Effectiveness and Safety of New Oral Antivirals for COVID-19 (ESOA-19)

Post-marketing Surveillance Study of the Effectiveness and Safety of New Oral Antivirals for Outpatients With Mild-moderate COVID-19

There is an increased lack of short- and long-term real-life effectiveness and safety data on new oral antivirals authorised and commercialised to treat COVID-19. To date, only two clinical trials have been published with data on the efficacy and safety of the use of the Paxlovid® and Lagevrio®. Since there is a public health, political, social and economic pressure to prevent severity, hospitalisation and death from COVID-19, monitoring the effectiveness and safety of commercialised oral antiviral therapies against COVID-19 has become emergent pharmacovigilance and public health task. The objective of the study is to monitor the post-marketing safety and effectiveness of the new oral antivirals indicated for the treatment of COVID-19, namely Nirmatrelvir/Ritonavir (Paxlovid®) and Molnupiravir (Lagevrio®), having as holders of the Authorization of Market introduction to Pfizer Europe MA EEIG and Merck Sharp & Dohme B.V., respectively.

Study Overview

• Status: Active, not recruiting
• Conditions: COVID-19
• Intervention / Treatment: Drug: Nirmatrelvir/ritonavir; Drug: Molnupiravir

Detailed Description

There is an increased lack of short- and long-term real-life effectiveness and safety data on new oral antivirals authorised and commercialised to treat COVID-19. To date, only two clinical trials have been published with data on the efficacy and safety of the use of the Paxlovid® and Lagevrio®. Since there is a public health, political, social and economic pressure to prevent severity, hospitalisation and death from COVID-19, monitoring the effectiveness and safety of commercialised oral antiviral therapies against COVID-19 has become emergent pharmacovigilance and public health task6.

A real-life cohort event monitoring system allows for the monitoring of newly introduced oral antivirals, in addition to existing spontaneous reporting systems and healthcare database studies (i.e., secondary data), as it is complementary to these systems in several ways. First, it is better suited to capture the more frequent AE, including those that are not medically attended. It generates more comprehensive safety data, e.g. on disease course and the impact of the AE. Moreover, there is insufficient data on these new medicines in real clinical practice, particularly from large-scale studies on the long-term efficacy or safety.

This work, with scientific and academic interest but, essentially, clinical and regulatory importance, constitutes a duty of the regional pharmacovigilance units. As such, it is also an obligation of the Pharmacy and Therapeutics Commissions, based on the legislation in force, to "collaborate in studies to monitor the safety and effectiveness of medicines promoted in the context of the National Pharmacovigilance System".

• Study Type: Observational
• Enrollment (Actual): 211

Contacts and Locations

• Study Contact: Name: Renato Ferreira da Silva, MPharm, PhDc; Phone Number: (+351)916599298; Email: rsilva@med.up.pt
• Study Contact Backup: Name: Janete Santos, PhD; Phone Number: (+351) 225 513 600; Email: investigaclinica@med.up.pt

Study Locations

• Portugal
  • Açores, Portugal
    • Hospital do Divino Espírito Santo de Ponta Delgada, EPE
  • Lisboa, Portugal
    • Centro Hospitalar de Lisboa Ocidental, EPE
  • Porto, Portugal
    • Centro Hospitalar de Vila Nova de Gaia/Espinho, EPE
  • Porto, Portugal
    • Centro Hospitalar e Universitário de São João, EPE
  • Porto, Portugal
    • Centro Hospitalar Universitário de Santo António, EPE
  • Porto, Portugal
    • Unidade de Saúde Familiar - Homem do Leme (ACES Porto Ocidental)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Patients receiving the oral antivirals against COVID-19 - Paxlovid® or Lagevrio®.

Description

Inclusion Criteria:

Participants eligible to be included in the study are identified by medical prescribing of one of the drugs under study, and either the medicine recipient or their proxy should:

1. Comply with the eligibility criteria for prescribing these drugs (including patients ≥ 18 years old), according to Norm nr 005/2022 of the General Directorate of Health of Portugal*;
2. Enrol in the study within the first 72 hours after dispensing treatment;
3. Be able to understand the Portuguese language;
4. Available for follow-up during study time;

5. Provide informed consent.

   • Compliance with the eligibility criteria for prescribing these drugs is the sole responsibility of the prescriber who assesses the patient, so the study centres only include patients referred by the prescriber.

