PLoS Clinical Trials

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EISSN : 1555-5887
Current Publisher: Public Library of Science (PLoS) (10.1371)
Total articles ≅ 64
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Charles Kooperberg, Mary Cushman, Judith Hsia, Jennifer G Robinson, Aaron K Aragaki, John K Lynch, Alison E Baird, Karen C Johnson, Lewis H Kuller, Shirley A. A Beresford, et al.
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020028

The Women's Health Initiative hormone trials identified a 44% increase in ischemic stroke risk with combination estrogen plus progestin and a 39% increase with estrogen alone. We undertook a case-control biomarker study to elucidate underlying mechanisms, and to potentially identify women who would be at lower or higher risk for stroke with postmenopausal hormone therapy (HT). The hormone trials were randomized, double-blind, and placebo controlled. The Women's Health Initiative trials were conducted at 40 clinical centers in the United States. The trials enrolled 27,347 postmenopausal women, aged 50–79 y. We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo. Stroke was ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial. No baseline clinical characteristics, including gene polymorphisms, identified women for whom the stroke risk from HT was higher. Paradoxically, women with higher baseline levels of some stroke-associated biomarkers had a lower risk of stroke when assigned to estrogen plus progestin compared to placebo. For example, those with higher IL-6 were not at increased stroke risk when assigned to estrogen plus progestin (odds ratio 1.28) but were when assigned to placebo (odds ratio 3.47; p for difference = 0.02). Similar findings occurred for high baseline PAP, leukocyte count, and D-dimer. However, only an interaction of D-dimer during follow-up interaction with HT and stroke was marginally significant (p = 0.03). Biomarkers did not identify women at higher stroke risk with postmenopausal HT. Some biomarkers appeared to identify women at lower stroke risk with estrogen plus progestin, but these findings may be due to chance. NCT00000611
, Berend Terluin, , Daniëlle A. W. M Van Der Windt, Frank Rijmen, Willem Van Mechelen, Wim A. B Stalman
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020026

Mental health problems often affect functioning to such an extent that they result in sick leave. The worldwide reported prevalence of mental health problems in the working population is 10%–18%. In developed countries, mental health problems are one of the main grounds for receiving disability benefits. In up to 90% of cases the cause is stress-related, and health-care utilisation is mainly restricted to primary care. The aim of this study was to assess the effectiveness of our Minimal Intervention for Stress-related mental disorders with Sick leave (MISS) in primary care, which is intended to reduce sick leave and prevent chronicity of symptoms. Cluster-randomised controlled educational trial. Primary health-care practices in the Amsterdam area, The Netherlands. A total of 433 patients (MISS n = 227, usual care [UC] n = 206) with sick leave and self-reported elevated level of distress. Forty-six primary care physicians were randomised to either receive training in the MISS or to provide UC. Eligible patients were screened by mail. The primary outcome measure was duration of sick leave until lasting full return to work. The secondary outcomes were levels of self-reported distress, depression, anxiety, and somatisation. No superior effect of the MISS was found on duration of sick leave (hazard ratio 1.06, 95% confidence interval 0.87–1.29) nor on severity of self-reported symptoms. We found no evidence that the MISS is more effective than UC in our study sample of distressed patients. Continuing research should focus on the potential beneficial effects of the MISS; we need to investigate which elements of the intervention might be useful and which elements should be adjusted to make the MISS effective. ISRCTN43779641
, Ug Taylor, Ronald Roddy, Ghiorghis Belai, Pamela Phillips, , , Edith Essie Kekawo Clarke, Anderson Sama Doh, Renee Ridzon, et al.
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020027

The objective of this trial was to investigate the safety and preliminary effectiveness of a daily dose of 300 mg of tenofovir disoproxil fumarate (TDF) versus placebo in preventing HIV infection in women. This was a phase 2, randomized, double-blind, placebo-controlled trial. The study was conducted between June 2004 and March 2006 in Tema, Ghana; Douala, Cameroon; and Ibadan, Nigeria. We enrolled 936 HIV-negative women at high risk of HIV infection into this study. Participants were randomized 1:1 to once daily use of 300 mg of TDF or placebo. The primary safety endpoints were grade 2 or higher serum creatinine elevations (>2.0 mg/dl) for renal function, grade 3 or 4 aspartate aminotransferase or alanine aminotransferase elevations (>170 U/l) for hepatic function, and grade 3 or 4 phosphorus abnormalities (<1.5 mg/dl). The effectiveness endpoint was infection with HIV-1 or HIV-2. Study participants contributed 428 person-years of laboratory testing to the primary safety analysis. No significant differences emerged between treatment groups in clinical or laboratory safety outcomes. Study participants contributed 476 person-years of HIV testing to the primary effectiveness analysis, during which time eight seroconversions occurred. Two were diagnosed in participants randomized to TDF (0.86 per 100 person-years) and six in participants receiving placebo (2.48 per 100 person-years), yielding a rate ratio of 0.35 (95% confidence interval = 0.03–1.93), which did not achieve statistical significance. Owing to premature closures of the Cameroon and Nigeria study sites, the planned person-years of follow-up and study power could not be achieved. Daily oral use of TDF in HIV-uninfected women was not associated with increased clinical or laboratory adverse events. Effectiveness could not be conclusively evaluated because of the small number of HIV infections observed during the study. NCT00122486
, Adoke Yeka, Hasifa Bukirwa, Myers Lugemwa, John B Rwakimari, Sarah G Staedke, Ambrose O Talisuna, , , Philip J Rosenthal, et al.
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020020

