The SOLIDARITY Megatrial: A Promise to Humanity

By Maria Rizwan.


What is ‘SOLIDARITY’?
Heralded on the 18th of March 2020, SOLIDARITY is an international endeavour brought together by the World Health Organization, WHO, to reconnoitre the effects of previous efficacious drugs on the novel corona virus. Employing the repurposing method, they aim to narrow down the potential candidates for the pending cure. Drug repositioning or repurposing is the strategy of salvaging a licensed drug for a different purpose than its initial one. It is the most auspicious measure to execute amidst a pandemic as drug development could grasp a few years or so and staggering amounts of money.

Over 100 countries collectively are participating in rush to seek asylum from the wreaked chaos; to list a few: South Africa, France, and Iran. Many of which who are also financially subsidizing this effort. During March, funds from 203,000 individual donations, charitable organizations, governments and 45 nations, leading management and finance summed up to $108 million USD. This coalition aids in acquiring required PPE equipment or rather supply of the to-be-tested drugs.

The nominees of the repositioning trials consist of Remdesivir, Lopinavir/Ritonavir, Interferon beta-1a and Hydroxychloroquine. They are the illustrious miracle drugs that have battled a variety of illnesses, holding great potential to unlock desirable behaviours against SARS-CoV-2, the corona virus.


Rationale and Nature of Study

They say, ‘drastic times call for drastic measures’, befitting our response to the pandemic and lockdown. Similarly, as owed to the unfortunate circumstances, the study is advancing at a fastidious pace. A fastidious pace may possibly result arbitrary findings, however a balance of order is retained. Although, randomized clinical trials take a plethora of years to design and conduct, SOLIDARITY will condense the stereotypical timings by 80%.

Exercising an ‘Adaptive Design’, alterations are on the whim. As results emerge, the trial designs are revised to correspond with clinical necessities. The trial may conceivably reduce durations and subjects in hope of accruing expenditures if interim results are negative. The sooner fruitful findings are attained, the sooner modifications can be made to the international locations of the megatrial, to further ensue anticipated outcomes and cease the tests.


Individual participation

Adults ≥ 18 years of age admitted as of COVID-19 in participant hospitals of SOLIDARITY, are eligible to participate. Accordingly, then they are requested for consent by a brief of potential risks and gains of the trial. Initially, basal checks are recorded digitally and monitored by a medical team allotted to the patient, to supervise any inapt treatments to their systems or any underlying health issues, namely diabetes, heart disease, chronic lung disease, chronic liver disease and asthma, extending to HIV and tuberculosis in the African region. The enrolment and height of nursing of the patient is determined by the gravity of illness, accounted on entry by shortness of breath, supply of oxygen, ventilator requirement, and, if lungs imaged, major bilateral abnormality.

Following the vitals and methodical check-throughs, patients are randomly allocated by a computer into either of the 4 conditions. Consisting of Local standard care (control) or local standard care in addition to either: Remdesivir, Lopinavir/Ritonavir, Interferon beta-1a and Hydroxychloroquine.

An independent group of experts notably known as The Global Data and Safety Monitoring Committee, witness the interim trial analyses. Participant groups may acquire further quantitative and qualitative data to maintain an organized research.

Innominate information of the patients is accumulated only at two checkpoints: the randomization stage and when the victim is discharged/passes. Entailed by the drug doses and its span of consumption, whether ventilation or intensive care was provided, and it’s start date, date of discharge or death and its cause.

As of 3rd June, the SOLIDARITY trial has been observed by nearly 35 nations, in which over 400 hospitals are actively recruiting participants. A dozen more show interest in partaking but are yet to join. WHO is exhorting their pending participation by providing the chosen drug supplements, identification of participant hospitals, training on digital randomized allocations and data systems, and ethical and regulatory approvals of the WHO core protocol.


IV: The Drugs

• Remdesivir (Veklury)

Alternatively termed as GS-5734, Remdesivir is an anti-viral drug developed by the company Gilead. More commonly known as the drug proven worthy against the Ebola virus, though the triumph was short-lived and limited. Nevertheless, it is also generating promising behaviours against SARS and MERS both, shaping hopes for the fight against COVID-19.

Dating back to 2017, a paper published by the Journal of Science and Translational Medicine noted that Remdesivir may lose efficacy against the disease as it or its symptoms’ duration lengthens. Concluding that it may prevail to be efficient solely in early course of the disease or with no (asymptomatic)/less symptoms. However, it wasn’t the same case for Ebola. Therefore, the nature of Remdesivir against the ever-so-evolving SARS-CoV-2 is indeterminate.

• Lopinavir/Ritonavir (Kaletra)

Entitled as one of the safest and elemental medications under the World Health Organization’s List of Essential Medicines, the LPV/r combination of HIV/AIDS licenced medication is notoriously known in the markets as Kaletra. The company, Abbott Laboratories initially developed the drugs separately but observed greater heights of success when amalgamated in fixed amounts. Lopinavir is an inhibitor of the HIV-1 protease, retroviral aspartyl, counteracting it from causing further harm. On the other hand, a small dose Ritonavir suppresses an enzyme called CYP3A functioning as a metaboliser for Lopinavir. Therefore, Ritonavir allows Lopinavir to prevail in the system by slowing its breakdown.

