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Efficacy of the novel nasal steroid S0597 tested in an environmental exposure unit
Ann Allergy Asthma Immunol 117 (2016) 310e317
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Efficacy of the novel nasal steroid S0597 tested in an environmental exposure unit Anne K. Ellis, MD *, y; Lisa M. Steacy, BSc y; Abhijeet Joshi, BPharm, MBA z; Shravanti Bhowmik, MD z; Atul Raut, MD, PhD z * Division
of Allergy and Immunology, Department of Medicine, Queen’s University, Kingston, Ontario, Canada Allergy Research Unit, Kingston General Hospital, Kingston, Ontario, Canada z Sun Pharma Advanced Research Company Ltd, Mumbai, India y
A R T I C L E
I N F O
Article history: Received for publication April 13, 2016. Received in revised form June 28, 2016. Accepted for publication July 13, 2016.
A B S T R A C T
Background: S0597 is a novel glucocorticosteroid that was formulated as an intranasal spray to treat seasonal allergic rhinitis (SAR). In a previous phase 2 study, doses of 100 to 400 mg twice daily were well tolerated and more effective than placebo for improving nasal symptoms induced by grass pollen. Objective: To assess the clinical efficacy and safety of a once-daily S0597 nasal spray for treatment of SAR induced by ragweed pollen in an environmental exposure unit (EEU). Methods: A single-center, phase 2, randomized, double-blind study in 222 adults with SAR and a positive skin prick test result to short ragweed. Participants underwent ragweed pollen challenge in the EEU at the screening or priming visit and on days 1, 7, and 14 and received 50, 200, or 400 mg of S0597 or placebo in the evening for 13 days. The primary efficacy end point was change in total nasal symptom score (TNSS) from baseline to day 14. Results: Improvement in TNSS from baseline to day 14 was statistically significant in all S0597 groups compared with placebo. Least-squares mean differences in change from baseline between active treatment and placebo were 1.18, 1.84, and 1.17 for the 50-, 200-, and 400-mg/d S0597 groups, respectively (P < .05). The 200-mg group demonstrated statistically significant improvements in all TNSS subscales (rhinorrhea, nasal congestion, sneezing, nasal itching) compared with placebo at days 7 and 14. Conclusion: Treatment with 50 to 400 mg of S0597 once daily was well tolerated and significantly more effective than placebo in relieving nasal symptoms of SAR associated with ragweed pollen. Trial Registration: clinicaltrials.gov Identifier: NCT01940146. Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Allergic rhinitis (AR) is a significant public health concern worldwide, affecting an estimated 500 million people.1e4 Intranasal glucocorticosteroids (INSs) are regarded as the most effective pharmacologic treatment for AR and are recommended by the Allergic Rhinitis and its Impact on Asthma guidelines as a first-line therapy.3,5 INSs have a good safety profile with a low risk of
Reprints: Anne K. Ellis, MD, Allergy Research Unit, Kingston General Hospital, 76 Stuart St, Watkins 1D, Kingston, Ontario, Canada; E-mail: [email protected]. Disclosures: Dr Ellis reported serving on the speaker’s bureau for AstraZeneca, Meda, Merck, Novartis, Pfizer, and Takeda, receiving research grants to the institution from Circassia Ltd, GlaxoSmithKline, Merck, Novartis, Pfizer, and Sun Pharma Advanced Research Company Ltd, and serving as an adviser to ALK Abello, Circassia, Merck, and Novartis. Mr Joshi, Dr Bhowmik, and Dr Raut reported being employees of Sun Pharma Advanced Research Company Ltd. No other disclosures were reported. Funding Sources: This study was funded by Sun Pharma Advanced Research Company Ltd.
systemic adverse effects (AEs) attributable to their low systemic bioavailability.6 This profile is especially true for newer INSs, such as ciclesonide, mometasone furoate, and fluticasone furoate, which all have systemic bioavailability of less than 1%.7 S0597 is a novel glucocorticosteroid that has been formulated as an intranasal spray for the treatment of seasonal allergic rhinitis (SAR). The short form of its International Union of Pure and Applied Chemistry name is SFDAC. Results of a phase 1, multiple ascendingdose study indicated that intranasal S0597 was safe and well tolerated at doses up to 3,200 mg once daily. No clinically significant suppression of the hypothalamic-pituitary-adrenal (HPA) axis was observed, and the plasma concentration of S0597 was below the lower limit of quantification at most time points for all participants.8 In a 15-day, randomized, placebo-controlled, double-blind, parallel-group, single-center phase 2 study, the dose-related efficacy and safety of S0597 nasal spray was assessed in participants with SAR using repeated grass pollen challenges in the Fraunhofer Institute for Toxicology and Experimental Medicine’s
http://dx.doi.org/10.1016/j.anai.2016.07.018 1081-1206/Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
A.K. Ellis et al. / Ann Allergy Asthma Immunol 117 (2016) 310e317
environmental challenge chamber. All doses (100, 200, and 400 mg twice daily) were well tolerated and significantly improved nasal symptoms in participants with SAR.9 The aim of the present study was to assess the clinical efficacy, safety, and tolerability of 3 oncedaily doses (50, 200, and 400 mg) of S0597 intranasal spray compared with placebo in participants with SAR who were exposed to ragweed pollen challenges in an environmental exposure unit (EEU). Controlled allergen challenge facilities (CACFs), such as the aforementioned environmental challenge chamber or EEU, are accepted models to test antiallergic treatment in early clinical development. The advantage lies in the ability to control environmental conditions, such as temperature, humidity, and allergen concentration. Thus, compared with field studies, fewer participants are needed to reveal significant treatment effects. Several CACFs in Europe, North America, and Japan have been used to test antiallergic treatments, including INSs, in numerous clinical trials.10e16 The EEU in Kingston, Ontario, Canada, was the first such facility to be developed in North America and has been used previously to demonstrate the efficacy and onset of action of nasal corticosteroids.10,11 Allergen challenges with ragweed pollen in the EEU are designed to mimic outdoor allergen challenges but with much greater control over environmental variables, so participants experience allergy symptoms analogous to those experienced in outdoor conditions.17 Methods Study Design This was a phase 2, randomized, double-blind, placebocontrolled, single-center, 4-arm, parallel study conducted in the EEU at Kingston General Hospital, Kingston, Ontario, Canada, from October 2 to December 17, 2014. Adults with documented SAR during ragweed pollen season were exposed to controlled levels of ragweed pollen in the EEU. The study was given ethical clearance by the Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board. It was conducted in accordance with the Declaration of Helsinki (Somerset West Amendment 1996) and the International Council for Harmonisation Guideline on Good Clinical Practice. Participants For inclusion in the study, adult participants (aged 18e65 years) were required to have a minimum 2-year history of SAR attributable to ragweed pollen, a positive skin prick test result to short ragweed (defined as a wheal 3 mm larger than the negative control) within 12 months before enrollment, a total nasal symptom score (TNSS) of at least 6 at least once during a 1- to 3-hour screening or priming challenge in the EEU and within the first 2 hours of the baseline visit, and forced expiratory volume in 1 minute (FEV1) of at least 80% of predicted during screening. The main exclusion criteria were symptomatic perennial AR; clinically significant nasal septum deformation or nasal polyps; respiratory tract infection within 2 weeks before the screening challenge; pulmonary disease other than AR or mild asthma (defined as controlled by b2-agonists alone used <2 times per week); history of cataracts, glaucoma, or ocular hypertension; receiving other medications that might interfere with study measurements or rescue medication (Table 1); pregnancy; breastfeeding; and participation in another clinical trial within 30 days before screening. Patients receiving escalating doses of allergen immunotherapy within 2 years before screening were also excluded (however, participants taking stable maintenance doses could be included provided they were not scheduled for injection[s] during the study treatment phase).
