Loratadine vs Rupatadine: Unearthing the Capital Choice in Chronic Idiopathic Urticaria (CIU) - A Randomized Controlled Trial.

Background: Chronic Idiopathic Urticaria (CIU) is a debilitating disease characterised by almost daily presence of urticarial symptoms like short-lived wheals, itching, and erythema for at least 6 weeks without an identifiable cause there by leading to impairment of quality of life of the patient. Aim: To evaluate the efficacy and safety of loratadine and rupatadine in chronic idiopathic urticaria.
Methods: This is a prospective, randomized, single-blind, parallel arm study conducted to evaluate the efficacy and safety of loratadine and rupatadine in patients with CIU. The study was registered prospectively with Clinical Trial registry of India (CTRI/2017/05/008624). Institutional Ethics Committee clearance was obtained. Written informed consent was obtained from all the participants before enrolment into the trial. The study was conducted in the outpatient department of Dermatology, SRM Medical College, Kattankulathur, Tamil Nadu, India, during the period from June 2017 to August 2018. Patients with CIU enrolled into the study based on inclusion-exclusion criteria were given the intervention drugs; Loratadine 10 mg once daily or rupatadine10 mg once daily orally for 6 weeks.
Results: Rupatadine is more efficacious than loratadine in the reduction of Total Leucocyte Count, Differential Count and Absolute Eosinophil Count, the key determinants of allergy. Rupatadine also produced better improvement in Total symptom Score, Dermatology Life Quality Index in patients with CIU.
Conclusion: Analysis of all the parameters of efficacy and safety establishes the probable superiority of rupatadine over loratadine for the treatment of urticaria. Copyright:

Introduction

Chronic idiopathic urticaria (CIU) is characterized by the development of wheals, which persists for 6 weeks or more, associated with unknown or inconsistent cause, with or without associated angioedema.[12] It is estimated that the point prevalence of CIU is 0.5% across several populations studied.[34] Chronic spontaneous urticaria (CSU) accounts for the majority of chronic urticaria cases.[5] It is estimated that 66% to 93% of chronic urticaria cases are idiopathic. Patients with CIU often report a substantially impaired quality of life (QoL) as well.[6]

Urticaria, a mast cell-driven disease causes release of histamine and other mediators, such as platelet-activating factor (PAF) and cytokines, resulting in activation of sensory nerves, vasodilatation and leukocyte recruitment to urticarial lesions on exposure to triggering factors. The edematous skin lesions often involve upregulation of endothelial cell adhesion molecules and perivascular infiltration of neutrophils, eosinophils, macrophages, and T-cells.[7] Approximately 30%–60% of patients with CIU have an autoimmune component as substantiated by finding of anti-IgE antibodies and functional antibodies against the α chain of the high-affinity IgE receptor on mast cells, basophils, and antigen-presenting cells that have been isolated from the serum of patients with CIU.[8]

Guidelines to the management of CIU has been developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma, and Immunology; American College of Allergy, Asthma & Immunology; and the Joint Council of Allergy, Asthma & Immunology.[129]

Antihistamines are the first-line drugs for patients with CIU. First-generation H1 antihistamines like promethazine, chlorpheniramine, pheniramine, hydroxyzine, meclizine and diphenhydramine are non-specific and cross blood–brain barrier to cause sedation which is a major drawback; Second Generation H1 antihistamines such as loratadine, desloratadine, levocetirizine, fexofenadine, cetirizine, loratadine, mizolastine and terfenadine are drugs with less sedating potential.[10]

Refractory cases are managed with drugs like cyclosporine, omalizumab, theophylline, attenuated androgens, anticoagulants, nonsteroidal anti-inflammatory drugs, β-agonists, cyclophosphamide, plasmapheresis, cromolyn, and nifedipine.

Rupatadine is an antihistamine with PAF receptor antagonist activity and anti-TNFα activity and have been indicated in the treatment of CIU with the benefit of a better safety profile. It also possesses a broader anti-inflammatory profile inhibiting both inflammatory cells and a range of mediators involved in both the early and late-phase inflammatory responses.

