Comparison of scores associating symptoms and rescue medication use for evaluating the efficacy of allergy immunotherapy in seasonal allergic rhinoconjunctivitis: results from five trials.

BACKGROUND: Over the past decade, regulatory bodies and scientific societies recommended, as primary efficacy outcome, a score that reflects both symptom severity and use of rescue medication for clinical trials in allergy immunotherapy (AIT). OBJECTIVE: We sought to compare the results obtained with two subject-specific scores, the Combined Score (CS) and the Adjusted Symptom Score (AdSS), for assessment of AIT in seasonal allergic rhinoconjunctivitis due to birch and grass pollen allergens. METHODS: CS and AdSS were evaluated in subjects receiving a 300IR dose of allergen extract daily, by sublingual route, in four clinical trials with the 5-grass pollen tablet (NCT00367640, NCT00409409, NCT00955825 and NCT00418379) and one with the birch pollen solution (NCT01731249). The CS is derived from the Rhinoconjunctivitis Total Symptom Score (RTSS) and the Rescue Medication Score (RMS) giving equal weight to symptoms and medication use. The AdSS is a symptom score adjusting for rescue medication use. Efficacy end-points were analysed using an analysis of covariance linear model. RESULTS: In all trials, despite the different constructs of the two scores, Combined Score or Adjusted Symptom Score were similarly reduced in the 300IR group compared to the placebo group. Treatment effect was consistently demonstrated with both scores, CS and AdSS, used as either daily scores or average of the daily scores over the pollen season. Minor differences with the same statistical conclusions were observed between the results, leading to the same interpretation. CONCLUSIONS AND CLINICAL RELEVANCE: The two scores, combined and adjusted scores, for evaluation of clinical efficacy of AIT have led to similar results, with similar statistical conclusions and similar interpretation.

Pharmacological treatment optimization for stable chronic obstructive pulmonary disease. Proposals from the Société de Pneumologie de Langue Française.

The Société de Pneumologie de Langue Française proposes a decision algorithm on long-term pharmacological COPD treatment. A working group reviewed the literature published between January 2009 and May 2016. This document lays out proposals and not guidelines. It only focuses on pharmacological treatments except vaccinations, smoking cessation treatments and oxygen therapy. Any COPD diagnosis, based on pulmonary function tests, should lead to recommend smoking cessation, vaccinations, physical activity, pulmonary rehabilitation in case of activity limitation, and short-acting bronchodilators. Symptoms like dyspnea and exacerbations determine the therapeutic choices. In case of daily dyspnea and/or exacerbations, a long-acting bronchodilator should be suggested (beta-2 agonist, LABA or anticholinergics, LAMA). A clinical and lung function reevaluation is suggested 1 to 3 months after any treatment modification and every 3-12 months according to the severity of the disease. In case of persisting dyspnea, a fixed dose LABA+LAMA combination improves pulmonary function (FEV1), quality of life, dyspnea and decreases exacerbations without increasing side effects. In case of frequent exacerbations and a FEV1≤70%, a fixed dose long-acting bronchodilator combination or a LABA+ inhaled corticosteroids (ICS) combination can be proposed. A triple combination (LABA+LAMA+ICS) is indicated when exacerbations persist despite one of these combinations. Dyspnea in spite of a bronchodilator combination or exacerbations in spite of a triple combination should lead to consider other pharmacological treatments (theophylline if dyspnea, macrolides if exacerbations, low-dose opioids if refractory dyspnea).

The minimally important difference in the Rhinoconjunctivitis Total Symptom Score in grass-pollen-induced allergic rhinoconjunctivitis.

