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Original Research
9 August 2022

Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19: A Randomized Controlled TrialFREE

Publication: Annals of Internal Medicine
Volume 175, Number 9
Visual Abstract. Ensovibep for Adults Hospitalized With COVID-19.
Novel therapies for SARS-CoV-2 infection have been a focus of research, and many promising compounds have emerged. This multinational clinical trial compared one such compound—ensovibep, a designed ankyrin repeat protein—versus standard of care to determine whether it improved outcomes among patients hospitalized with COVID-19.



Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection.


To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone.


Double-blind, randomized, placebo-controlled, clinical trial. ( NCT04501978)


Multinational, multicenter trial.


Adults hospitalized with COVID-19.


Intravenous ensovibep, 600 mg, or placebo.


Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90.


An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR < 1 would favor ensovibep).


The trial was prematurely stopped because of futility, limiting power for the primary outcome.


Compared with placebo, ensovibep did not improve clinical outcomes for hospitalized participants with COVID-19 receiving standard care, including remdesivir; no safety concerns were identified.

Primary Funding Source:

National Institutes of Health.
Oral antivirals, intravenous remdesivir, and antispike neutralizing antibodies are effective at preventing disease progression in early COVID-19 (1–5). However, for hospitalized patients, finding effective antiviral therapy remains a challenge (6–8). Monoclonal antibody treatments in inpatients have been assessed (6, 7, 9), and although the combination of casirivimab and imdevimab improved clinical outcomes, this was only among patients without detectable antibodies to SARS-CoV-2 at randomization, and before the emergence of the Omicron variant (10).
Designed ankyrin repeat proteins (DARPins) are a new class of engineered protein therapeutics. Derived from naturally occurring ankyrin repeats, they are designed to bind with high affinity and specificity to other proteins (11, 12). Ensovibep (previously MP0420) was selected to bind the SARS-CoV-2 spike protein with in vitro ribosome display based on a physical library with a diversity of approximately 1 trillion DARPin molecules. After a screening process to identify the most potent monovalent DARPin domains that neutralize angiotensin-converting enzyme 2, ensovibep was assembled to generate a multispecific neutralizing candidate against variants of SARS-CoV-2 (13). It consists of 5 linked DARPin domains, 3 of which cooperatively engage the 3 receptor-binding domains of the trimeric SARS-CoV-2 spike protein to inhibit angiotensin-converting enzyme 2 interaction and cellular entry and 2 of which bind to serum albumin for systemic half-life extension, thereby enabling single-dose administration (13, 14).
In a therapeutic hamster model of COVID-19, ensovibep reduced virus replication in both the lower and upper respiratory tract and protected against severe disease (13). In a recently completed phase 2 study (EMPATHY [Randomized, Double-blind, Placebo-controlled, Multicenter Study of Ensovibep in Ambulatory Patients With Symptomatic COVID-19] [15]) in outpatients with mild to moderate COVID-19, ensovibep demonstrated antiviral and clinical efficacy with a 78% (95% CI, 16% to 95%) reduction in hospitalizations, emergency department visits caused by COVID-19, or deaths (15). Here we report results from the TICO (Therapeutics for Inpatients With COVID-19) platform trial comparing ensovibep versus placebo, on a background of remdesivir plus other standard care, among adults hospitalized with COVID-19.


Trial Design and Oversight

TICO is a master protocol to evaluate the safety and efficacy of multiple investigational agents targeting either the host immune response to SARS-CoV-2 infection or viral control (16). The trial is a phase 3, randomized, double-blind, controlled platform trial. For efficiency, the design of the study allows pooling of control participants from more than 1 concurrent trial therapy.
The study protocol (Supplement 2) was approved by a governing institutional review board for each participating center. All enrolled participants or their legal representative gave written informed consent. All trials done under the master protocol are overseen by an independent data and safety monitoring board (DSMB).

Study Participants and Stratification

Hospitalized adults (aged ≥18 years) were eligible for randomization if they had SARS-CoV-2 infection documented by a nucleic acid amplification test or equivalent and if their COVID-19 symptoms had been present for at most 12 days at the time of randomization. Vaccination against SARS-CoV-2 was not exclusionary. The study protocol excluded persons requiring any of the following interventions at baseline: invasive mechanical ventilation, extracorporeal membrane oxygenation or other forms of mechanical circulatory support, vasopressor therapy, or commencement of renal replacement therapy during admission (a complete list of exclusion criteria is in Supplement 1).

Randomization and Blinding

Eligible participants at each site were randomly assigned in a 1:1 ratio to receive ensovibep or placebo. When possible, placebo controls were shared among investigational agents. The study medication was prepared by unblinded pharmacists at local pharmacies, and all other study staff and recipients remained blinded (Supplement 1).

Interventions and Treatments

Participants were randomly assigned and given their blinded study infusion on study day 0. Ensovibep was administered intravenously over 1 hour in a 1-time infusion containing 600 mg. Supplement 1 describes blinding procedures. Remdesivir was provided to all study participants, including those who had already started receiving this agent, as standard of care unless contraindicated; it was administered as a 200-mg intravenous loading dose followed by a 100-mg intravenous maintenance dose once daily while hospitalized up to a 10-day total course. Dexamethasone or other corticosteroids were administered per the local standard of care.

