Analysis of integrated clinical safety data of tadalafil in patients receiving concomitant antihypertensive medications.

This pooled safety analysis assessed the incidence of hypotension-related treatment-emergent adverse events (TEAEs) and major adverse cardiovascular events (MACEs) in patients with concomitant use of tadalafil and antihypertensive medications. Data were pooled from seventy-two Phase II-IV studies conducted on patients with a diagnosis of erectile dysfunction (ED) and/or benign prostate hyperplasia (BPH). Studies were categorized as either All placebo-controlled studies or All studies. The incidences of hypotension-related TEAEs and MACEs were analyzed by indication; by use of concomitant antihypertensive medications; and by the number of concomitant antihypertensive medications. A total of 15 030 and 22 825 patients were included in the analyses for All placebo-controlled studies and All studies, respectively. In the All placebo-controlled studies, the incidence of hypotension-related TEAEs and MACEs was ranging between 0.6-1.5% and 0.0-1.0%, respectively, across all indications. Tadalafil was associated with an increase in hypotension-related TEAEs only in the ED as-needed group not receiving any concomitant antihypertensive medications (p-value = .0070); no significant difference was reported between placebo and tadalafil in the groups of patients receiving ≥1 antihypertensive medication (p-values ≥ .7386). Similarly, no significant differences (p-values≥ .2238) were observed in the incidence of MACEs between tadalafil and placebo treatment groups, with or without concomitant use of antihypertensive medications, and across all indication categories. In the All studies group, results were similar. The pooled analysis showed no evidence that taking tadalafil alongside antihypertensive medications increases the risk of hypotension-related TEAEs or MACEs compared with antihypertensive medications alone.

Intranasal triamcinolone and growth velocity.

BACKGROUND: Inadequate designs and conflicting results from previous studies prompted the US Food and Drug Administration to publish guidelines for the design of clinical trials evaluating the effects of orally inhaled and intranasal corticosteroids on the growth of children. This study conformed to these guidelines to evaluate the effect of triamcinolone acetonide aqueous nasal spray (TAA-AQ) on the growth of children with perennial allergic rhinitis (PAR). METHODS: This randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluated the effect of once-daily TAA-AQ (110 µg) on the growth velocity (GV) of children aged 3-9 years with PAR by using stadiometry at baseline (4-6 months), during treatment (12 months), and at follow-up (2 months). Hypothalamus-pituitary-adrenal (HPA) axis function was assessed by measuring urinary cortisol levels. Details of adverse events were recorded. RESULTS: Of 1078 subjects screened, 299 were randomized, and 216 completed the study (placebo, 107; TAA-AQ, 109). In the primary analysis (modified intent-to-treat: placebo, 133; TAA-AQ, 134), least-squares mean GV during treatment was lower in the TAA-AQ group (5.65 cm/year) versus placebo (6.09 cm/year). The difference (-0.45 cm/year; 95% confidence interval: -0.78 to -0.11; P = .01), although clinically nonsignificant, was evident within 2 months of treatment and stabilized thereafter. At follow-up, the GV approached baseline (6.70 cm/year) in the TAA-AQ group (6.59 cm/year) and decreased slightly in the placebo group (5.89 cm/year vs 6.06 cm/year at baseline). No HPA axis suppression was observed. CONCLUSIONS: By using rigorous Food and Drug Administration-recommended design elements, this study detected a small, statistically significant effect of TAA-AQ on the GV of children with PAR.

Effect of intranasal triamcinolone acetonide on basal hypothalamic-pituitary-adrenal axis function in children with allergic rhinitis.

Intranasal corticosteroids are the most effective medication class for controlling allergic rhinitis (AR) symptoms. However, limited data are available on their effects on basal hypothalamic-pituitary-adrenal (HPA) axis function in children. This study was designed to determine the effect of 6-week triamcinolone acetonide aqueous (TAA-AQ) nasal spray treatment on HPA axis function by measuring 24-hour serum cortisol area under the curve (AUC(0-24h)) in children with AR aged 2-11 years. This phase 4, multicenter, double-blind, placebo-controlled, parallel-group study randomized children with AR to receive TAA-AQ (110 µg, 2-11 years old, or 220 µg, 6-11 years old) or placebo. At pre- and posttreatment domiciled visits, 24-hour serum cortisol and reflective total nasal symptom scores (rTNSSs) were assessed. Safety assessment included treatment-emergent adverse events (TEAEs) at each visit and trough levels of 24-hour serum cortisol. A total of 140 subjects (mean age, 7.2 years; males, 59%) were randomized; 66 from each group completed treatment. The ratio of TAA-AQ to placebo for change from baseline in serum cortisol AUC(0-24h) was 0.966 (95% confidence interval, 0.892-1.045). Reduction from baseline in mean rTNSS was significantly greater in the TAA-AQ than in the placebo group (difference: least square mean ± SE = -0.85 ± 0.24; p = 0.0007). The safety profile was similar (TEAEs, TAA-AQ, 27.5%; placebo, 25.4%), and so was the mean change in serum cortisol trough level (TAA-AQ, -0.4 µg/dL; placebo, -0.1 µg/dL; p = 0.1818 for treatment difference) from pre- to posttreatment. TAA-AQ was safe, well tolerated, and not associated with clinically meaningful suppression of serum cortisol AUC(0-24h) in children with AR. Clinical trial NCT01154153, www.clinicaltrials.gov.

