key: cord-1030389-3w5clbtv
authors: Lee, Shinwon; Ok Lee, Soon; Eun Lee, Jeong; Kim, Kye-Hyung; Hee Lee, Sun; Hwang, Soyoon; Kim, Shin-Woo; Chang, Hyun-Ha; Kim, Yoonjung; Bae, Sohyun; Kim, A-Sol; Tae Kwon, Ki
title: Regdanvimab in patients with mild-to-moderate SARS-CoV-2 infection: A propensity score–matched retrospective cohort study
date: 2022-02-04
journal: Int Immunopharmacol
DOI: 10.1016/j.intimp.2022.108570
sha: afd01683fb8dff15541eabfbee6468f6a61c19c7
doc_id: 1030389
cord_uid: 3w5clbtv

BACKGROUND: Regdanvimab (CT-P59) is a neutralizing antibody authorized in Republic of Korea for the treatment of adult patients with moderate or mild-COVID-19 who are not on supplemental oxygen and have high risk of progressing to severe disease (age ≥50 years or comorbidities). This study evaluated the clinical efficacy, safety and medical utilization/costs associated with real-world regdanvimab therapy. METHODS: This non-interventional, retrospective cohort study included adult patients with confirmed mild-to-moderate SARS-CoV-2 infection. Patients treated with regdanvimab were compared with controls who had received other therapies. The primary endpoint was the proportion of patients progressing to severe/critical COVID-19 or death due to SARS-CoV-2 infection up to Day 28. Propensity score matching was applied to efficacy analyses. RESULTS: Overall, 552 patients were included in the Safety and Efficacy Sets (regdanvimab, n=156; control, n=396) and 274 patients in the propensity score–matched (PSM) Efficacy Set (regdanvimab, n=113; control, n=161). In the PSM Set, the risk of severe/critical COVID-19 or death was significantly lower in the regdanvimab group (7.1% vs 16.1%, P=0.0263); supplemental oxygen was required by 8.0% and 18.6% of patients in the regdanvimab and control groups, respectively (P=0.0128). There were no unexpected safety findings in the regdanvimab group. Medical utilization analysis showed an overall cost reduction with regdanvimab compared with control treatments. CONCLUSIONS: Regdanvimab significantly reduced the proportion of patients progressing to severe/critical disease or dying of SARS-CoV-2 infection. This study shows the potential benefits of regdanvimab in reducing disease severity and improving medical utility in patients with COVID-19.

To date, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 265 million confirmed cases of coronavirus disease 2019 (COVID-19) and more than 5.2 million COVID-19-related deaths globally [1] . A highly successful, mass immunization program is currently being rolled out worldwide, but this represents a huge undertaking and it will be a number of years before the virus is controlled on a global scale [2] . Infection and mortality rates continue to increase in many regions, particularly in developing countries where immunization rates are lower owing to the lack of vaccine supply/uptake and scarcity of public health infrastructure and primary care facilities [3] . While the COVID-19 vaccines have been developed extremely quickly using new technologies, their effectiveness appears to wane over time [4, 5] . Limited duration of protection requires booster doses, yet the emergence of SARS-CoV-2 variants may reduce the effectiveness of existing vaccines against new viral strains [6, 7] . The emergence of new SARS-CoV-2 variants with higher transmissibility is therefore likely to present many ongoing challenges to public health services resulting from the consequent increase in COVID-19 cases, hospitalizations and deaths [3, 8, 9] .

The urgent need for effective new treatments has led to an unprecedented research effort, with clinical evaluation of many potential therapeutic candidates, including antiviral drugs, anti-inflammatory agents, anticoagulants, antifibrotics and targeted immunomodulatory therapies [10] . One possible therapeutic approach involves targeting of the SARS-CoV-2 spike (S) protein, which is responsible for entry of the coronavirus into host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor located on epithelial and endothelial cells [11, 12] . Indeed, proof of principle for the use of antibody therapy that targets the SARS-CoV-2 S protein has been demonstrated in several studies [13] [14] [15] [16] , and clinical studies have reported reduced hospitalizations, clinical symptoms and viral titers in patients with SARS-CoV-2 infection administered antibodies to the S protein [12, [17] [18] [19] .

Regdanvimab (CT-P59) is a potent neutralizing antibody against various SARS-CoV-2 isolates (including the D614G S-protein variant) that blocks the interaction regions of the SARS-CoV-2 S-protein receptor-binding domain for the ACE2 receptor [20] (Fig. 1) .

Preclinical data suggest that regdanvimab is active against several variants of SARS-CoV-2 [21] [22] [23] .

