{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:55:20Z","timestamp":1792652120726,"version":"4.5.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T00:00:00Z","timestamp":1622160000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T00:00:00Z","timestamp":1622160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Parasites Vectors"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p><jats:italic>Dirofilaria immitis,<\/jats:italic>a globally distributed filarial parasite of dogs, is known to cause serious or fatal cardiopulmonary disease. Client-owned dogs were enrolled in a clinical field study in the USA to evaluate the clinical effectiveness and field safety of an orally administered combination investigational product (IP) containing milbemycin oxime and lotilaner (Credelio<jats:sup>\u00ae<\/jats:sup>Plus) as compared to a control product (CP) for the prevention of heartworm disease when administered monthly for 11 consecutive months.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this 11-month field study, 319 dogs\u2009\u2265\u20098\u00a0weeks old confirmed to be heartworm-negative were enrolled from eight geographically distinct US veterinary clinics, including sites in the southern USA and Mississippi River Valley. The dogs were treated with either the IP combination product at 0.75\u20131.53\u00a0mg\/kg milbemycin oxime and 20\u201341.5\u00a0mg\/kg lotilaner (<jats:italic>n<\/jats:italic>\u2009=\u2009159) or the CP (Sentinel<jats:sup>\u00ae<\/jats:sup>Flavor Tabs<jats:sup>\u00ae<\/jats:sup>; milbemycin oxime\/lufenuron) at the label-recommended dose rate (<jats:italic>n<\/jats:italic>\u2009=\u2009158.) On day 330, effectiveness was evaluated in each dog using antigen and microfilarial (modified Knott\u2019s) testing to assess the establishment of any patent adult heartworm infections.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All dogs treated with the IP combination product and the CP tested negative (100% prevention) for heartworm infection on day 330. The IP combination product tablets containing milbemycin oxime and lotilaner were well tolerated based on the safety assessments in all treated dogs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This multi-site clinical study using client-owned dogs demonstrated that monthly use of flavored, chewable tablets containing a combination of milbemycin oxime and lotilaner administered orally under end use conditions is safe for dogs. None of the enrolled dogs developed heartworm infections. Eleven consecutive monthly treatments of the IP provided 100% prevention of heartworm disease caused by<jats:italic>D. immitis<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Graphical Abstract<\/jats:title><\/jats:sec>","DOI":"10.1186\/s13071-021-04767-6","type":"journal-article","created":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T00:26:26Z","timestamp":1622161586000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Field study to investigate the effectiveness and safety of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio\u00ae Plus) for the prevention of heartworm disease (Dirofilaria immitis) in client-owned dogs in the USA"],"prefix":"10.1186","volume":"14","author":[{"given":"Lisa M.","family":"Young","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Wiseman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Crawley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Wallace","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4091-6297","authenticated-orcid":false,"given":"Daniel E.","family":"Snyder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,28]]},"reference":[{"key":"4767_CR1","first-page":"195","volume":"66","author":"JW Mcall","year":"2008","unstructured":"Mcall JW, Genchi C, Kramer LH, Guerrero J. Heartworm disease in animals and humans (Chapter 4). Adv Parasitol. 2008;66:195\u2013285.","journal-title":"Adv Parasitol."},{"key":"4767_CR2","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1016\/j.cvsm.2009.06.003","volume":"39","author":"D Bowman Dwight","year":"2009","unstructured":"Bowman Dwight D, Atkins Clarke E. Heartworm biology, treatment, and control. Vet Clin Small Anim. 2009;39:1127\u201358.","journal-title":"Vet Clin Small Anim."