Chloroquine, other approaches

“Solidarity” clinical trial for COVID-19 treatments

https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments

“Solidarity” is an international clinical trial to help find an effective treatment for COVID-19, launched by the World Health Organization and partners.

The Solidarity trial will compare four treatment options against standard of care, to assess their relative effectiveness against COVID-19. By enrolling patients in multiple countries, the Solidarity trial aims to rapidly discover whether any of the drugs slow disease progression or improve survival. Other drugs can be added based on emerging evidence.

Until there is sufficient evidence, WHO cautions against physicians and medical associations recommending or administering these unproven treatments to patients with COVID-19 or people self-medicating with them. WHO is concerned by reports of individuals self-medicating with chloroquine and causing themselves serious harm. WHO guidance on compassionate use can be found here.

Key Links
Landscape analysis of therapeutics

21 March 2020

18 March 2020
WHO Director-General’s opening remarks at the media briefing on COVID-19 – 18 March 2020
Rationale
The pressure COVID-19 puts on health systems means that WHO considered the need for speed and scale in the trial. While randomized clinical trials normally take years to design and conduct, the Solidarity trial will reduce the time taken by 80%.

Enrolling patients in one single randomized trial will help facilitate the rapid worldwide comparison of unproven treatments. This will overcome the risk of multiple small trials not generating the strong evidence needed to determine the relative effectiveness of potential treatments.

Participation in Solidarity
The Solidarity trial provides simplified procedures to enable even overloaded hospitals to participate, with no paperwork required. As of March 27 2020, over 70 countries have already confirmed they will contribute to the trial, with many others in the process of joining.

The greater the number of participating countries, the faster results will be generated. WHO is facilitating access to thousands of treatment courses for the trial through donations from a number of manufacturers. WHO is also inviting developers and companies to collaborate on ensuring affordability and availability of the treatment options if they prove effective.

Treatment options under study
Based on evidence from laboratory, animal and clinical studies, the following treatment options were selected: Remdesivir; Lopinavir/Ritonavir; Lopinavir/Ritonavir with Interferon beta-1a; and Chloroquine or Hydroxychloroquine.

Remdesivir was previously tested as an Ebola treatment. It has generated promising results in animal studies for Middle East Respiratory Syndrome (MERS-CoV) and severe acute respiratory syndrome (SARS), which are also caused by coronaviruses, suggesting it may have some effect in patients with COVID-19.

Lopinavir/Ritonavir is a licensed treatment for HIV. Evidence for COVID-19, MERS and SARS is yet to show it can improve clinical outcomes or prevent infection. This trial aims to identify and confirm any benefit for COVID-19 patients. While there are indications from laboratory experiments that this combination may be effective against COVID-19, studies done so far in COVID-19 patients have been inconclusive.

Interferon beta-1a is used to treat multiple sclerosis.

Chloroquine and hydroxychloroquine are very closely related and used to treat malaria and rheumatology conditions respectively. In China and France, small studies provided some indications of possible benefit of chloroquine phosphate against pneumonia caused by COVID-19 but need confirmation through randomized trials.

Support for Solidarity
“The quest for knowledge about the coronavirus is a global effort. The Solidarity trial is an import part of the puzzle. I am proud that Norway will contribute both by having the first patient included in the study. I would like to commend the WHO for the global leadership and its initiative in setting up the Solidarity trial.”

– Bent Høie, Minister of Health and Care Services, Norway

“There is only one way the world can exit this pandemic – and that is through science. We need diagnostics to detect and limit the spread of this virus, vaccines to provide long-term protection, treatments to save lives in the shorter-term and social science to understand the behavioural and societal implications. It’s critical that the global research effort is rapid, robust and is conducted at scale and co-ordinated across multiple countries. The World Health Organization’s Solidarity trial will provide this by testing existing and new drugs to treat COVID-19 and ensure equitable access to any drugs that prove effective. The start of these clinical trials is hugely important and an incredible achievement. Global powers must now step-up to ensure the WHO has all the support needed.”

– Dr Jeremy Farrar, Director of Wellcome and Chair of the WHO R&D Blueprint Scientific Advisory Group

How the Solidarity trial works
Adults with COVID-19 admitted to participant hospitals can join this study. Eligible patients will be asked to sign to show they understand the possible risks and benefits and consent to joining the study. The medical team responsible for each patient will check whether any of the study treatments would definitely be unsuitable.

