Paxlovid for COVID-19

(CanTreatCOVID Trial)

Recruiting at 5 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Unity Health Toronto

Must not be taking: Paxlovid

Disqualifiers: Hospitalized, Pregnancy, Breastfeeding, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 21

Duration: 4 weeks

10000 Participants Needed

Trial Summary

What is the purpose of this trial?

CanTreatCOVID is an open-label, individually randomized, multi-centre, national trial. CanTreatCOVID aims to establish an adaptive platform trial aimed at evaluating the clinical- and cost-effectiveness, practical challenges, and outcomes of therapeutics for SARS-CoV-2 for non-hospitalized patients in Canada. Participants will be randomized to receive usual care (i.e. supportive care and symptom relief) or a study therapeutic, which will be determined by the Canadian COVID-19 Out-Patient Therapeutics Committee. The primary outcomes being evaluated is hospitalization and/or death at 28 days, as well as time to recovery.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you must stop taking your current medications. However, if you are taking a drug that is contraindicated or not recommended with Paxlovid, you may need to stop it. Please consult with the trial investigator for specific guidance.

What data supports the idea that Paxlovid for COVID-19 is an effective drug?

The available research shows that Paxlovid, a combination of nirmatrelvir and ritonavir, is effective in reducing the risk of hospitalization and death in high-risk adults with COVID-19. One study found that it reduced these risks by 89% in high-risk, ambulatory adults. Other studies have also shown that Paxlovid helps prevent severe outcomes in symptomatic, high-risk patients. This suggests that Paxlovid is a strong option for treating COVID-19, especially for those at high risk of severe illness. ^{1 2 3 4 5}

What safety data is available for Paxlovid (nirmatrelvir/ritonavir) for COVID-19 treatment?

Safety data for Paxlovid includes nonclinical safety assessments and clinical studies. Nonclinical studies in animals showed transient increases in locomotor activity, respiratory rate, blood pressure, and decreases in heart rate at high doses, but no adverse findings in repeat dose toxicity studies. Clinical studies have shown Paxlovid reduces hospitalization and death in high-risk COVID-19 patients, with some adverse events reported. Drug interactions due to ritonavir's effect on CYP3A4 are also noted. ^{1 2 5 6 7}

Is Paxlovid a promising drug for treating COVID-19?

Yes, Paxlovid is a promising drug for treating COVID-19. It is designed to prevent severe illness in people with mild symptoms or those who are asymptomatic, which can help reduce hospitalizations and deaths. Paxlovid is taken orally and is especially aimed at people at high risk of severe COVID-19. ^{3 4 5 6 8}

Eligibility Criteria

This trial is for Canadians with COVID-19 who aren't hospitalized. It's for those over 50, or 18-49 with conditions like heart disease, diabetes, or weakened immune systems. They must start treatment within 5 days of symptoms and not be in another conflicting COVID-19 drug study.

Inclusion Criteria

I am over 50 or have a chronic condition or a weakened immune system.

I can start the study treatment within 5 days of showing COVID-19 symptoms.

You have tested positive for SARS-CoV-2, and can provide a picture of the positive test result.

Exclusion Criteria

I or my caregiver cannot give informed consent.

I have been in the hospital or emergency department for over 24 hours.

Previously randomized to CanTreatCOVID

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive usual care or a study therapeutic determined by the Canadian COVID-19 Out-Patient Therapeutics Committee

4 weeks

Weekly visits (virtual or in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of symptom severity and quality of life

36 weeks

Visits at 21 days, 28 days, 90 days, and 36 weeks

Long-term follow-up

Cost-utility analysis and long-term outcomes are assessed

24 months

Treatment Details

Interventions

• Paxlovid

Trial Overview The trial compares usual care to Paxlovid and other treatments decided by a committee. Patients are randomly chosen to get either the standard support or a new therapy. The main focus is on whether these prevent hospitalization/death within 28 days and how quickly patients recover.

