Double-blind group comparative study of 2% nedocromil sodium eye drops with 2% sodium cromoglycate and placebo eye drops in the treatment of seasonal allergic conjunctivitis

A 4 week, multicentre, double-blind, double dummy, placebo controlled group comparative study was carried out during the birch pollen season to compare the efficacy and tolerability of 2% nedocromil sodium eye drops (twice daily) and 2% sodium cromoglycate eye drops (four times daily). Participants with a history of seasonal allergic conjunctivitis (SAC) were randomized to receive nedocromil sodium (60), sodium cromoglycate (61) or placebo (64). Clinical assessment of SAC showed improvement with both active treatments compared to placebo but symptomatology was low and only changes in photophobia and grittiness reached significance (P < 0.05). Patient diaries showed significant control of itching by both active treatments, compared to placebo, with no differences between the active preparations. Patients' opinions indicated a marked placebo effect: 73% of this group reported full or moderate control of symptoms, compared with 75% in sodium cromoglycate and 80% in the nedocromil sodium group. Unusual symptoms were most common (27 patients) with nedocromil sodium eye drops: P < 0.05 vs. placebo (15 patients). There were no serious adverse events. Nedocromil sodium eye drops (b.d.) and sodium cromoglycate eye drops (q.i.d.) were both considered clinically more effective than placebo in controlling symptoms of SAC due to birch pollen.     

Clinical Experience with Tilavist: An Overview of Efficacy and Safety

A programme of clinical studies was carried out to determine the basic efficacy and safety of 2% nedocromil sodium eye drops (Tilavist) in treating allergic conjunctivitis, in 2,905 patients from 3–76 years of age. Results of all the double-masked placebo comparative studies completed to date - five in vernal keratoconjunctivitis (VKC), five in perennial (PAC) and 16 in seasonal allergic conjunctivitis (SAC) - have been assessed in a statistical overview analysis. Nedocromil sodium, administered four times daily to 153 patients with VKC, was significantly more effective than placebo (155 patients) and in the clinicians' opinion gave good control in 76% of cases, compared with 46% for placebo (p < 0.001). Patients with chronic symptoms of PAC also responded better to nedocromil sodium given four times daily (n = 146) rather than twice daily (n = 86), and significantly more patients (p < 0.001) were effectively controlled by four times daily treatment with nedocromil sodium (72%) than with placebo (47%; n= 156). Twice-daily dosage with nedocromil sodium (n = 677) was adequate for SAC, however, and the treatment was statistically better than placebo (p < 0.01-p < 0.001) whether dosed twice or four times daily. Speed of action was assessed in seven SAC studies in which 79% of all patients (n = 295) using nedocromil sodium had experienced relief of symptoms when questioned, half of them within 15 minutes and 74% during the first hour after dosing. Test treatments were well-accepted by both adults and children, and there were no major adverse events. Minor irritations reported more frequently with nedocromil sodium than placebo were stinging or burning of the eyes on application of the drops and a distinctive taste, noted by 5% of the active treatment group (n = 1,552).     

Double-blind group comparative study of 2% nedocromil sodium eye drops with placebo eye drops in the treatment of seasonal allergic conjunctivitis

A multicenter double-blind group comparative study was carried out in 126 patients, 64 of whom received 2% nedocromil sodium eye drops, and 62 placebo eyedrops twice each day for the treatment of seasonal allergic conjunctivitis to birch pollen. The patients were evaluated at 2 week intervals for clinical signs of conjunctivitis and kept daily diary records of eye symptoms (0-4 severity scales) and concomitant therapy. Diary trends favored active treatment, and reached significance for excessive lacrimation (P less than .05) during peak pollen challenge. Clinic assessments showed the same directional trend and final opinions of treatment efficacy were significantly in favor of nedocromil sodium (P = .003, patients; P = .006, clinicians). In addition, the placebo group used significantly more topical (P less than .05) and oral (P less than .01) concomitant antihistamine therapy. Nedocromil sodium and placebo treatments were equally acceptable and well tolerated. The results show that 2% nedocromil sodium used topically twice each day is an effective therapy for seasonal allergic conjunctivitis.     

