Paxlovid + Remdesivir for Post-COVID Syndrome

(DEFEND Trial)

Recruiting in Palo Alto (17 mi)

+3 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: Mount Sinai Hospital, Canada

Must not be taking: CYP3A inducers

Disqualifiers: Severe allergy, Oxygen, Pregnancy, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The DEFEND trial will be the world's first clinical trial to study the effectiveness of Paxlovid or Veklury in the prevention of cardiovascular post-acute sequelae of SARS-CoV-2 among hospitalized adults. Additionally, this pilot study will inform the design and conduct of a future full-scale multi-centre trial by testing the feasibility and accuracy of this study design.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are taking drugs that interact with Paxlovid or Veklury. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Paxlovid (nirmatrelvir/ritonavir) for treating Post-COVID Syndrome?

Research shows that Paxlovid (nirmatrelvir/ritonavir) is effective in reducing the risk of severe COVID-19 outcomes, like hospitalization or death, in high-risk patients. Some case series suggest it may also help people with Long COVID, although more research is needed to confirm its benefits for Post-COVID Syndrome. ^{1 2 3 4 5}

Is Paxlovid safe for humans?

Paxlovid, a combination of nirmatrelvir and ritonavir, has been shown to reduce the risk of hospitalization and death in COVID-19 patients, but it may cause skin reactions and has interactions with other medications. Some patients experience a return of symptoms after treatment, but these are usually mild. ^{5 6 7 8 9}

How is the drug Paxlovid + Remdesivir unique for treating Post-COVID Syndrome?

Paxlovid, which combines nirmatrelvir and ritonavir, is unique because it is an oral antiviral treatment that targets the main protease of the virus, helping to prevent severe COVID-19 in high-risk patients. This combination is now being explored with Remdesivir, another antiviral, to address Post-COVID Syndrome, a condition with no standard treatment, potentially offering a novel approach by combining two antiviral mechanisms. ^{2 3 4 5 8}

Eligibility Criteria

This trial is for hospitalized adults who have recovered from COVID-19 but are at risk of long-term heart problems. Details on specific inclusion and exclusion criteria were not provided, so participants should inquire about these requirements.

Inclusion Criteria

I tested positive for COVID-19 within 5 days before hospital admission.

I do not need extra oxygen.

I can sign the consent form myself or have someone who can do it for me.

Exclusion Criteria

I cannot take Paxlovid or Veklury due to severe allergies or because I'm on certain medications.

I have not taken Paxlovid or Veklury in the last 14 days.

Known positive SARS-CoV-2 PCR or rapid antigen test 5-90 days prior to admission

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive either Paxlovid orally twice daily for 5 days or Veklury intravenously once daily for 5 days, or placebo

1 week

Daily visits (in-person) for 5 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of post-acute sequelae of COVID-19

12 months

Periodic visits (in-person and virtual)

Data Validation

Validation of administrative data to collect participant hospital-based outcome measures

12 months

Treatment Details

Interventions

• Nirmatrelvir/ritonavir (Antiviral)
• Remdesivir (Antiviral)

Trial Overview The DEFEND trial is testing whether Paxlovid (Nirmatrelvir/ritonavir) or Veklury (Remdesivir) can prevent heart issues after COVID-19. It's a pilot study to set up for a larger future trial.

Participant Groups

Group I: Veklury Experimental Treatment 1 Intervention

Veklury vs. placebo

Group II: Paxlovid Experimental Treatment 1 Intervention

Paxlovid vs. placebo

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Niagara Health System St. Catharines, Canada

Kingston Health Sciences Centre Kingston, Canada

Mount Sinai Hospital, Sinai Health System Toronto, Canada

St. Joseph's Health Centre, Unity Health Toronto Toronto, Canada

Who Is Running the Clinical Trial?

Mount Sinai Hospital, Canada Lead Sponsor

Kingston Health Sciences Centre (Kingston) Collaborator

Niagara Health System Collaborator

Unity Health Toronto Collaborator

References

1. United States pubmed.ncbi.nlm.nih.gov

Impact of extended-course oral nirmatrelvir/ritonavir (Paxlovid) in established Long COVID: Case series and research considerations. [2023] Prior case series suggest that a 5-day course of oral Paxlovid (nirmatrelvir/ritonavir) benefits some people with Long COVID, within and/or outside of the context of an acute reinfection. To the best of our knowledge, there have been no prior case series of people with Long COVID who have attempted longer courses of nirmatrelvir/ritonavir.

2. New Zealand pubmed.ncbi.nlm.nih.gov

Nirmatrelvir plus ritonavir in COVID-19: a profile of its use. [2023] Oral nirmatrelvir plus ritonavir (Paxlovid™) is an effective treatment option for coronavirus disease 2019 (COVID-19), the illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nirmatrelvir inhibits the main protease of SARS-CoV-2, with ritonavir acting as a pharmacokinetic booster. In the phase II/III EPIC-HR trial, nirmatrelvir plus ritonavir reduced the risk of progression to severe COVID-19 in symptomatic, unvaccinated, non-hospitalized adults with mild-to-moderate COVID-19 at high risk for progression to severe disease. The incidence of COVID-19-related hospitalization or death through day 28 was significantly lower with nirmatrelvir plus ritonavir than with placebo. The efficacy of nirmatrelvir plus ritonavir has also been demonstrated in the real-world setting. Nirmatrelvir plus ritonavir is generally well tolerated, with most adverse events being of mild or moderate severity.

