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Original Article

An Open Label, Active Controlled, Multicentric Clinical Trial to Assess the Efficacy and Safety of Fluticasone Furoate Nasal Spray in Adult Indian Patients Suffering from Allergic RhinitisAmit H Kubavat*, Prafulla Pawar*, Ravindra Mittal*, Vikas Sinha**, Umakant B Shah***, Tarun Ojha†, Narendra Khippal‡, Tushar Patel#

*Cadila Healthcare ltd., Zydus Tower, 9th Floor, Satellite Cross-roads, Ahmedabad – 380015, Gujarat; **Professor & Head, Dept. of ENT, M. P. Shah Medical College, Jamanagar; ***Professor & Head, Dept. of ENT, N. H. l. Municipal Medical College and Sheth V. S. General Hospital, Ahmedabad; †Associate Professor, Dept. of ENT, Mahatma Gandhi National Institute of Medical Sciences, Jaipur; ‡Associate Professor, Dept. of Chest & TB, S.M.S. Medical College & Hospital, Jaipur; #Consultant Pulmonologist & Critical Care Specialist, Allergy, Sleep Health, Respiratory & Intensive Care and Interventional Pulmonology Associates, AhmedabadReceived: 24.02.2010; Accepted: 18.03.2010

AbstractBackground: Allergic rhinitis is a common upper respiratory tract inflammation associated with a significant morbidity in all the age groups. Fluticasone furoate is a new potent topical glucocorticoid for the treatment of allergic rhinitis. Objective: To compare efficacy and safety of fluticasone furoate (FF) nasal spray 110 µg/day with fluticasone propionate (FP) nasal spray 200 µg/day for the relief of symptoms of allergic rhinitis in adult Indian patients. Methods: Clinically symptomatic patients (n=220) with allergic rhinitis received treatment with FF or FP for 2 weeks in this comparative, open label, multicentric, clinical trial. Nasal symptoms (nasal congestion, rhinorrhea, nasal itching, and sneezing) and ocular symptoms (itching/burning eyes, tearing/watering eyes, and eye redness) were recorded on a 4-point categoric scale by the patients. The efficacy was assessed by the change in nasal and ocular symptom scores as their subtotals (Total Nasal Symptom Score and Total Ocular Symptom Score) and grand total (Total Symptom Score). Results: FF produced significantly better improvement in Total Symptom Score (-10.4 ± 3.2 vs. -8.9 ± 3.5, p<0.005) and Total Nasal Symptom Score (-7.3 ± 2.2 vs. -6.2 ± 2.6, p<0.005) as compared to FP. Also a significantly larger percentage of patients achieved complete symptomatic relief with FF (45.3% vs. 31.4%, p<0.05). FF was also better tolerated than FP. Conclusion: FF nasal spray is significantly more effective and better tolerated than FP nasal spray for the treatment of allergic rhinitis in adult Indian patients.

Introduction

Allergic rhinitis is a common inflammatory disease condition of upper respiratory tract. The old classification of allergic

rhinitis into “seasonal” or “perennial” is now replaced by a classification based on the duration of symptoms as “persistent” or “intermittent” along with severity of symptoms as “mild” or “moderate-severe” according to ARIA (Allergic Rhinitis & its Impact on Asthma) guidelines, which is currently accepted internationally to guide the medical treatment.1 Its prevalence is about 10-40% among all age-groups in united States and other western countries.2 Prevalence is reported to range from 10-13% in Delhi state of North India.3 Also, symptoms of rhinitis are reported in 75% of children and 80% of asthmatic adults in India, while it still continues to be considered a trivial disease.4 Though, it is not a life-threatening disease, it can significantly

impair patient’s quality of life and productivity.5 In children also, physical, social, psychological well-being and academic performance is adversely affected by the illness.6

