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Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial
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This analysis of the largest randomised trial involving people vaccinated against SARS-CoV-2 infection who are at increased risk of adverse outcomes in the community and unwell with COVID-19 showed that the early addition of molnupiravir to usual care did not reduce hospital admissions or death (which were low in both treatment groups). However, participants in the molnupiravir plus usual care group recovered faster than those in the usual care group, had a higher rate of early sustained recovery, and had fewer general practitioner consultations. This faster patient-reported recovery was consistent with a reduction in detectable virus and viral load in participants who received molnupiravir compared with those who received usual care only. We did not identify any patient subgroup in which molnupiravir was associated with a reduced chance of hospital admission, and benefits in terms of time to first self-report of recovery were evenly distributed across subgroups. We recorded few serious adverse events in the trial, and none definitely related to molnupiravir.
Median time from randomisation to first recovery was 9 days (IQR 5-23) in the molnupiravir plus usual care group and 15 days (7-not reached) in the usual care group (estimated benefit 4⋅2 days [95% BCI 3⋅8-4⋅6]; posterior probability of superiority of >0⋅99; figure 3; table 2). Estimated median time to first recovery was 10⋅4 days (95% BCI 10⋅1-10⋅6) in the molnupiravir plus usual care versus 14⋅6 days (14⋅2-15⋅0) in the usual care group (hazard ratio 1⋅36 [95% BCI 1⋅32-1⋅40]), which met the prespecified superiority threshold (table 2). Subgroup analyses showed that this benefit was consistent across all studied groups (figure 4).
Compared with the usual care group, participants in the molnupiravir plus usual group more often reported early sustained recovery, higher self-rated wellness (appendix p 182), reduced time to sustained recovery, reduced time to alleviation of all symptoms (and each symptom; appendix pp 183-84), reduced time to sustained alleviation of all symptoms (appendix pp 183-84), reduced time to reduction of symptom severity (appendix p 185), fewer moderate or severe symptoms at days 7, 14, and 28 (table 2), and less contact with general practitioners (table 2). Emergency department attendance and the number of new infections in participants' households were similar in both groups (table 2).
In the intensively sampled virology cohort, SARS-CoV-2 viral load was undetectable on day 7 in seven (21%) of 34 participants in the molnupiravir plus usual care group and one (3%) of 39 in the usual care group (p=0⋅039; table 3). The geometric mean viral load was 6603 (SD 25) in the molnupiravir plus usual care group and 8 5025 (24) in the usual care group (p<0⋅0001; table 3). In the less intensively sampled virology cohort, viral loads were lower in the molnupiravir plus usual care group than in the usual care group at day 5 (table 3). Viral load at day 14 was low overall but slightly higher in the molnupiravir plus usual care group than in the usual care group (table 3). Serious adverse events were reported for 50 (0⋅4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0⋅3%) of 12 934 in the usual care group (appendix p 188). No serious adverse events that were definitely related to the intervention were reported. 145 (1⋅1%) of 12 774 participants in the molnupiravir plus usual care group withdrew because of adverse effects that were attributed to molnupiravir. No adverse events of special interest were reported.
Summary
Background
The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population.
Methods
PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older-or aged 18 years or older with relevant comorbidities-and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031.
Findings
Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56⋅6 years (SD 12⋅6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1⋅06 [95% Bayesian credible interval 0⋅81-1⋅41]; probability of superiority 0⋅33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0⋅4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0⋅3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir.
Interpretation
Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community.
Funding
UK National Institute for Health and Care Research
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