Paxlovid + Remdesivir for Post-COVID Syndrome

(DEFEND Trial)

Recruiting at 3 trial locations

Overseen By Dr. Kieran Quinn

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Mount Sinai Hospital, Canada

Must not be taking: CYP3A inducers

Disqualifiers: Severe allergy, Oxygen, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

Duration: 1 week

118 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether Paxlovid (Nirmatrelvir/ritonavir) or Veklury (Remdesivir) can prevent heart problems that sometimes occur after COVID-19 in hospitalized patients. Researchers aim to determine the effectiveness of these treatments in stopping these issues from developing. The trial compares each drug against a placebo (a pill with no active drug). Candidates for this trial include individuals who tested positive for COVID-19 within the last five days, are hospitalized but not on oxygen, and have no severe allergies to the treatments. As a Phase 4 trial, this research seeks to understand how these FDA-approved treatments benefit more patients.

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 is the safety track record for these treatments?

Research shows that both Paxlovid (nirmatrelvir/ritonavir) and Veklury (remdesivir) have undergone safety testing in people.

Studies suggest that Paxlovid is generally well-tolerated. In trials, patients taking Paxlovid showed no major health differences compared to those taking a placebo, a harmless pill used for comparison. This suggests Paxlovid is likely safe, though more research is needed to determine its effectiveness for long COVID.

Real-world data indicate that Veklury might reduce the risk of long-COVID symptoms in people hospitalized with COVID-19. Safety reviews have found that serious side effects, such as heart problems, were rare.

The FDA has approved both treatments for COVID-19, indicating they are considered safe for their approved uses. However, their safety and effectiveness for post-COVID conditions remain under study. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about Paxlovid and Veklury for addressing post-COVID syndrome because of their novel mechanisms of action. Unlike most treatments that primarily focus on symptom management, Paxlovid, with its active ingredient nirmatrelvir/ritonavir, directly targets the virus's ability to replicate, potentially reducing the overall viral load. Meanwhile, Veklury, known as Remdesivir, disrupts viral replication by inhibiting the RNA polymerase enzyme. These approaches could offer more direct and effective relief for individuals suffering from lingering effects of COVID-19, compared to current standard treatments that might not target the virus as precisely.

What evidence suggests that this trial's treatments could be effective for post-COVID syndrome?

This trial will compare Paxlovid (nirmatrelvir/ritonavir) and Veklury (remdesivir) for their effects on post-COVID syndrome. Studies have suggested that Paxlovid might lower the risk of developing long COVID, especially when taken soon after symptoms begin. However, some studies have shown mixed results, leaving its effectiveness in preventing long COVID unclear. Research on Veklury has indicated it might reduce the risk of certain long COVID symptoms in people hospitalized with COVID-19. Data shows that those treated with remdesivir face a slightly lower chance of long-term complications. Both treatments show promise, but their specific effects on long COVID are still under investigation in this trial. ^{3 6 7 8 9}

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Nirmatrelvir/ritonavir
• Remdesivir

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.

How Is the Trial Designed?

Group I: Veklury Experimental Treatment 1 Intervention

Veklury vs. placebo

Group II: Paxlovid Experimental Treatment 1 Intervention

Paxlovid vs. placebo

Who Is Running the Clinical Trial?

Mount Sinai Hospital, Canada

Lead Sponsor

Trials

210

Recruited

70,700+

Kingston Health Sciences Centre

Collaborator

Trials

32

Recruited

34,400+

Kingston Health Sciences Centre (Kingston)

Collaborator

Trials

3

Recruited

12,300+

Niagara Health System

Collaborator

Trials

9

Recruited

2,800+

Unity Health Toronto

Collaborator

Trials

572

Recruited

470,000+

Published Research Related to This Trial

A case series of 13 individuals with Long COVID who took extended courses of oral nirmatrelvir/ritonavir (7.5-30 days) showed that some experienced a meaningful reduction in symptoms, although the benefits were not consistent for all participants.

While some individuals reported improvements, one participant experienced significant side effects (intense stomach pain), highlighting the need for further research to determine who may benefit from this treatment and the optimal duration for effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of extended-course oral nirmatrelvir/ritonavir (Paxlovid) in established Long COVID: Case series and research considerations. Cohen, AK., Jaudon, TW., Schurman, EM., et al.[2023]

Nirmatrelvir/ritonavir (Paxlovid®) is an effective oral antiviral treatment for COVID-19, showing good tolerability and the potential to prevent severe complications when administered early in mild-to-moderate cases.

While it enhances the efficacy of nirmatrelvir, ritonavir can cause drug-drug interactions that may limit its use in patients on certain chronic medications, and there is a risk of infection relapse after treatment.

NCBI (Pubmed)

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. Pagliano, P., Spera, A., Sellitto, C., et al.[2023]

Nirmatrelvir-ritonavir (Paxlovid) has been authorized for emergency use to treat COVID-19, but it is associated with various skin-related side effects that need to be monitored.

There are significant drug-to-drug interactions between Paxlovid and commonly used dermatological medications, which could complicate treatment plans for patients with skin conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nirmatrelvir-ritonivir, COVID-19, and possible adverse cutaneous reactions. Albrecht, JM., Cooper, BR., Waller, JD., et al.[2023]

In a study of 5,287 patients treated with Paxlovid for mild to moderate COVID-19, only 6 hospitalizations and 39 emergency department encounters related to COVID-19 were reported within 5-15 days after treatment, indicating that severe outcomes are rare after early treatment.