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Table 1 Required Washout Periods Before the First Priming Visit for Participants Receiving Medications That May Interfere With Study Measurements or Rescue Medication Drug
Washout time before the priming visit
Systemic or inhaled corticosteroids Nasal corticosteroids or topical corticosteroids (except hydrocortisone 1% on <10% of the body surface) Histamine1-antihistamines, cromoglycates, leukotriene modifiers, and topical decongestants Drugs with potential to interfere with rescue medication for anaphylaxis (eg, b-blockers)
4 wk 2 wk
72 h 1 wk
To exclude those with signs or symptoms of perennial AR of significant intensity to be judged by the investigator to potentially interfere with the study outcomes, all participants were tested to a panel of allergens (ragweed, rye grass, timothy grass, birch, tree mix, Alternaria, Dermatophagoides farinae, Dermatophagoides pteronyssinus, cat, and dog). Participants who tested positive to 1 of the perennial allergens were questioned by the physician to determine whether they indeed exhibited any symptoms while in the presence of the allergen; participants who then reported having no symptoms or symptoms that were mild in severity were included in the study. The exception was participants who had symptoms while in the presence of a cat and/or dog; if they did not live with a cat or dog and agreed to avoid exposure to these animals throughout the study they were included. Allergen Challenge and Study Treatments The EEU ventilation system used filtered outdoor air, with controlled temperature (18 Ce22 C) and humidity (40%e60%). Air within the unit was exhausted directly outside. The allergen level was maintained at a mean (SD) of 3,500 (500) grains/m3 throughout the exposure period. The pollen concentration was monitored via Rotorod impact samplers placed in 7 different locations in the room. Sampling rods, rotating at 2,400 rpm, sampled 47.3 L of air per minute and collected pollen grains on their greased surfaces. Pollen grains were manually enumerated by examining the rods microscopically. Samples were taken for 30 seconds at 30-minute intervals, which corresponded with the time points for participant symptom scoring. Participants remained under constant supervision by medical staff inside the unit. A schematic of the EEU is shown in Figure 1.18 Screening was conducted from days 90 to 1 to assess participants for eligibility. During the screening process, participants attended a minimum of 1 and a maximum of 3 priming visits (days 6 to 1) to reawaken allergic reactivity and allow for development of SAR symptoms. Standard challenge allergen, Ambrosia artemisiifolia pollen, was purchased from Greer Source Materials, Lenoir, North Carolina. Participants attended a 3-hour baseline pollen challenge on day 1 of the treatment phase. Allergen challenge was performed again on days 7 and 14. At the day 1 visit, the site dispensed study medication for the 13 days of treatment along with rescue medication (antihistamine oral tablets, 10 mg of loratadine), and participants were instructed to record study medication administration time, any missed doses, and any use of rescue medication in a take-home diary. Participants were randomized to either S0597 at doses of 50, 200, or 400 mg/d or placebo as a nasal spray to be administered once daily in the evening on days 1 to 13. Study medication was taken on site after the completion of the EEU exposure on day 1 (baseline visit) and day 7. On days 2 to 6 and 8 to 13, participants self-administered the medication once daily at
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A.K. Ellis et al. / Ann Allergy Asthma Immunol 117 (2016) 310e317
Figure 1. Schematic of the environmental exposure unit. Adapted with permission from Ellis et al.18 Gray arrows indicate direction of airflow.
A.K. Ellis et al. / Ann Allergy Asthma Immunol 117 (2016) 310e317
home at approximately 9 PM. Each dose consisted of two 50-mL sprays per nostril of 0.025%, 0.1%, or 0.2% solutions of S0597 or placebo, respectively, from a primed spray pump. Assessments Nasal symptoms were monitored at the priming visit and on baseline day 1, day 7, and day 14 immediately before pollen exposure in the EEU and at 6 time points (30, 60, 90, 120, 150, and 180 minutes) during the challenge. Nasal assessments included TNSS, total ocular symptom score (TOSS), total rhinoconjunctivitis symptom score (TRSS), and peak nasal inspiratory flow (PNIF). The severity of each component symptom was scored from 0 to 3, and the total scores were calculated by adding the scores for each symptom (Table 2). The mean score during the 6 time points during the challenge was the test result for each visit. The primary efficacy end point was TNSS change from baseline to day 14. Secondary efficacy end points were TNSS change from baseline to day 7 and to day 14 in each of the TNSS subscales. Prespecified exploratory efficacy end points were TOSS, TRSS, PNIF, and peak expiratory flow rate (PEFR). Safety was assessed as the incidence and intensity of AEs, vital signs (pulse rate and blood pressure), lung function (FEV1 and PEFR), and physical examination. Samples for laboratory assessments were taken during the screening, treatment, and day 14 exit visits. Statistical Analyses In the previous CACF study of S0597,9 the mean change from baseline in TNSS associated with S0597 nasal delivery after 2 weeks of treatment was 2.4 to 2.8 units, and the mean reduction associated with placebo treatment was approximately 1.5 units. The mean (SD) difference between active and placebo was approximately 1 (1.5e1.8) unit. Hence, assuming a mean (SD) difference in the change from baseline in TNSS of 1 (1.7) unit between S0597 and placebo, a sample size of 200 evaluable participants was required to ensure at least 80% power at a 2-sided a level of .05, using a t test statistic for equal group sizes. Approximately 288 participants were to be screened to randomize 220 participants to the study. The safety population consisted of all randomized participants receiving at least 1 dose of the study treatment or placebo. The primary and secondary efficacy analyses were conducted for the intent-to-treat population using the last observation carried forward method. Least-squares mean changes in TNSS, TNSS subscales, TOSS, TRSS, PNIF, and PEFR scores from baseline to day 14 were compared among groups using repeated-measures analysis of covariance, with treatment, visit, and treatment visit interaction as fixed effects and baseline value as the covariate (treatment comparison at the 2-sided .05 significance level). Pairwise treatment comparisons of each dose of S0597 vs placebo were
Table 2 Seasonal Allergic Rhinitis Symptoms for Efficacy Analysisa Symptom
TNSS
TRSS
Runny nose (rhinorrhea) Nasal congestion Sneezing Nasal itching Red, itchy, or burning eyes Watery eyes Itching of the ears, palate, or throat
X X X X
X X X X X X X
TOSS
X X
Abbreviations: TNSS, total nasal symptom score; TOSS, total ocular symptom score; TRSS, total rhinoconjunctivitis symptom score. a Total score was the sum of scores for the symptoms indicated by X. Therefore, TNSS ranged from 0 to 12, TRSS from 0 to 21, and TOSS from 0 to 6.
