Age of Data at the Time of Publication of Contemporary Clinical Trials.

Importance: As medical knowledge and clinical practice rapidly evolve over time, there is an imperative to publish results of clinical trials in a timely way and reduce unnecessary delays. Objectives: To characterize the age of clinical trial data at the time of publication in journals with a high impact factor and highlight the time from final data collection to publication. Design and Setting: A cross-sectional analysis was conducted of all randomized clinical trials published from January 1 through December 31, 2015, in the Annals of Internal Medicine, BMJ, JAMA, JAMA Internal Medicine, Lancet, and New England Journal of Medicine. Multivariable linear regression analyses were conducted to assess whether data age (adjusted for follow-up duration) and publication time were associated with trial characteristics. Main Outcomes and Measures: The outcome measures were the midpoint of data collection until publication (data age), the time from first participant enrollment to last participant enrollment (enrollment time), and the time from final data collection to publication (publication time). Results: There were 341 clinical trials published in 2015 by the 6 journals. For assessment of the primary end point, 37 trials (10.9%) had a follow-up period of less than 1 month, 172 trials (50.4%) had a follow-up period of 1 month to 1 year, and 132 trials (38.7%) had a follow-up period of more than 1 year. For all trials, the median data age at publication was 33.9 months (interquartile range, 23.5-46.3 months). Among trials with a follow-up period of 1 month or less, the median data age was 30.6 months (interquartile range, 18.6-39.0 months). A total of 68 trials (19.9%) required more than 4 years to complete enrollment. The median time from the completion of data collection to publication was 14.8 months (interquartile range, 7.4-22.2 months); publication time was 2 or more years in 63 trials (18.5%). In multivariable regression analyses adjusted for follow-up time, inconclusive or unfavorable trial results were significantly associated with older data age (>235 days). Compared with trials funded only by private industry, trials funded by government were associated with a significantly longer time to publication (>180 days). Conclusions and Relevance: Clinical trials in journals with a high impact factor were published with a median data age of nearly 3 years. For a substantial proportion of studies, time for enrollment and time from completion of data collection to publication were quite long, indicating marked opportunities for improvement in clinical trials to reduce data age.

Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: HIV-infected patients have a high risk of myocardial infarction. We aimed to assess the ability of statin treatment to reduce arterial inflammation and achieve regression of coronary atherosclerosis in this population. METHODS: In a randomised, double-blind, placebo-controlled trial, 40 HIV-infected participants with subclinical coronary atherosclerosis, evidence of arterial inflammation in the aorta by fluorodeoxyglucose (FDG)-PET, and LDL-cholesterol concentration of less than 3.37 mmol/L (130 mg/dL) were randomly assigned (1:1) to 1 year of treatment with atorvastatin or placebo. Randomisation was by the Massachusetts General Hospital (MGH) Clinical Research Pharmacy with a permuted-block algorithm, stratified by sex with a fixed block size of four. Study codes were available only to the MGH Research Pharmacy and not to study investigators or participants. The prespecified primary endpoint was arterial inflammation as assessed by FDG-PET of the aorta. Additional prespecified endpoints were non-calcified and calcified plaque measures and high risk plaque features assessed with coronary CT angiography and biochemical measures. Analysis was done by intention to treat with all available data and without imputation for missing data. The trial is registered with ClinicalTrials.gov, number NCT00965185. FINDINGS: The study was done from Nov 13, 2009, to Jan 13, 2014. 19 patients were assigned to atorvastatin and 21 to placebo. 37 (93%) of 40 participants completed the study, with equivalent discontinuation rates in both groups. Baseline characteristics were similar between groups. After 12 months, change in FDG-PET uptake of the most diseased segment of the aorta was not different between atorvastatin and placebo, but technically adequate results comparing longitudinal changes in identical regions could be assessed in only 21 patients (atorvastatin Δ -0.03, 95% CI -0.17 to 0.12, vs placebo Δ -0.06, -0.25 to 0.13; p=0.77). Change in plaque could be assessed in all 37 people completing the study. Atorvastatin reduced non-calcified coronary plaque volume relative to placebo: median change -19.4% (IQR -39.2 to 9.3) versus 20.4% (-7.1 to 94.4; p=0.009, n=37). The number of high-risk plaques was significantly reduced in the atorvastatin group compared with the placebo group: change in number of low attenuation plaques -0.2 (95% CI -0.6 to 0.2) versus 0.4 (0.0, 0.7; p=0.03; n=37); and change in number of positively remodelled plaques -0.2 (-0.4 to 0.1) versus 0.4 (-0.1 to 0.8; p=0.04; n=37). Direct LDL-cholesterol (-1.00 mmol/L, 95% CI -1.38 to 0.61 vs 0.30 mmol/L, 0.04 to 0.55, p<0.0001) and lipoprotein-associated phospholipase A2 (-52.2 ng/mL, 95% CI -70.4 to -34.0, vs -13.3 ng/mL, -32.8 to 6.2; p=0.005; n=37) decreased significantly with atorvastatin relative to placebo. Statin therapy was well tolerated, with a low incidence of clinical adverse events. INTERPRETATION: No significant effects of statin therapy on arterial inflammation of the aorta were seen as measured by FDG-PET. However, statin therapy reduced non-calcified plaque volume and high-risk coronary plaque features in HIV-infected patients. Further studies should assess whether reduction in high-risk coronary artery disease translates into effective prevention of cardiovascular events in this at-risk population. FUNDING: National Institutes of Health, Harvard Clinical and Translational Science Center, National Center for Research Resources.

High-density lipoprotein-mediated cholesterol efflux capacity is improved by treatment with antiretroviral therapy in acute human immunodeficiency virus infection.

BACKGROUND: Individuals infected with human immunodeficiency virus (HIV) have decreased high-density lipoprotein (HDL)-cholesterol and increased cardiovascular disease (CVD). Reverse cholesterol transport from macrophages may be inhibited by HIV and contribute to increased CVD. Human studies have not investigated longitudinal effects of HIV and antiretroviral therapy (ART) on cholesterol efflux. METHODS: Subjects with acute HIV infection were randomized to ART or not. Cholesterol efflux capacity was determined ex vivo after exposure of murine macrophages to apolipoprotein B-depleted patient sera obtained at baseline and after 12 weeks. RESULTS: After 12 weeks, HIV RNA decreased most in subjects randomized to ART. Available data on cholesterol demonstrated that efflux capacity from Abca1(+/+) macrophages was increased most by sera obtained from ART-treated subjects (20.5% ± 5.0% to 24.3 % ± 6.9%, baseline to 12 weeks, P = .007; ART group [n = 6] vs 18.0 % ± 3.9% to 19.1 % ± 2.9%, baseline to 12 weeks, P = .30; untreated group [n = 6] [P = .04 ART vs untreated group]). Change in HIV RNA was negatively associated with change in Abca1(+/+) macrophage cholesterol efflux (r = - 0.62, P = .03), and this finding remained significant (P = .03) after controlling for changes in HDL-cholesterol, CD4(+) cells, and markers of monocyte or macrophage activation. CONCLUSIONS: In subjects acutely infected with HIV, ATP-binding cassette transporter A1-mediated cholesterol efflux was stimulated to a greater degree over time by apolipoprotein B-depleted serum from subjects randomized to ART. The improvement in cholesterol efflux capacity is independently related to reduction in viral load.