Study Procedures

Participants were followed per TICO study protocols (6, 7, 16) and assessed for clinical outcomes and adverse events daily from randomization through day 7 and retrospectively on days 14, 28, 60, and 90. Supplement 1 describes adverse event grading and reporting. Blood samples were collected from participants before administration of the study infusion for plasma measurement of neutralizing antibody concentrations against the receptor-binding domain of the SARS-CoV-2 spike protein (GenScript SARS-CoV-2 Surrogate Virus Neutralisation assay; GenScript), total antibody concentration against SARS-CoV-2 nucleocapsid antigen (Bio-Rad Platelia SARS-CoV-2 Total Ab assay; Bio-Rad), and SARS-CoV-2 nucleocapsid antigen concentrations (Quanterix assay; Quanterix). The SARS-CoV-2 RNA load in the nasal swab material was determined using extraction, master mix preparation, and reverse transcriptase polymerase chain reaction as described in the Centers for Disease Control and Prevention's instructions for the 2019-Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel. The lower limit of quantification for this measurement is 399 copies/mL. Advanced Biomedical Laboratories centrally measured viral RNA. In addition, the presence of the Delta variant versus other variants was determined with a reverse transcriptase polymerase chain reaction assay. Supplement 1 describes these assays in detail.


The initial futility assessment evaluated two 7-category ordinal outcomes collected at day 5 after randomization, the pulmonary and the pulmonary-plus ordinal scales (for details of the futility outcome, see the Trial Design and Treatments section in Supplement 1). The first scale classifies participants according to the intensity of respiratory support, whereas the second also includes extrapulmonary manifestations. These ordinal scales were originally used in influenza studies (17) and have been used in previous COVID-19 studies (18, 19).
The primary efficacy outcome was time to sustained clinical recovery up to day 90, defined as the time from randomization to return to home (the participant's residence or a facility that provided the same or a less intensive level of clinical care before COVID-19) for 14 consecutive days. Mortality through 90 days and time to hospital discharge were also assessed. Supplement 1 details the composite safety outcomes at days 5, 28, and 90, along with all study outcomes.

Statistical Analysis

The planned sample size was 1000 participants; this was intended to coincide with 843 sustained recovery events, which would provide 90% power to detect a subhazard ratio (sHR) of 1.25 comparing the time to sustained recovery between the treatment groups at a 1-sided significance level of 0.025. An independent DSMB reviewed interim data and used prespecified guidelines to assess futility. On 15 November 2021, the DSMB recommended stopping the study for futility (Supplement 1).
After the end of enrollment, all participants were followed for at least 90 days. The analysis population for efficacy and safety outcomes was restricted to participants who received a complete or partial infusion of ensovibep or placebo (modified intention to treat). The distributions of the pulmonary and pulmonary-plus ordinal scales were compared between treatment groups using proportional odds models, as described in the Methods section and Supplement Table 3. Proportional odds models were fitted with the same covariates for the ordinal outcomes at days 1 to 7, 14, and 28.
The cumulative incidences of sustained recovery and hospital discharge were estimated using the Aalen–Johansen estimator, treating death as a competing risk. The cumulative incidence of death was estimated using Kaplan–Meier methods. Subhazard ratios comparing the time to sustained recovery and hospital discharge were estimated using the Fine–Gray model. A Cox proportional hazards model was used to estimate the HR comparing time to death between the treatment groups; models were stratified by study site pharmacy (Supplement Table 3).
The composite safety outcome up to day 5 was compared between groups using logistic regression stratified by study site pharmacy. Times to the composite safety outcomes through days 28 and 90 were analyzed using Cox proportional hazards models, also stratified by study site pharmacy. To assess the consistency of the overall findings for the various outcomes, the following subgroups based on baseline characteristics were considered: pulmonary ordinal scale on day 0, duration of symptoms, age, gender, race and ethnicity, antibody and antigen levels, vaccination status, and immunosuppressive status. For the subgroup analysis based on SARS-CoV-2 antigen levels, baseline antigen levels were dichotomized into those above and below the median value.
All analyses were done using SAS, version 9.4 (SAS Institute), or R, version 4.0 (R Foundation). The master protocol for the TICO study is registered at (NCT04501978).

Role of the Funding Source

The funding organizations had no direct involvement in the decisions related to the trial or the drafting or revision of the manuscript.


Study Enrollment and Patient Characteristics

Between 11 June 2021 and 15 November 2021, the study enrolled 496 participants; 255 were assigned to the ensovibep group and 241 to the placebo control. Among the 496 participants, 485 persons from 62 sites in 10 countries received the blinded infusion and are included in the modified intention-to-treat analyses (Figure 1). Sites, enrollment status, and infusion information are detailed in Supplement Tables 1 to 3.
Figure 1. Study flow diagram.
mITT = modified intention-to-treat.
The 2 groups were similar with respect to baseline characteristics (Table 1; Supplement Tables 4 to 7). Overall, the median age was 57 years (IQR, 45 to 68 years), and 49.5% of participants were non-Hispanic White, 24.7% were non-Hispanic Black, and 16.1% were Hispanic. Of note, 47.1% of participants had a body mass index of 30 kg/m2 or greater. The median time between onset of symptoms and randomization was 8 days (IQR, 6 to 9 days).
Table 1. Baseline Characteristics of the Modified Intention-to-Treat Population Used as the Primary Analytic Population
Participants entered the trial in 1 of the following 4 pulmonary ordinal categories: no supplemental oxygen (19.6%), conventional supplemental oxygen at less than 4 L/min (29.9%), conventional supplemental oxygen at 4 L/min or higher (30.3%), or high-flow nasal oxygen or noninvasive ventilation (20.2%). Corticosteroids (>10 mg of prednisone or equivalent) were used by 72% of participants, 72% had received remdesivir before enrollment, and 68% were unvaccinated. Concomitant use of medication at day 5 and day 28 was also similar between groups (Supplement Table 8).

