Randomized comparison of the type 4 phosphodiesterase inhibitor cipamfylline cream, cream vehicle and hydrocortisone 17‐butyrate cream for the treatment of atopic dermatitis A randomised, double-blind trial to demonstrate bioequivalence of GP2013 and reference rituximab combined with methotrexate in patients with active rheumatoid arthritis Generalisability of clinical trials in otitis media with effusion. Adherence to initial PDE-5 inhibitor treatment: randomized open-label study comparing tadalafil once a day, tadalafil on demand, and sildenafil on demand in patients with erectile dysfunction. Prednisolone versus dexamethasone in croup: a randomised equivalence trial Indirect comparison in evaluating relative efficacy illustrated by antimicrobial prophylaxis in colorectal surgery. Aerobic walking and strengthening exercises have similar effectiveness for knee osteoarthritis. Indirect comparisons of competing interventions. A prospective, randomized, multicenter acceptability and safety study of direct buprenorphine/naloxone induction in heroin-dependent individuals. Heuristic comparison of sertraline with nortriptyline for the treatment of depression in frail elderly patients. Do randomized clinical trials with inadequate blinding report enhanced placebo effects for intervention groups and nocebo effects for placebo groups? Some concerns about adverse event reporting in randomized clinical trials. Sleep Misperception and Chronic Insomnia in the General Population: Role of Objective Sleep Duration and Psychological Profiles Comparison of rofecoxib and celecoxib, two cyclooxygenase-2 inhibitors, in postoperative dental pain: a randomized, placebo- and active-comparator-controlled clinical trial. Comparison of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment: a randomised clinical trial Rates of virological failure in patients treated in a home-based versus a facility-based HIV-care model in Jinja, southeast Uganda: a cluster-randomised equivalence trial The challenge of evaluating surgical procedures. Double-blind randomised trial of modest salt restriction in older people ASSESS-3: A randomised, double-blind, flexible-dose clinical trial of the efficacy and safety of oral sildenafil in the treatment of men with erectile dysfunction in Taiwan Biological treatments for moderate-to-severe psoriasis: indirect comparison. A randomised, double-blind comparison of the efficacy and safety of citalopram compared to mianserin in elderly, depressed patients with or without mild to moderate dementia. Non-randomized studies as a source of complementary, sequential or replacement evidence for randomized controlled trials in systematic reviews on the effects of interventions. Vardenafil in men with stable statin therapy and dyslipidemia.
Summary Background Therapeutic options to treat atopic dermatitis are limited . Leukocytes from atopic patients have an abnormally high activity of cyclic adenosine monophosphate (AMP)–phosphodiesterase ( PDE ) , which can be normalized in vitro by PDE inhibitors . Cipamfylline is a new potent and selective inhibitor of PDE‐4 Objectives The aim of this report is to demonstrate pharmacokinetic ( PK ) and pharmacodynamic ( PD ) equivalence as well as similar efficacy , safety and immunogenicity between GP2013 , a biosimilar rituximab , and innovator rituximab ( RTX ) in patients with rheumatoid arthritis ( RA ) with inadequate response or intolerance to tumour necrosis factor inhibitor ( TNFi ) treatment . Methods In this multinational , r and omised , double-blind , parallel-group study , 312 patients with active disease despite prior TNFi therapy were r and omised to receive GP2013 or either the EU ( RTX-EU ) or the US ( RTX-US ) reference product , along with methotrexate ( MTX ) and folic acid . The primary endpoint was the area under the serum concentration – time curve from study drug infusion to infinity ( AUC0-inf ) . Additional PK and PD parameters , along with efficacy , immunogenicity and safety outcomes were also assessed up to week 24 . Results The 90 % CI of the geometric mean ratio of the AUCs were within the bioequivalence limits of 80 % to 125 % for all three comparisons ; GP2013 versus RTX-EU : 1.106 ( 90 % CI 1.010 to 1.210 ) ; GP2013 versus RTX-US : 1.012 ( 90 % CI 0.925 to 1.108 ) ; and RTX-EU versus RTX-US : 1.093 ( 90 % CI 0.989 to 1.208 ) . Three-way PD equivalence of B cell depletion was also demonstrated . Efficacy , safety and immunogenicity profiles were similar between GP2013 and RTX . Conclusions Three-way PK/PD equivalence of GP2013 , RTX-EU and RTX-US was demonstrated . Efficacy , safety and immunogenicity profiles were similar between GP2013 and RTX . Trial registration number NCT01274182 ; Results OBJECTIVE The impact of a r and omised controlled trial ( RCT ) upon practice depends on its external validity ( generalisability ) . This paper summarises and illustrates a framework for judging and augmenting external validity , emphasising its application to treatment trials in otitis media with effusion ( OME ) so as to permit stronger inferences in the future . METHODS The external validity of two surgical trials in the field of OME ( TARGET , UK and KNOOP-3 , the Netherl and s ) has been examined within a framework emphasising effect modification , in four specific ways : ( 1 ) comparison of the demographic characteristics of the trial population with the domain population ; ( 2 ) study ing the distributions on possible effect modifiers ( i.e. variables conditioning the benefit from intervention ) ; ( 3 ) study ing whether effect modification occurs in the analyses ; and ( 4 ) comparing outcome measures between the r and omised and the eligible but non-r and omised children . RESULTS For neither KNOOP-3 and TARGET were large discrepancies found between r and omised and non-r and omised children for any of the demographic variables . Differences in distributions along possible effect modifiers were found , but the overlaps were large enough for it still to