Rhinitis, Allergic, Perennial and/or Seasonal
Conditions
Brief summary
The primary objective was to evaluate the effect of a 6-week treatment with TAA-AQ (110 μg) and TAA-AQ (220 μg) once daily (QD) versus placebo on hypothalamic-pituitary-adrenal (HPA) axis function as measured by serum cortisol AUC(0-24 hr) in children (\>=2 to \<12 years old) with allergic rhinitis (AR).
Detailed description
The study consisted of a run-in single-blind screening phase (prerandomization) followed by an approximately 6-week double-blind treatment phase (postrandomization). Total study duration per participant lasted from 7.5 to 13 weeks and consisted of: * Screening and single-blind phases (these 2 phases ran concurrently, prerandomization) for 8 to 24 days. During the screening phase participants were given a single-blind placebo nasal spray to enable them to practice their intranasal application technique once daily in the morning (1 actuation/nostril). * Randomization to the double-blind treatment phase. Treatment assignment was randomized with stratification by sex and age group (\>=2 to \<6, \>=6 to \<12 years old). * Double-blind treatment phase which lasted at least 42 days and ran up to 47 days. Participants were administered either TAA-AQ nasal spray or placebo nasal spray. * An evaluation at the end of treatment 1-3 days after completion of the double-blind phase.
Interventions
DRUGPlacebo nasal spray
1 spray/nostril, once daily in the morning, for 8 to 24 days during the screening phase.
DRUGTriamcinolone acetonide aqueous (TAA-AQ) nasal spray (NASACORT AQ)
Treatment assignment was randomized with stratification by sex and age group (\>=2 to \<6, \>=6 to \<12 years old). * For children who were \>=2 to \<6 years old, 1 spray/nostril (110 µg TAA-AQ), once daily in the morning, for 6 weeks, during the double-blind treatment phase. * For children who were \>=6 yrs to \<12 years old, either 1 spray/nostril (110 µg TAA-AQ) or 2 sprays/nostril (220 µg TAA-AQ), once daily in the morning, for 6 weeks, during the double-blind treatment phase.
DRUGClaritin® Syrup
Children's Claritin® Syrup \[5 mg of loratadine per 5 mL\] could be taken orally for the relief of AR symptoms throughout the study on an as needed basis, according to the Food and Drug Administration-approved manufacturer's label.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
2 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
Participants who met the following criteria were eligible for this study: Inclusion Criteria: * History of AR documented by the investigator, as follows: * At least a 1-year clinical history (6-month history if the participant was \>= 2 to \< 4 years of age) of perennial allergic rhinitis (PAR); or a clinical history of seasonal allergic rhinitis (SAR) over 2 seasons and * positive skin test (prick or intradermal) to a seasonal or perennial allergen that was present in the participant's environment at time of screening. * Written informed consent and ability of parent/legal guardian of the participant to give a written informed consent before any study related procedures. Participants \>=7 years of age (or younger according to the governing institutional review board \[IRB\]) had to provide a signed assent form
Exclusion criteria
* Concomitant medical condition that might have interfered with the administration of a nasal spray, including anatomical abnormalities of the nose, face (eg, polyposis, markedly deviated septum) * Presence of any active, untreated, or clinically significant musculoskeletal, endocrinologic, gastrointestinal, hepatic, respiratory, cardiovascular, or neurological condition that might have interfered with the study * Any conditions or treatment that might have affected the HPA axis or the plasma cortisol assay, including but not limited to: * Documented disorder involving the hypothalamus, pituitary, or adrenal gland * Current use of serotonergic, dopaminergic, adrenergic, cholinergic agonists and antagonists, opiates, immunomodulatory, hormonal drugs, and lipid-lowering agents * Treatment with systemic corticosteroids (oral, intravenous, intramuscular, or intra-articular) within 3 months prior to Visit 1 * Treatment with systemic corticosteroids for \> 2 courses received up to 1 year before Visit 1 was exclusionary. Up to 2 courses of systemic corticosteroids, each course not exceeding 14 days, up to 1 year before Visit 1 was allowed * Treatment with inhaled, intranasal, or high-potency topical corticosteroids within 6 weeks of Visit 1 * History of hospitalization due to asthma within 1 year before screening. Participants with mild asthma that was well-controlled without the use of inhaled corticosteroids within 6 weeks prior to Visit 1 were eligible for the study * Any clinically significant (as determined by the investigator) abnormal laboratory test at Visit 1 * Morning