***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Correctable weaknesses in the design , conduct , and analysis of biomedical and public health research studies can produce misleading results and waste valuable re sources . Small effects can be difficult to distinguish from bias introduced by study design and analyses . An absence of detailed written protocol s and poor documentation of research is common . Information obtained might not be useful or important , and statistical precision or power is often too low or used in a misleading way . Insufficient consideration might be given to both previous and continuing studies . Arbitrary choice of analyses and an overemphasis on r and om extremes might affect the reported findings . Several problems relate to the research workforce , including failure to involve experienced statisticians and method ologists , failure to train clinical research ers and laboratory scientists in research methods and design , and the involvement of stakeholders with conflicts of interest . Inadequate emphasis is placed on recording of research decisions and on reproducibility of research . Finally , reward systems incentivise quantity more than quality , and novelty more than reliability . We propose potential solutions for these problems , including improvements in protocol s and documentation , consideration of evidence from studies in progress , st and ardisation of research efforts , optimisation and training of an experienced and non-conflicted scientific workforce , and reconsideration of scientific reward systems BACKGROUND AND OBJECTIVE Enrichment strategies which select subjects who appear to respond to the drug have been used in drug studies to demonstrate clinical efficacy . We have used clinical trial simulation techniques to examine factors that are relevant in clinical trial design based on enrichment where poor responders are excluded from the double-blind phase of the study . METHODS Simulations were performed for an analgesic trial design involving an open-dose titration phase ( enrichment phase ) followed by a double-blind , r and omized , placebo-controlled maintenance phase . Enrichment was examined by excluding subjects above a predefined pain score ( cutoff ) from analysis of efficacy for the maintenance phase . Cutoff pain scores ranging from 4 to 7 on a 0 to 10 categorical scale were examined . A data base consisting of chronic pain patients who participated in studies with a new formulation of buprenorphine  was used to build the simulation model . Since no data were available for the key model variable " correlation between treatment and placebo response " , values of 0.25 , 0.5 , and 0.75 were used for the simulations . RESULTS A correlation between treatment and placebo effect ranging from 0.75 to 0.25 will cause the likelihood of trial success to vary from 50 % to 95 % . This model also shows that recruitment efficiency will decrease with the use of lower cutoff pain scores . CONCLUSION Prior to using enrichment techniques , investigators must consider the correlation between treatment effect and placebo response to optimize clinical trial design Background Knee osteoarthritis ( OA ) is a major cause of pain and functional limitation in older adults , yet longer-term studies of medical treatment of OA are limited . Objective To evaluate the efficacy and safety of glucosamine and chondroitin sulphate ( CS ) , alone or in combination , as well as celecoxib and placebo on painful knee OA over 2 years . Methods A 24-month , double-blind , placebo-controlled study , conducted at nine sites in the US ancillary to the Glucosamine/chondroitin Arthritis Intervention Trial , enrolled 662 patients with knee OA who satisfied radiographic criteria ( Kellgren/Lawrence grade 2 or 3 changes and baseline joint space width of at least 2 mm ) . This subset continued to receive their r and omised treatment : glucosamine 500 mg three times daily , CS 400 mg three times daily , the combination of glucosamine and CS , celecoxib 200 mg daily , or placebo over 24 months . The primary outcome was a 20 % reduction in Western Ontario and McMaster University Osteoarthritis Index ( WOMAC ) pain over 24 months . Secondary outcomes included an Outcome Measures in Rheumatology/Osteoarthritis Research Society International response and change from baseline in WOMAC pain and function . Results Compared with placebo , the odds of achieving a 20 % reduction in WOMAC pain were celecoxib : 1.21 , glucosamine : 1.16 , combination glucosamine/CS : 0.83 and CS alone : 0.69 , and were not statistically significant . Conclusions Over 2 years , no treatment achieved a clinical ly important difference in WOMAC pain or function as compared with placebo . However , glucosamine and celecoxib showed beneficial but not significant