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Pranlukast, a Novel Leukotriene Receptor Antagonist 525 Thorax 1997;52:523±527 523 Pranlukast, a novel leukotriene receptor Thorax: first published as 10.1136/thx.52.6.523 on 1 June 1997. Downloaded from antagonist: results of the ®rst European, placebo controlled, multicentre clinical study in asthma N C Barnes, J-C Pujet on behalf of an International Study Group Abstract asthma. It increased FEV1 within one hour Background ± Leukotriene receptor ant- of dosing, improved patient summary agonists have been shown to protect symptom and night-time asthma scores, against bronchoconstriction induced by and reduced the use of rescue broncho- antigens, exercise, and cold air. There are dilators, thus providing further evidence relatively few clinical studies reported in of a role for leukotrienes in the patho- patients with asthma. The present study genesis of asthma. is the ®rst clinical evaluation of pranlukast (Thorax 1997;52:523±527) (SB 205312, ONO-1078) outside Japan in patients with asthma. Keywords: leukotriene receptor antagonist, asthma, Methods ± A randomised, double blind, pranlukast, SB 205312, ONO-1078. placebo controlled, parallel group, multi- centre four week study of the safety and tolerability of oral pranlukast, 225 or Since the structure of leukotrienes was de- 337.5 mg twice daily, was performed in scribed in 1979,1 considerable eVort has been patients with mild to moderate asthma. made to develop drugs that block the leuko- Preliminary eYcacy data were obtained; triene receptor or inhibit synthesis of leuko- the main eYcacy variables evaluated were trienes. Challenge studies using a number forced expiratory volume in one second of leukotriene receptor antagonists or 5-lip- http://thorax.bmj.com/ (FEV1) and morning domiciliary (home) oxygenase inhibitors have shown that leuko- peak expiratory ¯ow rates (PEFR). Clinic trienes play an important part in the early and PEFR and daytime and night-time asthma late responses to bronchoconstriction induced symptom scores were also recorded. by inhaled antigen,23 exercise,4 and cold air.5 Results ± Compared with the placebo Comparatively few reports have evaluated group the improvement in morning home leukotriene antagonists or synthesis inhibitors PEFR was statistically signi®cant at all in patients who have chronic asthma.6±8 time points for patients receiving pran- Pranlukast (SB 205312, ONO-1078) is the lukast 337.5 mg twice daily and at weeks 1 ®rst leukotriene receptor antagonist on the mar- and 2 for those treated with pranlukast in ket and is available in Japan for the treatment on October 2, 2021 by guest. Protected copyright. a dose of 225 mg twice daily. Mean morning of asthma. It has been shown to block bron- home PEFR increased by 10.8 to 18.6 l/ choconstriction induced by leukotriene D4 910 min (95% CI 0.2 to 29.3 l/min) in patients (LTD4) and antigen. The present clinical The London Chest treated with pranlukast compared with a study was the ®rst European multicentre evalu- Hospital, Department ation of pranlukast, in doses of 225 mg twice of Respiratory slight deterioration in those given placebo. Medicine, Bonner FEV1 signi®cantly increased within one daily (the marketed dose in Japan) or 337.5 mg Road, London E2 9JX, hour after the ®rst dose of pranlukast com- twice daily compared with placebo, in patients UK with asthma. The doses were chosen to assess N C Barnes pared with baseline and this increase was maintained for eight hours. Improvements whether compensation for greater Caucasian Du Centre de body weight would be necessary. The primary in trough FEV1 ± that is, at the end of the Diagnostic et de objectives of the study were to evaluate the Readaptation Cardio- dosing interval ± were statistically sig- Respiratoire, 74 Rue ni®cant for the group treated with pran- safety and tolerability of pranlukast and to de la Colonie, 75013 lukast 225 mg twice daily compared with obtain preliminary evidence of the eYcacy of Paris, France the drug in patients with chronic asthma. J-C Pujet placebo at week 4. Mean increases in FEV1 ranged from 210 ml to 340 ml (95% CI 60 to This study was presented in part at the American 500 ml) at trough in the pranlukast group. Thoracic Society Meeting, Patients treated with pranlukast also Methods Seattle, Washington, USA in May 1995. showed improvements in summary symp- patient selection Correspondence to: tom and night-time asthma scores. Pran- Men or women aged 18±70 years with an Dr N C Barnes. lukast was well tolerated, and no drug established diagnosis of asthma, a forced ex- Received 21 November 1995 related changes in haematological and bio- piratory volume in one second (FEV1) of 50± Returned to authors 9 February 1996 chemical variables were observed. 80% of predicted values, and an improvement Revised version received Conclusions ± Pranlukast, an oral leuko- of at least 15% within 30 minutes of taking 27 February 1997 Accepted for publication triene receptor antagonist, is well tolerated salbutamol (200±400 lg) from a metered dose 28 February 1997 and is eVective for the treatment of inhaler were eligible to participate in the study. 