Study design and oversight. This phase 2/3, randomized, parallel-group, placebo-controlled, double-blind study (NCT04602000; EudraCT: 2020-003369-20) enrolled outpatients with mild-to-moderate SARS-CoV-2 infection. The disease was classified as mild or moderate at baseline based on guidance from the World Health Organization26: a patient was considered to have moderate disease based on the presence of radiography-confirmed pneumonia, and to have mild disease based on the absence of radiography-confirmed pneumonia at baseline. Part 1 of the study (reported to 28 days in the present manuscript) comprised three periods: screening (days –7 to day 1), treatment (day 1 to day 90 end-of-treatment [EOT] visit), and follow-up (EOT visit to day 180). Patients received a single infusion of study drug on day 1. Part 2 of the study (ongoing) aims to confirm the effect of CT-P59 on clinical symptoms requiring hospitalization, oxygen therapy, or mortality due to SARS-CoV-2 infection, and will be reported separately.
The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and in compliance with the International Council for Harmonisation Good Clinical Practice and applicable regulatory requirements. The protocol and all applicable amendments were reviewed and approved by local or national independent ethics committees prior to study initiation and the study was monitored by an independent data safety monitoring board. All participants provided written informed consent.
Participants. Eligible participants were aged ≥18 years, diagnosed with SARS-CoV-2 infection at the study centers at screening using the sponsor-supplied rapid SARS-CoV-2 diagnostic test (DiaTrust™, Celltrion, Inc., Incheon, Republic of Korea) or locally conducted reverse transcription polymerase chain reaction (RT-PCR), had an oxygen saturation of >94% on room air, and did not require supplemental oxygen. Participants were required to have symptom onset (feverishness, cough, shortness of breath, sore throat, body/muscle pain, fatigue, headache, chills, nasal congestion, loss of taste or smell, or diarrhea) within 7 days before study drug administration. Patients with a current serious health condition or with ongoing or history of active or severe infections were excluded. Comprehensive eligibility criteria are provided in the protocol (see Supplementary Information).
Randomization and masking. Randomization was performed using an interactive web response system and a randomization schedule prepared by unblinded biostatisticians. Randomization was stratified by age (≥60 vs <60 years), region (USA vs Asia vs EU vs other), baseline comorbidities (yes vs no for having at least one of cardiovascular disease, chronic respiratory disease, hypertension, diabetes mellitus, or pneumonia), and participation in the pharmacokinetic (PK) substudy (yes vs no). Participants, personnel, and outcome assessors were blinded to treatment allocation for the duration of the study. CT-P59 and placebo were supplied in identical vials identified by a study drug number. Designated unblinded personnel prepared the study drug for infusion.
Procedures. Participants were assigned randomly (1:1:1 ratio) to receive a single dose of CT-P59 40 mg/kg, CT-P59 80 mg/kg, or placebo. CT-P59 and placebo were reconstituted in 250 mL of 0.9% sodium chloride and administered via intravenous infusion over 90 ± 15 minutes. All patients received optimal standard-of-care treatment, including rehydration therapy, antipyretics, or antitussives at the investigator’s discretion, but excluding antiviral drugs and/or possible SARS-CoV‑2 active drugs (only to be administered as rescue therapies).
Nasopharyngeal swabs for assessment of viral shedding (based on quantitative RT-PCR [RT-qPCR]) were taken predose on day 1, and at 24, 48, 72, 96, 120, 144, 216, 312 (day 10), 384 (day 17), 480 (day 21), and 648 (day 28) hours after study drug administration.
Participants were required to complete a patient diary on days 1–28, which included a SARS-CoV-2 symptom checklist. The checklist, which was to be completed by all patients at screening and twice daily from days 1–28, included seven symptoms of SARS-CoV-2 infection (fever, cough, shortness of breath or difficulty breathing, sore throat, body pain or muscle pain, fatigue, and headache).
Disease status monitoring was performed throughout the study (e.g., requirement for supplemental oxygen, intensive care unit [ICU] transfer, mechanical ventilation use, hospitalization, and rescue therapy use).