BACKGROUND: The minimally important difference (MID) has been defined as the smallest improvement considered worthwhile by a patient. The MID has not been estimated for the Rhinoconjunctivitis Total Symptom Score (RTSS). METHODS: In a prospective multicentre study, patients consulting for grass-pollen-induced allergic rhinitis (AR) recorded a 15-point global rating of change scale (GRCS) score and the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score on a weekly basis and the individual symptom scores comprising the RTSS on a daily basis over two consecutive weeks. The MID in the RTSS was determined with anchor-based methods (using the GRCS and the RQLQ) and a distribution-based method [based on the RTSS' standard deviation (SD)]. RESULTS: The study population comprised 806 patients (253 children, 250 adolescents and 303 adults). During the first week of the study, the mean ± SD RTSSs for these age groups were 6.5 ± 3.3, 6.8 ± 3.4 and 7.0 ± 3.4, respectively. For an improvement of 2 points in the GRCS or 0.5 points in the RQLQ score, the regression analysis yielded MIDs in the RTSS of 1.24 ± 0.17 and 1.12 ± 0.14 in children, 1.33 ± 0.14 and 1.20 ± 0.13 in adolescents and 1.13 ± 0.14 and 0.89 ± 0.12 in adults, respectively. When applying distribution-based methods, the MID ranged from 1.09 to 1.13 (based on 0.33 SDs of the first-week RTSS) and from 1.22 to 1.40 (based on 0.5 SDs of the difference in RTSSs between the first and second weeks). CONCLUSION: The MID in the RTSS was consistently estimated as 1.1-1.3 (and could conceivably be rounded to 1) in patients with grass-pollen-induced AR.

Analysis of allergen immunotherapy studies shows increased clinical efficacy in highly symptomatic patients.

BACKGROUND: The assessment of allergen immunotherapy (AIT) efficacy in the treatment for seasonal allergic rhinoconjunctivitis (SAR) symptoms is challenging. Allergen immunotherapy differs from symptomatic therapy in that while symptomatic therapy treats patients after symptoms appear and aims to reduce symptoms, AIT is administered before symptoms are present and aims to prevent them. Thus, clinical studies of AIT can neither establish baseline symptom levels nor limit the enrolment of patients to those with the most severe symptoms. Allergen immunotherapy treatment effects are therefore diluted by patients with low symptoms for a particular pollen season. The objective of this analysis was to assess the effect possible to achieve with AIT in the groups of patients presenting the most severe allergic symptoms. METHODS: Study centres were grouped into tertiles categorized according to symptom severity scores observed in the placebo patients in each centre (low, middle and high tertiles). The difference observed in the average score in each tertile in active vs placebo-treated patients was assessed. This allowed an estimation of the efficacy that could be achieved in patients from sites where symptoms were high during the pollen season. RESULTS: An increased treatment effect was observed in the most severe patients and was independent of the study analysed and symptom score used. CONCLUSIONS: The use of a tertile approach to analyse efficacy in AIT in SAR clinical studies can give a more accurate assessment of potential clinical benefit.

How to design and evaluate randomized controlled trials in immunotherapy for allergic rhinitis: an ARIA-GA(2) LEN statement.

Specific immunotherapy (SIT) is one of the treatments for allergic rhinitis. However, for allergists, nonspecialists, regulators, payers, and patients, there remain gaps in understanding the evaluation of randomized controlled trials (RCTs). Although treating the same diseases, RCTs in SIT and pharmacotherapy should be considered separately for several reasons, as developed in this study. These include the severity and persistence of allergic rhinitis in the patients enrolled in the study, the problem of the placebo, allergen exposure (in particular pollen and mite), the analysis and reporting of the study, the level of symptoms of placebo-treated patients, the clinical relevance of the efficacy of SIT, the need for a validated combined symptom-medication score, the differences between children and adults and pharmacoeconomic analyses. This statement reviews issues raised by the interpretation of RCTs in sublingual immunotherapy. It is not possible to directly extrapolate the rules or parameters used in medication RCTs to SIT. It also provides some suggestions for the research that will be needed. Interestingly, some of the research questions can be approached with the available data obtained from large RCTs.

The average Adjusted Symptom Score, a new primary efficacy end-point for specific allergen immunotherapy trials.

