A double-blind group comparative study of ophthalmic sodium cromoglycate, 2% four times daily and 4% twice daily, in the treatment of seasonal allergic conjunctivitis

In a multicenter, double-blind, single-dummy, group-comparative study, 169 patients received ophthalmic sodium cromoglycate 2% four times daily, and 170 patients received 4% ophthalmic sodium cromoglycate twice daily, together with placebo eye-drops twice daily, for the treatment of seasonal allergic conjunctivitis (SAC) to birch pollen. The treatment period was 4 weeks during the birch pollen season. Daily pollen counts were used to identify the peak 14-d period. Clinical examinations were made before the start of treatment, after 1 week of treatment, and at the end of the treatment period. Patients kept daily diary record cards of eye symptom severity and concomitant therapy. Symptoms were generally mild and, except for chemosis (week 4) and soreness (weeks 2 and 3), which were less in the 4% group (P0.05), no significant treatment differences were seen for symptoms or for antihistamine rescue therapy. Both treatments were considered to be very or moderately effective by more than 90% of patients, and no treatment differences occurred in either clinicians' or patients' opinions of efficacy. The results indicate that the use of 4% sodium cromoglycate eye-drops twice daily is as effective and well tolerated as 2% sodium cromoglycate four times daily in the treatment of birch-pollen conjunctivitis.     

A comparison of topical levocabastine and sodium cromoglycate in the treatment of pollen-provoked allergic conjunctivitis

A total of 71 patients with documented birch and grass pollen allergy participated in this randomized, double-blind, parallel-group study initiated to compare the long-term therapeutic efficacy of twice daily levocabastine, a new topical H₁-receptor blocker, with that of sodium cromoglycate four times daily in the treatment of pollen-provoked conjunctivitis. There was no statistically significant difference in therapeutic efficacy between the two treatment groups, although a positive trend in favour of levocabastine was observed. Global evaluations of therapeutic efficacy were similar in both treatment groups. A total of 94% of levocabastine-treated patients rated treatment to be excellent or good compared with 86% of patients in the sodium cromoglycate group. Moreover, there were no significant differences in the severity of allergic symptoms reported on the patient diary cards. Patients were permitted to use rescue medication (oral terfenadine and betamethasone nasal spray) if symptoms became severe. The use of rescue medication was lower in the levocabastine group than in the sodium cromoglycate group. The mean number of days on which rescue medication was used was 12.8 and 26.9 in the two groups, respectively. The incidence, and type, of adverse reactions was similar in both patient groups. Levocabastine is well-tolerated and at least as effective as sodium cromoglycate in the treatment of pollen-provoked conjunctivitis.     

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.     

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.     

Efficacy, cost-effectiveness, and tolerability of mometasone furoate, levocabastine, and disodium cromoglycate nasal sprays in the treatment of seasonal allergic rhinitis.

BACKGROUND: Current guidelines recommend intranasal glucocorticosteroids as first-line therapy for seasonal allergic rhinitis. OBJECTIVE: To compare the efficacy, cost-effectiveness, and tolerability of the topical glucocorticosteroid mometasone furoate, the topical antihistamine levocabastine hydrochloride, and the cromone disodium cromoglycate in seasonal allergic rhinitis. METHODS: This study was performed during the 2003 grass pollen season as an open, randomized, parallel-group, single-center study of 123 patients assigned to receive mometasone furoate (200 microg once daily), levocabastine hydrochloride (200 microg twice daily), or disodium cromoglycate (5.6 mg 4 times daily). Symptom scores and nasal inspiratory peak flow measurements were recorded in a patient diary. The global efficacy of the study medication was evaluated by patients after treatment. Eosinophil cationic protein concentrations were measured in nasal secretions before and after treatment. Cost-effectiveness was evaluated as medication cost per treatment success. RESULTS: Mometasone furoate therapy was significantly superior to the use of levocabastine or disodium cromoglycate with respect to all nasal symptoms, the global evaluation of efficacy, and eosinophil cationic protein concentration. Furthermore, mometasone furoate therapy was significantly superior to disodium cromoglycate therapy with respect to nasal inspiratory peak flow. Medication cost per treatment success was lowest with mometasone furoate use and highest with levocabastine use. CONCLUSION: This is the first study to compare mometasone furoate nasal spray with nonsteroidal topical treatments for seasonal allergic rhinitis. Mometasone furoate nasal spray was confirmed as a first-choice topical treatment option for seasonal allergic rhinitis.     