be possible to study whether these factors indeed modified the outcome . Results for the r and omised and non-r and omised but eligible patients were similar . The results of both trials therefore appear to be generalisable to their domain population s. CONCLUSIONS A superficial contrast in the results ( KNOOP null , TARGET positive ) does not amount to a contradiction , because of differences in the clinical question appropriate to the respective age and population s defined . Attention to quality of design and external validity of r and omised controlled trials should achieve higher applicability INTRODUCTION Phosphodiesterase type 5 ( PDE-5 ) inhibitor treatment for erectile dysfunction ( ED ) is frequently discontinued ; adherence may vary depending on the initial regimen . AIM To evaluate the effects of initiating treatment with tadalafil once a day ( OaD ) , tadalafil on dem and ( pro re nata [ PRN ] ) , or sildenafil PRN on treatment adherence . METHODS In this multicenter , open-label study , men ( ≥ 18 years ) with ED , naïve to PDE-5 inhibitors , were r and omized ( 1:1:1 ) to tadalafil 5 mg OaD , tadalafil 10 mg PRN , or sildenafil 50 mg PRN . An 8-week r and omized treatment ( RT ) period ( dose adjustment possible ) was succeeded by 16 weeks of pragmatic treatment ( switches between PDE-5 inhibitors allowed ) . MAIN OUTCOME MEASURES Treatment adherence was measured as time to discontinuation of RT ( any cause ) , estimated by Kaplan-Meier product-limit method . Treatment-group differences were estimated as hazard ratio ( HR ; Cox proportional hazards ) . RESULTS Seven hundred seventy patients ( mean age 53 years ) were r and omized to tadalafil OaD ( N = 257 ) , tadalafil PRN ( N = 252 ) , and sildenafil PRN ( N = 261 ) . Kaplan-Meier estimates for patients discontinuing RT were 52.2 , 42.0 , and 66.7 % , respectively . Median time to discontinuation of RT was significantly longer for tadalafil OaD and PRN ( 130 and > 168 days ) compared with sildenafil ( 67 days ) ( HR [ 97.5 % confidence interval ] : 0.66 [ 0.51 , 0.85 ] and 0.49 [ 0.37 , 0.65 ] ; P < 0.001 ) . Reasons for discontinuation with significant differences between groups ( P < 0.05 ) included " lack of efficacy ( duration of erection ) " ( sildenafil 9.2 % vs. tadalafil OaD 4.3 % , PRN 2.8 % ) , " time constraints due to short window of action "  ( sildenafil 4.2 % vs. tadalafil OaD 0 % , PRN 0.4 % ) , and " feel medication controls my sexual life "  ( sildenafil 2.7 % vs. tadalafil OaD 0 % ) . No between-group differences were found in International Index of Erectile Function-Erectile Function domain change from baseline to end of RT ( least squares mean : 9.4 - 10.0 , P = 0.359 ) or discontinuations due to adverse events ( 1.2 - 1.6 % ) . The most common adverse event ( ≥ 4 % ) was headache . CONCLUSIONS ED patients assigned to tadalafil OaD or PRN adhered significantly longer to initial treatment than patients assigned to sildenafil PRN . Improvement of erectile function and safety profiles were similar in all three treatment groups Background : Croup remains a common respiratory problem presenting to emergency departments . A single oral treatment of oral dexamethasone results in improved outcome .  Prednisolone has similar pharmacokinetic properties and has a significant advantage in that it is commercially available in liquid preparations . Objective : To ascertain whether a single oral dose of prednisolone was equivalent to a single oral dose of dexamethasone ( matched for potency ) in children with mild to moderate croup . Design : A double blind , r and omised , controlled equivalence trial Setting : Tertiary paediatric emergency department . Patients : 133 children aged 3 to 142 months presenting with mild to moderate croup . Interventions : Children received either a single oral dose of dexamethasone 0.15 mg/kg or single oral dose of prednisolone 1 mg/kg . Outcome : The main outcome measure was unscheduled re-presentation to medical care as determined by telephone follow up at 7 to 10 days . Croup score , adrenaline ( epinephrine ) use , time spent in the emergency department , and duration of croup and viral symptoms were secondary outcome measures . Results : Children treated with prednisolone were more likely to re-present : 19 of 65 children ( 29 % ) reattended medical care compared with 5 of 68 ( 7 % ) from the dexamethasone group . The confidence intervals around this 22 % difference in outcome were 8 % to 35 % , outside the 0 % to 7.5 % range of equivalence . There were no significant differences in other outcome measures . Conclusion : A single oral dose of prednisolone is less effective than a single oral dose of dexamethasone in reducing unscheduled re-presentation to medical care in children with mild to moderate croup This paper aims to explore the potential usefulness and limitations of indirect comparisons in evaluating the relative efficacy of interventions . From a systematic review of antimicrobial prophylaxis in colorectal surgery , we identified 11 sets of r and omized trials that can be used to compare antibiotics both directly and indirectly . The discrepancy between the direct and the indirect comparison is defined as the absolute value of difference in log odds ratio . The adjusted indirect comparison has the advantages that the prognostic factors of participants in different trials can be partially taken into account and more uncertainty be incorporated into its result by providing a wider confidence interval . However , considerable discrepancies exist between the direct and the adjusted indirect comparisons . When there is no direct comparison , the adjusted indirect method may be used to obtain some evidence about the relative efficacy of competing interventions , although such indirect results should be interpreted with great caution . Further empirical and method ologic research is needed to explore the validity and generalizability of the adjusted indirect comparison for evaluating different interventions