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Impact of Doxofylline Compared to Theophylline in Asthma a Pooled

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Impact of Doxofylline Compared to Theophylline in Asthma a Pooled Pulmonary Pharmacology & Therapeutics 53 (2018) 20–26 Contents lists available at ScienceDirect Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt Impact of doxofylline compared to theophylline in asthma: A pooled analysis of functional and clinical outcomes from two multicentre, double- T blind, randomized studies (DOROTHEO 1 and DOROTHEO 2) Luigino Calzettaa, Nicola A. Hananiab, Frank L. Dinic, Marc F. Goldsteind, ∗ William R. Fairweathere, William W. Howardf, Mario Cazzolaa, a Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata”, Rome, Italy b Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, USA c Cardiopulmonary and Vascular Department, University of Pisa, Pisa, Italy d The Asthma Center, Philadelphia, PA, USA e Flower Valley Consulting, Inc., Rockville, MD, USA f Alitair Pharmaceuticals, Inc., Morristown, NJ, USA ARTICLE INFO ABSTRACT Keywords: This pooled analysis of double-blind, randomized, placebo-controlled trials aimed to investigate the impact of Asthma DOxofylline compaRed tO THEOphylline (DOROTHEO 1 and DOROTHEO 2 studies) on functional and clinical Doxofylline outcomes in asthma. Asthmatic patients ≥16 years of age with forced expiratory volume in 1 s (FEV1) ≥50% Theophylline and < 80% and with ≥15% post-bronchodilator increase in FEV1 were randomized in a 1:1:1:1 ratio in DOR- Pooled analysis OTHEO 1 to receive doxofylline 200 mg, doxofylline 400 mg, theophylline 250 mg, or placebo; in DOROTHEO 2 patients were randomized in a 1:1:1 ratio to receive doxofylline 400 mg, theophylline 250 mg, or placebo. All double-blind treatments were taken orally with immediate release formulations and three times daily. Data evaluating the effect of doxofylline 400 mg, theophylline 250 mg and placebo on FEV1, asthma events rate, use of salbutamol as rescue medication and adverse events (AEs) were pooled from both studies. The pooled-analysis of 483 patients demonstrated that both doxofylline 400 mg and theophylline 250 mg significantly increased FEV1, reduced the rate of asthma events and use of salbutamol to relieve asthma symptoms compared to placebo (p < 0.01). No significant differences were detected between doxofylline 400 mg and theophylline 250 mg. Doxofylline 400 mg did not significantly (p > 0.05) increase the risk of AEs compared to placebo, conversely in patients treated with theophylline 250 mg the risk of AEs was significantly (p < 0.05) greater than in those that received placebo. We conclude that doxofylline seems to offer a promising alternative to theophylline with a superior efficacy/safety profile in the management of patients with asthma. 1. Introduction Doxofylline is a newer generation xanthine with bronchodilating and anti-inflammatory actions [7–11]. In experimental animals, this Xanthines are structurally related drugs, used in clinical manage- drug has also been shown to have anti-inflammatory activity in a rat ment of patients with chronic obstructive respiratory disorders, in- pleurisy model and to inhibit human eosinophil activation by affecting cluding asthma and chronic obstructive pulmonary disease (COPD). Ca++ activated K+ channels [12,13]. Doxofylline is also able to pro- However, commonly used xanthines (theophylline, aminophylline) vide prophylactic effects against bronchoconstriction induced by pla- have a major drawback in that they have a very narrow therapeutic telet-activating factor and methacholine in guinea-pigs and dogs window and propensity for many pharmacological interactions [1–6]. [13–15]. The advent of other classes of drugs, such as the new inhaled corti- In human, two multicenter, double-blind, randomized trials, carried costeroids (ICSs) and long-acting bronchodilator agents, has limited the out in 21 Italian pulmonary clinics to investigate the therapeutic effi- use of xanthines, despite their clear clinical benefit in the treatment of cacy and tolerability of doxofylline compared to slow-release theo- some patients with chronic obstructive respiratory disorders [3]. phylline or aminophylline, demonstrated that doxofylline is an effective ∗ Corresponding author. Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata”, Via Montpellier 1, 00133, Rome, Italy. E-mail address: [email protected] (M. Cazzola). https://doi.org/10.1016/j.pupt.2018.09.007 Received 19 July 2018; Received in revised form 10 September 2018; Accepted 12 September 2018 Available online 13 September 2018 1094-5539/ © 2018 Published by Elsevier Ltd. Downloaded for Anonymous User (n/a) at Drexel University from ClinicalKey.com by Elsevier on September 27, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. L. Calzetta et al. Pulmonary Pharmacology & Therapeutics 53 (2018) 20–26 and well tolerated agent in patients suffering from chronic reversible treatments; ii) the change from baseline in asthma events rate (n/day) airways obstruction [16,17]. A number of other studies confirmed the after 12 weeks of treatment and the overall change during the study beneficial