An Investigator-Blind Randomized Controlled Trial Comparing Effectiveness, Safety of Levocetirizine and Bepotastine in Chronic Urticaria.

INTRODUCTION: Chronic urticaria is common and distressing dermatosis where the search for newer agents with improved effectiveness and tolerability profile is a felt need. Bepotastine, a second-generation antihistamine, with added effect on suppression of eosinophil migration has a prospect in the management of chronic urticaria. AIMS: To assess and compare effectiveness and safety of bepotastine versus levocetirizine in chronic urticaria.
MATERIALS AND METHODS: Single-center, investigator-blind, randomized, active-controlled, parallel-group phase IV trial (CTRI REF/2018/04/019692) conducted on adult patients of chronic urticaria of either sex. Patients were randomized into receiving either bepotastine besilate 10 mg tablet twice daily or levocetirizine 5 mg tablet once daily with fortnightly follow-up for 6 follow-up visits after thebaseline evaluation. The primary outcome measures were Urticaria Activity Score 7 (UAS7) and Urticaria Total Severity Score (TSS). Routine hematological, biochemical tests, treatment-emergent adverse events were monitored for safety.
RESULTS: Thirty patients in the bepotastine group and 29 patients in the levocetirizine group were analyzed by modified-intention-to-treat criteria. The study groups were comparable at the baseline with respect to the severity of chronic urticaria. UAS7 and TSS reduced significantly (P < 0.001, Friedman's ANOVA) in both treatment groups from 1st follow-up visit and 2nd follow-up visits (P < 0.05, Post Hoc Dunn's test) At the test-of-cure visit, UAS7 (5.13 ± 8.21 vs 7.48 ± 8.96) and TSS (5.10 ± 4.06 vs 7.07 ± 4.48) were less with bepotastine than levocetirizine although not statistically significant (P = 0.188 and 0.073, respectively, Mann-Whitney U test). Sedation during daytime was found to be significantly more (P < 0.001, Fischer's exact test) with levocetirizine than bepotastine (73.3% vs 17.2%).
CONCLUSION: Bepotastine is comparable to levocetirizine with respect to its effectiveness with an edge in terms of side-effect (sedation during day time); thus, it offers a new therapeutic option in chronic urticaria. Copyright:

Introduction

Chronic urticaria is a common and distressing dermatosis where the release of mast cell mediators causes inflammation and accumulation and activation of other cells consisting of CD4+ and CD8+ T lymphocytes, eosinophils, basophils, and neutrophils. The primary aim of the treatment of chronic urticaria is symptomatic relief and avoidance of triggering factors. The impact of chronic urticaria on quality of life is overwhelming, including problems in home management, personal care, recreation and social interaction, mobility, emotional factors, sleep, rest, and work that can lead to social isolation and altered emotional reactions.

In the search for newer modalities to supplement the pharmacotherapy for urticaria, bepotastine, a second-generation antihistamine, with added effect on suppression of eosinophil migration and pro-inflammatory cytokines with fewer adverse effects can be explored to reduce the burden of pills while maintaining a symptom-free interval.[1] Bepotastine could prove to be an important addition to the armamentarium for controlling chronic urticaria. Thus, the present study was conducted with the objectives of assessing the clinical effectiveness, the safety of bepotastine, and comparing the same with the standard drug, levocetirizine, in chronic urticaria.

Materials and Methods

The study was designed as an institution-based, single-blind (investigator blind), randomized (1:1), active-controlled, parallel-group trial and was carried out at the dermatology out-patient department of a tertiary care center. Institutional ethics committee permission was obtained before the commencement of the study and bears the clinical trial registration number CTRI REF/2018/04/019692.

Operational definition

For the study, all cases of chronic urticaria appearing daily or near-daily (at least three times a week) for at least 6 weeks with a UAS7 score of more than or equal to 7 were considered eligible for screening for participation.[2]

Inclusion and exclusion criteria

Adult consenting patients of either gender reporting to the OPD and suffering from chronic urticaria were included. Pregnant and lactating women, patients who were immunosuppressed due to drug or disease, or those suffering from comorbid conditions requiring treatment were excluded. Patients having an allergy to either of the study medications, working in night shifts or likely to change the usual sleep/wake cycle, those driving automobiles, having a history of substance or alcohol abuse, participation in a clinical trial in the last 3 months, or unable to come for follow-ups were also excluded.

Randomization and blinding

The participants were randomized using computer-generated random number sequence (WINPEPI software, ETCETERA version 2.32) into two equal groups receiving either the study medication, bepotastine, or the control drug, levocetirizine. The allocation ratio was 1:1. The allocation was concealed using sequentially numbered opaque sealed envelope (SNOSE) technique.

