International Journal of Otorhinolaryngology and Head and Neck Surgery | January 2021 | Vol 7 | Issue 1 Page 83
International Journal of Otorhinolaryngology and Head and Neck Surgery
Panchal S et al. Int J Otorhinolaryngol Head Neck Surg. 2021 Jan;7(1):83-90
http://www.ijorl.com
pISSN 2454-5929 | eISSN 2454-5937
Original Research Article
Evaluation of efficacy and safety of montelukast and levocetirizine FDC
tablet compared to montelukast and levocetirizine tablet in patients
with seasonal allergic rhinitis: a randomized, double blind, multicentre,
phase III trial
Sagar Panchal*, Saiprasad Patil, Hanmant Barkate
INTRODUCTION
Allergic rhinitis is a common inflammatory condition of
the upper respiratory tract and is characterized by one or
more symptoms including sneezing, itching, nasal
congestion, and rhinorrhoea. The symptoms of allergic
rhinitis result from a complex allergen-driven mucosal
inflammation caused by interplay between resident and
infiltrating inflammatory cells and a number of
vasoactive and pro-inflammatory mediators. Seasonal
allergic rhinitis (SAR) is one type of allergic rhinitis and
is commonly referred to as ‘hay fever’. Seasonal allergic
rhinitis is caused by an IgE-mediated reaction to seasonal
aeroallergens and is fairly easy to identify because of the
rapid and reproducible onset and offset of symptoms in
association with pollen exposure. SAR can result in hyper
responsiveness to allergens such as cigarette smoke, once
pollen season is over.1 Allergic rhinitis affects between
10% and 30% of all adults and as many as 40% of
children1. Allergic rhinitis is an extremely common
ABSTRACT
Background: To evaluate efficacy, safety and tolerability of Montelukast 10 mg+levocetirizine 5 mg FDC compared
to either montelukast 10 mg or levocetirizine 5 mg given alone in seasonal allergic rhinitis (SAR) patients.
Methods: Phase III, multicentre, randomized, double blind, parallel group, active controlled study was conducted in
279 SAR patients at 16 sites across India. Efficacy was assessed using daytime nasal symptoms score (Primary
efficacy outcome), night-time symptoms score, daytime eye symptom score, patient's global evaluation, physician's
global evaluation, rhino-conjunctivitis quality-of-life score.
Results: At end of treatment there was statistically significant evidence from the per protocol analysis that patients on
FDC had a greater improvement in change from baseline in daytime nasal symptoms score than patients who received
Montelukast (p=0.0266) or Levocetirizine (p=0.0409). These results were consistent with the Intent to treat analysis.
Analysis of the secondary efficacy endpoints provided numerically greater improvement in the nighttime symptoms
score, daytime eye symptoms score, and rhinoconjunctivitis quality-of-life scores in the FDC group as compared to
the Montelukast group or Levocetirizine group. The FDC of Montelukast and Levocetirizine was found to be safe and
generally well tolerated. The majority of adverse events were mild in severity, resolved without treatment and were
unrelated to study medication.
Conclusions: Fixed dose combination of Montelukast and Levocetirizine was safe, generally well tolerated and
superior on efficacy compared to Montelukast or Levocetirizine in patients of seasonal allergic rhinitis.
Keywords: Allergy, Histamine, Leukotriene, LTRA, SGAH
Global Medical Affairs, Glenmark Pharmaceuticals Limited, Mumbai, Maharashtra, India
Received: 27 October 2020
Accepted: 04 December 2020
*Correspondence:
Dr. Sagar Panchal,
E-mail: Sagar.panchal@glenmarkpharma.com
Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access article distributed under
the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial
use, distribution, and reproduction in any medium, provided the original work is properly cited.
DOI: https://dx.doi.org/10.18203/issn.2454-5929.ijohns20205625
Panchal S et al. Int J Otorhinolaryngol Head Neck Surg. 2021 Jan;7(1):83-90
International Journal of Otorhinolaryngology and Head and Neck Surgery | January 2021 | Vol 7 | Issue 1 Page 84
health problem affecting 10-25% of the world’s
population.2 A survey carried out in India shows that 20-
30% of the population suffer from allergic rhinitis.
