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Abstract
BACKGROUND/AIMS Lodoxamide tromethamine andN-acetyl-aspartyl glutamic acid (NAAGA) are mast cell stabilisers, both of which have been shown to be effective in the treatment of allergic conjunctivitis. The aim of this study was to compare the two compounds in patients with common ocular allergic disorders.
METHODS 73 patients participated in a double masked, randomised multicentre study. Diagnoses were chronic allergic conjunctivitis, vernal conjunctivitis, seasonal and atopic conjunctivitis. 36 patients were treated with lodoxamide 0.1% and 37 with NAAGA 4.9%, the drops being instilled four times daily for up to 56 days.
RESULTS The overall opinion of the physicians and the patients was in favour of lodoxamide at day 10 of the study. At this time, 86% of lodoxamide treated and 49% of NAAGA treated patients considered they had improved. The patients’ opinion favoured lodoxamide at day 28 and both physicians’ and patients’ evaluations were in favour of lodoxamide at day 42. Evaluation of signs and symptoms indicated superiority of lodoxamide at days 42 and 56. Both treatments were well tolerated.
CONCLUSION While both lodoxamide and NAAGA treatments are associated with clinical improvements in patients with allergic conjunctivitis, lodoxamide may have an earlier onset of action.
- allergic conjunctivitis
- lodoxamide
- NAAGA
- topical therapy
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A variety of ocular conditions involving some degree of allergic component in their pathophysiology exist. Some allergic conditions, such as atopic keratoconjunctivitis and some severe cases of papillary conjunctivitis, can pose serious threats to vision and are therefore treated aggressively. Others, such as seasonal allergic conjunctivitis associated with hay fever, are less serious but are prevalent and present an important social problem.1-3 In the treatment of ocular allergies, topical antihistamines and vasoconstrictors lack efficacy except in relatively mild cases and rebound vasodilator responses may occasionally occur. The long term use of steroid drugs for the more severe cases is complicated by the risk of developing steroid induced glaucoma, cataract, and exacerbating external eye conditions.4 5 The discovery of mast cell stabilisers opened up a new therapeutic approach to the treatment of allergic disorders and both systemically and topically administered cromolyn sodium has been widely and successfully used.
Lodoxamide tromethamine 0.1% is a more recently developed mast cell stabiliser. In an in vivo allergic conjunctivitis model in rats, topical lodoxamide immediately before allergen challenge produced a dose dependent inhibition of allergic response. Its antiallergic activity was associated with mast cell mediator release and not end organ antagonism of released mediators.6 In a placebo controlled trial in patients with allergic conjunctivitis, topical lodoxamide has been shown to improve clinical signs and symptoms and to reduce the eosinophil number in conjunctival scrapings.7Studies comparing topical lodoxamide with cromolyn sodium have demonstrated similar safety of the two compounds but indicated that lodoxamide 0.1% is clinically superior to both 2% and 4% solutions of cromolyn sodium.8-10 Another compound currently on the market in several European countries for the treatment of allergic eye conditions and allergic rhinitis is the magnesium salt ofN-acetyl-aspartyl glutamic acid (NAAGA). NAAGA is a naturally occurring dipeptide in mammalian brain.11 A mast cell degranulation inhibitor, which also inhibits complement activation and leukotriene release,12 it had been shown to be similar in efficacy to cromolyn sodium in the symptomatic treatment of seasonal allergic rhinitis13 and to modulate allergen induced nasal symptoms and mediator release.14 Although it has been reported to be ineffective in giant papillary conjunctivitis,15 a study in allergic conjunctivitis showed it be as effective as cromolyn sodium.16
In the present study, topical lodoxamide and NAAGA were compared in patients suffering from common allergic eye disorders.
Methods
This was a randomised, double masked comparison of the safety and efficacy of lodoxamide 0.1% with NAAGA 4.9% in patients diagnosed with allergic conjunctivitis. Patients were eligible for the study if they had an ocular diagnosis of atopic keratoconjunctivitis, seasonal allergic conjunctivitis, chronic allergic conjunctivitis, or vernal keratoconjunctivitis (Table 1). They had to have at least mild hyperaemia of the bulbar conjunctiva and at least one other sign (discharge, limbal erythema/swelling, erythema/swelling of eyelids) together with at least mild itching and one other symptom (lacrimation, photophobia, discomfort, foreign body sensation). The patients preferably had to have a positive RAST skin test or skin prick test within 1 year before entry to confirm the allergic origin of the conjunctivitis. Patients had to be aged 4 years or older. Specifically excluded were patients taking concomitant ocular medications which might interfere with the evaluation of response (such as steroids or antihistamines), patients who had had ocular surgery within the past 6 months, those who had ocular hypertension (defined as intraocular pressure > 21 mm Hg), those with any presumed infectious ocular disease, keratoconjunctivitis sicca, or any presumed ocular disease that could be progressive. Patients with diabetes with proliferative retinopathy, cardiovascular, hepatic or renal disease not on a stable medical regimen, pregnant women or those who may become pregnant, and contact lens wearers were also excluded.