Topical levocabastine protects better than sodium cromoglycate and placebo in conjunctival provocation tests

Levocabastine is a new H1 receptor blocking antihistamine which is intended for topical use in the treatment of allergic conjunctivitis. The protective effect of the drug in conjunctival provocation test (CPT) was evaluated in a double blind study of 25 children aged 9-17 years with confirmed pollen allergy. One drop of levocabastine, cromoglycate or placebo was instilled into the conjunctival sac of both eyes. After 15 min CPT was performed, starting with 320 BU of pollen extract. The allergen dose was increased every 10 min in half 10-log steps in the right eye until a positive reaction occurred, or the top dose 320,000 BU was reached. The lowest dose resulting in a positive CPT reaction, i.e. at least 50% of the conjunctiva with erythema, was defined as the allergenic threshold dose (ATD). Pretreatment with levocabastine resulted in a median ATD of 32,000 BU, compared with 10,000 after cromoglycate (P less than 0.001) or placebo (P less than 0.01). Levocabastine was also superior in reducing subjective itch in the eyes. Determination of the ATD can be used as a relatively quick assessment of drugs intended for the treatment of allergic conjunctivitis.     

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.     

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 topical budesonide and levocabastine on nasal symptoms and plasma exudation responses in seasonal allergic rhinitis

This study compares the effects of two topical nasal treatments for allergic rhinitis, budesonide and levocabastine, on symptom development during seasonal pollen exposure. Additionally, the protective effects of drug treatments on allergen-challenge-induced responses (symptoms and microvascular exudation of plasma) are examined late into the pollen season. Forty-four patients with seasonal allergic rhinitis to birch pollen participated in this single-blind, randomized, and placebo-controlled study. Topical nasal treatment with either levocabastine (200 p.g b.i.d.: n = 16), budesonide (200 μg b.i.d.; n = 16), or placebo (n= 12) was instituted before the start of the pollen season and continued for 5 weeks until the end of the birch pollen season. The participants kept diaries for scores of nasal and ocular symptoms. Nasal allergen challenges with increasing doses of a birch pollen extract (10², 10³ and lC SQ-U) were carried out both before, when patients were asymptomatic and without treatment, and late into the pollen season. A nasal lavage followed each challenge, and the lavage fluid levels of albumin were measured as an index of the acute inflammatory response of the allergic mucosa. The birch pollen season was rather mild, producing only small increases in nasal symptoms. Budesonide treatment reduced the total nasal symptoms compared to placebo (P<0.01) and to levocabastine (P<0.05), while levocabastine treatment did not differ significantly from placebo. Ocular symptoms and use of rescue medication did not differ between placebo and the active treatments. At the end of the pollen season, both treatments reduced allergen-challenge-induced nasal symptoms compared to placebo (P<0.01). Only budesonide reduced allergen-challenge- induced increments of albumin levels in postchallenge nasal lavage fluids (P<0.05, in comparison with placebo). The results suggest that budesonide reduces both seasonal and allergen-challenge-induced nasal symptoms, while levocabastine is effective against allergen-challenge-induced symptoms also during the season. In addition, the topical steroid treatment, but not the antihistamine, inhibits the inflammatory exudation evoked by allergen challenge in patients with active seasonal disease.     

Double-blind comparison of levocabastine eye drops with sodium cromoglycate and placebo in the treatment of seasonal allergic conjunctivitis

The efficacy and tolerance of topical administration (one drop in each eye q.i.d.) of levocabastine (0.5 mg/ml) was compared with that of sodium cromoglycate (20 mg/ml) and placebo in a 4-week double-blind trial in patients with seasonal allergic conjunctivitis. The investigator rated the treatment as globally good or excellent in significantly more patients treated with levocabastine (89%) than with cromoglycate (67%, P = 0.03) or placebo (48%, P = 0.007). The patients felt that the treatment was more efficacious in 95% (levocabastine), 35% (cromoglycate) and 36% (placebo) of the cases in which they had taken previous antiallergic medication. Total symptom severity according to the patients' diary data was consistently lower with levocabastine than with cromoglycate or placebo for all ocular symptoms. The difference was mainly apparent at the beginning of treatment. The percentage of symptom-free days was higher in the levocabastine group (53%) than in the cromoglycate (31%, P = 0.02) and the placebo group (34%, P = 0.08). Particularly at high-pollen days, levocabastine was superior to cromoglycate in eliminating moderate or severe symptoms. Adverse effects did not occur more frequently with levocabastine or cromoglycate than with placebo. It is concluded that levocabastine is an efficacious, fast-acting and well-tolerated drug in the management of seasonal allergic conjunctivitis.     