Prevalence of allergic rhinitis is reported to range from
10-13% in Delhi, India. In India, symptoms of rhinitis
were reported in 75% of children and 80% of asthmatic
adults.3-6
Pharmacotherapy for allergic rhinitis includes oral and
intranasal antihistamines, intranasal corticosteroids, oral
and intranasal decongestants, intranasal anticholinergic,
intranasal cromolyn and leukotriene receptor
antagonists.1,7 Antihistamines are effective in reducing
pruritus, sneezing and watery rhinorrhea and are a
mainstay therapy for allergic rhinitis. Most newer second
generation antihistamines have minimal or no sedating
properties and less anticholinergic effects and are
therefore preferable to first generation antihistamines in
most cases.2 Second generation antihistamines are in
general recommended for mild to moderate disease as
first line therapy.7,8 Levocetirizine is a third-generation
antihistamine that has been approved for the relief of
symptoms of seasonal allergic rhinitis (SAR) and
perennial allergic rhinitis (PAR) in adults and children
aged >6 years.9 Leukotrienes plays an important role in
the pathogenesis of AR especially in the late phase of
allergic response. Montelukast- a leukotriene antagonist
competitively and reversibly inhibits cysteinyl
leukotrienes (CysLTs), specifically leukotrienes D4
(LTD4) that provides significant relief from symptoms of
seasonal allergic rhinitis.10
There are only limited studies available for the effect of
combination therapy of Montelukast and Levocetirizine.
Hence this study was planned to assess the efficacy and
safety of FDC of Montelukast with Levocetirizine,
developed by Glenmark Pharmaceuticals Limited as a
treatment for seasonal allergic rhinitis.
METHODS
Study was planned to evaluate the primary objective of
efficacy of FDC of Montelukast 10mg and Levocetirizine
5mg tablet compared to Montelukast 10mg tablet and
Levocetirizine 5mg tablet in patients with SAR. While
secondary objective was to evaluate the safety and
tolerability of a FDC of Montelukast 10mg and
Levocetirizine 5mg tablet compared to Montelukast
10mg tablet and Levocetirizine 5mg tablet in patients
with SAR.
Patients were men or women of age >18 years and <60
years, documented clinical history of seasonal allergic
rhinitis (for at least 2 years) with exacerbations during the
study season associated with regular daytime nasal
symptoms of at least mild- to-moderate severity for the
following symptoms of nasal congestion, nasal pruritus
and rhinorrhea during the screening period and/or
exhibiting a positive skin prick test (wheal diameter at
least 3 mm greater than saline control) to one of the
regional allergens active during the study season, Willing
to give their written informed consent. Exclusion criteria
includes pregnant/lactating women, known
hypersensitivity to any of the components of FDC,
History of anaphylaxis to skin testing, alcohol/ drug
dependence, perennial rhinitis with little or no seasonal
exacerbations, non-allergic rhinitis, active pulmonary
disorder, on current immune-therapy, etc.
Study design
This Phase III, multicentre, randomized, double blind,
parallel group, active controlled study was conducted at
16 sites across India. Study was conducted in accordance
with International conference on harmonization –good
clinical practice (ICH-GCP) guidelines and all applicable
local regulatory guidelines after obtaining approval from
institutional ethics Committee (IEC). Total study duration
was 16 days which included 14 days of active treatment
phase and 2 days of window period for the study visit.
Patients had 5 visits during the study period (day -1-
screening, day 1, day 3, day 7, after day 14). All Vital
signs and clinical parameters were measured at all the 5
study visits (Figure 1) (Figure 2).
Efficacy assessments
Primary efficacy parameter- daytime nasal symptoms
score. The day time nasal symptoms (nasal congestion,
rhinorrhea, nasal pruritus and sneezing) were rated by the
patient in the patient diary card each night before bed
(immediately before study drug administration) on the
screening visit and the blinded treatment period of 14
days. The day time nasal symptoms were rated on a 4-
point scale as follows:
• Score 0; Grade none: symptoms not noticeable
• Score 1; Grade mild: symptoms noticeable but not
bothersome
• Score 2; Grade moderate: symptoms noticeable and
bothersome some of the time
• Score 3; Grade severe; symptoms bothersome most
of the time and/or very bothersome some of the
time.