serum cortisol outside the reference range at Visit 1 * Any of the following missing serum cortisol samples from the Visit-2 collection: first sample (before administration of investigational product), 20-hour sample, 24-hour sample, or any 2 consecutive samples * Any medical condition where use of corticosteroids might have been contraindicated or could have led to disease exacerbation (eg, glaucoma, cataract, ocular herpes simplex, tuberculosis, growth retardation) * History of hypersensitivity to corticosteroids or to the rescue medication, investigational product, or to any of their excipients * Unresolved upper respiratory tract infection, sinus infection, or nasal candidiasis (ie, symptomatic or under treatment) within the last 2 weeks prior to Visit 1 and Visit 3 * Females of childbearing potential not protected by effective contraceptive method of birth control or were unwilling to abstain from sexual activity and/or, were unwilling or unable to test for pregnancy. Only female adolescent with onset of menses were to be checked by serum pregnancy test at Visit 1 * Pregnant female adolescent (who tested positive for pregnancy at Visit 1) The above information was not intended to contain all considerations relevant to potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ratio of Serum Cortisol Area Under Curve [AUC(0-24 hr)] at the End of Treatment to Baseline | 1-3 days prerandomization and 6 weeks postrandomization | Blood samples were collected over a 24-hour period (at 0, 2, 4, 8, 12, 20, and 24 hours), with 0 hour being between 8:00AM to 9:00AM, immediately prior to investigational product (IP) administration. AUC (0-24hr) was calculated using the trapezoid rule, and was normalized by dividing the AUC(0-24 hr) by the actual sample collection interval between 0-hour and 24-hour blood draw times. Ratio in Serum Cortisol AUC(0-24 hr) = (Serum Cortisol AUC\[0-24 hr\] at 6 weeks postrandomization)/(Serum Cortisol AUC\[0-24 hr\] at 1-3 days prerandomization). Log transformation was used for the analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Reflective Total Nasal Symptom Score (rTNSS) | From 8-24 days prerandomization up to 6 weeks postrandomization | Every morning, participants rated the severity of symptoms experienced over the previous 24 hours using scale from 0-3, where 0=symptoms absent, 1=mild, 2=moderate, and 3=severe symptoms (interfere with daily living or sleep) for each symptom (nasal congestion, nasal itching, sneezing, and runny nose). The rTNSS was the sum of the individual symptom scores, ranged from 0-12 (where 12 reflected the worst symptoms). Change from baseline in the rTNSS = mean rTNSS (double-blind treatment phase) - mean rTNSS (screening phase). |
| Number of Participants by Relief Level as Evaluated by the Physician | At end of study (43-50 days after randomization) | Efficacy of treatment was assessed by the physician using a scale from 0-4 for relief levels, where 0 = no relief (symptoms unchanged or worsened than before), 1 = slight relief (symptoms present and only minimally improved), 2 = moderate relief (symptoms are present and may be troublesome, but are noticeably improved), 3 = marked relief (symptoms are greatly improved and although present are scarcely troublesome) and 4 = complete relief (virtually no symptom present). |
| Number of Participants by Relief Level as Evaluated by the Participant | At end of study (43-50 days after randomization) | Efficacy of treatment was assessed by the participant using a scale from 0-4 for relief levels, where 0 = no relief (symptoms unchanged or worsened than before), 1 = slight relief (symptoms present and only minimally improved), 2 = moderate relief (symptoms are present and may be troublesome, but are noticeably improved), 3 = marked relief (symptoms are greatly improved and although present are scarcely troublesome) and 4 = complete relief (virtually no symptom present). |
| Number of Participants Using Rescue Medication | From 8 to 24 days prerandomization and randomization to end of study (43-50 days postrandomization) | The number of participants using the rescue medication (Claritin®) during the single-blind screening phase (the time from 8-24 days before randomization up to the day before randomization) and during the double-blind treatment phase (the time from randomization to end of study). |
| The Percent of Days of Rescue Medication Use During the Double-blind Treatment Phase | From randomization to 43-50 days postrandomization | The percent of days of rescue medication used during the double-blind treatment phase was calculated. For participants who did not use any rescue medication, the percentage of days using rescue medication was set to be 0. |
Countries
United States
Participant flow
Recruitment details
The study was performed in 8 study centers in the United States.