Definitions of allergic conjunctivitis
All patients had the details of the study explained to them and written informed consent was obtained. In the case of minors, informed consent was obtained from the parent or legal representative. The study was conducted at six centres in France and Italy. The study was approved by the appropriate ethics committees and was conducted in accordance with the Declaration of Helsinki.
CLINICAL PROCEDURES
Patients were examined and a detailed medical history was taken at entry to the study (day 0). The following five symptoms and eight signs were assessed using a provided manual of definitions to standardise scoring: discomfort, lacrimation, photophobia, itching, discharge, limbal changes (hyperaemia and swelling), epithelial disease, active papillae/follicles, inactive papillae/follicles, palpebral conjunctiva, bulbar conjunctiva hyperaemia, erythema/swelling of eyelids and surrounding periorbital tissue. All were assessed using a four point scale as 0 (absent), 1 (mild), 2 (moderate), or 3 (severe) with two exceptions. Itching was assessed on a scale of 0–4; an additional category of very mild was added. The hyperaemia/erythema of the inferior bulbar conjunctiva was assessed on a scale of 0 to 5 where 0 was normal and 1, 2, 3, 4, and 5 were minimal, mild, moderate, moderately severe, and severe, respectively. Patients were then provided with ophthalmic drops (0.1% lodoxamide or 4.9% NAAGA) according to a predetermined randomisation schedule and were instructed to instil one drop of study treatment into each affected eye four times a day (during waking hours) for a total of 56 days. The patients were told not to wear contact lenses during the study.
Clinical assessments were repeated on day 10 (SD 5 days), day 28 (3 days), day 42 (3 days), and day 56 (3 days). In addition, the physician evaluated the overall clinical condition and made one of the following judgments regarding therapeutic response: clinical cure, satisfactory clinical response, slight clinical improvement, clinically unchanged, slightly clinically worse, significantly clinically worse. The patients was also asked to judge the effectiveness of treatment according to the same scale. Visual acuity and intraocular pressure were measured in both eyes on entry and upon completing the study. Clinical adverse events were noted with details of the onset and duration, intensity, severity, possible contributing factors, action taken, outcome, and possible relation of the event to the study treatment. Patients were withdrawn from treatment if they showed deterioration in two or more signs or symptoms in either previously affected eye, if they developed a clinically significant adverse reaction to the study treatment, or if warranted clinically for any other reason. Patients were considered to have completed the study as planned if they completed the day 56 examination or if a rating of clinical cure was given at any time before the last scheduled follow up.
ANALYSIS OF RESULTS
The scores for the five ocular symptoms were added to give a total symptoms score; similarly, the scores for the eight signs were added to give the total signs score. Total signs and symptoms scores were compared between groups at baseline and at each follow up visit. The changes in individual sign/symptom scores from baseline were also calculated and compared between the two groups. The groups were compared statistically using the non-parametric Mann–Whitney rank score test.
Two analyses were performed; the main focus was an intention to treat analysis and this was supported by an efficacy subgroup analysis. The intention to treat population included all patients. The efficacy analysis included 57 patients (29 lodoxamide, 28 NAAGA) who met all inclusion criteria without any violation during the study. In addition, certain visits or data from certain eyes were also excluded. The most common reason for exclusion was that bulbar conjunctiva hyperaemia and/or itching scores were less than required; this was the reason for 14 totally excluded patients plus three excluded eyes. In the intention to treat analysis, the scores used were the means of the two eyes because all patients had both eyes involved. In the efficacy subanalysis the same method was used apart from for three patients who only had one eye considered.
Results
A total of 73 patients participated, of whom 36 were treated with lodoxamide and 37 with NAAGA. Patient details are summarised in Table2. The most frequent diagnosis was chronic allergic conjunctivitis. Twenty seven patients in each group completed the study of whom one lodoxamide treated and two NAAGA treated patients completed before day 56 because they were clinically cured. Two patients per group failed to complete the study because of adverse events while one NAAGA treated patient was non-compliant. Other patients not completing to day 56 were either lost to follow up (one patient per group) or did not wish to continue (six patients per group).
