Re: Covid-19: trials of four potential treatments to generate “robust data” of what works
WHO’s Solidarity Trial is warmly welcomed by the international community in response to the global CoViD-19 pandemic crises. It is however criticized that WHO's response was too slow in responding to the global crises. The lack of reliable guidelines for the clinical management of CoViD-19 resulted in the emergence of various poorly designed trials or rather ‘reports of clinical use’ appreciating the emergency response of clinicians across the world to save critically ill CoViD-19 patients fighting for their life.
The launch of WHO's Solidarity Trial came as good news for many, the public in general and clinicians in particular who are at the front line to manage these crises. WHO mentioned in their press release to test 4 different drugs or their combinations to roll out across the world, 45 countries and counting. The availability of four drugs or their combination through a multinational trial brought great hope for the CoViD-19 patients and their families .
We had a closer look at the Solidarity Trial (ClinicalTrials.gov Identifier: NCT04321616) to review the details of the trial design and the drugs and combinations included in the trial . We stumbled over various questions that are listed below in this article for the interest of the clinicians and healthcare researchers.
1. The official title of the Solidarity Trial (NCT04321616) is "Norwegian Solidarity Multicentre Trial on the Efficacy of Different Anti-viral Drugs in SARS-CoV-2 Infected Patients". Why the title does not include antimalarials (chloroquine or hydroxychloroquine)?
2. There are only two drugs included in the trial (NCT04321616), i.e., hydroxychloroquine (the antimalarial) and remdesivir (a new/investigational antiviral drug) or their combination against a control. Why the four drugs or their combinations are not included in this trial as mentioned by the WHO in the press release ?
3. Remdesivir is an intravenous investigational new antiviral drug with very limited safety data compared to existing antivirals. We already know that remdesivir was not effective in preventing deaths from the Ebola virus in a previous clinical trial . Why remdesivir was preferred over the other antivirals?
4. Why other antiviral drugs not included in this trial (NCT04321616), for instance: ribavirin, lopinavir-ritonavir which are also available to administer orally? Their preliminary results were promising.
5. Why interferons are not included in the trial? The evidence in 2004 from SARS-CoV-1 was very promising [4-6].
6. Although hydroxychloroquine is included in the trial, why chloroquine is not included in the trial? The current preliminary evidence favours the inclusion of both antimalarial drugs in a large multi-cohort trial .
7. 18 years or over subjects with CoViD-19 are eligible to join the trial – what are the provisions for under 18 CoViD19 patients otherwise eligible for the trial?
Recently, on 1st April 2020, the Canadian arm of the Solidarity trial appeared in the trial registry (ClinicalTrials.gov Identifier: NCT04330690)  to investigate the effect of lopinavir/ritonavir against the control. This raises further questions such as:
8. It seems like the Solidarity Trial has multiple arms investigating varying treatment options across different centers around the world; so is it not a global trial then? This raises questions like, why Canadian patients will be devoid of other treatment options, such as interferons, antimalarials, ribavirin, etc? Similarly, why Norwegian  or patients across other countries be devoid of all treatment options?
9. There are only 700 and 440 patients estimated to participate in the Norwegian  and Canadian  Solidarity Trials, respectively. Why the trial is not offered to a larger cohort of CoViD-19 patients who can benefit from the trial drugs anyways; would current trial design give enough statistical power to draw significant conclusions?
10. WHO has emphasised in their statement that “the SOLIDARITY trial was a response to fears that multiple small trials with different methodologies may not give us the clear, strong evidence we need about which treatments help to save lives” and this trial “is designed to generate the robust data we need, to show which treatments are the most effective” . It currently appears that the Solidarity trial seems similar to ‘multiple small trials with different methodologies’ which in WHO’s own words raise the same question if even WHO’s Solidarity Trial would give us the ‘strong evidence and the robust data’ that we desperately need?
11. There are as many as 7 variants of human coronavirus that have been reported  and there have been reports of CoV-2 being further genetically evolving during the current CoViD-19 outbreak . If the global Solidarity Trial will not offer all drug options/combinations across the world in a single coordinated trial, we fear that the data from different countries may not be directly comparable to draw any meaningful comparison.
 World Health Organization. WHO Director-General’s opening remarks at the media briefing on COVID-19. 18 March 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-re...
 The Efficacy of Different Anti-viral Drugs in (Severe Acute Respiratory Syndrome-Corona Virus-2) SARS-CoV-2. ClinicalTrial.gov trial identifier NCT04321616, https://clinicaltrials.gov/ct2/show/NCT04321616
 Mulangu et al., 2019. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. N Engl J Med 2019; 381:2293-2303, DOI: 10.1056/NEJMoa1910993
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 Hasan S., Kow C. S. & Merchant H. A. (2020) “Is it worth the wait? Should Chloroquine or Hydroxychloroquine be allowed for immediate use in CoViD-19?”, British Journal of Pharmacy. 5(1). doi: https://doi.org/10.5920/bjpharm.745
 Treatments for COVID-19: Canadian Arm of the SOLIDARITY Trial (CATCO). ClinicalTrials.gov Identifier: NCT04330690. https://clinicaltrials.gov/ct2/show/NCT04330690
 Mukunthan Murthi, Rapid Response: Re: Covid-19: trials of four potential treatments to generate “robust data” of what works. BMJ 2020;368:m1206
 Xiaolu Tang, Changcheng Wu, Xiang Li, Yuhe Song, Xinmin Yao, Xinkai Wu, Yuange Duan, Hong Zhang, Yirong Wang, Zhaohui Qian, Jie Cui, Jian Lu, On the origin and continuing evolution of SARS-CoV-2, National Science Review, nwaa036, https://doi.org/10.1093/nsr/nwaa036
Competing interests: No competing interests