"On 5 June, researchers in the United Kingdom announced the results from the largest trial yet, Recovery, in a press release.
In a group of 1542 hospitalized patients treated with hydroxychloroquine, 25.7% had died after 28 days, compared with 23.5% in a group of 3132 patients who had only received standard care.
“These data convincingly rule out any meaningful mortality benefit,” wrote the investigators, who ended the study early and promised to publish the full results as soon as possible."
"Statement from the Chief Investigators of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial on hydroxychloroquine, 5 June 2020
No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19
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Professor Peter Horby and Professor Martin Landray, chief investigators of the RECOVERY Trial, said
‘In March this year, RECOVERY was established as a randomised clinical trial to test a range of potential drugs for COVID-19, including hydroxycholoroquine.
‘The trial has proceeded at unprecedented speed, enrolling over 11,000 patients from 175 NHS hospitals in the UK. Throughout this time, the independent Data Monitoring Committee has reviewed the emerging data about every two weeks to determine if there is evidence that would be strong enough to affect national and global treatment of COVID-19.
‘On Thursday 4 June, in response to a request from the UK Medicines and Healthcare Products Regulatory Agency (MHRA), the independent Data Monitoring Committee conducted a further review of the data. Last night, the Committee recommended the chief investigators review the unblinded data on the hydroxychloroquine arm of the trial.
'We have concluded that there is no beneficial effect of hydroxychloroquine in patients hospitalised with COVID-19. We have therefore decided to stop enrolling participants to the hydroxychloroquine arm of the RECOVERY trial with immediate effect. We are now releasing the preliminary results as they have important implications for patient care and public health.
‘A total of 1542 patients were randomised to hydroxychloroquine and compared with 3132 patients randomised to usual care alone.
There was no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs. 23.5% usual care; hazard ratio 1.11 [95% confidence interval 0.98-1.26]; p=0.10).
There was also no evidence of beneficial effects on hospital stay duration or other outcomes.
‘These data convincingly rule out any meaningful mortality benefit of hydroxychloroquine in patients hospitalised with COVID-19. Full results will be made available as soon as possible.
Peter Horby, Professor of Emerging Infectious Diseases and Global Health in the Nuffield Department of Medicine, University of Oxford, and Chief Investigator for the trial said:
‘Hydroxychloroquine and chloroquine have received a lot of attention and have been used very widely to treat COVID patients despite the absence of any good evidence.
The RECOVERY trial has shown that hydroxychloroquine is not an effective treatment in patients hospitalised with COVID- 19.
Although it is disappointing that this treatment has been shown to be ineffective, it does allow us to focus care and research on more promising drugs.’
Martin Landray,
Professor of Medicine and Epidemiology at the Nuffield Department of Population Health, University of Oxford, and Deputy Chief Investigator, said
‘There has been huge speculation and uncertainty about the role of hydroxychloroquine as a treatment for COVID-19, but an absence of reliable information from large randomised trials.
Today’s preliminary results from the RECOVERY trial are quite clear – hydroxychloroquine does not reduce the risk of death among hospitalised patients with this new disease.
This result should change medical practice worldwide and demonstrates the importance of large, randomised trials to inform decisions about both the efficacy and the safety of treatments.’
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Notes
Full details of the study protocol and related materials are available at www.recoverytrial.net.
A range of potential treatments have been suggested for COVID-19 but it has been unclear whether any of them will turn out to be more effective in improving survival than the usual standard of hospital care which all patients will receive.
The RECOVERY Trial is a large, randomised controlled trial of possible treatments for patients admitted to hospital with COVID-19. Over 11,000 patients have been randomised to the following treatment arms, or no additional treatment:
Lopinavir-Ritonavir(commonlyusedtotreatHIV)
Low-dose Dexamethasone (a type of steroid, which is used in a range of conditions typically to reduce inflammation)
Hydroxychloroquine (related to an anti-malarial drug)
Azithromycin (a commonly used antibiotic)
Tocilizumab (an anti-inflammatory treatment given by injection)
Convalescent plasma (collected from donors who have recovered from COVID-19 and contains antibodies against the SARS-CoV-2 virus).
For this particular analysis, follow-up is complete for just over 80% of participants. The lower bound of the confidence interval rules out any meaningful benefit.
The RECOVERY trial is conducted by the registered clinical trials units with the Nuffield Department of Population Health in partnership with the Nuffield Department of Medicine.
The trial is supported by a grant to the University of Oxford from UK Research and Innovation/National Institute for Health Research (NIHR) and by core funding provided by
NIHR Oxford Biomedical Research Centre,
Wellcome, the Bill and Melinda Gates Foundation,
the Department for International Development,
Health Data Research UK,
the Medical Research Council Population Health Research Unit, and
NIHR Clinical Trials Unit Support Funding.
The RECOVERY trial involves many thousands of doctors, nurses, pharmacists, and research administrators at 175 NHS Trusts across the whole of the UK, supported by staff at the NIHR Clinical Research Network, Public Health England, Department of Health & Social Care, and the NHS in England, Scotland, Wales and Northern Ireland.
Recovery...DOSE SIZE
“Last week, I was alerted to the fact that India’s ICMR, its official medical research agency, had written to the WHO, telling WHO that the hydroxychloroquine doses being used in the Solidarity trial were 4 times higher than the doses being used in India. Then I learned that Singapore had been hesitant to participate in the WHO trial due to the hydroxychloroquine dose. “
“The HCQ dosing regimen used in the Recovery trial was 12 tablets during the first 24 hours (800mg initial dose, 800 mg six hours later, 400 mg 6 hrs later, 400 mg 6 hours later), then 400 mg every 12 hours for 9 more days. This is 2.4 grams during the first 24 hours, and a cumulative dose of 9.2 grams over 10 days.”
“Even more disturbing than this, babies weighing 5 kg could be given a dose of 300 mg HCQ in the first 24 hours in the Recovery trial, which is 233 mg of the base, nearly 4 times the recommended maximum.”
Hmmm
“Landray also claimed in an interview with Paris Soir that the maximum allowed HCQ dose was “6 or 10 times” the dose used in Recovery, and that he was using the hydroxychloroquine dose that is used for amebic dysentery. However, the accepted use for HCQ in amebiasis is only for a liver abscess and only then in pregnancy, when other drugs cannot be used. That dose is 600 mg per day for 2 days, then 300 mg per day, considerably less than half the Recovery dose. Co-Principal Investigator Peter Horby said “
“We know that in Brazil, both a high HCQ dose and a low HCQ dose were trialed, and by April 17 the high dose arm was stopped prematurely due to an excess of deaths. The high dose arm used 600 mg HCQ twice daily for ten days, with cumulative dose of 12 grams. EKG changes typical of toxicity were seen in 25% of high dose subjects. The low dose trial continues in Brazil.”
“What is a toxic dose? All experts agree. “... chloroquine has a small toxic to therapeutic margin,” according to Goldfrank’s Toxicologic Emergencies.”
“The WHO hired a consultant to explore the toxicity of hydroxychloroquine in 1979. The consultant, H. Weniger, looked at 335 episodes of adult poisoning by chloroquine drugs. Weniger on page 5 notes that a single dose of 1.5-2 grams of hydroxychloroquine base “may be fatal.”
The Recovery trial used 1.86 grams hydroxychloroquine base (equal to 2400 mg of hydroxychloroquine) in the first 24 hours for treatment of already very ill, hospitalized Covid-19 patients, a potentially lethal dose. “