Summary Background Despite preventive vaccines for oncogenic human papillomaviruses (HPVs), cervical intraepithelial neoplasia (CIN) is common, and current treatments are ablative and can lead to ...long-term reproductive morbidity. We assessed whether VGX-3100, synthetic plasmids targeting HPV-16 and HPV-18 E6 and E7 proteins, delivered by electroporation, would cause histopathological regression in women with CIN2/3. Methods Efficacy, safety, and immunogenicity of VGX-3100 were assessed in CIN2/3 associated with HPV-16 and HPV-18, in a randomised, double-blind, placebo-controlled phase 2b study. Patients from 36 academic and private gynaecology practices in seven countries were randomised (3:1) to receive 6 mg VGX-3100 or placebo (1 mL), given intramuscularly at 0, 4, and 12 weeks. Randomisation was stratified by age (<25 vs ≥25 years) and CIN2 versus CIN3 by computer-generated allocation sequence (block size 4). Funder and site personnel, participants, and pathologists were masked to treatment. The primary efficacy endpoint was regression to CIN1 or normal pathology 36 weeks after the first dose. Per-protocol and modified intention-to-treat analyses were based on patients receiving three doses without protocol violations, and on patients receiving at least one dose, respectively. The safety population included all patients who received at least one dose. The trial is registered at ClinicalTrials.gov (number NCT01304524 ) and EudraCT (number 2012-001334-33). Findings Between Oct 19, 2011, and July 30, 2013, 167 patients received either VGX-3100 (n=125) or placebo (n=42). In the per-protocol analysis 53 (49·5%) of 107 VGX-3100 recipients and 11 (30·6%) of 36 placebo recipients had histopathological regression (percentage point difference 19·0 95% CI 1·4–36·6; p=0·034). In the modified intention-to-treat analysis 55 (48·2%) of 114 VGX-3100 recipients and 12 (30·0%) of 40 placebo recipients had histopathological regression (percentage point difference 18·2 95% CI 1·3–34·4; p=0·034). Injection-site reactions occurred in most patients, but only erythema was significantly more common in the VGX-3100 group (98/125, 78·4%) than in the placebo group (24/42, 57·1%; percentage point difference 21·3 95% CI 5·3–37·8; p=0·007). Interpretation VGX-3100 is the first therapeutic vaccine to show efficacy against CIN2/3 associated with HPV-16 and HPV-18. VGX-3100 could present a non-surgical therapeutic option for CIN2/3, changing the treatment outlook for this common disease. Funding Inovio Pharmaceuticals.
Background p38 mitogen-activated protein kinase (MAPK) mediates cytokine production and amplification of the inflammatory cascade. Through inhibition of p38 MAPK, losmapimod appears to attenuate the ...inflammatory response in the vascular wall and thus may help stabilize plaques. Study design The LATITUDE-TIMI 60 trial is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study planned to be conducted in a 3-stage design. Overall, the trial is designed to include 25,500 patients hospitalized with non–ST-elevation or ST-elevation myocardial infarction (MI) randomized to oral losmapimod (7.5 mg twice daily) versus matching placebo. Part A consists of a leading cohort (n = 3,500) that will provide an initial assessment of safety and exploratory efficacy before progressing to part B. Part B (n = ~22,000) of the study is event driven and will provide the primary assessment of efficacy. An independent safety review will be conducted after 3,500 patients in part B1 to determine whether a more focused schedule of clinic visits and laboratory assessments can be implemented (part B2). All patients are to be treated with study drug until week 12 and followed up until week 24. The primary end point is the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization. The key secondary end point is the composite of cardiovascular death or MI. The trial is designed to provide ≥90% power for the primary end point. Conclusions The LATITUDE-TIMI 60 trial will determine the efficacy and safety of short-term p38 MAPK inhibition with losmapimod in acute MI. The trial design adopts a stepwise approach to decision making and collection of data.
Background Troponin is the preferred biomarker for risk stratification in non-ST elevation ACS. The incremental prognostic use of the initial magnitude of troponin elevation and its value in ...conjunction with ST-segment resolution (STRes) in ST elevation myocardial infarction (STEMI) is less well defined. Methods Troponin T (TnT) was measured in 1,250 patients at presentation undergoing fibrinolysis for STEMI in CLARITY-TIMI 28. ST-segment resolution was measured at 90 minutes. Multivariable logistic regression was used to examine the independent association between TnT levels, STRes, and 30-day cardiovascular (CV) mortality. Results Patients were classified into undetectable TnT at baseline (n = 594), detectable but below the median of 0.12 ng/mL (n = 330), and above the median (n = 326). Rates of 30-day CV death were 1.5%, 4.5%, and 9.5%, respectively ( P < .0001). Compared with those with undetectable levels and adjusting for baseline factors, the odds ratios for 30-day CV death were 4.56 (1.72-12.08, P = .002) and 5.81 (2.29-14.73, P = .0002) for those below and above the median, respectively. When combined with STRes, there was a significant gradient of risk, and in a multivariable model both baseline TnT ( P = .004) and STRes ( P = .003) were significant predictors of 30-day CV death. The addition of TnT and STRes to clinical risk factors significantly improved the C-statistic (from 0.86 to 0.90, P = .02) and the integrated discriminative improvement (7.1% increase) ( P = .0009). Conclusions Baseline TnT and 90-minute STRes are independent predictors of 30-day CV death in patients with STEMI. Use of these 2 simple, readily available tools can aid clinicians in early risk stratification.
Background Diabetes is an established risk factor for complications following total joint arthroplasty. However, the correlation between postoperative blood glucose and preoperative hemoglobin A1C ...levels with complications following total joint arthroplasty is not well described. Methods All patients undergoing elective primary total joint arthroplasty at our institution from 2004 through 2011 with both postoperative blood glucose and preoperative hemoglobin A1C levels were identified in a retrospective review. From among 1702 patients, those with wound complications within thirty days after the index arthroplasty were identified. A control group matched for exact age, sex, procedure, tourniquet use, surgical approach, and use of antibiotic cement was also created. Thirty patients met the study group inclusion criteria. The mean patient age was seventy-two years (range, fifty-three to eighty-nine years); the majority (53%) of patients were female. Results The odds ratio for developing a wound complication was 3.75 (95% confidence interval, 1.25 to 11.22; p = 0.02) in patients with a mean postoperative glucose of >200 mg/dL, 3.0 (95% confidence interval, 0.97 to 9.30; p = 0.08) in patients with a maximum postoperative blood glucose of >260 mg/dL, and 9.0 (95% confidence interval, 1.14 to 71.20; p = 0.03) in patients with a preoperative hemoglobin A1C value of >6.7%. Conclusions Patients with a mean postoperative blood glucose of >200 mg/dL or a preoperative hemoglobin A1C level of >6.7% are at increased risk for wound complications following elective primary total joint arthroplasty. These results show that poor preoperative and postoperative glucose control is independently associated with wound complications. Level of Evidence Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.
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