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They have been particularly affected by the opioid crisis. However, no study to date has used a randomized controlled design to test preventive interventions of opioid and other drug use among this vulnerable population. Resolution of youth homelessness through housing and supportive services including prevention services, often referred to as \u201cHousing First,\u201d has great potential to reduce the likelihood for the development of an opioid use disorder as well as other problem behaviors associated with living on the streets. Housing First has been tested through randomized trials among homeless adults with mental health and substance use disorders, but has not been empirically tested for opioid prevention among homeless youth.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Homeless youth will be recruited from a drop-in shelter site frequented by disconnected youth; they will be screened for eligibility, including current homelessness, age 18\u201324\u00a0years, and not currently meeting criteria for opioid use disorder (OUD). In a controlled trial, 240 youth will then be randomized to one of two conditions, (1) housing\u2009+\u2009opioid and related risk prevention services, or (2) opioid and related risk prevention services alone. This project utilizes existing efficacious models of prevention to address opioid-related risks, including motivational interviewing, strengths-based outreach and advocacy, and an HIV risk preventive intervention. Follow-up will be conducted at 3, 6, 9 and 12-months post-baseline. The economic cost of each intervention will be determined to support implementation decisions with other providers and their funders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>This study will provide essential information for researchers and providers on the efficacy of housing\u2009+\u2009opioid and related risk prevention services in an RCT for effects on opioid use and mechanisms underlying change. Because youth experiencing homelessness are at increased risk for a variety of adverse outcomes, the proposed intervention may produce substantial health care benefits to the youths and society at large.<\/jats:p><jats:p><jats:italic>Trial registration<\/jats:italic>ClinicalTrials.gov, NCT04135703, Registered October 13, 2019,<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04135703?term=NCT04135703&amp;draw=2&amp;rank=1#contacts\">https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04135703?term=NCT04135703&amp;draw=2&amp;rank=1#contacts<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1186\/s13722-021-00237-7","type":"journal-article","created":{"date-parts":[[2021,5,12]],"date-time":"2021-05-12T19:02:43Z","timestamp":1620846163000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Housing, opportunities, motivation and engagement (HOME) for homeless youth at-risk for opioid use disorder: study protocol for a randomized controlled trial"],"prefix":"10.1186","volume":"16","clinical-trial-number":[{"clinical-trial-number":"nct04135703","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Natasha","family":"Slesnick","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Chavez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Bunger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruri","family":"Famelia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jodi","family":"Ford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Higgins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Holowacz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soren","family":"Jaderlund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellison","family":"Luthy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen","family":"Mallory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5128-5374","authenticated-orcid":false,"given":"Jared","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Walsh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tansel","family":"Yilmazer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Kelleher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,12]]},"reference":[{"issue":"2","key":"237_CR1","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.drugalcdep.2005.05.009","volume":"81","author":"WM Compton","year":"2006","unstructured":"Compton WM, Volkow ND. 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