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Active Comparator (active + comparator)
Selected AbstractsMulticenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder,DEPRESSION AND ANXIETY, Issue 5 2010Vladimir Coric M.D. Abstract Background: Antagonism of corticotropin-releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF-1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). Method: This was a multicenter, randomized, double-blind, placebo-controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100,mg/day (after a 1 week loading dose of 300,mg/day), placebo or escitalopram 20,mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. Results: Pexacerfont 100,mg/day did not separate from placebo on the primary outcome measure. The half-powered active comparator arm, escitalopram 20,mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2-2016) with the HAM-A psychic subscale score for the entire cohort at baseline (FDR-adjusted P=.015). Conclusions: Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment. Depression and Anxiety, 2010. © 2010 Wiley-Liss, Inc. [source] Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomized, placebo-controlled trialsBIPOLAR DISORDERS, Issue 2 2010Christoph U Correll Correll CU, Sheridan EM, DelBello MP. Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomized, placebo-controlled trials. Bipolar Disord 2010: 12: 116,141. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objective:, To compare antipsychotic and mood stabilizer (MS) efficacy and tolerability in youth and adults with bipolar mania. Methods:, Medline/PubMed search for studies including: (i) youth (< 18 years) or adults (, 18 years); (ii) bipolar I disorder; (iii) double-blind, randomized, placebo-controlled trial (DB-RPCT); (iv) , 12 weeks of treatment; and (v) calculable effect sizes (ES) and/or numbers needed to treat/harm (NNT/NNH) ± 95% confidence intervals (CI). Non-overlapping 95% CIs determined significant group differences. Results:, We identified nine DB-RPCTs in youth (n = 1,609), 5 evaluating second-generation antipsychotics (SGAs) (n = 1,140) and 4 evaluating MSs (n = 469). We also identified 23 DB-RPCTs in adults (n = 6,501), 14 including SGAs (n = 3,297), 5 using haloperidol as an active comparator (n = 580), and 11 including MSs (n = 2,581). Young Mania Rating Scale scores improved significantly more with SGAs than MSs in youth (ES = 0.65, CI: 0.53,0.78 versus 0.24, CI: 0.06,0.41) and adults (ES = 0.48, CI: 0.41,0.55 versus 0.24, CI: 0.17,0.31). After excluding topiramate studies, SGAs had larger ES than MSs only in youth (ES = 0.65, CI: 0.53,0.78 versus 0.20, CI: 0.02,0.39), but not adults (ES = 0.48, CI: 0.41,0.55 versus 0.46, CI: 0.37,0.55). However, in adults SGAs had significantly larger ES regarding Clinical Global Impressions scores than MSs, even without topiramate (ES = 0.75, CI: 0.68,0.82 versus 0.24, CI: 0.07,0.41). Rates of response, remission, and discontinuation due to any reason compared to placebo were similar between medication and age groups, except for more favorable NNTs for remission with SGAs than MSs in adults after excluding topiramate. SGAs caused more weight gain than MSs in youth (ES = 0.53, CI: 0.41,0.66 versus 0.10, CI: ,0.12,0.33), but not in adults (ES = 0.13, CI: 0.05,0.22 versus 0.00, CI: ,0.08,0.08). However, results were heterogeneous and not significant in either age group after excluding topiramate. Nevertheless, SGA-related weight gain was significantly greater in youth than adults. In youth, SGA-related somnolence was greater than with MSs (NNH = 4.7, CI: 3.9,6.0 versus 9.5, CI: 6.3,23.5), and more likely than in adults (NNH = 7.1, CI: 6.1,8.8). Conversely, youth experienced less akathisia with SGAs than adults (NNH = 20.4, CI: 14.1,36.5 versus 10.2, CI: 8.1,13.7), likely due to lower doses/slower titration. Conclusions:, In treating mania, potentially greater short-term efficacy compared to placebo with SGAs versus MS needs to be balanced against increased adverse events, especially in youth. [source] Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trialsBIPOLAR DISORDERS, Issue 1 2006Stuart F Kushner Objective:, To evaluate the efficacy and tolerability of topiramate monotherapy in adults with acute manic or mixed episodes of bipolar I disorder. Methods:, In four trials, adults hospitalized with acute mania, a diagnosis of bipolar I disorder, history of ,1 previous manic or mixed episodes, and ,20 Young Mania Rating Scale (YMRS) score were randomized to double-blind treatment with topiramate (target doses: 200, 400, or 600 mg/day) or placebo; two trials included an active comparator (lithium, 1500 mg/day). The core study duration in all trials was 3 weeks; three trials also had 9-week double-blind extensions. The primary efficacy variable was mean change from baseline in YMRS in the core 3-week study. Results:, Changes in YMRS score during 3 weeks were not significantly different for topiramate versus placebo (mean YMRS reductions, ,5.1 to ,8.4). Mean YMRS reductions in lithium-treated groups were significantly greater (p , 0.001 versus placebo and topiramate). A similar pattern was observed after 12 weeks of double-blind treatment in studies with double-blind extensions. Paresthesia, appetite decrease, dry mouth, and weight loss were more frequently associated with topiramate than with placebo. Conclusions:, These studies do not support the efficacy of topiramate as monotherapy in acute mania or mixed episodes in adults