Efficacy Outcomes

The day 5 ordinal outcome was assessed for 95% of participants, and the sustained recovery outcome at day 90 was known for more than 96% of participants (Figure 1). The adjusted odds ratio (OR) (ensovibep vs. placebo) for participants having a better pulmonary ordinal score at day 5 was 0.93 (CI, 0.67 to 1.30; OR > 1 would favor ensovibep) (Table 2 and Figure 2; Supplement Table 9). Results were similar for the pulmonary-plus ordinal score at day 5 (adjusted OR for ensovibep vs. placebo, 0.95 [CI, 0.69 to 1.32]) (Table 2; Supplement Table 10). One-sided P values were greater than 0.30, the guideline for assessing futility, for both the pulmonary and pulmonary-plus outcomes. The percentage of participants with an improvement in the 7-category ordinal scale between baseline and day 5 was 44.6% in the ensovibep group versus 46.8% in the placebo group (Supplement Table 11). No evidence suggested that the assumption of proportional odds was violated (Supplement Table 12). The adjusted ORs for the pulmonary ordinal outcome for other time periods also showed no evidence of benefit of ensovibep versus placebo (Figure 2; Supplement Tables 13 to 15). Sustained recovery by day 90 was achieved by 82% in the ensovibep group and 80% in the placebo group (sHR, 1.06 [CI, 0.88 to 1.28]) (Table 2 and Figure 3). The sHR for hospital discharge was 1.07 (CI, 0.90 to 1.28; sHR > 1 would favor ensovibep) (Table 2; Supplement Figure 1). Through day 90, a total of 30 participants (12.1%) in the ensovibep group and 35 (14.7%) in the placebo group died (HR, 0.83 [CI, 0.51 to 1.35]) (Table 2 and Figure 3).
Table 2. Summary of Key Clinical Outcomes
Figure 2. Distribution of patients on the pulmonary ordinal scale on day 5, 14, and 28.
ECMO = extracorporeal membrane oxygenation; OR = odds ratio.
Figure 3. Time to sustained recovery and death through day 90 for ensovibep vs. placebo.
The rate ratios were calculated with Fine–Gray models to account for the competing risk for death and stratified according to study pharmacy. Left. Sustained recovery. Right. Death.

Safety Outcomes

Four participants (2 in each group) had their infusion paused for adverse reactions. There was no evidence of a difference between treatment groups with respect to infusion reactions; incidence or prevalence of adverse events by day 7, 14, or 28; or serious adverse events through day 90 (Supplement Tables 16 to 22). The percentage developing the composite safety outcome (all-cause mortality, serious adverse event, grade 3 or 4 adverse event, organ failure, or serious co-infection) through day 5 was 24.7% in the ensovibep group and 29.0% in the placebo group (OR, 0.80 [CI, 0.53 to 1.21]; OR < 1 would favor ensovibep) (Table 2). Through day 28, these percentages were 34.0% and 40.3%, respectively (HR, 0.81 [CI, 0.60 to 1.09]; HR < 1 would favor ensovibep) (Table 2; Supplement Figure 2). Through day 90, the composite safety outcome (all-cause mortality, serious adverse event, organ failure, or serious co-infection) through day 90 occurred in 78 participants (31.6%) in the ensovibep group and 70 (29.4%) in the placebo group (HR, 1.07 [CI, 0.77 to 1.47]) (Table 2; Supplement Figure 3).
Individual components of the composite safety outcomes also did not differ between treatment groups through day 5, 28, or 90 (Supplement Tables 23 to 25). Incidence of clinical organ failure through day 90, including liver and renal dysfunction and cardiovascular and thromboembolic events, was similar between groups (Supplement Table 26). The most common events were respiratory failure (ensovibep vs. control, 42 vs. 35 events), intercurrent serious infection (26 vs. 19 events), hypotension requiring a vasopressor (19 vs. 25 events), and thromboembolic events (13 vs. 10 events). Rash was a safety event of special interest for this trial and occurred in 7 participants in the ensovibep group and 4 in the placebo group (1.6% and 1.3%, respectively) (Supplement Table 27). In both groups, most of these events did not present with concurrent events (Supplement Table 27).

Subgroup Analyses

Subgroup analyses provided no evidence for heterogeneity in the treatment effect for either efficacy or safety outcomes (Supplement Figure 4 and Supplement Tables 28 to 37).