Current therapeutic modalities for the management of allergic rhinitis include; H1 receptor antagonists (antihistamines), decongestants, mast-cell stabilizers, leukotriene receptor antagonists, corticosteroids and anti-cholinergic agents in oral or topical nasal formulations. Intranasal corticosteroids (INS) are considered to be a first line therapeutic option for the management of intermittent as well as persistent allergic rhinitis.1

Fluticasone Furoate (FF) is a new topical glucocorticoid with a high relative receptor affinity, selectivity and potency as well as a long duration of anti-inflammatory activity in comparison to other glucocorticoids currently in usage.7,8 It has a low absolute systemic bioavailability after intranasal administration9 and does not affect hypothalamic-pituitary-adrenal (HPA) axis function at recommended doses in children 2 years of age to adults.10,11 It has also been shown not to interfere with growth in pre-pubertal children in a short term study.12 Several placebo controlled clinical trials have shown that FF consistently improves nasal as well ocular symptoms of seasonal/perennial allergic rhinitis at an optimal dose of 110 µg/day.13,14 The efficacy and safety of FF is well established internationally in adults, adolescents and children aged ≥ 2 years.15

The present study was conducted to demonstrate efficacy and

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redness) symptoms at baseline on a 4-point categoric scale: 0 = none/ no symptoms; 1 = mild symptoms, but not affecting any activities during the day/sleep at night; 2 = moderate symptoms affecting at least one activity or disturbing sleep; 3 = severe symptoms affecting >2 daily activities or disturbing sleep all night or most of the night. For inclusion into the study, patients were required to be clinically symptomatic, with a total nasal symptom score (TNSS; the sum of all the 4 individual nasal symptom scores) of 6 or greater and/or a total ocular symptom score (TOSS; the sum of all the 3 individual ocular symptom scores) of 4 or greater. The symptoms assessed as well as the scale used are the same reflective patient reported outcomes used in clinical trials conducted with FF internationally. Patients were given diary cards in which they recorded severity of nasal and ocular symptoms as mentioned above on a daily basis. Symptoms were re-evaluated by the investigator at the end of one and two weeks of treatment.

Patients were allocated to receive either 110 mg Fluticasone furoate once daily administered as 2 sprays (27.5 mg/spray) in each nostril or 200 mg Fluticasone propionate once daily administered as 2 sprays (50 mg/spray) in each nostril for the entire duration of the study i.e., 2 weeks.

Hematological and biochemical investigations like complete haemogram, liver and renal function tests were done at the screening visit and at the end of treatment. Clinical adverse events, if any, were recorded at the end of week 1 and week 2, along with their nature, intensity, action taken, relationship to the study drug and outcome.

All efficacy and safety assessments were carried out on the intent-to-treat population, which comprised all the enrolled patients who received at least 7 days’ treatment. The primary efficacy end point was the change in Total Symptom Score (TSS; the sum of TNSS and TOSS) at the end of study as compared to baseline. Secondary efficacy end points were the change in TNSS, TOSS and individual nasal and ocular symptom scores at the end of study as compared to baseline. Symptom scores are presented as mean ± SD. Statistical analysis was carried out using two-tailed t-test assuming unequal variance and chi-square test.

ResultsPatients

A total of 223 patients were screened in 5 centers, and 220 patients were found to be eligible for enrollment, who participated in this clinical trial in Indian patients – 110 patients each in the Fluticasone furoate (FF) group and the Fluticasone propionate (FP) group. 106 (96.4%) patients in FF group and 105 (95.5%) patients in FP group were eligible for intention to treat efficacy analysis, while 110 (100%) patients in FF Group and 109 (99.1%) patients in FP Group were eligible for safety analysis as mentioned in materials and methods and Fig. 1. Demographic and baseline characteristics of the enrolled patients are shown in Table 1. Patients in both the groups were comparable in demographic characteristics and in severity of symptoms reflected as a similar TSS, TNSS and TOSS.Efficacy analysis

For the primary efficacy endpoint (i.e. change in TSS at the end of study as compared to baseline), reduction in TSS was observed in both the groups; while a statistically significant reduction was noted in FF group (-10.4 ± 3.2) as compared to FP group (-8.9 ± 3.5) at the end of therapy (p < 0.005). The mean TSS reduced from 12.4 ± 3.5 at Day 0 to 2.0 ± 2.2 at Day 14 in FF

safety of FF nasal spray 110 µg/day for the relief of nasal and ocular symptoms of allergic rhinitis in adult Indian patients in comparison with fluticasone propionate nasal spray 200 µg/day.

