FormalPara Key Summary Points

Why carry out this study?

Symptoms experienced by patients with COVID-19 are heterogenous and vary in duration, with some patients reporting difficulties with self-care, activities of daily living, and emotional/psychological well-being, which can persist months after the initial infection.

Little is known about the effects of COVID-19 treatments on how patients feel and function.

This analysis sought to assess the effects of a monoclonal antibody (mAb) combination (casirivimab plus imdevimab) on symptoms, daily function, and overall health-related quality of life.

What was learned from the study?

In outpatients with COVID-19 caused by SARS-CoV-2 susceptible variants, symptoms resolved sooner and time to return to usual health and activities was shortened following treatment with a mAb combination.

MAbs may reduce the humanistic burden of COVID-19.

Introduction

According to the World Health Organization, as of the end of 2023, COVID-19 has resulted in over 770 million infections and over 7 million deaths worldwide [1]. While the introduction of comprehensive vaccine programs has reduced the number of deaths due to COVID-19 [2], the virus that causes COVID-19, SARS-CoV-2, continues to evolve and the number of new infections continues to rise [1]. The global impact of COVID-19 has been substantial, and the repercussions of the disease continue to impact healthcare resources, economies, and individuals. In-depth interviews with patients indicate that the impact of living with COVID-19 is significant, and a substantial part of this is due to symptoms, which are frequently persistent [3, 4].

The symptoms experienced by patients with COVID-19 are heterogeneous and vary in duration from days to months and even years [4,5,6,7]. For example, patients with COVID-19 report systemic symptoms, such as fatigue, weakness, and joint pain, along with symptoms of the upper and lower respiratory tract (e.g., dyspnea), the gastrointestinal system, depression/anxiety, and cognitive functioning [3, 5, 8, 9]. While some symptoms like headache, fever, and chills are associated with early stages of the infection and resolve within days, other symptoms such as cough, dyspnea, and loss of taste/smell tend to occur later in the disease trajectory and can become persistent [10]. Studies have estimated that nearly three-quarters of patients have persistent COVID-19-related symptoms, i.e., symptoms lasting at least 60 days after diagnosis [9, 11]. Symptom manifestation is not only burdensome but negatively impacts patients’ daily lives [3, 12, 13]. Specifically, patients with COVID-19 report difficulties with self-care, activities of daily living, and emotional/psychological well-being [3], which can persist months after the initial infection [4]. The impact of COVID-19 on patients has been so profound that there is a call to action for the mental well-being of patients, including increased attention to mental health [14]. Furthermore, research has found that patients with certain risk factors (e.g., higher age, obesity, and comorbidities such as diabetes mellitus) are more likely to experience severe symptoms, even after the introduction of vaccine programs [10, 15].

At the start of the pandemic, clinical trials investigating therapeutics for COVID-19 typically focused on reducing mortality and hospitalizations. However, as the introduction of vaccine programs has reduced the number of severe COVID-19 cases, the focus of outcomes has shifted, and reliable data on the long-term impact of symptoms on patients’ daily lives has become increasingly important for individual patient care, healthcare resource planning, and development of public health policy. Patient-reported outcomes (PROs) are now central to the management of patients with COVID-19, as they reveal the effect of COVID-19 on patients’ health-related quality of life (HRQoL) and inform physicians of possibly more serious complications [16]. PROs directly measure the experience from the patient perspective, without third-party judgment or interpretation from others such as clinicians or researchers [17], and therefore assist regulators with the evaluation of treatment benefit and risk [18]. Their importance in clinical trials and drug approvals was further affirmed when the US Food and Drug Administration (FDA) issued guidance for approaches that measure and analyze common COVID-19-related symptoms in outpatient clinical trials [18]. Furthermore, the benefits of PROs extend beyond clinicians and regulators to inform treatment decisions with patients [19].