Question To compare the efficacy of aerobic walking and home based quadriceps strengthening exercises in reducing  pain and disability in knee osteoarthritis . Design Systematic review of r and omised controlled trials . Setting / population People with knee osteoarthritis . Interventions Comparison of aerobic walking or home based quadriceps strengthening exercise with a non-exercise control group . Strengthening exercise was considered to be ‘ home based ' where it was undertaken exclusively in the subject 's home environment or , where exercise was partly supervised , the regimen was intended to be continued at home unsupervised . Outcomes Pain and disability . Results 13 studies were included . One study provided a direct comparison between aerobic walking and home based strengthening exercises and control . Nine RCTs evaluated quadriceps strengthening exercises , and in three studies the exercise intervention was predominantly aerobic walking . Control interventions included education and lifestyle advice , support by telephone calls , and no intervention . When comparing aerobic walking with no exercise interventions , the pooled effect sizes for pain and disability were 0.52 ( 95 % CI 0.34 to 0.70 ) and 0.46 ( 95 % CI 0.25 to 0.67 ) respectively . Corresponding effect size for quadriceps strengthening was 0.32 ( 95 % CI 0.23 to 0.42 ) for both pain and disability . Conclusion Both aerobic walking and home based quadriceps strengthening exercises are effective at reducing pain and disability in subjects with knee osteoarthritis . No advantage of one form of exercise over the other was found on indirect comparison OBJECTIVES To survey the frequency of use of indirect comparisons in systematic review s and evaluate the methods used in their analysis and interpretation . Also to identify alternative statistical approaches for the analysis of indirect comparisons , to assess the properties of different statistical methods used for performing indirect comparisons and to compare direct and indirect estimates of the same effects within review s. DATA SOURCES Electronic data bases . REVIEW METHODS The Data base of Abstract s of Review s of Effects ( DARE ) was search ed for systematic review s involving meta- analysis of r and omised controlled trials ( RCTs ) that reported both direct and indirect comparisons , or indirect comparisons alone . A systematic review of MEDLINE and other data bases was carried out to identify published methods for analysing indirect comparisons . Study design s were created using data from the International Stroke Trial . R and om sample s of patients receiving aspirin , heparin or placebo in 16 centres were used to create meta-analyses , with half of the trials comparing aspirin and placebo and half heparin and placebo . Methods for indirect comparisons were used to estimate the contrast between aspirin  and  heparin . The whole process was repeated 1000 times and the results were compared with direct comparisons and also theoretical results . Further detailed case studies comparing the results from both direct and indirect comparisons of the same effects were undertaken . RESULTS Of the review s identified through DARE , 31/327 ( 9.5 % ) included indirect comparisons . A further five review s including indirect comparisons were identified through electronic search ing . Few review s carried out a formal analysis and some based analysis on the naive addition of data from the treatment arms of interest . Few method ological papers were identified . Some valid approaches for aggregate data that could be applied using st and ard software were found : the adjusted indirect comparison , meta-regression and , for binary data only , multiple logistic regression ( fixed effect models only ) . Simulation studies showed that the naive method is liable to bias and also produces over-precise answers . Several methods provide correct answers if strong but unverifiable assumptions are fulfilled . Four times as many similarly sized trials are needed for the indirect approach to have the same power as directly r and omised comparisons . Detailed case studies comparing direct and indirect comparisons of the same effect show considerable statistical discrepancies , but the direction of such discrepancy is unpredictable . CONCLUSIONS Direct evidence from good- quality RCTs should be used wherever possible . Without this evidence , it may be necessary to look for indirect comparisons from RCTs . However , the results may be susceptible to bias . When making indirect comparisons within a systematic review , an adjusted indirect comparison method should ideally be used employing the r and om effects model . If both direct and indirect comparisons are possible within a review , it is recommended that these be done separately before considering whether to pool data . There is a need to evaluate methods for the analysis of indirect comparisons for continuous data and for empirical research into how different methods of indirect comparison perform in cases where there is a large treatment effect . Further study is needed into when it is appropriate to look at indirect comparisons and when to combine both direct and indirect comparisons . Research into how evidence from indirect comparisons compares to that from non-r and omised studies may also be warranted . Investigations using individual patient data from a meta- analysis of several RCTs using different protocol s and an evaluation of the impact of choosing different binary effect measures for the inverse variance method would also be useful AIMS To provide controlled data on direct induction with buprenorphine/naloxone ( BNX ) versus indirect buprenorphine (BPN)-to-BNX induction . DESIGN Phase 4 , prospect i ve , r and omized , active-drug controlled , parallel-group trial consisting of a 2-day , double-blind , double-dummy induction phase followed by 26 days of open-label treatment with BNX . SETTING Nineteen sites in 10 European countries from March 