Materials and MethodsPatients

Patients of either sex aged ≥18 years, and presenting with complaints of allergic rhinitis having nasal and/or ocular symptoms were screened for the study after taking their informed consent.

Patients with severe physical nasal obstruction or injury, nasal ulcers, recent nasal surgery, asthma, rhinitis medicamentosa, acute or chronic sinusitis, glaucoma, cataract, any psychiatric disorder, adrenal insufficiency, bacterial or viral infection within 2 weeks of participation in the study were excluded from the study. Patients with measles, chickenpox, active or quiescent tuberculous infections of the respiratory tract, ocular herpes simplex and candida species infection of the nose were also not included. Patients with known hypersensitivity to fluticasone furoate or fluticasone propionate or any of the components of the medications, continuing history of alcohol and / or drug abuse and those who have participated in another clinical trial in the past 3 months were also excluded from the study. Pregnant and lactating women and persons suffering from significant uncontrolled disease of any body system were also not included in the study.

Concomitant medication with any other antiallergic medications, corticosteroids (systemic or inhaled or intranasal), CyP3A4 inhibitors such as ketoconazole, ritonavir, etc. and use of ocular preparations (including artificial tears, eye wash/irrigation solutions or lubricants) was not permitted during the study period.Procedures

This open label, multicentric, comparative clinical study was approved by the Drugs Controller General of India (DCGI) and institutional/independent ethics committees of each of the participating centre.

To determine symptom severity, patients rated their nasal (nasal congestion, rhinorrhea, nasal itching, and sneezing) and ocular (itching/burning eyes, tearing/watering eyes, and eye

Fig. 1 : Flow diagram of the patients enrolled in the study

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Group, while it decreased from 12.3 ± 3.3 at Day 0 to 3.4 ± 3.3 at Day 14 in FF Group as can be seen from Fig. 2. Patients attaining complete relief from all the nasal and ocular symptoms i.e. a total symptom score of zero during the course of the study were 45.3% in FF Group and 31.4% in FP group (p<0.05).

In the secondary efficacy endpoints of change in TNSS, TOSS and individual nasal and ocular symptom scores at the end of therapy, reductions were observed in both the groups as shown in Table 2. A statistically significant reduction was observed in TNSS in FF group in comparison with FP group (p <0.05), while the reductions did not reach statistical significance for TOSS. In FF group, 46.2% and 53.3% patients achieved complete relief

from all the nasal and ocular symptoms respectively, while it was so in 32.4% and 44.6% patients in FP group at the end of study. The percentage of patients achieving a complete relief from individual nasal and ocular symptoms of allergic rhinitis is shown in Table 3.

At the end of the study, all the investigators gave their overall assessment of efficacy to FF and FP on a 4-point rating scale as excellent, good, fair or poor. This comparative assessment according to global impression of symptomatic improvement is shown in Fig. 3.Safety analysis

Safety to FF and FP was assessed by the estimation of

Table 1: Demographics and baseline characteristics of the patients

Characteristics FF(n=110)

FP(n=110)

Age (y)Mean ± SD 35.2 ± 11.8 36.4 ± 11.9Minimum-maximum 18-75 18-69Sex, n (%)Female 32 (70.9%) 46 (58.2%)Male 78 (29.1%) 64 (41.8%)Height (cm)Mean ± SD 164.0 ± 7.6 162.2 ± 8.1Minimum-maximum 144-180 145-178Weight (kg)Mean ± SD 64.5 ± 15.1 64.2 ± 13.9Minimum-maximum 34-105 39-103Duration of illness (y)Mean ± SD 6.7 ± 5.6 6.1 ± 5.9