Monoclonal antibodies (mAbs) have been used therapeutically since 1985, including in the management of cancers, autoimmune diseases, and infections. They are widely regarded as being highly specific for their target antigen, are generally well tolerated, and can be rapidly developed. In the race to decrease the healthcare, patient, and economic burden of COVID-19, anti-SARS-CoV-2 mAbs were investigated across different settings and patient groups, and found to effectively prevent hospitalizations and other complications associated with COVID-19 [20,21,22,23]. Consequently, four mAbs received Emergency Use Authorizations from the FDA for the treatment of COVID-19; however, none are currently approved in the USA as the currently dominant variants (Omicron lineage) are not thought to be susceptible to the currently available anti-SARS-CoV-2 mAbs [24]. Given the efficacy seen with earlier mAbs in the management of COVID-19 and the continual increase in infection rates, a number of new mAbs are currently under investigation, and clinicians, patients, and policy decision makers are keen to see if this next generation of anti-SARS-CoV-2 mAbs can positively impact clinical endpoints, such as deaths and hospitalizations, but also, and maybe more importantly, PROs, such as symptom relief, activities of daily living, and emotional/psychological well-being.

To date, there is limited evidence from controlled studies regarding patients’ experiences with COVID-19 and the impact of mAbs on their symptoms, functioning, and overall HRQoL. An adaptive, randomized phase 1/2/3 trial conducted before the emergence of Omicron-lineage variants found that a mAb combination (casirivimab plus imdevimab [CAS + IMD]) in patients with confirmed SARS-CoV-2 infection and ≥ 1 risk factor for severe COVID-19 decreased time to symptom resolution by 4 days compared to placebo [23]. The difference was evident from day 3 and consistent across patient subgroups [23]. Here, we further assessed the effects of a mAb combination on symptoms, daily function, and overall HRQoL using PRO data collected from outpatients in this trial.

Methods

Study Design

Details of the study design of the randomized, double-blind, placebo-controlled, adaptive phase 1/2/3 trial that evaluated the safety, tolerability, and efficacy of a mAb combination treatment (CAS + IMD) in outpatients with mild-to-moderate COVID-19 (NCT04425629) have been published previously [23]. In the phase 3 portion of the trial, symptomatic patients were initially randomized 1:1:1 to receive the mAb combination at 8000 mg (4000 mg of each mAb) or 2400 mg (1200 mg of each mAb), or saline placebo intravenously [23]. The design was subsequently amended such that patients were randomized 1:1:1 to receive the mAb combination at 2400 mg, 1200 mg (600 mg of each mAb), or saline placebo [23]. For the analyses reported here, data were for patients receiving mAb (CAS + IMD) 1200 mg or placebo (pooled across the original and amended phase 3 portions). The study was conducted from September 24, 2020 to February 18, 2021. For context, early 2021 marked the emergence of the Alpha variant (B.1.1.7), followed by the Delta variant (B.1.617.2) in summer 2021, and the Omicron variant (B.1.1.529) in December 2021 [25]. Notably, in vitro studies showed that CAS + IMD retained activity against all SARS-CoV-2 variants of concern, including B.1.1.7, B.1.429, B.1.617, and E484K-containing variants [26, 27], until the emergence of the Omicron variant, against which CAS + IMD showed reduced potency, suggesting that it was unlikely to remain efficacious.

Patients

Inclusion and exclusion criteria were also published previously [23]. Briefly, eligible patients were ≥ 18 years old and not hospitalized. All patients had confirmed COVID-19 with a SARS-CoV-2-positive diagnostic test result received ≤ 72 h before randomization and symptom onset ≤ 7 days before randomization.

Assessments

The Symptoms Evolution of COVID-19 (SE-C19) instrument [28, 29], an electronic diary presenting 23 symptoms, was incorporated into phases 1/2/3 of the study to assess patient symptoms. In the SE-C19, patients indicated the COVID-19 symptoms they experienced and rated the severity of each experienced symptom in the past 24 h at its worst using four response categories: no symptom, mild, moderate, and severe. The SE-C19 was assessed daily for 29 days.

During amendments of the phase 1/2/3 trial, and given the increasing importance of including additional PROs beyond symptoms in COVID-19 clinical trials, return to usual health [18], return to usual activities [18], the EuroQol 5 Dimension 5 Level (EQ-5D-5L) questionnaire [30, 31], and the Work Productivity, Activity Impairment, and Classroom Impairment Questions (WPAI + CIQ):COVID-19 Infection [32, 33] questionnaire were added to the study protocol to assess patients’ broader health and well-being. Because of the logistics involved in translation and deployment during the trial, these assessments were not immediately available to all patients for completion. Time to return to usual health and activities and the EQ-5D-5L were assessed daily for 29 days, and the WPAI + CIQ:COVID-19 Infection was assessed on days 7, 15, 22, and 29. Details regarding all assessments are provided in the Supplemental Appendix, Online Supplementary Material.