},{"key":"4767_CR3","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1186\/1756-3305-5-138","volume":"5","author":"D Bowman","year":"2012","unstructured":"Bowman D. Heartworms, macrocyclic lactones, and the specter of resistance to prevention in the United States. Parasit Vectors. 2012;5:138.","journal-title":"Parasit Vectors"},{"key":"4767_CR4","unstructured":"Current canine guidelines for the diagnosis, prevention and management of heartworm (Dirofilaria immitis) infection in dogs (revised 2020). American Heartworm Society. https:\/\/www.heartwormsociety.org\/veterinary-resources\/american-heartworm-society-guidelines. Accessed 10 Sept 2020."},{"key":"4767_CR5","unstructured":"Companion Animal Parasite Council (CAPC). CAPC Guidelines: Heartworm; 2020. https:\/\/capcvet.org\/guidelines\/heartworm\/. Accessed 10 Sept 2020."},{"key":"4767_CR6","unstructured":"Guidelines for clinical management of canine heartworm disease. European Society for Dirofilariosis and Angiostrongylosis https:\/\/www.esda.vet\/wp-content\/uploads\/2017\/11\/GUIDELINES-FOR-CLINICAL-MANAGEMENT-OF-CANINE-HEARTWORM-DISEASE.pdf. Accessed 10 Sept 2020."},{"key":"4767_CR7","unstructured":"European Scientific Counsel Companion Animal Parasites (ESCCAP). Control of Vector-Borne Diseases in Dogs and Cats. ESCCAP Guideline 05 Third Edition\u2013March 2019. https:\/\/www.esccap.org\/uploads\/docs\/znkh6j1d_0775_ESCCAP_Guideline_GL5_v8_1p.pdf. Accessed 10 Sept 2020."},{"key":"4767_CR8","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1111\/j.1939-1676.2010.0657.x","volume":"25","author":"DE Snyder","year":"2011","unstructured":"Snyder DE, Wiseman S, Cruthers LR, Slone RL. Ivermectin and milbemycin oxime in experimental adult heartworm (Dirofilaria immitis) infection of dogs. J Vet Int Med. 2011;25:61\u20134.","journal-title":"J Vet Int Med"},{"key":"4767_CR9","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.vetpar.2015.04.002","volume":"210","author":"C Bourguinat","year":"2015","unstructured":"Bourguinat C, Lee A, Lizunda R, Blagburn B, Liotta J, Kraus M, et al. Macrocyclic lactone resistance in Dirofilaria immitis: failure of heartworm preventives and investigation of genetic markers for resistance. Vet Parasitol. 2015;210:167\u201378.","journal-title":"Vet Parasitol"},{"key":"4767_CR10","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1186\/s13071-014-0494-6","volume":"7","author":"CN Pulaski","year":"2014","unstructured":"Pulaski CN, Malone JB, Bourguinat C, Prichard R, Geary T, Ward DR, et al. Establishment of macrocyclic lactone resistant Dirofilaria immitis isolate in experimentally infected laboratory dogs. Parasit Vectors. 2014;7:494.","journal-title":"Parasit Vectors"},{"key":"4767_CR11","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.vetpar.2014.08.013","volume":"206","author":"CE Atkins","year":"2014","unstructured":"Atkins CE, Murray MJ, Olavessen LJ, Burton KW, Marshall JW, Brooks CC. Heartworm \u2018lack of effectiveness\u2019 claims in the Mississippi delta: computerized analysis of owner compliance \u2013 2004\u20132011. Vet Parasitol. 2014;206:106\u201313.","journal-title":"Vet Parasitol"},{"key":"4767_CR12","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.ijpddr.2019.06.002","volume":"10","author":"RK Prichard","year":"2019","unstructured":"Prichard RK, Geary TG. Perspectives on the utility of moxidectin for the control of parasitic nematodes in the face of developing anthelmintic resistance. Int J Parasitol Drugs Drug Resist. 2019;10:69\u201383.","journal-title":"Int J Parasitol Drugs Drug Resist"},{"key":"4767_CR13","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.vetpar.2011.11.012","volume":"184","author":"B Schnitzler","year":"2012","unstructured":"Schnitzler B, Hayes B, Wiseman S, Snyder DE. Confirmation of the effectiveness of a combination tablet of spinosad and milbemycin oxime against naturally acquired infections of canine intestinal nematode parasites. Vet Parasitol. 2012;184:279\u201383.","journal-title":"Vet Parasitol"},{"key":"4767_CR14","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1016\/j.vetpar.2011.03.034","volume":"180","author":"DE Snyder","year":"2011","unstructured":"Snyder DE, Wiseman S, Bowman DD, McCall JW, Reinemeyer CR. Assessment of the effectiveness of a combination product of spinosad and milbemycin oxime on the prophylaxis of canine heartworm infection. Vet Parasitol. 