Nedocromil sodium 2% eye drops for twice-daily treatment of seasonal allergic conjunctivitis: a Swedish multicentre placebo-controlled study in children allergic to birch pollen

This was a multicentre, double-blind, randomized group comparative study in which 77 children, aged 6–16 years, received 2% nedocromil sodium eye drops and 72 received placebo, one drop into each eye twice daily. The treatment period was 4 weeks, covering the peak birch pollen season. Prior to the start or the season, patients who had mended the clinic the previous 2 years because of seasonal allergic conjunctivitis (SAC) to birch pollen, entered a one week baseline period during which symptoms were assessed, diary cards completed, and routine sampling of blood and urine earned out. The double-blind treatment period then commenced at the onset of the birch pollen season. Patients parents kept daily diary record cards of eye symptom severity and concomitant therapy. Conjunctivitis was mild in both treatment groups but nedocromil sodium was more effective than placebo in controlling symptoms. During the 2–3 weeks of peak pollen counts, this therapeutic effect was statistically significant for itching (P <0–01), watering (P <0.05) and total symptom score (P <0.01), but was not significant for grittiness (P= 0.08) or redness (P = 0.06). Global opinions of efficacy showed no difference between treatments, due to a high placebo effect (however, the diary card data indicated a significant improvement with nedocromil sodium). We therefore conclude that nedocromil sodium 2% eye drops, administered twice daily, is an effective treatment for SAC in children.     

Effects of adding nedocromil sodium (Tilade®) to the routine therapy of patients with bronchial asthma

In a 12-week double-blind, group comparative trial, preceded by a 2-week baseline period, 38 asthmatic subjects of mixed aetiology and varying severity received either 4 mg nedocromil sodium by metered dose inhaler twice a day or a matching placebo preparation, in addition to their existing maintenance therapy of inhaled corticosteroids plus inhaled bronchodilators. Asthma severity and lung function were assessed at 4-weekly clinic visits, and symptomatology (morning tightness, daytime asthma, cough, night-time asthma), morning, afternoon and evening PEFR, and the use of inhaled bronchodilators were recorded on daily diary cards. Treatment with nedocromil sodium led to significant (P less than 0.05) improvements in clinic assessment of FEV1 and PEFR both before and after an inhaled bronchodilator from at least the eighth week onwards. Mid-study FVC was also significantly (P less than 0.05) improved. Daily PEFR increased throughout the study in the nedocromil sodium-treated subjects and the diurnal variation was reduced. Daily symptom severity was also reduced and these improvements occurred despite the similar or slightly reduced use of inhaled bronchodilators. However, none of these improvements in diary card parameters reached statistical significance. By the final week of the study subjects treated with nedocromil sodium predominantly had a mild form of asthma or no symptoms at all, and both patients and clinicians reported the effectiveness of nedocromil sodium; the subjects but not the clinicians finding it significantly more effective (P less than 0.05) than placebo. Nedocromil sodium was well tolerated although one patient was withdrawn owing to a persistent sore throat after 7 weeks of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Steroid sparing effect of nedocromil sodium in asthmatic patients on high doses of inhaled steroids