The trial was carried out as a single-blind study where the assessing physician was made unaware of the medicine dispensed. The assessing and dispensing physicians were seated in separate rooms, and the participants were asked not to divulge any information regarding the dosage of the medications.

Study medications

Group A received the test medication – bepotastine besilate 10 mg twice daily (Tab. Bepozoic, Glenmark Pharmaceuticals) and Group B received the control medication – levocetirizine 5 mg once daily (Tab. Levocetirizine, generic supply from hospital).

Visits and follow-ups

A screening visit was conducted where patients were evaluated clinically, and informed consent was obtained. After a wash-out period of 1 week, the baseline visit was carried out. The participants were randomized, clinical parameters were noted, study medications were noted, and laboratory tests were carried out during the baseline visit. Laboratory tests included routine hemogram, liver function tests (LFT), serum urea, serum creatinine, and fasting blood sugar. Six follow-up visits were carried out 2 weeks apart. Effectiveness and safety parameters were noted at all follow-ups. In the last visit, laboratory parameters were repeated. The total duration of a participant to be in the study was 15 weeks.

Study parameters

The primary effectiveness variables were weekly Urticaria Activity Score 7 (UAS7)[34] and Urticaria Total Severity Score (TSS).[5] TSS was estimated from the number and size of wheals, the intensity of pruritus, duration of persistence of urticaria lesions, frequency of appearance of lesions, and the frequency of antihistamine use with each parameter having a score of 0–3, the maximum score being 18.

The secondary outcome variables were patients' global assessment of disease activity improvement and physicians' global assessment of disease activity improvement, both scored on a 5-point Likert scale (0: no improvement; 1: mild improvement; 2: moderate improvement; 3: marked improvement; 4: excellent improvement).[6]

Safety was assessed by recording the treatment of emerging adverse events, changes in laboratory values like routine hemogram, liver function tests (LFT), serum urea and creatinine, and fasting blood glucose before and after the treatment.

Sample size

The calculated sample size was 30 in each treatment arm, with a total of 60 participants. This was calculated as the difference between two means, to detect a difference of 1.15 in UAS7 between the groups, standard deviation of 1.5 (effect size and standard deviation obtained from pilot study conducted on 6 chronic urticaria patients), 80% Power, 0.05 Type 1 error, and 10% possible dropout rate.

Statistical analysis

Modified intention to treat analysis was done with participants reporting for at least one follow-up. Safety analysis was done for all participants of the study. Numerical variables were expressed as mean ± standard deviation or median, interquartile range. Categorical variables were expressed as percentages. The data were analyzed using students' t-test, ANOVA test for parametric data, and Mann-Whitney's U test, Wilcoxon rank-sum test, or Friedman's ANOVA with post hoc test for nonparametric data (as applicable). Categorical data were analyzed by using Chi-Square test and Fischer's exact test as applicable. The statistical software Medcalc® v 9.6.4.0 was used for analysis.

Results and Analysis

The flow of the study participants is shown in Figure 1. Out of 73 patients screened, 60 were randomized equally into two study groups. In the levocetirizine group, one participant was lost to follow-up in the first follow-up visit, making 29 participants evaluable in that group. All 30 participants in the bepotastine group were evaluated.

Figure 1

Flow of study participants

Middle-aged males (mean age = 33.63 ± 8.80 years) of rural residence were mostly involved and were comparable across the treatment groups. The demographic profile is expressed in Table 1.

Table 1

Demographic profile of study population

Category	Bepotastine (n=30)	Levocetirizine (n=29)	P (between groups)
Age (in years)
Range	18,56	19,56	0.126
Mean±SD	31.9±8.5	35.4±8.9
Median (IQR)	30 (26,38)	35 (30,42)
Sex
Male	18 (60%)	18 (62%)	0.917
Female	12 (40%)	11 (38%)
Residence
Urban	8 (%)	13 (%)	0.236
Rural	22 (%)	16 (%)

SD=Standard deviation; IQR=Interquartile range. P value is from Student’s unpaired t-test for age, Fisher’s exact test for sex distribution and residence

UAS7 score was evaluated at the baseline and all follow-up visits. The baseline values were comparable in both treatment arms (P = 0.712). UAS7 decreased significantly in both bepotastine and levocetirizine arms (P < 0.001). When compared with the baseline, the decrease was significant from the 1st follow-up onwards in both the study groups. The scores of UAS7 in the bepotastine group were persistently lower than those in the levocetirizine from the 4th follow-up onwards although not significant [Table 2].