Secondary efficacy outcomes include night-time
symptoms score, Daytime eye symptom score, Patient's
global evaluation of AR, Physician's global evaluation of
AR, rhino-conjunctivitis quality-of-life score.
Safety assessment: All AEs and Serious Adverse Events
(SAEs) were recorded from the time of signing the
informed consent till the end of study.
Sample size: sample size of 279 (93 per arm) was
selected to detect a significant difference in the daytime
nasal symptom score and assuming 20 % drop out rate.
Statistical analysis Efficacy endpoints were analysed
using both Intent to treat (ITT) and per-protocol
Panchal S et al. Int J Otorhinolaryngol Head Neck Surg. 2021 Jan;7(1):83-90
International Journal of Otorhinolaryngology and Head and Neck Surgery | January 2021 | Vol 7 | Issue 1 Page 85
population (PP). However, PP population was the
primary analysis. The least square mean change in
efficacy scores from baseline to end of treatment was
summarized and compared between treatment groups
using analysis of covariance (ANCOVA). The 95%
confidence intervals for the difference in mean change in
symptoms score or RQOL score was constructed for the
treatment groups. P-value of ≤0.05 was considered
statistically significant. The change within each treatment
arm was compared using paired t-test. Patient's and
physician’s global evaluation of allergic rhinitis was
summarized descriptively. Safety data is presented as
individual listings and summary tables as appropriate.
There were no changes in the conduct of the study or the
planned analysis.
RESULTS
Demographic and other baseline characteristics
Of the 273 patients randomized in the study, 93 in each
treatment group, 263 patients completed the study and
included in the full analysis set. Their baseline
characteristics are summarized in the Table 1. Treatment
groups showed no marked imbalances in any of the
patient characteristics.
Table 1: Demography and baseline characteristics (safety population).
Parameter
Statistics
Montelukast 10 mg +
Levocetirizine 5 mg (N=93)
Montelukast 10 mg
(N=93)
Levocetirizine 5 mg
(N=93)
Age (year)
Mean (SD)
35.29 (11.583)
32.54 (10.951)
32.22 (10.184)
Median
34.00
30.00
30.00
Min., Max
19.0, 62.0
18.0, 58.0
18.0, 58.0
Gender, n (%)
Male
52(55.9)
52(55.9)
58(62.4)
Female
41 (44.1)
41 (44.1)
35 (37.6)
Body weight
(kg)
Mean (SD)
63.96 (11.622)
61.63 (10.958)
63.03 (10.486)
Median
62.00
61.00
62.00
Min., Max
39.0, 97.0
40.0, 89.0
41.0, 88.0
Height (cm)
Mean (SD)
160.51 (13.649)
161.13 (8.500)
162.30 (8.251)
Median
162.00
162.00
164.00
Min., Max
60.2, 183.0
140.0, 174.0
141.0, 182.0
Table 2: Mean change in efficacy parameters.
Visit
Efficacy parameter
Montelukast 10 mg +
Levocetirizine 5 mg
(N = 82) LSM (SE)
Montelukast
10 mg (N = 82)
LSM (SE)
Levocetirizine 5 mg
(N = 84) LSM (SE)
P-value1
Mean
change
from
baseline
(day 1 to
day 14)
Daytime nasal symptom score
(ITT) (N= 92)
-1.10 (0.056)
-0.93 (0.053)
-0.98 (0.057)
0.0159
Daytime nasal symptom score (PP)
-1.09(0.053)
-0.95 (0.053)
-0.96(0.055)
0.0483
Night-time symptom score (PP)
-0.71 (0.047)
-0.61 (0.048)
-0.68 (0.050)
0.2909
Daytime eye symptom score (PP)
-1.61 (0.040)
-0.59 (0.040)
-0.61 (0.039)
0.9644
RQOL (PP)
-1.34 (0.068)
-1.17 (0.068)
-1.28 (0.067)
0.2111
1p-value is calculated for the comparison of treatment groups using ANCOVA with baseline Daytime Nasal Symptoms Score as
covariate. LSM- least square mean, ITT- Intention to treat, PP – per protocol , RQOL- rhino-conjunctivitis quality of life.