clinical effects of doxofylline in asthma and COPD [1,5,18]. period vs. placebo between active treatments; and iii) the change from In summary, bronchodilatory effects of doxofylline have been de- baseline in salbutamol use rate (puffs/day) after 12 weeks of treatment monstrated in patients suffering from asthma or COPD [1,2,15,19–21] and the overall change during the study period vs. placebo between but, to the best of our knowledge, large scale data comparing the effi- active treatments. cacy and safety of doxofylline to those of the more commonly used This pooled analysis assessed the effect of doxofylline 400 mg, theophylline in the treatment of asthma are still lacking. To explore theophylline 250 mg, or placebo in asthmatic patients. The effect of this, we examined data from two independent, double-blind, rando- doxofylline 200 mg was investigated only in DOROTHEO 1 [22] and mized, placebo-controlled trials that aimed to investigate the impact of therefore was not included in this pooled analysis. DOxofylline compaRed tO THEOphylline (DOROTHEO 1 and DOROT- The patients used diary cards to record the date and time that each HEO 2 studies) [22,23] in asthma. Data were pooled in order to perform dose of study medication was taken, date and time of asthma episodes, a pre-specified analysis of the two studies, which together are powered date and time of each salbutamol use, and date and time of any AEs. to provide more reliable estimates of the effect of the investigated drugs on lung function, asthma events rate, use of salbutamol to relieve 2.4. Assessment of safety and drop-outs asthma symptoms, and adverse events (AEs). All clinical AEs were recorded and graded as mild, moderate or 2. Materials and methods severe. Their relationships with active treatments were classified as follows: 1) not related, 2) possibly related, 3) definitely related or 4) 2.1. Study design unknown. Also recorded for each event were the duration of the symptoms and the action taken (none, reduction of the dose or dis- DOROTHEO 1 and DOROTHEO 2 were Phase III, multicentre, continuation of treatment). Subjects were removed from therapy or double-blind, randomized, parallel-group, placebo-controlled, clinical assessment for: 1) non-adherence to treatment, 2) persistent drug-re- trials, conducted in 37 centres in the United States [22,23]. Each study lated AEs with patient's willingness to discontinue treatment, 3) serum had one week run-in period during which the subject took placebo theophylline levels exceeding 20 μg/mL or 4) elevated doxofylline followed by 12-week treatment period and a 1-week single-blind pla- concentrations (> 2 standard deviations above the mean) in the pre- cebo run-out phase at the end of the study. Patients were randomized in sence of any drug-related AE. a 1:1:1:1 ratio in DOROTHEO 1 to receive doxofylline 200 mg, dox- ofylline 400 mg, theophylline 250 mg, or placebo. Patients were ran- 2.5. Statistical analysis domized in a 1:1:1 ratio in DOROTHEO 2 to receive doxofylline 400 mg, theophylline 250 mg, or placebo. All treatments were taken Data are expressed as mean ± standard error of the mean (SEM). orally with immediate release formulations and three times daily (tid) The statistical analysis compared FEV1 measured by spirometry ob- during all the study phases. tained at baseline (immediately prior to the start of double-blind The studies were conducted in accordance with the Declaration of treatment) with the results obtained 2 h after administration of study Helsinki, International Conference on Harmonisation/Good Clinical medication (2-h postdose FEV1) at each visit during double-blind Practice Guidelines and local regulations. The study protocols were treatment. The derived variable was the percent change between these reviewed and approved by Institutional Review Boards at each study two assessments. Absolute changes were calculated for the asthma centre. The studies have been registered in the International Standard events rate (total number of events divided by total number of days on Randomized Controlled Trial Number (ISRCTN65297911 and study medication) and salbutamol use rate (total number of puffs di- ISRCTN22374987) and detailed information can be found at http:// vided by total number of days on study medication). Baseline for the www.isrctn.com/ISRCTN65297911 and http://www.isrctn.com/ latter two variables was defined as the value obtained from the diaries ISRCTN22374987. during the placebo run-in phase. The safety analysis was performed by calculating the risk of AEs compared to placebo, and data were reported 2.2. Study population as risk ratio (RR) and 95% confidence interval (95%CI). The DOROTHEO 1 and DOROTHEO 2 studies [22,23] had similar Patients with asthma who were ≥16 years old, who had forced protocol, with the same treatment groups, except that DOROTHEO 1 expiratory volume in 1 s (FEV1) within 50%–80% of the predicted and included also a low dose doxofylline group (200 mg tid). who showed at least 15% post-bronchodilator (salbutamol 180 μg) in- The analysis of the changes from baseline was performed by using t- crease in FEV1 were enrolled.
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