Predictors of progression of recently diagnosed atrial fibrillation in REgistry on Cardiac Rhythm DisORDers Assessing the Control of Atrial Fibrillation (RecordAF)-United States cohort.

The progression of atrial fibrillation (AF) to a more sustained form is associated with increased symptoms and morbidity. The aims of the REgistry on Cardiac Rhythm DisORDers Assessing the Control of Atrial Fibrillation (RecordAF)-United States (US) cohort study were to identify the risk factors of AF progression and the effects of management approaches. RecordAF is the first worldwide, 1-year observational study of the treatment of community-based patients with recent-onset AF. We assessed AF progression at 12 months in the US cohort. AF progression was defined as a change of AF to a more sustained form (either paroxysmal becoming persistent or permanent, or persistent becoming permanent). The US cohort included 955 patients, with mean age of 68.9 years; 56.8% were men and 88.8% were white. At entry, 59.6% of patients were selected for rate-control and 40.4% for rhythm-control therapy. At 12 months, the management strategy was unchanged for 68.2% of the patients in the rate- and 77.7% of the patients in the rhythm-control groups. Overall, AF progression had occurred in 18.6% of patients at 12 months. The progression rate was significantly greater in the rate-control (27.6%) than in the rhythm-control (5.8%) group (p <0.001). Progression to permanent AF occurred in 16.4% of patients. In addition to a rate-control strategy, older age, AF rhythm at entry, persistent AF at baseline, and a history of stroke or transient ischemic attack independently predicted AF progression. Rate control was associated with AF progression, with a propensity score adjusted odds ratio of 2.67 (p <0.001). In conclusion, rate control was the preferred treatment of recent-onset AF in the US but was associated with more AF progression than rhythm control.

Bayesian modeling and inference for meta-data with applications in efficacy evaluation of an allergic rhinitis drug.

Allergic rhinitis is an allergic inflammation of the nasal membranes. The symptoms include disorders in nose and eyes. Studies have been carried out on safety and efficacy evaluation of triamcinolone acetonide aqueous nasal spray. To combine the results from different studies, we propose random-coefficient regression models. The properties of the proposed models are examined. The models are compared via the deviance information criterion (DIC), and Bayesian computations are carried out via MCMC sampling. A set of meta-data from nine clinical trials is analyzed in detail via the proposed methodology.

Validation of the sleep impact scale in patients with major depressive disorder and insomnia.

OBJECTIVES: Chronic insomnia and depression are often associated. Measuring the impact on quality of life associated with changes in sleep in co-treatment of insomnia and depression requires a valid and reliable patient reported outcome (PRO) instrument. This study aimed to assess the validity of the Sleep Impact Scale (SIS), a sleep-specific PRO instrument, in a population comorbid with Major Depressive Disorder (MDD) and insomnia to support its use in clinical or clinical trial applications. RESEARCH DESIGN AND METHODS: Data from 379 subjects enrolled in a 27 week US, multi-center, phase IV, randomized, double-blind, parallel group, placebo-controlled trial of zolpidem tartrate extended-release taken in combination with escitalopram vs. placebo combined with escitalopram were pooled across treatment groups. Results from multi-trait analyses, tests of internal consistency and test-retest reliability, concurrent validity, known-groups validity, responsiveness, and thresholds for minimal important difference (MID) were examined. RESULTS: Mean baseline scores on the SIS ranged from 22.85 (+/-13.41) on Satisfaction with Sleep to 43.49 (+/-21.12) on Mental Fatigue, reflecting impairments due to sleep problems. The SIS was found to be internally consistent (alpha > or = 0.70 for all domains) and have good construct validity. The item-domain correlations were > or = 0.52 with no instance of an item correlating more highly with a domain other than its own. There were some floor and no ceiling effects. The test-retest reliability of the SIS domains ranged between 0.68 and 0.83. Clinical validity assessed through known groups methods was supported. The SIS was responsive to changes on all domains. Preliminary estimates of minimum important difference (MID) were obtained to interpret changes in SIS domains. LIMITATIONS: Limitations include the need for further qualitative research on content validity and the lack of a patient global assessment of change. CONCLUSIONS: This study yielded adequate evidence of the validity of the SIS for use in clinical trials and research on MDD patients with comorbid insomnia.

Efficacy of fexofenadine in the prophylactic control of cat allergen-induced allergic rhinitis.

