Phase 4 Fluticasone Furoate Nasal Spray (VERAMYST) Long Term Pediatric Growth Study.

Study Overview
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Brief Summary
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The primary objective of this study is to characterize, as accurately as possible, the estimation of the difference in pre-pubescent growth velocities between subjects treated continuously for one year with FFNS 110mcg QD, the highest dose approved for pediatric use in the US, and placebo nasal spray as determined by stadiometry.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multi-Center Study to Evaluate the Effects of a One-Year Course of Fluticasone Furoate Nasal Spray 110mcg QD on Growth in Pre-Pubescent, Pediatric Subjects With Perennial Allergic Rhinitis

Conditions
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Rhinitis, Allergic, Perennial

Intervention / Treatment
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* Drug: Fluticasone furoate nasal spray
* Drug: Placebo nasal spray


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Signed and dated informed consent obtained from the subject's legal parent/guardian. Adequate provisions for assent of children should be provided in accordance with the IRB and any local governance. Age: 5 to less than 7.5 years for females and 5 to less than 8.5 years for males at Visit 1. Subjects must have a diagnosis and history of perennial allergic rhinitis (PAR) as follows: At least a one year clinical history and treatment of PAR (written or verbal confirmation from the treating physician) and, A documented, positive skin test to an appropriate perennial allergen (animal dander, house dust mites, cockroaches and/or mold) or documented, historical, in vitro test results for a specific IgE (such as RAST, PRIST) within the past 12 months prior to Visit 1 will be allowed. A positive skin test during Visit 1 will also be allowed. A positive skin test is defined as a wheal 3mm larger than the diluent control for prick testing. Note: Subjects who meet the above criteria and who may also have seasonal allergic rhinitis (SAR) and/or non-allergic rhinitis (NAR) are eligible for randomization. At Visit 2, the daily rTNSS on any 4 of the last 7 days prior to Visit 2 must be 5. Subjects should refrain from using rescue medication during the 7 days prior to Visit 2. Pre-pubescence: Tanner Staging equal to 1 for all classifications as assessed by the investigator during each of the five baseline study visits (Visit 1 through Visit 5). The same investigator should perform this assessment throughout the study for a respective subject, if possible, for consistency of assessment. Details are provided in the SPM. Current height measurement via standardized stadiometer is within the 3rd and 97th percentile according to the CDC and any local longitudinal standard height charts for age and gender as provided in the SPM (Visit 1 through Visit 5). Body weight and body mass index between the 3rd and 97th percentile according to the US CDC standards and any local standards as assessed during each of the five baseline study visits (Visit 1 through Visit 5). The US CDC standards are provided in the SPM. Compliance: Subject's parent/guardian is literate and both subject and parent/guardian are deemed capable of complying with all study procedures to include proper study drug administration, daily e-diary completion, in-clinic laboratory assessments, and in-home 24 hour urine collection during the 76 weeks of study participation (Visit 1 through Visit 5). Exclusion criteria: A history or evidence of abnormal growth. Any previous or current condition that affects growth, including sleep disorders. Asthma, with the exception of mild intermittent asthma [National Asthma Education and Prevention Program, 2007] (Note: Subjects will be allowed to use short-acting inhaled beta2 agonists only on an as needed basis.) A history of nasal or sinus surgery, septal perforation, or severe obstruction in the nose (e.g. nasal polyps). Any other significant concomitant medical condition. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or which would confound the interpretation of the study results if the disease/condition exacerbated during the study. (Visit 1 through Visit 5) Any prior or current use of any medication/treatment that might affect growth including, but not limited to, methylphenidate hydrochloride, thyroid hormone, growth hormone, anabolic steroids, calcitonin, estrogens, progestins, biphosphonates, anticonvulsants or phosphate binding antacids. (Visit 1 through Visit 5). Use of corticosteroids, defined as: Inhaled, intranasal, or high potency topical (to include dermatological, optic and otic) corticosteroids within 6 weeks prior to Visit 1 or during the baseline period (Visit 1 through Visit 5). Systemic corticosteroids (to include oral and injectable) within 12 weeks prior to Visit 1 or during the baseline period (Visit 1 through Visit 5). Use of other allergy medications within an appropriate timeframe relative to Visit 1 to allow the medication to be eliminated or no longer producing an effect as well as during the baseline period (Visit 1 through Visit 5) including, but not limited to: Intranasal cromolyn - 14 days Short-acting