The TICO platform was designed to rapidly assess the safety and efficacy of candidate COVID-19 therapies with an early futility analysis based on 2 pulmonary ordinal outcomes through day 5 (16). Ensovibep was the fifth antiviral agent in the TICO platform trial to be tested in patients hospitalized with COVID-19 and is the first DARPin anti-infective to enter human clinical trials. This DARPin molecule, in contrast with conventional monoclonal antibodies, is designed as a pan-variant antiviral that can be produced efficiently through Escherichia coli fermentation and scaled up more easily (11, 13–15).
Ensovibep did not pass the protocol-defined futility assessment based on day 5 clinical data from 421 participants, and further participant accrual was halted per DSMB recommendation. Because enrollment was stopped for futility, the study was underpowered to assess many outcomes, with a wide 95% CI for the sHR comparing the primary end point of time to sustained recovery across treatment groups (CI, 0.88 to 1.28). The results of this trial are similar to those of trials testing other antiviral agents in the TICO platform, highlighting the difficulty of finding an effective therapy to improve outcomes among patients hospitalized with COVID-19 who are already receiving background remdesivir, corticosteroids, and other immune modulators. Bamlanivimab, sotrovimab, and BRII-196 plus BRII-198 did not pass the early futility assessment when tested in TICO (6, 7) despite having been found to be effective at reducing progression to hospitalization and death in outpatients with early disease (1, 5, 6). For a fourth monoclonal antibody, tixagevimab–cilgavimab, the full trial enrollment was achieved. This agent given with remdesivir as the standard of care was not associated with improved time to sustained recovery but was associated with lower mortality than standard care alone (8).
The data from this trial differ from the preliminary findings of the EMPATHY study of ensovibep versus placebo among outpatients with symptomatic COVID-19 (15). Results from the dose-finding part of this study were recently presented, and ensovibep met the primary end point of viral load reduction from baseline to day 8 in comparison with placebo, with a statistically significant reduction in viral load at all 3 doses tested (75 mg, 225 mg, and 600 mg). The study also showed a 78% (CI, 16% to 95%) reduction in the secondary end point of death, hospitalization, or emergency department visits related to COVID-19. The EMPATHY study enrolled persons within 7 days of symptom onset, and this finding is consistent with the hypothesis that treatments using a passive immunity approach (such as monoclonal antibodies) are more effective when given early and in patients who do not yet have COVID-19 complications necessitating hospitalization (1, 4, 7, 8, 20). Consistent with an antiviral effect of various passive immunotherapies in this situation, small-molecule antivirals have also consistently been shown to reduce risk for hospitalization early in the disease course of ambulatory COVID-19 (3, 5, 21, 22). Taken together with the reported result from the EMPATHY trial, our findings suggest that ensovibep treatment in COVID-19 may be effective at preventing progression rather than treating severe disease in patients with a shorter duration of symptoms.
Of note, the anti–SARS-CoV-2 monoclonal antibodies casirivimab–imdevimab and bamlanivimab (10, 23) were both reported to be more effective in seronegative patients, and as a result, an a priori hypothesis of this trial was that ensovibep would benefit patients who were seronegative for SARS-CoV-2 neutralizing antibodies at baseline. Analysis by major baseline subgroups, including serostatus, for time to sustained recovery and mortality identified no statistically significant interactions between treatment group and subgroup. With its early termination, however, this trial lacks precision in the point estimates for subgroups.
Strengths of this trial include enrollment of a diverse population from 62 sites across 10 countries. Antiviral treatment with remdesivir was standardized, and the trial was run with blinding of the investigational agent and continuous DSMB oversight. Regarding study limitations, as a result of its early termination, this study is underpowered to detect modest benefits from ensovibep, particularly among important subgroups, such as those defined by baseline serostatus, disease severity, or comorbid conditions. These factors should be incorporated into the design of future studies, including the study of ensovibep in ambulatory patients. Because ensovibep was tested in a population of patients who received background remdesivir treatment, the efficacy of ensovibep without remdesivir is unknown. Generalizing the results of this study must be considered in light of the fact that it was done primarily among patients with Delta variant infections, with a minority of patients (26%) fully vaccinated and only 30 (6%) categorized as immunosuppressed.
In conclusion, among patients hospitalized with COVID-19 receiving remdesivir and other standard care, ensovibep did not improve clinical outcomes. Ensovibep was well tolerated, even in seriously ill patients receiving high-flow nasal oxygen, with few hypersensitivity reactions. Overall, a broadly applicable and highly effective antiviral therapy for patients hospitalized with COVID-19 remains a major unmet need.

Supplemental Material

Supplement 1. Supplementary Material

Supplement 2. Study Protocol


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Teluguakula Narasaraju (1) PhD, Amita Krishnappa (1) MD, Marko Radic (2) PhD, and Vincent TK Chow (3) MD, PhD.7 September 2022
Testing an Efficacy of Ensovibep Therapy for COVID-19: A Requirement for Additional Criteria.

ACTIV-3/TICO Study Group (1) have analyzed the efficacy and safety of ensovibep a designed ankyrin repeat protein (DARP) that inhibits the interaction of SARS-CoV-2 spike protein with its host receptor, angiotensin-converting enzyme. This randomized control trial was a follow-up of earlier findings demonstrating antiviral activity of ensovibep in a hamster model of COVID-19, reduced hospitalizations and improved clinical outcomes in outpatients with mild-to-moderate COVID-19. In contrast to these findings, administration of ensovibep in hospitalized severely ill COVID-19 patients failed to exhibit any protection. This trial was prematurely stopped, as it failed early futility assessment and could not establish the power of primary outcome in hospitalized COVID-19 patients.  