2008 to December 2009 . PARTICIPANTS A total of 187 opioid-dependent men and women ≥ 15 years of age . MEASUREMENTS The primary objective was assessment of patient response to direct and indirect BNX induction  [ proportion of patients receiving the scheduled 16-mg BNX dose on day 3 ( i.e. first day post-induction ) ] . Secondary assessment s included illicit drug use , treatment retention and compliance , withdrawal scale scores , and safety . FINDINGS Patient response to direct- versus indirect-BNX induction was similar [ direct 91.4 % ( 85/93 ) versus indirect 90.4 % ( 85/94 ) ; 95 % confidence interval ( CI ) : -7.3 % , 9.2 % ] . Rapid dose induction ( 16 mg of BPN equivalent on day 2 ) was acceptable and 72 % of patients completed treatment ( day 28 ) . There were no significant differences in secondary measures across groups . An average BNX maintenance dose of 15.3 mg across groups was associated with substantial reductions in illicit opioid use and no self-reported intravenous misuse . Treatment compliance and retention rates were similar ( 98.5 % and 81.3 % , respectively ) . Treatment-emergent adverse event rates were comparable : 75 % versus 74 % for direct- versus indirect-induction groups , respectively . CONCLUSIONS Direct buprenorphine/naloxone induction was a safe and effective strategy for maintenance treatment of opioid dependence . Response to high-dose direct buprenorphine/naloxone induction appears to be similar to indirect buprenorphine-to-buprenorphine/naloxone induction and was not associated with reports of intravenous buprenorphine/naloxone misuse Studies have demonstrated that the selective serotonin reuptake inhibitor antidepressants have similar efficacy to other agents , such as tricyclic antidepressants . However , data are limited for direct comparisons with other antidepressants . The authors conducted a contemporaneous comparison of nursing home residents treated with open-label sertraline in doses up to 100 mg/day with nursing home residents treated in a double-blind r and omized study of low vs. regular doses of nortriptyline . There were 97 patients enrolled in the study ( 28 treated with sertraline ) , with an average treatment duration of 55 days . There were no differences in the tolerability of sertraline vs. nortriptyline . However , in this group of frail older adults , sertraline was not as effective as  nortriptyline for the treatment of depression Background Studies suggest that expectations powerfully shape clinical outcomes . For subjective outcomes in adequately blinded trials , health improvements are substantial and largely explained by non-specific factors . The objective of this study was to investigate if unblinding in r and omized controlled trials ( RCTs ) is associated with enhanced placebo effects for intervention groups and nocebo effects for placebo groups . For these effects , a secondary objective was to explore potential moderating factors . Methods We included RCTs that investigated the efficacy of phosphodiesterase-5 ( PDE-5 ) inhibitors  for male erectile dysfunction by comparing one PDE-5 inhibitor to placebo . In addition , to be included studies must have reported scores for change from baseline , or baseline and final International Index of Erectile Functioning-Erectile Functioning domain score ( IIEF-EF )  , and be published in either English , French , Dutch , or German . We search ed for both published and unpublished relevant trials using PUBMED , EMBASE , the Cochrane Central Register of Controlled Trials , a clinical trials register ( clinical trials.gov ) and the Food and Drug Administration clinical review s through March 2012.We evaluated the blinding status of trials with the Cochrane Risk of Bias Tool , using the domains of allocation sequence concealment , blinding of participants , healthcare providers and outcome assessors . Across these four domains , studies that scored low risk of bias were judged to be adequately blinded and studies that scored unclear or high risk of bias were judged to be inadequately blinded . Results We included 110 studies ( 205 journal publications and 2 unpublished sources ) that involved 23,877 participants ; 93 ( 85 % ) , 51 ( 46 % ) , 93 ( 85 % ) and 93 ( 85 % ) studies were assessed with an unclear risk of bias for allocation concealment , blinding of participant , blinding of caregiver and blinding of outcome assessor , respectively . None of the studies reported testing of blinding . None of the 205 journal publications provided sufficient details to assess allocation concealment , blinding of participants , caregivers and outcome assessors . After contacting authors for additional information , we judged five studies to be adequately ( n = 1,202 ) and 16 to be inadequately ( n = 3,006 ) blinded . The IIEF-EF score for placebo groups in adequately blinded trials versus inadequately blinded trials was 1.92 points ( 95 % CI , 0.64 to 3.20 ) versus 1.56 ( 95 % CI , 0.93 to 2.20 ) , respectively . The IIEF-EF score for intervention groups in adequately blinded trials versus inadequately blinded trials was 9.40 ( 95 % CI , 6.96 to 11.83 ) versus 8.33 ( 95 % CI , 7.29 to 9.37 ) , respectively . In a secondary analysis , prior experience with the drug affected the scores ; in placebo groups with participants naïve to the intervention the score was 2.89 ( 95 % CI , 2.33 to 3.45 ) versus -0.11 ( 95 % CI , -2.06 to 1.84 ) with participants having prior experience . In the intervention groups , these scores were 7.99 ( 95 % CI , 6.85 to 9.14 ) versus 8.33 ( 95 % CI , 7.51 to 9.16 ) , respectively . Unblinding lowered placebo scores ( creating a nocebo effect ) by 19 % ( 0.33 points ; 95 % CI , -0.96 to 1.62 ) . Unblinding lowered intervention scores by 11 % ( 1.0 ; 95 % CI , -1.35 to 3.47 ) . The results provided no conclusive evidence for nocebo or enhanced placebo effects .  