BACKGROUND: To date, it is unknown whether fexofenadine mitigates the worsening of symptoms induced by the cat allergen Felis domesticus allergen 1. OBJECTIVE: To determine the effects of a single dose of fexofenadine hydrochloride, 180 mg, in preventing and controlling cat allergen-induced allergic rhinitis symptoms using the cat room challenge model. METHODS: This single-center, randomized, double-blind, placebo-controlled, 2-way crossover study consisted of a screening visit, 1 or 2 qualifying visits, and 2 treatment periods separated by a mean +/- SD washout period of 14 +/- 3 days. Patients were randomized to treatment sequence 1 (placebo followed by fexofenadine) or sequence 2 (fexofenadine followed by placebo). Baseline end points were obtained before study drug administration, and allergen challenges were initiated 1 1/2 hours after dosing. The primary end point was the change from predose baseline in the total symptom score (sum of rhinorrhea, itchy nose/palate/ throat, sneezing, and itchy/watery/red eyes) after 30 minutes of allergen exposure compared with placebo. RESULTS: Of 211 patients screened, 66 were randomized and 63 completed the study. Mean change in the total symptom score from predose baseline was significantly less with fexofenadine compared with placebo 30 minutes after initiation of the cat allergen challenge (2 hours after dosing) (P = .03). The overall incidence of treatment-emergent adverse events was low and comparable for both groups. CONCLUSION: Prophylactic treatment with a single dose of fexofenadine hydrochloride, 180 mg, significantly mitigated the worsening of allergic rhinitis symptoms induced by exposure to cat allergen compared with placebo use.

The bioequivalence of telithromycin administered orally as crushed tablets versus tablets swallowed whole.

This open-label, randomized, crossover study was conducted to demonstrate bioequivalence for telithromycin administered as crushed or whole tablets. Single 800-mg telithromycin doses (2x400-mg tablets) were administered as crushed tablets mixed in 240 mL nutritional supplement drink followed by 120 mL water or as whole tablets swallowed with 240 mL water. Plasma telithromycin concentrations were measured by liquid chromatography/mass spectrometry; pharmacokinetic parameters were determined using noncompartmental methods. Average bioequivalence criteria were applied. Thirty-two subjects received telithromycin by both methods. The 90% confidence intervals for the geometric mean ratios of maximum plasma concentration and area under the plasma concentration-time curve to 24 hours were within the 0.80 to 1.25 range. Median tmax was 3.00 hours for both treatments. Both methods of administration were well tolerated. Crushing telithromycin tablets and administering them with a nutritional supplement drink is bioequivalent to ingesting whole tablets and could be a viable method of administration for patients unable to swallow tablets whole.

Clinical performance of the LCx HCV RNA quantitative assay.

This study was conducted to assess the performance of the Abbott laboratories LCx HCV RNA Quantitative Assay (LCx assay) in the clinical setting. Four clinical laboratories measured LCx assay precision, specificity, and linearity. In addition, a method comparison was conducted between the LCx assay and the Roche HCV Amplicor Monitor, version 2.0 (Roche Monitor 2.0) and the Bayer VERSANT HCV RNA 3.0 Assay (Bayer bDNA 3.0) quantitative assays. For precision, the observed LCx assay intra-assay standard deviation (S.D.) was 0.060-0.117 log IU/ml, the inter-assay S.D. was 0.083-0.133 log IU/ml, the inter-lot S.D. was 0.105-0.177 log IU/ml, the inter-site S.D. was 0.099-0.190 log IU/ml, and the total S.D. was 0.113-0.190 log IU/ml. The specificity of the LCx assay was 99.4% (542/545; 95% CI, 98.4-99.9%). For linearity, the mean pooled LCx assay results were linear (r=0.994) over the range of the panel (2.54-5.15 log IU/ml). A method comparison demonstrated a correlation coefficient of 0.881 between the LCx assay and Roche Monitor 2.0, 0.872 between the LCx assay and Bayer bDNA 3.0, and 0.870 between Roche Monitor 2.0 and Bayer bDNA 3.0. The mean LCx assay result was 0.04 log IU/ml (95% CI, -0.08, 0.01) lower than the mean Roche Monitor 2.0 result, but 0.57 log IU/ml (95% CI, 0.53, 0.61) higher than the mean Bayer bDNA 3.0 result. The mean Roche Monitor 2.0 result was 0.60 log IU/ml (95% CI, 0.56, 0.65) higher than the mean Bayer bDNA 3.0 result. The LCx assay quantitated genotypes 1-4 with statistical equivalency. The vast majority (98.9%, 278/281) of paired LCx assay-Roche Monitor 2.0 specimen results were within 1 log IU/ml. Similarly, 86.6% (240/277) of paired LCx assay and Bayer bDNA 3.0 specimen results were within 1 log, as were 85.6% (237/277) of paired Roche Monitor 2.0 and Bayer specimen results. These data demonstrate that the LCx assay may be used for quantitation of HCV RNA in HCV-infected individuals.