This clinical study has several shortcomings in the study design. First, it failed to establish the proof-of-concept of antiviral efficacy of ensovibep. Second, although randomizing and blinding of participants provide an unbiased approach, the seven ordinal pulmonary or pulmonary plus outcome scales used unlikely provide any direct correlation or clinical signatures specific for ensovibep-mediated effects, including lung viral loads or virus-inflicted alveolar-epithelial cytopathic injury. Third, combining remdesivir together with ensovibep in the treatment regimen unlikely establishes any beneficial effects. Fourth, lack of realistic figures on viral replication and kinetics at the onset of the treatment questions the rationale for this clinical trial. Similarly, several clinical trials that evaluated combinations of monoclonal antibodies (e.g. tixagevimab−cilgavimab or sotrovimab, BRII-196 plus BRII-198) in hospitalized COVID-19 patients based on ordinal outcome scales also yielded inconsistent findings and fell short to prove their efficacy in these patients (2,3).

When evaluating drugs targeting virus entry or replication in the lungs, it is therefore essential to include additional criteria to support the proof-of-concept. Unfortunately, viral titers in nasopharyngeal or oropharyngeal samples do not correlate well with viral loads in the deeper lungs, and invasive methods to collect lung samples may not possible in hospitalized COVID-19 patients. Instead, measuring plasma viral RNA may be a better indicator to determine antiviral effects of ensovibep or monoclonal antibodies in hospitalized patients (4). In addition, markers of alveolar epithelial injury such as podoplanin (marker of alveolar type I epithelium) and surfactant protein C (marker of alveolar type II epithelium) (5) in the plasma or sputum may represent virus-inflicted alveolitis in the lungs. Hence, evaluating COVID-19 pathophysiology and clinical outcomes on ordinal outcome scales must be substantiated by more prudent methods that are relevant to drug-target-specific signatures.


  1. ACTIV-3/TICO Study Group*. Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19 : A Randomized Controlled Trial [published online ahead of print, 2022 Aug 9]. Ann Intern Med. 2022;M22-1503. doi:10.7326/M22-1503
  2. ACTIV-3–Therapeutics for Inpatients with COVID-19 (TICO) Study Group (2022). Tixagevimab-cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial. The Lancet. Respiratory medicine, S2213-2600(22)00215-6.
  3. ACTIV-3/Therapeutics for Inpatients with COVID-19 (TICO) Study Group (2022). Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial. The Lancet. Infectious diseases, 2022;22: 622–635.
  4. Jana L Jacobs, William Bain, Asma Naqvi, Brittany Staines, Priscila M S Castanha, Haopu Yang, Valerie F Boltz, Simon Barratt-Boyes, Ernesto T A Marques, Stephanie L Mitchell, Barbara Methé, Tolani F Olonisakin, Ghady Haidar, Thomas W Burke, Elizabeth Petzold, Thomas Denny, Chris W Woods, Bryan J McVerry, Janet S Lee, Simon C Watkins, Claudette M St Croix, Alison Morris, Mary F Kearney, Mark S Ladinsky, Pamela J Bjorkman, Georgios D Kitsios, John W Mellors, Severe Acute Respiratory Syndrome Coronavirus 2 Viremia Is Associated With Coronavirus Disease 2019 Severity and Predicts Clinical Outcomes, Clinical Infectious Diseases, 2022;74:1525–1533.
  5. Ashar HK, Pulavendran S, Rudd JM, Maram P, Achanta M, Chow VTK, Malayer JR, Snider TA, Teluguakula N. Administration of a CXC Chemokine Receptor 2 (CXCR2) Antagonist, SCH527123, Together with Oseltamivir Suppresses NETosis and Protects Mice from Lethal Influenza and Piglets from Swine-Influenza Infection. Am J Pathol. 2021;191:669-685. doi: 10.1016/j.ajpath.2020.12.013.
Eleftherios Mylonakis, MD, PhD; Christina Barkauskas, MD; Garyfallia Poulakou, MD, PhD; Barnaby E. Young, MD, PhD; on behalf of the ACTIV-3/TICO Study Group13 September 2022
Response to Narasaraju et al.

We share the need to improve the care of hospitalized individuals with COVID-19. The query that prompted this letter regarding the design of the ACTIV-3/TICO trial of ensovibep can be summarized as follows: 1) Failure to establish the efficacy of ensovibep; 2) The use of 7-category ordinal outcomes as primary outcome rather than a surrogate marker; and 3) Limitations imposed by combining remdesivir with ensovibep.

Concerning the first two points, as discussed in our manuscript, after several large clinical trials the antiviral management of hospitalized patients with COVID-19 remains a major challenge. ACTIV-3/TICO is a multi-arm, multi-stage platform master protocol which aims to rapidly evaluate the safety and efficacy of novel antiviral therapeutic candidates for adults hospitalized with COVID-19. Given these aims, the primary outcome for agents tested in this platform was chosen for its immediate clinical relevance: time to sustained recovery over 90 days of follow-up.  In order to efficiently evaluate multiple investigational agents, futility was assessed after 300 patients had completed Day 5 assessment visit or discontinued prematurely. This assessment was based on supplemental oxygen requirements and organ dysfunction on Day 5. These intermediate clinical outcomes were used to determine clinical progression and improvement and are strongly correlated with sustained recovery through to 90 days (1).

When selected judiciously, surrogate laboratory markers could be useful indicators of clinical response and there are established criteria for surrogacy (2). We are not aware of any work that has established a surrogate for the clinical outcomes that are most meaningful for the target population (i.e., patients hospitalized with COVID-19). Neither serum viral load (for example, in the study by Jacobs et al., viremia was detected only in 52.6% of the non-ICU patients (3)) nor the proposed markers studied in animals are sufficiently robust. Similarly, serum and sputum markers of lung alveolar epithelial cell injury such as podoplanin, or circulating epithelial cell markers are not clinically tested markers of antiviral efficacy. Along with other markers, such as serum nucleocapsid antigen level that was included in our study, these are important areas for further research (4).