Pre-assignment details
179 participants were screened in this study. 31 participants were screen failures and 8 participants did not continue to as the limit on the number of participants to be randomized had been reached. 140 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Children \>=2 to \<12 years old with AR symptoms who received placebo during the screening phase and placebo during the treatment phase. All children had the option to take rescue medication, (Claritin®) as needed to relieve symptoms of AR. | 71 |
| TAA-AQ Children \>=2 to \<12 years old with AR symptoms who received placebo during the screening phase and TAA-AQ (Nasacort AQ) during the treatment phase. All children had the option to take rescue medication, (Claritin®) as needed to relieve symptoms of AR. | 69 |
| Total | 140 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Poor compliance to protocol | 2 | 0 |
| Overall Study | Unable to use labs | 2 | 3 |
| Overall Study | Withdrew consent | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | TAA-AQ | Total |
|---|---|---|---|
| Age Continuous | 7.3 years STANDARD_DEVIATION 2.7 | 7.1 years STANDARD_DEVIATION 2.5 | 7.2 years STANDARD_DEVIATION 2.6 |
| Age, Customized >=2 to < 4 years | 6 participants | 5 participants | 11 participants |
| Age, Customized >=4 to < 6 years | 15 participants | 16 participants | 31 participants |
| Age, Customized >=6 to < 12 years | 50 participants | 48 participants | 98 participants |
| Primary Allergic Rhinitis (AR) diagnosis Both PAR and SAR | 55 Participants | 54 Participants | 109 Participants |
| Primary Allergic Rhinitis (AR) diagnosis PAR only | 11 Participants | 12 Participants | 23 Participants |
| Primary Allergic Rhinitis (AR) diagnosis SAR only | 5 Participants | 3 Participants | 8 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 22 participants | 22 participants | 44 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Others | 4 participants | 5 participants | 9 participants |
| Race/Ethnicity, Customized White | 43 participants | 42 participants | 85 participants |
| Region of Enrollment United States | 71 participants | 69 participants | 140 participants |
| Sex: Female, Male Female | 29 Participants | 28 Participants | 57 Participants |
| Sex: Female, Male Male | 42 Participants | 41 Participants | 83 Participants |
| Tanner Classification Stage 1 | 55 Participants | 60 Participants | 115 Participants |
| Tanner Classification Stage 2 | 12 Participants | 9 Participants | 21 Participants |
| Tanner Classification Stage 3 | 4 Participants | 0 Participants | 4 Participants |
| Tanner Classification Stage 4 | 0 Participants | 0 Participants | 0 Participants |
| Tanner Classification Stage 5 | 0 Participants | 0 Participants | 0 Participants |
| Time from the first Allergic Rhinitis symptom to Visit 1 | 4.82 Years STANDARD_DEVIATION 2.7 | 4.79 Years STANDARD_DEVIATION 2.48 | 4.80 Years STANDARD_DEVIATION 2.59 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 71 | 7 / 69 |
| serious Total, serious adverse events | 1 / 71 | 0 / 69 |
Outcome results
Primary
Ratio of Serum Cortisol Area Under Curve [AUC(0-24 hr)] at the End of Treatment to Baseline
Blood samples were collected over a 24-hour period (at 0, 2, 4, 8, 12, 20, and 24 hours), with 0 hour being between 8:00AM to 9:00AM, immediately prior to investigational product (IP) administration. AUC (0-24hr) was calculated using the trapezoid rule, and was normalized by dividing the AUC(0-24 hr) by the actual sample collection interval between 0-hour and 24-hour blood draw times. Ratio in Serum Cortisol AUC(0-24 hr) = (Serum Cortisol AUC\[0-24 hr\] at 6 weeks postrandomization)/(Serum Cortisol AUC\[0-24 hr\] at 1-3 days prerandomization). Log transformation was used for the analysis.