Statistical Analyses

All PROs were evaluated as prespecified exploratory analyses and assessed in the modified full analysis set (mFAS), which comprised all randomized outpatients who had a positive SARS-CoV-2 central lab-determined quantitative reverse transcription polymerase chain reaction test from nasopharyngeal swab samples at randomization and ≥ 1 risk factor for severe COVID-19 at baseline. Data for the EQ-5D-5L and the WPAI + CIQ:COVID-19 Infection were reported based on the number of patients expected to complete each assessment (the PRO analysis set) and the mFAS (sensitivity analysis).

A time to symptoms resolution endpoint with three response categories (0 [no symptom], 1 [mild/moderate], and 2 [severe]) was used, and 19 symptoms were assessed [28]. Time to sustained symptoms resolution for ≥ 2 or ≥ 3 consecutive days was evaluated daily. For all time to event analyses, median times and 95% confidence intervals (CIs) were estimated using the Kaplan–Meier method, and nominal p values were calculated using the log-rank test. Hazard ratios and 95% CIs were estimated using a stratified Cox proportional hazard model with the discrete method of tie handling and using country-based strata.

Longitudinal changes from baseline in health status were assessed via restricted maximum likelihood-based mixed-model repeated measures analysis of change from baseline in EQ-5D visual analog scale (VAS) from days 1 to 29. The model included each treatment arm, timepoint, and country as fixed-effect categorical factors, baseline PRO score, interaction between PRO score and time, and interaction of treatment and time.

Statistical analyses were performed using SAS version 9.3 or higher (SAS Institute; Cary, NC, USA). Additional statistical methods are described in the Supplemental Appendix, Online Supplementary Material.

Ethical Approval

The trial was conducted in accordance with the Declaration of Helsinki, the International Council for Harmonisation Good Clinical Practice guidelines, and all applicable regulatory requirements [23]. The local institutional review board or ethics committee at each trial site monitored trial conduct and documentation. Data were reported according to CONSORT-PRO guidelines. All patients provided written informed consent [23].

Results

Baseline Characteristics

Baseline demographics and clinical characteristics for the mFAS were previously described [23]. Overall, 2077 patients were included in this analysis; 736 received mAb treatment and 1341 received placebo. The median duration of COVID-19 symptoms before randomization was 3 days for both groups [23].

SE-C19

Completion rates for the SE-C19 instrument were high across both groups (> 89%) at baseline and exceeded 70% and 50% at days 7 and 29, respectively (see Supplementary Fig. 1, Online Supplementary Material). The median time to first day of symptoms resolution with mAb and placebo was reported previously and was 4 days shorter with mAb than placebo (p < 0.001) [23]. Compared with placebo, mAb was also associated with a shorter median time to sustained symptoms resolution for ≥ 2 consecutive days (14 vs 17 days; nominal p = 0.0017) and ≥ 3 consecutive days (17 vs 21 days; nominal p = 0.0046) (Fig. 1).

Fig. 1
figure 1

Time to sustained symptoms resolution for a ≥ 2 and b ≥ 3 consecutive days by treatment group. CAS + IMD casirivimab plus imdevimab, CI confidence interval, HR hazard ratio

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Time to Return to Usual Health and Time to Return to Usual Activities

Completion rate ranges for return to usual health during the study in the mAb and placebo groups were 47.5‒68.1% and 46.0‒62.3%, respectively (see Supplementary Fig. 2, Online Supplementary Material). Similar completion rates were observed for return to usual activities (47.5‒68.2% and 46.2‒62.1%, respectively) (see Supplementary Fig. 3, Online Supplementary Material). Median time to return to usual health for ≥ 1 day was 9 days for mAb versus 12 days for placebo (nominal p = 0.0001; Fig. 2a). This trend was sustained for ≥ 2 consecutive days (12 vs 15 days; nominal p = 0.0001) and ≥ 3 consecutive days (14 vs 18 days; nominal p = 0.0003) (Fig. 2b, c).

