Safety and Efficacy of Hydroxychloroquine for Treatment of Non-Severe COVID-19 in Adults in Uganda: A Randomized Open Label Phase II Clinical Trial
Pauline Byakika-Kibwika, Christine Sekaggya-Wiltshire, Jerome Roy Semakula, Jane Nakibuuka, Joseph Musaazi, James Kayima, Cornelius Sendagire, David Meya, Bruce Kirenga, Sarah Nanzigu, Arthur Kwizera, Fred Nakwagala, Ivan Kisuule, Misaki Wayengera, Henry G Mwebesa, Moses Kamya, William Bazeyo
doi:10.21203/rs.3.rs-506195/v1
Background Several repurposed drugs such as hydroxychloroquine (HCQ) have been investigated for treatment of COVID-19, but none was con rmed to be e cacious. While in vitro studies have demonstrated antiviral properties of HCQ, data from clinical trials were con icting regarding its bene t for COVID-19 treatment. Drugs that limit viral replication may be bene cial in the earlier course of the disease thus slowing progression to severe and critical illness.
Design We conducted a randomized open label Phase II clinical trial from October -December 2020.
Methods Patients diagnosed with COVID-19 using RT-PCR were included in the study if they were 18 years and above and had a diagnosis of COVID-19 made in the last 3 days. Patients were randomized in blocks, to receive either HCQ 400mg twice a day for the rst day followed by 200mg twice daily for the next 4 days plus standard of care (SOC) treatment or SOC treatment alone. SARS COV-2 viral load using nasal/orapharyngeal swabs was performed at baseline, day 2, 4, 6, 8 and 10. The primary outcome was median time from randomization to SARS COV-2 viral clearance by day 6.
Results Of the 105 participants enrolled, 55 were assigned to the intervention group (HCQ plus SOC) and 50 to the control group (SOC only). Baseline characteristics were similar across treatment arms. Viral clearance did not differ by treatment arm, 20 and 19 participants respectively had SARS COV-2 viral load clearance by day 6 with no signi cant difference, median (IQR) number of days to viral load clearance between the two groups was 4(3-4) vs 4(2-4): p=0.457. There were no signi cant differences in secondary outcomes (symptom resolution and adverse events) between the intervention group and the control group. There were no signi cant differences in speci c adverse events such as elevated alkaline phosphatase, prolonged QTc interval on ECG, among patients in the intervention group as compared to the control group.
Conclusion Our results show that HCQ 400mg twice a day for the rst day followed by 200mg twice daily for the next 4 days was safe but not associated with reduction in viral clearance or symptom resolution.
Table 3: Baseline clinical and laboratory features There were no signi cant differences in adverse events such as elevated alkaline phosphatase and prolonged QTc interval among patients in the intervention group and control group. Details of clinically signi cant laboratory abnormalities are as shown in Table 6 . (RESCLEAR/05) and the National Drug Authority (CTA 0143). Written informed consent was obtained from all study participants and the trial was conducted according to Good Clinical Practice Guidelines in accordance with the Declaration of Helsinki.
Consent for publication
Not applicable Competing interests: The authors declare no con ict of interest for this work.
Authors' contributions All authors made substantial contributions to trial conception and design. PBK and CSW led the data collection team, JM performed the data analysis. All authors reviewed and interpreted the data, took part in drafting and review of the manuscript and agreed to submit to the current journal; gave nal approval of the version to be published; and agree to be accountable for all aspects of the work.