Finally, regarding the last point, the goal is to improve standard-of-care in adults hospitalized with COVID-19. As per established treatment guidelines (5), standard-of-care among such patients could include remdesivir. Withholding the standard-of-care would challenge equipoise and would not advance the research question addressed in the trial: whether ensovibep improved relevant clinical outcomes when added to standard-of-care.


  1. ACTIV-3/TICO LY-CoV555 Study Group. A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19 N Engl J Med . 2021 Mar 11;384(10):905-914. doi: 10.1056/NEJMoa2033130. Epub 2020 Dec 22.
  2. Prentice RL, Surrogate endpoints in clinical trials: Definitions and operational criteria, Stat Med. 1989;8:431-40.
  3. Jacobs et al. Severe Acute Respiratory Syndrome Coronavirus 2 Viremia Is Associated With Coronavirus Disease 2019 Severity and Predicts Clinical Outcomes. 2022 May 3;74(9):1525-1533. doi: 10.1093/cid/ciab686.
  4. ACTIV-3/Therapeutics for Inpatients with COVID-19 (TICO) Study Group. Clinical and viral factors associated with baseline plasma SARS-CoV-2 nucleocapsid antigen level among patients hospitalized with COVID-19. Ann Intern Med (in press)
  5. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at Accessed [Sept. 12, 2022].

Information & Authors


Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 175Number 9September 2022
Pages: 1266 - 1274