Nedocromil sodium is a non-steroidal prophylactic agent developed for the management of asthma. We have assessed the steroid sparing potential of inhaled nedocromil sodium 4 mg four limes daily in a randomized, double blind, placebo controlled study in 69 asthmatic subjects controlled on inhaled beclomethasone dipropionate in the dose range 1000 2000 μg daily. Following a 4 week run-in period subjects added nedocromil sodium or placebo by metered dose inhaler to their usual medication for a further 4 weeks. The dose of inhaled steroid was then reduced at fortnightly intervals according to a predetermined schedule, with monitoring of asthma severity, symptom scores, bronchodilator use and peak flow recordings. Sixty subjects entered the steroid reduction phase and achieved median (range) % decreases in steroid dose of 80 (17-100)% with nedocromil sodium compared to 65 (0-100)% with placebo (P = 0.34) with 14 patients in the nedocromil sodium group and 10 in the placebo group being withdrawn completely from inhaled steroids. Subjective global assessment scores were significantly better with nedocromil sodium (mean 2.14) than with placebo (2.93; P<0.02) though there was no difference between individual daily symptom scores. In this study therefore in asthmatic patients controlled on high doses of inhaled steroids, nedocromil sodium was well tolerated but the smalt differences in steroid sparing effect between nedocromil and placebo were not statistically significant.     

Treating severe eye allergy

Allergic eye conditions, particularly seasonal allergic conjunctivitis (SAC), are common. Itching, oedema and hyperaemia are relieved with topical H₁-antagonists or sodium cromoglycate. The newer mast-cell stabilizing agent nedocromil sodium has a similar safety profile to sodium cromoglycate, but is more potent and has a more convenient twice-daily dosing regimen. When several placebo-controlled studies of its use in the treatment of SAC were analysed, it was found that 80% of patients reported symptom relief. In a further study, nedocromil sodium eyedrops (twice-daily dosing) had similar overall efficacy to sodium cromoglycate eyedrops (four-times-daily dosing) in subjects with SAC during the birch season, but during the period of highest pollen challenge, only the former agent was significantly more effective than placebo. Another study found that nedocromil sodium had efficacy equivalent to levocabastine over 7 days, but tended to have a more rapid onset of action. In patients with perennial allergic conjunctivitis (PAC) unresponsive to sodium cromoglycate, both clinicians and patients reported significantly better control of symptoms with nedocromil sodium eyedrops than with placebo. Recently, in a long-term study of treatment for vernal keratoconjunctivitis (VKC), it was found that nedocromil sodium 2% eyedrops produced a more rapid and marked improvement in symptoms than sodium cromoglycate 2% eyedrops and enabled lower use of steroid rescue medication. Both drugs were well tolerated and without serious side-effects.     

Comparative Therapeutic Studies with Tilavist

Comparative clinical trials which include known therapies as well as placebos are essential in constructing a solid basis from which to 'launch' any new drug. This applies especially to eye drops for treatment of seasonal allergic conjunctivitis, where the symptomatology, already dependent on the vagaries of the natural pollen challenge season, is further influenced by a positive washing action of the placebo eye drops. Tilavist (2% nedocromil sodium ophthalmic solution) has therefore been compared with sodium cromoglycate eye drops and non-sedating antihistamine tablets, both mainstays in the treatment of seasonal allergy, in a series of double-masked, placebo-controlled, mainly multicentre studies. Nedocromil sodium, twice or four times daily, proved as effective overall as sodium cromoglycate (2% or 4% four times daily) in three seasonal trials, and was the more effective treatment in a study of patients with vernal keratoconjunctivitis. Its efficacy was most evident during peak periods of pollen challenge, when neither placebo nor sodium cromoglycate eye drops controlled breakthrough symptoms. Three further seasonal studies showed nedocromil sodium eye drops to be as effective as standard oral doses of astemizole and terfenadine, whilst a faster onset of action than terfenadine was reported in one multicentre study.     

Airway constriction by isocapnic hyperventilation of cold, dry air: comparison of magnitude and duration of protection by nedocromil sodium and sodium cromoglycate

The protective effect of 1,2 and 4 mg of nedocromil sodium against airway constriction induced by hyperventilation of cold, dry air was compared with 10 mg sodium cromoglycate and placebo in a double-blind randomized trial. On 5 days, twelve asthmatic subjects received one of the trial medications from a metered dose inhaler. Twenty minutes, 2.5 and 5 hr later, airway responsiveness to hyperventilation of cold, dry air was measured. At 20 min, there was significant protection by all four active medications when compared to placebo, with a trend towards a nedocromil dose relationship but there was no statistical difference between the four active medications. All four showed a similar progressive decrease in protection over 5 hr. The results of this study suggest that nedocromil gives protection against hyperventilation-stimulated airway constriction and that the magnitude and duration of effect for all three doses is similar to 10 mg of cromoglycate.     