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conducted using the t test. All statistical analyses were performed using SAS statistical software, version 9.3 or subsequent versions (SAS Institute Inc, Cary, North Carolina). Confirmatory analysis was performed on all the participants in the per-protocol population who completed the study without any major protocol deviations. The imputation method was not applicable for the per-protocol population. Results Study Population A total of 222 participants were randomized into the study and received study medication. Thus, all were included in the population for safety analysis and the intent-to-treat population for the efficacy analysis. The mean (SD) age was 39 (10.4) years, 61.3% were female, and most were white (96.8%), followed by Asian (1.4%) (Table 3). Overall, 215 participants were included in the per-protocol analysis set. Of the 7 participants excluded, 3 did not complete the study, 3 had major protocol deviations, and 1 did not complete the study and had a major protocol deviation. Reasons for discontinuation were as follows: 2 because of AEs (1 in the 400-mg/d S0597 group and 1 in the placebo group; these participants discontinued study participation on day 14 and took all doses of study drug), 1 did not meet eligibility criteria (400-mg/d S0597 group), and 1 had a schedule conflict for the day 14 visit (200-mg/d S0597 group). Major protocol deviations were as follows: 2 not taking study drug on days approaching a study visit (1 in the 50-mg/d S0597 group and 1 in the placebo group), 1 not observing the 4-week washout for inhaled corticosteroids (50-mg/d S0597 group), and 1 using prohibited medication, namely, tobramycin 0.3% and dexamethasone 0.1% optic drops (400-mg/d S0597 group). Nasal Symptoms Mean baseline TNSS was between 8.87 and 9.43 across the treatment groups. Analysis of the primary efficacy end point of change in TNSS from baseline to day 14 demonstrated statistically significantly greater improvement in TNSS in all 3 S0597 dose groups compared with placebo (Table 4). TNSS decreased, demonstrating symptom improvement in all treatment groups during the 2-week treatment (Fig 2). The least-squares mean differences in change from baseline between active treatment and placebo were 1.18, 1.84, and 1.17 for the 50-, 200,- and 400-mg/d S0597 groups, respectively; all findings were statistically significant. None of the exploratory pairwise comparisons between S0597 dose groups reached significance (Table 4). The greater improvement from baseline in TNSS at day 7 was statistically significant for the 200-mg/d S0597 group (least-squares mean difference from placebo, 1.25; 95% confidence interval [CI], 0.32e2.18; P ¼ .009). Similar results were seen for the per-protocol analysis set. For each of the constituent components of the TNSS (rhinorrhea, nasal congestion, sneezing, nasal itching), numerically greater mean improvement from baseline to day 14 was observed in each of the S0597 groups compared with placebo. Notably, the greater effect of active treatment on rhinorrhea score was statistically significant for all 3 S0597 dose groups at day 14. The 200-mg S0597 group had the most consistent response, with statistically significant improvements in all the TNSS subscales compared with the placebo group at days 7 and 14. Table 5 gives the data for changes to day 14. Exploratory End Points The 200- and 400-mg/d S0597 groups had statistically significant improvement from baseline to day 14 in the exploratory efficacy end point of change in PNIF compared with placebo. Least-squares
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Table 3 Demographic Characteristics of the Participants at Screening (Safety Analysis Set) Characteristic
Placebo (n ¼ 56)
Total (N ¼ 222)
S0597 50 mg/d (n ¼ 55)
Age, mean (SD), y Sex, No. (%) Female Male Race, No. (%) White Asian Other Ethnicity, No. (%) Hispanic Non-Hispanic Height, mean (SD), cma Weight, mean (SD), kgb Body mass index, mean (SD)b,c
200 mg/d (n ¼ 56)
400 mg/d (n ¼ 55)
39 (10.8)
39 (9.5)
39 (10.9)
38 (10.6)
39 (10.4)
41 (73.2) 15 (26.8)
29 (52.7) 26 (47.3)
36 (64.3) 20 (35.7)
30 (54.5) 25 (45.5)
136 (61.3) 86 (38.7)
54 (96.4) 1 (1.8) 1 (1.8)
51 (92.7) 1 (1.8) 3 (5.5)
55 (98.2) 1 (1.8) 0
55 (100) 0 0
215 (96.8) 3 (1.4) 4 (1.8)
1 55 169 81 29
(1.8) (98.2) (8.0) (18.2) (6.6)
55 170 87 30
0 (100) (9.7) (22.4) (7.7)
56 169 88 30
0 (100) (8.6) (19.4) (7.2)
55 171 90 31
0 (100) (8.2) (18.9) (6.8)
1 221 170 87 30
(0.5) (99.5) (8.6) (19.9) (7.1)
Data are missing for 1 participant in the 50-mg/d S0597 group. Data are missing for 1 participant in the placebo group and 1 in the 50-mg/d group. c Body mass index was calculated as the weight in kilograms divided by the square of height in meters. a
b
placebo group, 3 with 50 mg/d of S0597, 2 with 200 mg/d of S0597, and 1 with 400 mg/d of S0597. The most common AE was decrease in blood cortisol, which occurred in 2 participants (3.6%) in the placebo group and in 3, 4, and 4 participants in the 50-, 200-, and 400-mg/d S0597 groups, respectively (Table 6). The investigator considered the AEs to be unrelated or unlikely to be related to the study medication in 40 of 222 participants (18%). Of the 23 of 222 participants (10.4%) with AEs reported as possibly related to study drug, 7 of 55 (12.7%) were in the 400-mg/d S0597 group, 5 of 56 (8.9%) in the 200-mg/d S0597 group, 6 of 55 (10.9%) in the 50-mg/d S0597 group, and 5 of 56 (8.9%) in the placebo group, suggesting no apparent dose-response relationship. The most common drug-related AE was decrease in blood cortisol (incidences as reported above). No treatment-related findings were observed in vital signs, lung function, or physical examination.
mean differences from placebo in change from baseline were 0.59 L/min (95% CI, 9.27 to 10.45 L/min), 11.9 L/min (95% CI, 21.7 to 1.99 L/min), and 12.2 L/min (95% CI, 22.2 to 2.27 L/min) for the 50-, 200-, and 400-mg/d S0597 treatment groups. Numerically greater mean improvement from baseline to day 14 was observed for all 3 S0597 dose groups compared with placebo in the exploratory end points of TRSS, TOSS, and PEFR; however, only the differences for the 200-mg group in TRSS at day 14 and the 50mg group in PEFR at day 7 and day 14 were statistically significant. Safety S0597 was well tolerated at all doses studied. No deaths or other serious AEs were reported during the study. No participants prematurely discontinued use of the study drug because of an AE. In total, 58 of the 222 participants (26.1%) had at least 1 AE reported during the study. This constituted 74 AEs. An overall test for a difference in the proportion of individuals who experienced an AE between treatment groups was not statistically significant (c2 test, P ¼ .501). In addition, pairwise tests for differences in the proportion of individuals who experienced an AE between treatment groups had P > .13; thus, no doseeresponse relationship was observed. The AEs were mild in 34 participants, moderate in 21, and severe in 9 (participants could be counted in >1 category but only once per category). The severe events were distributed as 3 in the
Discussion This randomized, double-blind, parallel-group, single-center study assessed the dose-related efficacy and safety of 3 doses of S0597, a novel INS, in participants with SAR who were challenged with ragweed pollen in an EEU. All participants reported nasal symptoms of SAR after pollen challenge, and all 3 doses of S0597 (50, 200, and 400 mg/d) produced a statistically significant reduction in nasal symptoms (TNSS) from baseline compared with
Table 4 TNSS Change From Baseline to Day 14 (Intent-to-Treat Population) TNSS
Baseline TNSS, mean (SD) Change from baseline to day 14, LS mean (SE) Difference from placebo, LS mean (95% CI) P value Differences between S0597 dose groups, P value vs 50 mg/d vs 200 mg/d
Placebo (n ¼ 56)
8.87 (1.878) 2.83 (0.381) NA
S0597 50 mg/d (n ¼ 55)
200 mg/d (n ¼ 56)
400 mg/d (n ¼ 55)
9.41 (1.695) 4.01 (0.378)
9.43 (1.657) 4.67 (0.378)
9.39 (1.538) 4.00 (0.385)
1.18 (0.12e2.24)
1.84 (0.78e2.90)
1.17 (0.10e2.25)
NA
.03
<.001
.03
NA NA
NA NA
.22 NA
.99 .22
Abbreviations: CI, confidence interval; LS, least squares; NA, not applicable; TNSS, total nasal symptom score.
A.K. Ellis et al. / Ann Allergy Asthma Immunol 117 (2016) 310e317
Figure 2. Total nasal symptom score (TNSS) over time (intent-to-treat population). EEU indicates environmental exposure unit.
