Key results

The evidence suggests that molnupiravir reduces the risk of hospitalisation or death and COVID-19-related death in unvaccinated, non-hospitalised people with mild or moderate COVID-19 who are at increased risk of developing severe COVID-19 disease, and may also reduce time to viral RNA clearance, compared to placebo.

What is the evidence informing this conclusion?

The evidence comes from two randomised controlled trials comparing 800 mg molnupiravir twice a day for five days with placebo in non-hospitalised adults with mild or moderate COVID-19 (Jayk Bernal 2021; Fischer 2021). Jayk Bernal 2021 is a phase III trial (known as MOVe-OUT) that included 1433 patients to either molnupiravir or placebo. Recruitment of participants was carried out in 20 countries.

Fischer 2021 is a phase IIa trial in which 55 patients received 800mg molnupiravir and 62 received placebo. This trial was conducted in the USA.

The published results were for people who had treatment within 5 days of symptom onset in MOVe-OUT and within 7 days in the Fischer 2021 study. In MOVe-OUT, standard-of-care treatment was allowed with antipyretic agents, anti-inflammatory agents, glucocorticoids, or a combination. Use of therapies for COVID-19 treatments, such as monoclonal antibodies and remdesivir, was prohibited until day 29. The study by Fischer 2021 did not report details about standard of care, however use of therapeutic interventions for COVID-19 prior to study entry was one of the exclusion criteria.

Publication status

Both studies are full publications.

Study characteristics

The MOVe-OUT study enrolled participants who were at increased risk of disease progression due to at least one of the following factors: age over 60, obesity, or another comorbidity including active cancer; chronic kidney disease; COPD; serious heart conditions, or diabetes mellitus. In the Fisher 2021 study, 60% of participants had at least one risk factor for developing severe COVID-19 disease (risk factors not reported). The MOVe-OUT trial followed up participants through to 29 days after randomisation while Fischer 2021 assessed outcomes for up to 28 days following treatment initiation. Pregnant women were excluded from both studies. Both studies excluded SARS-CoV-2 vaccinated participants. Both studies excluded patients who need supplemental oxygen or have an anticipated need for hospitalisation.

In the MOVe-OUT study, the median age of the participants was 43 (range 18–90). In Fischer 2021, the age range was 18 to 71 years. In MOVe-OUT, the proportion of females was 51.3% overall, and was higher in the molnupiravir group (53.6%) than the placebo group (49.0%). In Fischer 2021, 54.8% of the study population in placebo and 49.1% in molnupiravir were female.

What are the main results?

Our confidence in the results

Outcomes from both studies were rated as having a low risk of bias due to there being very few concerns around study design and results. In the MOVe-OUT trial, there was a greater proportion of females in the molnupiravir group (53.6%) compared with the placebo group (49%), however an analysis for the primary outcome of hospitalisation or death was adjusted for participant sex, and the results were consistent with the primary analysis.

In Fischer 2021, sample collection was carried out for antiviral efficacy and safety at day 1, 3, 5, 7, 14 and 28. However, no outcomes were reported at 28 days and only data at day 14 was available as an endpoint. Time to viral clearance was not reported in sufficient detail to be extracted and included in this review. Fischer 2021 did not report outcomes on hospitalisation or death.

Since both studies cited in this review took place before the emergence of the Omicron variant, and before the availability of vaccination against COVID-19, the populations measured in the study may not be directly relevant or comparable to current populations in the UK, where the Delta and Omicron variants are dominant and many people have been vaccinated against COVID-19. As a result, the certainty in all outcomes presented was downgraded due to indirectness.

Benefits and harms

The panel considered evidence presented in two randomised controlled trials: the MOVe-OUT trial and Fischer 2021. Both trials included people aged 18 and above, with at least one risk factor for progressing to severe disease and administered 800mg of molnupiravir for 5 days. Participants recruited to the MOVe-OUT trial had at least one risk factor for developing severe disease (including age over 60, obesity [BMI ≥30], diabetes, active cancer, chronic kidney disease, chronic obstructive pulmonary disease and serious heart conditions). In Fischer 2021, around 60% of the participants had at least one risk factor for developing severe disease. Both studies recruited people who did not require supplementary oxygen.

The panel noted that molnupiravir should not be offered in people below 18 years of age. There is no evidence for safety and efficacy in this age group in both trials. Both studies excluded people under 18 and pregnant women.

The panel noted that safety data in the summary of product characteristics raised concerns about the long-term safety of molnupiravir in children and young people, and that studies in animals have shown reproductive toxicity. They also acknowledged that there is no evidence on efficacy and safety of molnupiravir in people under 18 or pregnant women in either trial. Based on this information, the panel agreed that molnupiravir should not be offered to children and young people under 18, or pregnant women. For further information, see the summary of product characteristics.

The MOVe-OUT study suggested that molnupiravir statistically significantly reduced the risk of hospitalisation or death (all-cause) compared to placebo. Evidence from both studies suggested a larger reduction in viral load at day 3 and day 5 since baseline in people who received molnupiravir than those who received placebo. The panel noted that although reduction in viral load may not mean a reduction in time to recovery, it may shorten the time that the person is infectious. This may be an important factor for people living with vulnerable or at risk people. Overall, the panel noted that molnupiravir may have benefits in people at risk of progression to severe disease. In the MOVe-OUT study, the published results were for people who had treatment within 5 days of symptom onset, and the panel agreed that this was when treatment was likely to be most effective.