A trial comparing nedocromil sodium (Tilade®) and placebo in the management of bronchial asthma

Abstract. In a double-blind group comparative trial nedocromil sodium (Tilade®) at a dose of 4 mg four times daily was compared with placebo in the management of out-patients with bronchial asthma. Treatments were delivered by pressurized aerosol over a period of 28 days following a 2-week base-line during which patients continued on their usual therapy. Twenty-one patients entered the nedocromil sodium group and twenty entered the placebo group. All were using beclomethasone dipropionate aerosol as maintenance steroid therapy plus intermittent use of a bronchodilator taken by inhalation. The dose of steroid was reduced for all patients after 2 weeks of treatment and again for approximately half the patients after 3 weeks trial treatment. Patients in the nedocromil sodium treatment group improved in respect of Diary Card symptom scores and peak expiratory flow rate (PEFR), and in their requirements for inhaled bronchodilators. Patients in the placebo group were worse, particularly in respect of daytime asthma symptoms ( P < 0·01), bronchodilator use ( P < 0·05) and morning PEFR during the third week of trial treatment ( P < 0·05). More patients in the nedocromil sodium group than in the placebo group thought their treatment had been effective ( P < 0·05). Nedocromil was well tolerated. Despite the short duration of treatment imposed at this stage in the clinical evaluation of a new compound, our results were sufficiently encouraging to prompt further evaluation of nedocromil sodium over the longer period required (3–12 months) for the clinical assessment of a new treatment for chronic asthma.     

Effect of nedocromil sodium on exercise-induced bronchoconstriction in children

A double-blind, placebo-controlled, crossover study investigated the efficacy of nedocromil sodium in reducing bronchoconstriction subsequent to exercise challenge in asthmatic children. Twelve children aged 7-14 years (mean 10.8 years) were pretreated with nedocromil sodium aerosol (2 inhalations; 2 mg/inhalation) or matching placebo, 30 min prior to treadmill running. Lung function was measured at regular intervals postexercise and the mean maximum percentage decrease in PEF and FEV1 compared following nedocromil sodium or placebo pretreatment. Nedocromil sodium significantly reduced the fall in PEF (P less than 0.001) and FEV1 (P less than 0.001) and provided significantly greater protection (P less than 0.001) than placebo. No adverse reactions or unusual symptoms were observed.     

Effect of nedocromil sodium on the late asthmatic reaction to bronchial antigen challenge

The effect of inhaled nedocromil sodium (4 mg by pressurized aerosol) on the dual asthmatic reaction to bronchial antigen challenge was studied in eight patients with asthma. The following prechallenge/postchallenge treatment combinations were administered: nedocromil sodium/placebo, nedocromil sodium/nedocromil sodium, placebo/nedocromil sodium, and placebo/placebo. Each patient received three treatment combinations assigned with a balanced incomplete block design. Nedocromil sodium administered before antigen challenge was significantly more effective than placebo in blocking both the early (p less than 0.001) and late (p less than 0.01) fall in FEV1. Postchallenge administration of nedocromil sodium tended to delay the onset of late asthmatic reaction but did not provide significant protection compared to placebo. These results demonstrated that nedocromil sodium prevents both phases of the dual asthmatic reaction to bronchial antigen provocation when it is inhaled before challenge. Further investigation is necessary to elicit a definite answer to whether nedocromil sodium administered after bronchial challenge has an effect on late asthmatic reaction.     