prescription and OTC antihistamines - 3 days Long acting (second-generation) antihistamines (other than the loratadine syrup supplied by GSK to treat uncontrolled symptoms of PAR) including fexofenadine, cetirizine, desloratadine, and astemizole - 10 days Long-acting antihistamine: astemizole - 12 weeks Intranasal antihistamines (e.g. azelastine) -2 weeks Oral or intranasal decongestants - 3 days Intranasal, oral or inhaled anticholinergics - 3 days Oral antileukotrienes - 3 days Subcutaneous omalizumab - 5 months Immunotherapy initiated or adjusted within 30 days prior to Visit 1 or during the baseline period (Visit 1 through Visit 5) noting that no significant changes in the dose, concentration or dilution will be allowed during the study. Use of immunosuppressive medications 8 weeks prior to screening or during the baseline period (Visit 1 through Visit 5) of the study. Use of any medications that significantly inhibit the cytochrome P450 subfamily enzyme CYP3A4, including ritonavir and ketoconazole. (Visit 1 through Visit 5) Allergy/Intolerance Known hypersensitivity to corticosteroids or any excipients in the nasal spray Known hypersensitivity to the antihistamine or decongestant being provided for worsening symptoms of rhinitis during the conduct of the study. Exposure to varicella (Chickenpox) or measles during the 3 weeks prior to screening or during the baseline period (Visit 1 through Visit 5), if non-immune. A diagnosis of varicella or measles during the baseline period is exclusionary as well. Recent exposure to an investigational study drug within 30 days prior toVisit 1. Affiliation with investigational site. Findings of a clinically significant, abnormal screening (Visit 1) clinical laboratory test.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 8 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo nasal spray<br> | Drug: Placebo nasal spray<br>* Placebo nasal spray<br>|
| Experimental: Fluticasone furoate nasal spray<br> | Drug: Fluticasone furoate nasal spray<br>* Fluticasone furoate nasal spray 110mg QD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Growth Velocity of Pre-pubescent Pediatric Participants to the End of the 52-week Double-blind (DB) Treatment Period | Height was measured (triplicate measurements) in pre-pubescent pediatric participants via stadiometry at each clinic visit during the entire 76-week study period (16-week Baseline Period, 52-week DB Treatment Period and 8-week Follow-up Period). Growth velocity was calculated by fitting a regression line to all height measurements recorded for the participant during the period and was determined by the slope of the fitted regression line. Change from Baseline was calculated as the value over the 52-week Treatment Period minus the value over the 16-week Baseline Period. | Baseline Period (Weeks -16 to 0) and DB Treatment Period (Weeks 1 to 52) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean 24-hour Urinary Free Cortisol Excretion | Hypothalamic-pitiutary-adrenal (HPA) axis function was assessed by the measurement of urinary free cortisol, using urine samples collected over the course of 24 hours by the parent/guardian in the participants' home on an out-patient basis within 7 days prior to the indicated time points. Detailed verbal instructions and a take-home instruction card on how to conduct the 24-hour urine collection were provided to the parent/guardian before each collection interval. | Randomization/end of 16-week Baseline Period (Week 0), End of 52-week DB Treatment Period (Week 52), and end of 8-week Follow-up Period (Week 60) | 
| Number of Participants With the Indicated Shifts From Baseline in Nasal Examination (NE) Results | NE included the evaluation of the size of ulcers/polyps (of nasal turbinates/septa) and assessment for mucosal bleeding (MB) at all study visits. Polyps are non-cancerous growths; ulcers are breaks in the skin/mucous membrane with loss of surface tissue, disintegration, and necrosis of epithelial tissue. For MB, Improved=shift from present (>=1 nostril) to absent (both nostrils); Worsened=shift from absent (both nostrils) to present (>=1 nostril). For polyps/ulcers, Improved=shift from large to small or from small to none; Worsened=shift from none to small or from small to none (>=1 nostril). | Baseline Period (Weeks -16 to 0) and DB Treatment Period (Weeks 1 to 52) | 
| Mean Values for the Laboratory Parameters of Alkaline (Alk) Phosphatase (P), Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST) | Participants in the study were evaluated for the following clinical laboratory parameters at the indicated time points: Alk P, ALT, and AST. | Baseline Period (Weeks -16 to 0), DB Treatment Period (Weeks 1 to 52), and Follow-up Period (Weeks 53 to 60) | 
| Mean Values for the Laboratory Parameters if Albumin and Total Protein | Participants in the study were evaluated for the following clinical laboratory parameters at the indicated time points: Albumin and Total Protein. | Baseline Period (Weeks -16 to 0), DB Treatment Period (Weeks 1 to 52), and Follow-up Period (Weeks 53 to 60) | 