References
Abella, Jolkovsky, Biney, E cacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical Trial, JAMA Intern Med,
doi:10.1001/jamainternmed.2020.6319Barnabas, Brown, Bershteyn, Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection : A Randomized Trial, Ann Intern Med,
doi:10.7326/M20-6519Boulware, Pullen, Bangdiwala, A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2016638Cavalcanti, Zampieri, Rosa, Hydroxychloroquine with or without Azithromycin in Mildto-Moderate Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2019014Chen, Liu, Liu, A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19
Consortium, Whost, Pan, Peto, Repurposed Antiviral Drugs for Covid-19 -Interim WHO Solidarity Trial Results, N Engl J Med,
doi:10.1056/NEJMoa2023184De Wilde, Jochmans, Posthuma, Screening of an FDA-approved compound library identi es four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture, Antimicrob Agents Chemother,
doi:10.1128/AAC.03011-14Dhibar, Arora, Kakkar, Post-exposure prophylaxis with hydroxychloroquine for the prevention of COVID-19, a myth or a reality? The PEP-CQ Study, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2020.106224Fantini, Scala, Chahinian, Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2020.105960Food, Request for Emergency Use Authorization For Use of Chloroquine Phosphate or Hydroxychloroquine Sulfate
Gautret, Lagier, Parola, Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2020.105949Ghazy, Almaghraby, Shaaban, A systematic review and meta-analysis on chloroquine and hydroxychloroquine as monotherapy or combined with azithromycin in COVID-19 treatment, Sci Rep,
doi:10.1038/s41598-020-77748-xHamid, Abid, Amir, Current burden on healthcare systems in low-and middle-income countries: recommendations for emergency care of COVID-19, Drugs Ther Perspect,
doi:10.1007/s40267-020-00766-2Kaptein, Jacobs, Langendries, Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity, Proc Natl Acad Sci U S A,
doi:10.1073/pnas.2014441117Kashour, Riaz, Garbati, E cacy of chloroquine or hydroxychloroquine in COVID-19 patients: a systematic review and meta-analysis, J Antimicrob Chemother,
doi:10.1093/jac/dkaa403Keyaerts, Vijgen, Maes, In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine, Biochem Biophys Res Commun,
doi:10.1016/j.bbrc.2004.08.085Kirenga, Muttamba, Kayongo, Characteristics and outcomes of admitted patients infected with SARS-CoV-2 in Uganda, BMJ Open Respir Res,
doi:10.1136/bmjresp-2020-000646Liu, Cao, Xu, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov,
doi:10.1038/s41421-020-0156-0Ma, Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases, J Antimicrob Chemother,
doi:10.1093/jac/dkv018Mallat, Hamed, Balkis, Hydroxychloroquine is associated with slower viral clearance in clinical COVID-19 patients with mild to moderate disease, Medicine,
doi:10.1097/MD.0000000000023720Mitja, Corbacho-Monne, Ubals, A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2021801Rajasingham, Bangdiwala, Nicol, Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial, medRxiv,
doi:10.1101/2020.09.18.20197327Srinivasa, Tosounidou, Gordon, Increased Incidence of Gastrointestinal Side Effects in Patients Taking Hydroxychloroquine: A Brand-related Issue?, J Rheumatol,
doi:10.3899/jrheum.161063Tang, Cao, Han, Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial, BMJ,
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'abstract': '<jats:title>Abstract</jats:title>\n'
' <jats:p><jats:bold>Background</jats:bold>Several repurposed drugs such as '
'hydroxychloroquine (HCQ) have been investigated for treatment of COVID-19, but none was '
'confirmed to be efficacious. While in vitro studies have demonstrated antiviral properties of '
'HCQ, data from clinical trials were conflicting regarding its benefit for COVID-19 treatment. '
'Drugs that limit viral replication may be beneficial in the earlier course of the disease '
'thus slowing progression to severe and critical illness. <jats:bold>Design</jats:bold>We '
'conducted a randomized open label Phase II clinical trial from October -December '
'2020.<jats:bold>Methods</jats:bold>Patients diagnosed with COVID-19 using RT-PCR were '
'included in the study if they were 18 years and above and had a diagnosis of COVID-19 made in '
'the last 3 days. Patients were randomized in blocks, to receive either HCQ 400mg twice a day '
'for the first day followed by 200mg twice daily for the next 4 days plus standard of care '
'(SOC) treatment or SOC treatment alone. SARS COV-2 viral load using nasal/orapharyngeal swabs '
'was performed at baseline, day 2, 4, 6, 8 and 10. The primary outcome was median time from '
'randomization to SARS COV-2 viral clearance by day 6.<jats:bold>Results</jats:bold>Of the 105 '
'participants enrolled, 55 were assigned to the intervention group (HCQ plus SOC) and 50 to '
'the control group (SOC only). Baseline characteristics were similar across treatment arms. '
'Viral clearance did not differ by treatment arm, 20 and 19 participants respectively had SARS '
'COV-2 viral load clearance by day 6 with no significant difference, median (IQR) number of '
'days to viral load clearance between the two groups was 4(3-4) vs 4(2-4): p=0.457. There were '
'no significant differences in secondary outcomes (symptom resolution and adverse events) '
'between the intervention group and the control group. There were no significant differences '
'in specific adverse events such as elevated alkaline phosphatase, prolonged QTc interval on '
'ECG, among patients in the intervention group as compared to the control '
'group.<jats:bold>Conclusion</jats:bold>Our results show that HCQ 400mg twice a day for the '
'first day followed by 200mg twice daily for the next 4 days was safe but not associated with '
'reduction in viral clearance or symptom resolution. <jats:bold>Trial registration: '
'</jats:bold>NCT04860284</jats:p>',
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