Six months after the World Health Organisation received the first reports of a cluster of cases of pneumonia of unknown cause in China, the Covid-19 pandemic has claimed over 500,000 lives worldwide and over 17,000 in India. The hard reality, the WHO said, is that the pandemic is nowhere close to being over. With a vaccine still at least months away, the focus is on a few treatments that have shown encouraging results in clinical trials.
In an interview with Scroll.in, Dr SP Kalantri, Professor of Medicine and Medical Superintendent at the Mahatma Gandhi Institute of Medical Sciences, Sevagram, Maharashtra, unpacked the mammoth effort underway globally. He spoke about drugs that look promising, those that were merely hype, and why the Patanjali drug trial is a textbook example of how a study should not be conducted.
What are repurposed drugs? Are all of the ongoing clinical trials being done on already approved drugs that are being repurposed to treat Covid-19?
Yes, all the drugs in the ongoing or completed clinical trials are repurposed drugs: for example, hydroxychloroquine, chloroquine, remdesivir, dexamethasone, Lopinavir-ritonavir, and convalescent plasma.
Repurposed drugs, also called off-label agents, are ones that have been found to be effective for other diseases and are likely to be effective for Covid-19.
For most of these agents, there is insufficient data to know whether they have any role in treatment of Covid-19. Such agents are only to be used in the setting of a clinical trial. When used outside the context of a clinical trial, their use is governed by MEURI guidelines (Monitored Emergency Use of Unregistered and Investigational drugs).
Developing new drugs is a lengthy process. Drug repurposing means the safety profile of the medicine is established and therefore shorter time is taken for the trial process. Is that correct?
As no drug is available to treat Covid19, a life-threatening disease, and the death rate is significantly high, physicians and scientists are looking at using the concept of drug repurposing.
What is a randomised control trial?
The randomised control trial is a trial in which subjects are randomly assigned to one of two groups: one (the experimental group) receiving the intervention that is being tested, and the other (the comparison group or control) receiving an alternative (conventional) treatment.
The two groups are then followed up to see if there are any differences between them in outcome. The results and subsequent analysis of the trial are used to assess the effectiveness of the intervention, which is the extent to which a treatment, procedure, or service does patients more good than harm. RCTs are the most rigorous way of finding out if a cause-effect relation exists between the intervention and the outcome.
In the hierarchy of evidence-based medicine, this study design occupies the highest slot.
What are the parameters on which the drugs are being tested? We have been reading claims about certain drugs reducing recovery periods, but not being able to prevent mortality, etc. What does that mean?
All clinical trials are conducted to find out the effectiveness of the drug. The most meaningful outcome measures are called hard endpoints: death rate, length of stay in ICU, length of hospital stay, progression of disease, etc. What matters to an individual patient are hard endpoints and all clinical trials must be designed to examine if the experimental therapy is able to achieve these aims.
There are surrogate endpoints, which are considered weak. For example, viral clearance, recovery time, decrease in temperature, decrease in cough, etc.
Are the WHO’s Solidarity trials and UK’s RECOVERY trials, considered the leaders in efforts to find effective intervention, examples of randomised control trials?
Absolutely. The strengths of these trials are that each trial has asked a focused and meaningful clinical question. The trials are multicentric, have enrolled enough patients to find out if the drug works or doesn’t, have well-defined and clinically meaningful outcomes, the patient follow-up is complete, data collection is immaculate and have adhered to all the principles of a high-quality randomised controlled trial.
In addition, highly experienced researchers with outstanding research capabilities led these trials. Thus, these trials have generated evidence that we could trust, that is relevant in the care of our patients and can be applied at the patient’s bedside to improve their chances of going home from the hospital.
At the beginning of the Solidarity trials, the WHO said it is focusing on what it believes are the four most promising therapies: remdesivir, chloroquine and hydroxychloroquine, a combination of two HIV drugs lopinavir and ritonavir, and that combination plus interferon-beta. Could you please elaborate on these?
The Solidarity Trial is comparing four treatment options against standard 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.
The trial design is factorial – a number of interventions could be tested in a single trial.
The University of Oxford’s RECOVERY trial, launched in March, is a 176-centre, randomised, open-label, pragmatic trial comparing several treatments to usual care for patients hospitalised with Covid-19. It is the world’s largest randomised clinical trial of potential Covid-19 treatments. It is testing a range of potential therapies.
The RECOVERY Trial showed that steroids benefit – the dexamethasone arm enrolled 2,100 participants who received 6 milligrams of dexamethasone per day for 10 days, and compared how they fared against about 4,300 people who received standard care for coronavirus infection.
Dexamethasone reduced deaths by one-third in patients receiving invasive mechanical ventilation, by one-fifth in patients receiving oxygen without invasive mechanical ventilation but did not reduce mortality in patients not receiving respiratory support at randomisation.