Exclusion Criteria:

Will be considered ineligible participants those who:

1. Are not available for follow-up and monitoring;
2. Participate in phase I, II, III or IV clinical trials;
3. Life expectancy is less than one month.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Oral antiviral A; Patients with an indication for treatment with nirmatrelvir + ritonavir (Paxlovid®).	Drug: Nirmatrelvir/ritonavir; Nirmatrelvir/ritonavir; Other Names: Paxlovid
Oral antiviral B; Patients with an indication for treatment with molnupiravir (Lagevrio®).	Drug: Molnupiravir; Molnupiravir; Other Names: Lagevrio

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety outcome	The incidence of AE (with particular focus on AE of special interest) that emerge during or after the treatment period, serious AE, and AE leading to discontinuation of the treatment, as coded according to the MedDRA. Incidence data will be provided for each treatment group within the safety analysis population, including all patients who received at least one drug dose. The occurrence of AE will be asked in open question / unsolicited. For each reported AE, date of onset, outcome, duration of symptoms (if recovered), and severity/impact of the symptoms (including medical assistance & hospitalisation) will be asked.	6 days after onset treatment for both drugs.
Safety outcome	The incidence of AE (with particular focus on AE of special interest) that emerge during or after the treatment period, serious AE, and AE leading to discontinuation of the treatment, as coded according to the MedDRA. Incidence data will be provided for each treatment group within the safety analysis population, including all patients who received at least one drug dose. The occurrence of AE will be asked in open question / unsolicited. For each reported AE, date of onset, outcome, duration of symptoms (if recovered), and severity/impact of the symptoms (including medical assistance & hospitalisation) will be asked.	39 days after treatment onset for nirmatrelvir/ritonavir cohort.
Safety outcome	The incidence of AE (with particular focus on AE of special interest) that emerge during or after the treatment period, serious AE, and AE leading to discontinuation of the treatment, as coded according to the MedDRA. Incidence data will be provided for each treatment group within the safety analysis population, including all patients who received at least one drug dose. The occurrence of AE will be asked in open question / unsolicited. For each reported AE, date of onset, outcome, duration of symptoms (if recovered), and severity/impact of the symptoms (including medical assistance & hospitalisation) will be asked.	19 days after treatment onset for molnupiravir cohort.
Effectiveness outcome	The incidence of hospitalisation for any cause (defined as ≥24 hours of acute care in a hospital or any similar facility) or death for any cause through day 29.	29 days after treatment onset for both drugs.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adherence to treatment	Will be measured using the self-reported 7-item Measure Treatment Adherence (MTA) tool validated for the Portuguese Population. The MTA is a psychometric tool derived from the Morisky et al. questionnaire and evaluates the individuals' behaviour concerning the daily use of medication.	6 days after onset treatment for both drugs.

Collaborators and Investigators

• Sponsor: Universidade do Porto
• Collaborators: Centro de Investigação em Tecnologias e Serviços de Saúde (CINTESIS); Rede de Investigação em Saúde (RISE), Laboratório Associado; Faculty of Medicine (FMUP)
• Investigators: Study Director: Jorge Junqueira Polónia, MD, PhD, Faculty of Medicine (FMUP)

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2022
• Primary Completion (Estimated): January 31, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: May 31, 2023
• First Submitted That Met QC Criteria: June 6, 2023
• First Posted (Actual): June 8, 2023

Study Record Updates

• Last Update Posted (Actual): December 18, 2023
• Last Update Submitted That Met QC Criteria: December 15, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Safety; COVID-19; Effectiveness; Post-marketing surveillance; Antivirals
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Nirmatrelvir; Molnupiravir; Nirmatrelvir and ritonavir drug combination
• Other Study ID Numbers: ESOA-19; EUPAS48186 (Other Identifier: EU PAS Register - ENCePP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No