To compare the efficacy and safety of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) for treating uncomplicated falciparum malaria in Uganda. Randomized single-blinded clinical trial. Apac, Uganda, an area of very high malaria transmission intensity. Children aged 6 mo to 10 y with uncomplicated falciparum malaria. Treatment of malaria with AL or DP, each following standard 3-d dosing regimens. Risks of recurrent parasitemia at 28 and 42 d, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections. Of 421 enrolled participants, 417 (99%) completed follow-up. The unadjusted risk of recurrent falciparum parasitemia was significantly lower for participants treated with DP than for those treated with AL after 28 d (11% versus 29%; risk difference [RD] 18%, 95% confidence interval [CI] 11%–26%) and 42 d (43% versus 53%; RD 9.6%, 95% CI 0%–19%) of follow-up. Similarly, the risk of recurrent parasitemia due to possible recrudescence (adjusted by genotyping) was significantly lower for participants treated with DP than for those treated with AL after 28 d (1.9% versus 8.9%; RD 7.0%, 95% CI 2.5%–12%) and 42 d (6.9% versus 16%; RD 9.5%, 95% CI 2.8%–16%). Patients treated with DP had a lower risk of recurrent parasitemia due to non-falciparum species, development of gametocytemia, and higher mean increase in hemoglobin compared to patients treated with AL. Both drugs were well tolerated; serious adverse events were uncommon and unrelated to study drugs. DP was superior to AL for reducing the risk of recurrent parasitemia and gametocytemia, and provided improved hemoglobin recovery. DP thus appears to be a good alternative to AL as first-line treatment of uncomplicated malaria in Uganda. To maximize the benefit of artemisinin-based combination therapy in Africa, treatment should be integrated with aggressive strategies to reduce malaria transmission intensity. ISRCTN75606663
, Jeffrey Wright, Francie Chalmers, Linda Levenson, Julie C Brown, Paula Lozano, Dimitri A Christakis
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020025

Having shown previously that an electronic prescription writer and decision support system improved pediatric prescribing behavior for otitis media in an academic clinic setting, we assessed whether point-of-care delivery of evidence could demonstrate similar effects for a wide range of other common pediatric conditions. Cluster randomized controlled trial. A teaching clinic/clinical practice site and a primary care pediatric clinic serving a rural and semi-urban patient mix. A total of 36 providers at the teaching clinic/practice site and eight providers at the private primary pediatric clinic. An evidence-based message system that presented real-time evidence to providers based on prescribing practices for acute otitis media, allergic rhinitis, sinusitis, constipation, pharyngitis, croup, urticaria, and bronchiolitis. The proportion of prescriptions dispensed in accordance with evidence. The proportion of prescriptions dispensed in accordance with evidence improved four percentage points, from 38% at baseline to 42% following the intervention. The control group improved by one percentage point, from 39% at baseline to 40% at trial's conclusion. The adjusted difference between the intervention and control groups was 8% (95% confidence interval 1%, 15%). Intervention effectiveness did not decrease with time. For common pediatric outpatient conditions, a point-of-care evidence-based prescription writer and decision support system was associated with significant improvements in prescribing practices. NCT00368823
, Gijs Bleijenberg, Jos W. M Van Der Meer
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020019