Regdanvimab has demonstrated antiviral activity and clinical efficacy, along with good tolerability and safety, in a Phase 1 single-dose study in patients with mild SARS-CoV-2 infection [24] as well as in a Phase 2/3 randomized, placebo-controlled, double-blind study in outpatients with mild-to-moderate SARS-CoV-2 infection, including high-risk patients [25, 26] .

A reduced need for hospitalization or oxygen therapy up to Day 28 was demonstrated with regdanvimab in the Phase 2/3 study and led to full marketing authorization being granted by the South Korean Ministry of Food and Drug Safety on September 17, 2021, for the treatment of patients aged at least 50 years, or with at least one underlying medical condition with mild symptoms of COVID-19, and of adult patients with moderate symptoms of COVID-19 [27] . On November 12, 2021, regdanvimab was granted marketing authorization by the European Medicines Agency for treating COVID-19 in adults who do not require supplemental oxygen and who are at increased risk of their disease becoming severe [28] . Regdanvimab has also been selected by the European Commission as a preferred treatment as part of the EU strategy against COVID-19 [29] . Emergency use authorization was granted by the Indonesian National Agency for Drug and Food Control (Badan Pengawas Obat dan Makanan) [30] and the Brazilian National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária) [31] in July and August 2021, respectively, for the indication of mild-to-moderate COVID-19. Provisional approval was granted by the Therapeutic Goods Administration (TGA) of Australia on Dec 2021, for the indication of mild-to-moderate COVID-19 [32] .

Herein, we report 28-day results from a non-interventional, retrospective cohort study of regdanvimab for the treatment of patients with mild-to-moderate SARS-CoV-2 infection, including patients considered to be at high risk of severe disease. Using propensity score matching, the primary objective was to compare the real-world proportion of patients treated with regdanvimab versus standard of care who progress to severe/critical COVID-19 or die of SARS-CoV-2 infection.

This non-interventional, retrospective cohort study included patients with confirmed mild-tomoderate SARS-CoV-2 infection who were admitted to and received medical treatment at one of three hospitals in the Republic of Korea (Kyungpook National University Chilgok Hospital, Kyungpook National University Hospital or Pusan National University Hospital).

The first patient with COVID-19 reported in Korea occurred in January 2020, and the date of the first patient admitted to the hospital among analyzed patients in this study was March 2020. Regdanvimab acquired conditional marketing approval on February 5, 2021 in Korea.

From March 3, 2020 to February 4, 2021 before acquiring conditional marketing authorization, only the patients in control group were enrolled in this study. After approval of conditional marketing authorization of regdanvimab in Korea, both control and regdanvimab patients were enrolled in the study and the last patient was enrolled on July 15, 2021.The protocol and all applicable amendments were reviewed and approved by local institutional review boards (IRBs) prior to study initiation. In accordance with Article 16 of the Bioethics and Safety Act of the Republic of Korea, formal informed consent was not required for this retrospective analysis [33] . The medical records of all patients admitted to the study centers were reviewed to determine eligibility for the study. Data were recorded electronically for all eligible patients and anonymized on electronic data capture forms.

Eligible participants were adults (aged ≥18 years) with mild-to-moderate disease as defined by National Institutes of Health (NIH) guidance [34] , who had been diagnosed with SARS-CoV-2 infection at screening by means of reverse transcription-polymerase chain reaction.

Individuals were required to have oxygen saturation of >94% on room air, no need for supplemental oxygen, and onset of symptoms ≤7 days before study drug administration or admission for COVID-19 treatment. High-risk patients were included among the study population; in accordance with the Korean prescribing information of regdanvimab at the time of IRB submission, high risk was defined as age 60 years or having mild disease with underlying medical conditions (1 of the following: cardiovascular disease, chronic respiratory disease, diabetes or hypertension) [35] .

Patients who had received a COVID-19 vaccine or who had severe or critical illness at screening (per US National Institutes of Health [NIH] classification [34] ) were excluded from the study. 

The primary study objective was to evaluate the clinical efficacy of regdanvimab compared with a propensity score-matched control cohort receiving standard of care in a real-world setting, according to the proportion of patients progressing to severe/critical COVID-19 or death due to SARS-CoV-2 infection. Secondary objectives were to evaluate mortality, oxygen therapy and rescue treatment, and safety endpoints related to regdanvimab. Medical utilization of regdanvimab was evaluated as an exploratory objective.

