Abstract: medRxiv preprint doi: https://doi.org/10.1101/2021.07.25.21260838; this version posted July 29, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . Doxycycline is a safe alternative to Hydroxychloroquine + Azithromycin to prevent clinical worsening and hospitalization in mild COVID-19 patients: An open label randomized clinical trial (DOXYCOV) Eugene Sobngwi1,2,3,4, Sylvain Zemsi1,3, Magellan Guewo-Fokeng2,3,4, Jean-Claude Katte2,3, Charles Kounfack1,5, Liliane Mfeukeu-Kuate1,2, Armel Zemsi1, Yves Wasnyo1,3, Antoinette Assiga Ntsama1, Arnaud Ndi-Manga1,3, Joelle Sobngwi-Tambekou3, William Ngatchou6, Charlotte Moussi Omgba7, Jean Claude Mbanya1,2,4, Pierre Ongolo Zogo1,2,8, Pierre Joseph Fouda1,2 1 Yaounde Central Hospital, Yaounde, Cameroon 2 Faculty of Medicine and Biomedical Sciences, University of Yaounde 1, Yaounde, Cameroon 3 RSD Institute, Yaounde, Cameroon 4 The Biotechnology Centre, University of Yaounde 1, Yaounde, Cameroon 5 Faculty of Medicine and Pharmaceutical Sciences, University of Dschang, Dschang, Cameroon 6 Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Douala, Cameroon 7 Regional Delegation of Public Health, Centre Region, Ministry of Public Health, Cameroon 8 Center for the Development of Good Practices in Health, Yaounde, Cameroon Corresponding author Prof. Eugene Sobngwi Department of Internal Medicine and Specialities, Faculty of Medicine and Biomedical Sciences, University of Yaounde 1, Yaounde, Cameroon Yaounde Central Hospital, and RSD Institute, Yaounde, Cameroon Email: eugene.sobngwi@fmsb-uy1.cm Tel : 675088750 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2021.07.25.21260838; this version posted July 29, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . Abstract Objective: We aimed to compare the safety and efficacy of a doxycycline-based regimen against the national standard guidelines (Hydroxychloroquine plus Azithromycin) for the treatment of mild symptomatic COVID-19. Methods: We conducted an open-label, randomized, non-inferiority trial, in Cameroon comparing Doxycycline 100mg, twice daily for 7 days versus Hydroxychloroquine, 400 mg daily for 5 days and Azithromycin 500mg at day 1 and 250mg from day 2 through 5, in mild COVID19 patients. Clinical improvement, biological parameters and adverse events were assessed. The primary outcome was the proportion of clinical cure at day 3, 10 and 30. Non-inferiority was determined by the clinical cure rate between protocols with a 20 percentage points margin. Results: 194 participants underwent randomization and were treated with Doxycycline (n=97) or Hydroxychloroquine-Azithromycin (n=97). At day 3, 74/92 (80.4%) participants on Doxycycline versus 77/95 (81.1%) on Hydroxychloroquine-Azithromycin -based protocols were asymptomatic (p=0.91). At day 10, 88/92 (95.7%) participants on Doxycycline versus 93/95 (97.9%) on Hydroxychloroquine-Azithromycin were asymptomatic (p=0.44). At day 30 all participants..