Published online: 9 August 2022
Published in issue: September 2022




ACTIV-3/TICO Study Group
Note: Members of the writing group were Christina Barkauskas, MD; Eleftherios Mylonakis, MD, PhD; Garyfallia Poulakou, MD, PhD; Barnaby E. Young, MD, PhD; David M. Vock, PhD; Lianne Siegel, PhD; Nicole Engen, MS; Greg Grandits, MS; Nilima R. Mosaly, MD; Andrew M. Vekstein, MD; Ralph Rogers, MD; Fadi Shehadeh, MSc; Matthew Kaczynski, BSc; Evangelia K. Mylona, MSc; Konstantinos N. Syrigos, MD, PhD; Vasiliki Rapti, MD; David C. Lye, MBBS; Diong Shiau Hui, BBio, MSc; Lindsay Leither, DO; Kirk U. Knowlton, MD; Mamta K. Jain, MD, MPH; Rubria Marines-Price, PhD, DNP, APRN; Alice Osuji, RN, BSN, MSN; J. Scott Overcash, MD; Ioannis Kalomenidis, MD, PhD; Zafeiria Barmparessou, MD, PhD; Michael Waters, MD; Karla Zepeda, MD; Peter Chen, MD; Sam Torbati, MD; Francis Kiweewa, MBChB, MMED, MPH; Nicholus Sebudde, MBChB; Eyad Almasri, MD; Alyssa Hughes, MD; Sanjay R. Bhagani, MD; Alison Rodger, MD, PhD; Uriel Sandkovsky, MD, MS; Robert L. Gottlieb, MD, PhD; Eriobu Nnakelu, MD, MPH; Barbara Trautner, MD, PhD; Vidya Menon, MD; Joseph Lutaakome, MBChB, MPH, PhD; Michael Matthay, MD; Philip Robinson, MD; Konstantinos Protopapas, MD, PhD; Nikolaos Koulouris, MD, PhD; Ivan Kimuli, MBChB, MMED; Amiran Baduashvili, MD; Dominique L. Braun, MD; Huldrych F. Günthard, MD; Srikanth Ramachandruni; Robert Kidega, MBChB, MMED; Kami Kim, MD; Timothy J. Hatlen, MD; Andrew N. Phillips, PhD; Daniel D. Murray, PhD; Tomas O. Jensen, MD; Maria L. Padilla, MD; Evan X. Accardi, BA; Katy Shaw-Saliba, PhD; Robin L. Dewar, PhD; Marc Teitelbaum, MD, MS; Ven Natarajan, PhD; Sylvain Laverdure, PhD; Helene C. Highbarger, MS; M. Tauseef Rehman, MA; Susan Vogel, RN, BSN; David Vallée, PharmD, MPH; Page Crew, PharmD, MPH; Negin Atri, MPH; Adam J. Schechner, MD; Sarah Pett, MD, PhD; Fleur Hudson, BA; Jonathan Badrock, BSc; Giota Touloumi, PhD; Samuel M. Brown, MD; Wesley H. Self, MD, MPH; Crystal M. North, MD, MPH; Adit A. Ginde, MD, MPH; Christina C. Chang, MD, PhD; Anthony Kelleher, MBBS, PhD, BSc; Stephanie Nagy-Agren, MD; Shikha Vasudeva, MD; David Looney, MD; Hien H. Nguyen, MD; Adriana Sánchez, MS; Amy C. Weintrob, MD; Birgit Grund, PhD; Shweta Sharma, MS; Cavan S. Reilly, PhD; Roger Paredes, MD, PhD; Agnieszka Bednarska, MD, PhD; Norman P. Gerry; Abdel G. Babiker, PhD; Victoria J. Davey, PhD, MPH; Annetine C. Gelijns, PhD; Elizabeth S. Higgs, MD; Virginia Kan, MD; Gail Matthews, MBChB, PhD; B. Taylor Thompson, MD; Philippe Legenne, MD, MBA; Richa Chandra, MD, MBBS, MBA; H. Clifford Lane, MD; James D. Neaton, PhD; and Jens D. Lundgren, MD. Drs. Barkauskas, Mylonakis, Poulakou, and Young contributed equally to this work.
Disclaimer: The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the National Institutes of Health.
Financial Support: By the U.S. Operation Warp Speed program; the National Institute of Allergy and Infectious Diseases and Leidos Biomedical Research for the INSIGHT Network; the National Heart, Lung, and Blood Institute and the Research Triangle Institute for the Prevention and Early Treatment of Acute Lung Injury Network and the Cardiothoracic Surgical Trials Network; the U.S. Department of Veterans Affairs; and grants from the governments of Denmark (no. 126 from the National Research Foundation), Australia (from the National Health and Medical Research Council), the United Kingdom (MRC_UU_12023/23 from the Medical Research Council), and Singapore (COVID19RF-005 from the National Medical Research Council). The research was funded in part by National Institutes of Health agreement 1OT2HL156812-01 and National Cancer Institute contract 75N91019D00024, task order 75N91020F00039. Trial medications were donated by Molecular Partners (ensovibep) and Gilead Sciences (remdesivir).
Data Sharing Statement: The following data will be made available with publication: Investigators interested in accessing the data (deidentified data with a data dictionary) should fill out a form on the INSIGHT website (, which goes to a policy group for review. The following supporting documents will be made available with publication: Extensive details are part of Supplements 1 and 2.
Corresponding Author: Eleftherios Mylonakis, MD, PhD, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903; e-mail, [email protected].
Author Contributions: Conception and design: N. Atri, C. Barkauskas, S.M. Brown, R. Chandra, C.C. Chang, V.J. Davey, A.C. Gelijns, A.A. Ginde, E.S. Higgs, V. Kan, H.C. Lane, P. Legenne, J.D. Lundgren, J.D. Neaton, R. Paredes, A.N. Phillips, C.S. Reilly, U. Sandkovsky, A.J. Schechner, F. Shehadeh, B.T. Thompson, D.M. Vock.
Analysis and interpretation of the data: N. Atri, C. Barkauskas, D.L. Braun, R. Chandra, V.J. Davey, R.L. Dewar, N. Engen, A.A. Ginde, R.L. Gottlieb, G. Grandits, B. Grund, T.J. Hatlen, E.S. Higgs, M.K. Jain, T.O. Jensen, V. Kan, H.C. Lane, L. Leither, J.D. Lundgren, M. Matthay, G. Matthews, D.D. Murray, E.K. Mylona, E. Mylonakis, S. Nagy-Agren, J.D. Neaton, J.S. Overcash, M.L. Padilla, R. Paredes, G. Poulakou, U. Sandkovsky, A.J. Schechner, W.H. Self, K. Shaw-Saliba, F. Shehadeh, L.K. Siegel, M. Teitelbaum, B.T. Thompson, B. Trautner, D.M. Vock, A.C. Weintrob, B.E. Young.