Double-blind, randomized, placebo-controlled trial of effect of nedocromil sodium on clinical and inflammatory parameters of asthma in children allergic to dust mite

BACKGROUND: The purpose of this study was to determine the clinical effect of nedocromil sodium and its relationship with serum levels of inflammatory mediators by monitoring lung function and noninvasive markers of airway inflammation, such as eosinophil blood counts; serum ECP, sIL-2R, IL-4 and sICAM; and total IgE. Anti-inflammatory medications cause a reduction in the markers of airway inflammation, decrease the intensity of airway hyperresponsiveness, and improve clinical symptoms of asthma. Among the available choices is nedocromil sodium, which is favored in the treatment of asthmatic children due to its very mild side-effects. It has been previously shown to improve the clinical parameters of asthma, but there are limited data on its effect on inflammatory mediators in the serum of asthmatic children. METHODS: In this double-blind, randomized, placebo-controlled 8-week trial, 39 children, aged 9-16 years, with moderate atopic asthma were randomly allocated to receive either nedocromil sodium, two puffs twice daily, 0.002 g/puff, or placebo, two puffs twice daily. The primary end points were the clinical parameters of asthma measured by asthma symptom score, FEV1, and PC20H. Other end points included the serum levels of various inflammatory markers - ECP, sIL-2R, IL-4, sICAM, and IgE. RESULTS: Clinical and inflammatory parameters improved with the use of nedocromil sodium, compared with placebo. Nedocromil significantly decreased serum levels of inflammatory markers, as shown in the following table. No correlation was found between any of the measured parameters. CONCLUSION: Nedocromil sodium provided effective anti-inflammatory treatment for children with moderate atopic asthma.     

A comparative study of the effects of two different doses of nedocromil sodium and placebo given by pressurised aerosol in exercise-induced bronchoconstriction

Fourteen adult subjects with stable asthma were treated using a double-blind crossover, randomised protocol, with either nedocromil sodium (4 mg or 2 mg) or placebo. The agents were administered from matched pressurised aerosol inhalers 30 min before exposure to an exercise regimen which, on a previous screening day, resulted in a 24–53% (mean: 33.9%) decrease in peak expiratory flow (PEF). Both doses of nedocromil sodium were significantly superior to placebo in preventing the exercise-induced decrease in PEF and were without side effects. This study confirms and extends the results of earlier trials with nedocromil sodium and further supports the contention that this new agent may be of benefit in the treatment of reversible obstructive airways disease in the adult patient.     

Effect of nedocromil sodium on the immediate response to antigen challenge in asthmatic patients

In this double-blind placebo controlled crossover study the protective effect of nedocromil sodium against bronchial allergen challenge was evaluated in ten asthmatic patients. Single doses of 0.5, 1.0 and 2.0 mg nedocromil sodium, administered as a pressurized aerosol 3 hr prior to challenge, were each significantly more effective than placebo in inhibiting allergen-induced bronchoconstriction. The 1.0 and 2.0 mg doses of the active drug were significantly more effective than the 0.5 mg dose. No significant difference was demonstrated between the 1.0 and 2.0 mg doses. Duration of protection beyond 3 hr was not tested. The results suggest that nedocromil sodium may be a potentially useful therapeutic agent and is worthy of further evaluation for the treatment of reversible obstructive airways disease.     

Multicenter placebo-controlled study of nedocromil sodium 1% nasal solution in ragweed seasonal allergic rhinitis

An 8-week double-blind study was carried out in 177 ragweed patients with seasonal allergic rhinitis to compare nedocromil sodium 1% nasal solution (Tilarin, QID, Fisons plc) and placebo. Symptoms of rhinitis were significantly reduced by nedocromil sodium during the peak 3-week pollen season (P = .001 for diary summary score) and the active treatment was rated effective by 74% of patients.     