Table 2

Changes in Urticaria Activity Score (UAS 7) during the study period

Urticaria activity score 7	Bepotastine (n=30)	Levocetirizine (n=29)	P (between groups)
Baseline
Mean±SD	27.8±2.2	27.8±3.5	0.712
Median (IQR)	28 (28,28)	28 (28,28)
1st follow up
Mean±SD	25.7±3.8*	25.4±4.7*	0.406
Median (IQR)	28 (21,28)	28 (21,28)
2nd follow up
Mean±SD	22.2±4.9*	22.5±4.3*	0.867
Median (IQR)	21 (21,28)	21 (21,28)
3rd follow up
Mean±SD	17.0±6.8*	17.1±8.1*	0.931
Median (IQR)	21 (14,21)	21 (12.25,21)
4th follow up
Mean±SD	11.0±8.2*	14.7±8.4*	0.084
Median (IQR)	7 (7,14)	14 (7,21)
5th follow up
Mean±SD	7.0±8.0*	9.7±8.5*	0.135
Median (IQR)	7 (0,7)	7 (7,14)
6th follow up
Mean±SD	5.1±8.2*	7.5±9.0*	0.188
Median (IQR)	0 (0,7)	7 (0,8.75)
P (within groups)	<0.001	<0.001

Value for between group comparisons is from Mann-Whitney U test. *Denotes P<0.05 for within group comparison between the baseline visit and the particular visit (done using Friedman’s ANOVA followed by post hoc Dunn’s test).

The TSS scores were comparable at the baseline (P = 0.460). TSS decreased significantly in both groups over the study period (P < 0.001 in both groups). When compared with the baseline, the decrease was significant from the 2nd follow-up onwards in both arms. Intergroup comparison showed that the values of TSS in the bepotastine arm were lower than those in the levocetirizine arm, however, it was not significant [Table 3].

Table 3

Changes in Urticaria Total Severity Score (TSS) during the study period

TSS	Bepotastine (n=30)	Levocetirizine (n=29)	P (between groups)
Baseline			0.460
Mean±SD	15.6±1.5	15.3±1.6
Median (IQR)	16 (15,17)	15 (14,17)
1st follow up			0.969
Mean±SD	15.0±2.0	15.0±1.8
Median (IQR)	15 (14,16)	15 (13,16)
2nd follow up			0.872
Mean±SD	13.5±2.0*	13.6±1.9*
Median (IQR)	13 (12,15)	13 (12,15)
3rd follow up			0.691
Mean±SD	11.6±3.4*	11.6±2.8*
Median (IQR)	12 (11,13)	12 (10,13)
4th follow up			0.230
Mean±SD	9.1±3.9*	10.4±3.8*
Median (IQR)	9.50 (8,11)	10 (9,13)
5th follow up			0.204
Mean±SD	6.3±4.2*	7.8±4.5*
Median (IQR)	5 (3,9)	8 (3.75,10.25)
6th follow up			0.073
Mean±SD	5.1±4.1*	7.1±4.5*
Median (IQR)	3 (3,5)	5 (3,9)
P (within groups)	<0.001	<0.001

P value for between group comparisons is from Mann-Whitney U test. *Denotes P<0.05 for within group comparison between the baseline visit and the particular visit (done using Friedman’s ANOVA followed by post hoc Dunn’s test

Physicians' Global Assessment Scale, in which the treating physician measured the improvement, showed that the score improved (increased) significantly in both the groups receiving bepotastine (P < 0.001) and levocetirizine (P < 0.001). When compared with the baseline, the improvement was significant from the 2nd follow-up onwards in both the groups. The intergroup comparison was not significant [Table 4].

Table 4

Changes in Physicians’ global assessment score (PGA) during the study period

Physicians’ global assessment score	Bepotastine (n=30)	Levocetirizine (n=29)	P (between groups)
Baseline
Mean±SD	1.7±0.5	1.8±0.6	0.566
Median (IQR)	2 (1,2)	2 (1,2)
1st follow up
Mean±SD	1.8±0.7	2.1±0.7	0.172
Median (IQR)	2 (1,2)	2 (2,2.25)
2nd follow up
Mean±SD	2.3±0.6*	2.6±0.7*	0.0735
Median (IQR)	2 (2,3)	3 (2,3)
3rd follow up
Mean±SD	2.9±0.8*	2.6±0.8*	0.294
Median (IQR)	3 (2,3)	3 (2,3)
4th follow up
Mean±SD	3.3±0.7*	3.1±0.9*	0.447
Median (IQR)	3 (3,4)	3 (3,4)
5th follow up
Mean±SD	3.7±0.6*	3.4±0.9*	0.0752
Median (IQR)	4 (4,4)	4 (3,4)
6th follow up
Mean±SD	3.8±0.6*	3.5±0.8*	0.117
Median (IQR)	4 (4,4)	4 (3,4)
P (within groups)	<0.001	<0.001

