Covid-19: trials of four potential treatments to generate “robust data” of what works
BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m1206 (Published 24 March 2020) Cite this as: BMJ 2020;368:m1206Read our latest coverage of the coronavirus outbreak
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
Dear Editor
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 [1].
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 [2]. 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 [1]?
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 [3]. 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].
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) [8] 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 [2] 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 [2] and Canadian [8] 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” [1]. 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 [9] and there have been reports of CoV-2 being further genetically evolving during the current CoViD-19 outbreak [10]. 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.
References:
[1] 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...
[2] 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
[3] 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
[4] Tan EL, Ooi EE, Lin CY, Tan HC, Ling AE, Lim B, Stanton LW. Inhibition of SARS coronavirus infection in vitro with clinically approved antiviral drugs. Emerg Infect Dis. 2004 Apr;10(4):581-6. doi: 10.3201/eid1004.030458. PMID: 15200845; PMCID: PMC3323075.
[5] Ute Ströher, Antonino DiCaro, Yan Li, James E. Strong, Fred Aoki, Frank Plummer, Steven M. Jones, Heinz Feldmann, Severe Acute Respiratory Syndrome-Related Coronavirus Is Inhibited by Interferon-α, The Journal of Infectious Diseases, Volume 189, Issue 7, 1 April 2004, Pages 1164–1167, https://doi.org/10.1086/382597
[6] Hensley LE, Fritz LE, Jahrling PB, Karp CL, Huggins JW, Geisbert TW. Interferon-beta 1a and SARS coronavirus replication. Emerg Infect Dis. 2004 Feb;10(2):317-9. doi: 10.3201/eid1002.030482. PMID: 15030704; PMCID: PMC3322919.
[7] 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
[8] Treatments for COVID-19: Canadian Arm of the SOLIDARITY Trial (CATCO). ClinicalTrials.gov Identifier: NCT04330690. https://clinicaltrials.gov/ct2/show/NCT04330690
[9] Mukunthan Murthi, Rapid Response: Re: Covid-19: trials of four potential treatments to generate “robust data” of what works. BMJ 2020;368:m1206
[10] 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
Dear Editor
As has been published in multiple reports, Lopinavir/ritonavir has been widely used for patients with COVID-19. Its efficacy has not been proven, especially in those who are critically ill (1). Remedesvir has been suggested as a potentially effective medication, although much needs to be known about its true efficacy and safety profile. Moreover, the medication has currently no approval from any country for use in any disease. Clearly, there is an urgent need for anti-pathogen medication which can control the spread of this pandemic and reduce mortality.
Human coronavirus consists of 7 viruses divided into two groups as follows: Alpha coronavirus -- HCoV-NL63, HCV-229E -- and Beta coronavirus -- HCVOC43, HKU1, MERS CoV, SARS-CoV and SARS-CoV2. The attachment receptor and entry receptors are different in all these viruses.
Both HCoV-NL63 and SARS-CoV, which use ACE2 as an entry receptor, also utilize Heparan sulfate proteoglycans (HSPG) as attachment receptors (2,3). SARS-CoV-2, which also uses ACE2 for cell entry, may also use HSPG as attachment receptors, although no data on this topic is available yet.
HSPGs are ubiquitously expressed by most mammalian cell types. A wide variety of viruses, including HIV, have been shown to utilize HSPG to increase their concentration at the cell surface and increase the entry into cells (4).
Inhibition of HSPG has been shown to have anti-viral efficacy in multiple viruses including HIV, dengue virus, encephalitic flavivirus, etc, (5,6). Interestingly, blocking of HSPG has been shown to have an inhibitory function at the viral attachment stage for SARS pseudovirus (3).
The value of heparan sulfate mimetics:
Suramin, a competitive inhibitor of heparin, has been shown to curtail the entry of the chikungunya virus and Ebola virus effectively in in-vitro models (7,8). Another heparin analog drug, PI-88, has demonstrated significantly improved outcomes in mouse models of Dengue virus and flavivirus encephalitis (6). In vitro analyses have also shown that blocking of HSPG heparinase or exogenous heparin inhibited infection by SARS pseudovirus by curtailing early attachment phase (3).
It is plausible that such an effect can be observed for SARS-CoV-2 as well. Given the lack of effective treatment options for COVID-19, especially in those who are critically ill, medications directed at HSPG could be studied as a potential treatment for COVID-19.