Rupatadine has two distinct chemical structural components which mediate its dual mechanism of action; piperidinyl and lutidinyl moieties. The piperidinyl structure of rupatadine bears a close similarity to antihistamines desloratadine and loratadine, preserving the histamine H1 receptor antagonist activity. The lutidinyl skeleton is responsible for PAF receptor antagonist activity. This chemical configuration and due to the presence of some active metabolites rupatadine can be administered as a once-daily regimen.[111213]

Both loratadine[1415] and rupatadine[1216] are individually efficacious for the treatment of CIU. However, there are no studies comparing loratadine and rupatadine. Hence this study was undertaken to compare the therapeutic efficacy and safety in patients with CIU, to explore the potential efficacy and safety of either drug over the other.

Materials and Methods

Study design and participants

This is a prospective, randomized, single-blind, parallel-arm study conducted to evaluate the efficacy and safety of loratadine and rupatadine in patients with CIU. The study was registered prospectively with Clinical Trial registry of India (CTRI/2017/05/008624). The study protocol was reviewed and approved by Institutional Ethics Committee. Written informed consent was obtained from all the participants before enrolment into the trial. The study was conducted in the outpatient department of Dermatology, in a tertiary care teaching hospital, Tamilnadu, India during the period from June 2017 to August 2018.

Patients satisfying the following conditions were eligible for inclusion in the study: Male/female aged 18–65 years, documented history of active CIU (urticarial wheals) for at least three days per week over the last 6 weeks, total pruritus score (TPS, sum of daytime and night time scores) ≥2 and number of wheals score ≥1 for 3 consecutive days before inclusion in the study, ability to fill in the patient's diary correctly, those who are willing to join in the study and fulfil with its requirements by signing a written informed consent.

Patients meeting any of the following criteria were excluded from the study: patients suffering from urticaria, with other associated illness (like example psychiatric, malignancies or hepatic, endocrine or other major systemic diseases), women on oral contraceptive pills, lactating mothers and antenatal women, patients on steroids for one month or antihistaminic therapy for 72 hours were omitted from the study, patients with history of allergy to rupatadine/loratidine.

The 60 participants enrolled into the study were randomized and allocated in 1:1 ratio into the two treatment arms. Participants in Group 1 received loratidine 10 mg once daily (Lormeg 10 mg; Alembic) orally for 6 weeks while participants in Group 2 received rupatadine 10 mg (Rupanex 10 mg; Dr Reddys) once daily orally for 6 weeks. The participants were required to visit the study site four times. At visit 1 participants were screened for eligibility for inclusion in the study. At visit 2, potentially eligible participants entered a 1-week observation period. At visit 3, participants satisfying the eligibility criteria were enrolled to start the medications on the same day. The participants were followed up weekly over phone to check for compliance with the medication. At visit 4, at the end of 6 weeks, safety and efficacy evaluations were done. The CONSORT flow chart of the study procedure is depicted in Figure 1.

Figure 1

CONSORT flow chart of the study procedure

Study end points and efficacy assessments

The primary efficacy end point of this study was hematological parameters (Total Leucocyte Count TLC, Differential Count DC and Absolute Eosinophil Count AEC) and Total symptom Score (TSS). TSS was measured in terms of severity of pruritis, number of wheals, size of wheals and number of urticarial episodes; with 12 point of scale each of which consists of 0 as minimum and 3 as maximum which conclude 12 points scale. The severity of pruritis is graded 0 to 3 {(0) None, (1) Mild, (2) Moderate, (3) Severe)}; number of wheals are graded as 0 to 3 {(0) None, (1) 0 – 10, (2) 11 – 20, (3) more than 20)}, size of wheals are graded as 0 to 3; {(0) None, (1) more than 1.27 cm, (2) 1.27 cm–2.5 cm, (3) more than 2.5 cm)}, number of episodes assessed as {(0) 0, (1) 1, (2) 2-3, (3) more than 3}. These were assessed at baseline and at 6 weeks.

The secondary efficacy endpoint was the Dermatology Life Quality Index (DLQI) of patients which was assessed by self-administered validated questionnaire by asking the severity of disease which disturbs the QoL; not at all (0), mildly affected (1), moderately affected (2), very much (3); at baseline and end of treatment.

Safety assessment

Safety and tolerability of the drugs were also assessed by monitoring the incidence of side effects which were recorded in patient's diary and changes in vital signs and physical examination findings recorded before and at the end of treatment.

