PLoS clinical trials最新文献

{"title":"Factors that can affect the external validity of randomised controlled trials.","authors":"Peter M Rothwell","doi":"10.1371/journal.pctr.0010009","DOIUrl":"https://doi.org/10.1371/journal.pctr.0010009","url":null,"abstract":"Randomised controlled trials (RCTs) must be internally valid (i.e., design and conduct must eliminate the possibility of bias), but to be clinically useful, the result must also be relevant to a definable group of patients in a particular clinical setting (i.e., they must be externally valid). Lack of external validity is the most frequent criticism by clinicians of RCTs, systematic reviews, and guidelines, and is one explanation for the widespread underuse in routine practice of many treatments that have been shown to be beneficial in trials and are recommended in guidelines [1]. Yet medical journals, funding agencies, ethics committees, the pharmaceutical industry, and governmental regulators seem to give external validity a low priority. Admittedly, whereas the determinants of internal validity are intuitive and can generally be worked out from first principles, understanding of the determinants of the external validity of an RCT requires clinical rather than statistical expertise, and often depends on a detailed understanding of the particular clinical condition under study and its management in routine clinical practice. However, reliable judgments about the external validity of RCTs are essential if treatments are to be used correctly in as many patients as possible in routine clinical practice. \u0000 \u0000The results of RCTs or systematic reviews will never be relevant to all patients and all settings, but they should be designed and reported in a way that allows clinicians to judge to whom the results can reasonably be applied. Table 1 lists some of the important potential determinants of external validity, each of which is reviewed briefly below. Many of the considerations will only be relevant in certain types of trials, for certain interventions, or in certain clinical settings, but they can each sometimes undermine external validity. Moreover, the list is not exhaustive and requires more detailed annotation and explanation than is possible in this short review. \u0000 \u0000 \u0000 \u0000Table 1 \u0000 \u0000Main Issues That Can Affect External Validity and Should Be Addressed in Reports of the Results of Randomised Controlled Trials or Systematic Reviews and Considered by Clinicians \u0000 \u0000 \u0000 \u0000Some of the issues that determine external validity are relevant to the distinction between pragmatic trials and explanatory trials [2], but it would be wrong to assume that pragmatic trials necessarily have greater external validity than explanatory trials. For example, broad eligibility criteria, limited collection of baseline data, and inclusion of centres with a range of expertise and differing patient populations have many advantages, but they can also make it very difficult to generalise the overall average effect of treatment to a particular clinical setting.","PeriodicalId":87416,"journal":{"name":"PLoS clinical trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2006-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1371/journal.pctr.0010009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26168945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RTS,S/AS02A malaria vaccine does not induce parasite CSP T cell epitope selection and reduces multiplicity of infection.","authors":"Sonia Enosse,&nbsp;Carlota Dobaño,&nbsp;Diana Quelhas,&nbsp;John J Aponte,&nbsp;Marc Lievens,&nbsp;Amanda Leach,&nbsp;Jahit Sacarlal,&nbsp;Brian Greenwood,&nbsp;Jessica Milman,&nbsp;Filip Dubovsky,&nbsp;Joe Cohen,&nbsp;Ricardo Thompson,&nbsp;W Ripley Ballou,&nbsp;Pedro L Alonso,&nbsp;David J Conway,&nbsp;Colin J Sutherland","doi":"10.1371/journal.pctr.0010005","DOIUrl":"https://doi.org/10.1371/journal.pctr.0010005","url":null,"abstract":"<p><strong>Objective: </strong>The candidate malaria vaccine RTS,S/AS02A is a recombinant protein containing part of the circumsporozoite protein (CSP) sequence of Plasmodium falciparum, linked to the hepatitis B surface antigen and formulated in the proprietary adjuvant system AS02A. In a recent trial conducted in children younger than age five in southern Mozambique, the vaccine demonstrated significant and sustained efficacy against both infection and clinical disease. In a follow-up study to the main trial, breakthrough infections identified in the trial were examined to determine whether the distribution of csp sequences was affected by the vaccine and to measure the multiplicity of infecting parasite genotypes.