Evidence on adverse events was pooled from both studies. There was no significant difference in adverse events or serious adverse events between the molnupiravir and placebo groups. In the MOVe-OUT trial, the risk of COVID-19 related death was statistically lower in the molnupiravir group compared with placebo (1 COVID-19 related death was reported in the molnupiravir group compared with 9 in the placebo group). In the 14 days beyond the treatment period, there were 2 additional deaths in the placebo group and 1 in the molnupiravir group. The panel agreed that molnupiravir could potentially benefit people with high risk of developing severe disease compared with placebo. The panel considered that the absolute benefit would potentially be smaller among vaccinated people.

The panel also discussed the potential benefits and harms of combination treatment with an antiviral drug and a neutralising monoclonal antibody or another antiviral drug in people who do not need supplemental oxygen for COVID-19 and who are at high risk of progression to severe disease. The panel were not aware of any clinical trial evidence on combination treatment in this population.

Certainty of the evidence

The certainty of all outcomes from the included studies was downgraded due to indirectness, as the studies took place before the emergence of the Omicron variant of COVID-19 and because no patients in the studies had been vaccinated for COVID-19. The panel agreed that these factors meant evidence from the included studies was not directly relevant to the current situation of COVID-19 in the UK, where the Omicron variant is dominant and many people are vaccinated for COVID-19. The panel were aware that the ongoing UK-wide PANORAMIC study would provide more direct evidence on the effectiveness of molnupiravir in people with COVID-19 in the UK.

In the MOVe-OUT trial, the incidence of all-cause hospitalisation or death and COVID-19 related hospitalisation or death were graded as ‘moderate’ certainty due to indirectness of the study population. Change in viral load at days 3 and 5 were of ‘moderate’ certainty due to the same concern. Other outcomes such as adverse events and serious adverse events were of ‘low’ certainty, because the confidence intervals crossed the line of no effect in addition to indirectness. Imprecision resulted in downgrading of other outcomes to ‘low’ certainty such as risk of COVID-19 related hospitalisation and change in viral load at days 7–10 and days 14–15.

The panel noted that there were subgroup differences for the outcome of hospitalisation or death, according to serostatus. There was a statistically significant difference in all-cause hospitalisation or death in the seronegative subgroup, but not in the seropositive subgroup. The panel discussed this and agreed that as the result for the overall population showed a significant reduction, and the absolute numbers for the subgroup results were small, they would not differentiate between seronegative and seropositive groups in the recommendation. They also pointed out that it was unlikely to be possible to test for serostatus within the timeframes of these treatments, and that delaying for testing would reduce the benefit of treatment.

The panel noted that the evidence was from non-hospitalised people with COVID-19, however the results could also be generalised to people in hospital for reasons other than COVID-19 who meet the criteria set out in the recommendation.

There is no evidence on the safety and efficacy of molnupiravir in children and young people or pregnant women. The panel were not presented with risk of hospitalisation or risk of COVID-19 related death in these groups.

Values and preferences

The panel were not aware of any systematically collected data on peoples’ preferences and values. Molnupiravir can be administered orally and the current formulation is in 200mg capsules, meaning four capsules must be taken twice a day to achieve the dose recommended in the Summary of Product Characteristics (SmPC). The panel noted that the capsules are large and that some people might find them difficult to take. Therefore adherence and patient preferences might vary.

The panel noted that there is no evidence on the efficacy and safety of molnupiravir in children and young people, or pregnant women, and therefore it cannot be recommended in these groups. The panel believed that, if fully informed, most pregnant women and people under 18 would not choose molnupiravir because of the lack of evidence and the potential harms.

Resources

The recommendations were not informed by a cost effectiveness analysis, however use of molnupiravir on a large scale is likely to incur costs to the healthcare system. These costs may be offset by a reduction in hospitalisation of people with COVID-19 who are at risk of progressing to severe disease.

Equity

The panel noted that the ability to access molnupiravir in the community may benefit people who have limited access to healthcare facilities as it can be delivered to their home. This may be especially relevant for those who find it difficult to travel, for example due to poor access to transport, disability or mobility issues, or childcare or caring responsibilities. In addition, having treatment whilst self-isolating at home may also minimise spread of the virus. However, there may be challenges for some patient groups if travel is needed to access treatment.

The panel noted that the use of molnupiravir to prevent progression to severe COVID-19 disease may not be safe for children and young people under 18, or for pregnant women. The panel noted the inequity of access that this presents however they agreed that this was justified based on safety concerns..

Acceptability

The panel were not aware of any systematically collected evidence about acceptability. However, they noted that receiving a treatment outside of hospital may be more acceptable for many people. The panel noted that although the risks of long-term effects of molnupiravir were assessed as low in the Summary of Product Characteristics (SmPC), these concerns may cause some people to choose not to take molnupiravir. The panel discussed the potential harms of molnupiravir and concluded that there is not enough evidence in children and young people or pregnant women to recommend it. They agreed that its use in these groups is not likely to be acceptable.

Feasibility

The dosage administration of molnupiravir might cause adherence issues for some patients. The panel noted that four capsules of 200mg twice a day may be difficult for patients to adhere to for five days.