Conjunctivitis in dupilumab clinical trials.

BACKGROUND: Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-to-severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. OBJECTIVES: To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. METHODS: We evaluated randomized placebo-controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). RESULTS: In most AD trials, dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. CONCLUSIONS: Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab-treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most dupilumab AD trials, dupilumab-treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease-related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation-regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis. Patients who responded well to dupilumab had reduced incidence of conjunctivitis. Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab-treated patients with AD.

Peak Pruritus Numerical Rating Scale: psychometric validation and responder definition for assessing itch in moderate-to-severe atopic dermatitis.

BACKGROUND: Moderate-to-severe atopic dermatitis (AD) is a chronic disease characterized by intense, persistent and debilitating itch, resulting in sleep deprivation, signs of anxiety and depression, impaired quality of life and reduced productivity. The Peak Pruritus Numerical Rating Scale (NRS) was developed and validated as a single-item, patient-reported outcome (PRO) of itch severity. OBJECTIVES: To describe the content validity and psychometric assessment (test-retest reliability, construct validity, known-groups validity, sensitivity to change) of the Peak Pruritus NRS, and to derive empirically a responder definition to identify adults with a meaningful change in itch. METHODS: Content validity was assessed through in-depth patient interviews. Psychometric assessments used data from phase IIb and phase III dupilumab clinical trials and included test-retest reliability, construct validity, known-groups validity and sensitivity to change in patients with moderate-to-severe AD. RESULTS: Interview participants indicated that the Peak Pruritus NRS was a relevant, clear and comprehensive assessment of itch severity. Peak Pruritus NRS scores showed large, positive correlations with existing PRO measures of itch, and weak or moderate correlations with clinician-reported measures assessing objective signs of AD. Peak Pruritus NRS score improvements were highly correlated with improvements in other itch PROs, and moderately correlated with improvements in clinician-reported measures assessing objective signs of AD. The most appropriate threshold for defining a clinically relevant, within-person response was ≥ 2-4-point change in the Peak Pruritus NRS. CONCLUSIONS: The Peak Pruritus NRS is a well-defined, reliable, sensitive and valid scale for evaluating worst itch intensity in adults with moderate-to-severe AD.

A 12-week, placebo-controlled study of the efficacy and safety of ebastine, 10 and 20 mg once daily, in the treatment of perennial allergic rhinitis. Multicentre Study Group.

This double-blind, placebo-controlled, multicentre study investigated the ability of ebastine, 10 and 20 mg once daily, to control symptoms of perennial allergic rhinitis (PAR) over a 12-week period, and assessed additional benefits of the 20-mg dose. Following a 2-week baseline period, patients (12-63 years) were randomized to treatment with ebastine 10 mg (n=88) or 20 mg (n=102), or placebo (n=100). Patients scored symptom severity (0-3) twice daily, and mean changes from baseline scores showed ebastine to be significantly effective in week 1. Control of symptoms persisted over the 12 weeks, the average daily total nasal symptom score for nasal stuffiness plus nasal discharge plus sneezing plus itchy nose being reduced by both doses, with statistical significance at 20 mg (P=0.015 vs placebo) despite decreased usage of sodium cromoglycate rescue medications. Patient and clinician final opinions of treatment also significantly favoured ebastine, both 10 and 20 mg, over placebo. No serious adverse events occurred, and study treatments were well tolerated with a low incidence of central nervous system-related adverse events and headache. In conclusion, ebastine 10 or 20 mg once daily was rapidly effective in relieving symptoms of PAR in adult and adolescent patients; additional benefits of the 20-mg dose became apparent in the longer term.

[24-hour lung function in asthmatic patients: chrono-optimal theophylline therapy as once-daily Euphylong administration vs conventional twice-daily administration]. / 24-Stunden-Lungenfunktion bei Asthmatikern: chronooptimierte Theophyllintherapie als tägliche Einmalgabe (Euphylong) vs konventionelle Zweimalgabe.