The primary efficacy endpoint was the proportion of patients developing severe or critical disease (based on the NIH severity categories for SARS-CoV-2 infection) [34] or death due to SARS-CoV-2 infection, up to Day 28. The NIH definitions are as follows: severe illnessindividuals who have SpO 2 of <94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen of <300 mmHg, respiratory frequency >30 breaths/minute or lung infiltrates >50%; and critical illness -individuals who have respiratory failure, septic shock and/or multiple organ dysfunction [34] . Safety was analyzed according to reported adverse events (AEs), including serious AEs, infusion-related reactions (IRRs) and pregnancy test analyses. AEs were classified using the Common Terminology Criteria for Adverse Events, Version 5.0. Medical utilization and costs were also analyzed as exploratory endpoints. The medical utilization and cost endpoints were length of inpatient stay for each patient and total medical costs for each patient during hospitalization.

The proposed sample size was approximately 450 patients; this was based on the estimated number of patients admitted for COVID-19 at the study centers during the data collection period who would meet enrollment criteria, rather than a formal statistical hypothesis. The intention was for the final ratio of study participants (regdanvimab:no regdanvimab) to be approximately 1:2. Patients in the "no regdanvimab" group (hereafter referred to as the control cohort) were propensity score-matched to the "regdanvimab" cohort, using the following factors: sex, age, body mass index (BMI), Charlson Comorbidity index score and presence of pneumonia upon admission. Patients were also equally matched according to study center.

All statistical analyses were conducted using Statistical Analysis System (SAS) software, Efficacy endpoints were summarized by cohort (regdanvimab and control groups) using descriptive statistics or frequency tables. For categorical variables, the chi-squared test or Fisher exact test was used. For continuous variables, the Student t test was used. A P value of <0.05 was determined to indicate statistical significance. Medical utilization results were summarized by cohort (regdanvimab and control groups) using descriptive statistics or frequency tables.

A total of 627 patients with a confirmed COVID-19 diagnosis were admitted to one of the three study centers between March 3, 2020, and July 17, 2021 (Fig. 2) Baseline demographic and disease characteristics are summarized for the PSM Efficacy Set in Table 1 and for the Efficacy and Safety Sets in Supplementary Table S1 . Although the regdanvimab group tended to be older (median age: 66 vs 61 years), with a higher BMI (mean: 24.0 vs 23.3 kg/m²) and higher prevalence of pneumonia at baseline (37.8% vs 12.6%), due to propensity score matching, the differences between the regdanvimab and control groups were not statistically significant for the efficacy analyses, except for the presence of pneumonia (P=0.0263). Therefore, baseline characteristics in the PSM Efficacy Set were well balanced across the two treatment groups ( 

All efficacy analyses were conducted using the PSM Efficacy Set unless otherwise specified. 

Secondary endpoint data were analyzed up to Day 28 (except where noted) and are summarized in Table 3 

All safety analyses were conducted using the Safety set unless otherwise specified. In the regdanvimab group, 7 (4.5%) patients experienced treatment-emergent AEs (TEAEs). All

TEAEs were mild in severity (Grade 1) and patients recovered within 2 days of onset. Two 

Medical utilization differed significantly between treatment groups ( Table 4 . Medical utilization data, by treatment group (Medical Utilization Set**) *The mean duration of hospitalization used for estimating medical utilization comprised the total length of hospitalization for patients (i.e., including those hospitalized for more than 28 days); this differed from the estimation of the secondary efficacy endpoint "duration of hospitalization up to Day 28", which did not count days over Day 28. Two patients who died during the study were not included in the calculation of duration of hospitalization. **Patients with no information on medical billing in the PSM Efficacy Set were excluded from the Medical Utilization Set.

₩, Korean Won.

This non-interventional, propensity score-matched, retrospective cohort study of Korean patients demonstrates that regdanvimab is effective in the treatment of mild-to-moderate COVID-19. The primary analysis showed that regdanvimab significantly reduced the proportion of patients progressing to severe or critical disease severity or dying of SARS-CoV-2 infection. Regdanvimab was associated with significant reductions in the percentages of patients requiring treatment with supplemental oxygen, corticosteroids or remdesivir. In addition, a modest but statistically significant reduction in the duration of hospitalization was observed with regdanvimab, with no notable safety issues.

A crucial attribute of any COVID-19 treatment is preventing disease deterioration and death in patients with moderate disease. Increased disease severity is associated with worsened outcomes and increased healthcare and economic burden. In one study of hospitalized patients with COVID-19, the mortality rate among those who required mechanical ventilation was 88.1%, compared with 11.7% in individuals not requiring ventilation [36] . A second study, also conducted in hospitalized patients with COVID-19, showed marked increases in in-hospital mortality, length of hospital stay and hospital charges in patients who required admission to the intensive care unit (ICU) or invasive mechanical ventilation (IMV) [37] .