A 3-month evaluation of the efficacy of nedocromil sodium in asthma: a randomized, double-blind, placebo-controlled trial of nedocromil sodium conducted by a Canadian multicenter study group

Nedocromil sodium is a pyranoquinoline dicarboxylic acid derivative, formulated in a metered-dose inhaler. Because nedocromil sodium has in vitro and in vivo anti-inflammatory properties, it was evaluated in a group of steroid-dependent patients with asthma to observe how well it might be tolerated and for evidence of any beneficial effects. In a double-blind, group-comparative study, 127 patients received nedocromil sodium and 61 received placebo, administered as two puffs of 2 mg, four times per day, for 12 weeks. Ten patients developed adverse reactions, seven receiving active drug and three patients receiving placebo. Two patients of each group withdrew because of worsening asthma. Despite selecting patients whose asthma was stable, when they were receiving established therapeutic regimens that included steroids and bronchodilators, it was found that diary-card symptom scores, morning and evening peak expiratory flow rate values, and inhaled beta-agonist usage all demonstrated slight but significant benefit with addition of nedocromil sodium. It is concluded that the inhaled, anti-inflammatory agent, nedocromil sodium, may be added to asthma-treatment regimens with the reasonable expectation of further modest symptomatic benefit.     

Nedocromil sodium in exercise-induced bronchoconstriction in children

Twenty asthmatic children were studied in a double-blind within-patient comparative trial designed to assess the efficacy of nedocromil sodium (4 mg) and placebo in exercise-induced bronchoconstriction. The response to exercise challenge given 30 minutes after treatment showed statistically significant differences in favor of nedocromil sodium. No unusual symptoms were reported.     

The effectiveness of the nonsedating antihistamine loratadine plus pseudoephedrine in the symptomatic management of the common cold

A multicentered trial compared the effects of the non-sedating antihistamine, loratadine, 5 mg plus pseudoephedrine 120 mg with a placebo on the signs and symptoms of the common cold. One hundred forty-two (142) subjects were treated with the loratadine/pseudoephedrine combination and 141 subjects were treated with placebo twice daily for five days. Evaluations by both subjects and physicians suggest that this antihistamine/decongestant combination is superior to placebo in relieving symptoms of the common cold. Specific differences were found in symptoms including nasal congestion, sneezing, postnasal drainage, and nasal discharge. Differences between groups for the following side effects were found: dry mouth (9% for the combination vs 2% for placebo), insomnia (6% vs 3%), and nervousness (4% vs 2%). There were no differences between groups for the frequency of drowsiness.     

A double-blind, placebo-controlled study to assess the efficacy of nedocromil sodium in the management of childhood grass-pollen asthma

The aim of this double-blind placebo-controlled trial was to assess the efficacy and tolerance of nedocromil sodium at a dose of 4 mg four times daily, in the management of children suffering from grass-pollen asthma. Thirty-one children suffering from seasonal asthma (24 boys and seven girls, aged 4-21 yr, mean 11 yr) were enrolled in the study during the 1988 pollen season. Only one child was aged 4 yr, and she was a cooperative girl able to use the metered dose inhaler properly. In addition, in each group there was a patient aged 20 and 21 years, respectively, who had been followed up by us since childhood. Treatments were delivered by pressurized aerosol over a period of 4 weeks following a 1-week baseline, during which patients were required to show active disease by obtaining a minimum symptom score (almost 2 points of severity score on at least 3 days of the baseline period). The patients were randomly assigned to both treatment groups, all were taking inhaled or oral bronchodilators, when necessary. Twenty-nine patients completed the trial, 16 in the nedocromil sodium treatment group and 13 in the placebo group. One child of each group was withdrawn due to treatment failure. Statistically significant differences in favour of nedocromil sodium were found regarding morning tightness and mean morning PEFR values on diary cards (P less than 0.01 and P less than 0.05, respectively), bronchodilator usage (P less than 0.05), pulmonary function tests (PFT) at clinic visits (P less than 0.05), and in parents' opinion (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)