{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:43:29Z","timestamp":1776732209323,"version":"3.51.2"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HD070855"],"award-info":[{"award-number":["HD070855"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100024744","name":"Snow Foundation","doi-asserted-by":"crossref","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100024744","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000041","name":"American Diabetes Association","doi-asserted-by":"crossref","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100000041","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec015\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Wolfram syndrome, an ultra-rare condition, currently lacks effective treatment options. The rarity of this disease presents significant challenges in conducting clinical trials, particularly in achieving sufficient statistical power (e.g., 80%). The objective of this study is to propose a novel clinical trial design based on real-world data to reduce the sample size required for conducting clinical trials for Wolfram syndrome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec016\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We propose a novel clinical trial design with three key features aimed at reducing sample size and improve efficiency: (i) Pooling historical\/external controls from a longitudinal observational study conducted by the Washington University Wolfram Research Clinic. (ii) Utilizing run-in data to estimate model parameters. (iii) Simultaneously tracking treatment effects in two endpoints using a multivariate proportional linear mixed effects model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec017\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Comprehensive simulations were conducted based on real-world data obtained through the Wolfram syndrome longitudinal observational study. Our simulations demonstrate that this proposed design can substantially reduce sample size requirements. Specifically, with a bivariate endpoint and the inclusion of run-in data, a sample size of approximately 30 per group can achieve over 80% power, assuming the placebo progression rate remains consistent during both the run-in and randomized periods. In cases where the placebo progression rate varies, the sample size increases to approximately 50 per group.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec018\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>For rare diseases like Wolfram syndrome, leveraging existing resources such as historical\/external controls and run-in data, along with evaluating comprehensive treatment effects using bivariate\/multivariate endpoints, can significantly expedite the development of new drugs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0321598","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T13:58:13Z","timestamp":1746799093000},"page":"e0321598","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical trials for Wolfram syndrome neurodegeneration: Novel design, endpoints, 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