| Mean Values for the Laboratory Parameters of Total Bilirubin and Creatinine | Participants in the study were evaluated for the following clinical laboratory parameters at the indicated time points: Total Bilirubin and Creatinine. | Baseline Period (Weeks -16 to 0), DB Treatment Period (Weeks 1 to 52), and Follow-up Period (Weeks 53 to 60) | 
| Mean Values for the Laboratory Parameters of Glucose, Calcium, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) | Participants in the study were evaluated for the following clinical laboratory parameters at the indicated time points: Glucose, Calcium, Potassium, Sodium, and Urea/BUN. | Baseline Period (Weeks -16 to 0), DB Treatment Period (Weeks 1 to 52), and Follow-up Period (Weeks 53 to 60) | 
| Mean Hematology Values for Basophil, Eosinophil, Lymphocyte, White Blood Cell (WBC), Monocyte, Segmented Neutrophil (Neu), and Platelet Counts | Participants in the study were evaluated for the following hematology laboratory parameters at the indicated time points: Basophil, Eosinophil, Lymphocyte, White Blood Cell (WBC), Monocyte, Segmented Neutrophil (Neu), and Platelet counts. | Baseline Period (Weeks -16 to 0), DB Treatment Period (Weeks 1 to 52), and Follow-up Period (Weeks 53 to 60) | 
| Mean Values for Hemoglobin | Hemoglobin was assessed in participants at the indicated time points. | Baseline Period (Weeks -16 to 0), DB Treatment Period (Weeks 1 to 52), and Follow-up Period (Weeks 53 to 60) | 
| Mean Values for Hematocrit | Hematocrit was assessed in participants at indicated the time points. Hematocrit is the percentage of blood volume (BV) that is occupied by red blood cells (RBCs). | Baseline Period (Weeks -16 to 0), DB Treatment Period (Weeks 1 to 52), and Follow-up Period (Weeks 53 to 60) | 
| Mean Hematology Values for Red Blood Cells (RBCs) | RBCs was assessed in participants at the indicated time points. | Baseline Period (Weeks -16 to 0), DB Treatment Period (Weeks 1 to 52), and Follow-up Period (Weeks 53 to 60) | 
| Mean Values for Urine pH | Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). | Baseline Period (Weeks -16 to 0), DB Treatment Period (Weeks 1 to 52), and Follow-up Period (Weeks 53 to 60) | 
| Mean Values for Urine Specific Gravity | Specific gravity is a measure of the amount of material dissolved in the urine. Specific gravity is the ratio of the density (mass of a unit volume) of a substance to the density (mass of the same unit volume) of a reference substance. Normal urine has a specific gravity between 1.010 and 1.020. | Baseline Period (Weeks -16 to 0), DB Treatment Period (Weeks 1 to 52), and Follow-up Period (Weeks 53 to 60) | 
| Number of Participants With the Indicated Urinalysis Results for Urine Bilirubin and Urine Nitrite | Bilirubin is a normal body by-product (bile), and nitrite is a by-product of bacterial growth. Participants were categorized as Negative (Neg.) or Positive (Pos.) based on the absence or presence, respectively, of urine bilirubin (UB) and urine nitrate. | Baseline Period (Weeks -16 to 0), DB Treatment Period (Weeks 1 to 52), and Follow-up Period (Weeks 53 to 60) | 
| Number of Participants With the Indicated Urinalysis Results for Urine Glucose, Urine Ketones, and Urine Proteins | Urine glucose, urine ketones, and urine proteins were measured in participants using a dipstick (qualitative) test at the indicated time points. In this dipstick test, the level of glucose, ketones, and protein in urine samples was recorded as negative (Neg), trace (tr), 1+, 2+, and 3+ (the plus sign increases with a higher level of glucose, ketones, or proteins in the urine: 1+=slightly positive, 2+=positive, 3+=high positive). Participants were categorized as negative or positive based on the absence or presence, respectively, of glucose, ketones, and proteins in the urine. | Baseline Period (Weeks -16 to 0), DB Treatment Period (Weeks 1 to 52), and Follow-up Period (Weeks 53 to 60) | 
| Number of Participants With the Indicated Urinalysis Results for Urine Occult Blood (OB) and the Urine Leukocyte Esterase Test (LET) | Occult blood (OB) is blood that cannot be seen without a microscope. Normal urine does not contain any red blood cells. Leukocyte esterase is an enzyme and is not found in normal urine. In the dipstick (qualitative) test, the level of OB and leukocyte esterase in urine samples was recorded as negative (Neg), small, moderate, large, trace, 1+ (slightly positive), 2+ (positive), and 3+ (high positive). Participants were categorized as negative or positive based on the absence or presence, respectively, of OB and urine leukocyte esterase. | Baseline Period (Weeks -16 to 0), DB Treatment Period (Weeks 1 to 52), and Follow-up Period (Weeks 53 to 60) | 
| Number of Participants With the Indicated Urinalysis Results for Urine Appearance (App.)/Clarity and Color | Participants were assessed for their urine appearance, which was categorized as clear (normal), cloudy (presence of crystals, blood cells, or bacteria), of turbid. Also, participants were categorized by the color of urine: straw, yellow (normal urine), and dark yellow (DY) (which may be the result of bile in the urine). | Baseline Period (Weeks -16 to 0), DB Treatment Period (Weeks 1 to 52), and Follow-up Period (Weeks 53 to 60) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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allergic rhinitis, fluticasone furoate nasal spray, growth