REFERENCES:
1. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. New England Journal of Medicine 2020 doi: 10.1056/NEJMoa2001282
2. Milewska A, Zarebski M, Nowak P, et al. Human Coronavirus NL63 Utilizes Heparan Sulfate Proteoglycans for Attachment to Target Cells. Journal of Virology 2014;88(22):13221-30. doi: 10.1128/jvi.02078-14
3. Lang J, Yang N, Deng J, et al. Inhibition of SARS Pseudovirus Cell Entry by Lactoferrin Binding to Heparan Sulfate Proteoglycans. PLOS ONE 2011;6(8):e23710. doi: 10.1371/journal.pone.0023710
4. Cagno V, Tseligka ED, Jones ST, et al. Heparan Sulfate Proteoglycans and Viral Attachment: True Receptors or Adaptation Bias? Viruses 2019;11(7):596. doi: 10.3390/v11070596
5. Connell BJ, Chang S-Y, Prakash E, et al. A Cinnamon-Derived Procyanidin Compound Displays Anti-HIV-1 Activity by Blocking Heparan Sulfate- and Co-Receptor- Binding Sites on gp120 and Reverses T Cell Exhaustion via Impeding Tim-3 and PD-1 Upregulation. PloS one 2016;11(10):e0165386-e86. doi: 10.1371/journal.pone.0165386
6. Lee E, Pavy M, Young N, et al. Antiviral effect of the heparan sulfate mimetic, PI-88, against dengue and encephalitic flaviviruses. Antiviral Research 2006;69(1):31-38. doi: https://doi.org/10.1016/j.antiviral.2005.08.006
7. Henss L, Beck S, Weidner T, et al. Suramin is a potent inhibitor of Chikungunya and Ebola virus cell entry. Virol J 2016;13:149. doi: 10.1186/s12985-016-0607-2 [published Online First: 2016/09/02]
8. Chen Y, Maguire T, Hileman RE, et al. Dengue virus infectivity depends on envelope protein binding to target cell heparan sulfate. Nature Medicine 1997;3(8):866-71. doi: 10.1038/nm0897-866
Competing interests: No competing interests
Re: Covid-19: trials of four potential treatments to generate “robust data” of what works
Dear Editor
In a rapid reponse to this article by Mukunthan Murthi and Miguel Gonzalez the compound suramin was mentioned.
With respect to the potential use of suramin for the treatment of COVID-19, we would like to briefly call your attention towards the protein known as Fibroblast Growth Factor (FGF). This was the first pure growth factor to show angiogenic activity. Blood vessels always showed an inflammatory phenotype since the first in vivo studies that we carried out for characterizing FGF-induced angiogenesis (1). It was later shown that angiogenesis induced by FGF was rather the consequence of the inflammatory signature elicited by this protein in the endothelium, than a merely direct induction of angiogenesis (2,3). Inflammation elicited by FGF is prone to the consolidation of a positive inflammatory feedback loop, typical of chronic diseases, since it induces the upregulation of the synthesis of COX-2 and phospholipase A2, which reciprocally promote the expression of FGF (4). Inhibition of FGF obviously interrupts these loops, which probably explain the clinical benefits of the inhibition of FGF in several inflammatory diseases (5 -to quote a few cases-). It has also been shown that stressed cells excrete abundant amounts of FGF to the millieu, which further worsen the tissue inflammation (6).
Key for our studies on FGF inhibition has been a compound we singled out after many years of screening using suramin, an old antiparasitic drug, as leader compound. Following that lead we were able of identifying an already existing compound that showed a FGF inhibitory activity considerably much higher than that of suramin, which makes it suitable for potential clinical antiangiogenic applications. This compound, 2,5-dihydroxyphenyl sulfonic acid (2,5DHPS), was already marketed as a "vascular reinforcer" (dobesilate) of unknown mechanism of action. We have described the atomic basis of the FGF inhibitory activity by 2,5DHPS (7). This agent is able to revert the inflammatory angiogenic phenotype induced by FGF under many exploratory frames, in vitro as well as in vivo (as an example see reference 7).
Antiviral activities of suramin, based on the inhibition of viral binding to heparan sulfate, have been already described long time ago (8). We have shown that 2,5DHPS clearly ameliorates viral infections in the case of herpes labialis (9).The use of suramin and, in general, of heparin/heparan sulfate binding competitors in the case of COVID-19 has been recently proposed (10). Inhibition of alphaherpesviruses by 2,5-dihydroxybezoic acid, a close structural analog of 2,5DHPS, but a slightly poorer FGF inhibitor, have been also reported (11)
It seems that 2,5DHPS, an old pharmacological agent of extensive clinical use and excellent safety profile (12), might be an interesting drug worth exploring for treating COVID-19 patients, because it could contribute to dampen both the viral infectivity and the endothelial inflammation.
(1) Proceedings of the National Academy of Sciences 82 (1985) 6409
(2) J Cell Mol Med 2009;13:2083108.
(3) Eur Cytokine Netw 2009;20:3950
(4) Annu Rev Med 2007;58:23952.
(5) BMJ Case Rep 2011;2011: pii: bcr0820114579.; BMJ Case Rep 2011;2011: pii: bcr0620114351; BMJ Case Reports 2012;2012: pii: bcr2012006619; BMJ Case Reports 2013 doi 10.1136 bcr-2013-010203;Thrombosis and Haemostasis Open 2019_03(03) e230-e243
(6) Journal of Cellular Biochemistry 103 (2008) 1327
(7) The Journal of Biological Chemistry 285 (2010) 11714
(8) Antiviral Research 4 (1984) 231
(9) International Journal of Case Reports 2018 2:28
(10) BMJ 2020;368:m1206 doi: 10.1136/bmj.m1206 (rapid response); FASEB BioAdvances. 2020;2:296303.
(11) Viruses 2015, 7, 53435360
(12) Drug Safety 2004; 27 (9): 649-660
Competing interests: No competing interests