A Double-Blind Evaluation of Topical Levocabastine, a New Specific H1 Antagonist in Patients with Allergic Conjunctivitis

Forty patients suffering from allergic conjunctivitis, due to birch pollen, participated in a double-blind parallel group comparison between levocabastine (a potent new specific histamine (H1) antagonist) and placebo, both given as eye drops. Symptom scores were recorded during a 4-week period. A 1-week run-in period was followed by a 3-week treatment period. To enable a fair evaluation of the treatment effect on the ocular symptoms only, all patients were treated with topical nasal glucocorticoids for possible rhinitis symptoms during the whole study period. Plasma levels of levocabastine were determined in all subjects at the end of the 3 weeks' treatment period. Pollen counts for birch pollen were followed simultaneously. The evaluation of the symptom score cards revealed a significant reduction of ocular symptoms following use of the active compound. The resorption of the active substance through the conjunctiva was low. In accordance with the present trend of more topical treatment for allergic rhinitis, levocabastine may constitute a valuable compound for the topical treatment of allergic conjunctivitis.     

Topical levocabastine is more effective than sodium cromoglycate for the prophylaxis and treatment of seasonal allergic conjunctivitis

The efficacy, tolerability, and adverse-effect profile of the recently developed, topical antihistamine levocabastine were compared with those of sodium cromoglycate in a 4-week double-blind, placebo-controlled trial in 95 patients with seasonal allergic conjunctivitis. At the end of the trial, global therapeutic efficacy was considered to be excellent or good in 87% of levocabastine-treated patients, as compared with 68% of sodium cromoglycate-treated patients ( P = 0.006) and 63% of those who received placebo ( P = 0.05). After 4 weeks of treatment, levocabastine patients had experienced significantly greater relief from their most severe ocular symptom than patients in the sodium cromoglycate group ( P < 0.05). Furthermore, 37% of levocabastine-treated patients were virtually symptom-free for at least 75% of the treatment period, as compared with only 6% of patients in the sodium cromoglycate group ( P < 0.01) and 4% of those who received placebo ( P < 0.01). Moreover, this trend was maintained on days when the pollen count was high, when the corresponding figures were 33%, 6% ( P = 0.02), and 4% ( P = 0.02), respectively. Levocabastine was well tolerated. Indeed, the incidence of adverse reactions was no greater in the levocabastine group than in the placebo group. Topical levocabastine is an effective and well-tolerated drug for the prophylaxis and treatment of seasonal allergic conjunctivitis.     

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.     

Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study)

BACKGROUND: Children with allergic rhinitis are likely to develop asthma. OBJECTIVE: The purpose of this investigation was to determine whether specific immunotherapy can prevent the development of asthma and reduce bronchial hyperresponsiveness in children with seasonal allergic rhinoconjunctivitis. METHODS: From 6 pediatric allergy centers, 205 children aged 6 to 14 years (mean age, 10.7 years) with grass and/or birch pollen allergy but without any other clinically important allergy were randomized either to receive specific immunotherapy for 3 years or to an open control group. All subjects had moderate to severe hay fever symptoms, but at inclusion none reported asthma with need of daily treatment. Symptomatic treatment was limited to loratadine, levocabastine, sodium cromoglycate, and nasal budesonide. Asthma was evaluated clinically and by peak flow. Methacholine bronchial provocation tests were carried out during the season(s) and during the winter. RESULTS: Before the start of immunotherapy, 20% of the children had mild asthma symptoms during the pollen season(s). Among those without asthma, the actively treated children had significantly fewer asthma symptoms after 3 years as evaluated by clinical diagnosis (odds ratio, 2.52; P <.05). Methacholine bronchial provocation test results improved significant in the active group (P <.05). CONCLUSION: Immunotherapy can reduce the development of asthma in children with seasonal rhinoconjunctivitis.     

Intramuscular betamethasone dipropionate vs. topical beclomethasone dipropionate and placebo in hay fever

A double-blind, double-dummy comparative study was made of 30 adult birch pollen-allergic outpatients with seasonal rhinoconjunctivitis. They were treated with either topically applied beclomethasone dipropionate 100 micrograms in each nostril twice daily for 4 weeks, placebo, or an injection of 2 ml of a suspension containing 5 mg betamethasone dipropionate and 2 mg betamethasone disodium phosphate per ml (Diprospan) immediately prior to the birch pollen season. Placebo- and topical steroid-treated patients experienced an increase in rhinoconjunctivitis symptoms, i.e. nasal blockage, nasal itching, rhinorrhea, sneezing and eye symptoms, and placebo-treated patients used significantly more antihistamine tablets during the pollen season. Diprospan-treated patients experienced fewer symptoms on all measured parameters. We concluded that one injection of Diprospan immediately prior to the birch pollen season produces significantly fewer rhinoconjunctivitis symptoms than does placebo and topical steroid treatment.     

