MRI Quantification of Placebo Effect in Nonalcoholic Steatohepatitis Clinical Trials.
Abstract
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 <i>Online supplemental
material is available for this article.</i> See also the editorial by Yoon in this
issue.
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Journal articlePermalink
https://hdl.handle.net/10161/26265Published Version (Please cite this version)
10.1148/radiol.220743Publication Info
Nedrud, Marybeth A; Chaudhry, Mohammad; Middleton, Michael S; Moylan, Cynthia A; Lerebours,
Reginald; Luo, Sheng; ... Bashir, Mustafa R (2022). MRI Quantification of Placebo Effect in Nonalcoholic Steatohepatitis Clinical Trials.
Radiology. pp. 220743. 10.1148/radiol.220743. Retrieved from https://hdl.handle.net/10161/26265.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Mustafa Shadi Rifaat Bashir
Professor of Radiology
Hepatobiliary and pancreatic imagingLiver cancer (hepatocellular carcinoma)Fatty liver,
NAFLD, and NASHChronic liver disease and cirrhosisPancreatic cancerTechnical development
in MRIQuantitative imaging
Reginald (Gino) Lerebours
Biostatistician II
Education: Masters Degree, Biostatistics. Harvard University. 2017Bachelors Degree,
Statistics. North Carolina State University. 2015Overview: Gino currently collaborates
with researchers, residents, and clinicians in the Departments of Surgery, Radiology
and Infectious Diseases. His main research interests and experience are in statistical
programming, data management, statistical modeling, statistical consulting and statistical
education.
Sheng Luo
Professor of Biostatistics & Bioinformatics
Cynthia Ann Moylan
Associate Professor of Medicine
My research interests focus on the study of chronic liver disease and primary liver
cancer, particularly from nonalcoholic fatty liver disease (NAFLD). As part of the
NAFLD Research Team at Duke, I am investigating the role of epigenetics and genetics
on the development of advanced fibrosis from NAFLD. The long term goal of our research
is to develop non-invasive biomarkers to identify those patients at increased risk
for cirrhosis and end stage liver disease in order to risk stratif
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