Minimum-maximum 3 months - 27 years 4 months -30 years

Baseline symptom scores, mean ± SDNasal congestion 2.4 ± 0.7 2.3 ± 0.8Rhinorrhoea 2.2 ± 0.9 2.2 ± 0.8Nasal itching 1.9 ± 0.9 1.7 ± 0.9Sneezing 2.2 ± 0.9 2.3 ± 0.8Itching/burning eyes 1.5 ± 1.0 1.6 ± 1.0Tearing/watering eyes 1.3 ± 1.0 1.3 ± 0.9Eye redness 0.9 ± 0.9 0.9 ± 0.9TNSS 8.7 ± 1.8 8.5 ± 1.6TOSS 3.7 ± 2.3 3.8 ± 2.2TSS 12.4 ± 3.5 12.3 ± 3.3

Fig. 2 : Reduction in the mean TSS in both the study groups

Table 2: Reduction in TNSS, TOSS and individual nasal & ocular symptom scores in both the study groups

Symptom Scores(Reductions; Mean ± SD)

FF(n=106)

FP(n=105) p-value

Nasal congestion - 1.9 ± 0.8 - 1.6 ± 1.0 < 0.05Rhinorrhoea - 1.8 ± 0.9 - 1.7 ± 1.0 N.S.Nasal itching - 1.7 ± 0.9 - 1.2 ± 0.8 < 0.001Sneezing - 2.0 ± 1.0 - 1.8 ± 1.1 N.S.TNSS - 7.3 ± 2.2 - 6.2 ± 2.6 < 0.005Itching/burning eyes - 1.2 ± 0.9 - 1.1 ± 0.9 N.S.Tearing/watering eyes - 1.2 ± 0.9 - 0.9 ± 0.8 < 0.05Eye redness - 0.8 ± 0.9 - 0.7 ± 0.8 N.S.TOSS - 3.1 ± 2.0 - 2.7 ± 1.8 N.S.

Table 3: The percentage of patients achieving a complete relief from allergic rhinitis symptoms at the end of study in

both the groups

Parameter FF(n=106)

FP(n=105)

Difference(FF-FP)

Nasal congestion 54.7% 45.1% 9.6%Rhinorrhoea 67.7% 56.3% 11.4%Nasal itching 75.3% 61.0% 14.3%Sneezing 76.2% 60.6% 15.6%Itching/burning eyes 62.8% 51.8% 11.0%Tearing/watering eyes 78.8% 57.7% 21.1%Eye redness 79.0% 66.2% 12.8%TNSS 46.2% 32.4% 13.8%TOSS 53.3% 44.6% 8.7%TSS 45.3% 31.4% 13.9%

Fig. 3 : Investigators’ opinion on global assessment of efficacy

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laboratory parameters and adverse events’ recording as mentioned in materials and methods.

None of the patients discontinued the study medication due to adverse event in either FF or FP group during the study. Further, 5 adverse events were reported by 5 (4.5%) patients in FF group and 13 adverse events were reported by 13 (11.9%) patients in FP group during the course of the study. The complete list of these adverse events is given in Table 4.

All the 5 adverse events reported with FF were of “mild” intensity and 4 of them were considered to be related to FF use by the investigators. Out of 13 adverse events reported with FP, 4 and 9 events were of “moderate” and “mild” intensity respectively and were considered to be related to its usage. All the reported adverse events resolved completely, either spontaneously or by symptomatic treatment during the course of study. No serious adverse event was reported by any of the patients enrolled in either of the study group. Further, there was no significant alteration in any of the laboratory parameters as assessed at baseline and at the end of therapy with the study drug in any of the patients in this study.

