Nirmatrelvir-Ritonavir and Symptoms in Adults With Postacute Sequelae of SARS-CoV-2 Infection, 2024, Geng et al

Nirmatrelvir-Ritonavir and Symptoms in Adults With Postacute Sequelae of SARS-CoV-2 Infection

Key Points

Question What is the efficacy of 15 days of nirmatrelvir-ritonavir for improving select symptoms of postacute sequelae of SARS-CoV-2 infection (PASC)?

Findings This randomized clinical trial including 155 participants with PASC symptoms (≥3 months’ duration) found that a 15-day course of nirmatrelvir-ritonavir in a mostly vaccinated study cohort was generally safe, but did not show significant benefit in improving fatigue, brain fog, body aches, cardiovascular symptoms, shortness of breath, or gastrointestinal symptoms.

Meaning These findings indicate that further studies are needed to determine the role of antivirals in the treatment of PASC.

Abstract
Importance There is an urgent need to identify treatments for postacute sequelae of SARS-CoV-2 infection (PASC).

Objective To assess the efficacy of a 15-day course of nirmatrelvir-ritonavir in reducing the severity of select PASC symptoms.

Design, Setting, and Participants This was a 15-week blinded, placebo-controlled, randomized clinical trial conducted from November 2022 to September 2023 at Stanford University (California). The participants were adults with moderate to severe PASC symptoms of 3 months or longer duration.

Interventions Participants were randomized 2:1 to treatment with oral nirmatrelvir-ritonavir (NMV/r, 300 mg and 100 mg) or with placebo-ritonavir (PBO/r) twice daily for 15 days.

Main Outcomes and Measures Primary outcome was a pooled severity of 6 PASC symptoms (fatigue, brain fog, shortness of breath, body aches, gastrointestinal symptoms, and cardiovascular symptoms) based on a Likert scale score at 10 weeks. Secondary outcomes included symptom severity at different time points, symptom burden and relief, patient global measures, Patient-Reported Outcomes Measurement Information System (PROMIS) measures, orthostatic vital signs, and sit-to-stand test change from baseline.

Results Of the 155 participants (median [IQR] age, 43 [34-54] years; 92 [59%] females), 102 were randomized to the NMV/r group and 53 to the PBO/r group. Nearly all participants (n = 153) had received the primary series for COVID-19 vaccination. Mean (SD) time between index SARS-CoV-2 infection and randomization was 17.5 (9.1) months. There was no statistically significant difference in the model-derived severity outcome pooled across the 6 core symptoms at 10 weeks between the NMV/r and PBO/r groups. No statistically significant between-group differences were found at 10 weeks in the Patient Global Impression of Severity or Patient Global Impression of Change scores, summative symptom scores, and change from baseline to 10 weeks in PROMIS fatigue, dyspnea, cognitive function, and physical function measures. Adverse event rates were similar in NMV/r and PBO/r groups and mostly of low grade.

Conclusions and Relevance The results of this randomized clinical trial showed that a 15-day course of NMV/r in a population of patients with PASC was generally safe but did not demonstrate a significant benefit for improving select PASC symptoms in a mostly vaccinated cohort with protracted symptom duration. Further studies are needed to determine the role of antivirals in the treatment of PASC.

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2819901

 

The most interesting part for me is that this trial has, contrary to what had been assumed by everyone, shown that in fact Paxlovid cannot be placebo-controlled by placebo-ritonavir given the discrepancy of dysgeusia reported (63 [61.8%] in NMV/r group and 4 [7.5%] in the PBO/r group). In this case it was probably sensible for them to not report results earlier to not automatically unblind all other Paxlovid trials. I do wonder though why it was assumed that placebo-ritonavir would cause the same amount of dysgeusia as Paxlovid. Given the discrepancy in values it this should have been apparent to everyone organising these trials by simply talking to patients that had taken only ritonavir before. It also raises the question how well blinded any of these trials actually were. Since there's probably more potential for people to believe they are receiving Paxlovid if they experience dysgeusia, it suggests that the trial results are not driven by a placebo-effect, i.e. people that believe they are receiving the active substance are more likely to report improvement. However, this could still be a danger for other Paxlovid trials. But overall it seems like a further argument against psychological believes.

Whilst I understand their argument and it is perfectly reasonable to abort a trial that shows no efficacy, I also find the argument for the necessity of larger trials given the heterogeneity and different subgroups of LC to be somewhat in contradiction to them aborting the trial preliminarily due to a lack of efficacy. If the authors believe that hetreogeneity and subgroups are partially responsible for the null results should they not have wanted to collect more data to see if this might be the case?

 

I didn't see whether patients were asked whether they believed if they received the drug or the control substance and for what reason. I have never understood why that is not a necessary part in every DBPCRCT, at least Fluge and Mella did do this.