Fig. 2
figure 2

Time to return to usual health for a ≥ 1, b ≥ 2, and c ≥ 3 consecutive days. CAS + IMD casirivimab plus imdevimab, CI confidence interval, HR hazard ratio

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Similarly, median time to return to usual activities for ≥ 1 day was shorter with mAb versus placebo (8 vs 10 days; nominal p = 0.0003) (Fig. 3a). Median time to return to usual activities for ≥ 2 and ≥ 3 consecutive days was also shorter with mAb than with placebo (≥ 2 consecutive days, 9 vs 11 days; ≥ 3 consecutive days, 10 vs 13 days) (Fig. 3b, c).

Fig. 3
figure 3

Time to return to usual activities for a ≥ 1, b ≥ 2, and c ≥ 3 consecutive days. CAS + IMD casirivimab plus imdevimab, CI confidence interval, HR hazard ratio

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EQ-5D-5L

Completion rate ranges for the EQ-5D-5L during the study in the mAb and placebo groups were 42.0‒100% and 44.3‒100%, respectively (see Supplementary Fig. 4, Online Supplementary Material). In both groups (mAb vs placebo), most patients reported problems with pain/discomfort (81.0% vs 72.5%), usual activities (67.9% vs 57.2%), and anxiety/depression (39.4% vs 36.2%) at baseline (see Supplementary Fig. 5a, Online Supplementary Material). By day 7, a numerically greater proportion of patients reported improvement (Fig. 4; see Supplementary Fig. 6, Online Supplementary Material), and fewer patients reported problems with pain/discomfort (38.9% vs 49.6%), usual activities (46.3% vs 52.5%), and anxiety/depression (26.8% vs 27.3%), with mAb treatment than with placebo (see Supplementary Fig. 5b, Online Supplementary Material). Comparable results were observed in the mFAS cohort (see Supplementary Fig. 5c and d, Online Supplementary Material). This trend was maintained for mobility and usual activities at day 29 (mobility, 5.4% vs 5.9%; self-care, 1.1% vs 0%; usual activities, 12.0% vs 17.8%; pain/discomfort, 17.4% vs 15.8%; anxiety/depression, 13.0% vs 12.9%).

Fig. 4
figure 4figure 4

Proportion of patients with improvement or worsening in each item of the EQ-5D-5L by treatment group in the PRO analysis set: a mobility, b self-care, c usual activities, d pain/discomfort, and e anxiety/depression. CAS + IMD casirivimab plus imdevimab, EQ-5D-5L EuroQol 5 Dimension 5 Level, PRO patient-reported outcome

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Mean (standard deviation [SD]) EQ-5D VAS scores were comparable between both groups at baseline (65.6 [18.9] for mAb and 66.0 [18.8] for placebo). During the study, mean EQ-5D VAS scores were generally greater (more favorable) for patients receiving mAb compared with those receiving placebo (see Supplementary Fig. 7a, Online Supplementary Material). At day 7, mean (SD) EQ-5D VAS scores were numerically higher with mAb compared with placebo (mAb, 82.4 [12.1]; placebo, 78.9 [14.4]) (see Supplementary Fig. 7a, Online Supplementary Material). At day 29, mean (SD) EQ-5D VAS scores were 93.0 (9.4) and 92.3 (8.9), respectively. Similar results were observed in the mFAS cohort (see Supplementary Fig. 7b, Online Supplementary Material).

Longitudinal Changes in EQ-5D VAS

Differences in least squares (LS) mean change from baseline in the EQ-5D VAS between the mAb and placebo groups were greatest from days 5 to 8 and at day 10 (Fig. 5). However, LS mean changes were comparable after day 10. Furthermore, the overall LS (95% CI) mean difference between mAb and placebo was 1.50 (−0.10 to 3.10; nominal p = 0.07). Similar trends were observed in the mFAS cohort (see Supplementary Fig. 8, Online Supplementary Material).

