MRI Quantification of Placebo Effect in Nonalcoholic Steatohepatitis Clinical Trials.

Background Several early-phase clinical trials for the treatment of nonalcoholic steatohepatitis (NASH) use liver fat content as measured with the MRI-derived proton density fat fraction (PDFF) for a primary outcome. These trials have shown relative reductions in liver fat content with placebo treatment alone, a phenomenon termed the placebo effect. This phenomenon confounds the results and limits generalizability to future trials. Purpose To quantify the effect of placebo treatment on change in the absolute PDFF value and to identify variables associated with this observed change. Materials and Methods This is a secondary analysis of prospectively collected data from seven early phase clinical trials that included participants with a diagnosis of NASH based on MRI and/or liver biopsy who received placebo treatment. The primary outcome was a greater than or equal to 30% relative reduction in PDFF after placebo treatment. Normalization of PDFF, relative change in alanine aminotransferase (ALT) level, and normalization of ALT level were also examined. An exploratory linear mixed-effects model was used to estimate an overall change in absolute PDFF and to explore parameters associated with this response. Results A total of 187 participants (median age, 52 years [IQR, 43-60 years]; 114 women) who received placebo treatment were evaluated. A greater than or equal to 30% relative reduction in baseline PDFF was seen in 20% of participants after 12 weeks of placebo treatment (10 of 49), 9% of participants after 16 weeks (two of 22), and 28% of participants after 24 weeks (34 of 122). A repeated-measures linear mixed-effects model estimated a decrease of 2.3 units (median relative reduction of 13%) in absolute PDFF values after 24 weeks of placebo treatment (95% CI: 3.2, 1.4; P < .001). Conclusion In this analysis of 187 participants, a clinically relevant decrease in PDFF was observed with placebo treatment. Based on the study model, assuming an absolute PDFF decrease of approximately 3 units (upper limit of 95% CI) to account for this placebo effect in sample size calculations for future clinical trials is suggested. Clinical trial registration nos. NCT01066364, NCT01766713, NCT01963845, NCT02443116, NCT02546609, NCT02316717, and NCT02442687 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Yoon in this issue

Ideal high sensitivity troponin baseline cutoff for patients with renal dysfunction

OBJECTIVE: High-sensitivity cardiac troponin assays (hs-cTn) aid in diagnosis of myocardial infarction (MI). These assays have lower specificity for non-ST Elevation MI (NSTEMI) in patients with renal disease. Our objective was to determine an optimized cutoff for patients with renal disease. METHODS: We conducted an a priori secondary analysis of a prospective FDA study in adults with suspected MI presenting to 29 academic urban EDs between 4/2015 and 4/2016. Blood was drawn 0, 1, 2-3, and 6-9 h after ED arrival. We recorded cTn and estimated glomerular filtrate rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration equation. The primary endpoint was NSTEMI (Third Universal Definition of MI), adjudicated by physicians blinded to hs-cTn results. We generated an adjusted hscTn rule-in cutoff to increase specificity. RESULTS: 2505 subjects were enrolled; 234 were excluded. Patients were mostly male (55.7%) and white (57.2%), median age was 56 years 472 patients [20.8%] had an eGFR \u3c60 mL/min/1.73 m2. In patients with eGFR \u3c15 mL/min/1.73 m2, a baseline rule-in cutoff of 120 ng/L led to a specificity of 85.0% and Positive Predictive Value (PPV) of 62.5% with 774 patients requiring further observation. Increasing the cutoff to 600 ng/L increased specificity and PPV overall and in every eGFR subgroup (specificity and PPV 93.3% and 78.9%, respectively for eGFR \u3c15 mL/min/1.73m(2)), while increasing the number (79) of patients requiring observation. CONCLUSIONS: An eGFR-adjusted baseline rule-in threshold for the Siemens Atellica hs-cTnI improves specificity with identical sensitivity. Further study in a prospective cohort with higher rates of renal disease is warranted

Ideal high sensitivity troponin baseline cutoff for patients with renal dysfunction

OBJECTIVE: High-sensitivity cardiac troponin assays (hs-cTn) aid in diagnosis of myocardial infarction (MI). These assays have lower specificity for non-ST Elevation MI (NSTEMI) in patients with renal disease. Our objective was to determine an optimized cutoff for patients with renal disease. METHODS: We conducted an a priori secondary analysis of a prospective FDA study in adults with suspected MI presenting to 29 academic urban EDs between 4/2015 and 4/2016. Blood was drawn 0, 1, 2-3, and 6-9 h after ED arrival. We recorded cTn and estimated glomerular filtrate rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration equation. The primary endpoint was NSTEMI (Third Universal Definition of MI), adjudicated by physicians blinded to hs-cTn results. We generated an adjusted hscTn rule-in cutoff to increase specificity. RESULTS: 2505 subjects were enrolled; 234 were excluded. Patients were mostly male (55.7%) and white (57.2%), median age was 56 years 472 patients [20.8%] had an eGFR \u3c60 mL/min/1.73 m2. In patients with eGFR \u3c15 mL/min/1.73 m2, a baseline rule-in cutoff of 120 ng/L led to a specificity of 85.0% and Positive Predictive Value (PPV) of 62.5% with 774 patients requiring further observation. Increasing the cutoff to 600 ng/L increased specificity and PPV overall and in every eGFR subgroup (specificity and PPV 93.3% and 78.9%, respectively for eGFR \u3c15 mL/min/1.73m(2)), while increasing the number (79) of patients requiring observation. CONCLUSIONS: An eGFR-adjusted baseline rule-in threshold for the Siemens Atellica hs-cTnI improves specificity with identical sensitivity. Further study in a prospective cohort with higher rates of renal disease is warranted

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