Patients taking a PDE-5 inhibitor for the first time experience a larger placebo effect that accounts for 35 % of the total effect . Conclusions Given the overall poor reporting of blinding in clinical trial reports and the small number of trials that could be rated as adequately or inadequately blinded , we could not draw any robust conclusions about the existence or absence of nocebo and enhanced placebo effects . A large placebo effect was found for patients taking PDE-5 inhibitors for the first time . It was not clear if previous exposure to the drug impacted trial blinding . We found clear evidence that studies assessing a subjective continuous outcome fail to report on measures taken to secure double blinding . Although we observed a trend for the presence of a nocebo effect , there was insufficient evidence to quantify its impact on expectations . RCTs with patients with no prior experience with PDE-5 inhibitors reported larger placebo effects and possibly these studies were better blinded . Future research should further investigate the factors that contribute to blinding and their impact on health outcomes in r and omized trials of subjectively assessed conditions . This research is part of a PhD project and has no external funding . The authors have no competing interests to declare Reporting of adverse events ( AEs ) in r and omized clinical trials ( RCTs ) is often lacking and with limited application in the real world , as RCTs are of short duration , include small numbers of patients , and are selective for subjects lacking in comorbid conditions . It is not surprising that new and unexpected safety concerns emerge with any new drug after it has been launched and used by many more patients . Part of the problem is inherent to the way safety data are reported in RCTs . This article focuses on some of the shortcomings of AE reporting in RCTs , especially those involving tumor necrosis factor ( TNF ) inhibitors . Discussion focuses on reporting of " time-to-event " issues , use of st and ardized incidence ratios for comparison to normal population or disease controls , use of " patient-years " when reporting AEs , and the problem of adequate sample size and power calculations that are lacking in safety outcome data trials Objective : To examine the role of objective sleep duration , a novel marker in phenotyping insomnia , and psychological profiles on sleep misperception in a large , general population sample . Sleep misperception is considered by some investigators a common characteristic of chronic insomnia , whereas others propose it as a separate diagnosis . The frequency and the determinants of sleep misperception in general population sample s are unknown . Methods : A total of 142 insomniacs and 724 controls selected from a general r and om sample of 1,741 individuals ( aged ≥20 years ) underwent a polysomnographic evaluation , completed the Minnesota Multiphasic Personality Inventory-2  , and were split into two groups based on their objective sleep duration : “ normal sleep duration ” ( ≥6 hours ) and “ short sleep duration ” ( < 6 hours ) . Results : The discrepancy between subjective and objective sleep duration was determined by two independent factors . Short sleepers reported more sleep than they objective ly had , and insomniacs reported less sleep than controls with similar objective sleep duration . The additive effect of these two factors result ed in underestimation only in insomniacs with normal sleep duration . Insomniacs with normal sleep duration showed a Minnesota Multiphasic Personality Inventory-2 profile of high depression and anxiety and low ego strength , whereas insomniacs with short sleep duration showed a profile of a medical disorder . Conclusions : Underestimation of sleep duration is prevalent among insomniacs with objective normal sleep duration . Anxious-ruminative traits and poor re sources for coping with stress seem to mediate the underestimation of sleep duration . These data further support the validity and clinical utility of objective sleep measures in phenotyping insomnia . BMI = body mass index ; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition ; MANCOVA = multivariate analysis of covariance ; MMPI-2 = Minnesota Multiphasic Personality Inventory-2 ; PLMS = periodic limb movements ; SDB = sleep disordered breathing Pain is a common complaint , often occurring in conjunction with inflammation . Nonsteroidal anti-inflammatory drugs ( NSAIDs ) are the most commonly used analgesic agents in ambulatory patients . In recent studies , the cyclooxygenase-2 ( COX-2 ) inhibitor rofecoxib demonstrated analgesic effects similar to those of NSAIDs in the treatment of acute pain and primary dysmenorrhea . The present r and omized , single-dose , double-blind , double-dummy , placebo- and active-comparator-controlled , parallel-group study was undertaken to compare the analgesic efficacy of the COX-2 inhibitors rofecoxib 50 mg and celecoxib 200 mg with that of ibuprofen 400 mg and placebo in patients with postoperative dental pain . Two hundred and seventy-two patients experiencing pain after the removal of > or = 2 third molars were r and omized according to pain severity ( moderate vs severe ) to receive a single dose of placebo ( n = 45 ) , rofecoxib 50 mg ( n = 90 ) , celecoxib 200 mg ( n = 91 ) , or ibuprofen 400 mg ( n = 46 ) . Using a patient diary , patients recorded pain intensity , pain relief , and global evaluations throughout the 24-hour period after dosing . The overall analgesic effect , onset of action , peak effect , and duration of effect were evaluated , with the primary end point being total pain relief over 8 hours ( TOPAR8 ) . The safety profile was assessed on the basis of physical findings , laboratory results , and spontaneous reports of adverse experiences . The results showed that compared with celecoxib , rofecoxib had superior analgesic effects on all measures of analgesic efficacy , including overall analgesic effect ( TOPAR8 , 18.3 vs. 12.5 ; P<0.001 ) , time to onset of effect ( 30 vs. 60 minutes ; P = 0.003 ) , peak pain relief ( score , 2.8 vs 2.3 ; P<0.05 ) , and