with bipolar I disorder. Topiramate was not associated with mood destabilization measured as mania exacerbation or treatment-emergent depression. Lithium was confirmed as an effective therapy in this population. [source] Effect of single doses of maraviroc on the QT/QTc interval in healthy subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2008John D. Davis AIMS To assess the effect of a single dose of maraviroc on the QTc interval in healthy subjects and to evaluate the QTc interval,concentration relationship. METHODS A single-dose, placebo- and active-controlled, five-way crossover study was conducted to investigate the effects of maraviroc (100, 300, 900 mg) on QTc in healthy subjects. Moxifloxacin (400 mg) was used as the active comparator. The study was double-blind with respect to maraviroc/placebo and open label for moxifloxacin. There was a 7-day wash-out period between each dose. QT interval measurements obtained directly from the electrocardiogram (ECG) recorder were corrected for heart rate using Fridericia's correction (QTcF). A placebo run-in day was conducted before period 3, when ECGs were collected at intervals while subjects were resting or during exercise. These ECGs plus other predose ECGs were used to evaluate the QT/RR relationship for each subject to enable calculation of an individual's heart rate correction for their QT measurements (QTcI). ECGs were taken at various intervals pre- and postdose in each study period. Pharmacokinetic parameters were determined for each maraviroc dose. The end-points that were evaluated were QTcF at median time to maximum concentration (Tmax) based on the machine readings and QTcI at median Tmax based on manual over-reads of the QT/RR data. A separate analysis of variance was used for each of the pair-wise comparisons for each end-point. The relationship between QTc interval and plasma concentration was also investigated using a mixed-effects modelling approach, as implemented by the NONMEM software system. A one-stage model was employed in which the relationship between QT and RR and the effects of maraviroc plasma concentration on QT were estimated simultaneously. RESULTS The mean difference from placebo in machine-read QTcF at median Tmax for maraviroc 900 mg was 3.6 ms [90% confidence interval (CI) 1.5, 5.8]. For the active comparator, moxifloxacin, the mean difference from placebo in machine-read QTcF was 13.7 ms. The changes from placebo for each of the end-points were similar for men and women. No subjects receiving maraviroc or placebo had a QTcF ,,450 ms (men) or QTcF ,,470 ms (women), nor did any subject experience a QTcF increase ,,60 ms from baseline at any time point. Analysis based on the QTcI data obtained from the manual over-readings of the ECGs gave numerically very similar results. The QT:RR relationship was similar pre- and postdose and was not related to maraviroc concentration. The population estimate of the QT:RR correction factor was 0.324 (95% CI 0.309, 0.338). The population estimate of the slope describing the QT,concentration relationship was 0.97 ,s ml ng,1 (95% CI ,0.571, 2.48), equivalent to an increase of 0.97 ms in QT per 1000 ng maraviroc plasma concentration. Most adverse events were mild to moderate in severity. CONCLUSIONS Single doses of maraviroc, up to and including 900 mg, had no clinically relevant effect on QTcF or QTcI. At all maraviroc doses and for both end-points, the mean difference from placebo for QTc was <4 ms. There was no apparent relationship between QT interval and maraviroc plasma concentration up to 2363 ng ml,1. This conclusion held in both male and female subjects, and there was no evidence of a change in the QT/RR relationship with concentration. [source] What's new in atopic eczema?CLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 6 2008An analysis of the clinical significance of systematic reviews on atopic eczema published in 200 Summary This review summarizes clinically important findings from 19 systematic reviews published between January 2006 and August 2007 on the topic of atopic eczema (AE). The evidence suggests that avoidance of allergenic foods during pregnancy or the use of hydrolyzed or soy formula milks does not prevent eczema. Delayed introduction of solids may decrease eczema risk. Asthma typically develops in around a third of children with eczema, and wheezing in early infancy is a predictor of risk. Established topical corticosteroids such as betamethasone should be used just once daily. Topical tacrolimus and pimecrolimus can be used for people who become dependent on topical corticosteroids, especially on sensitive sites such as the face. Wet wraps are useful in secondary care for inducing remission in a child, but they are not a treatment for mild eczema and they should not be used long term. Oral ciclosporin can be used for inducing a remission in severe eczema, and azathioprine can be considered for maintenance treatment. Narrowband ultraviolet (UV)B phototherapy can be used for chronic AE, and UVA1 may be useful for acute eczema. There is little convincing evidence of a clinical benefit with evening primrose oil for eczema, but there is some good new evidence that educational support to eczema families is beneficial. Future trials need to be larger, and include active comparators, patient-reported outcomes and longer-term aspects of disease control. They should be better reported, and registered on a public clinical trials register. [source] | ||||||||||