Fig. 5
figure 5

LS mean change from baseline in EQ-5D VAS by treatment group* in the PRO analysis set. *The LS mean change from baseline in EQ-5D VAS was assessed using a mixed model for repeated measures that assumed an autoregressive order (1) covariance structure for within-subject repeated measurements. CAS + IMD casirivimab plus imdevimab, CI confidence interval, EQ-5D VAS EuroQol 5 Dimension visual analog scale, LS least squares, PRO patient-reported outcome

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WPAI + CIQ:COVID-19 Infection

Completion rates for the mAb and placebo groups were 100% for both groups at day 7, and 61.0% and 62.9%, respectively at day 29 (see Supplementary Fig. 9, Online Supplementary Material). At day 7, mean (SD) work impairment and classroom impairment scores were comparable between both groups (75.4 [27.8] vs 74.3 [27.1] and 54.5 [34.6] vs 56.5 [36.9] for mAb vs placebo, respectively) (see Supplementary Tables 1 and 2, Online Supplementary Material). At day 29, mean work impairment scores were lower in the mAb group than the placebo group (see Supplementary Table 1, Online Supplementary Material). In contrast, mean classroom impairment scores were higher with mAb than with placebo at day 29 (see Supplementary Table 2, Online Supplementary Material). Mean activity impairment scores were lower with mAb than with placebo throughout the study (see Supplementary Table 3, Online Supplementary Material).

Mean absenteeism and presenteeism scores were comparable between mAb and placebo at day 7 (see Supplementary Tables 4 and 5, Online Supplementary Material). Mean absenteeism scores were numerically lower with mAb than with placebo at days 15, 22, and 29 (see Supplementary Table 4, Online Supplementary Material). However, this trend was observed for mean presenteeism scores at days 22 and 29 only (see Supplementary Table 5, Online Supplementary Material).

Safety

Details of the safety of the mAb combination has been previously reported [23]. In brief, the safety profile was as expected for a fully human antibody against an exogenous target, with low incidence of serious adverse events.

Discussion

In this study, the SE-C19 and other PROs were used to assess effects of an anti-SARS-CoV-2 mAb combination treatment (CAS + IMD) on COVID-19 symptoms, health status, and HRQoL in outpatients from the phase 3 portion of a placebo-controlled phase 1/2/3 trial. Previous studies have reported that mAb treatment reduces symptom duration compared with placebo by 4 days [23], but this is one of the first studies to report data regarding a more comprehensive patient experience with mAb treatment, including sustained symptoms resolution and impact on daily lives, in the context of a clinical trial and, more broadly, the effects of a COVID-19 treatment on HRQoL.

In this analysis, we found that patients receiving mAb treatment consistently experienced a shorter time to sustained symptoms resolution and a shorter time to return to usual health and usual activities compared with patients receiving placebo. Moreover, a lower proportion of patients receiving mAb experienced problems with pain/discomfort, usual activities, and anxiety/depression at day 7 compared with patients receiving placebo. Work and activity impairment scores were also lower with mAb compared with placebo. Although higher classroom impairment scores were observed with mAb than with placebo at day 29, this observation may have been due to small sample size (each n = 6). Collectively, the PRO data suggest that mAb treatment compared with placebo improved overall HRQoL in outpatients with COVID-19 prior to the emergence of the latest SARS-CoV-2 strains, including Omicron lineages.

Findings from this analysis were generally consistent with those of other studies that have reported the impact of COVID-19 symptoms on outpatients. An observational study in outpatients with COVID-19 reported a median time to return to usual health and median time to return to usual activities of 20 and 17 days, respectively [34], longer than those reported for the placebo group in this study. These differences may be attributed to use of the influenza-specific FLU-PRO tool [35], the fact that symptoms were not evaluated daily, and differences in endpoint definitions between studies. However, another study of outpatients with COVID-19 also reported significant impairment to usual activities and pain/discomfort via the EQ-5D-5L [36]. Another observational study used the 36-item Short Form Health Survey to measure quality of life in outpatients with COVID-19 and found that patients with persistent (> 5 months) symptoms were more likely to have poor mental and physical component summary scores compared to patients who did not have persistent symptoms [11].

In contrast to previous studies, this study provided a comprehensive assessment of COVID-19 symptoms and their effect on HRQoL in outpatients using a gamut of PRO tools/instruments. We employed rigorous scientific methods in line with FDA PRO guidance for COVID-19 [17, 18, 37] to develop the SE-C19, which measured symptom evolution and was validated on the basis of regulatory guidance [28, 29]. We also assessed time to sustained return to usual health and usual activities in outpatients with COVID-19, endpoints that have not commonly been used to assess health status in this patient population. Moreover, we collected patient-reported data daily, in contrast to another study that evaluated symptoms over a longer recall period [38]. Although a recent study reported the development of a 26-item COVID-19-specific PRO instrument, this instrument evaluated the severity of the most prevalent COVID-19 symptoms only and did not assess HRQoL [38].

