Baseline in Urinary Free Cortisol-Uncorrected for Urine Creatinine |  | weeks 0-6 | 
| Number of Subjects Experiencing AEs |  | weeks 0-6 | 
| Percentage of Subjects Experiencing AEs |  | weeks 0-6 | 
| Number of Subjects Experiencing Nasal AEs, Including Epistaxis, Nasal Ulceration, and Nasal Perforation. | Local Treatment-Emergent Adverse Events (ITT Population) | weeks 0-6 | 
| Percentage of Subjects Experiencing Nasal AEs, Including Epistaxis, Nasal Ulceration, and Nasal Perforation. | Local Treatment-Emergent Adverse Events (ITT Population) | weeks 0-6 | 
| AUC(0-24h) | Area under the concentration-time curve from time 0 to 24 hours. Collected at 0, 30 min, 60 min, 90 min, 2 hours (h), 4 h, 8 h, 12 h, 16 h, and 24h after dosing. | Week 6 | 
| Maximum Observed Concentration | Cmax (ng/mL) (PK Population) | Week 6 | 
| Time to the Occurrence of Cmax | tmax (hour) (PK Population) | Week 6 | 
| Terminal Half Life (t1/2) | Terminal half-life (t1/2) (hour) | Weeks 6 | 
| Apparent Clearance of the Drug (CL/F) | CL/F liter per hour (L/hour) is the apparent clearance of the drug | Week 6 | 
| Apparent Volume of Distribution (Vz/F) | Vz/F Liters (L) is the apparent volume of distribution | Week 6 | 
| Ratio (Percentage) of the Number of Correct Advances of the Dose Indicator to the Number of Expected Advances Based on Subject Self-report of Study Medication Administration Plus Extra Non-nasal Actuations |  | weeks 0-6 | 
| Number of Devices With Actuation Consistency, Where Actuation Consistency is Defined as a Dose Indicator Count Within ± 20% of the Subject Self-report of Study Medication Administration |  | weeks 0-6 | 
| Percentage of Devices With Actuation Consistency, Where Actuation Consistency is Defined as a Dose Indicator Count Within ± 20% of the Subject Self-report of Study Medication Administration |  | weeks 0-6 | 
| Change From Baseline in Averaged Daily Subject-reported AM and PM Reflective 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 symptoms 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 | weeks 0-6 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Perennial Allergic Rhinitis, PAR