Table 3: Summary of treatment emergent adverse events.
Montelukast 10 mg+Levocetirizine
5 mg (N=93) n (%)
Montelukast 10 mg
(N=93) n (%)
Levocetirizine 5 mg
(N=93) n (%)
TEAEs
16 (17.2)
9 (9.7)
13 (14.0)
Serious adverse event (SAE)
00 (00.0)
00 (00.0)
00 (00.0)
AE by relationship
Yes
1 (1.1)
00 (00.0)
5 (5.4)
No
15 (16.1)
9 (9.7)
9 (9.7)
AE by severity
Mild
12 (12.9)
8 (8.6)
11 (11.8)
Moderate
7 (7.5)
1 (1.1)
2 (2.2)
Severe
1 (1.1)
00 (00.0)
00 (00.0)
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International Journal of Otorhinolaryngology and Head and Neck Surgery | January 2021 | Vol 7 | Issue 1 Page 86
Analysis of efficacy
At end of treatment there was statistically significant
evidence from the per protocol analysis that patients on
FDC had a greater improvement in change from baseline
in daytime nasal symptoms score than patients who
received Montelukast (p=0.0266) or Levocetirizine
(p=0.0409) (Table 2). These results were consistent with
the Intent to treat analysis. In the ITT population
statistically significant differences for the mean change in
daytime nasal symptom scores were also observed for the
FDC group compared to Montelukast (p=0.0054) and
Levocetirizine groups (p=0.0425) (Table 2).
Figure 1: Study design.
Figure 2: Clinical trial participant flowchart.
*Patient was withdrawn from the study due to signs and symptoms of hypersensitivity.
Figure 3: Daily mean daytime nasal symptoms score (PP).
Panchal S et al. Int J Otorhinolaryngol Head Neck Surg. 2021 Jan;7(1):83-90
International Journal of Otorhinolaryngology and Head and Neck Surgery | January 2021 | Vol 7 | Issue 1 Page 87
Figure 4: Daily mean night time symptoms score (PP).
Figure 5: Daily mean daytime eye symptoms score (PP).
Analysis of the secondary efficacy endpoints (nighttime
symptoms score, daytime eye symptoms score, and
rhinoconjunctivitis quality-of- life score) provided
numerically greater improvement in the nighttime
symptoms score, daytime eye symptoms score, and
rhinoconjunctivitis quality-of-life scores in the FDC
group as compared to the Montelukast group or
Levocetirizine group. It was also noted that a greater
number of patients in the FDC group demonstrated
improvement in symptoms of allergic rhinitis as
compared to patients in the Montelukast group and
Levocetirizine group for the Physician's and Patient’s
global evaluation of allergic rhinitis at end of study
(Figure 4-6).
Safety evaluation
A total of 38 out of 279 patients (13.6%) experienced at
least one adverse event during the study; after
randomization (treatment emergent adverse events).
Adverse events were reported for 17.2% (16/93) patients
in the FDC of Montelukast 10mg and Levocetirizine 5mg
group, 9.7% (9/93) patients in the Montelukast 10mg
group, and 14% (13/93) patients in the Levocetirizine
5mg group. A total of 69 AEs were reported during the
study. The majority of adverse events were mild in
severity and resolved without treatment. Most of the AEs
reported in this study were assessed by the investigator as
not related to study drug.
Figure 6: Summary of patient’s global evaluation of
allergic rhinitis (PP) with montelukast 10 mg
+levocetirizine 5 mg.
