The EPIC-HR trial evaluated whether the drug Paxlovid (nirmatrelvir/ritonavir) is safe and effective for treating high-risk adults with COVID-19 who do not require hospitalization. The double-blind, randomized, placebo-controlled trial found that Paxlovid reduced the risk of hospitalization or death by 89% compared to placebo when taken within three days of symptom onset. Paxlovid also led to a greater reduction in viral load and had a safety profile comparable to the placebo. The results provide support for using Paxlovid to significantly reduce hospitalization and death in high-risk patients with mild COVID-19 symptoms initiated within five days of symptom onset.

1. EPIC-HR Trial
Presenter : Dr Mohamad Syahiirul Afifi Bin Bahtiar
Supervisor : Dr Hazlan

2. Introduction
• Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients
• The purpose of this study is to determine whether PAXLOVID PF-
07321332/ritonavir (Nirmatrelvir/ritonavir) is safe and effective for
the treatment of adults who are ill with COVID-19 and do not need to
be in the hospital, but are at an increased risk of developing severe
illness.
• Reduced the risk of hospitalization or death for any cause by 89%
compared to placebo in non-hospitalized, high-risk adult patients with
COVID-19 treated within three days of symptom onset

3. • Paxlovid ( nirmatrelvir+ ritonavir) is a SARS-
CoV-2 main protease inhibitor
• Design to inhibit viral replication at the stage
known as proteolysis
• Ritonavir inhibit CYP3A , slowing nirmatrelvir to
be metabolized . So it remains in the body for
longer time to combat the virus
Mechanism of action

4. Study design
• Phase 2-3
• Double Blind
• Randomized placebo controlled trial
• Dose: 300 mg of nirmatrelvir plus 100 mg of ritonavir or placebo
every 12 hours for 5 days.
• To evaluate efficacy , viral load and safety associated with the use of
paxlovid in non hospitalized, symptomatic adult with Covid-19 who at
least have 1 risk of progression to severe form.
• The trial planned to enroll 3000 patient. Due to efficacy of this drug
the enrollment was ceased in November 2021 .

6. Inclusion criteria
• Confirmed SARS-CoV-2 infection within 5 days prior to randomization
• Initial onset of COVID-19 signs/symptoms within 5 days prior to the
day of randomization and at least 1 of the specified COVID-19
signs/symptoms present on the day of randomization
• Has at least 1 characteristic or underlying medical condition
associated with an increased risk of developing severe illness from
COVID-19

7. Exclusion criteria
• History of or need for hospitalization for the medical treatment of COVID-
19
• Prior to current disease episode, any confirmed SARS-CoV-2 infection
• Known medical history of active liver disease
• Receiving dialysis or have known moderate to severe renal impairment
• Known human immunodeficiency virus (HIV) infection with a viral load
greater than 400 copies/mL or taking prohibited medications for HIV
treatment
• Suspected or confirmed concurrent active systemic infection other than
COVID-19
• History of hypersensitivity or other contraindication to any of the
components of the study intervention

8. • Current or expected use of any medications or substances that are highly
dependent on CYP3A4 for clearance or are strong inducers of CYP3A4
• Has received or is expected to receive convalescent COVID-19 plasma
• Has received or is expected to receive any dose of a SARS-CoV-2 vaccine before
the Day 34 visit
• Participating in another interventional clinical study with an investigational
compound or device, including those for COVID-19 through the long-term follow-
up visit
• Known prior participation in this trial or other trial involving PF-07321332
• Oxygen saturation of <92% on room air, or on their standard home oxygen
supplementation for those who regularly receive chronic supplementary oxygen
for an underlying lung condition
• Females who are pregnant or breastfeeding

10. 6.31%
0.72 %
0.72% vs 6.45%
0% vs 1.32%
Relative risk reduction
of 89%

11. Among patients 65
years older, relative risk
reduction was 94%

12. This panel show adjusted mean change in viral load from baseline.
Paxlovid reduce viral load at day 5 when the treatment is initiated within 3 days after symptoms onset

14. Results
• Result from interim analysis in patient who complete 28 days follow
up found 89% reduction in covid-19 related hospitatization or death
in patient treated within 3 days of symptoms onset
• In the overall study population thoughout day 28 , no death were
reported in patient who received paxlovid as compared to 12 death in
placebo ( 1.2%)
• Paxlovid reduce viral load by approximately 10 fold or 0.93 log10
copies/mL relative to placebo.
• Comparable safety profile between paxlovid (22.6%) and placebo
(23.9%). Those in treatment group were less likely to have serious
adverse event ( 1.6 vs 6.6 % ).

16. Take home message
• In high risk covid -19 patients with symptoms of less than 5 days ,
Paxlovid can significantly reduce hospitalization and death.
• Most helpful for people with mild COVID symptoms who are at high
risk of developing severe disease
• Good safety profile

17. Thank You