BACKGROUND: In clinical trials, the efficacy of immunotherapy for allergic rhinoconjunctivitis symptoms is often evaluated with the average Rhinoconjunctivitis Total Symptom Score (ARTSS). Effective treatment is associated with a lower ARTSS vs. placebo but use of rescue medication to alleviate symptoms reduces the RTSS and decreases the mean difference between active treatment and placebo groups. OBJECTIVE: To develop and describe the average Adjusted Symptom Score (AdSS), a new end-point reflecting symptom severity and rescue medication use in allergic rhinoconjunctivitis trials. METHODS: To calculate the AdSS, the RTSS is adjusted as follows: if a patient takes rescue medication on day d, the day's AdSS (AdSS(d)) is defined as the value of RTSS(d) or AdSS(d-1), whichever is higher. The AdSS on the following day (AdSS(d+1)) is defined as the value of RTSS(d+1) or AdSS(d), whichever is higher. The average of the daily AdSSs (during the season) was calculated post hoc for two trials investigating the efficacy of five-grass pollen sublingual immunotherapy tablets in adult and paediatric patients and compared with the ARTSS and three other outcome measures (the average Rescue Medication Score (ARMS), the ARTSS and the average Combined Score). RESULTS: The average AdSS clearly discriminated between active and placebo treatments and confirmed the original ARTSS results. Adjustment for rescue medication use decreased the observed placebo effect. CONCLUSION AND CLINICAL RELEVANCE: The average AdSS can be a valuable alternative to the ARTSS as a primary efficacy end-point in grass pollen allergic rhinoconjunctivitis trials. By adjusting the RTSS for rescue medication use, the AdSS can estimate symptom severity and the treatment effect more accurately. The AdSS is now being tested prospectively in large clinical trials.

The allergen challenge chamber: a valuable tool for optimizing the clinical development of pollen immunotherapy.

The clinical development of allergen immunotherapy for allergic rhinoconjunctivitis because of pollen is complicated by seasonal, geographical and subject-related variability in allergen exposure. Using an allergen challenge chamber (ACC), a room that enables reproducible challenges with controlled levels of inhalant allergens for several hours, these factors can be controlled. The ACC has often been used to evaluate symptomatic medications but is underexploited in the field of allergen immunotherapy. When used in conjunction with a programme of natural-exposure trials, the ACC enables researchers to (i) facilitate the allergen immunotherapy dose-finding process, (ii) accelerate the transition from Phase I/II to Phase III trials, (iii) characterize the onset and maintenance of action, (iv) avoid the confounding effects of rescue medication, (v) better characterize the baseline or pretreatment characteristics of trial subjects, (vi) perform better-standardized physical and laboratory measurements during an acute challenge, (vii) simplify trial logistics and use smaller numbers of subjects than would be required in equivalent natural-exposure studies and (viii) support (but not replace) Phase III natural-exposure trials for the investigation into long-term and disease-modifying effects. ACC studies can further increase levels of evidence for allergen immunotherapy--the only current therapy potentially capable of modifying the underlying allergic disease.

[Pharmacology of glucocorticoids and ENT pathology]. / Pharmacologie des glucocorticoïdes et pathologies ORL.