28%
23%
44%
4% 1% 0% 0% Very much better
Much better
Better
Unchanged
Worse
Much worse
Very much worse
Panchal S et al. Int J Otorhinolaryngol Head Neck Surg. 2021 Jan;7(1):83-90
International Journal of Otorhinolaryngology and Head and Neck Surgery | January 2021 | Vol 7 | Issue 1 Page 88
Figure 7: Summary of patient’s global evaluation of
allergic rhinitis (PP) with montelukast 10 mg
Figure 8: Summary of patient’s global evaluation of
allergic rhinitis (PP) with levocetirizine 5 mg.
Adverse events considered to be related to study
medication were reported for 1.1% (1/93) (hypersomnia)
and 5.4% (5/93) (sedation, somnolence, tremor and
diarrhea) of patients in the FDC group and Levocetirizine
5mg group respectively. No adverse event was reported
as related to study drug in the Montelukast 10 mg group.
The most frequent AEs were nervous system disorders
(11 patients across all groups), gastrointestinal disorders
(9 patients across all groups) and respiratory disorders (7
patients across all groups). The most common single
adverse event reported was headache and was reported in
5 patients across all treatment groups. Adverse events of
pyrexia, urinary tract infection and cough were also
common and each of these AEs were reported in 4
patients across all treatment groups. No serious adverse
events or discontinuations due to adverse events were
reported, and no deaths occurred during the study.
DISCUSSION
A total of 279 patients participated in the study with 93
patients in each treatment group. 263 patients completed
the study. Clinical studies done in the past shows that
Montelukast as monotherapy has been effective in
improving daytime and night-time symptoms in patients
with allergic rhinitis.11,12 Levocetirizine has been
associated with significant improvements in symptom
scores for sneezing, rhinorrhea, and ocular/nasal pruritus.
In a review of clinical trials, Levocetirizine was effective
in relieving the nasal congestion associated with allergic
rhinitis (AR) compared with placebo and was an
appropriate option for the treatment of nasal congestion
in patients with AR.9,13 Hence combining Montelukast
with Levocetirizine does appear to have additional
benefits in comparison to each agent alone and could be
considered for the treatment of patients with allergic
rhinitis.11,14
In the present study significant improvement as compared
to baseline occurred for all the efficacy measures in the
three treatment groups. Analysis of the primary efficacy
endpoint the daytime nasal symptoms score provided
evidence that FDC of Montelukast 10mg and
Levocetirizine 5 mg was superior to Montelukast 10mg
monotherapy or Levocetirizine 5 mg monotherapy in the
treatment of patients with seasonal allergic rhinitis.
In the previous clinical studies, combination of
Montelukast and Levocetirizine has shown a significant
improvement in total nasal symptom scores (TNSS) in
patients on the combination therapy as compared to
placebo or giving both the drugs as monotherapy.15,16 In a
randomized, double-blind, placebo-controlled crossover
study to investigate the effects of 6 weeks of treatment
for persistent allergic rhinitis (AR), the greatest
improvement in nasal symptoms occurred after
combination treatment of Montelukast (10 mg) and
Levocetirizine (5 mg).15 In another 32-week randomized,
placebo-controlled, crossover, double-armed study16 by
Ciebiada et.al in 40 adult patients with history of
persistent AR, there were four 6-week treatment periods
separated by 2-week washout periods. The combination
of Montelukast and Levocetirizine significantly improved
nasal symptoms during the first 24 hours and
improvement gradually increased during the 6 weeks of
treatment especially in patients receiving the combination
therapy. Also, Improvement at 6 weeks of treatment was
significantly greater than that achieved on the 1st day of
therapy in patients treated with the combination of
Montelukast and Levocetirizine.16
In a prospective, randomized, double-blind, parallel,
active-controlled, comparative 4-week trial by Mahatme
et al. (N=70) combination of montelukast and
Levocetirizine showed significant reduction in total nasal
symptom score (TNSS).17 Kim et al in 4-week,
randomized, multicenter, double-blind, Phase III trial (N=