P value for between group comparisons is from Mann-Whitney U test. *Denotes P<0.05 for within group comparison between the baseline visit and the particular visit (done using Friedman’s ANOVA followed by post hoc Dunn’s test

The patients also scored their improvement, and the Patients' Global Assessment Score showed a comparative baseline (P = 0.566) in both bepotastine and levocetizine arms. The score improved significantly from the 1st follow-up onwards (P < 0.001) in both groups. The between-group comparison was not significant [Table 5].

Table 5

Changes in Patients’ global assessment score (PGA) during the study period

Patients’ global assessment score	Bepotastine (n=30)	Levocetirizine (n=29)	P (between groups)
Baseline
Mean±SD	0.9±0.5	1.0±0.6	0.247
Median (IQR)	1 (1,1)	1 (1,1)
1st follow up
Mean±SD	1.6±0.6*	1.7±0.7*	0.688
Median (IQR)	2 (1,2)	2 (1,2)
2nd follow up
Mean±SD	2.0±0.6*	2.0±0.6*	0.986
Median (IQR)	2 (2,2)	2 (2,2)
3rd follow up
Mean±SD	2.5±0.9*	2.3±0.9*	0.873
Median (IQR)	2 (2,3)	3 (2,3)
4th follow up
Mean±SD	3.1±0.8*	2.7±1.0*	0.154
Median (IQR)	3 (3,4)	3 (2,3)
5th follow up
Mean±SD	3.5±0.9*	3.2±1.0*	0.194
Median (IQR)	4 (3,4)	4 (2.75,4)
6th follow up
Mean±SD	3.5±0.9*	3.3±1.1*	0.404
Median (IQR)	4 (3,4)	4 (2.75,4)
P (within groups)	<0.001	<0.001

P value for between group comparisons is from Mann-Whitney U test. *Denotes P<0.05 for within group comparison between the baseline visit and the particular visit (done using Friedman’s ANOVA followed by post hoc Dunn’s test

Complete cure was noted in 18 (60%) patients in the bepotastine group, whereas in 12 (41.37%) participants in the levocetizine group, which was not significant (P = 0.196) when compared to each other (Fischer's exact test).

The laboratory parameters were within the normal range when compared before and after the study. Regarding the adverse events, sedation during daytime was reported significantly greater (P = 0.023) in the levocetirizine group than that in the bepotastine group.

Discussion

In chronic urticaria, histamine release from mast cells coupled with the inflammatory cascade involving eosinophils, leukotrienes, cytokines, chemokines, and platelet-activating factor (PAF) is the primary pathophysiology. Bepotastine, a nonsedating second-generation antihistamine, inhibits IL-5 action or its production which promotes eosinophil activation, migration, and eosinophil-mediated inflammation.[78] Bepotastine is also a mast cell stabilizer and inhibits the production of LTB4 and 5-alfahydroxyeicosatetraenoic acid.[910] This inturn decreases the cysteinyl leukotrienes LTC4, LTD4. Inhibition of leukotriene B4, IL-5, PAF, and substance P contributes to its antipruritic effects.[111] Suppression of nitric oxide production in vascular endothelial cells decreases itch induced by substance P. Pro-inflammatory cytokines like interleukin-5, interleukin-1a is decreased by bepotastine.[12] Bepotastine inhibits intercellular cell adhesion molecule (ICAM-1) also decreases the inhibition of inflammatory site.[13] The added anti-inflammatory action makes bepotastine a potent antiallergic useful in allergic rhinitis,[1415] allergic conjunctivitis,[16] atopic dermatitis, eczema,[17] pruritus associated with different allergic skin conditions,[17] and urticaria.[18]

