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The following is a summary of “Nirmatrelvir–ritonavir versus placebo–ritonavir in individuals with long COVID in the USA (PAX LC): a double-blind, randomised, placebo-controlled, phase 2, decentralised trial,” published in the April 2025 issue of Lancet Infectious Diseases by Sawano et al. 

Researchers conducted a retrospective study to evaluate the efficacy, safety, and tolerability of nirmatrelvir–ritonavir in treating post-COVID-19 condition (long COVID). 

They carried out a randomized controlled trial (RCT) across 48 contiguous U.S. states, adults (aged ≥18 years) with documented SARS-CoV-2 infection and long COVID symptoms persisting for at least 12 weeks. Exclusion criteria included nirmatrelvir–ritonavir use within 2 months, CYP3A4-dependent medications or strong inducers, acute illness such as SARS-CoV-2 infection in the past 2 weeks, active liver disease, renal impairment, and immunocompromise. Participants were randomly assigned (1:1) via stratified block randomization software to receive either nirmatrelvir (150 mg, 2 tablets) plus ritonavir (100 mg) or placebo plus ritonavir (100 mg), taken orally twice daily for 15 days, stratified by age, sex at birth, and COVID-19 vaccination status. Blinding was maintained for participants, clinicians, and the study team. The primary efficacy endpoint was the change in the Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Physical Health Summary Score (PHSS) from baseline to day 28, analyzed by intention to treat. Safety outcomes were monitored from baseline to week 6. This trial was registered with ClinicalTrials.gov (NCT05668091).  

The results showed that from April 14, 2023, to February 26, 2024, 119 individuals were screened, and 100 were enrolled (66% female [66 of 100], 34% male [34 of 100]). The nirmatrelvir–ritonavir group included 49 individuals, while the placebo–ritonavir group had 51 (intention-to-treat population), 5 withdrew before treatment initiation (3 in the nirmatrelvir–ritonavir group, 2 in the placebo–ritonavir group) and were excluded from the safety analysis. The mean PROMIS-29 PHSS at baseline was 39.6 (95% CI, 37.4 to 41.9) in the nirmatrelvir–ritonavir group and 36.3 (95% CI, 34.4 to 38.2) in the placebo–ritonavir group. Adjusted changes from baseline to day 28 were 0.45 (95% CI, –0.93 to 1.83) for nirmatrelvir–ritonavir and 1.01 (95% CI, –.30 to 2.31) for placebo–ritonavir (adjusted mean difference, –0.55 [95% CI, –2.32 to 1.21]; P =0.54). No deaths or serious adverse events (AEs) occurred through week 6. Treatment-emergent AEs were more frequent with nirmatrelvir–ritonavir (76% [35 of 46]) than placebo–ritonavir (55% [27 of 49]), primarily due to dysgeusia. Treatment discontinuation due to AEs occurred in 2 individuals receiving nirmatrelvir–ritonavir and 1 receiving placebo–ritonavir.  

Investigators concluded that a 15-day course of nirmatrelvir-ritonavir did not improve long COVID outcomes compared to placebo-ritonavir at 28 days. 

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