Identifying patterns in the course of COVID-19 disease deterioration may highlight optimal timepoints for interventions to prevent deterioration, and a Chinese observational study of patients hospitalized for moderate COVID-19 has provided important information in this regard. Among patients who deteriorated to severe or critical status, the median time to deterioration was 11 days from symptom onset; exacerbation to a critical condition occurred after a median of 3 days in a severe condition [38] . Initiating treatment early in the disease course before patients experience disease deterioration would therefore appear to be advantageous, and this is supported by the efficacy observed across both arms of our study, in which patients were required to have symptom onset within 7 days of study drug administration.

several are under evaluation for EU marketing authorization as treatments for COVID-19, including anakinra, baricitinib, and tocilizumab. However, the only drug that has so far been approved in the US and European Union (EU) for the treatment of COVID-19, besides monoclonal antibody (mAb) treatment, is remdesivir [39, 40] . Clinical studies evaluating the efficacy of remdesivir have not consistently demonstrated a statistically significant difference in comparison with control in terms of mean time to clinical improvement and mortality [41, 42] . The large, international, Solidarity study, conducted by the WHO, found in-hospital mortality rates with remdesivir and control to be comparable, and that remdesivir treatment did not reduce initiation of ventilation or the duration of hospitalization, as compared with control [43] . As a result, the WHO has recommended against the use of remdesivir for treatment of COVID-19, citing insufficient supporting evidence [44] . More recently, in

December 2021, nirmatrelvir with ritonavir and molnupiravir, become the first oral antiviral treatments for SARS-CoV-2 to be issued emergency use authorizations by the US FDA [45] .

However, some caution is still needed with these agents as they may not be suitable for all patients. Hepatotoxicity has been observed with ritonavir [46] and metabolism of the coadministered agent nirmatrelvir is highly dependent on CYP3A enzymes. The nirmatrelvir with ritonavir combination is therefore contraindicated with certain medications that are dependent on hepatic clearance [46] . Molnupiravir may affect bone and cartilage growth in adolescents and cause fetal harm in pregnant women [47] .

Unlike these antiviral drugs, the safety of antibody drugs have been well demonstrated in both clinical studies and accumulating real world data. Several antibody treatments including casirivimab/imdevimab and sotrovimab have received EU Marketing Authorizations based on evidence of efficacy in preventing progression, reducing mortality or accelerating recovery from COVID-19 [48, 49] . Additionally, data on the therapeutic effectiveness and safety of antibody drugs has been accumulated through real world data, including studies of bamlanivimab and casirivimab/imdevimab [50] [51] [52] [53] [54] [55] , and this has influenced key regulatory decisions in this setting. With these strengths, mAb prescription remains feasible in patients with limited capacity for oral drugs.

A medical utilization framework developed in the US suggests that treatments that reduce mortality in hospitalized patients with COVID-19 are likely to be cost-effective [59] . In this study, the incidence of mortality was too low to come to a definitive conclusion (n=2, both in the control group) regarding whether regdanvimab reduced mortality. [ 

Limitations of this study include the non-interventional, retrospective study design; the specific nature of the patient population (Korean patients admitted to one of three hospitals for treatment of mild-to-moderate SARS-CoV-2 infection; although the research institutes are representative hospitals in each region, patients were only recruited from two hospitals, not from multiple institutions) and the relatively short follow-up of 28 days. In addition, no information on SARS-CoV-2 variants was collected during the study.

The key strengths of our study are the large number of patients analyzed and the real-world setting. Propensity score matching adjusted for differences between the two treatment groups and ensured that the study groups were well balanced, thus reducing the risk of confounding factors. Therefore, we consider our results to be highly applicable to real-world clinical practice in Korea. The inclusion of cost and medical utilization data is another strength, enabling the financial implications of using regdanvimab to be evaluated.

In conclusion, this retrospective analysis demonstrates that regdanvimab reduces the risk of severe/critical disease or death due to SARS-CoV-2 infection among patients with high risk mild-or-moderate COVID-19. Propensity score matching ensured that the study groups were well balanced and therefore that the outcomes were robust. H-HC has been an investigators for clinical trials sponsored by Green Cross Corporation, Celltrion, Inc., Shin Poong Parmaceutical Co., Ltd., and Gilead Sciences, outside the scope of the submitted work and also reports consulting fees from Green Cross Corporation.