In this study we examined the efficacy and pharmacokinetics of a new chrono-optimized theophylline sustained release preparation for once-daily dosing in the evening for treating bronchial asthma. In a randomized, open crossover study, Euphylong (administered once daily at 2000 hours) was compared with the same dose of a reference preparation (subdivided into two equal doses taken at 800 and 2000 hours). Administration and dosage were in accordance with prior determination of clearance. The patients were outpatients during the first six days of every phase, whereas for the following 24-hour measurement period they were admitted as inpatients for measuring the requisite pharmacokinetic and pharmacodynamic data (PEF, FEV1, PEF 25 = 75, FVC). The theophylline levels remained practically constant for 24 hours under conventional theophylline treatment with twice-daily administration. In contrast, the variations of the theophylline serum levels and the night levels were higher after once-daily dosage of Euphylong, and the daytime levels and especially at the end of the dosage interval were lower. Compared with the standard profile without medication, both sustained release preparations improved the airway obstruction significantly and comparably during a 24-hour period. However, in the early morning hours between 200 and 600 both PEF and FEV1 were significantly higher under Euphylong. Between the improvement of PEF and FEV1 and the theophylline serum concentrations there was a significant correlation between 200 and 600 under Euphylong only. It is concluded that the treatment of asthma with the chrono-optimized once-daily theophylline preparation Euphylong over night is more effective than treatment with a conventional preparation in twice-daily dosage.

[Efficacy of a theophylline retard preparation administered at 3 different intake times additionally to basic medication]. / Wirksamkeit eines zu drei verschiedenen abendlichen Einnahmezeiten zusätzlich zu einer Basismedikation gegebenen Theophyllinretardpräparates.

In this randomised crossover study in 26 outpatients with bronchial asthma the efficacy of a new once-daily theophylline formulation given in addition to a baseline medication was investigated; moreover, under steady state conditions, the effect of three evening intake times (6, 8 and 10 p.m.) on 24-hour pharmacokinetics and peak-expiratory flow profiles was evaluated. The theophylline dose had been individually titrated. The pharmacodynamic results show a marked improvement in 24-hour lung function data after adding theophylline to a drug therapy including inhalative anti-cholinergics in 50% of the treated outpatients. No significant differences between the pharmacokinetic characteristics and the 24-hour averages (mesors) of peak expiratory flow at the three different intake times 6, 8 and 10 p.m. were found; however, intake at 10 p.m. resulted in the highest nocturnal excess of serum theophylline concentrations and the highest peak expiratory flow during the early morning hours between 2 and 6 a.m.

[Long-term stability of morning serum theophylline level in asthma patients under minimally 1-year therapy with Euphylong]. / Langzeitstabilität morgendlicher Theophyllinserumspiegel bei Asthmatikern unter mindestens einjähriger Therapie mit Euphylong.

The long-term stability of morning serum theophylline concentrations (STC) and peak expiratory flow (PEF) was investigated for at least one year in 21 asthmatic patients who received individualised theophylline doses in addition to a baseline medication (beta 2-agonists, corticosteroids, anticholinergics by MDI). All patients had previously participated in a randomised crossover study with the new sustained-release theophylline formulation Euphylong, so that 24-hour steady-state STC profiles were available. During the 15 (13-18) months' follow-up, the theophylline dose was increased by about 6% on average; the largest increase of 33% (from 750 mg to 1000 mg) occurred in 4 patients. The morning STCs between 8 and 9 a.m. were intra-individually averaged over the longest interval with a constant dose; median and range were 11.6 (9.7-15.8) mg/l. The coefficient of variation was less than 10% in 8 patients and between 11 and 20% in 10 patients. The corresponding peak-flow values were 474 (239-622) l/min with a coefficient of variation of up to 10% in 16 patients and between 11 and 20% in 3 patients. The long-term study over more than one year confirmed the reproducibility of the Euphylong plateau profile previously found in controlled short-term pharmacokinetic studies and clinical trials.

Twenty-four hour lung function in adult patients with asthma. Chronoptimized theophylline therapy once-daily dosing in the evening versus conventional twice-daily dosing.