Statistical analysis

Statistical analysis was done using SPSS v21. Quantitative data following a normal distribution were presented as mean ± standard deviation or n (%) and comparison was done using the unpaired “t” test. Data that were not normally distributed were displayed as median and comparison was done using the Mann–Whitney Wilcoxon test. Categorical variables were summarized by frequencies and percentages with P values from a χ2 test or Fisher exact test wherever appropriate. A two-sided P value lower than 0.05 was considered as statistically significant.

Results

Seventy-seven patients provided written informed consent and underwent screening for study eligibility of which 17 were excluded as they did not meet the inclusion criteria or could not comply with the study procedures. Baseline TSS and TLC, DCN, DCL, DCE, AEC, TSS and DLQI were recorded. The participants in two groups were followed up for 6 weeks and the above parameters were repeated and patient's diary was also examined. The disposition of study subjects are schematically illustrated in Figure 1.

The demographics and baseline characteristics of the study population are illustrated in Table 1. The two arms were comparable with respect to demographic and baseline clinical characteristics.

Table 1

Baseline demographic and clinical characteristics of study population

Parameter	Group 1 (n=25)	Group 2 (n=26)	P
Age, years	33.81±10.10	31.88±7.30	P=0.43
Male sex, n %	16 (64)	12 (46)	P=0.68
Female sex	9 (36)	14 (54)	P=0.58
BMI, kg/m2	25.08±3.19	25.76±4.06	P=0.51
TLC, cells/mm3	8738.72±896.01	8601.38±691.50	P=0.54
Differential Neutrophil Count, (%)	55.64±7.90	56.27±6.77	P=0.76
Differential Lymphocyte Count,(%)	31.32±5.75	32.46±5.46	P=0.46
Differential Eosinophil Count, (%)	3.52±0.59	3.27±0.60	P=0.14
Absolute Eosinophil Count,	198.16±99.57	197.77±105.81	P=0.98
TSS	7.80±1.12	7.69±1.01	P=0.71
DLQI	2.08±0.64	2.12±0.52	P=0.80

Group 1 - Participants on Loratidine, Group 2 - Participants on Rupatadine, TLC - Total Leucocyte Count, TSS - Total Symptom Score, DLQI - Dermatology Life Quality Index

The change in hematological parameters, TSS and DLQI for each loratadine and rupatadine groups from baseline to 6 weeks are illustrated in Tables 2–4 respectively. Both loratadine and rupatadine produced statistically significant difference between baseline and 6 weeks in each of the parameters analyzed (P < 0.001). Further analysis of the mean difference of the individual groups also produced statistically significant difference (P < 0.001).

Table 2

Change in hematological parameters from baseline to 6 weeks

Parameter	Arm	Baseline	6 weeks	Mean difference	P
TLC	Group 1 (n=25)	8738.72±896.01	8614±884.82	124.52±48.45	P<0.001
	Group 2 (n=26)	8601.38±691.50	8406.88±689.47	194.50±78.40	P<0.001
DCN	Group 1 (n=25)	55.64±7.90	50.76±7.66	4.88±3.23	P<0.001
	Group 2 (n=26)	56.27±6.77	49.19±6.30	7.08±3.10	P<0.001
DCL	Group 1 (n=25)	31.32±5.75	27.48±5.48	3.84±1.80	P<0.001
	Group 2 (n=26)	32.46±5.46	26.46±5.35	6.0±2.37	P<0.001
DCE	Group 1 (n=25)	3.52±0.59	1.80±0.71	1.72±0.54	P<0.001
	Group 2 (n=26)	3.27±0.60	1.50±0.58	1.77±0.71	P<0.001
AEC	Group 1 (n=25)	198.16±99.57	185.72±96.36	12.44±8.21	P<0.001
	Group 2 (n=26)	197.77±105.81	172.50±97.96	25.27±12.23	P<0.001

Group 1 - Participants on Loratidine, Group 2 - Participants on Rupatadine, TLC - Total Leucocyte Count, DCN - Differential Count Nuetrophil, DCL - Differential Count Lymphocyte, DCE - Differential Count Eosinophil, ACE - Absolute Eosinophil Count

Table 4

Dermatology Life Quality Index before and after treatment

	Baseline	6 weeks	Mean difference	P
Group 1 (n=25)	2.08±0.64	0.60±0.76	1.48±0.82	P<0.001
Group 2 (n=26)	2.12±0.52	0.08±0.27	2.04±0.45	P<0.001

The mean time for symptom relief in group 1 and group 2 were 45±12.25 min and 51.35±10.54 min (P<0.001)

Safety analysis

No clinically significant changes in vital signs, laboratory parameters or physical examination were observed during the study in any group. To compare the incidence of adverse effects of the two groups, the Fischer's Exact test was performed and it was found to be statistically non-significant (P = 0.064). The adverse events and adverse drug reactions reported in this trial are summarized in Figure 2.