Safety was assessed throughout the study based on the incidence, type, severity, and causality of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), and TEAEs of special interest. TEAEs were coded according to the Medical Dictionary for Regulatory Activities, Version 23.1, and graded for severity according to the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. Hypersensitivity monitoring was performed before and after administration of study drug on day 1. Vital signs measurements, physical examination findings (before study drug administration and EOT only), electrocardiogram (ECG) findings, and clinical laboratory analyses were assessed periodically throughout the study.
Details of the study drug formulation; SARS-CoV-2 symptom checklist; and PK, serology (including anti-drug antibodies [ADAs]), and virology assessments are described in the Supplementary Information.
Study endpoints. The primary study endpoints were time to conversion to negative nasopharyngeal swab specimen based on RT-qPCR (negative titer threshold: 2.33 log10 copies/ml) up to day 28 and time to clinical recovery up to day 14.
Patients who had negative RT-qPCR results at two or more consecutive time points were considered as satisfying the criteria for conversion to negative nasopharyngeal swab specimen based on RT-qPCR result (the first of the two consecutive time points was taken as the time to conversion to negative RT-qPCR result). Clinical recovery was defined as all symptom scores of “absent” or “mild” for ≥24 hours based on checklist results; symptoms scored as moderate or severe at baseline were required to be scored as mild or absent at recovery, whereas symptoms rated as mild or absent at baseline were required to be rated as absent at recovery.
Secondary efficacy endpoints included the following: the proportion of patients with clinical symptoms requiring hospitalization (≥24 hours of acute care), oxygen therapy (≥24 hours of supplemental oxygen care, with oxygen saturation of ≤94% on room air prior to administration), or death due to due to SARS-CoV-2 up to day 28; the proportion of patients with conversion to negative RT-qPCR result; and the proportions of patients with hospital admission requiring supplemental oxygen, with mechanical ventilation use, requiring rescue therapy, with ICU admission (individual endpoints; each due to SARS-CoV-2 infection), or with all-cause mortality.
Primary endpoint definitions and a comprehensive list of efficacy, PK, and virology endpoints are described in the Supplementary Information.
Statistical analysis. It was estimated that a sample size of 100 individuals per group would provide at least 80% power at a two-sided significance level of 0.05 to detect an increase in the improvement rate ratio between CT-P59 groups and placebo for the primary endpoints.
Efficacy was assessed in the intent-to-treat infected (ITTI) population, which comprised all randomly assigned patients with confirmed SARS-CoV-2 infection assessed by pre-infusion RT-qPCR on day 1 and receiving a partial or complete dose of study drug. If the pre-infusion result on day 1 was confirmed negative or missing and the day 2 result was confirmed positive, the patient was also considered as having confirmed SARS-CoV-2 infection. The safety population included all randomized participants who received a partial or full dose of the study drug.
Primary efficacy analyses were performed using stratified log-rank test for time-to-event endpoints. Improvement/clinical recovery rate ratios (with 95% confidence intervals [CIs]) were estimated using a stratified Cox proportional hazards model. Adjustments for multiple testing were not performed. Secondary efficacy endpoints were summarized using descriptive statistics, frequency tables, or Kaplan-Meier (time-to-event) methods.
Subgroup analyses of the primary endpoints and one of the secondary efficacy endpoints were conducted according to SARS‑CoV‑2 severity (mild vs moderate; prespecified) and age (≥50 years; exploratory). Post-hoc analyses of the primary efficacy outcome – time to conversion to negative RT-qPCR – were conducted based on negative titer thresholds of 3.0 and 4.0 log10 copies/ml.
All statistical analyses were conducted using Statistical Analysis System (SAS) software, Version 9.4 (SAS Institute Inc., Cary, NC, USA). Sample size calculation assumptions, definitions of additional analysis populations, and statistical methodologies (including missing data handling) are included in the statistical analysis plan (see Supplementary Information).
The study protocol and statistical analysis plan are available online as supplementary information. Individual participant data cannot be made available.