The complex pathology of COVID-19 has compelled researchers to explore the combination therapies for COVID-19 treatment. This article discusses the clinical trials in testing these various combination therapies and the results they yielded.

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10.5% of global COVID-19 clinical trials are testing combination therapies, with the majority exploring dual combinations comprising antivirals and anti-inflammatory/immunomodulatory therapies.

The complex pathology of COVID-19 necessitates the need to look beyond monotherapies and explore combination therapies to improve therapeutic efficacy in a much wider population and across the disease pathway.

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Antiviral agents - Major findings from the analysis of the trials landscape

1. Hydroxychloroquine, azithromycin and lopinavir/ritonavir – Limited clinical benefit

Drugs, such as hydroxychloroquine, azithromycin and lopinavir/ritonavir, which were initially claimed to have antiviral activity against SARS-CoV-2 were reported to have limited clinical benefit towards COVID-19. This was concluded after assessing results from several randomised trials.

2. Remdesivir - Currently being tested in seven dual therapy pivotal trials

Remdesivir, another well-known drug, is being tested in combination with anti-inflammatories/immunomodulators such as baricitinib, tocilizumab, bamlanivimab, risankizumab and lenzilumab. The combinations are being evaluated to target the viral proliferation and the hyperimmune response - two critical stages of COVID-19.

1. Remdesivir and baricitinib- The combination of remdesivir and baricitinib has demonstrated significant improvement in clinical status and reduction in recovery time when compared with the remdesivir-only group.
2. Remdesivir and tocilizumab-The combination did not meet its endpoints in terms of improved time to hospital discharge or likelihood of death or progression to mechanical ventilation.
3. Remdesivir and bamlanivimab- The combination did not show any benefits in hospitalised COVID-19 patients.
4. Remdesivir and hyperimmune immunoglobulin (hIG)- The study evaluating the combination of remdesivir and hIG did not meet its endpoints as there was no reduction in the risk of disease progression in adults hospitalised with COVID-19.

Apart from remdesivir, favipiravir is another antiviral candidate being explored for dual combination therapy trials. A critical factor to note with antiviral therapies is the timing of treatment as antivirals are generally more effective during incubation and early symptomatic phase of the disease.

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Anti-inflammatories/immunomodulators in combination therapies

Anti-inflammatory interventions should be preferably used at the symptomatic and early pulmonary phases in the disease pathway to prevent the progression of COVID-19.

Neutralising monoclonal antibodies for the treatment of COVID-19: Neutralising monoclonal antibodies prevent virus entry into the host cell. They do this by binding and inactivating the spike glycoprotein (S protein) of SARS-CoV-2. The trials exploring antibodies have shown significant benefits on survival and reduction in mortality for COVID-19 patients.

Monoclonal antibody therapy bamlanivimab monotherapy was granted Emergency Use Authorisation (EUA) by the FDA. But the EUA was revoked considering the sustained increase in resistant variants of SARS-CoV-2. Nevertheless, bamlanivimab is still undergoing evaluation in combination therapy trials.

Tocilizumab is being analysed to target the cytokine storm of the immune system: Elevated IL-6 levels is a key signal to predict COVID-19. Tocilizumab is an IL-6 inhibitor being evaluated to target the excessive inflammatory response (cytokine storm) of the immune system.

As a monotherapy, tocilizumab has been reported to benefit COVID-19 patients, however, its benefit in combination therapy warrants further pivotal trials. Tocilizumab monotherapy improves patient symptoms, shortens hospital stay, and reduces overall mortality from severe COVID-19. Administration of tocilizumab monotherapy at the beginning of inflammation is recommended to improve its efficacy.

Baricitinib: Baricitinib has shown beneficial effects when combined with remdesivir as well as corticosteroids. The combination of baricitinib with corticosteroids has shown significant improvement in respiratory function in patients with COVID-19 pneumonia. When combined with remdesivir, baricitinib is shown to enhance the clinical efficacy of remdesivir.

Colchicine can be considered as a supportive treatment: Evidence suggests colchicine decreases cytokine production and improves patient survival when administered early in the disease process. It may be considered as a supportive treatment for hospitalised COVID-19 patients.

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Combination therapies should be tailored to the individual patient

The patient’s disease stage, health status and geographic region are some key factors to consider. Assessing the risk-benefit ratio is necessary when administrating anti-inflammatory interventions to immunocompromised patients. This is because anti-inflammatory interventions may alter host defence and delay the elimination of the virus.

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The rationale for exploring combination therapies for COVID-19 

Combination therapies for COVID-19 treatment can be beneficial as drugs with different mechanisms of action can be explored to treat different pathologies of the disease. For example, antiviral agents can be used to decrease the viral load while immune-modulators can help suppress the hyperimmune response. Another point for exploring combination therapies is the increased antiviral efficacy by combining drugs.

Though beneficial, very low numbers of combination drugs are currently being tested in trials for COVID-19. Safety concerns, potential interactions, and adverse effects are the reasons for these low numbers.

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Interventions being tested for the prevention and treatment of COVID-19 worldwide

As of 29 March 2021, 744 interventions are being tested for the prevention and treatment of COVID-19 in 2879 clinical trials worldwide. Of the 2879 clinical trials, 241 trials are testing dual combinations of interventions. Almost 60% of the dual combination pivotal trials explore combinations involving antivirals and/or immunomodulatory interventions.

The interventions being studied include antivirals, antibiotics, anti-inflammatories/immunomodulators, cell-based therapies and others like antimalarials, antihypertensives, antithrombotics, antifibrotics and dietary supplements.

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