Figure 2

Adverse events reported during trial

Discussion

The efficacy and safety of loratadine 10 mg and rupatadine 10 mg once daily were evaluated in adult patients with CIU in this randomized, single-blind, parallel arm interventional study to address the uncovered need to find out a better therapeutic choice among antihistamines in the management of CIU.

The two study groups were homogenous wrt demographic and clinical parameters. Primary analysis proved that the primary and secondary outcome variables exhibited statistically significant improvements with both loratadine and rupatadine. The important roles of these blood cells in the pathogenesis of CIU have already been described. Hence, both these drugs contribute to symptom relief in CIU. Further analysis proved that rupatadine is more efficacious than loratadine in improving the above parameters (P < 0.001 for each).

The long period of the disease can have a profoundly negative effect on a patient's sense of wellbeing and most of the patients have lower QoL levels. Here, Rupatadine produced better improvement in TSS (P < 0.001) compared to loratadine using the 12-point assessment tool. Rupatadine also showed marked improvement in the DLQI compared to loratadine. From these findings we can conclude that rupatadine is more efficacious than loratadine in bringing out marked improvement in these treatment prognostic parameters of CIU.

The mean time for symptom relief was lesser in the rupatadine group (P < 0.001), indicating its faster onset of action. This is a significant finding as patients seek faster relief from urticarial symptoms, thereby significantly contributing to relatively quicker improvement in the QoL. Rupatadine also produced sustained symptom relief. Given the impact of CIU on daily activities and QoL, it is of capital importance to provide treatment that provides rapid and sustained symptom relief.

Similar results were observed in the study by Gimenez-Arnau et al.[17] who compared rupatadine once daily with placebo in a randomized, double-blind trial of 6-week duration. In the pooled analysis performed by Mullol et al.[18] rupatadine 10 and 20 mg compared with placebo confirmed the significant improvement in MPS scores after 7 days and throughout the 4-week study period. Rupatadine has demonstrated rapid symptom relief compared to placebo in the above studies.

The overall improved efficacy of rupatadine over loratadine in CIU could be attributed to its PAF receptor antagonist activity and anti-TNFα activity. The important role of PAF and histamine in allergic response is well known and hence antihistamines targeting both these determinants could be the advisable therapeutic option in treating this condition.

Although the overall incidence of adverse effects in the rupatadine group has been found to be lower than in the loratadine group, there was no statistically significant difference between the two groups. Similar results were observed in the study by Saint-Martin et al.[19]

Thus rupatadine has been shown in several clinical trials to be an effective and well-tolerated treatment for reducing allergic symptoms in CIU. It has a rapid onset of action, providing immediate symptom relief, and an extended duration of clinical activity, allowing for once-daily administration. Importantly, rupatadine had no negative cardiovascular effects in preclinical or extensive clinical testing, nor did it have any negative significant effects on cognition or psychomotor performance.[20] Based on results from QoL questionnaires and patient global rating scores in clinical trials, it improved patients' overall well-being. Rupatadine is also found to be effective and well-tolerated in treatment for urticaria in children with CSU.[21]

Analysis of all the parameters of efficacy and safety establishes the probable superiority of rupatadine over loratadine for the treatment of urticaria. This was a single center study done in a limited number of patients with CIU. The findings of this interventional study need to be further explored by multicentric, randomized-controlled, double-blind large population trials.

The study has certain limitations. First of all, this was a short period study with only six weeks follow-up and a small sample size. Larger clinical trials with more sample size and more period of follow-ups are required to find out the other potential benefits of rupatadine in CIU.

Newer molecules with better pharmacokinetic and safety profile are available in the market. But considering the cost factor in those patients with poor affordability and in those patients who are intolerant to the newer drugs, these drugs are promising options.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Table 3

Total Symptom Score before and after treatment

	Baseline	6 weeks	Mean difference	P
Group 1 (n=25)	7.80±1.12	4.00±1.44	3.80±1.32	P<0.001
Group 2 (n=26)	7.69±1.01	3.85±0.88	3.85±1.49	P<0.001