2011;180:262\u20136.","journal-title":"Vet Parasitol"},{"key":"4767_CR15","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.2460\/javma.252.9.1084","volume":"252","author":"T Grant","year":"2018","unstructured":"Grant T, Wiseman S, Snyder DE. The safety of milbemycin oxime after administration to heartworm positive microfilaremic dogs. JAVMA. 2018;252:1084\u20139.","journal-title":"JAVMA"},{"key":"4767_CR16","doi-asserted-by":"crossref","first-page":"513","DOI":"10.2460\/ajvr.1991.53.04.513","volume":"53","author":"BL Blagburn","year":"1992","unstructured":"Blagburn BL, Hendrix CM, Lindsay DS, Vaughan JL, Hepler DI, Wright JC. Effectiveness of milbemycin oxime against naturally acquired or experimentally induced Ancylostoma spp and Trichurs vulpis infections in dogs. Am J Vet Res. 1992;53:513\u20136.","journal-title":"Am J Vet Res"},{"key":"4767_CR17","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.vetpar.2014.07.023","volume":"205","author":"DD Bowman","year":"2014","unstructured":"Bowman DD, Reinemeyer CR, Wiseman S, Snyder DE. Effectiveness of milbemycin oxime in combination with spinosad in the treatment of larval and immature adult stages of Ancylostoma caninum and Toxocara canis in experimentally infected dogs. Vet Parasitol. 2014;205:134\u20139.","journal-title":"Vet Parasitol"},{"key":"4767_CR18","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1186\/s13071-017-2476-y.19","volume":"10","author":"M Murphy","year":"2017","unstructured":"Murphy M, Garcia R, Karadzovska D, Cavalleri D, Snyder D, Seewald W, et al. Laboratory evaluations of the immediate and sustained effectiveness of lotilaner (CredelioTM) against four common species of ticks affecting dogs in North America. Parasit Vectors. 2017;10:523. https:\/\/doi.org\/10.1186\/s13071-017-2476-y.19.","journal-title":"Parasit Vectors"},{"key":"4767_CR19","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s13071-019-3873-1","volume":"13","author":"L Young","year":"2020","unstructured":"Young L, Karadzovska D, Wiseman S, Helbig R. Effectiveness of lotilaner (CredelioTM) against the adult cat flea, Ctenocephalides felis and flea eggs following oral administration to dogs. Parasit Vectors. 2020;13:25.","journal-title":"Parasit Vectors"},{"key":"4767_CR20","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1186\/s13071-018-2970-x","volume":"11","author":"I Wright","year":"2018","unstructured":"Wright I. Lotilaner - a novel formulation for cats provides systemic tick and flea control. Parasit Vectors. 2018;11:407. https:\/\/doi.org\/10.1186\/s13071-018-2970-x.","journal-title":"Parasit Vectors"},{"key":"4767_CR21","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1186\/s13071-017-2472-2","volume":"10","author":"DE Snyder","year":"2017","unstructured":"Snyder DE, Wiseman S, Liebenberg JE. Effectiveness of lotilaner (CredelioTM), a novel oral isoxazoline against naturally occurring mange mite infestations in dogs caused by Demodex spp. Parasit Vectors. 2017;10:532. https:\/\/doi.org\/10.1186\/s13071-017-2472-2.","journal-title":"Parasit Vectors"},{"key":"4767_CR22","unstructured":"FDA, Guidance for Industry. Good Clinical Practice, VICH GL9. https:\/\/www.fda.gov\/files\/animal%20&%20veterinary\/published\/CVM-GFI--85-(VICH-GL9)-Good-Clinical-Practice.pdf. Accessed 10 Sept 2020."},{"issue":"Suppl. 2","key":"4767_CR23","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1186\/s13071-017-2428-6","volume":"10","author":"K Bourguinat","year":"2017","unstructured":"Bourguinat K, Keller K, Xia J, Lepage P, McTier TL, Woods DJ, et al. Genetic profiles of ten Dirofilaria immitis isolates susceptible or resistant to macrocyclic lactone heartworm preventives. Parasit Vectors. 2017;10(Suppl. 2):504.","journal-title":"Parasit Vectors"},{"key":"4767_CR24","unstructured":"FDA, FOI. NADA 141\u2013321 TRIFEXIS Chewable Tablets for Dogs (Spinosad and Milbemycin oxime). https:\/\/animaldrugsatfda.fda.gov\/adafda\/app\/search\/public\/document\/downloadFoi\/878. Accessed 10 June 2020."},{"key":"4767_CR25","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1136\/vr.161.22.755","volume":"161","author":"K Hubbard","year":"2007","unstructured":"Hubbard K, Skelly BJ, McKelvie J, Wood JLN. Risk of vomiting and diarrhoea in dogs. Vet Rec. 2007;161:755.","journal-title":"Vet Rec"},{"key":"4767_CR26","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/S0165-2427(01)00296-3","volume":"81","author":"A Hillier","year":"2001","unstructured":"Hillier A, Griffin CE. The ACVD task force on canine atopic dermatitis (I): incidence and prevalence. Vet Immunol Immunopathol. 