placebo on day 14. The mean improvement in each of the constituent items of the TNSS (rhinorrhea, nasal congestion, sneezing, nasal itching) from baseline to day 14 was also greater in each of the S0597 groups compared with placebo. There was no evidence that the efficacy response consistently increased with increased dose. The 200-mg/d S0597 group had the most consistent response, with statistically significant improvements in all the nasal symptoms compared with placebo on days 7 and 14. The difference from placebo for change in the rhinorrhea score was statistically significant with all 3 doses of S0597 on day 14. In addition to these symptom scores, there was a statistically significant improvement in measurements of PNIF. One of the objectives of this study was to identify the lowest effective dose of S0597. The first CACF study had 200-, 400-, and 800-mg/d doses, all of which were effective and demonstrated dose response.9 In this study, a dose response on the primary end point (TNSS) was not seen with the selected doses, which may be attributable to a response plateau at the lowest dose of 50 mg/d. However, 200 mg/d led to significant change on all primary and secondary end points and thus would likely be the minimally effective dose. The mean (SD) pollen concentration of 3,500 (500) grains/m3 used in the EEU in the present study has been shown (for grass, birch, and ragweed pollen) to trigger a symptom burden suitable
315
for studying the effects of the disease and its improvement with treatment. In addition, the priming phase awakens the allergic responsiveness but also equalizes the responsiveness before randomization to the study treatments. These factors support the applicability of findings from the EEU to the real-life experience of individuals with symptoms of SAR.12,17e20 In keeping with previous studies,9,21,22 the current study excluded patients who had been receiving escalating doses of allergen specific immunotherapy in the 2 years before screening. One participant in this study received a maintenance dose of immunotherapy that was a mix that included ragweed. Our study was conducted outside all local pollen seasons. As per the exclusion criteria, participants were excluded if they had signs or symptoms of active perennial AR of significant intensity to be judged by the investigator to potentially interfere with the study outcomes. Choice of evening dose was attributable to operational issues at the EEU facility. Participants would check in between 5 and 6 PM, then undergo prechallenge testing, followed by EEU challenge and assessments at 6 time points during the next 3 hours. They would then receive the study medication and leave the study site. In the phase 1 study at the highest intranasal dose of 3,200 mg/d, there was no significant change in serum cortisol levels.8 Therefore, the drug was assumed safe at doses selected for administration irrespective of time of day or night. Although we recognize that dosing in the evening is not standard for nasal corticosteroid studies, it was believed by the team that dosing immediately after baseline challenge while under the direct supervision of the investigator to optimize adherence and ensure proper inhalation technique was the ideal approach and would limit the total number of required study visits, optimizing recruitment considerations. We then carefully weighed the pros and cons of having participants continue to dose in the evening vs switching to dosing the following morning and decided it was best to maintain consistent dosing times through the entire study rather than have dose 2 occur potentially 11 hours after dose 1. As with other new INS therapies, S0597 was well tolerated at the doses tested. The most common AE in each of the treatment groups, including placebo, was a decrease in blood cortisol levels; the incidence appeared to be somewhat higher among S0597-treated participants compared with those who received placebo, but the event rates were low (2 participants in the placebo group compared with 3 or 4 in each of the S0597 groups). Although the highest-dose group (400 mg/d) had the greatest total number of AEs, the incidence of individual AEs other than decrease in cortisol was low in all groups, and there was no clear evidence for a dose-response relationship from 0 to 200 mg/d of S0597. No dose-response relationship was observed among the treatment groups for the
Table 5 TNSS Subscales Change From Baseline to Day 14 (Intent-to-Treat Population) TNSS subscale
Baseline rhinorrhea score, mean (SD) Difference from placebo in change from baseline, LS mean (95% CI) P value Baseline nasal congestion score, mean (SD) Difference from placebo in change from baseline, LS mean (95% CI) P value Baseline sneezing score, mean (SD) Difference from placebo in change from baseline, LS mean (95% CI) P value Baseline nasal itching score, mean (SD) Difference from placebo in change from baseline, LS mean (95% CI) P value
Placebo (n ¼ 56)
2.33 NA NA 2.51 NA NA 1.68 NA NA 2.35 NA NA
(0.535)
(0.454)
(0.888)
(0.537)
S0597 50 mg/d (n ¼ 55)
200 mg/d (n ¼ 56)
400 mg/d (n ¼ 55)
2.51 0.42 .008 2.57 0.27 .07 1.88 0.31 .03 2.45 0.16 .32
2.46 (0.471) 0.50 (0.19e0.81) .002 2.46 (0.509) 0.43 (0.14e0.73) .004 1.98 (0.747) 0.51 (0.23e0.80) <.001 2.53 (0.373) 0.33 (0.02e0.64) .04
2.51 0.36 .02 2.50 0.25 .10 1.92 0.29 .05 2.46 0.24 .13
(0.491) (0.11e0.73) (0.386) (0.02 to 0.57) (0.891) (0.02e0.59) (0.511) (0.15 to 0.46)
Abbreviations: CI, confidence interval; LS, least squares; NA, not applicable; TNSS, total nasal symptom score.
(0.460) (0.05e0.67) (0.422) (0.05 to 0.55) (0.812) (0.00 to 0.57) (0.432) (0.07 to 0.55)
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Table 6 Summary of AEs (Safety Analysis Set) AE
Participants with any AE, No. (%) Total No. of AEs Participants with AEs by intensity,a No. (%) Mild Moderate Severe AEs reported in >1 participant,b No. (%) Blood cortisol decreased Headache Sinus headache Oropharyngeal pain Epistaxis Throat irritation Cough Dry throat Nasal congestion Productive cough Myalgia Back pain Urinary tract infection
Placebo (n ¼ 56)
S0597 50 mg/d (n ¼ 55)
200 mg/d (n ¼ 56)
400 mg/d (n ¼ 55)
15 (26.8)
11 (20.0)
14 (25.0)
18 (32.7)
20
13
17
24
8 (14.3) 6 (10.7) 3 (5.4)
5 (9.1) 3 (5.5) 3 (5.5)
9 (16.1) 5 (8.9) 2 (3.6)
2 (3.6) 1 (1.8) 0 1 (1.8) 1 (1.8) 0 1 (1.8) 1 (1.8) 1 (1.8) 1 (1.8) 0 1 (1.8) 0
3 (5.5) 1 (1.8) 1 (1.8) 0 1 (1.8) 0 0 0 0 0 1 (1.8) 0 0
4 (7.1) 2 (3.6) 0 0 0 0 0 0 0 1 (1.8) 1 (1.8) 1 (1.8) 1 (1.8)
12 (21.8) 7 (12.7) 1 (1.8)
4 2 1 3 1 2 1 1 1
(7.3) (3.6) (1.8) (5.5) (1.8) (3.6) (1.8) (1.8) (1.8) 0 1 (1.8) 0 1 (1.8)
Abbreviation: AE, adverse event. a Participants can be counted in more than 1 category but only once per category (in the most severe category if they had multiple AEs of different intensities). b Number of participants with each AE.
incidence of AEs considered severe or for those considered possibly related to study drug. Because cortisol levels fluctuate diurnally, 1 study included assessment of 24-hour cortisol profiles and found a reduction in the area under the concentration time curve for serum cortisol from baseline to day 14 with S0597, fluticasone propionate, and placebo. Although this was statistically significant for 800 and 1,600 mg/d of S0597, it was not significant in the group receiving 3,200 mg/d. Furthermore, the difference between each active treatment group and placebo for change in the area under the concentration time curve of serum cortisol was not statistically significant, leading to the conclusion that it was unlikely to represent a clinically significant suppression of the HPA axis.8 However, tests for serum cortisol levels have a limited role in determining the HPA axis function.23 S0597 has a low binding affinity to other sex steroid receptors and aldosterone and in preclinical models had local antiinflammatory activity and a low potential for systemic AEs.8 Overall, the safety profile of S0597 appears to compare favorably with that of other INS therapies. In conclusion, this study found that all 3 tested doses of S0597 were effective in relief of nasal symptoms of SAR compared with placebo and that S0597 is a novel intranasal corticosteroid that warrants further development. Acknowledgments Medical writing support was provided by Keith Day, PhD, of PAREXEL in compliance with the guidelines of the International Committee of Medical Journal Editors and was funded by Sun Pharma Advanced Research Company Ltd. We acknowledge the efforts of Terry Walker and Daniel Adams for their contribution to the conduct of the study. References [1] Asher MI, Montefort S, Bjorksten B, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry crosssectional surveys. Lancet. 2006;368:733e743.
[2] Bauchau V, Durham SR. Prevalence and rate of diagnosis of allergic rhinitis in Europe. Eur Respir J. 2004;24:758e764. [3] Bousquet J, Khaltaev N, Cruz AA, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008;63(suppl 86):8e160. [4] Katelaris CH, Lee BW, Potter PC, et al. Prevalence and diversity of allergic rhinitis in regions of the world beyond Europe and North America. Clin Exp Allergy. 2012;42:186e207. [5] Brozek JL, Bousquet J, Baena-Cagnani CE, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol. 2010;126: 466e476. [6] Lumry WR. A review of the preclinical and clinical data of newer intranasal steroids used in the treatment of allergic rhinitis. J Allergy Clin Immunol. 1999; 104:S150eS158. [7] Blaiss MS. Safety update regarding intranasal corticosteroids for the treatment of allergic rhinitis. Allergy Asthma Proc. 2011;32:413e418. [8] Thennati R, Khanna A, Khanna M, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of compound SFDAC by intranasal administration of multiple escalating dose in healthy male subjects. Clin Pharmacol Drug Dev. 2014;3:428e438. [9] Badorrek P, Hohlfeld JM, Krug N, et al. Efficacy and safety of a novel nasal steroid, S0597, in patients with seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2015;115:325e329. [10] Day JH, Buckeridge DL, Clark RH, et al. A randomized, double-blind, placebocontrolled, controlled antigen delivery study of the onset of action of aerosolized triamcinolone acetonide nasal spray in subjects with ragweedinduced allergic rhinitis. J Allergy Clin Immunol. 1996;97:1050e1057. [11] Day JH, Briscoe MP, Rafeiro E, et al. Onset of action of intranasal budesonide (Rhinocort aqua) in seasonal allergic rhinitis studied in a controlled exposure model. J Allergy Clin Immunol. 2000;105:489e494. [12] Ellis AK, North ML, Walker T, et al. Environmental exposure unit: a sensitive, specific, and reproducible methodology for allergen challenge. Ann Allergy Asthma Immunol. 2013;111:323e328. [13] Hashiguchi K, Tang H, Fujita T, et al. Bepotastine besilate OD tablets suppress nasal symptoms caused by Japanese cedar pollen exposure in an artificial exposure chamber (OHIO Chamber). Expert Opin Pharmacother. 2009;10: 523e529. [14] Krug N, Hohlfeld JM, Geldmacher H, et al. Effect of loteprednol etabonate nasal spray suspension on seasonal allergic rhinitis assessed by allergen challenge in an environmental exposure unit. Allergy. 2005;60: 354e359. [15] Patel D, Garadi R, Brubaker M, et al. Onset and duration of action of nasal sprays in seasonal allergic rhinitis patients: olopatadine hydrochloride versus mometasone furoate monohydrate. Allergy Asthma Proc. 2007;28: 592e599. [16] Zieglmayer P, Zieglmayer R, Bareille P, et al. Fluticasone furoate versus placebo in symptoms of grass-pollen allergic rhinitis induced by exposure in the Vienna Challenge Chamber. Curr Med Res Opin. 2008;24:1833e1840.