The trial also showed that hydroxychloroquine does not work in hospitalised Covid-19 patients and was instrumental in stopping this drug in the treatment of Covid-19 patients in several countries.
Has any specific antiviral drug been approved to date?
Of the two antiviral drugs tested in high-quality randomised controlled trials, remdesivir was found superior to placebo in shortening the time to recovery in adults hospitalised with Covid-19 and evidence of lower respiratory tract infection. [In a clinical trial on 1,059 patients, of which 538 were assigned remdesivir and 521 received a placebo] the drug improved recovery time from 15 days to 11 days. However, the drug failed to show statistically significant reduction in the death rates of Covid-19 hospitalised patients.
Lopinavir-Ritonavir: This antiviral test was tested in 199 patients with laboratory-confirmed Covid-19 infection. In hospitalised adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19% versus 25%). The percentages of patients with detectable viral RNA at various time points were similar.
Lopinavir-ritonavir showed “no beneficial effect” in hospitalised patients not on ventilators, according to the University of Oxford’s RECOVERY trial.
Some of these drugs are being prescribed by doctors. Does that mean the trial process is complete or is it on the basis of interim findings?
Remdesivir and dexamethasone, used in hospitalised patients, have proven efficacy – as shown by high-quality randomized controlled trials. Their use is evidence-based. These drugs must be used in the right patient, at the right time for a right indication, though.
Hydroxychloroquine has not been found to benefit hospitalised patients nor has been found effective in reducing the risk of infection among those who were exposed to the virus. Its use is not justified.
Lopinavir-Ritonavir has failed in two clinical trials. These antivirals should not be used to treat Covid-19 patients.
Convalescent plasma and tocilizumab should not be used outside the clinical trial setting. The hospitals using plasma to treat Covid-19 patients must ensure that it fulfils the MEURI guideline advocated by WHO.
Despite the trials showing that chloroquine doesn’t work, why is it still being used in some hospitals for treatment?
Medicine is quick to embrace practices based on shaky evidence but slow to drop them once they have been torn apart by solid proof generated by powerful data. Hydroxychloroquine belongs to that category. Now that the current evidence conclusively shows that hydroxychloroquine does not work in hospitalized patients, policymakers and physicians must act on this evidence. The quicker the doctors delete the drug from their prescriptions for COVID patients, the better.
Is there a distinction to be made between chloroquine and hydroxycholoroquine when we say that evidence conclusively shows that HCQ does not work in hospitalised patients?
Both drugs are more or less similar.
What do you make of the accelerated approval given by the Drugs Controller General of India to Favipiravir? Has any data been made available on clinical trials that may have been conducted? There has been a reference made, to an observational study in China. Is that credible?
Glenmark received “accelerated approval” from the DCGI for “restricted emergency use in India”. The New Drugs and Clinical Trial Rules, 2019 allow the DCGI to approve certain drugs based on approvals granted overseas. However, DCGI’s website doesn’t explain the scientific basis of its approval of favipiravir for COVID-19. The onus lies on DGHS (Directorate General of Health Services) to share its rationale for such a decision.
The observational study from China on 80 patients and published in a journal called Engineering concluded that those who got the drug tended to have faster disappearance of virus and quicker improvement of shadows in their chest x-rays. The study has limitations: its design is observational, it enrolled only mildly sick patients, has no comparison group, it looks at only viral clearance and x-rays, and the sample size is small. We do not know whether the patients improved on their own or because of the drug.
Can a therapeutic drug be given prophylactically (as a preventive)? Can healthcare workers, who are at high risk be given the drug prophylactically?
No, not at all.
Has the Patanjali Ayurvedic drug, that is under fire for its false claims, undergone the kind of clinical trials that the drugs we discussed earlier are undergoing? What are the red flags?
This trial is a textbook example of how a study should not be designed or conducted. It is a poorly designed trial. The research question is not focused, scientific background not explained, study hypothesis and objectives lack clarity. There is no clarity on blinding of interventions, the sample size is grossly inadequate, pre-specified primary and secondary outcome measures do not include hard outcomes, there are no interim analyses and stopping guidelines.
Although the hyped study – with exaggerated results and tall claims – was shared with the press and media almost 10 days ago, the researchers are yet to analyse and publish the study. A sample of just 90 patients should not take more than a few hours to be analysed and reported.
Within a week, the investigators say that the study didn’t aim at cure – this is what they said earlier – but at management. It is not clear if the drug is an “immunity booster” or a therapy for patients proven to have laboratory-confirmed Covid-19. The study claims that no patient experienced adverse events – a fact biologically impossible to accept.
The 100% success rate is too good to be believed. And short of a publication in a peer-reviewed journal it would be impossible to figure out what the study is up to.