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Lower limb amputations are a devastating comorbid complication of diabetes mellitus. Osteomyelitis increases the risk of amputation fourfold and commonly presages death.<\/jats:p>\n<jats:p>Antimicrobial therapy for diabetic foot osteomyelitis (DFO) varies greatly, indicating that high quality data are needed to inform clinical decision making. Several small trials have indicated that the addition of rifampin to backbone antimicrobial regimens for osteomyelitis outside the setting of the diabetic foot results in 28 to 42% higher cure rates.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods\/design<\/jats:title>\n<jats:p>This is a prospective, randomized, double-blind investigation of the addition of 6 weeks of rifampin, 600\u2009mg daily, vs. matched placebo (riboflavin) to standard-of-care, backbone antimicrobial therapy for DFO. The study population are patients enrolled in Veteran Health Administration (VHA), ages \u226518 and\u2009\u2264\u200989\u2009years with diabetes mellitus and definite or probable osteomyelitis of the foot for whom an extended course of oral or intravenous antibiotics is planned. The primary endpoint is amputation-free survival. The primary hypothesis is that using rifampin as adjunctive therapy will lower the hazard rate compared with the group that does not use rifampin as adjunctive therapy. The primary hypothesis will be tested by means of a two-sided log-rank test with a 5% significance level. The test has 90% power to detect a hazard ratio of 0.67 or lower with a total of 880 study participants followed on average for 1.8\u2009years.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Discussion<\/jats:title>\n<jats:p>VA INTREPID will test if a rifampin-adjunctive antibiotic regimen increases amputation-free survival in patients seeking care in the VHA with DFO. A positive finding and its adoption by clinicians would reduce lower extremity amputations and their associated physical and emotional impact and reduce mortality for Veterans and for the general population with diabetic foot osteomyelitis. Given that rifampin-adjunctive regimens are currently employed for therapy for the majority of DFO cases in Europe, and only in a small minority of cases in the United States, the trial results will impact therapeutic decisions, even if the null hypothesis is not rejected.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Trial registration<\/jats:title>\n<jats:p>Registered January 6, 2017 at ClinicalTrials.gov, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03012529?term=NC\">NCT03012529<\/jats:ext-link>.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s12879-019-4751-3","type":"journal-article","created":{"date-parts":[[2020,1,8]],"date-time":"2020-01-08T16:02:47Z","timestamp":1578499367000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["A multicenter randomized placebo controlled trial of rifampin to reduce pedal amputations for osteomyelitis in veterans with diabetes (VA INTREPID)"],"prefix":"10.1186","volume":"20","author":[{"given":"Mary T.","family":"Bessesen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gheorghe","family":"Doros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam M.","family":"Henrie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly M.","family":"Harrington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Hermos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Bonomo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan E.","family":"Ferguson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant D.","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4563-4854","authenticated-orcid":false,"given":"Sheldon T.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,8]]},"reference":[{"issue":"10","key":"4751_CR1","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1001\/jama.2015.10029","volume":"314","author":"A Menke","year":"2015","unstructured":"Menke A, Casagrande S, Geiss L, Cowie CC. 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All subjects participate in a thorough informed consent process supervised by the local site investigator, and document that by signature on an IRB approved informed consent form.Ancillary and post-trial care: The clinical care team at each participating site will provide needed medical care to participants. If a participant is injured as a result of taking part in this study, the VA will provide necessary medical treatment at no cost to the participant unless the injury was due to not following study procedures.Confidentiality: Personal identifiable information will be maintained in the secure electronic medical record. All study data will be collected on case report forms with a subject code, and maintained in DataLabs, a secure research database.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"23"}}