2001;81:147.","journal-title":"Vet Immunol Immunopathol"},{"key":"4767_CR27","unstructured":"The United States Pharmacopeial Convention, Inc. MACROCYCLIC LACTONES (Veterinary\u2014Systemic). https:\/\/cdn.ymaws.com\/www.aavpt.org\/resource\/resmgr\/imported\/macrocyclicLactones.pdf. Accessed 10 June 2020."},{"key":"4767_CR28","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/s13071-017-1986-y","volume":"10","author":"D Cavalleri","year":"2017","unstructured":"Cavalleri D, Murphy M, Seewald W, Drake J, Nanchen S. A randomized, controlled study to assess the effectiveness and safety of lotilaner (CredelioTM) in controlling ticks in client-owned dogs in Europe. Parasit Vectors. 2017;10:53.","journal-title":"Parasit Vectors"},{"key":"4767_CR29","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1186\/s13071-017-2479-8","volume":"10","author":"D Cavalleri","year":"2017","unstructured":"Cavalleri D, Murphy M, Seewald W, Drake J, Nanchen S. A randomised, blinded, controlled field study to assess the effectiveness and safety of lotilaner tablets (CredelioTM) in controlling fleas in client-owned dogs in European countries. Parasit Vectors. 2017;10:526.","journal-title":"Parasit Vectors"},{"key":"4767_CR30","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1186\/s13071-017-2469-x","volume":"10","author":"D Karadzovska","year":"2017","unstructured":"Karadzovska D, Chappell K, Coble S, Murphy M, Cavalleri D, Wiseman S, et al. A randomized, controlled field study to assess the effectiveness and safety of lotilaner flavored chewable tablets (CredelioTM) in eliminating fleas in client-owned dogs in the USA. Parasit Vectors. 2017;10:528.","journal-title":"Parasit Vectors"},{"key":"4767_CR31","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1186\/s13071-017-2468-y","volume":"10","author":"EA Kuntz","year":"2017","unstructured":"Kuntz EA, Kammanadiminti S. Safety evaluation of lotilaner in dogs after oral administration as flavoured chewable tablets (CredelioTM). Parasit Vectors. 2017;10:538.","journal-title":"Parasit Vectors"}],"container-title":["Parasites &amp; Vectors"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13071-021-04767-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13071-021-04767-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13071-021-04767-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,31]],"date-time":"2024-08-31T18:07:18Z","timestamp":1725127638000},"score":1,"resource":{"primary":{"URL":"https:\/\/parasitesandvectors.biomedcentral.com\/articles\/10.1186\/s13071-021-04767-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,28]]},"references-count":31,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["4767"],"URL":"https:\/\/doi.org\/10.1186\/s13071-021-04767-6","relation":{},"ISSN":["1756-3305"],"issn-type":[{"value":"1756-3305","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,28]]},"assertion":[{"value":"3 February 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 May 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 May 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Participating dog owners were required to sign an informed consent form for their dog to participate in the study after details of the study design and products under investigation had been explained.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"These studies were funded by Elanco Animal Health. All authors are current or former employees of Elanco Animal Health. Credelio\u00a0is a trademark of Elanco or its\u00a0affiliates. Sentinel<sup>\u00ae<\/sup> Flavor Tabs<sup>\u00ae<\/sup> is a trademark of Merck. Some of the handling editors have been involved in consulting services (Filipe Dantas-Torres), research projects (Filipe Dantas-Torres, Adnan Hod\u017ei\u0107) and meetings (Filipe Dantas-Torres) sponsored by different veterinary pharmaceutical companies in the past 10 years, including Elanco. They declare that each manuscript in this collection was handled impartially and peer reviewed rigorously by at least two independent external reviewers. The other handling editors (Jeba R J Jesudoss Chelladurai) declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"284"}}