UNLABELLED: 1. NATURAL AND SYNTHETIC HORMONES: Glucocorticoids are indispensable circulating hormones implicated in carbohydrate and protein metabolism. They also have strong antiinflammatory effects used in therapy. This antiinflammatory activity has led to the development of synthetic compounds with an antiinflammatory action that is much greater than that of the natural hormones (cortisol, cortisone) with reduced mineralocorticoid activity. 2. ANTIINFLAMMATORY EFFICACY OF GLUCOCORTICOIDS: The action of glucocorticoids on the majority of the cells involved in inflammatory reactions, particularly in allergy, and their induction of synthesis of new inflammation mediators explains their antiinflammatory effect. 3. MECHANISMS OF ACTION: The antiinflammatory properties of glucocorticoids result basically from their inhibitory effect on synthesis of proinflammatory proteins, in particular many cytokines. Corticoids reduce the production of prostanoids by inhibiting the expression of COX-2, but are much less effective on the production of leukotrienes. Corticoids inhibit the degranulation of human basophils (histamine release) but have no effect on mast cells. 4. ACTIVATION OF A CYTOPLASMIC RECEPTOR: The antiinflammatory effect of glucocorticoids is mediated by binding to a cytoplasmic receptor which, when activated, migrates to the nucleus. The activated receptor can interact with transcription factors (NF-kappa B, AP-1) inhibiting the synthesis of proinflammatory proteins (cytokines, COX-2...). This "transrepressive" activity explains most of the antiinflammatory effects of glucocorticoids. 5. ACTION OF THE ACTIVATED RECEPTOR: The activated receptor can bind to specific sites present on the regulator region of target genes, inducing their transcription (or transactivation). This induction effect on protein synthesis concerns the renin-angiotensin system, neoglucogenesis, and bone metabolism. Increased production of these proteins explain the metabolic and endocrine effects of glucocorticoids which, when exaggerated, particularly with general administration, can lead to undesirable effects. At the present time, our knowledge suggests it would be best to have molecules with a predominant transrepressive activity (antiinflammatory activity) since the transactivator effects appeared to be associated with the undesirable metabolic effects of glucocorticoids. 6. OTHER PHARMACEUTICAL PROPERTIES: Glucocorticoids also have properties that do not require gene expression. These "non-genomic" effects could occur at high dosage "pulse" therapy. We will have to wait for more pertinent clinical information on these effects to use the power of these non-genomic effects to guide our choice of the appropriate glucocorticoid in given clinical situations. 7. LOCAL TREATMENT FOR ALLERGIC RHINITIS: Given locally glucocorticoids reduce the concentration of many inflammatory mediators and the number of inflammatory cells in secretions and nasal biopsies. The efficacy of glucocorticoids is perfectly established in this indication as well as in nasal polyposis. 8. LOCAL TOLERANCE: During the first days of treatment, local application of corticoids on the inflammatory mucosal surface can cause irritation and/or sneezing. These manifestations generally subside in a few days and are more frequent with solutions containing glycol. The dry nose sensation, sometimes associated with minimal epistaxis, is classically reported, though at a low frequency. A few rare cases of ulceration of perforation of the septum have been report and it would be difficult to exclude a mechanical cause related to administration route. It is clear that the risk of mucosal atrophy has been eliminated with the use of nasal corticosteroids. 9. EVALUATION OF THE SYSTEMIC EFFECT OF NASAL CORTICOSTEROIDS: Most of the studies have examined the hypothalamo-pituitary-adrenal axis. These studies have rarely demonstrated, an then in isolated cases, any significant modification at recommended doses. Likewise for other markers of passage into the systemic circulation such as osteocalcine or the number of circulating eosinophils. There is also very little risk of growth impairment in children or cataracts in adults. 10. SHORT-COURSE GENERAL CORTICOSTEROID THERAPY: Short periods are sometimes recommended for rhinitis, sinusitis, polyposis or laryngitis. Use of a short duration treatment (about one week) at doses in the 1 mg/kg/d range, induce a transient inhibition of the corticoadrenal axis in about half the patients; this inhibition disappears in most all cases in two weeks. The clinical risk associated with this alteration in patients under stress (infection, trauma...) remains hypothetical. In any case, it would be advisable to avoid repeating short-course general corticosteroid therapy at close intervals.

Antagonistic effects of losartan on thromboxane A2-receptors in human isolated gastroepiploic artery and saphenous vein.

In addition to its AT1-receptor antagonist activity, losartan has been shown to antagonize thromboxane A2 (TXA2)-induced contraction of animal vessels. We investigated for the first time in human isolated gastroepiploic artery (GEA) and saphenous vein (SV) the TXA2/PGH2-receptor antagonist activity of losartan in the presence of indomethacin (1 microM) and N(omega)-nitro-L-arginine (100 microg). Losartan at concentrations of > or =1 microM on GEA and from 10 microM on SV significantly shifted U46619-induced contractions to the right. In addition, 100 microM losartan decreased by 34% the amplitude of the contraction to U46619 on both GEA and SV. The potency of losartan for the TXA2 receptor was 50- and 80-fold lower than that for the AT1 receptor on human GEA and SV, respectively. This inhibitory effect of losartan appeared selective for angiotensin II and TXA2-induced contractions because 100 microM losartan did not modify either endothelin-1- or KCl-induced contraction in human SV, although a reduction of norepinephrine- and 5-hydroxytryptamine-induced contraction was observed in human GEA and SV, respectively. In conclusion, losartan is an antagonist of TXA2 receptor on human GEA and SV. However, this antagonist activity occurred for a relative high dose of losartan, suggesting that it contributes at a low level, if any, to its antihypertensive effect.