524 Barnes, Pujet on behalf of an International Study Group Patients abstained from salbutamol for eight hours. At subsequent visits to the clinic patients hours prior to this acute bronchodilator test. were asked not to take their morning drug dose Thorax: first published as 10.1136/thx.52.6.523 on 1 June 1997. Downloaded from Patients were permitted to take inhaled ster- until after the spirometry and PEFR had been oids (up to 1000 lg/day beclomethasone di- measured. They only had measurements made propionate or its equivalent) and on-demand for eight hours on the ®rst day of drug dosing. salbutamol during the study. However, they The primary eYcacy variables were the could not take disodium cromoglycate or nedo- trough FEV1 measured in the morning in the cromil sodium for six weeks or oral steroids for clinic, and morning domiciliary PEFR. Pul- eight weeks before entry to the study. Oral monary function was assessed in the clinic methylxanthines, oral and inhaled long acting by measuring FEV1, forced vital capacity, and b2 agonists, inhaled anticholinergics, and oral PEFR three times before the administration of antihistamines had to be withdrawn at least study medication (the highest reading of each ®ve half lives before the start of the study to was used for statistical analysis). Patients also ensure no residual eVects. measured their PEFR at home twice a day with Patients who had poorly controlled asthma, the peak ¯ow meter, before the morning dose an active smoking history (within six months and after the evening dose of study medication; of entry to the study), recent upper or lower each time three values were recorded and the respiratory infections, or other clinically sig- highest value was used on the diary card. Each ni®cant or potentially confounding diseases inhalation of salbutamol and inhaled cortico- were excluded. steroids was also recorded on the diary card, All patients provided written informed con- as well as daytime and night-time asthma symp- sent before participating in the study, and the tom severity which was rated on a ®ve point protocol was approved by the ethics committee scale: 0=none (no symptoms), 1=mild, 2= at each research centre. moderate, 3=severe, and 4=very severe symp- toms. The daytime and night-time asthma symptom scores were combined into an overall study design summary symptom score. The study was of a randomised, double blind, Safety was assessed at each visit based on placebo controlled, multicentre, parallel group the incidence of adverse experiences, vital signs, design with a two week single blind placebo laboratory evaluations, ECG tracings, and run-in phase, followed by a four week double physical and respiratory examinations. Patients blind treatment phase, and a 1±2 week run- who withdrew from the study because of ad- out phase. During the treatment phase patients verse experiences were followed to determine were randomised to one of three treatment the ®nal outcome of these events. groups: pranlukast 225 mg (n=46), 337.5 mg http://thorax.bmj.com/ (n=45), or matching placebo (n=44) twice daily. Both doses of pranlukast and placebo statistical analyses were administered as identical capsules. All analyses of eYcacy were performed using Patients who successfully completed all data from all patients who received at least screening assessments (routine history and ex- one dose of randomised treatment. Analysis of amination, haematology, biochemistry, urin- variance (ANOVA) was used to assess diVer- alysis, and 12 lead ECG) and satis®ed study ences between treatment groups for normally inclusion and exclusion criteria were given distributed, continuous variables. Within treat- placebo capsules on a single blind basis. They ment comparisons were made using paired t on October 2, 2021 by guest. Protected copyright. were instructed to take capsules with water 30 tests. Because the primary objective of the study minutes before breakfast (08.00 hours) and in was to assess the safety and tolerability of pran- the evening (20.00 hours) after a meal. In lukast, no formal sample size calculations were addition, patients were given peak ¯ow meters performed. The goal was to have at least 120 (mini-Wright, Airmed, Harlow, Essex, UK) patients enrolled to yield at least 90 evaluable and were instructed in their use. Diary cards patients (30 in each treatment group). For were used to record symptom severity and eYcacy analyses, statistical tests were per- use of all medications, including on-demand formed at a signi®cance level of 5% (a=0.05, salbutamol (100 lg/actuation). Patients were two tailed test). scheduled to visit the clinic at the same time The primary between treatment comparisons of day 14 days after screening, at the end were the analyses of trough FEV1 (the clinic of one, two, and four weeks of double blind measurement before daily dosage) and morning treatment, and 1±2 weeks after treatment was home PEFR measurements.
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