A.K. Ellis et al. / Ann Allergy Asthma Immunol 117 (2016) 310e317 [17] Ellis AK, Ratz JD, Day AG, et al. Factors that affect the allergic rhinitis response to ragweed allergen exposure. Ann Allergy Asthma Immunol. 2010;104:293e298. [18] Ellis AK, Steacy LM, Hobsbawn B, et al. Clinical validation of controlled grass pollen challenge in the Environmental Exposure Unit (EEU). Allergy Asthma Clin Immunol. 2015;11:5. [19] North ML, Walker TJ, Steacy LM, et al. Add-on histamine receptor-3 antagonist for allergic rhinitis: a double blind randomized crossover trial using the environmental exposure unit. Allergy Asthma Clin Immunol. 2014;10:33. [20] Soliman M, Steacy LM, Adams DE, et al. Clinical validation of controlled birch pollen challenge in the environmental exposure unit [abstract]. Ann Allergy Asthma Immunol. 2015;115(5 suppl 1):A119.
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[21] Day JH, Briscoe M, Widlitz MD. Cetirizine, loratadine, or placebo in subjects with seasonal allergic rhinitis: effects after controlled ragweed pollen challenge in an environmental exposure unit. J Allergy Clin Immunol. 1998;101: 638e645. [22] Day JH, Briscoe MP, Rafeiro E, et al. Randomized double-blind comparison of cetirizine and fexofenadine after pollen challenge in the Environmental Exposure Unit: duration of effect in subjects with seasonal allergic rhinitis. Allergy Asthma Proc. 2004;25:59e68. [23] Chrousos GP, Kino T, Charmandari E. Evaluation of the hypothalamicpituitary-adrenal axis function in childhood and adolescence. Neuroimmunomodulation. 2009;16:272e283.
Contents lists available at ScienceDirect
Efficacy of the novel nasal steroid S0597 tested in an environmental exposure unit Anne K. Ellis, MD *, y; Lisa M. Steacy, BSc y; Abhijeet Joshi, BPharm, MBA z; Shravanti Bhowmik, MD z; Atul Raut, MD, PhD z * Division
of Allergy and Immunology, Department of Medicine, Queen’s University, Kingston, Ontario, Canada Allergy Research Unit, Kingston General Hospital, Kingston, Ontario, Canada z Sun Pharma Advanced Research Company Ltd, Mumbai, India y
A R T I C L E
I N F O
Article history: Received for publication April 13, 2016. Received in revised form June 28, 2016. Accepted for publication July 13, 2016.
A B S T R A C T
Background: S0597 is a novel glucocorticosteroid that was formulated as an intranasal spray to treat seasonal allergic rhinitis (SAR). In a previous phase 2 study, doses of 100 to 400 mg twice daily were well tolerated and more effective than placebo for improving nasal symptoms induced by grass pollen. Objective: To assess the clinical efficacy and safety of a once-daily S0597 nasal spray for treatment of SAR induced by ragweed pollen in an environmental exposure unit (EEU). Methods: A single-center, phase 2, randomized, double-blind study in 222 adults with SAR and a positive skin prick test result to short ragweed. Participants underwent ragweed pollen challenge in the EEU at the screening or priming visit and on days 1, 7, and 14 and received 50, 200, or 400 mg of S0597 or placebo in the evening for 13 days. The primary efficacy end point was change in total nasal symptom score (TNSS) from baseline to day 14. Results: Improvement in TNSS from baseline to day 14 was statistically significant in all S0597 groups compared with placebo. Least-squares mean differences in change from baseline between active treatment and placebo were 1.18, 1.84, and 1.17 for the 50-, 200-, and 400-mg/d S0597 groups, respectively (P < .05). The 200-mg group demonstrated statistically significant improvements in all TNSS subscales (rhinorrhea, nasal congestion, sneezing, nasal itching) compared with placebo at days 7 and 14. Conclusion: Treatment with 50 to 400 mg of S0597 once daily was well tolerated and significantly more effective than placebo in relieving nasal symptoms of SAR associated with ragweed pollen. Trial Registration: clinicaltrials.gov Identifier: NCT01940146. Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Allergic rhinitis (AR) is a significant public health concern worldwide, affecting an estimated 500 million people.1e4 Intranasal glucocorticosteroids (INSs) are regarded as the most effective pharmacologic treatment for AR and are recommended by the Allergic Rhinitis and its Impact on Asthma guidelines as a first-line therapy.3,5 INSs have a good safety profile with a low risk of
Reprints: Anne K. Ellis, MD, Allergy Research Unit, Kingston General Hospital, 76 Stuart St, Watkins 1D, Kingston, Ontario, Canada; E-mail: [email protected]. Disclosures: Dr Ellis reported serving on the speaker’s bureau for AstraZeneca, Meda, Merck, Novartis, Pfizer, and Takeda, receiving research grants to the institution from Circassia Ltd, GlaxoSmithKline, Merck, Novartis, Pfizer, and Sun Pharma Advanced Research Company Ltd, and serving as an adviser to ALK Abello, Circassia, Merck, and Novartis. Mr Joshi, Dr Bhowmik, and Dr Raut reported being employees of Sun Pharma Advanced Research Company Ltd. No other disclosures were reported. Funding Sources: This study was funded by Sun Pharma Advanced Research Company Ltd.
systemic adverse effects (AEs) attributable to their low systemic bioavailability.6 This profile is especially true for newer INSs, such as ciclesonide, mometasone furoate, and fluticasone furoate, which all have systemic bioavailability of less than 1%.7 S0597 is a novel glucocorticosteroid that has been formulated as an intranasal spray for the treatment of seasonal allergic rhinitis (SAR). The short form of its International Union of Pure and Applied Chemistry name is SFDAC. Results of a phase 1, multiple ascendingdose study indicated that intranasal S0597 was safe and well tolerated at doses up to 3,200 mg once daily. No clinically significant suppression of the hypothalamic-pituitary-adrenal (HPA) axis was observed, and the plasma concentration of S0597 was below the lower limit of quantification at most time points for all participants.8 In a 15-day, randomized, placebo-controlled, double-blind, parallel-group, single-center phase 2 study, the dose-related efficacy and safety of S0597 nasal spray was assessed in participants with SAR using repeated grass pollen challenges in the Fraunhofer Institute for Toxicology and Experimental Medicine’s
http://dx.doi.org/10.1016/j.anai.2016.07.018 1081-1206/Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
A.K. Ellis et al. / Ann Allergy Asthma Immunol 117 (2016) 310e317
environmental challenge chamber. All doses (100, 200, and 400 mg twice daily) were well tolerated and significantly improved nasal symptoms in participants with SAR.9 The aim of the present study was to assess the clinical efficacy, safety, and tolerability of 3 oncedaily doses (50, 200, and 400 mg) of S0597 intranasal spray compared with placebo in participants with SAR who were exposed to ragweed pollen challenges in an environmental exposure unit (EEU). Controlled allergen challenge facilities (CACFs), such as the aforementioned environmental challenge chamber or EEU, are accepted models to test antiallergic treatment in early clinical development. The advantage lies in the ability to control environmental conditions, such as temperature, humidity, and allergen concentration. Thus, compared with field studies, fewer participants are needed to reveal significant treatment effects. Several CACFs in Europe, North America, and Japan have been used to test antiallergic treatments, including INSs, in numerous clinical trials.10e16 The EEU in Kingston, Ontario, Canada, was the first such facility to be developed in North America and has been used previously to demonstrate the efficacy and onset of action of nasal corticosteroids.10,11 Allergen challenges with ragweed pollen in the EEU are designed to mimic outdoor allergen challenges but with much greater control over environmental variables, so participants experience allergy symptoms analogous to those experienced in outdoor conditions.17 Methods Study Design This was a phase 2, randomized, double-blind, placebocontrolled, single-center, 4-arm, parallel study conducted in the EEU at Kingston General Hospital, Kingston, Ontario, Canada, from October 2 to December 17, 2014. Adults with documented SAR during ragweed pollen season were exposed to controlled levels of ragweed pollen in the EEU. The study was given ethical clearance by the Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board. It was conducted in accordance with the Declaration of Helsinki (Somerset West Amendment 1996) and the International Council for Harmonisation Guideline on Good Clinical Practice. Participants For inclusion in the study, adult participants (aged 18e65 years) were required to have a minimum 2-year history of SAR attributable to ragweed pollen, a positive skin prick test result to short ragweed (defined as a wheal 3 mm larger than the negative control) within 12 months before enrollment, a total nasal symptom score (TNSS) of at least 6 at least once during a 1- to 3-hour screening or priming challenge in the EEU and within the first 2 hours of the baseline visit, and forced expiratory volume in 1 minute (FEV1) of at least 80% of predicted during screening. The main exclusion criteria were symptomatic perennial AR; clinically significant nasal septum deformation or nasal polyps; respiratory tract infection within 2 weeks before the screening challenge; pulmonary disease other than AR or mild asthma (defined as controlled by b2-agonists alone used <2 times per week); history of cataracts, glaucoma, or ocular hypertension; receiving other medications that might interfere with study measurements or rescue medication (Table 1); pregnancy; breastfeeding; and participation in another clinical trial within 30 days before screening. Patients receiving escalating doses of allergen immunotherapy within 2 years before screening were also excluded (however, participants taking stable maintenance doses could be included provided they were not scheduled for injection[s] during the study treatment phase).