trends . Adverse reactions were similar among treatment groups and serious adverse events were rare for all treatments OBJECTIVES Patients with chronic noncancer pain frequently report symptoms of depression and anxiety ( negative affect ) , which are associated with higher ratings of pain intensity and a greater likelihood of being prescribed chronic opioid therapy . The purpose of this secondary analysis was to test the hypothesis that initial levels of negative affect can predict treatment-related outcomes in a double-blind , placebo-controlled study of extended-release ( ER ) hydromorphone among opioid-tolerant patients with chronic low back pain . METHODS Four hundred fifty-nine ( N = 459 ) patients participated in the titration/conversion phase of a multicenter study , of which 268 were r and omized to receive once-daily hydromorphone or placebo . All patients completed the Hospital Anxiety and Depression Scale ( HADS ) at baseline and were divided evenly into Low ( N = 157 ) , Moderate ( N = 155 ) , and High ( N = 147 ) negative affect groups based on their scores . Group differences in numerical pain intensity measures at home and in the clinic , Rol and -Morris Disability ratings , and measures of symptoms from the Subjective Opiate Withdrawal Scale ( SOWS ) throughout the trial were analyzed . RESULTS Two hundred sixty-eight of the initial 459 subjects who entered the 2 to 4-week titration/conversion phase ( pretreatment ) were successfully r and omized to either placebo or ER hydromorphone ; a total of 110 patients then completed this double-blind phase of the study . Those in the Moderate and High negative affect groups tended to drop out more often during the titration/conversion phase because of the adverse effects or lack of efficacy of their prescribed opioid than those in the Low negative mood group ( P < 0.05 ) . Overall , those patients in the Moderate and High groups reported significantly higher pain intensity scores in at-home and in-clinic pain intensity ratings ( P < 0.05 ) , greater disability on the Rol and -Morris Scale ( P < 0.01 ) , and more withdrawal symptoms on the SOWS ( P < 0.05 ) than those in the Low group . Higher negative affect scores also predicted less favorable ratings of the study drug during the titration phase ( P < 0.05 ) . Interestingly , the High negative affect group showed the most improvement in pain in the placebo condition ( P < 0.05 ) . CONCLUSIONS Negative affect is associated with diminished benefit during a trial of opioid therapy and is predictive of dropout in a controlled clinical trial OBJECTIVE To compare the analgesic efficacy and safety of nonprescription doses of naproxen sodium , ibuprofen , and placebo in patients with osteoarthritis ( OA ) of the knee . METHODS In 2 identical multicenter , r and omized , double-blind , placebo-controlled , multidose , parallel- design studies , patients aged > or = 25 years with OA were r and omized to daily doses of naproxen sodium 660 mg , naproxen sodium 440 mg ( patients > or = 65 years ) , ibuprofen 1200 mg , or placebo , for 7 days . RESULTS For investigator and patient assessment of knee joint pain , naproxen sodium ( 440/660 mg ) and ibuprofen were clinical ly effective at relieving pain compared with placebo ( n = 444 ) ; both treatments reduced the mean symptom score by 30 - 45 % , compared with a 20 - 25 % reduction with placebo . Naproxen sodium ( 440/660 mg ) significantly improved all 7 symptoms from baseline compared with placebo , while ibuprofen significantly improved 5 of the symptoms . For the subgroup of patients aged > or = 65 years ( n = 183 ) , naproxen sodium 440 mg was significantly superior to placebo in all symptoms except pain on weight-bearing ;  ibuprofen only significantly reduced day pain . For daily diary evaluations , naproxen sodium and ibuprofen were effective in reducing all 6 symptoms ; there was a trend toward higher efficacy for night-time pain with naproxen sodium 440/660 mg compared with ibuprofen . There were no significant differences in adverse event reporting between groups . CONCLUSION Over-the-counter doses of naproxen sodium ( 440/660 mg ) and ibuprofen ( 1200 mg ) effectively relieve pain in patients with mild to moderate OA of the knee .  