Introduction

Allergic rhinitis(AR) is a mucosal inflammation of the mucous membrane of the nose which is mainly caused  due to allergens to which the person is particularly susceptible to, like pollen, dust, molds, mites, and animal dander etc. (1)AR is a global health problem affecting about 10-30% of adults and up to 40% of children (2)with the prevalence in India ranges about 75% in children and 80% in asthmatic adults.(3)Symptoms of allergic rhinitis ranges from sneezing, itching, nasal congestion, and rhinorrhoea to sometimes ocular symptoms.  In severe cases and recurrent attack of allergic rhinitis, other problems like paranasal sinus pressure and pain or eustachian tube dysfunction may also appear.(4–6)

The patho-physiological approach of allergic rhinitis appears to be complex. A strong genetic component may be associated with the allergic response seen in patients of allergic rhinitis which involves mucosal infiltration and action on plasma cells, mast cells, and eosinophils.

The allergic response has got two phases, i.e. "early" and "late" phase response. Early phase response appears within minutes of exposure with the allergen and symptoms appear as sneezing, itching, and rhinorrhoea. This phase is followed by “late phase response” which according to its name appears late i.e. occurs within 4 to 8 hours after exposure which is characterised by nasal congestion, fatigue, malaise and irritability.(4)                 

Anti-histamines i.e. H1-receptor antagonists, are one of the most commonly prescribed pharmacotherapy for the treatment of AR. (2)The mainstay of treatment includes oral first and second generation H1 receptor antagonists, intranasal corticosteroids, oral and intranasal decongestants, intranasal anti-cholinergic, and leukotriene receptor antagonistslike montelukast. Second generation H1 receptor antagonists are generally recommended for mild to moderate disease as first line therapy due to its less severe anti-cholinergic side effects. Oral decongestants like pseudoephedrine are indicated in combination with oral antihistamines like cetirizine for nasal congestion(6)

Topical preparations of intranasal decongestants should not be used for prolonged period of time and should be limited for less than 10 days as prolonged use may cause tachyphylaxis leading to a condition called as rhinitis medica mentosa, which is a rebound swelling of the nasal mucosal membranes and is called as drug induced rhinitis.(7)

 Mast cell stabilizers are regarded as safe, but are usually not as effective asH1 receptor antagonists and nasal steroids. Anti-cholinergic nasal sprays are used to reduce rhinorrhoea which are not controlled by other medications. The other important drug which is indicated for Allergic rhinitis therapy is the leukotriene-receptor antagonist like montelukast. Montelukast is an orally active, highly selective cysteinyl leukotriene type-1 receptor antagonist of leukotriene D4. (6)It works by blocking the action of leukotriene D4 in the lungs resulting in decreased inflammation and relaxation of smooth muscle.(8).As a result, broncho-constriction is inhibited with decreased airway and blood eosinophils leading to improved control over asthma and allergic rhinitis.

H1 receptor antagonists are considered very effective in reducing pruritus, sneezing and watery rhinorrhoea, and are considered mainstay of therapy for allergic rhinitis. (9)Although, first generation antihistamines are generally more effective in controlling rhinorrhoea as compared with second generation antihistamines but their use has been markedly limited due to greater anti-cholinergic side effects. Due to the longer duration of action, better efficacy, lower incidence of sedation and performance impairment of second generation antihistamines  particularly of bilastine, has made it the anti-allergic of choice.(10)

Second generation antihistamines like bilastine have shown favourable effect against anti-cholinergic side effects and are in general recommended for mild to moderate disease as first-line therapy (4)The combined therapy of leukotriene receptor antagonist with H1 receptor antagonist provides enhancing and complimentary effects, thereby reducing the symptoms effectively.(11)