After those checks, brief identifying details and any other conditions are digitally recorded for the patient, who is then randomly allocated to one of the study options. This may or may not involve one of the study treatments. Neither the patient nor the medical staff choose which of the study options a patient will receive, as a computer makes this allocation at random.

Critical anonymized information for the trial will only be collected at the randomization stage and when the patient is discharged or dies: which study drugs were given (and for how many days); whether ventilation or intensive care was received (and, if so, when it began), date of discharge, or date and cause of death while still in hospital.

Interim trial analyses are monitored by a Global Data and Safety Monitoring Committee, which is an independent group of experts.

Countries, or particular groups of hospitals, may want to collaborate in making further serial measurements or observations, relating to areas such as virology, blood gases or chemistry and lung imaging. It also possible to incorporate documentation of other aspects of disease status, for example, through linking in electronic healthcare records and routine medical databases. While well-organised additional research studies of the natural history of the disease or of the effects of the trial treatments could well be valuable, they are not core requirements.

Adults (age ≥18 years) recently hospitalised, or already in hospital, with confirmed COVID-19 and, in the view of the responsible doctor, no contra-indication to any of the study treatments will be randomly allocated between

● Local standard of care,

OR local standard of care plus one of

● Remdesivir

● Chloroquine or Hydroxychloroquine

● Lopinavir with Ritonavir

● Lopinavir with Ritonavir plus Interferon beta-1a.

Underlying conditions recorded are: diabetes, heart disease, chronic lung disease, chronic liver disease and asthma, extending to HIV and tuberculosis in the African region.

Severity of illness at entry is determined by recording: shortness of breath, being given oxygen, already on a ventilator, and, if lungs imaged, major bilateral abnormality.

Heated disagreement breaks out in Situation Room over hydroxychloroquine
CNN Digital Expansion 2017 Jim AcostaKaitlan Collins byline

https://www.cnn.com/2020/04/05/politics/white-house-malaria-drug-hydroxychloroquine-disagreement/index.html

(CNN)There was a heated disagreement in the Situation Room this weekend over the efficacy of the anti-malaria drug hydroxychloroquine — but multiple sources say it was mostly one-sided, as President Donald Trump’s top trade adviser Peter Navarro feuded with other officials over the drug’s unproven effectiveness to treat coronavirus.

The debate is not a new one inside the coronavirus task force — and medical experts have repeatedly explained to the President that there is a risk in enthusiastically touting hydroxychloroquine in case the drug doesn’t ultimately work to combat the virus. But other aides and outside advisers have sided with Trump, including Navarro, who is still not a formal part of the task force but has wedged himself into the meetings.
Axios first reported on the disagreement inside the White House about the drug.
While discussing the latest on hydroxychloroquine this weekend, an exasperated Navarro lashed out at Dr. Anthony Fauci, one of the advisers who has urged caution about the drug, a person familiar with the meeting told CNN.
Navarro had brought a stack of paperwork with him into the Situation Room on the drug, arguing it was proof that it could work to treat coronavirus, which Fauci, the nation’s top infectious disease expert, disagreed with because it was not data.
“What are you talking about?” Fauci asked — a question that set Navarro off. He became indignant, and at one point, accused Fauci of opposing Trump’s travel restrictions on China, which confused many in the room, given Fauci was one of the initial few to agree with Trump on the move, the source said.

A source close to the task force said Fauci is not backing off of his belief that hydroxychloroquine is not a proven treatment for coronavirus. When CNN’s Jeremy Diamond asked Fauci to comment on the matter Sunday night, Trump stepped in and didn’t allow Fauci to answer. But a source said the doctor has already offered his opinion on the drug in other venues and would continue to do so.
Several aides later said they were unfazed by Navarro’s outburst, given he has them regularly. But the argument highlights how deep the divide runs over the task force’s response to the coronavirus pandemic.
Another source told CNN that despite the disagreement in the Situation Room between Fauci and Navarro, Fauci continues to have a good relationship with Trump and Pence, though some staffers have shown irritation when his opinions differ.

BTW there’s a lot of misleading info out there in the right-wing media about treatments and the data regarding them. The 2nd quotation here is from a great article.

1.

. https://www.statnews.com/2020/04/06/trump-hydroxychloroquine-fact-check/

In press releases, the FDA has stressed that “there are no currently approved treatments for COVID-19.” However, the agency says both hydroxychloroquine and chloroquine phosphate “have shown activity in laboratory studies against coronaviruses,” referring to a broad category of illnesses known as coronaviruses, not the 2019 strain that causes Covid-19. A number of federal agencies are currently working to facilitate clinical trials to determine whether or not the drug is effective.

