Jan 302022

Jon-Emile S. Kenny MD [@heart_lung]

“… but prejudices, like odorous bodies, have a double existence, both solid and subtle – solid as the pyramids, subtle as the twentieth echo of an echo, or as the memory of hyacinths which once scented the darkness.”

-Mary Ann Evans


As previously described, the SARS-CoV-2 main protease inhibitor [Mpro] is an existential feature of the virus.  Mpro cleaves into action various non-structural proteins that go on to form important viral replication machines within the infected cell. Nirmatrelvir, is a beta-coronavirus [e.g., SARS-CoV-1, SARS-CoV-2, MERS-CoV, etc.] Mpro inhibitor and it has been paired with ritonavir – as a pharmacological boost – to form Nirmatrelvir-Ritonavir [NIR-RIT, Paxlovid].

The EPIC-HR study [Evaluation of Protease Inhibition for COVID-19 in High-Risk patients] founded a very recent Emergency Use Authorization granted by the US FDA with for NIR-RIT. The wording of the authorization is as follows:

Paxlovid is authorized for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age older weighing at least 40kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.”

This is a relatively broad indication given that it is formed by the results of EPIC-HR.  This study enrolled only completely immunologically-naïve patients [i.e., unvaccinated and no previous infection] and with at least 1 medical co-morbidity that increases the risk of severe disease. The risk factors were:


-BMI >25 kg/m2

-chronic cardiovascular [including hypertension], pulmonary or renal disease

-current smoker

-immunosuppressive disease/immunosuppressive treatment

-sickle cell disease

-neuro-developmental disorders

-active cancer

-age over 60 years.

Given that the fraction of individuals with the aforementioned risk factors who are also unvaccinated is decreasing, the question then becomes – do vaccinated, but otherwise high-risk patients derive clinical benefit from NIR-RIT?  What about unvaccinated patients who are otherwise low-risk?

To answer these questions, the on-going EPIC-SR [Evaluation of Protease Inhibition for COVID-19 in Standard-Risk] patients is on-going. An interim analysis of this study appears to have played some role in the emergency use authorization described above, as well.

What they are doing

1140 adult participants are being randomized to either NIR-RIT or placebo. The study is double-blinded and randomization is 1:1.

Patients are included if they have: confirmed SARS-CoV-2 infection within 5 days prior to randomization, signs or symptoms of COVID-19 within 5 days of randomization, agreed to use highly effective contraception if fertile, at least 1 underlying medical condition associated with increased risk of severe COVID-19.

Patients are excluded if they have: received, or are expected to receive, SARS-CoV2 vaccine unless the patient has an underlying risk factor for severe disease, then vaccination is allowed, previously had SARS-CoV-2 infection, oxygen saturation of less than 92%, active liver disease, dialysis or moderate-to-severe renal insufficiency, HIV with a viral load more than 400 copies/mL, current use of medications dependent upon or inducers of CYP 3A4, pregnancy, received convalescent plasma, participation in another COVID-19 interventional trial.

The primary outcome measure was the proportion of patients with COVID-19-related hospitalization or death from any cause through 28 days. The secondary outcomes evaluated were many, including: adverse events, treatment-emergent adverse events, duration and severity of symptoms, all-cause death, nasal swab viral titres, COVID-19-related medical visits other than hospitalization, number of days in the hospital and ICU for COVID-19 therapy if hospitalized.

What is reported

The interim analysis of the ‘novel primary endpoint’ – self-reported, sustained alleviation of all symptoms for four consecutive days – was not statistically improved for those randomized to NIR-RIT as compared to placebo.  The data were reviewed by an independent Data Monitoring Committee [DMC]; the DMC recommended that the trial continue.

Regarding secondary end-points at the interim analysis [45% of the trial’s planned enrollment] 0.6% of those randomized to NIR-RIT were hospitalized [i.e., 2/333 hospitalized with no deaths], compared to 2.4% of patients who received placebo [i.e., 8/329 hospitalized with no deaths].

A follow-on analysis at 80% of enrolled patients was consistent with these findings. Treatment-emergent adverse events and rates of serious adverse events were also between NIR-RIT and placebo.


The results of EPIC-SR [i.e., standard risk] better answers whether there is benefit to treating either 1. unvaccinated, otherwise healthy individuals or 2. vaccinated, medically-susceptible individuals with NIR-RIT.  Recall that if the patient is both unvaccinated and medically-susceptible, then the results of EPIC-HR better apply.  In both studies, only mild-to-moderate, outpatient disease was studied.

Given that both of the interim analyses – at 45% and 80% enrollment – gave nearly equal absolute risk reductions for hospitalization, it seems reasonable that this effect magnitude will hold when enrollment concludes.  There was no clinically-significant difference in mortality noted in the interim analyses, but the number needed to treat to prevent one hospitalization for COVID-19, in this patient population, will likely be around 55.

Though we must wait until these preliminary results are scrutinized and published, the treatment effects of NIR-RIT are noteworthy.  If they hold up, there will likely be comparisons with other outpatient COVID-19 therapies such as inhaled budesonide, fluvoxamine and monoclonal antibodies.  Though there are well-founded criticisms of fluvoxamine in COVID-19, there are two, well-conducted, randomized controlled trials supporting fluvoxamine.  For instance, the patients enrolled in the TOGETHER trial were comparable to those in EPIC-HR [i.e., high-risk, unvaccinated].  Fluvoxamine showed no mortality benefit by intention-to-treat, but did significantly reduce hospitalizations with an NNT of roughly 20. The PRINCIPLE study was somewhat of a mix between EPIC-HR and EPIC-SR given that high-risk patients were enrolled, with variable vaccination status; that investigation found an approximate NNT of 50 to prevent hospitalization or death.

The rapid adoption of NIR-RIT certainly stems from the sound biological mechanism of the medications and the great success of protease-inhibitors for other viral scourges.  On the other hand, the trepidation with other, less expensive, outpatient therapeutics always reminds me of this study where ‘expensive’ placebo resulted in better outcome than ‘cheap’ placebo in patients with Parkinson’s Disease.  Might treating clinicians suffer from prejudices in this way?

Given that enrollment in EPIC-SR will overlap with the omicron variant, there might concern that this confounds final results.  However, the Mpro enzyme that is targeted by Nirmatrelvir is quite conserved between the beta-coronaviridae.  Mpro is 100% homologous with SARS-CoV-1.  Thus, this therapeutic should be fairly specific for additional variants as well as MERS-CoV, when it returns.

Happy Birthday Lina!


Dr. Kenny is the cofounder and Chief Medical Officer of Flosonics Medical; he is also the creator and author of a free hemodynamic curriculum at heart-lung.org.  Download his free textbook here.

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Nirmatrelvir-Ritonavir for ‘Standard Risk’ COVID-19