Many patients with asthma experience a worsening of symptoms at night and in the early morning, resulting in sleep disruption and possibly altered daily performance. A bronchodilator agent that exerts its maximal effect overnight to control nocturnal symptoms, without a worsening of the disease during the daytime, should improve the treatment of asthma. This investigation examined the efficacy and kinetics of a new chronotherapeutically optimized, sustained-release theophylline formulation administered once daily (OD) in the evening at 8:00 P.M. in comparison with a conventional sustained-release theophylline administered twice daily (TD) at 8:00 A.M. and at 8:00 P.M. in the same dose. After a theophylline clearance study to substantiate normal or slow metabolism of the drug, a dose-titration period, and a 24-h baseline spirometric study of patients not receiving any medication, participants were randomized to 7-day treatment phases with either OD or TD. Each outpatient segment of 6 days of OD and TD was followed by a 24-h inpatient study on Day 7 when serum drug level and spirometric (PEF, FEV1, and FEF25-75) parameters were obtained every 2 h. The conventional TD treatment was associated with a constant serum theophylline level over the 24 h. In contrast, the OD treatment was associated with larger peak-to-trough drug level fluctuation, with higher levels produced overnight and lower ones in the evening at the end of the dosing interval. Compared with the baseline references, both OD and TD significantly improved airflow over the entire 24 h and to a comparable extent. However, between 2:00 and 6:00 A.M., PEF and FEV1 were significantly greater with OD than with TD. The improvement in PEF and FEV1 at this time, because of OD, was correlated with the serum theophylline level. This was not the case for TD. The improvement in airflow over baseline values between 2:00 and 6:00 P.M. was not correlated with theophylline level with either treatment regime. Overall, the chronotherapeutically conceptualized OD treatment administered in the evening resulted in better airflow levels overnight than did the TD regime without loss of airflow in the afternoon.

Efficacy of sustained release theophylline given at three different evening intake times in addition to a baseline medication.

In this randomized crossover study of 26 outpatients with bronchial asthma the efficacy of a new once-daily theophylline formulation given in addition to a baseline medication was investigated; moreover, under steady state conditions, the effect of three evening intake times (6, 8 and 10 p.m.) on 24 h pharmacokinetics and peak-expiratory flow profiles was evaluated. The theophylline dose had been individually titrated. The pharmacodynamic results show a marked improvement of 24 h peak expiratory flow values after adding theophylline to a drug therapy including inhalative beta 2-agonists and corticosteroids in nearly all and inhalative anticholinergics in 50% of the treated outpatients. No significant differences between the pharmacokinetic characteristics and the 24 hr averages (mesors) of peak expiratory flow at the three different intake times 6, 8 and 10 p.m. were found; however, intake at 10 p.m. resulted in the highest nocturnal excess of serum theophylline concentrations and the highest peak expiratory flow during the early morning hours between 2 and 6 a.m.

An M1-selective muscarinic receptor antagonist telenzepine improves lung function in patients with chronic obstructive bronchitis.

The effect of an M1-selective muscarinic receptor antagonist telenzepine on lung function was investigated in 18 patients with chronic obstructive bronchitis in a double blind, placebo-controlled, randomized crossover study. FEV1, FEF50, PEF and FVC were measured every 0.5 h up to 2 h, then every 1 h up to 6 h after administration of a single, oral dose of 5 mg in the morning. Compared with placebo, telenzepine increased (time average over 6 hours; median and 68%-range): 1) FEV1 from 1.46 (0.81, 2.06) to 1.67 (1.06, 2.40) l, p less than 0.01; 2) PEF from 3.58 (2.33, 4.55) to 3.88 (3.10, 5.07) l/s, p less than 0.01; 3) FEF50 from 0.93 (0.45, 1.58) to 1.17 (0.67, 1.90) l/s, p less than 0.001. Whereas the median increase in FEV1 15 min after 2 puffs of salbutamol was 20% (range 15 to 74%), FEV1 improved by 32% (range -15 to 130%) at the time of maximum difference between placebo and telenzepine. The heart rate did not change. We conclude that in patients with chronic obstructive bronchitis substantial improvement of lung function parameters can be achieved by an M1-receptor antagonist. It is possible that with the dose administered direct actions on muscarinic receptors on the smooth muscle (M3) contribute to the observed bronchodilatation. The unchanged heart rate indicates little effect on cardiac M2-receptors.

Theophylline therapeutic drug monitoring in the case of a new sustained-release pellet formulation for once-daily evening administration.

In view of the large interindividual differences in theophylline clearance and the narrow therapeutic range it is essential to individualize the theophylline dose. In order to do so, estimation of minimum and maximum serum theophylline concentrations during one dosing interval from one or two blood samples is desirable, particularly in the case of once-daily administration. Whereas the minimum (trough) concentration can be readily estimated from the pre-dose level, the maximum (peak) concentration occurs at night. For Euphylong, a new sustained-release theophylline pellet formulation, administered once-daily in the evening, for example between 7 p.m. and 8 p.m., the nocturnal maximum concentration can be calculated as 110-120% of the serum theophylline concentration determined from a blood sample taken in the early morning, for example between 7 a.m. and 8 a.m. This procedure works not only for mean data but also on an individual basis. The procedure is based on the extended nocturnal plateau profile of Euphylong with its high reproducibility and cannot be transferred to other formulations.