duration of effect ( > 24 vs. 5.1 hours ; P<0.001 ) . In addition , rofecoxib 's analgesic efficacy was similar to that of ibuprofen ( TOPAR8 , 18.3 vs. 17.0 ; P = 0.460 ) , but the duration was longer ( P<0.05 ) ; with ibuprofen , the time to on set was 24 minutes , peak pain relief score was 2.9 , and duration of analgesic effect was 8.9 hours . The safety profile was similar across all treatment groups . Thus rofecoxib provided analgesic efficacy superior to that of celecoxib and comparable to that of ibuprofen in the treatment of patients with acute postoperative dental pain Abstract Aims /hypothesisThere are limited data comparing dipeptidyl peptidase-4 ( DPP-4 ) inhibitors directly . We compared the safety and efficacy of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment ( RI ) . Methods This study was a parallel-arm , r and omised , multicentre , double-blind , 24 week study conducted in 87 centres across Brazil and the USA . Patients with type 2 diabetes , either drug naive or treated with any glucose-lowering agents , who had inadequate glycaemic control ( HbA1c 6.5–10.0 % [ 48–86 mmol/mol ] ) and an estimated GFR < 30 ml min−1 [ 1.73 m]−2 were r and omised ( via interactive voice response technology ) to vildagliptin 50 mg once daily or sitagliptin 25 mg once daily . These doses are recommended in this patient population and considered maximally effective . Participants , investigators and the sponsor were blinded to group assignment . Efficacy endpoints included change in HbA1c and fasting plasma glucose ( FPG ) at all visits and the primary safety endpoint was assessment of treatment-emergent adverse events . Results In total , 148 patients were r and omised , 83 to vildagliptin and 65 to sitagliptin . All patients were analysed . After 24 weeks , the adjusted mean change in HbA1c was −0.54 % ( 5.9 mmol/mol ) from a baseline of 7.52 % ( 59 mmol/mol ) with vildagliptin and −0.56 % ( 6.1 mmol/mol ) from a baseline of 7.80 % ( 62 mmol/mol ) with sitagliptin ( p = 0.874 ) . FPG decreased by 0.47 ± 0.37 mmol/l with vildagliptin and increased by 0.16 ± 0.43 mmol/l with sitagliptin ( p = 0.185 ) . Both treatments were well tolerated with overall similar safety profiles . Conclusions /interpretationAt their recommended doses for severe RI , vildagliptin ( 50 mg once daily ) compared with sitagliptin ( 25 mg once daily ) demonstrated similar efficacy and both drugs were well tolerated . This study provides further support for the use of DPP-4 inhibitors in patients with severe RI . Trial registration : Clinical Trials.gov NCT00616811 ( completed ) Funding : This study was planned and conducted by BACKGROUND Identification of new ways to increase access to antiretroviral therapy in Africa is an urgent priority . We assessed whether home-based HIV care was as effective as was facility-based care . METHODS We undertook a cluster-r and omised equivalence trial in Jinja , Ug and a. 44 geographical areas in nine strata , defined according to ratio of urban and rural participants and distance from the clinic , were r and omised  to home-based or facility-based care by drawing sealed cards from a box . The trial was integrated into normal service delivery . All patients with WHO stage IV or late stage III disease or CD4-cell counts fewer than 200 cells per microL who started antiretroviral therapy between Feb 15 , 2005 , and Dec 19 , 2006 , were eligible , apart from those living on isl and s. Follow-up continued until Jan 31 , 2009 . The primary endpoint was virological failure , defined as RNA more than 500 copies per mL after 6 months of treatment . The margin of equivalence was 9 % ( equivalence limits 0.69 - 1.45 ) . Analyses were by intention to treat and adjusted for baseline CD4-cell count and study stratum . This trial is registered at http://is rct n.org , number IS RCT N 17184129 . FINDINGS 859 patients ( 22 clusters ) were r and omly assigned to home and 594 ( 22 clusters ) to facility care . During the first year , 93 ( 11 % ) receiving home care and 66 ( 11 % ) receiving facility care died , 29 ( 3 % ) receiving home and 36 ( 6 % ) receiving facility care withdrew , and 8 ( 1 % ) receiving home and 9 ( 2 % ) receiving facility care were lost to follow-up . 117 of 729 ( 16 % ) in home care had virological failure versus 80 of 483 ( 17 % ) in facility care : rates per 100 person-years were 8.19 ( 95 % CI 6.84 - 9.82 ) for home and 8.67 ( 6.96 - 10.79 ) for facility care ( rate ratio [ RR ] 1.04 , 0.78 - 1.40 ; equivalence shown ) . Two patients from each group were immediately lost to follow-up . Mortality rates were similar between groups ( 0.95 [ 0.71 - 1.28 ] ) . 97 of 857 ( 11 % ) patients in home and 75 of 592 ( 13 % ) in facility care were admitted at least once ( 0.91 , 0.64 - 1.28 ) . INTERPRETATION This home-based HIV-care strategy is as effective as is a clinic-based strategy , and therefore could enable improved and equitable access to HIV treatment , especially in areas with poor infrastructure and access to clinic care All new interventions and procedures must be properly assessed in comparison to the currently accepted method ( s ) . It is unethical not to do so . The optimum method is by R and omised Controlled Trial ( RCT ) . This is ideally suited to the testing of drugs because the trial can usually be double blind and placebo controlled . RCTs are less commonly used for the evaluation of new surgical techniques . There are valid and invalid reasons for this and these are discussed BACKGROUND Stroke is directly related to blood pressure and treatment trials in older hypertensive individuals show a reduction in strokes . However , the majority of strokes occur in normotensive individuals in whom no attempt is made to lower blood pressure . We compared the effects of modest salt restriction on blood pressure in older hypertensive and normotensive people . METHODS 47 untreated elderly people ( 24 men , age range 60 - 78 years ; blood-pressure range 123 - 205 mm Hg systolic and 64 - 112 