</p><p><strong>Design: </strong>P. falciparum DNA from isolates collected during the trial was used for genotype studies.</p><p><strong>Setting: </strong>The main trial was carried out in the Manhiça district, Maputo province, Mozambique, between April 2003 and May 2004.</p><p><strong>Participants: </strong>Children from the two cohorts of the main trial provided parasite isolates as follows: children from Cohort 1 who were admitted to hospital with clinical malaria; children from Cohort 1 who were parasite-positive in a cross-sectional survey at study month 8.5; children from Cohort 2 identified as parasite-positive during follow-up by active detection of infection.</p><p><strong>Outcome: </strong>Divergence of DNA sequence encoding the CSP T cell-epitope region sequence from that of the vaccine sequence was measured in 521 isolates. The number of distinct P. falciparum genotypes was also determined.</p><p><strong>Results: </strong>We found no evidence that parasite genotypes from children in the RTS,S/AS02A arm were more divergent than those receiving control vaccines. For Cohort 1 (survey at study month 8.5) and Cohort 2, infections in the vaccine group contained significantly fewer genotypes than those in the control group, (p = 0.035, p = 0.006), respectively, for the two cohorts. This was not the case for children in Cohort 1 who were admitted to hospital (p = 0.478).</p><p><strong>Conclusions: </strong>RTS,S/AS02A did not select for genotypes encoding divergent T cell epitopes in the C-terminal region of CSP in this trial. In both cohorts, there was a modest reduction in the mean number of parasite genotypes harboured by vaccinated children compared with controls, but only among those with asymptomatic infections.</p>","PeriodicalId":87416,"journal":{"name":"PLoS clinical trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2006-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1371/journal.pctr.0010005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26167373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Introducing PLoS clinical trials: a different approach to publishing trial results.","authors":"Emma Veitch","doi":"10.1371/journal.pctr.0010008","DOIUrl":"https://doi.org/10.1371/journal.pctr.0010008","url":null,"abstract":"","PeriodicalId":87416,"journal":{"name":"PLoS clinical trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2006-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1371/journal.pctr.0010008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26168944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artemisinin combination therapies for treatment of uncomplicated malaria in Uganda.","authors":"Hasifa Bukirwa, Adoke Yeka, Moses R Kamya, Ambrose Talisuna, Kristin Banek, Nathan Bakyaita, John Bosco Rwakimari, Philip J Rosenthal, Fred Wabwire-Mangen, Grant Dorsey, Sarah G Staedke","doi":"10.1371/journal.pctr.0010007","DOIUrl":"10.1371/journal.pctr.0010007","url":null,"abstract":"<p><strong>Objectives: </strong>To compare the efficacy and safety of artemisinin combination therapies for the treatment of uncomplicated falciparum malaria in Uganda.</p><p><strong>Design: </strong>Randomized single-blind controlled trial.</p><p><strong>Setting: </strong>Tororo, Uganda, an area of high-level malaria transmission.</p><p><strong>Participants: </strong>Children aged one to ten years with confirmed uncomplicated P. falciparum malaria.</p><p><strong>Interventions: </strong>Amodiaquine + artesunate or artemether-lumefantrine.</p><p><strong>Outcome measures: </strong>Risks of recurrent symptomatic malaria and recurrent parasitemia at 28 days, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections.</p><p><strong>Results: </strong>Of 408 participants enrolled, 403 with unadjusted efficacy outcomes were included in the per-protocol analysis. Both treatment regimens were highly efficacious; no recrudescences occurred in patients treated with amodiaquine + artesunate, and only two occurred in those treated with artemether-lumefantrine. However, recurrent malaria due to new infections was common. The unadjusted risk of recurrent symptomatic malaria was significantly lower for participants treated with artemether-lumefantrine than for those treated with amodiaquine + artesunate (27% versus 42%, risk difference 15%, 95% CI 5.9%-24.2%). Similar results were seen for the risk of recurrent parasitemia (51% artemether-lumefantrine versus 66% amodiaquine + artesunate, risk difference 16%, 95% CI 6.2%-25.2%). Amodiaquine + artesunate and artemether-lumefantrine were both well-tolerated. Serious adverse events were uncommon with both regimens.