Therefore, several combination therapy has been available in market for the treatment of allergic rhinitis, of which montelukast and levocetirizine is one of the highly prescribed drug currently available in market because the results have shown that concomitant treatment with levocetirizine and montelukast fixed dose combination is better when compared with monotherapy with levocetirizine on symptoms and quality of life in allergic rhinitis patients(6)and hence is a well established fixed drug combination. Bilastine is a new drug which was approved by DCGI(12) in the year February 2019 in India for symptomatic treatment of allergic rhino-conjunctivitis (seasonal and perennial) and urticaria in adults.(12)Bilastine is a substrate for P-glycoprotein and hence it limits its permeability across the blood–brain barrier (13)and not clinically relevant interactions have been reported to date. Thus, having a favourable side effect profile compared to other 2^nd generation antihistamines. Bilastine is a “piperidine” classes of antihistamines same as loratadine, desloratadine, and fexofenidine. There has been Few In vitro studies which have shown that bilastine has a high specific affinity for the H1-receptor but it has negligible or no effect for 30 other known tested receptors. The affinity for the H1 receptor is 3 and 6 times higher than for cetirizine and fexofenidine, respectively. (14)

Few studies have shown that in case of allergic rhinitis, the decrease in TNSS was more in montelukast-fexofenidine combination group (where fexofenidine belongs to same group as bilastine) than montelukast-levocetirizine group. (11)

The fixed dose combination of bilastine with montelukast has been approved newly by DCGI in march 2020 (18)  and at present there is no head to head study of this group with any other pre-existing anti-allergic drug available in the market, in India.

Aims

1.      To evaluate and compare the efficacy of montelukast/bilastine and montelukast/levocetirizine combination in allergic rhinitis..

2.      To evaluate the direct cost of these two FDCs.

3.       Compare the cost effectiveness between the montelukast/bilastine and montelukast/levocetirizine combination.

Objectives

1.      To evaluate and compare the efficacy of montelukast/bilastine versus montelukast/levocetirizine in relieving symptoms of allergic rhinitis.

2.      To evaluate and compare the safety profile of montelukast/bilastine& montelukast/levocetirizine in patients with allergic rhinitis

3.      To compare the cost-effectiveness of these two FDCs, considering the direct costs of medications and any associated healthcare costs due to adverse effects or inadequate symptom control.

Materials and Method

Ø  Study design: Prospective randomised open label comparative study

Ø  Study Duration: Study will be conducted between July  2024 to December 2024

Ø  Study centre: Study will be conducted indept. of pharmacology in collaboration with dept of  ENT, AIIMS Nagpur

Ø  Inclusion criteria

1.      Patients suffering from allergic rhinitis of either gender, in age group 18-65 yrs.

2.      History of intermittent or persistent allergic rhinitis of any severity with no obvious cause prior to inclusion in study.

3.      Patients with TNSS>=8 not treated with anti-histamines in last 7 days.

4.      Patient willing to give written informed consent

Ø  Exclusion criteria

1.      H/o asthma requiring chronic use of inhaled corticosteroids

2.      Had been unresponsive to anti-histamine in the past

3.      H/o allergy to the study medication or unable to tolerate anti-histamines

4.      Use of study drug in last 1 week prior to baseline

5.      Pregnant and nursing women

6.      Subjects with history of significant haematopoietic, hepatic, renal, cardiovascular, neurological, psychiatric or autoimmune disease

Ø  Calculation of sample size

By considering power of 80%, significance level of 0.05,   standard deviation of 2 and expected mean difference 1.46, the calculated sample size came to be 30 in each group.(11) Considering 10% drop out and non-compliance, the total sample size in each group will be 33.

 Ã˜  Enrolment of the patient

Study will be conducted after getting approval from research cell & institutional ethics committee. Patients attending ENT OPD will be screened by ENT surgeon and principle investigator. Diagnosis of allergic rhinitis will be made on the basis of patient’s chief complaints and past history. Those meeting with the inclusion criteria will be briefed about the study. Total 66 patients will be enrolled in the study who are willing to give written informed consent to participate in the study. Patient information sheet will be given to all prospective participants.

Ø  Randomization:

Patients will be randomized into group A (montelukast + bilastine) or group B (montelukast + levocetirizine) using simple computer generated random number table.

Ø  Study groups:

Patients will be divided into two groups:

Group A:  montelukast + bilastine

Group B: montelukast + levocetirizine 

Ø  Study product:

Tab montelukast 10 mg + bilastine 20 mg (FDC)

Drugs will be purchased by the investigator and distributed to the patients free of cost. There will not be any financial burden on the patients. Drugs will be purchased from the local market and will be of same company and of same batch.