mm Hg diastolic ) completed a 2-month double-blind r and omised placebo-controlled crossover study of modest salt restriction with slow sodium and placebo to give a salt intake of either 10 g ( equivalent to the normal amount for the UK population ) or 5 g. FINDINGS On the normal salt intake for the UK population , supine blood pressure was 163/90 ( SD 21/10 ) mm Hg with urinary sodium excretion of 177 ( 49 ) mmol/day . With modest sodium restriction , blood pressure fell to 156/87 ( 22/9 ) mm Hg ( p < 0.001/0.004 ) with a urinary sodium excretion of 94 ( 50 ) mmol/day . A reduction in sodium intake of 83 mmol/day was associated with a reduction of 7.2/3.2 mm Hg . There was no significant difference in the blood-pressure fall between 18 normotensive and 29 hypertensive participants ( 8.2/3.9 vs 6.6/2.7 mm Hg ) . INTERPRETATION A modest reduction in salt intake leads to a fall in blood pressure in both normotensive and hypertensive older people similar to that in outcome trials of thiazide-based treatment . Since the majority of strokes in older people occur below the current definition of hypertension , our results have important implication s for the prevention of stroke The efficacy and safety of sildenafil were evaluated in a r and omised , double-blind , placebo-controlled , flexible-dose study in Taiwanese men aged 26 to 80 y with erectile dysfunction ( ED ) of broad-spectrum aetiology and more than 6 months ' duration . A total of 236 patients were r and omised at six medical centres in Taiwan to receive either sildenafil ( 50 mg initially increased if necessary to 100 mg or decreased to 25 mg depending on efficacy and toleration ) ( n=119 ) or matching placebo ( n=117 ) taken on an ‘ as needed ’ basis 1 h prior to anticipated sexual activity for a period of 12 weeks . At the end of 12 weeks , the primary efficacy variables relating to the achievement and maintenance of erections sufficient for sexual intercourse , and the secondary efficacy variables , which included : ( 1 ) the five separate domains of sexual functioning of the IIEF ( International Index of Erectile Function ) scale , ( 2 ) the percentage of successful intercourse attempts ; and ( 3 ) a global assessment of erections , were all statistically significantly improved by sildenafil in comparison with placebo ( P<0.0001 ) . Treatment-related adverse events occurred in 43.7 % of patients receiving sildenafil and 18.8 % receiving placebo . The most common adverse events with sildenafil were flushing , dizziness and headache ( 25.2 , 6.7 and 5.9 % of patients , respectively ) , and most were mild in nature . The efficacy and safety of sildenafil in the population of Taiwanese men appears similar to that reported in other studies in western population WHAT IS KNOWN AND OBJECTIVE Psoriasis is a chronic skin disease for which there is an increasing range of treatment options . Biological agents ( ustekinumab , adalimumab , infliximab and etanercept ) are indicated for moderate-to-severe plaque-type psoriasis in adults who fail to respond to , have a contraindication to , or are intolerant to other systemic therapies including cyclosporine , methotrexate and PUVA  Unfortunately , with new drugs , the pivotal trials leading to their licensing are often placebo-controlled trials rather than comparative trials vs. established therapies . Therefore , inference on comparative effectiveness of the newer agents must be derived indirectly , through estimation of effects of the new agents vs. a common comparator . The objective of this study is to compare the relative efficacy of the biological agents through a systematic review of the indirect clinical trial evidence . METHODS A systematic literature search was performed for clinical trials of biological agents in psoriasis . Pivotal , r and omized , double-blind , controlled ( placebo )  trials using intention-to-treat analysis were selected for detailed analysis . Trials must include PASI 75 as a primary end point . The indirect comparison was performed using the method of Bucher adjusted with the ITC calculator ( Indirect Treatment Comparisons of the Canadian Agency for Drugs and Technologies in Health ) , etanercept being the reference drug . We defined delta value for therapeutic equivalence as a difference in the efficacy of 25 % among the different treatment options . RESULTS AND DISCUSSION Fourteen studies ( four for ustekinumab , three for adalimumab , three for infliximab and four for etanercept ) were included . The indirect comparison results reveal that ustekinumab , adalimumab and infliximab were statistically superior to etanercept with an absolute risk difference for PASI 75 of 12 % ( 95 % CI = 5·9 - 18 % ) , 11 % ( 95 % CI = 5·3 - 16·7 % ) and 24 % ( 29·7 - 18·3 % ) respectively . However , in all situations , the 95 % confidence interval does not achieve clinical relevance as no delta exceeds the previously set value ( 25 % ) . WHAT IS NEW AND CONCLUSION Ustekinumab , adalimumab , infliximab and etanercept can be regarded as clinical equivalents for the treatment of psoriasis . Choice between these agents therefore depends on their relative safety profiles , individual contra-indications and cost effectiveness Depression is the most common psychiatric disorder among the elderly and in old age may interact with emotional and cognitive functioning . Depression in old age has been shown to be associated with degenerative changes in the brain . It is , therefore , important that in this patient population antidepressants with a favourable tolerability profile , such as the selective serotonin reuptake inhibitors ( SSRIs ) , are examined for both antidepressant efficacy and effect on cognitive function and emotional impairment . This r and omised , double-blind study compared the efficacy and tolerability of citalopram and mianserin in 336 elderly , depressed patients with or without dementia . Patients received either citalopram 20 - 40 mg/day or mianserin 30 - 60 mg/day for 12 weeks . The treatments