311
Table 1 Required Washout Periods Before the First Priming Visit for Participants Receiving Medications That May Interfere With Study Measurements or Rescue Medication Drug
Washout time before the priming visit
Systemic or inhaled corticosteroids Nasal corticosteroids or topical corticosteroids (except hydrocortisone 1% on <10% of the body surface) Histamine1-antihistamines, cromoglycates, leukotriene modifiers, and topical decongestants Drugs with potential to interfere with rescue medication for anaphylaxis (eg, b-blockers)
4 wk 2 wk
72 h 1 wk
To exclude those with signs or symptoms of perennial AR of significant intensity to be judged by the investigator to potentially interfere with the study outcomes, all participants were tested to a panel of allergens (ragweed, rye grass, timothy grass, birch, tree mix, Alternaria, Dermatophagoides farinae, Dermatophagoides pteronyssinus, cat, and dog). Participants who tested positive to 1 of the perennial allergens were questioned by the physician to determine whether they indeed exhibited any symptoms while in the presence of the allergen; participants who then reported having no symptoms or symptoms that were mild in severity were included in the study. The exception was participants who had symptoms while in the presence of a cat and/or dog; if they did not live with a cat or dog and agreed to avoid exposure to these animals throughout the study they were included. Allergen Challenge and Study Treatments The EEU ventilation system used filtered outdoor air, with controlled temperature (18 Ce22 C) and humidity (40%e60%). Air within the unit was exhausted directly outside. The allergen level was maintained at a mean (SD) of 3,500 (500) grains/m3 throughout the exposure period. The pollen concentration was monitored via Rotorod impact samplers placed in 7 different locations in the room. Sampling rods, rotating at 2,400 rpm, sampled 47.3 L of air per minute and collected pollen grains on their greased surfaces. Pollen grains were manually enumerated by examining the rods microscopically. Samples were taken for 30 seconds at 30-minute intervals, which corresponded with the time points for participant symptom scoring. Participants remained under constant supervision by medical staff inside the unit. A schematic of the EEU is shown in Figure 1.18 Screening was conducted from days 90 to 1 to assess participants for eligibility. During the screening process, participants attended a minimum of 1 and a maximum of 3 priming visits (days 6 to 1) to reawaken allergic reactivity and allow for development of SAR symptoms. Standard challenge allergen, Ambrosia artemisiifolia pollen, was purchased from Greer Source Materials, Lenoir, North Carolina. Participants attended a 3-hour baseline pollen challenge on day 1 of the treatment phase. Allergen challenge was performed again on days 7 and 14. At the day 1 visit, the site dispensed study medication for the 13 days of treatment along with rescue medication (antihistamine oral tablets, 10 mg of loratadine), and participants were instructed to record study medication administration time, any missed doses, and any use of rescue medication in a take-home diary. Participants were randomized to either S0597 at doses of 50, 200, or 400 mg/d or placebo as a nasal spray to be administered once daily in the evening on days 1 to 13. Study medication was taken on site after the completion of the EEU exposure on day 1 (baseline visit) and day 7. On days 2 to 6 and 8 to 13, participants self-administered the medication once daily at
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A.K. Ellis et al. / Ann Allergy Asthma Immunol 117 (2016) 310e317
Figure 1. Schematic of the environmental exposure unit. Adapted with permission from Ellis et al.18 Gray arrows indicate direction of airflow.
A.K. Ellis et al. / Ann Allergy Asthma Immunol 117 (2016) 310e317
home at approximately 9 PM. Each dose consisted of two 50-mL sprays per nostril of 0.025%, 0.1%, or 0.2% solutions of S0597 or placebo, respectively, from a primed spray pump. Assessments Nasal symptoms were monitored at the priming visit and on baseline day 1, day 7, and day 14 immediately before pollen exposure in the EEU and at 6 time points (30, 60, 90, 120, 150, and 180 minutes) during the challenge. Nasal assessments included TNSS, total ocular symptom score (TOSS), total rhinoconjunctivitis symptom score (TRSS), and peak nasal inspiratory flow (PNIF). The severity of each component symptom was scored from 0 to 3, and the total scores were calculated by adding the scores for each symptom (Table 2). The mean score during the 6 time points during the challenge was the test result for each visit. The primary efficacy end point was TNSS change from baseline to day 14. Secondary efficacy end points were TNSS change from baseline to day 7 and to day 14 in each of the TNSS subscales. Prespecified exploratory efficacy end points were TOSS, TRSS, PNIF, and peak expiratory flow rate (PEFR). Safety was assessed as the incidence and intensity of AEs, vital signs (pulse rate and blood pressure), lung function (FEV1 and PEFR), and physical examination. Samples for laboratory assessments were taken during the screening, treatment, and day 14 exit visits. Statistical Analyses In the previous CACF study of S0597,9 the mean change from baseline in TNSS associated with S0597 nasal delivery after 2 weeks of treatment was 2.4 to 2.8 units, and the mean reduction associated with placebo treatment was approximately 1.5 units. The mean (SD) difference between active and placebo was approximately 1 (1.5e1.8) unit. Hence, assuming a mean (SD) difference in the change from baseline in TNSS of 1 (1.7) unit between S0597 and placebo, a sample size of 200 evaluable participants was required to ensure at least 80% power at a 2-sided a level of .05, using a t test statistic for equal group sizes. Approximately 288 participants were to be screened to randomize 220 participants to the study. The safety population consisted of all randomized participants receiving at least 1 dose of the study treatment or placebo. The primary and secondary efficacy analyses were conducted for the intent-to-treat population using the last observation carried forward method. Least-squares mean changes in TNSS, TNSS subscales, TOSS, TRSS, PNIF, and PEFR scores from baseline to day 14 were compared among groups using repeated-measures analysis of covariance, with treatment, visit, and treatment visit interaction as fixed effects and baseline value as the covariate (treatment comparison at the 2-sided .05 significance level). Pairwise treatment comparisons of each dose of S0597 vs placebo were
Table 2 Seasonal Allergic Rhinitis Symptoms for Efficacy Analysisa Symptom
TNSS
TRSS
Runny nose (rhinorrhea) Nasal congestion Sneezing Nasal itching Red, itchy, or burning eyes Watery eyes Itching of the ears, palate, or throat
X X X X
X X X X X X X
TOSS
X X
Abbreviations: TNSS, total nasal symptom score; TOSS, total ocular symptom score; TRSS, total rhinoconjunctivitis symptom score. a Total score was the sum of scores for the symptoms indicated by X. Therefore, TNSS ranged from 0 to 12, TRSS from 0 to 21, and TOSS from 0 to 6.