Topical levocabastine, a selective H1 antagonist, in seasonal allergic rhinoconjunctivitis

Sixty-six patients with seasonal allergic rhinitis due to birch pollens, participated in an efficacy evaluation of topically applied, nasal and ocular, levocabastine, a highly selective H1 antagonist. A single blind comparison was performed between nasal levocabastine and flunisolide, a topical glucocorticoid preparation. Ocular levocabastine was compared with topical naphazoline/antazoline eye drops. Nasal and ocular symptom scores were recorded during a 31-day period. Pollen counts of birch pollens were done simultaneously. A global assessment of treatment efficacy was also made. In the comparison between the ocular treatments a significantly higher number of patients cited levocabastine excellent--it also had the advantage of fewer daily administrations. For nasal symptom scores the topical glucocorticosteroid therapy was in favour by number of sneezes. As for side effects, 44% of the patients complained of local irritation from naphazoline/antazoline eye drops or flunisolide nasal spray, but none with the levocabastine preparations. Topical levocabastine may provide an interesting alternative in the treatment of allergic rhinoconjunctivitis.     

Topical sodium cromoglycate (Opticrom®) relieves ongoing symptoms of allergic conjunctivitis within 2 minutes

Montan P, Zetterström O, Eliasson E, Strömquist L-H. Topical sodium cromoglycate (Opticrom®) relieves ongoing symptoms of allergic conjunctivitis within 2 minutes.
Twelve patients with seasonal allergic conjunctivitis caused by either birch or timothy grass pollen were challenged out of season in both eyes, with the relevant allergen. Itching, redness, swelling, and tearing were assessed on a 0–3 scale. When a positive reaction, i.e., at least 4 points, had occurred in both eyes, one drop of 2% sodium cromoglycate was administered to one eye and one drop of placebo to the other eye in each patient, in a double-blind, randomized fashion. Symptoms were then assessed after 2, 10, 30, and 60 min. Sodium cromoglycate was statistically better than placebo in reducing the symptoms at 2, 10, and 30 min after the treatment had been administered, showing that topical application of 2% sodium cromoglycate can quickly relieve ongoing symptoms of allergic inflammation in the eve.     

Intra-nasal beclomethasone dipropionate and intra-nasal sodium cromoglycate: a comparative trial

Ten patients with either seasonal allergic or perennial rhinitis were treated with intra-nasal beclomethasone dipropionate B.P. (Beconase) and nine comparable patients were treated with sodium cromoglycate B.P. (Rynacrom). The beclomethasone dipropionate was administered as 50 μg per puff into each nostril three times a day and the sodium cromoglycate as one capsule insufflated into each nostril four times a day. Treatments were allocated on a randomized basis and each patient received a course of treatment lasting 2 weeks during the summer of 1973 when the pollen counts were high. Utilizing patient daily symptom diary cards, physician's assessment and by examination of the nasal mucosa prior to and at the end of treatment, it was concluded that both intra-nasal beclomethasone dipropionate and intra-nasal sodium cromoglycate effect a reduction in the symptoms associated with rhinitis. No side effects of importance were noted, nor were there any adverse changes observed in the state of the nasal mucosa.     

Prevention of pollen rhinitis symptoms: comparison of fluticasone propionate aqueous nasal spray and disodium cromoglycate aqueous nasal spray

Fluticasone propionate aqueous spray, a new intranasal corticosteroid preparation, and disodium eromoglyeate 2% aqueous nasal spray, an established preventive treatment for seasonal allergic rhinitis, were compared in a double-blind, double-dummy, parallel-group, multicentric study in France. A total of 218 patients with seasonal allergic rhinitis caused by grass pollen (verified by positive skin prick test) were preventively treated before the onset of the grass pollen season with either fluticasone propionate 200 μg once daily or disodium cromoglycate 5.2 mg four times daily. Half of these doses was given in each nostril. Treatment started before the onset of the pollen season in most patients (178/218). Diary cards, including symptoms of rhinitis and usage of nasal sprays, were filled in twice daily for 5 weeks.
Terfenadine in 60-mg tablets and eye-drops could be used as rescue medications. We treated 110 patients with fluticasone propionate and 108 patients with disodium cromoglycate. Patients treated with flutieasone propionate had significantly more days free of primary efficacy symptoms of sneezing ( P < 0.001) and nasal discharge during the day ( P = 0.002), as well as free of all the other nasal symptoms ( P < 0.0l), and significantly lower median scores ( P < 0.05) for all nasal symptoms except nasal discharge than patients treated with disodium cromoglycate. There was no difference in eye symptoms or in rescue medication use between the two groups. Compliance with the treatment was assessed. Eleven patients recorded incorrect use of both nasal sprays for over 25% of days, and 55 patients recorded incorrect use of four-times-daily spray only; no patient recorded incorrect use of morning spray only. Both treatments were generally well tolerated.     

Double-blind group comparative trial of sodium cromoglycate eye ointment and placebo in the treatment of allergic eye diseases

Thirty-one patients with allergic eye diseases were treated three times daily for 4 weeks in a double-blind trial comparing sodium cromoglycate eye ointment with placebo. Patients' and clinician's assessment of symptoms and overall opinions of treatment showed sodium cromoglycate was significantly better than placebo and was well tolerated.