Participant Groups

Group I: Paxlovid Experimental Treatment 1 Intervention

Nirmatrelvir/ritonavir (Paxlovid™) BD x 5 days (this arm has been closed of Sept 30th 2024)

Group II: Other Emerging Interventions (arm 4) Experimental Treatment 1 Intervention

Additional treatment regimens will be decided by the Canadian COVID-19 Out-Patient Therapeutics Committee based on doses and durations studied in past trials and the latest evidence

Group III: Antioxidant Therapy - Intervention (arm 3) Experimental Treatment 1 Intervention

Antioxidant therapy (comprising of selenium, zinc, lycopene, and vitamin C)

Group IV: Control group Active Control 1 Intervention

Usual care (i.e., supportive care and symptom relief)

Paxlovid is already approved in United States, European Union, Canada, Japan, Switzerland for the following indications:

Approved in United States as Paxlovid for:

• COVID-19

Approved in European Union as Paxlovid for:

• COVID-19

Approved in Canada as Paxlovid for:

• COVID-19

Approved in Japan as Paxlovid for:

• COVID-19

Approved in Switzerland as Paxlovid for:

• COVID-19

Who Is Running the Clinical Trial?

Unity Health Toronto

Lead Sponsor

Trials

572

Recruited

470,000+

Health Canada

Collaborator

Trials

36

Recruited

38,700+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Findings from Research

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]

In a study of 552 COVID-19 patients, treatment with Paxlovid® did not significantly reduce hospitalisation rates or all-cause mortality compared to a matched control group, indicating limited effectiveness in this local setting.

While adverse effects from Paxlovid® were common, they were generally not severe, suggesting that while the drug may not lower hospitalisation or death rates, it is relatively safe for use in high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of nirmatrelvir/ritonavir (Paxlovid®) in preventing hospitalisation and death among COVID-19 patients: a prospective cohort study. Chew, LS., Lim, XJ., Chang, CT., et al.[2023]

Nirmatrelvir/ritonavir (Paxlovid) shows low-certainty evidence of reducing all-cause mortality and hospital admissions in high-risk, unvaccinated outpatients with mild COVID-19, particularly during the Delta variant wave, based on a review of 2 RCTs involving 2510 participants.

In inpatients with moderate to severe COVID-19, the evidence regarding the efficacy of nirmatrelvir/ritonavir is very low, with no significant findings on mortality or viral clearance, highlighting the need for further research in this population.

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]

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]

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, which combines nirmatrelvir and ritonavir, is an effective oral antiviral treatment for COVID-19, with nirmatrelvir specifically targeting the SARS-CoV-2 main protease to inhibit viral replication.

Ritonavir enhances the effectiveness of nirmatrelvir by slowing its metabolism, but it also poses a risk for drug interactions due to its role as a CYP3A4 inhibitor, necessitating careful management of other medications during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interactions listed in the Paxlovid fact sheet, classified according to risks, pharmacological groups, and consequences. Azanza, JR., Mensa, J., González Del Castillo, J., et al.[2022]

Nirmatrelvir, the active ingredient in Paxlovid, showed a favorable safety profile in nonclinical studies, with no significant adverse effects observed in repeat dose toxicity studies conducted in rats and monkeys for up to one month.

The drug effectively targets the SARS-CoV-2 3CL protease, essential for viral replication, and demonstrated efficacy in high-risk COVID-19 patients, supporting its use in preventing severe outcomes like hospitalization and death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive Nonclinical Safety Assessment of Nirmatrelvir Supporting Timely Development of the SARS-COV-2 Antiviral Therapeutic, Paxlovid™. Sathish, JG., Bhatt, S., DaSilva, JK., et al.[2022]

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]

References

1. 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]

2. Malaysia pubmed.ncbi.nlm.nih.gov

Effectiveness of nirmatrelvir/ritonavir (Paxlovid®) in preventing hospitalisation and death among COVID-19 patients: a prospective cohort study. [2023]

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

Nirmatrelvir combined with ritonavir for preventing and treating COVID-19. [2023]

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

[Nirmatrelvir/ritonavir (Paxlovid®), a treatment for Covid-19]. [2022]

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

Nirmatrelvir combined with ritonavir for preventing and treating COVID-19. [2023]

6. Spain pubmed.ncbi.nlm.nih.gov

Interactions listed in the Paxlovid fact sheet, classified according to risks, pharmacological groups, and consequences. [2022]

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

Comprehensive Nonclinical Safety Assessment of Nirmatrelvir Supporting Timely Development of the SARS-COV-2 Antiviral Therapeutic, Paxlovid™. [2022]

8. 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]