Given that COVID-19 cases continue to rise and may become endemic in many regions [1, 39], developing effective treatments remains important. Furthermore, several studies have reported that COVID-19 is associated with greater disease burden compared with other respiratory diseases such as seasonal influenza, including higher mortality and prolonged recovery [40,41,42]. While the current study was conducted before the emergence of Omicron-lineage variants, against which current mAbs are not active, our findings suggest that mAb treatment does improve how patients feel and function, and that they may be of great utility for future susceptible SARS-CoV-2 variants. Next-generation broadly neutralizing mAbs that retain activity against Omicron-lineage variants are in development and it will be important to include PRO endpoints in these clinical studies to assess how these treatments can reduce patient burden.

Importantly, these PRO findings are consistent with the virologic and clinical data reported from the phase 3 portion of the same trial [23]. Previously reported decreases in viral load and COVID-19-related hospitalizations [23] with mAb treatment were associated with concomitant improvements in patient feel and function as observed in this analysis. These observations suggest that improvements in virologic and clinical endpoints with mAbs are associated with clinically meaningful improvement in outpatients with COVID-19.

Improvement in the daily lives of patients treated with mAbs may decrease healthcare resource utilization and lost productivity costs. Given that patients treated with mAbs had a markedly shorter time to symptom resolution [23], sustained symptoms resolution, time to return to usual health, and time to return to usual activities than patients treated with placebo, mAbs may allow patients with COVID-19 to resume their daily lives more quickly with reduced disruptions to work productivity, thereby helping to mitigate the ongoing economic impact of COVID-19. Despite the observed faster return to usual activities with mAb treatment, work productivity index was comparable between the mAb and placebo groups. This is likely attributed to COVID-19 control measures during this study that required isolation for ≥ 10 days after infection regardless of clinical status. In future clinical studies of mAbs, the current WPAI + CIQ:COVID-19 questionnaire may require modification to account for the effects of public health restrictions on productivity.

This study had several limitations. First, low completion rates were observed for return to usual health and activities, EQ-5D-5L, and WPAI + CIQ:COVID-19 Infection and may have restricted further evaluation of mAb effects on patient feel and function as well as differences between mAb treatment and placebo. This was partly attributed to limited availability of PRO instruments. Second, WPAI + CIQ:COVID-19 Infection data were not collected at baseline, precluding analyses of improvement at day 7. This study was also conducted at the height of the COVID-19 pandemic before widespread vaccination programs and the emergence of Omicron-lineage variants. Patients in this study were predominantly naïve to SARS-CoV-2, and the observed symptom profile may differ from that experienced now, where most patients have been exposed to SARS-CoV-2 and variants including BA.5 are dominant. Finally, an inability to distinguish whether missed work was due to illness or mandated quarantine may have limited the interpretation of absenteeism data for mAb treatment and placebo.

Results from clinical studies to date suggest that mAbs provide a promising treatment option for infectious diseases. Future studies are necessary to further characterize the effects of newer mAbs on COVID-19 symptoms. Given that in this analysis PRO data were obtained in the context of a clinical trial over 29 days, additional studies will be required to understand the long-term impact of mAbs on symptoms and HRQoL, particularly in the context of long-term COVID-19. Moreover, future studies should explore the effectiveness of mAbs against current SARS-CoV-2 strains and the patient experience in real-world settings. For example, prevention of symptom worsening and hospitalization may further support the efficacy of mAbs. This would be relevant to various stakeholders who are interested in PROs to support treatment decisions [17, 19, 43].

Conclusions

The PRO data reported here are compelling and show that treatment of COVID-19 with mAbs improved the overall HRQoL of outpatients infected with susceptible SARS-CoV-2 variants compared with placebo. MAb treatment had a more pronounced impact on improvement of usual activities, pain and discomfort, and anxiety and depression than placebo by day 7, suggesting that mAbs may improve the humanistic burden of COVID-19.