Abstract: www.nature.com/scientificreports
OPEN
The PRINCIPLE randomised
controlled open label platform trial
of hydroxychloroquine for treating
COVID19 in community based
patients at high risk
F. D. Richard Hobbs1, Jienchi Dorward1, Gail Hayward1, Ly-Mee Yu1, Benjamin R. Saville2,3,
Christopher C. Butler1 on behalf of the PRINCIPLE Investigators
Early on in the COVID-19 pandemic, we aimed to assess the effectiveness of hydroxychloroquine
on reducing the need for hospital admission in patients in the community at higher risk of
complications from COVID-19 syndromic illness (testing was largely unavailable at the time, hence
not microbiologically confirmed SARS-CoV-2 infection), as part of the national open-label, multi-arm,
prospective, adaptive platform, randomised clinical trial in community care in the United Kingdom
(UK). People aged 65 and over, or aged 50 and over with comorbidities, and who had been unwell
for up to 14 days with suspected COVID-19 were randomised to usual care with the addition of
hydroxychloroquine, 200 mg twice a day for seven days, or usual care without hydroxychloroquine
(control). Participants were recruited based on symptoms and approximately 5% had confirmed
SARS-COV2 infection. The primary outcome while hydroxychloroquine was in the trial was hospital
admission or death related to suspected COVID-19 infection within 28 days from randomisation.
First recruitment was on April 2, 2020, and the hydroxychloroquine arm was suspended by the UK
Medicines Regulator on May 22, 2020. 207 were randomised to hydroxychloroquine and 206 to usual
care, and 190 and 194 contributed to the primary analysis results presented, respectively. There
was no swab result available within 28 days of randomisation for 39% in both groups: 107 (54%)
in the hydroxychloroquine group and 111 (55%) in the usual care group tested negative for SARSCov-2, and 13 (7%) and 11 (5%) tested positive. 13 participants, (seven (3·7%) in the usual care plus
hydroxychloroquine and six (3.1%) in the usual care group were hospitalized (odds ratio 1·04 [95% BCI
0·36 to 3.00], probability of superiority 0·47). There was one serious adverse event, in the usual care
group. More people receiving hydroxychloroquine reported nausea. We found no evidence from this
treatment arm of the PRINCIPLE trial, stopped early and therefore under-powered for reasons external
to the trial, that hydroxychloroquine reduced hospital admission or death in people with suspected,
but mostly unconfirmed COVID-19.
Keywords Primary health care, SARS-COV-2, Serious COVID, Repurposed medicines, Hydroxychloroquine
Hydroxychloroquine for treating COVID-19 was widely promoted early on in the pandemic and over 100
trials evaluating hydroxychloroquine were quickly registered. This was supported by in vitro studies that
found hydroxychloroquine has anti SARS-CoV-2 activity, although some data was later questioned1,2. Various
mechanisms of action have been suggested, including a hydroxychloroquine induced reduction in the
glycosylation of host cell surface enzymes preventing viral attachment3, and inhibition of the production of certain
pro-inflammatory cytokines that are mediators of acute respiratory distress syndrome4. Hydroxychloroquine is
generally safe and well tolerated5,6, cheap and widely available. If effective in speeding recovery and preventing
1Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK. 2Berry Consultants,
Austin, TX, USA. 3Department of..
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:p>Early on in the COVID-19 pandemic, we aimed to assess the effectiveness of hydroxychloroquine on reducing the need for hospital admission in patients in the community at higher risk of complications from COVID-19 syndromic illness (testing was largely unavailable at the time, hence not microbiologically confirmed SARS-CoV-2 infection), as part of the national open-label, multi-arm, prospective, adaptive platform, randomised clinical trial in community care in the United Kingdom (UK). People aged 65 and over, or aged 50 and over with comorbidities, and who had been unwell for up to 14 days with suspected COVID-19 were randomised to usual care with the addition of hydroxychloroquine, 200 mg twice a day for seven days, or usual care without hydroxychloroquine (control). Participants were recruited based on symptoms and approximately 5% had confirmed SARS-COV2 infection. The primary outcome while hydroxychloroquine was in the trial was hospital admission or death related to suspected COVID-19 infection within 28 days from randomisation. First recruitment was on April 2, 2020, and the hydroxychloroquine arm was suspended by the UK Medicines Regulator on May 22, 2020. 207 were randomised to hydroxychloroquine and 206 to usual care, and 190 and 194 contributed to the primary analysis results presented, respectively. There was no swab result available within 28 days of randomisation for 39% in both groups: 107 (54%) in the hydroxychloroquine group and 111 (55%) in the usual care group tested negative for SARS-Cov-2, and 13 (7%) and 11 (5%) tested positive. 13 participants, (seven (3·7%) in the usual care plus hydroxychloroquine and six (3.1%) in the usual care group were hospitalized (odds ratio 1·04 [95% BCI 0·36 to 3.00], probability of superiority 0·47). There was one serious adverse event, in the usual care group. More people receiving hydroxychloroquine reported nausea. We found no evidence from this treatment arm of the PRINCIPLE trial, stopped early and therefore under-powered for reasons external to the trial, that hydroxychloroquine reduced hospital admission or death in people with suspected, but mostly unconfirmed COVID-19.</jats:p>",
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