3. England pubmed.ncbi.nlm.nih.gov

Preclinical discovery and development of nirmatrelvir/ritonavir combinational therapy for the treatment of COVID-19 and the lessons learned from SARS-COV-2 variants. [2023] Label="INTRODUCTION">Nirmatrelvir/ritonavir (Paxlovid®) represent an oral antiviral therapy approved for the treatment of COVID-19. Extensive in vitro and in vivo studies have reported the promising activity of nirmatrelvir/ritonavir against numerous emerging viruses. This combination consists of nirmatrelvir, a protease reversible inhibitor of coronavirus 3CLpro mainly metabolized by cytochrome P450 (CYP)3A4, and ritonavir, an inhibitor of the CYP3A isoforms that enhances the efficacy of nirmatrelvir by fixing its suboptimal pharmacokinetic properties.

4. France pubmed.ncbi.nlm.nih.gov

[Nirmatrelvir/ritonavir (Paxlovid®), a treatment for Covid-19]. [2022] The nirmatrelvir-ritonavir (Paxlovid®) is a treatment against Covid-19 available in pharmacies since February 4, 2022. Administered orally, it is intended only for people at very high risk of contracting one or more severe forms of the disease.

5. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of Paxlovid in severe adult patients with SARS-Cov-2 infection: a multicenter randomized controlled study. [2023] Nirmatrelvir plus ritonavir (Paxlovid) reduced the risk of hospitalization or death by 89% in high-risk, ambulatory adults with COVID-19. We aimed at studying the efficacy and safety of Paxlovid in hospitalized adult patients with SARS-Cov-2 (Omicron BA.2.2 variant) infection and severe comorbidities.

6. England pubmed.ncbi.nlm.nih.gov

Nirmatrelvir combined with ritonavir for preventing and treating COVID-19. [2023] Oral nirmatrelvir/ritonavir (Paxlovid®) aims to avoid severe COVID-19 in asymptomatic people or those with mild symptoms, thereby decreasing hospitalization and death. Due to its novelty, there are currently few published study results. It remains to be evaluated for which indications and patient populations the drug is suitable. OBJECTIVES: To assess the efficacy and safety of nirmatrelvir/ritonavir (Paxlovid®) plus standard of care compared to standard of care with or without placebo, or any other intervention for treating COVID-19 and for preventing SARS-CoV-2 infection. To explore equity aspects in subgroup analyses. To keep up to date with the evolving evidence base using a living systematic review (LSR) approach and make new relevant studies available to readers in-between publication of review updates.

7. United States pubmed.ncbi.nlm.nih.gov

Nirmatrelvir-ritonivir, COVID-19, and possible adverse cutaneous reactions. [2023] Nirmatrelvir-ritonivir (Paxlovid) recently received emergency use authorization for the treatment of coronavirus disease 2019 (COVID-19). Literature has linked numerous cutaneous adverse effects to nirmatrelvir and ritonavir, the copackaged tablets within Paxlovid. A review and comparison of these adverse effects to the common cutaneous manifestations of COVID-19 is provided. Numerous drug-to-drug interactions exist between nirmatrelvir-ritonivir and commonly-used medications within dermatology.

8. China pubmed.ncbi.nlm.nih.gov

COVID-19 rebound after oral treatment in a nursing home facility: A case series. [2023] Paxlovid (nirmatrevir/ritonavir) is a 2 drug regimen taken together twice daily for 5 days was authorized for emergency use for nonhospitalized patients who are at risk for the progression of coronavirus disease (COVID-19). However, recurrence of symptoms 2-8 days after completing the treatment course has been recently recognized. In some cases patients tested negative on a direct SARS-CoV-2 viral test and then tested positive again (rebound COVID-19). The disease is mild and requires no additional antiviral treatment. Data are limited based on anecdotal case reports and few studies. According to the available data it is unclear if rebound symptoms are due to the drug treatment, drug resistance, re-infection or impaired immunity.

9. United States pubmed.ncbi.nlm.nih.gov

Hospitalization and Emergency Department Encounters for COVID-19 After Paxlovid Treatment - California, December 2021-May 2022. [2022] Nirmatrelvir/ritonavir (Paxlovid) is a combination protease inhibitor that blocks replication of SARS-CoV-2 (the virus that causes COVID-19) and has been shown to reduce the risk for hospitalization and death among patients with mild to moderate COVID-19 who are at risk for progression to severe disease* (1). In December 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for early treatment with Paxlovid among persons with mild to moderate cases of COVID-19 who are at high risk for progression to severe disease (2). FDA and a small number of published case reports have documented recurrence of COVID-19 symptoms or a positive viral test result (COVID-19 rebound) 2-8 days after recovery or a negative SARS-CoV-2 test result among patients treated with Paxlovid (3-7); however, large-scale studies investigating severe illness after Paxlovid treatment are limited. This study used electronic health record (EHR) data from a large integrated health care system in California (Kaiser Permanente Southern California [KPSC]) to describe hospital admissions and emergency department (ED) encounters related to SARS-CoV-2 infections during the 5-15 days after pharmacy dispensation of a 5-day treatment course of Paxlovid. Among 5,287 persons aged ≥12 years who received Paxlovid during December 31, 2021-May 26, 2022, 73% had received ≥3 doses of COVID-19 vaccine†, and 8% were unvaccinated. During the 5-15 days after Paxlovid treatment was dispensed, six hospitalizations and 39 ED encounters considered to be related to SARS-CoV-2 infection were identified, representing <1% of all patients to whom Paxlovid treatment was dispensed during the study period. Among these 45 persons, 21 (47%) were aged ≥65 years, and 35 (78%) had at least one underlying medical condition§ (8). This study found that hospitalization or ED encounters for COVID-19 during the 5-15 days after Paxlovid treatment was dispensed for mild to moderate COVID-19 illness were rarely identified. When administered as an early-stage treatment, Paxlovid might prevent COVID-19-related hospitalization among persons with mild to moderate cases of COVID-19 who are at risk for progression to severe disease.