Patient population
CLINICAL RESPONSE
As judged by the investigators’ overall opinion, the two treatments in the intention to treat group were significantly different by day 10 when 81% of the lodoxamide group but only 46% of the NAAGA group were judged to be cured, to have a satisfactory response or slight improvement (p=0.002) (Table 3). The groups also differed significantly at day 42. In the efficacy subanalysis, the two groups differed significantly at day 10 when 80% of the lodoxamide and 40% of the NAAGA group showed improvement (p=0.002).
Clinical efficacy
In the opinion of the patient, lodoxamide treatment was associated with significantly greater improvement from baseline up to day 42 with the difference between the groups at day 56 just missing significance. On day 10, 86% of lodoxamide treated and 49% of NAAGA treated patients considered themselves as cured or improved. The efficacy subanalysis showed a significant difference between groups at day 10 only when 83% of the lodoxamide group and 47% of the NAAGA group considered themselves cured or improved.
The total symptom score decreased from baseline with both treatments but was significantly lower for lodoxamide than NAAGA at days 42 and 56 (Table 4). With respect to individual symptoms, the response to lodoxamide was superior to that obtained with NAAGA for discomfort at day 28 (p=0.036) and day 42 (p=0.028) and for photophobia at day 42 (p=0.009) and day 56 (p=0.019) (data not shown). The efficacy subanalysis showed a significant difference for total symptom score at day 42 only (p=0.040).
Total symptoms and signs scores
The total signs score also decreased from baseline with both treatments. The total score was significantly lower for lodoxamide than NAAGA at day 28 (p=0.050) and at day 42 and 56 (p=0.030 and 0.020) (Table 4). The treatments differed significantly with respect to palpebral conjunctiva at day 28 (p=0.042) and day 42 (p=0.040) and bulbar conjunctiva hyperaemia at day 28 (p=0.04) and day 42 (p=0.021) (data not shown). The efficacy subanalysis showed no significant difference for total signs score between the treatments.
SAFETY
Four patients treated with lodoxamide and two treated with NAAGA experienced adverse events. Adverse events with lodoxamide treatment were all mild or moderate in severity while those on NAAGA were severe. Table 5 summarises the reported adverse events; related events are those described as possibly, probably, or definitely related to treatment while unrelated events are those described as unlikely to be related or definitely unrelated to treatment. Four patients withdrew because of adverse events (those which were moderate or severe in intensity). One lodoxamide treated patient withdrew with eye discomfort and blurred vision. One patient with hyperthyroidism also withdrew. This patient experienced a sudden onset of hyperthyroidism (Basedow Graves’ disease related to an intercurrent illness). In the NAAGA group, one patient with eye discomfort and one with corneal ulcers left the study prematurely. The corneal ulcers were considered sight threatening; they followed an earlier resolved external eye infection with discharge. They resolved with treatment in 15 days and were not believed to be related to NAAGA treatment.
Incidence of adverse events
No clinically significant decrease in visual acuity was observed in either group. Similarly there was no clinically significant increase or decrease in intraocular pressure.
Discussion
Both intention to treat and efficacy subpopulation analyses showed lodoxamide to be more effective than NAAGA in that the overall resolution of allergic conjunctivitis was significantly better at earlier assessment points. At the last assessment (day 56), the groups did not differ significantly although there was a trend for greater improvement with lodoxamide in the opinions of the patients themselves. One patient in the lodoxamide treatment group and two in the NAAGA treatment group left the study before day 56 as they were considered clinically cured. Of those still in the study at day 56, the only ones to be considered to be cured had used lodoxamide. The results thus suggest that lodoxamide may have a more rapid onset of action in allergic conjunctivitis. It may also be more effective in the longer term. The patients and their physicians were in good agreement about the effectiveness of treatment. The decrease in symptoms and signs scores also indicated superiority of lodoxamide treatment over NAAGA, the scores being significantly lower at days 42 and 56 with lodoxamide treatment.
The side effects experienced in the two groups were comparable and were typical of many ophthalmic preparations instilled into the eye. None of the side effects noted with the systemic preparation of lodoxamide, principally nausea and headache,17-19 were noted in this study.
Previous publications have reported superiority of topical lodoxamide over cromolyn sodium in the treatment of allergic conjunctivitis7 and comparable efficacy of NAAGA and cromolyn sodium in this disease.14 The results of the present study confirmed the efficacy of lodoxamide and NAAGA. In addition, the data indicated that lodoxamide may have some advantages over NAAGA treatment, particularly in time to onset of action and in the longer term outcome.
Acknowledgments
This study was supported financially by Alcon Laboratories Incorporated, Fort Worth, Texas, USA.