Naproxen sodium provided more effective pain relief for most variables compared with placebo , and for night pain compared with ibuprofen . Efficacy was combined with good safety and tolerability Background : The ancient Indian ( Asian ) Ayurvedic medicinal system uses herbomineral drugs to treat arthritis . Despite centuries of use , very few have been tested by drug trials . RA-11 ( ARTREX , MENDAR ) , a st and ardized multiplant Ayurvedic drug ( Withania somnifera , Boswellia serrata , Zingiber officinale , and Curcuma longa ) is currently used to treat arthritis . Objective : The objective of this study was to evaluate the efficacy and safety of RA-11 in patients with symptomatic osteoarthritis ( OA ) of the knees . Methods : A total of 358 patients with chronic knee pain were screened free-of-cost in “ arthritis camps ” in an Indian metropolis . Ninety patients with primary OA of the knees ( ACR classification ; Arthritis Rheum 1986;29:1039–1049 ) were found eligible ( postanalgesic washout pain visual analog score [ VAS ] ≥40 mm in either or both knees on body weight-bearing activities ) to enroll into a r and omized , double-blind , placebo-controlled , parallel efficacy , single-center , 32-week drug trial ( 80 % power to detect 25 % difference , P = 0.05 , 2-sided ) . Concurrent analgesics/nonsteroidal antiinflammatory drugs and steroids in any form were not allowed . Lifestyle and /or dietary restrictions , as per routine Ayurveda practice s , were not imposed . Pain VAS ( maximum pain in each knee recorded by the patient during the preceding 48 hours ) and modified WOMAC ( Western Ontario McMaster University OA Index , Likert scale , version 3.0 ) were the primary efficacy variables . The WOMAC section on “ physical function difficulty ” was modified for Indian use and vali date d before the trial . Routine laboratory testing was primarily done to monitor drug safety . At baseline , the groups ( active = 45 , placebo = 45 ) were well matched for several measures ( mean pain VAS : active = 6.17 ; placebo = 6.5 ) . Results :1 ) Efficacy : Compared with placebo , the mean reduction in pain VAS at week 16 ( active = 2.7 , placebo = 1.3 ) and week 32 ( active = 2.8 , placebo = 1.8 ) in the active group was significantly ( P < 0.05 , analysis of variance [ ANOVA ] ) better . Similarly , the improvement in the WOMAC scores at week 16 and week 32 were also significantly superior ( P < 0.01 , ANOVA ) in the active group . 2 ) Safety : Both the groups reported mild adverse events ( AE ) without any significant difference . 3 ) Withdrawals : Twenty-eight patients were discontinued . None reported drug-related toxicity . The majority failed follow up/compliance . No differences were observed between the groups . Conclusion : This controlled drug trial demonstrates the potential efficacy and safety of RA- 11 in the symptomatic treatment of OA knees over 32 weeks of therapy Properly conducted r and omised trials can aid clinical decision-making by providing unbiased estimates of the average size of treatment effects . This paper , the first of two , discusses how readers of clinical trials can extract simple estimates of treatment effect size from trial reports when trial outcomes are measured on a continuous scale . When making decisions about therapy for individual patients , these estimates can be modified on the basis of patient characteristics . Modified estimates of treatment effect size can be used to determine if the effect of treatment is likely to be large enough to be " clinical ly worthwhile " . This approach optimises clinical decision-making by combining unbiased estimates of the size of treatment effect from clinical trials with clinical intuition and patient preferences OBJECTIVE To compare the efficacy of etoricoxib 30 mg with the generally maximum recommended dose of celecoxib , 200 mg , in the treatment of osteoarthritis ( OA ) in two identically design ed studies . METHODS Two multi-centre , 26-week , double-blind , placebo-controlled , non-inferiority studies were conducted , enrolling patients who were prior non-steroidal anti-inflammatory drug ( NSAID ) or acetaminophen users . There were 599 patients in study 1 and 608 patients in study 2 r and omized 4:4:1:1 to etoricoxib 30 mg qd , celecoxib 200 mg qd or one of two placebo groups for 12 weeks . After 12 weeks , placebo patients were evenly distributed to et 
    Output:
    
There were no overall differences in effect sizes between enriched and nonenriched design s for pain intensity .
There was a significant difference for a reduction in any adverse events favouring enriched design s for opioids , but not for other analgesics or the outcome serious adverse events .
There was an association between effect size and method ological quality , with failure to blind the outcome assessor and failure to use intention-to-treat analysis being associated with larger effect sizes .
There is no evidence that the use of an enriched study design changes the treatment effect size estimate for pain .
There is some evidence that clinical trials that employ enriched design s report a reduced risk of adverse events in trials for chronic musculoskeletal pain , but it is unclear whether enriched design s influence estimates of serious adverse events .
Features of trial design and study quality were associated with treatment effect estimates