Ø  Treatment details

       Ã˜  Methodology

It will be an open label randomised clinical study in which after initial screening, the data regarding age, gender, height, weight, past medical history, family history, physical examination and clinical examination will be recorded in the case record form as given in annexure. Lab investigations like total leukocyte count (TLC) and differential leukocyte count (DLC), will be carried out in the department of pathology and biochemistry of AIIMS Nagpur. Lab investigations will be carried out at 0 week for screening and at the end of study for assessment of safety of investigational drugs. For investigations, 5 ml of venous blood sample from anti-cubital vein will be withdrawn from each patient taking all aseptic precautions. The study subjects will be given labelled plastic container containing one of the combinations. Patient as well as the investigator is aware about the treatment being given. Drugs will be issued to the patients for the duration of 2 week at a time. Patients will be instructed to take tablet once in a day at night time after meal, orally with a glass full of water.

The patients will be given a symptom diary at visit one (screening visit). A few extra day diaries will be given in case if patient could not report on the scheduled day and patients will be requested to record their symptoms once a week for 4 weeks. The 1st visit on day 1, with the past 7-days anti-allergic medication off, subjects will be educated to record their allergic symptomology according to its severity in the dairy provided to them and baseline scoring will be recorded. Diaries will be given to the patient and they will be asked to document the symptom score on subjective basis once a week.

Patient is required to bring the diary at each 2 weekly follow up visit. Those diaries will be collected from them on their follow-up visitand the new two diaries will be allotted to record next weekly score.

Ø  Clinical assessment and TNS Score:

Clinical assessment of the patients will be done by the principle investigator and the ENT consultant. Patients will be assessed for Total Nasal Symptom Score (TNSS) at each visit by the principal investigator and the ENT surgeon. Symptom severity will be determined by TNS score which consists of sneezing, rhinorrhoea, itching and nasal congestion to be scored on severity grade 0 to 3, such that the maximum possible TNSS will be 15. The symptom score will be compared between baseline and change in score on twice weekly basis while being on the treatment, from those collected diaries. Improvement in the scores by two or more will be considered significant. On final follow-up visit, the TNSS will be compared between the baseline and final score after completion of the treatment.

The TNSS score of the two groups will be finally compared to see the better efficacy in terms of improvement of the score and time taken for such improvement

Ø  Follow-up visits:

Drugs will be issued to the patients for the duration of 2 week at a time. Patients will be given a new supply of drug at the end of 2 weekly visits. Patients will be asked to bring the unused drugs and 2 weekly diaries during follow-up.  The medical compliance of the patients will be determined from the unused tablet number. The returned tablets will be discarded.

Ø  Last follow up visit:

All the patients will be instructed to report to the ENT OPD at the end of 4 weeks. Patients will be assessed for Total Nasal Symptom Score (TNSS) and Laboratory parameters will be repeated and compared with the baseline.

Ø  Concomitant medication restriction

During study period, concomitant treatment with other anti-allergic therapy(anti histamines, corticosteroids) or with any drug capable of depressing the central nervous system like hypnotics or sedatives will be restricted, If needed, those patients will be excluded from study.

Ø  Concomitant medication used other than the Anti-allergics

Patients who are on medication for their other conditions like diabetes and hypertension will be recorded

 Outcome Measures

·     Calculation of TNSS score:

Symptom severity will be determined by Total Nasal Symptom Score (TNSS) which will consist of 5 parameters i.e. sneezing, rhinorrhoea, itching (nose, palate and ear) nasal congestion and eye symptoms (itching, lacrimation and congestion) and will be  scored on a severity scale from 0 to 3, such that maximum possible TNSS will be 15. Improvement in the scores by two or more will be considered significant.(11)

·         Assessment of Cost effectiveness

For cost effectiveness analysis, only direct cost parameters will be taken into consideration. Direct cost parameters will include the cost of medications used. Cost effectiveness ratio of both treatment groups will be calculated based on the following formula:

Cost effectiveness ratio = cost/outcome

Where cost of the treatment is direct health cost of the drug only. For that, cost of each tablet of montelukast/bilastine combination and montelukast/ levocetirizine combination and the cost of total treatment in both the groupswill be considered.

·         Safety assessment

Adverse events will be recorded in CRF and will be analysed and that will be informed immediately to IEC. Any medical aid, arising due to medication will be addressed with no extra cost to the patients.

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