A statistical analysis plan for the Adjunctive Corticosteroids for Tuberculous meningitis in HIV-positive adults (ACT HIV) clinical trial

TBM is the most severe form of tuberculosis. Clinical trial data are required to provide an evidence base for adjunctive dexamethasone in HIV-positive individuals with TBM, and to guide clinical practice. This document details the planned analyses at 12 months post randomisation for the ACT HIV clinical trial (NCT03092817); 'a randomised double-blind placebo-controlled trial of adjunctive dexamethasone for the treatment of HIV co-infected adults with tuberculous meningitis (TBM)'. The primary endpoint of the ACT HIV trial is death (from any cause) over the first 12 months after randomisation. This statistical analysis plan expands upon and updates the analysis plan outlined in the published study protocol

Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis. METHODS: In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein-Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS), in which higher scores indicate better health status. RESULTS: In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P<0.001) and a lower rate of decline in KCCQ-OS score (P<0.001). The incidence and types of adverse events were similar in the two groups. CONCLUSIONS: In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .)

Selepressin for Patients With Septic Shock-Reply.

In Reply We agree with Dr Rehberg and colleagues that our study demonstrated that selepressin had a number of advantageous physiologic effects on blood pressure, urine output, and other features associated with septic shock [...

Randomized Trial of Stent versus Surgery for Asymptomatic Carotid Stenosis

Previous clinical trials have suggested that carotid-artery stenting with a device to capture and remove emboli ("embolic protection") is an effective alternative to carotid endarterectomy in patients at average or high risk for surgical complications. In this trial, we compared carotid-artery stenting with embolic protection and carotid endarterectomy in patients 79 years of age or younger who had severe carotid stenosis and were asymptomatic (i.e., had not had a stroke, transient ischemic attack, or amaurosis fugax in the 180 days before enrollment) and were not considered to be at high risk for surgical complications. The trial was designed to enroll 1658 patients but was halted early, after 1453 patients underwent randomization, because of slow enrollment. Patients were followed for up to 5 years. The primary composite end point of death, stroke, or myocardial infarction within 30 days after the procedure or ipsilateral stroke within 1 year was tested at a noninferiority margin of 3 percentage points. Stenting was noninferior to endarterectomy with regard to the primary composite end point (event rate, 3.8% and 3.4%, respectively; P=0.01 for noninferiority). The rate of stroke or death within 30 days was 2.9% in the stenting group and 1.7% in the endarterectomy group (P=0.33). From 30 days to 5 years after the procedure, the rate of freedom from ipsilateral stroke was 97.8% in the stenting group and 97.3% in the endarterectomy group (P=0.51), and the overall survival rates were 87.1% and 89.4%, respectively (P=0.21). The cumulative 5-year rate of stroke-free survival was 93.1% in the stenting group and 94.7% in the endarterectomy group (P=0.44). In this trial involving asymptomatic patients with severe carotid stenosis who were not at high risk for surgical complications, stenting was noninferior to endarterectomy with regard to the rate of the primary composite end point at 1 year. In analyses that included up to 5 years of follow-up, there were no significant differences between the study groups in the rates of non-procedure-related stroke, all stroke, and survival. (Funded by Abbott Vascular; ACT I ClinicalTrials.gov number, NCT00106938.)

Design and Rationale of the Phase 3 ATTR-ACT Clinical Trial (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial)

Transthyretin amyloidosis is a rare, life-threatening disease resulting from aggregation and deposition of transthyretin amyloid fibrils in various tissues. There are 2 predominate phenotypic presentations of the disease: transthyretin familial amyloid polyneuropathy, which primarily affects the peripheral nerves, and transthyretin cardiomyopathy (TTR-CM), which primarily affects the heart. However, there is a wide overlap with symptoms at presentation and disease course being highly variable and influenced by the underlying transthyretin mutation, age of the affected individual, sex, and geographic location. Treatment of transthyretin amyloidosis is typically focused on symptom management. Although tafamidis has been shown to delay neurologic progression of transthyretin familial amyloid polyneuropathy, there are no approved pharmacologic therapies shown to improve survival in TTR-CM. The natural history of TTR-CM is poorly characterized, which presents difficulties for the design of large-scale trials for new treatments. This review provides a brief overview of TTR-CM and the challenges of identifying clinically meaningful end points and study parameters to determine the efficacy of treatments for rare diseases. The design and rationale behind the ongoing phase 3 ATTR-ACT study (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), an international, multicenter, double-blind, placebo-controlled, randomized clinical trial, is also outlined. The ATTR-ACT study will provide important insight into the efficacy and safety of tafamidis for the treatment of TTR-CM