228) showed similar reduction in TNSS and other
symptoms of allergic rhinitis using combination of
montelukast and levocetirizine compared to either of the
drug alone.18 In contrast to most studies, clinical study by
andhale et al (N=75) did not show any significant
difference in terms daytime symptoms, night time
symptoms and eye symptoms in combination arm
(montelukast+levocetirizine) compared to monotherapy
with either drugs.19 In patients of persistent allergic
rhinitis, adsule et al showed better clinical outcomes with
15%
32%
40%
7%
5% 1% 0% Very much better
Much better
Better
Unchanged
Worse
Much worse
Very much worse
23
22
29
9
100Very much better
Much better
Better
Unchanged
Worse
Much worse
Very much worse
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International Journal of Otorhinolaryngology and Head and Neck Surgery | January 2021 | Vol 7 | Issue 1 Page 89
combination therapy than monotherapy of montelukast or
levocetirizine.14 Similar to this study, saverno et al
proved that montelukast and levocetirizine improves
quality of life in patients of allergic rhinitis. 20
In this study, The FDC of Montelukast 10mg and
Levocetirizine 5mg was found to be safe and generally
well tolerated. There were no unexpected AEs as per
Prescribing Information of Montelukast or Levocetirizine
reported for the treatment groups. The highest incidence
of treatment emergent adverse events was in the nervous
system disorders system organ class with the most
common adverse event being headache. There were no
serious adverse events, deaths, withdrawals due to
adverse events or unexpected safety findings reported
during the study. There were no clinically significant
findings in clinical laboratory evaluations, vital signs,
ECG and physical examinations performed during the
study. Safety assessments of this study are comparable to
studies done in the past by Ciebiada et al, Mahatme et al
with combination of montelukast and levocetirizine in
patients of allergic rhinitis.16,17
Results of our study substantiated evidence for the
primary efficacy endpoint that (Montelukast 10
mg+Levocetirizine 5 mg) FDC was superior to
monotherapy with either drugs in the treatment of
patients with seasonal allergic rhinitis. The secondary
efficacy variables (night-time symptoms score, daytime
eye symptoms score and rhino-conjunctivitis quality-of-
life score) provided evidence of a numerically greater
reduction in these scores which were observed for the
fixed dose combination. Assessment of the Physician's
and Patient’s Global Evaluation of Allergic Rhinitis
indicated that a greater number of patients in the FDC
group demonstrated improvement in symptoms of
allergic rhinitis compared monotherapy.
Fixed dose combination of Montelukast and
Levocetirizine was safe, generally well tolerated and
superior on efficacy compared to Montelukast or
Levocetirizine in patients of seasonal allergic rhinitis.
This FDC also maintains the quality of life in allergic
rhinitis patient which further helps in improving the
compliance of the patient to the therapy.
CONCLUSION
Fixed dose combination of Montelukast and
Levocetirizine was safe, generally well tolerated and
superior on efficacy compared to Montelukast or
Levocetirizine in patients of seasonal allergic rhinitis.
ACKNOWLEDGEMENTS
Authors would like to thank all investigators, trial team,
and patients for participating in this trial. List of
Investigators: Dr. Karanam Gowrinath, Dr. Kagollu
Mallikarjuna, Dr. B. Kiran, Dr. C. V. Srinivas, Dr.
Prateek Nayak, Dr. S. Balamurugan, Dr. D. Sudeena, Dr.
G. Eswar, Dr. Ch. Manoj Kumar, Dr. Manish Kumar
Jain, Dr. Narendra Khippal, Dr. K.K.Pandey, Dr.
Nagendra Prasad, Dr. Rajesh Chavan, Dr. R.K. Patel, Dr.
Noor Khan.
Funding: Study was sponsored by Glenmark
Pharmaceuticals Ltd
Conflict of interest: None declared
Ethical approval: The study was approved by the
Institutional Ethics Committee
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Cite this article as: Panchal S, Patil S, Barkate H.
Evaluation of efficacy and safety of montelukast and
levocetirizine FDC tablet compared to montelukast
and levocetirizine tablet in patients with seasonal
allergic rhinitis: a randomized, double blind,
multicentre, phase III trial. Int J Otorhinolaryngol
Head Neck Surg 2021;7:83-90.