DiscussionThe present study was carried out to assess the comparative

efficacy and safety of 2 intranasal corticosteroids (INS), Fluticasone Furoate and Fluticasone Propionate, for the treatment of allergic rhinitis in adult Indian patients. The results indicate that for the relief of both nasal and ocular symptoms of allergic rhinitis, FF is better as compared to FP, though a statistically significant difference was not found for each of the symptoms assessed. Complete symptomatic relief was reported in a higher percentage of patients treated with FP in comparison to FF treated patients. In terms of safety also, FF was shown to be better tolerated as compared to FP with a lower incidence and lesser severity of adverse events reported during the treatment.

An earlier study has demonstrated non-inferiority of FF as compared to FP in patients with Japanese cedar pollinosis.16 This study did show better resolution of symptoms of sneezing, rhinorrhoea and nasal congestion (3TNSS) with FF as compared to FP (-1.23 ± 0.140 vs -1.06 ± 0.142) but a direct statistical comparison was not made due to a non-inferiority trial design. A faster onset of action of FF from the 1st day of treatment was demonstrated in this study as compared to FP. During our study also, it was noted that FF caused more reduction in total nasal as well as ocular symptom scores from Day 3 of assessment which was persistently better than FP during the entire course of study.

Another study has compared patient preferences with regards to sensory attributes of FF and FP nasal sprays.17 It was demonstrated that after single administration in adult patients

with allergic rhinitis, FF have a preferable sensory attributes like odour, aftertaste, drip down the throat, nose run-off and overall than FP. Though this study demonstrated that FF can lead to a better patient compliance, it did not directly compare the efficacy and tolerability of both INS. Our study also showed a better patient tolerability of FF with a lesser incidence of drug related adverse events reported as compared to FP, which is consistent with the findings of the above study.

Andrews CP et al conducted two comparative studies of FF with oral fexofenadine and placebo and reported that FF nasal spray is significantly more effective for the relief of night time nasal and ocular symptoms relative to both the comparators over a treatment period of 2 weeks.18 Further, there are several placebo controlled studies conducted during the clinical development of FF and also thereafter, which have consistently showed therapeutic efficacy as well safety of FF nasal spray in a patient population ranging from children 2 years of age to adults, for which it has been approved internationally.8,13-15,19,20

LimitationsThis study demonstrates the efficacy and safety of FF in

Indian patients. The open label design of the study is likely to be affected by the investigator bias, which is inherent to all open label studies. However, trial design incorporating use of an active comparator that is current standard of care and patient reported outcomes as key primary and secondary efficacy variables ensure validity of the results of study.Conclusion

The results of this open label, multicentric, active controlled clinical trial demonstrate that fluticasone furoate nasal spray, 110 µg/day is significantly more effective for the relief of nasal symptoms in adult patients suffering from allergic rhinitis when compared with fluticasone propionate nasal spray, 200 µg/day. Though, relief from ocular symptoms is better, the difference is not statistically significant. Moreover, fluticasone furoate also has a better tolerability profile and therefore is likely to enhance patient compliance to treatment. Based on these findings fluticasone furoate nasal spray can present a first-line treatment option for the treatment of allergic rhinitis in Indian patients.

AcknowledgementCadila Healthcare ltd., Zydus Tower, 9th Floor, Satellite

Cross-roads, Ahmedabad – 380015, Gujarat.

References1. Brunton SA, Fromer lM. Treatment options for the management of

perennial allergic rhinitis, with a focus on intranasal corticosteroids. South Med J 2007;100:701-8.

2. Dykewicz MS, Fineman S. Executive Summary of Joint Task Force Practice Parameters on Diagnosis and Management of Rhinitis. Ann Allergy Asthma Immunol 1998;81:463-8.

3. Gaur SN, Gupta K, Rajpal S, Singh AB, Rohtagi A. Prevalence of bronchial asthma and allergic rhinitis among urban and rural adult population of Delhi. Indian J Allergy Asthma Immunol 2006;20:90-97.

4. Shah A, Pawankar R. Allergic rhinitis and co-morbid asthma: perspective from India - ARIA Asia-Pacific Workshop report. Asian Pac J Allergy Immunol 2009;27:71-7.