Paxlovid appears to effectively prevent hospitalization in high-risk patients with mild to moderate COVID-19, supporting its use as an early treatment option authorized by the FDA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hospitalization and Emergency Department Encounters for COVID-19 After Paxlovid Treatment - California, December 2021-May 2022. Malden, DE., Hong, V., Lewin, BJ., et al.[2022]

In the phase II/III EPIC-HR trial, the combination of nirmatrelvir and ritonavir (Paxlovid™) significantly reduced the risk of severe COVID-19 in symptomatic, unvaccinated adults with mild-to-moderate disease, showing lower rates of hospitalization or death compared to placebo.

Nirmatrelvir plus ritonavir is generally well tolerated, with most side effects being mild or moderate, indicating a favorable safety profile for this treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nirmatrelvir plus ritonavir in COVID-19: a profile of its use. Blair, HA.[2023]

Nirmatrelvir-ritonavir (Paxlovid®) is an oral treatment for Covid-19 that has been available since February 4, 2022.

It is specifically designed for individuals at very high risk of developing severe forms of the disease, highlighting its targeted use for vulnerable populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Nirmatrelvir/ritonavir (Paxlovid®), a treatment for Covid-19]. Buxeraud, J., Faure, S., Fougere, É.[2022]

In a study of 264 hospitalized adults with severe comorbidities, Paxlovid (nirmatrelvir plus ritonavir) did not significantly reduce all-cause mortality or the duration of SARS-CoV-2 RNA clearance compared to standard treatment alone.

The incidence of adverse events was similar between the Paxlovid group and the standard treatment group, indicating that Paxlovid does not increase safety risks in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of Paxlovid in severe adult patients with SARS-Cov-2 infection: a multicenter randomized controlled study. Liu, J., Pan, X., Zhang, S., et al.[2023]

Nirmatrelvir/ritonavir (Paxlovid®) has low-certainty evidence suggesting it significantly reduces the risk of all-cause mortality and hospital admissions in unvaccinated, high-risk COVID-19 patients with mild symptoms, based on a study of 2246 participants.

The treatment appears to be safe, with moderate-certainty evidence indicating it may reduce serious adverse events compared to placebo, although it may increase some treatment-related side effects like dysgeusia and diarrhea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nirmatrelvir combined with ritonavir for preventing and treating COVID-19. Reis, S., Metzendorf, MI., Kuehn, R., et al.[2023]

Paxlovid, a two-drug regimen taken for 5 days, is authorized for emergency use to treat nonhospitalized patients at risk for severe COVID-19, but some patients experience symptom recurrence 2-8 days after treatment ends.

The cause of these rebound symptoms, which are generally mild and do not require further antiviral treatment, remains uncertain, with possibilities including drug treatment effects, drug resistance, re-infection, or impaired immunity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

COVID-19 rebound after oral treatment in a nursing home facility: A case series. Betrosian, AP., Christou, SM., Kalathaki, S.[2023]

Citations

1. nature.com nature.com/articles/s41467-025-64851-8

Greater benefits of immediate nirmatrelvir-ritonavir initiation ... Nirmatrelvir-ritonavir is generally recommended to be initiated within five days of COVID-19 symptom onset.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11213188/

Real-World Effectiveness of Nirmatrelvir in Protecting Long ... Paxlovid effectiveness. At 180 days of follow-up, the estimated risk of Long COVID was 30.51 events per 100 persons (95% confidence interval (CI), 30.25 to 30. ...

3. rupress.org rupress.org/jhi/article/2/1/e20250107/278440/Nirmatrelvir-ritonavir-use-reduces-risk-for-long

Nirmatrelvir/ritonavir use reduces risk for long COVID in ... While nirmatrelvir/ritonavir has proven effective in decreasing the severity of acute COVID-19, its impact on long COVID remains uncertain (2).

4. academic.oup.com academic.oup.com/ofid/article/12/10/ofaf567/8255716

Risk of Post-COVID-19 Conditions Among Adolescents and ... Results using real-world data suggest a protective relationship between nirmatrelvir-ritonavir during acute illness and PCC risk among older adults, but not ...

5. cidrap.umn.edu cidrap.umn.edu/covid-19/studies-show-mostly-poor-long-covid-protection-paxlovid

Studies show mostly poor long-COVID protection for ... Two new studies find limited evidence of the usefulness of Paxlovid (nirmatrelvir-ritonavir) to prevent the development of long COVID—but ...

6. nature.com nature.com/articles/s43856-024-00668-8

Impact of extended-course oral nirmatrelvir/ritonavir in ... Our results suggest that extended courses of nirmatrelvir/ritonavir could be beneficial for some people with Long COVID.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40188838/

a double-blind, randomised, placebo-controlled, phase 2, ... Nirmatrelvir-ritonavir administered for 15 days did not significantly improve health outcomes in participants with long COVID compared with placebo-ritonavir ...

8. thelancet.com thelancet.com/journals/laninf/article/PIIS1473-3099(25)00073-8/fulltext

Nirmatrelvir–ritonavir versus placebo– ... - The Lancet In the PAX LC trial, we aimed to investigate the efficacy, safety, and tolerability of a 15-day nirmatrelvir–ritonavir regimen in individuals ...

9. academic.oup.com academic.oup.com/ofid/article/12/1/ofae756/7935346

Effect of Nirmatrelvir-Ritonavir on Short- and Long-term ... This retrospective cohort study found that patients kidney disease who received nirmatrelvir/ritonavir for COVID-19 were less likely to be hospitalized wit.