Nirmatrelvir–ritonavir treatment for up to 25 days did not improve cognitive dysfunction, autonomic dysfunction, or exercise intolerance among patients with long COVID compared with placebo.
Investigators conducted the randomized, double-blind, placebo-controlled phase 2 RECOVER-VITAL trial at 69 US sites. Adults aged 18 years or older were eligible if they had persistent symptoms for at least 12 weeks following suspected, probable, or confirmed SARS-CoV-2 infection and met criteria for cognitive, autonomic, or exercise-related symptom phenotypes. Of 964 patients randomly assigned, 959 were included in the modified intention-to-treat population: 332 with the cognitive phenotype, 334 with the autonomic phenotype, and 332 with the exercise phenotype. The median age was 49 years, 67% were female, and 78% were White.
Patients were randomly assigned 1:1:1 to receive nirmatrelvir 300 mg plus ritonavir 100 mg twice daily for 15 days followed by placebo plus ritonavir for 10 days, nirmatrelvir–ritonavir for 25 days, or placebo plus ritonavir for 25 days. The primary outcome was clinically meaningful improvement at day 90 on phenotype-specific patient-reported measures of cognitive function, orthostatic symptoms, or postexertional malaise. Secondary outcomes included phenotype-specific performance measures, and patients were followed for 6 months.
Neither active-treatment regimen produced a statistically significant improvement in the primary outcome for any of the 3 phenotypes. Among patients with cognitive dysfunction, 58% receiving 25 days of nirmatrelvir–ritonavir and 53% receiving 15 days improved at day 90, compared with 55% receiving placebo, with adjusted differences of 3% and −2%, respectively. Among patients with autonomic dysfunction, improvement occurred in 62% receiving 25 days of treatment, 70% receiving 15 days, and 70% receiving placebo, with adjusted differences of −6% and less than 1%, respectively.
For the exercise phenotype, 25% of patients receiving the 25-day regimen and 34% receiving the 15-day regimen improved, compared with 33% receiving placebo. The adjusted differences were −8% for 25 days and 1% for 15 days. The researchers also found no differences in secondary outcomes.
Results were consistent at other assessment points and among patients with high treatment adherence. Prespecified subgroup analyses found no evidence of differential treatment effects by vaccination status, time since the infection associated with long COVID, race, ethnicity, sex, or treatment received during the initial SARS-CoV-2 infection.
No new safety signals emerged with the longer treatment courses. Serious adverse events occurred in 42 of 963 patients, or 4%, with similar rates among treatment groups, and no deaths occurred.
The investigators noted substantial improvement over time on patient-reported outcomes across treatment groups, including among patients receiving placebo. They reported that this improvement exceeded assumptions used to design the trial and may have limited the ability to detect a treatment effect. Improvement was less pronounced on performance-based measures, underscoring differences between patient-reported and performance outcomes.
Several limitations affected interpretation of the findings. The authors noted difficulties establishing long COVID with homogeneous specificity and the absence of validated long COVID-specific symptom assessment tools. The study population was 78% White, potentially limiting generalizability. Patients also had symptoms for a prolonged period before enrollment, potentially placing some beyond the point when antiviral treatment could have an effect. The trial did not establish which patients had viral persistence at baseline, and whether treatment longer than 25 days would be needed for long COVID related to persistent virus remains uncertain. Analyses of collected blood samples for evidence of persistent virus and changes in viral antigen following treatment are pending.
The findings did not support nirmatrelvir–ritonavir for up to 25 days for the cognitive, autonomic, or exercise-related long COVID phenotypes studied,although it remains unclear whether patients with demonstrated viral persistence might respond differently. “Antiviral treatment with nirmatrelvir–ritonavir in patients with long COVID for up to 25 days did not improve cognitive, autonomic, or exercise symptomatology as measured by symptom-specific PROMs and performance measures,” wrote lead study author Lindsey R. Baden, MD, of Brigham and Women’s Hospital and Harvard Medical School, and colleagues.
Several authors reported relationships with pharmaceutical companies, including Pfizer; others reported no competing interests.
Source: The Lancet Infectious Diseases