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7. Salter M, Biggadike K, Matthews JL, West MR, Haase MV, Farrow SN, et al. Pharmacological properties of the enhanced-affinity

Table 4 : List of adverse events reported in both the study groups

Sr.No.

Nature of adverse event

FF Group (n=110)

FP Group (n=109)

No. ofEvents Incidence No. of

Events Incidence

1. Nasal irritation - - 7 6.4%2. Headache 3 2.7% 3 2.7%3. Cough 2 1.8% 2 1.8%4. Sneezing - - 1 0.9%5. Fever - - 1 0.9%6. Giddiness - - 1 0.9%

TOTAl 5 4.5% 13 11.9%

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glucocorticoid fluticasone furoate in vitro and in an in vivo model of respiratory inflammatory disease. Am J Physiol Lung Cell Mol Physiol 2007;293:l660-l667.

8. Goyal N, Hochhaus G. Fluticasone furoate nasal spray in allergic rhinitis. Drugs Today (Barc) 2008;44:251-60.

9. Allen A, Down G, Newland A, Reynard K, Rousell V, Salmon E, et al. Absolute bioavailability of intranasal fluticasone furoate in healthy subjects. Clin Ther 2007;29:1415-20.

10. Patel D, Ratner P, Clements D, Wu W, Faris M, Philpot E. lack of effect on adult and adolescent hypothalamic-pituitary-adrenal axis function with use of fluticasone furoate nasal spray. Ann Allergy Asthma Immunol 2008;100:490-6.

11. Tripathy I, levy A, Ratner P, Clements D, Wu W, Philpot E. HPA axis safety of fluticasone furoate nasal spray once daily in children with perennial allergic rhinitis. Pediatr Allergy Immunol 2009;20:287-94.

12. Gradman J, Caldwell MF, Wolthers OD. A 2-week, crossover study to investigate the effect of fluticasone furoate nasal spray on short-term growth in children with allergic rhinitis. Clin Ther 2007;29:1738-47.

13. Giavina-Bianchi P, Agondi R, Stelmach R, Cukier A, Kalil J. Fluticasone furoate nasal spray in the treatment of allergic rhinitis. Ther Clin Risk Manag 2008;4:465-72.

14. Sorbera lA, Serradell N, Bolos J. Fluticasone Furoate. Drugs of the Future 2007;37:12-16.

15. McCormack PL, Scott LJ. Fluticasone furoate: intranasal use in allergic rhinitis. Drugs 2007;67:1905-15.

16. Okubo K, Nakashima M, Miyake N, Komatsubara M, Okuda M. Comparison of fluticasone furoate and fluticasone propionate for the treatment of Japanese cedar pollinosis. Allergy Asthma Proc 2009;30:84-94.

17. Meltzer EO, Stahlman JE, Leflein J, Meltzer S, Lim J, Dalal AA, et al. Preferences of adult patients with allergic rhinitis for the sensory attributes of fluticasone furoate versus fluticasone propionate nasal sprays: a randomized, multicenter, double-blind, single-dose, crossover study. Clin Ther 2008;30:271-9.

18. Andrews CP, Martin BG, Jacobs Rl, Mohar DE, Diaz JD, Amar NJ, et al. Fluticasone furoate nasal spray is more effective than fexofenadine for nighttime symptoms of seasonal allergy. Allergy Asthma Proc 2009;30:128-38.

19. Nathan RA, Berger W, yang W, Cheema A, Silvey M, Wu W, et al. Effect of once-daily fluticasone furoate nasal spray on nasal symptoms in adults and adolescents with perennial allergic rhinitis. Ann Allergy Asthma Immunol 2008;100:497-505.

20. Kaiser HB, Naclerio RM, Given J, Toler TN, Ellsworth A, Philpot EE. Fluticasone furoate nasal spray: a single treatment option for the symptoms of seasonal allergic rhinitis. J Allergy Clin Immunol 2007;119:1430-7.

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