</p><p><strong>Conclusions: </strong>Amodiaquine + artesunate and artemether-lumefantrine were both highly efficacious for treatment of uncomplicated malaria. However, in this holoendemic area, despite the excellent performance of both regimens in terms of efficacy, many patients experienced recurrent parasitemia due to new infections. Artemether-lumefantrine was superior to amodiaquine + artesunate for prevention of new infections. To maximize the benefit of artemisinin combination therapy in Africa, treatment should be integrated with strategies to prevent malaria transmission. The impact of frequent repeated therapy on the efficacy, safety, and cost-effectiveness of new artemisinin regimens should be further investigated.</p>","PeriodicalId":87416,"journal":{"name":"PLoS clinical trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2006-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1488893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26168943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Principles for strengthening the integrity of clinical research.","authors":"David Korn,&nbsp;Susan Ehringhaus","doi":"10.1371/journal.pctr.0010001","DOIUrl":"https://doi.org/10.1371/journal.pctr.0010001","url":null,"abstract":"‘‘All true universities, whether public or private, are public trusts designed to advance knowledge by safeguarding the free inquiry of impartial teachers and scholars. Their independence is essential because the university provides knowledge not only to its students, but also to the public agency in need of expert guidance and the general society in need of greater knowledge;... these latter clients have a stake in disinterested professional opinion, stated without fear or favor, which the institution is morally required to respect.’’ — American Association of University Professors [1]","PeriodicalId":87416,"journal":{"name":"PLoS clinical trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2006-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1371/journal.pctr.0010001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26167369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Randomised controlled trial of unsolicited occupational therapy in community-dwelling elderly people: the LOTIS trial.","authors":"Anton J M de Craen,&nbsp;Jacobijn Gussekloo,&nbsp;Gerard J Blauw,&nbsp;Charles G Willems,&nbsp;Rudi G J Westendorp","doi":"10.1371/journal.pctr.0010002","DOIUrl":"https://doi.org/10.1371/journal.pctr.0010002","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this trial, the Leiden 85-Plus Occupational Therapy Intervention Study (LOTIS), was to assess whether unsolicited occupational therapy, as compared to no therapy, can decelerate the increase in disability in high-risk elderly people.</p><p><strong>Design: </strong>This was a randomised controlled trial with 2-y follow-up.</p><p><strong>Setting: </strong>The study took place in the municipality of Leiden in the Netherlands.</p><p><strong>Participants: </strong>The participants were 402 community-dwelling 85-y-old people, with a Mini-Mental State Examination score of >18 points at baseline.</p><p><strong>Interventions: </strong>Participants in the intervention group were visited by an occupational therapist who provided training and education about assistive devices that were already present and who gave recommendations and information about procedures, possibilities, and costs of assistive devices and community-based services. Control participants were not visited by an occupational therapist.</p><p><strong>Outcome measures: </strong>The primary outcome measure was the score achieved on the Groningen Activity Restriction Scale. Secondary outcome measures included self-evaluations of well-being and feelings of loneliness.</p><p><strong>Results: </strong>THE PARTICIPANTS WERE EVENLY DIVIDED BETWEEN THE TWO GROUPS: 202 participants were allocated to the intervention group and 200 participants to the control group. Of the 202 participants randomised to occupational therapy, 55 participants declined the proposed intervention. An occupational therapist indicated that of the remaining 147 participants, 66 (45%) needed an occupational therapy intervention. A total of 44 new assistive devices and five community-based services were implemented. During follow-up there was a progressive increase in disability in the intervention group (mean annual increase, 2.0 points; SE 0.2; p < 0.001) and control group (mean annual increase, 2.1 points; SE 0.2; p < 0.001). The increase in disability was not significantly different between study groups (0.08 points; 95% CI, -1.1-1.2; p = 0.75). There was also no difference between study groups for any of the secondary outcome measures.