An investigation conducted back in March clouds doubts in the minds of many. The trial’s paper states the study was steered on a 1:1 ratio with a set of control participants. They examined the efficacy of the HIV/AIDS combo of severe SARS-CoV-2 infectees, but unfortunately did not observe a clear distinction between its effect and the control, standard care. Nonetheless, it was a relatively small study summing up to merely 199 participants, hence sparking controversy.

• Hydroxychloroquine (Plaquenil)

Granted the SOLIDARITY trials were set to be resumed with Hydroxychloroquine and Chloroquine, Hydroxychloroquine (HCQ) solely pursued. HCQ is a chief combatant against autoimmune diseases, rheumatic disorders and certain types of malaria.

Information on HCQ is quite limited due to its early discontinuation status. As of June 17th, WHO announced the suspension of the HCQ-arm trials. Advised by the Executives and principle investigators, interim-evaluated data concluded no difference in mortality rates when compared to local standard care. In light of the public’s dubiety, it was also briefed that patients midst an HCQ course may continue or inhibit their course at their physician’s discretion and that pre/post-exposure prophylactic treatments for COVID-19 patients are permissible.


4) Interferon beta-1a (Avonex)

Although interferon beta-1a is prescribed to the patients with LPV/r, it is an efficacious anti-viral protein that works relatively well against other diseases. It’s most commonly used to treat multiple sclerosis as it condenses the relapse rate.

Treatment navigated by this combination successfully suppresses viral loads in all clinical specimens (materials derived from patients as samples), namely: nasopharyngeal swabs, posterior oropharyngeal saliva, and stool tests, merely 8 days from the prescription commencement date. Moreover, it alleviates symptoms fastidiously in barely 4 days and abridges IL-6 levels.

A study conducted on the prognosis of differed Interleukin-6 levels found that, high IL-6 levels predict upcoming respiratory failure accurately and assist physicians in prophylactic treatments, therefore deeming its account to be crucial in Intensive Care Units and relevant facilities. Owed to the combination, hospital stays have been shortened and controlled.

Not only is this triple blend a contemporary candidate for SARS-CoV-2 but for MERS additionally as well. An ongoing study, prominently known as MIRACLE (MERS-CoV Infection treated with A Combination of Lopinavir/ritonavir and interferon-β1b) has been continuously testing on this combo’s impact on the MERS corona virus since 2016. However, its promise is yet to be proven.


Withal Hydroxychloroquine, Interferon beta-1a has been excluded from SOLIDARITY trials. As verbalized by WHO, “The International Steering Committee formulated the recommendation in light of the evidence for hydroxychloroquine vs standard-of-care and for lopinavir/ritonavir vs standard-of-care from the Solidarity trial interim results, and from a review of the evidence from all trials presented at the 1-2 July WHO Summit on Covid-19 research and innovation.”.

Considering SOLIDARITY’s International Steering Committee’s suggestion, WHO, at July 4th, had discontinued the usage of Interferon beta-1a against primal COVID infections. Interim data once again, displayed no progress in condensing mortality rates.

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The nature of SOLIDARITY is obscure and cannot be foreseen, but just as humanity lucratively accommodated to the new norms, as will the Megatrial. The development of the vaccine can only be encouraged with harmony. Coherently, from the ends of the world, we can bring together the end of this catastrophe.

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Sources:
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"Solidarity" Clinical Trial for COVID-19 Treatments. www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments.
Sheahan, Timothy P., et al. “Broad-Spectrum Antiviral GS-5734 Inhibits Both Epidemic and Zoonotic Coronaviruses.” Science Translational Medicine, American Association for the Advancement of Science, 28 June 2017, stm.sciencemag.org/content/9/396/eaal3653?utm_campaign=toc_stm_2017-06-28&et_rid=17050501&et_cid=1410533.
Cao, Bin, et al. “A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19: NEJM.” New England Journal of Medicine, 7 May 2020, www.nejm.org/doi/full/10.1056/NEJMoa2001282.
YM. Arabi, HH. Balkhy, et al. “Treatment of Middle East Respiratory Syndrome with a Combination of Lopinavir/Ritonavir and Interferon-β1b (MIRACLE Trial): Statistical Analysis Plan for a Recursive Two-Stage Group Sequential Randomized Controlled Trial.” Trials, BioMed Central, 1 Jan. 1970, trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3846-x.
“Solidarity Trial.” Wikipedia, Wikimedia Foundation, 12 July 2020, en.wikipedia.org/wiki/Solidarity_trial#Support_and_participation.
“WHO Discontinues Hydroxychloroquine and Lopinavir/Ritonavir Treatment Arms for COVID-19.” World Health Organization, World Health Organization, www.who.int/news-room/detail/04-07-2020-who-discontinues-hydroxychloroquine-and-lopinavir-ritonavir-treatment-arms-for-covid-19.
Hung, Ivan Fan-Ngai, et al. “Triple Combination of Interferon Beta-1b, Lopinavir-Ritonavir, and Ribavirin in the Treatment of Patients Admitted to Hospital with COVID-19: an Open-Label, Randomised, Phase 2 Trial.” Lancet (London, England), Elsevier Ltd., 30 May 2020, www.ncbi.nlm.nih.gov/pmc/articles/PMC7211500/.