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 Sobngwi, Sylvain Zemsi, Magellan Guewo-Fokeng, Jean-Claude Katte, Charles Kounfack, Liliane Mfeukeu-Kuate, Armel Zemsi, Yves Wasnyo, Antoinette Assiga Ntsama, Arnaud Ndi-Manga, Joelle Sobngwi-Tambekou, William Ngatchou, Charlotte Moussi Omgba, Jean Claude Mbanya, Pierre Ongolo Zogo, Pierre Joseph Fouda
doi:10.1101/2021.07.25.21260838
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 COVID-19 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 were asymptomatic. SARS-CoV2 PCR was negative at Day 10 in 60/92 (65.2%) participants allocated to Doxycycline and 63/95 (66.3%) participants allocated to Hydroxychloroquine-Azithromycin. None of the participants were admitted for worsening of the disease after treatment initiation.
Conclusion: Doxycycline 100 mg twice daily for 7 days is as effective and safe as Hydroxychloroquine-Azithromycin, for preventing clinical worsening of mild symptomatic or asymptomatic COVID-19, and achieving virological suppression.
Patient consent
Obtained
Competing interests The authors declare no competing interests
Ethical approval The study received ethical clearance from the Cameroon National Ethics Committee (N° 2020/07/1585/L/CNERSH/SP). The trial was prospectively registered on ClinicalTrials.gov under number NCT04715295.
Author Contribution Statement Contributors: E-S designed the work, acquired funding, implemented the trial, monitored data collection for the whole trial, monitored statistical analysis, drafted the paper, revised the paper and gave final approval to be published. S-Z designed the work, implemented the trial, monitored data collection, wrote the statistical analysis plan, cleaned and analyzed the data, drafted and revised the paper. M-GF designed the work, revised the draft paper. JC-K designed the work, revised the draft paper. CK member of the data safety monitoring board. LM-K member of the data safety monitoring board. AZ designed the work. YW .
References
Abena, Decloedt, Bottieau, Suleman, Adejumo et al., Chloroquine and Hydroxychloroquine for the Prevention or Treatment of COVID-19 in Africa: Caution for Inappropriate Off-label Use in Healthcare Settings, Am J Trop Med Hyg. juin
Alam, Mahmud, Rahman, Simpson, Aggarwal et al., Clinical Outcomes of Early Treatment With Doxycycline for 89 High-Risk COVID-19 Patients in Long-Term Care Facilities in New York, Cureus
Bowie, Effective treatment of urethritis. A practical guide, Drugs. août
Gautret, Lagier, Parola, Hoang, Meddeb et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int J Antimicrob Agents. juill
Henehan, Montuno, Benedetto, Doxycycline as an anti-inflammatory agent: updates in dermatology, J Eur Acad Dermatol Venereol. nov
Hopkins, Coronavirus and COVID-19: Younger Adults Are at Risk, Too
Lu, Cochran-Mantel, -Haenszel Weighted Miettinen & Nurminen Method for Confidence Intervals of the Difference in Binomial Proportions from Stratified 2x2 Samples
Malek, Granwehr, Kontoyiannis, Doxycycline as a potential partner of COVID-19 therapies, IDCases
Mercuro, Yen, Shim, Maher, Mccoy et al., Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19), JAMA Cardiol
Mfeukeu-Kuate, Ngatchou, Temgoua, Kouanfack, Lemoungoum et al., Electrocardiographic Safety of Daily Hydroxychloroquine 400 mg Plus Azithromycin 250 mg as an Ambulatory Treatment for COVID-19 Patients in Cameroon, World Journal of Cardiovascular Diseases
Molina, Delaugerre, Goff, Lima, Ponscarme et al., No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection, Med Mal Infect. juin
Nelson, Levy, The history of the tetracyclines, Ann N Y Acad Sci
Rothan, Paydar, Rahman, Yusof, Inhibitory effect of doxycycline against dengue virus replication in vitro, Arch Virol. avr
Skipper, Pastick, Engen, Bangdiwala, Abassi et al., Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19, Ann Intern Med [Online
Tarighi, Eftekhari, Chizari, Sabernavaei, Jafari et al., A review of potential suggested drugs for coronavirus disease (COVID-19) treatment, European Journal of Pharmacology
Wang, Zhou, Zhang, Zhao, Du et al., Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial, Trials
Wilcox, Covington, Paez, Doxycycline as a modulator of inflammation in chronic wounds, Wounds. déc
Zhang, Cao, Tan, Dong, Wang et al., Clinical, radiological and laboratory characteristics and risk factors for severity and mortality of 289 hospitalized COVID-19 patients, Allergy