</p><p><strong>Conclusion: </strong>Unsolicited occupational therapy in high-risk elderly participants does not decelerate the increase in disability over time.</p>","PeriodicalId":87416,"journal":{"name":"PLoS clinical trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2006-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1371/journal.pctr.0010002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26167370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute effect of folic acid, betaine, and serine supplements on flow-mediated dilation after methionine loading: a randomized trial.","authors":"Margreet R Olthof,&nbsp;Michiel L Bots,&nbsp;Martijn B Katan,&nbsp;Petra Verhoef","doi":"10.1371/journal.pctr.0010004","DOIUrl":"https://doi.org/10.1371/journal.pctr.0010004","url":null,"abstract":"<p><strong>Objectives: </strong>We investigated whether reducing post-methionine homocysteine concentrations via various treatments other than folic acid affects vascular function, as measured through flow-mediated dilation (FMD) of the brachial artery. High fasting and post-methionine homocysteine concentrations are associated with cardiovascular disease risk, but homocysteine might be a surrogate marker for low folate status.</p><p><strong>Design: </strong>This was a randomized, placebo-controlled, double-blind, crossover study.</p><p><strong>Setting: </strong>The study took place at Wageningen University in Wageningen in the Netherlands.</p><p><strong>Participants: </strong>Participants were 39 apparently healthy men and women, aged 50-70 y.</p><p><strong>Interventions: </strong>Participants ingested 10 mg of folic acid, 3 g of betaine, 5 g of serine, and placebo together with an oral methionine load. Each supplement was tested on two different days.</p><p><strong>Outcome measures: </strong>On each of the eight treatment days, plasma homocysteine concentrations and FMD were measured before (t = 0 h, fasting) and 6 h (t = 6 h) after methionine loading.</p><p><strong>Results: </strong>The mean (+/- SD) fasting homocysteine concentrations averaged over the eight test days were 9.6 +/- 2.1 micromol/l. Mean fasting FMD was 3.1 +/- 2.4 FMD%. A methionine load with placebo increased homocysteine concentrations by 17.2 +/- 9.3 micromol/l at 6 h after loading, similar to the increase following methionine loading with folic acid. A methionine load together with betaine and with serine increased homocysteine by 10.4 +/- 2.8 micromol/l (p < 0.001 relative to placebo) and by 12.1 +/- 8.2 micromol/l (p < 0.001 relative to placebo), respectively. Methionine loading with placebo did not affect FMD, and neither did methionine loading with folic acid, betaine, or serine; differences relative to placebo were +0.7 FMD% (95%CI, -0.6; 1.9), +0.2 FMD% (-1.0; 1.3), and +0.3 FMD% (-0.8; 1.4), respectively.</p><p><strong>Conclusions: </strong>Experimentally induced acute changes in homocysteine concentrations did not affect FMD in healthy volunteers. This implies that potential adverse effects of high homocysteine concentrations on the cardiovascular system are not mediated through vascular function. However, homocysteine or folate may affect cardiovascular disease risk through other mechanisms.</p>","PeriodicalId":87416,"journal":{"name":"PLoS clinical trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2006-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1371/journal.pctr.0010004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26167372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient safety requires a new way to publish clinical trials.","authors":"Richard Smith,&nbsp;Ian Roberts","doi":"10.1371/journal.pctr.0010006","DOIUrl":"https://doi.org/10.1371/journal.pctr.0010006","url":null,"abstract":"The way medical journals publish the results of clinical trials has become a serious threat to public health. You may find this assertion shocking and counterintuitive, but we hope that by the end of this short article you will agree and will join us in arguing for the better way of making medical information publicly available that we outline.","PeriodicalId":87416,"journal":{"name":"PLoS clinical trials","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2006-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1371/journal.pctr.0010006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26168942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}