were equivalent with respect to change in Montgomery-Asberg Depression Rating Scale ( MADRS ) total score ; patients in both treatment groups responded well . Patients with dementia showed a smaller decrease in total MADRS score than patients without dementia . Both treatments were well tolerated with a relatively low incidence of adverse events . Fatigue and somnolence were more frequent with mianserin , while insomnia was more frequent with citalopram . Overall , this study showed that the two treatments were equivalent in efficacy , and that citalopram is an effective , well-tolerated and non-sedative treatment for elderly depressed patients with or without dementia The terms applicability , generalizability , external validity and transferability are related , sometimes used interchangeably and have in common that they lack a clear and consistent definition in the classic epidemiological literature . However , all of these terms generally describe one overarching theme : whether or not available research evidence can be directly utilized to answer the healthcare questions at h and , ideally supported by a judgment about the degree of confidence for this utilization . This concept has been called directness . The objectives of this paper were to delineate how non-r and omized studies ( NRS ) inform judgments in relation to directness and the concepts that it encompasses in the context of systematic review s. We will briefly review what is known and describe the theoretical and practical issues as well as offer guidance to those tackling the challenges of judging directness and using research evidence to answer healthcare questions with evidence from NRS . In particular , we suggest a framework in which authors can use NRS as a complement , sequence or replacement for r and omized controlled trials ( RCTs ) by focusing on judgments about the population , intervention , comparison and outcomes . Authors of systematic review s will use NRS to complement judgments about the inconsistencies , the rationale and credibility of subgroup analysis , the baseline risk estimates for the determination of absolute benefits and downsides , and the directness of surrogate outcomes . This evidence includes context ual or supplementary evidence . Authors of systematic review and other summaries of the evidence use NRS as sequential evidence to provide evidence when insufficient evidence is available for an outcome from RCTs , but NRS evidence is available ( e.g. , long-term harms ) . Use of evidence from NRS may also serve to replace RCT evidence when NRS provide equivalent ( or potentially higher ) confidence in the evidence ( i.e. quality ) compared to indirect evidence from RCTs . These judgments will be made in the context of other domains that influence the overall quality of the body of evidence , including the risk of bias , publication bias ( i.e. limitations in the detailed study design and execution ) , inconsistency , imprecision and factors that increase our confidence in effects . This article will support systematic review ers in their interaction with decision makers , that is , those who use the systematic review to develop guidelines , address health policy makers , and make clinical decisions , by making these judgments transparent . Copyright © 2013 John Wiley & Sons , INTRODUCTION Phosphodiesterase type-5 ( PDE-5 ) inhibitors have previously been evaluated for their efficacy and safety in various clinical trials in men with erectile dysfunction ( ED ) with or without associated comorbidities . AIM This is the first prospect i ve , r and omized , double-blind , placebo-controlled study to evaluate the efficacy and safety of a PDE-5 inhibitor ( i.e. , vardenafil ) in an exclusive population of men with ED and dyslipidemia . MAIN OUTCOME MEASURES Three co primary efficacy measurements ( Sexual Encounter Performance [SEP]2 , SEP3 , International Index of Erectile Function-Erectile Function [ IIEF-EF ] domain scores ) were used to assess the differential effect of vardenafil vs. placebo in this patient population . Adverse events ( AEs ) safety data were obtained to compare safety outcomes . METHODS This 12-week of r and omized , double-blind , placebo-controlled study was conducted in 59 U.S. centers . Patients received either on-dem and , flexible-dose vardenafil 10 mg ( titrated to 5 mg or 20 mg based upon efficacy and safety ) or placebo . RESULTS Of the 712 patients screened and entered into the study , 395 were r and omized . Baseline demographics for the intent-to-treat population included : mean age , 54.4 years ( + /-7.5 st and ard deviation [ SD ] ) ; 76 % Caucasian ; mean body mass index ( BMI ) , 31.7 kg/m(2 ) ( + /-12.7 SD ) ; 47 % past/present smoker ; and 42 % severe ED . Aside from dyslipidemia , other comorbidities included hypertension , 61 % ; obesity ( i.e. , BMI > /= 30 ) , 51 % ; and type 1 or 2 diabetes , 40 % . During the 12-week treatment period , the least squares ( LS ) adjusted mean success rates in patients on vardenafil vs. placebo were : SEP2 , 79.09 % vs. 51.92 % ; and SEP3 , 66.69 % vs. 33.83 % ( P < 0.001 ) . The LS adjusted mean IIEF-EF domain score for week 12 using LOCF was 21.99 in patients on vardenafil therapy vs. 14.83 in those on placebo ( P < 0.001 ) . The most commonly encountered AEs were headache and nasal congestion . CONCLUSIONS Vardenafil was demonstrated to be safe and effective for managing ED in men with ED and associated dyslipidemia . The results of this study support the role of exp and ed research on outcomes related to effective ED treatment and aggressive lipid control
For common outcomes there was similar efficacy between PDE-5 inhibitors
Background There are no r and omised and properly blinded trials directly comparing one PDE-5 inhibitor with another in a normal home setting .
Valid indirect comparisons with a common comparator must examine equivalent doses , similar duration , similar population s , with the same outcomes reported in the same way .