Pharmacokinetic profile of a new sustained-release theophylline pellet formulation for once-daily evening administration.

Euphylong is a new anhydrous theophylline sustained-release pellet formulation developed for once-daily administration in the evening in normal and slow metabolizers, and unequally divided twice-daily administration in fast metabolizers. Its pharmacokinetics have been investigated with respect to bioavailability, peak-trough fluctuation, nocturnal plateau profile, food effects, predictability and reproducibility between subjects and from day to day. To this end, 7 single-dose and 4 multiple-dose, randomized, cross-over studies were performed in a total of 168 healthy, normal, male volunteers. In order to match the dosage strengths of three reference products, capsules containing different amounts of pellets--also referred to as Euphylong pellets--have been used. Absolute bioavailability of theophylline from Euphylong was 88 and 100%, depending on the rate and the total dose of the intravenous reference infusions. Relative bioavailability ranged between 85 and 112%, depending on the reference formulations. The peak-trough fluctuation was reduced for Euphylong pellets in comparison with other once-daily theophyllines, by more than 30% in the case of a reference tablet. In contrast to another once-daily theophylline capsule, Euphylong pellets seem to be hardly affected by meals. Moreover, in view of the known variability of theophylline pharmacokinetics both between subjects and from day to day, the nocturnal plateau profile, which is characteristic of Euphylong, is extremely reproducible. The nocturnal excess is consistently 30-40% and the plateau time is consistently 11-12 h in normal metabolizers. The long nocturnal plateau profile together with the high reproducibility of Euphylong pharmacokinetics enable an easy and safe adjustment of the dose tailored to the needs of the individual patient. In addition, the time of the evening dose and its relationship to meals is not critical in the case of Euphylong pellets. Particularly patients presenting with nocturnal asthma, which is one of the major areas of theophylline therapy, should have a clinically relevant benefit from Euphylong.

Steady state pharmacokinetics, metabolism and pharmacodynamics of theophylline in children after unequal twice-daily dosing of a new sustained-release formulation.

This was an open-label study in 19 children aged 9-13 years, weighing 27-44 kg, with bronchial asthma. Twenty-four-hour steady-state concentrations of theophylline and its metabolites 1,3-dimethyl uric acid, 3-methyl xanthine and 1-methyl uric acid were assessed after daily dosing of 600 mg (ca 18 mg/kg/day) of the sustained-release theophylline micro-pellet sprinkle system BY158K, for 4 days. The dosing regimen used was an unequal twice-daily dose of 200 mg in the morning after breakfast and 400 mg in the evening after dinner. Twenty-four-hour peak expiratory flow (PEF) profiles were compared before treatment and at steady-state, along with lung function parameters after bronchial provocation. Mean values +/- SD (n = 16) of the steady-state characteristics were Cmin 6.8 +/- 2.1 mg/l, Cmax 14.5 +/- 4.8 mg/l and Cav 10.5 +/- 2.9 mg/l, the plateau time was 11.7 +/- 4.8 hr and peak-trough fluctuation and swing were 72 +/- 21 and 118 +/- 52%, respectively. There was an excellent reproducibility of theophylline pre-dose levels at corresponding time points of the 24-hr sampling period [r = 0.864 (p less than 0.001)]. Mean values +/- SD of the 24 hr average serum metabolite levels were 0.9 +/- 0.2 mg/1 for 1,3-dimethyl uric acid, 0.6 +/- 0.1 mg/1 for 3-methyl xanthine and 0.4 +/- 0.1 mg/1 for l-methyl uric acid. Lung function (n = 17) following bronchial provocation, improved in 10 children after theophylline treatment of 4 days, remained stable in 2 patients and deteriorated in 5 patients. Serum theophylline profiles and PEF profiles ran largely in parallel over the 24-hr period. Six children exhibited typical theophylline induced side-effects, headache (n = 3), nausea (n = 4), dizziness (n = 1), vomiting (n = 4), sleep disturbances (n = 1), pallor (n = 1) and tremor (n = 1), necessitating in 3 children one dose omission/reduction (n = 2) or subsequent dose reduction (n = 1). It has been shown that a twice daily dosing regimen with unequal doses of anhydrous theophylline (BY158K) is well suited to this population of fast metabolisers. The patients were well protected throughout the day, including the critical early morning hours.