It is unclear whether insulin-like growth factor (IGF) function is involved in the pathophysiology of chronic fatigue syndrome (CFS). Unpublished data and reports in patient organization newsletters suggest that Acclydine, a food supplement, could be effective in the treatment of CFS by increasing biologically active IGF1 levels. Here we aimed to measure the IGF1 and IGF binding protein (IGFBP) 3 status of CFS patients compared to age- and gender-matched neighborhood controls, and to assess the effect of Acclydine on fatigue severity, functional impairment, and biologically active IGF1 level (IGFBP3/IGF1 ratio). A randomized, placebo-controlled, double-blind clinical trial. Radboud University Nijmegen Medical Centre, The Netherlands. Fifty-seven adult patients who fulfilled the US Centers for Disease Control and Prevention criteria for CFS. IGF status of 22 CFS patients was compared to that of 22 healthy age- and gender-matched neighborhood control individuals. Acclydine or placebo for 14 wk. Outcomes were fatigue severity (Checklist Individual Strength, subscale fatigue severity [CIS-fatigue]), functional impairment (Sickness Impact Profile-8 [SIP-8]), and biologically active IGF1 serum concentrations. Analyses were on an intention-to-treat basis. There was no difference in IGF status in 22 CFS patients compared to healthy age- and gender-matched control individuals. Treatment with Acclydine did not result in significant differences compared with the placebo group on any of the outcome measures: CIS-fatigue +1.1 (95% CI −4.4 to +6.5, p = 0.70), SIP-8 +59.1 (95% CI −201.7 to +319.8, p = 0.65), and IGFBP3/IGF1 ratio −0.5 (95% CI −2.8 to +1.7, p = 0.63). We found no differences in IGF1 status in CFS patients compared to healthy matched neighborhood controls. In addition, the results of this clinical trial do not demonstrate any benefit of Acclydine over placebo in the treatment of CFS. ISRCTN77271661
Lola Fourcade, , , Lucie Ronceray, Gabriel Baron,
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020022

The aim of this study was to develop and evaluate a pedagogical tool to enhance the understanding of a checklist that evaluates reports of nonpharmacological trials (CLEAR NPT). Paired randomised controlled trial. Clinicians and systematic reviewers. We developed an Internet-based computer learning system (ICLS). This pedagogical tool used many examples from published randomised controlled trials to demonstrate the main coding difficulties encountered when using this checklist. Randomised participants received either a specific Web-based training with the ICLS (intervention group) or no specific training. The primary outcome was the rate of correct answers compared to a criterion standard for coding a report of randomised controlled trials with the CLEAR NPT. Between April and June 2006, 78 participants were randomly assigned to receive training with the ICLS (39) or no training (39). Participants trained by the ICLS did not differ from the control group in performance on the CLEAR NPT. The mean paired difference and corresponding 95% confidence interval was 0.5 (−5.1 to 6.1). The rate of correct answers did not differ between the two groups regardless of the CLEAR NPT item. Combining both groups, the rate of correct answers was high or items related to allocation sequence (79.5%), description of the intervention (82.0%), blinding of patients (79.5%), and follow-up schedule (83.3%). The rate of correct answers was low for items related to allocation concealment (46.1%), co-interventions (30.3%), blinding of outcome assessors (53.8%), specific measures to avoid ascertainment bias (28.6%), and intention-to-treat analysis (60.2%). Although we showed no difference in effect between the intervention and control groups, our results highlight the gap in knowledge and urgency for education on important aspects of trial conduct. ISRCTN07698599
Hamdee Attallah, Anne L Friedlander, Matilde Nino-Murcia,
PLoS Clinical Trials, Volume 2; doi:10.1371/journal.pctr.0020021

Recombinant human growth hormone (GH) and pioglitazone (PIO) in abdominally obese adults with impaired glucose tolerance were evaluated under the hypothesis that the combination attenuates GH-induced increases in glucose concentrations, reduces visceral adipose tissue (VAT), and improves insulin sensitivity over time. Randomized, double-blind, placebo-controlled, 2 × 2 factorial design. Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States. 62 abdominally obese adults aged 40–75 with impaired glucose tolerance. GH (8 μg/kg/d, or placebo) and pioglitazone (30 mg/d, or placebo) for 40 wk. Baseline and after 40 wk of treatment, VAT content was quantified by CT scan, glucose tolerance was assessed using a 75-g oral glucose tolerance test, and insulin sensitivity was measured using steady-state plasma glucose levels obtained during insulin suppression test. Baseline: body mass index (BMI), plasma glucose, and visceral fat content were similar. 40 wk: visceral fat area declined 23.9 ± 7.4 cm2 in GH group, mean difference from placebo: −28.1 cm2 (95% CI −49.9 to −6.3 cm2; p = 0.02). Insulin resistance declined 52 ± 11.8 mg/dl with PIO, mean difference from placebo of −58.8 mg/dl (95% CI −99.7 to −18.0 mg/dl; p = 0.01). VAT and SSPG declined with GH and PIO combined, mean differences from placebo of −31.4 cm2 (95% CI −56.5 cm2 to −6.3 cm2; p = 0.02) and −55.3 mg/dl (95% CI −103.9 to −6.7 mg/dl; p = 0.02), respectively. Fasting plasma glucose increased transiently in GH group. No significant changes in BMI were observed. Addition of PIO to GH attenuated the short-term diabetogenic effect of GH; the drug combination reduced VAT and insulin resistance over time. GH plus PIO may have added benefit on body composition and insulin sensitivity in the metabolic syndrome. NCT00352287
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