Time frame: 1-3 days prerandomization and 6 weeks postrandomization
Population: The per protocol (PP) population included all randomized participants who took at least one dose of study medication and had no major protocol violations. Major protocol violations were those deemed most likely to affect the interpretation of the results and included poor compliance, use of prohibited medication, missing blood samples.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Placebo | Ratio of Serum Cortisol Area Under Curve [AUC(0-24 hr)] at the End of Treatment to Baseline | 0.938 Ratio |
| TAA-AQ | Ratio of Serum Cortisol Area Under Curve [AUC(0-24 hr)] at the End of Treatment to Baseline | 0.898 Ratio |
Comparison: Missing cortisol values were imputed with multiple imputation. AUC(0-24 hr) was calculated for each imputation and analyzed with log-transformation using an ANCOVA model and analyzed with treatment, sex, and age group as fixed effects, and log-transformed baseline value as a covariate. The mean difference in log scale between treatments and its standard error were calculated by Least Squares mean. Results from multiply imputed data were combined using SAS procedure MIANALYZE.95% CI: [0.892, 1.045]ANCOVA
Secondary
Change From Baseline in the Reflective Total Nasal Symptom Score (rTNSS)
Every morning, participants rated the severity of symptoms experienced over the previous 24 hours using scale from 0-3, where 0=symptoms absent, 1=mild, 2=moderate, and 3=severe symptoms (interfere with daily living or sleep) for each symptom (nasal congestion, nasal itching, sneezing, and runny nose). The rTNSS was the sum of the individual symptom scores, ranged from 0-12 (where 12 reflected the worst symptoms). Change from baseline in the rTNSS = mean rTNSS (double-blind treatment phase) - mean rTNSS (screening phase).
Time frame: From 8-24 days prerandomization up to 6 weeks postrandomization
Population: The per protocol (PP) population included all randomized participants who took at least one dose of study medication and had no major protocol violations. Major protocol violations were those deemed most likely to affect the interpretation of the results and included poor compliance, use of prohibited medication, missing blood samples.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Reflective Total Nasal Symptom Score (rTNSS) | -0.22 Score on a scale | Standard Deviation 1.12 |
| TAA-AQ | Change From Baseline in the Reflective Total Nasal Symptom Score (rTNSS) | -1.07 Score on a scale | Standard Deviation 1.66 |
p-value: 0.000795% CI: [-1.34, -0.37]ANCOVA
Secondary
Number of Participants by Relief Level as Evaluated by the Participant
Efficacy of treatment was assessed by the participant using a scale from 0-4 for relief levels, where 0 = no relief (symptoms unchanged or worsened than before), 1 = slight relief (symptoms present and only minimally improved), 2 = moderate relief (symptoms are present and may be troublesome, but are noticeably improved), 3 = marked relief (symptoms are greatly improved and although present are scarcely troublesome) and 4 = complete relief (virtually no symptom present).
Time frame: At end of study (43-50 days after randomization)
Population: The per protocol (PP) population included all randomized participants who took at least one dose of study medication and had no major protocol violations. Major protocol violations were those deemed most likely to affect the interpretation of the results and included poor compliance, use of prohibited medication, missing blood samples.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants by Relief Level as Evaluated by the Participant | Relief level 1 (Slight relief) | 17 Participants |
| Placebo | Number of Participants by Relief Level as Evaluated by the Participant | Relief level 3 (Marked relief) | 14 Participants |
| Placebo | Number of Participants by Relief Level as Evaluated by the Participant | Relief level 2 (Moderate relief) | 16 Participants |
| Placebo | Number of Participants by Relief Level as Evaluated by the Participant | Relief level 4 (Complete relief) | 5 Participants |
| Placebo | Number of Participants by Relief Level as Evaluated by the Participant | Relief level 0 (No relief) | 9 Participants |
| TAA-AQ | Number of Participants by Relief Level as Evaluated by the Participant | Relief level 4 (Complete relief) | 9 Participants |
| TAA-AQ | Number of Participants by Relief Level as Evaluated by the Participant | Relief level 0 (No relief) | 5 Participants |
| TAA-AQ | Number of Participants by Relief Level as Evaluated by the Participant | Relief level 1 (Slight relief) | 22 Participants |
| TAA-AQ | Number of Participants by Relief Level as Evaluated by the Participant | Relief level 2 (Moderate relief) | 13 Participants |
| TAA-AQ | Number of Participants by Relief Level as Evaluated by the Participant | Relief level 3 (Marked relief) | 16 Participants |
p-value: 0.3314Cochran-Mantel-Haenszel
Secondary
Number of Participants by Relief Level as Evaluated by the Physician
Efficacy of treatment was assessed by the physician using a scale from 0-4 for relief levels, where 0 = no relief (symptoms unchanged or worsened than before), 1 = slight relief (symptoms present and only minimally improved), 2 = moderate relief (symptoms are present and may be troublesome, but are noticeably improved), 3 = marked relief (symptoms are greatly improved and although present are scarcely troublesome) and 4 = complete relief (virtually no symptom present).