313
conducted using the t test. All statistical analyses were performed using SAS statistical software, version 9.3 or subsequent versions (SAS Institute Inc, Cary, North Carolina). Confirmatory analysis was performed on all the participants in the per-protocol population who completed the study without any major protocol deviations. The imputation method was not applicable for the per-protocol population. Results Study Population A total of 222 participants were randomized into the study and received study medication. Thus, all were included in the population for safety analysis and the intent-to-treat population for the efficacy analysis. The mean (SD) age was 39 (10.4) years, 61.3% were female, and most were white (96.8%), followed by Asian (1.4%) (Table 3). Overall, 215 participants were included in the per-protocol analysis set. Of the 7 participants excluded, 3 did not complete the study, 3 had major protocol deviations, and 1 did not complete the study and had a major protocol deviation. Reasons for discontinuation were as follows: 2 because of AEs (1 in the 400-mg/d S0597 group and 1 in the placebo group; these participants discontinued study participation on day 14 and took all doses of study drug), 1 did not meet eligibility criteria (400-mg/d S0597 group), and 1 had a schedule conflict for the day 14 visit (200-mg/d S0597 group). Major protocol deviations were as follows: 2 not taking study drug on days approaching a study visit (1 in the 50-mg/d S0597 group and 1 in the placebo group), 1 not observing the 4-week washout for inhaled corticosteroids (50-mg/d S0597 group), and 1 using prohibited medication, namely, tobramycin 0.3% and dexamethasone 0.1% optic drops (400-mg/d S0597 group). Nasal Symptoms Mean baseline TNSS was between 8.87 and 9.43 across the treatment groups. Analysis of the primary efficacy end point of change in TNSS from baseline to day 14 demonstrated statistically significantly greater improvement in TNSS in all 3 S0597 dose groups compared with placebo (Table 4). TNSS decreased, demonstrating symptom improvement in all treatment groups during the 2-week treatment (Fig 2). The least-squares mean differences in change from baseline between active treatment and placebo were 1.18, 1.84, and 1.17 for the 50-, 200,- and 400-mg/d S0597 groups, respectively; all findings were statistically significant. None of the exploratory pairwise comparisons between S0597 dose groups reached significance (Table 4). The greater improvement from baseline in TNSS at day 7 was statistically significant for the 200-mg/d S0597 group (least-squares mean difference from placebo, 1.25; 95% confidence interval [CI], 0.32e2.18; P ¼ .009). Similar results were seen for the per-protocol analysis set. For each of the constituent components of the TNSS (rhinorrhea, nasal congestion, sneezing, nasal itching), numerically greater mean improvement from baseline to day 14 was observed in each of the S0597 groups compared with placebo. Notably, the greater effect of active treatment on rhinorrhea score was statistically significant for all 3 S0597 dose groups at day 14. The 200-mg S0597 group had the most consistent response, with statistically significant improvements in all the TNSS subscales compared with the placebo group at days 7 and 14. Table 5 gives the data for changes to day 14. Exploratory End Points The 200- and 400-mg/d S0597 groups had statistically significant improvement from baseline to day 14 in the exploratory efficacy end point of change in PNIF compared with placebo. Least-squares
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Table 3 Demographic Characteristics of the Participants at Screening (Safety Analysis Set) Characteristic
Placebo (n ¼ 56)
Total (N ¼ 222)
S0597 50 mg/d (n ¼ 55)
Age, mean (SD), y Sex, No. (%) Female Male Race, No. (%) White Asian Other Ethnicity, No. (%) Hispanic Non-Hispanic Height, mean (SD), cma Weight, mean (SD), kgb Body mass index, mean (SD)b,c
200 mg/d (n ¼ 56)
400 mg/d (n ¼ 55)
39 (10.8)
39 (9.5)
39 (10.9)
38 (10.6)
39 (10.4)
41 (73.2) 15 (26.8)
29 (52.7) 26 (47.3)
36 (64.3) 20 (35.7)
30 (54.5) 25 (45.5)
136 (61.3) 86 (38.7)
54 (96.4) 1 (1.8) 1 (1.8)
51 (92.7) 1 (1.8) 3 (5.5)
55 (98.2) 1 (1.8) 0
55 (100) 0 0
215 (96.8) 3 (1.4) 4 (1.8)
1 55 169 81 29
(1.8) (98.2) (8.0) (18.2) (6.6)
55 170 87 30
0 (100) (9.7) (22.4) (7.7)
56 169 88 30
0 (100) (8.6) (19.4) (7.2)
55 171 90 31
0 (100) (8.2) (18.9) (6.8)
1 221 170 87 30
(0.5) (99.5) (8.6) (19.9) (7.1)
Data are missing for 1 participant in the 50-mg/d S0597 group. Data are missing for 1 participant in the placebo group and 1 in the 50-mg/d group. c Body mass index was calculated as the weight in kilograms divided by the square of height in meters. a
b
placebo group, 3 with 50 mg/d of S0597, 2 with 200 mg/d of S0597, and 1 with 400 mg/d of S0597. The most common AE was decrease in blood cortisol, which occurred in 2 participants (3.6%) in the placebo group and in 3, 4, and 4 participants in the 50-, 200-, and 400-mg/d S0597 groups, respectively (Table 6). The investigator considered the AEs to be unrelated or unlikely to be related to the study medication in 40 of 222 participants (18%). Of the 23 of 222 participants (10.4%) with AEs reported as possibly related to study drug, 7 of 55 (12.7%) were in the 400-mg/d S0597 group, 5 of 56 (8.9%) in the 200-mg/d S0597 group, 6 of 55 (10.9%) in the 50-mg/d S0597 group, and 5 of 56 (8.9%) in the placebo group, suggesting no apparent dose-response relationship. The most common drug-related AE was decrease in blood cortisol (incidences as reported above). No treatment-related findings were observed in vital signs, lung function, or physical examination.
mean differences from placebo in change from baseline were 0.59 L/min (95% CI, 9.27 to 10.45 L/min), 11.9 L/min (95% CI, 21.7 to 1.99 L/min), and 12.2 L/min (95% CI, 22.2 to 2.27 L/min) for the 50-, 200-, and 400-mg/d S0597 treatment groups. Numerically greater mean improvement from baseline to day 14 was observed for all 3 S0597 dose groups compared with placebo in the exploratory end points of TRSS, TOSS, and PEFR; however, only the differences for the 200-mg group in TRSS at day 14 and the 50mg group in PEFR at day 7 and day 14 were statistically significant. Safety S0597 was well tolerated at all doses studied. No deaths or other serious AEs were reported during the study. No participants prematurely discontinued use of the study drug because of an AE. In total, 58 of the 222 participants (26.1%) had at least 1 AE reported during the study. This constituted 74 AEs. An overall test for a difference in the proportion of individuals who experienced an AE between treatment groups was not statistically significant (c2 test, P ¼ .501). In addition, pairwise tests for differences in the proportion of individuals who experienced an AE between treatment groups had P > .13; thus, no doseeresponse relationship was observed. The AEs were mild in 34 participants, moderate in 21, and severe in 9 (participants could be counted in >1 category but only once per category). The severe events were distributed as 3 in the
Discussion This randomized, double-blind, parallel-group, single-center study assessed the dose-related efficacy and safety of 3 doses of S0597, a novel INS, in participants with SAR who were challenged with ragweed pollen in an EEU. All participants reported nasal symptoms of SAR after pollen challenge, and all 3 doses of S0597 (50, 200, and 400 mg/d) produced a statistically significant reduction in nasal symptoms (TNSS) from baseline compared with
Table 4 TNSS Change From Baseline to Day 14 (Intent-to-Treat Population) TNSS
Baseline TNSS, mean (SD) Change from baseline to day 14, LS mean (SE) Difference from placebo, LS mean (95% CI) P value Differences between S0597 dose groups, P value vs 50 mg/d vs 200 mg/d
Placebo (n ¼ 56)
8.87 (1.878) 2.83 (0.381) NA
S0597 50 mg/d (n ¼ 55)
200 mg/d (n ¼ 56)
400 mg/d (n ¼ 55)
9.41 (1.695) 4.01 (0.378)
9.43 (1.657) 4.67 (0.378)
9.39 (1.538) 4.00 (0.385)
1.18 (0.12e2.24)
1.84 (0.78e2.90)
1.17 (0.10e2.25)
NA
.03
<.001
.03
NA NA
NA NA
.22 NA
.99 .22
Abbreviations: CI, confidence interval; LS, least squares; NA, not applicable; TNSS, total nasal symptom score.