Drafting of the article: E. Almasri, C. Barkauskas, P. Chen, R.L. Dewar, N. Engen, G. Grandits, T.J. Hatlen, E.S. Higgs, T.O. Jensen, L. Leither, J. Lutaakome, R. Marines-Price, N.R. Mosaly, E.K. Mylona, E. Mylonakis, S. Nagy-Agren, J.D. Neaton, H.H. Nguyen, J.S. Overcash, G. Poulakou, S. Ramachandruni, V. Rapti, P. Robinson, U. Sandkovsky, F. Shehadeh, L.K. Siegel, D.M. Vock, S. Vogel, B.E. Young.
Critical revision for important intellectual content: E. Almasri, A.G. Babiker, C. Barkauskas, S.R. Bhagani, D.L. Braun, S.M. Brown, R. Chandra, C.C. Chang, V.J. Davey, N. Eriobu, A.C. Gelijns, A.A. Ginde, R.L. Gottlieb, H.F. Günthard, T.J. Hatlen, E.S. Higgs, M.K. Jain, V. Kan, A. Kelleher, K. Kim, F. Kiweewa, N. Koulouris, H.C. Lane, D. Looney, J.D. Lundgren, D.C. Lye, M. Matthay, G. Matthews, D.D. Murray, E. Mylonakis, S. Nagy-Agren, J.D. Neaton, H.H. Nguyen, C.M. North, M.L. Padilla, R. Paredes, S. Pett, A.N. Phillips, G. Poulakou, R. Rogers, U. Sandkovsky, N. Sebudde, W.H. Self, K. Shaw-Saliba, F. Shehadeh, L.K. Siegel, K.N. Syrigos, B.T. Thompson, G. Touloumi, B. Trautner, D. Vallée, A.M. Vekstein, D.M. Vock, B.E. Young.
Final approval of the article: E.X. Accardi, E. Almasri, N. Atri, A.G. Babiker, J. Badrock, A. Baduashvili, C. Barkauskas, Z. Barmparessou, A. Bednarska, S.R. Bhagani, D.L. Braun, S.M. Brown, R. Chandra, C.C. Chang, P. Chen, P. Crew, V.J. Davey, R.L. Dewar, S.H. Diong, N. Engen, N. Eriobu, A.C. Gelijns, N.P. Gerry, A.A. Ginde, R.L. Gottlieb, G. Grandits, B. Grund, H.F. Günthard, T.J. Hatlen, E.S. Higgs, H.C. Highbarger, F. Hudson, A. Hughes, M.K. Jain, T.O. Jensen, M. Kaczynski, I. Kalomenidis, V. Kan, A. Kelleher, R. Kidega, K. Kim, I. Kimuli, F. Kiweewa, K.U. Knowlton, N. Koulouris, H.C. Lane, S. Laverdure, P. Legenne, L. Leither, D. Looney, J.D. Lundgren, J. Lutaakome, D.C. Lye, R. Marines-Price, M. Matthay, G. Matthews, V. Menon, N.R. Mosaly, D.D. Murray, E.K. Mylona, E. Mylonakis, S. Nagy-Agren, V. Natarajan, J.D. Neaton, H.H. Nguyen, C.M. North, A. Osuji, J.S. Overcash, M.L. Padilla, R. Paredes, S. Pett, A.N. Phillips, G. Poulakou, K. Protopapas, S. Ramachandruni, V. Rapti, M. Tauseef Rehman, C.S. Reilly, P. Robinson, A. Rodger, R. Rogers, A. Sánchez, U. Sandkovsky, A.J. Schechner, N. Sebudde, W.H. Self, S. Sharma, K. Shaw-Saliba, F. Shehadeh, L.K. Siegel, K.N. Syrigos, M. Teitelbaum, B.T. Thompson, S. Torbati, G. Touloumi, B. Trautner, D. Vallée, S. Vasudeva, A.M. Vekstein, D.M. Vock, S. Vogel, M. Waters, A.C. Weintrob, B.E. Young, K. Zepeda.
Provision of study materials or patients: A. Baduashvili, C. Barkauskas, S.R. Bhagani, D.L. Braun, S.M. Brown, R. Chandra, S.H. Diong, R.L. Gottlieb, H.F. Günthard, T.J. Hatlen, M.K. Jain, T.O. Jensen, A. Kelleher, K. Kim, I. Kimuli, F. Kiweewa, K.U. Knowlton, N. Koulouris, D. Looney, J. Lutaakome, D.C. Lye, G. Matthews, N.R. Mosaly, E. Mylonakis, H.H. Nguyen, A. Osuji, R. Paredes, G. Poulakou, V. Rapti, P. Robinson, N. Sebudde, F. Shehadeh, K.N. Syrigos, S. Torbati, G. Touloumi, B. Trautner, S. Vasudeva, S. Vogel, B.E. Young.
Statistical expertise: A.G. Babiker, N. Engen, G. Grandits, B. Grund, J.D. Neaton, A.N. Phillips, C.S. Reilly, F. Shehadeh, L.K. Siegel, D.M. Vock.
Obtaining of funding: V.J. Davey, H.C. Lane, J.D. Lundgren, D.C. Lye, J.D. Neaton, F. Shehadeh, B.T. Thompson, B.E. Young.
Administrative, technical, or logistic support: E.X. Accardi, E. Almasri, N. Atri, J. Badrock, A. Baduashvili, S.M. Brown, C.C. Chang, P. Crew, S.H. Diong, A.C. Gelijns, N.P. Gerry, R.L. Gottlieb, H.C. Highbarger, F. Hudson, A. Kelleher, K.U. Knowlton, N. Koulouris, H.C. Lane, P. Legenne, J.D. Lundgren, E.K. Mylona, J.D. Neaton, M. Tauseef Rehman, R. Rogers, A. Sánchez, S. Sharma, K. Shaw-Saliba, F. Shehadeh, M. Teitelbaum, B.T. Thompson, D. Vallée, A.C. Weintrob.
Collection and assembly of data: N. Atri, A. Baduashvili, C. Barkauskas, Z. Barmparessou, A. Bednarska, S.R. Bhagani, D.L. Braun, S.M. Brown, C.C. Chang, P. Chen, R.L. Dewar, S.H. Diong, N. Eriobu, A.C. Gelijns, N.P. Gerry, A.A. Ginde, R.L. Gottlieb, G. Grandits, H.F. Günthard, H.C. Highbarger, A. Hughes, M.K. Jain, T.O. Jensen, M.A. Kaczynski, I. Kalomenidis, A. Kelleher, R. Kidega, I. Kimuli, F. Kiweewa, K.U. Knowlton, N.G. Koulouris, S. Laverdure, L. Leither, D. Looney, J. Lutaakome, D. Lye, R. Marines-Price, G. Matthews, V.P. Menon, D.D. Murray, E.K. Mylona, V. Natarajan, J.D. Neaton, H.H. Nguyen, A.A. Osuji, R. Paredes, G. Poulakou, K. Protopapas, S. Ramachandruni, C.S. Reilly, A. Rodger, R. Rogers, U. Sandkovsky, N. Sebudde, W.H. Self, S. Sharma, F. Shehadeh, K. Syrigos, A.M. Vekstein, D.M. Vock, M. Waters, B.E. Young, K.A. Zepeda.
This article was published at on 9 August 2022.
* For the writing group members, see end of text. For a list of all members of the ACTIV-3/TICO Study Group, see Supplement 1.

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ACTIV-3/TICO Study Group . Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19: A Randomized Controlled Trial. Ann Intern Med.2022;175:1266-1274. [Epub 9 August 2022]. doi:10.7326/M22-1503

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