2.

. https://rantt.com/right-wing-media-misrepresents-hydroxychloroquine-poll

The Post incorrectly reported: “Of the 6,227 physicians surveyed in 30 countries, 37 percent rated hydroxychloroquine the ‘most effective therapy’ for combating the potentially deadly illness, according to the results released Thursday.”

A press release from Sermo, the company that conducted the survey, said: “Hydroxychloroquine was overall chosen as the most effective therapy amongst COVID-19 treaters.”

The Sermo survey shows that the subgroup of COVID-19 treaters is 2171 — not 6227, as multiple news outlets have since reported.

This is a study from @waynestate, by the way, the university where I'm faculty. It's not truly randomized, but it is depressing. It suggests that, instead of benefiting #COVID19 patients, #Hydroxychloroquine might well cause harm. At the very least, this study shows zero benefit. https://t.co/DC6Shyhd7N

— David Gorski, MD, PhD (@gorskon) April 11, 2020

Link: https://theness.com/neurologicablog/index.php/hydroxychloroquine-not-looking-good-for-covid-19/

We have been tracking the story of the hype surrounding hydroxychloroquine over at Science-Based Medicine, but there is a brief follow up I wanted to comment on. The short version of the story so far is that one very bad French study claimed to show dramatic reduction in detected virus in those treated. This study, however, was not only preliminary, it was a horrible study, so much so that the results are uninterpretable. The big problem was that it did not count patients who became too sick or died. That is a classic way to make a treatment look better than it is. The author is also a climate change denier who initially mocked China for taking steps to mitigate Covid-19. He does not exactly have street cred within the scientific community.

But that one horrible study from a sketchy researcher was enough to spark media hype, at least in certain circles, and capture the attention of a president apparently desperate to make this problem go away. Amid the fear of a pandemic, that was a toxic combination. The notion that hydroxychloroquine (with our without the antibiotic, azythromycin) might fight the SARS-Cov2 virus is not implausible. But most things in medicine that are “not implausible” don’t work out. We need high quality clinical science to ultimately tell.

The big question always is – what is the risk vs benefit? Hydroxychloroquine and Azythromycin both have the same potentially deadly side effect, prolonging the QT interval of the heart, which increases the risk for sudden cardiac death. This is a manageable side effect in the right setting, but is potentially serious. This is not a good drug or combination to be taking just on the chance it might help.

The entire episode is a good reason to remind everyone why science-based medicine is so important, the nature of clinical research, and the pitfalls of falling for preliminary data. After that initial terrible study there were two more preliminary studies, the kind that are done to see if there is any potential for the treatment that deserves more rigorous study. An open-label study in China found no benefit from hydroxychloroquine. There was also a French study attempting to replicate the results of the original study, and could not. They also found no benefit from the drug – no reduction in the virus, directly contradicting the original study.

But perhaps most devastating is the most recent study to show results – this was a VA retrospective study comparing patients treated with hydroxychloroquine, hydroxychloroquine + azithromycin, and just usual care. They found no benefit on any measure for those treated with the drugs. However, those treated with the drugs were twice as likely to die:

Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively.

That is a huge red flag, the kind of preliminary finding that could kill the prospects for a new drug. That is exactly the reason that small preliminary studies are done, to make sure the treatment isn’t killing people before doing a larger study. Even these results are not the final word, however. This is a retrospective study, which means subjects were not randomized. It is therefore possible that sicker patients were given the drugs, for example. But we can look at all the preliminary data we have so far and conclude that it’s not looking good for the prospects of hydroxychloroquine as a treatment for Covid-19. Further, this drug has a serious potential side effect that may actually increase the risk of death for those given the treatment.

Certainly, this is not the stage when this drug or combination should be hyped or recommended. It is nothing less than dangerously reckless to do so. Further, hydroxychloroquine is a proven treatment for some autoimmune diseases, like Lupus, and some patients who rely it are finding it difficult to get the drug because demand has spiked due to the hype. It’s pretty much a lose-lose all around.

At this point we do need a double-blind randomized placebo controlled trial of hydroxychloroquine in Covid-19 to get some rigorous evidence. One solid negative trial, however, should end it. If the results are promising, then further study should be done. There would be many finer questions about dose, who should get the drug, who should not get it, etc. But at this point the odds are in favor of this treatment not working out, and in fact being harmful. No one should be taking this drug for Covid-19 outside an approved clinical trial.