A.K. Ellis et al. / Ann Allergy Asthma Immunol 117 (2016) 310e317
Figure 2. Total nasal symptom score (TNSS) over time (intent-to-treat population). EEU indicates environmental exposure unit.
placebo on day 14. The mean improvement in each of the constituent items of the TNSS (rhinorrhea, nasal congestion, sneezing, nasal itching) from baseline to day 14 was also greater in each of the S0597 groups compared with placebo. There was no evidence that the efficacy response consistently increased with increased dose. The 200-mg/d S0597 group had the most consistent response, with statistically significant improvements in all the nasal symptoms compared with placebo on days 7 and 14. The difference from placebo for change in the rhinorrhea score was statistically significant with all 3 doses of S0597 on day 14. In addition to these symptom scores, there was a statistically significant improvement in measurements of PNIF. One of the objectives of this study was to identify the lowest effective dose of S0597. The first CACF study had 200-, 400-, and 800-mg/d doses, all of which were effective and demonstrated dose response.9 In this study, a dose response on the primary end point (TNSS) was not seen with the selected doses, which may be attributable to a response plateau at the lowest dose of 50 mg/d. However, 200 mg/d led to significant change on all primary and secondary end points and thus would likely be the minimally effective dose. The mean (SD) pollen concentration of 3,500 (500) grains/m3 used in the EEU in the present study has been shown (for grass, birch, and ragweed pollen) to trigger a symptom burden suitable
315
for studying the effects of the disease and its improvement with treatment. In addition, the priming phase awakens the allergic responsiveness but also equalizes the responsiveness before randomization to the study treatments. These factors support the applicability of findings from the EEU to the real-life experience of individuals with symptoms of SAR.12,17e20 In keeping with previous studies,9,21,22 the current study excluded patients who had been receiving escalating doses of allergen specific immunotherapy in the 2 years before screening. One participant in this study received a maintenance dose of immunotherapy that was a mix that included ragweed. Our study was conducted outside all local pollen seasons. As per the exclusion criteria, participants were excluded if they had signs or symptoms of active perennial AR of significant intensity to be judged by the investigator to potentially interfere with the study outcomes. Choice of evening dose was attributable to operational issues at the EEU facility. Participants would check in between 5 and 6 PM, then undergo prechallenge testing, followed by EEU challenge and assessments at 6 time points during the next 3 hours. They would then receive the study medication and leave the study site. In the phase 1 study at the highest intranasal dose of 3,200 mg/d, there was no significant change in serum cortisol levels.8 Therefore, the drug was assumed safe at doses selected for administration irrespective of time of day or night. Although we recognize that dosing in the evening is not standard for nasal corticosteroid studies, it was believed by the team that dosing immediately after baseline challenge while under the direct supervision of the investigator to optimize adherence and ensure proper inhalation technique was the ideal approach and would limit the total number of required study visits, optimizing recruitment considerations. We then carefully weighed the pros and cons of having participants continue to dose in the evening vs switching to dosing the following morning and decided it was best to maintain consistent dosing times through the entire study rather than have dose 2 occur potentially 11 hours after dose 1. As with other new INS therapies, S0597 was well tolerated at the doses tested. The most common AE in each of the treatment groups, including placebo, was a decrease in blood cortisol levels; the incidence appeared to be somewhat higher among S0597-treated participants compared with those who received placebo, but the event rates were low (2 participants in the placebo group compared with 3 or 4 in each of the S0597 groups). Although the highest-dose group (400 mg/d) had the greatest total number of AEs, the incidence of individual AEs other than decrease in cortisol was low in all groups, and there was no clear evidence for a dose-response relationship from 0 to 200 mg/d of S0597. No dose-response relationship was observed among the treatment groups for the
Table 5 TNSS Subscales Change From Baseline to Day 14 (Intent-to-Treat Population) TNSS subscale
Baseline rhinorrhea score, mean (SD) Difference from placebo in change from baseline, LS mean (95% CI) P value Baseline nasal congestion score, mean (SD) Difference from placebo in change from baseline, LS mean (95% CI) P value Baseline sneezing score, mean (SD) Difference from placebo in change from baseline, LS mean (95% CI) P value Baseline nasal itching score, mean (SD) Difference from placebo in change from baseline, LS mean (95% CI) P value
Placebo (n ¼ 56)
2.33 NA NA 2.51 NA NA 1.68 NA NA 2.35 NA NA
(0.535)
(0.454)
(0.888)
(0.537)
S0597 50 mg/d (n ¼ 55)
200 mg/d (n ¼ 56)
400 mg/d (n ¼ 55)
2.51 0.42 .008 2.57 0.27 .07 1.88 0.31 .03 2.45 0.16 .32
2.46 (0.471) 0.50 (0.19e0.81) .002 2.46 (0.509) 0.43 (0.14e0.73) .004 1.98 (0.747) 0.51 (0.23e0.80) <.001 2.53 (0.373) 0.33 (0.02e0.64) .04
2.51 0.36 .02 2.50 0.25 .10 1.92 0.29 .05 2.46 0.24 .13
(0.491) (0.11e0.73) (0.386) (0.02 to 0.57) (0.891) (0.02e0.59) (0.511) (0.15 to 0.46)
Abbreviations: CI, confidence interval; LS, least squares; NA, not applicable; TNSS, total nasal symptom score.
(0.460) (0.05e0.67) (0.422) (0.05 to 0.55) (0.812) (0.00 to 0.57) (0.432) (0.07 to 0.55)
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Table 6 Summary of AEs (Safety Analysis Set) AE
Participants with any AE, No. (%) Total No. of AEs Participants with AEs by intensity,a No. (%) Mild Moderate Severe AEs reported in >1 participant,b No. (%) Blood cortisol decreased Headache Sinus headache Oropharyngeal pain Epistaxis Throat irritation Cough Dry throat Nasal congestion Productive cough Myalgia Back pain Urinary tract infection
Placebo (n ¼ 56)
S0597 50 mg/d (n ¼ 55)
200 mg/d (n ¼ 56)
400 mg/d (n ¼ 55)
15 (26.8)
11 (20.0)
14 (25.0)
18 (32.7)
20
13
17
24
8 (14.3) 6 (10.7) 3 (5.4)
5 (9.1) 3 (5.5) 3 (5.5)
9 (16.1) 5 (8.9) 2 (3.6)
2 (3.6) 1 (1.8) 0 1 (1.8) 1 (1.8) 0 1 (1.8) 1 (1.8) 1 (1.8) 1 (1.8) 0 1 (1.8) 0
3 (5.5) 1 (1.8) 1 (1.8) 0 1 (1.8) 0 0 0 0 0 1 (1.8) 0 0
4 (7.1) 2 (3.6) 0 0 0 0 0 0 0 1 (1.8) 1 (1.8) 1 (1.8) 1 (1.8)
12 (21.8) 7 (12.7) 1 (1.8)
4 2 1 3 1 2 1 1 1
(7.3) (3.6) (1.8) (5.5) (1.8) (3.6) (1.8) (1.8) (1.8) 0 1 (1.8) 0 1 (1.8)
Abbreviation: AE, adverse event. a Participants can be counted in more than 1 category but only once per category (in the most severe category if they had multiple AEs of different intensities). b Number of participants with each AE.
incidence of AEs considered severe or for those considered possibly related to study drug. Because cortisol levels fluctuate diurnally, 1 study included assessment of 24-hour cortisol profiles and found a reduction in the area under the concentration time curve for serum cortisol from baseline to day 14 with S0597, fluticasone propionate, and placebo. Although this was statistically significant for 800 and 1,600 mg/d of S0597, it was not significant in the group receiving 3,200 mg/d. Furthermore, the difference between each active treatment group and placebo for change in the area under the concentration time curve of serum cortisol was not statistically significant, leading to the conclusion that it was unlikely to represent a clinically significant suppression of the HPA axis.8 However, tests for serum cortisol levels have a limited role in determining the HPA axis function.23 S0597 has a low binding affinity to other sex steroid receptors and aldosterone and in preclinical models had local antiinflammatory activity and a low potential for systemic AEs.8 Overall, the safety profile of S0597 appears to compare favorably with that of other INS therapies. In conclusion, this study found that all 3 tested doses of S0597 were effective in relief of nasal symptoms of SAR compared with placebo and that S0597 is a novel intranasal corticosteroid that warrants further development. Acknowledgments Medical writing support was provided by Keith Day, PhD, of PAREXEL in compliance with the guidelines of the International Committee of Medical Journal Editors and was funded by Sun Pharma Advanced Research Company Ltd. We acknowledge the efforts of Terry Walker and Daniel Adams for their contribution to the conduct of the study. References [1] Asher MI, Montefort S, Bjorksten B, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry crosssectional surveys. Lancet. 2006;368:733e743.
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