The dose-dependent, long-term action of bepotastine has the advantage in the treatment of chronic diseases like urticaria. It was found that bepotastine inhibited histamine-induced wheals and erythema to a significantly (P < 0.01) greater extent than the placebo in healthy volunteers. This improvement was maintained for at least 12 h.[1719] The dose of 10 mg twice daily had been introduced in India in 2017 for allergic rhinitis, pruritic dermatoses, and urticaria. Our study showed bepotastine to be as effective as the standard antihistamine levocetirizine to treat chronic urticaria. The primary effectiveness parameters – UAS7 and TSS – were significantly reduced by bepotastine and so were the assessment by patients and physicians although intergroup comparisons were comparable. This reduction is consistent with the RCT by Narayanan et al.[13] comparing bepotastine to fexofenadine for 4 weeks in a treatment trial. Narayanan et al.[13] included 30 participants of eczema, pruritic skin conditions like psoriasis, tinea of which urticaria constituted 6 patients. They found that the pruritus score and VAS symptom score significantly improved with both bepotastine and fexofenadine. Wheal score decreased (but not significant) with both bepotastine and fexofenadine; however, intergroup comparison was not significant in all the parameters. Both the RCTs prove that bepotastine is comparable in its efficacy to reduce itch and wheals to standard antihistamines levocetirizine (2nd generation antihistamine) and fexofenadine (3rd generation antihistamine). Bepotastine compared to terfenadine showed a similar number of participants having an improvement with respect to itch (74.0% vs. 73.7%) or wheals (69.5% vs. 68.6%).[117] Terfenadine is out of use in the present day because of its side-effect profile and drug-interaction, hence a study comparing the present-day standard drug treatment is much needed. Bepotastine was also shown to be effective in a study on 3415 patients, capturing data from clinics, where improvement of pruritus, wheals, redness, or angioedema was above 80% for each symptom.[20] A comparative table of the RCTs with bepotastine is given in Table 6.

Table 6

Comparison of the RCTs on Bepotastine

Parameters	Sil et al	Narayanan et al[13]	Ishibashi et al[17]
Medications used	Bepotastine versus levocetirizine	Bepotastine versus Fexofenadine	Bepotastine 20 mg/day versus terfenadine 120 mg/day
Publication year	Not yet published	2018	1997
Number of participants	60	30 participants of which 6 were urticaria patients	305
Type of Study	RCT	RCT	RCT (Phase III)
Type of lesion	Chronic urticaria	Chronic urticaria	Chronic urticaria
Comparator arm	Levocetirizine	Fexofenadine	Terfenadine
Randomization	1:1	Not mentioned	1:1
Blinding	Investigator blind	Not blinded	Not mentioned
Duration of treatment	12 weeks	4 weeks	2 weeks
Duration of non-treatment follow-up	Nil	Nil	Nil
Dose of active medication	20 mg/day	20 mg/day	20 mg/day
Outcome	UAS 7, TSS, Physicians’ and Patients’ Global assessment of improvement score was comparable between groups	UAS, VAS symptom score, DLQI was comparable between groups	The final global improvement rating (measured as ‘marked’, ‘moderate’, ‘slight’, ‘unchanged’ or ‘worsened’) did not differ significantly between groups
Adverse events	Sedation during daytime	Drowsiness	Non-serious fluctuations in laboratory values.

UAS – Urticaria Activity Score, TSS – Urticaria total symptom score, VAS – Visual assessment scale, DLQI – Dermatology life quality index

The safety of bepotastine was established in our study, where no adverse event was noted other than sedation during daytime though significantly lesser than the control drug –levocetirizine. Similarly, mild drowsiness was reported by Narayanan et al.[13] in the first week of therapy. Bepotastine being a 2nd generation antihistamine poorly penetrates the blood-brain barrier lending it the less sedating effect. Also, binding to other receptors like H3, adrenergic a1, a2, b, dopamine D2L, serotonin 5-HT2, muscarinic, or benzodiazepine receptors was not found with bepotastine.[1] It was found in a pooled analysis of clinical trials that, 9.5% of the bepotastine recipients reported adverse events, the primary being drowsiness (5.7% patients) and thirst (1.1%).[21] The frequency and type of adverse events do not increase with long-term use of bepotastine.[1] Our study did not find any abnormality in the laboratory values at the study end. In some studies, an increase in alanine aminotransferase (ALT) (2.1% of participants), presence of urinary occult blood (1.1% of patients included), and increased aspartate aminotransferase (AST) (0.7% of participants) were noted.[21] The study comparing bepotastine to terfenadine showed that the changes in laboratory values were significantly lower in the bepotastine patients than those in the terfenadine patients of chronic urticaria.[17]

Our study was limited by the fact that a longer follow-up could not be done due to logistic issues and double-blinding could not be done.

Conclusion

Our study comparing bepotastine to levocetirizine showed that bepotastine is safe and effective in the treatment of chronic urticaria. Being less sedative than the standard drug without hampering the efficacy, it offers a new therapeutic option for this chronic disease. Further studies with long-term follow-up are required to establish its efficacy in medicine sans periods.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.