Time frame: At end of study (43-50 days after randomization)
Population: The per protocol (PP) population included all randomized participants who took at least one dose of study medication and had no major protocol violations. Major protocol violations were those deemed most likely to affect the interpretation of the results and included poor compliance, use of prohibited medication, missing blood samples.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants by Relief Level as Evaluated by the Physician | Relief Level 1 (Slight relief) | 18 Participants |
| Placebo | Number of Participants by Relief Level as Evaluated by the Physician | Relief Level 3 (Marked relief) | 13 Participants |
| Placebo | Number of Participants by Relief Level as Evaluated by the Physician | Relief Level 2 (Moderate relief) | 16 Participants |
| Placebo | Number of Participants by Relief Level as Evaluated by the Physician | Relief Level 4 (Complete relief) | 3 Participants |
| Placebo | Number of Participants by Relief Level as Evaluated by the Physician | Relief Level 0 (No relief) | 11 Participants |
| TAA-AQ | Number of Participants by Relief Level as Evaluated by the Physician | Relief Level 4 (Complete relief) | 6 Participants |
| TAA-AQ | Number of Participants by Relief Level as Evaluated by the Physician | Relief Level 0 (No relief) | 9 Participants |
| TAA-AQ | Number of Participants by Relief Level as Evaluated by the Physician | Relief Level 1 (Slight relief) | 13 Participants |
| TAA-AQ | Number of Participants by Relief Level as Evaluated by the Physician | Relief Level 2 (Moderate relief) | 20 Participants |
| TAA-AQ | Number of Participants by Relief Level as Evaluated by the Physician | Relief Level 3 (Marked relief) | 17 Participants |
p-value: 0.1332Cochran-Mantel-Haenszel
Secondary
Number of Participants Using Rescue Medication
The number of participants using the rescue medication (Claritin®) during the single-blind screening phase (the time from 8-24 days before randomization up to the day before randomization) and during the double-blind treatment phase (the time from randomization to end of study).
Time frame: From 8 to 24 days prerandomization and randomization to end of study (43-50 days postrandomization)
Population: The per protocol (PP) population included all randomized participants who took at least one dose of study medication and had no major protocol violations. Major protocol violations were those deemed most likely to affect the interpretation of the results and included poor compliance, use of prohibited medication, missing blood samples.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants Using Rescue Medication | Prerandomization period | 8 Participants |
| Placebo | Number of Participants Using Rescue Medication | Postrandomization period | 24 Participants |
| TAA-AQ | Number of Participants Using Rescue Medication | Prerandomization period | 8 Participants |
| TAA-AQ | Number of Participants Using Rescue Medication | Postrandomization period | 19 Participants |
Secondary
The Percent of Days of Rescue Medication Use During the Double-blind Treatment Phase
The percent of days of rescue medication used during the double-blind treatment phase was calculated. For participants who did not use any rescue medication, the percentage of days using rescue medication was set to be 0.
Time frame: From randomization to 43-50 days postrandomization
Population: The per protocol (PP) population included all randomized participants who took at least one dose of study medication and had no major protocol violations. Major protocol violations were those deemed most likely to affect the interpretation of the results and included poor compliance, use of prohibited medication, missing blood samples.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Percent of Days of Rescue Medication Use During the Double-blind Treatment Phase | 4.02 Percentage of days | Standard Deviation 12.77 |
| TAA-AQ | The Percent of Days of Rescue Medication Use During the Double-blind Treatment Phase | 3.07 Percentage of days | Standard Deviation 11.82 |