A-SK declares no conflict of interest.

Celltrion, Inc. funded the study and contributed to statistical analyses. Celltrion, Inc.

reviewed the manuscript throughout development for scientific accuracy.

All data are available upon request. Please contact the corresponding author Ki Tae Kwon for enquiries.

The 

World Health Organization, WHO coronavirus disease (COVID-19) dashboard

COVID-19 vaccines: the pandemic will not end overnight

India's COVID-19 emergency

COVID-19 vaccines: where we stand and challenges ahead

Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study

Centers for Disease Control and Prevention, Science Brief: COVID-19 Vaccines and Vaccination

Effectiveness of Pfizer-BioNTech and Moderna Vaccines in Preventing SARS-CoV-2 Infection Among Nursing Home Residents Before and During Widespread Circulation of the SARS-CoV

2 (Delta) Variant -National Healthcare Safety Network

Adapting hospital capacity to meet changing demands during the COVID-19 pandemic

Accelerated vaccine rollout is imperative to mitigate highly transmissible COVID-19 variants

transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

The relevance of monoclonal antibodies in the treatment of COVID-19

Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike

A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2

A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2

Potently neutralizing and protective human antibodies against SARS-CoV-2

REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19

SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19

Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial

A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein

Therapeutic effect of CT-P59 against SARS-CoV-2 South African variant

Celltrion Healthcare

CoV-2 variants with anti-COVID-19 monoclonal antibody treatment regdanvimab (CT-P59)

Celltrion's monoclonal antibody treatment for COVID-19, regdanvimab (CT-P59), demonstrates strong neutralising activity against delta variant

%99s-Monoclonal-Antibody-Treatment-for-COVID-19-regdanvimab-CT-P59-Demonstrates

Safety, virologic efficacy, and pharmacokinetics of CT-P59, a neutralizing monoclonal antibody against SARS-CoV-2 spike receptor-binding protein: two randomized, placebo-controlled, phase I studies in healthy individuals and patients with mild SARS-CoV-2 infection

Therapeutic Effect of Regdanvimab in Patients with Mild to

Moderate COVID-19: Day 28 Results from a Multicentre, Randomised, Controlled Pivotal Trial

The Korean Economic Daily, Celltrion's COVID-19 treatment reduces incidence of severity by 70%

Celltrion's monoclonal antibody treatment for COVID-19, regdanvimab (CT-P59) becomes the first authorized COVID-19 treatment approved from the Korean Ministry of Food and Drug Safety (MFDS

%99s-monoclonal-antibody-treatment-for-COVID-19-regdanvimab-CT-P59-becomes-thefirst-authorized-COVID-19-treatment-approved-from-the-Korean-Ministry-of-Food-and-Drug-Safety-MFDS

Regkirona: summary of product characteristics

EU picks antibody treatments, arthritis drug as preferred COVID-19 therapies

Indonesian National Agency for Drug and Food Control (Badan Pengawas Obat dan

Regkirona (regdanvimab) product information

Anvisa authorizes emergency use of new drug for Covid-19

Australian Government Department of Health Therapeutic Goods Administration, TGA Provisional Approval of Celltrion Healthcare Australia Pty Ltd COVID-19 treatment, regdanvimab (REGKIRONA)

Statutes of the Republic of Korea

COVID-19 treatment guidelines. Clinical spectrum of SARS-CoV-2 infection

Korean Ministry of Food and Drug Safety, Regkirona 960 mg (regdanvimab

monoclonal antibody, recombinant)

Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area

Health outcomes and economic burden of hospitalized COVID-19 patients in the United States

Patterns of deterioration in moderate patients with COVID-19 from

Veklury: summary of product characteristics

Food and Drug Administration, Veklury prescribing information

Comparison of time to clinical improvement with vs without remdesivir treatment in hospitalized patients with COVID-19

Remdesivir for the treatment of COVID-19: a systematic review and meta-analysis of randomized controlled trials

Repurposed antiviral drugs for Covid-19 -interim WHO Solidarity Trial results

A living WHO guideline on drugs for covid-19

The COVID-19 Treatment Guidelines Panel's Statement on Therapies for High-Risk, Nonhospitalized Patients With Mild to Moderate COVID-19

Fact sheet for healtcare providers: Emergency use authorization for Paxlovid (nirmatreivir tablets

Fact sheet for healthcare providers: Emergency use authorization for Molnuprivir

Ronapreve: summary of product characteristics

Xevudy: summary of product characteristics

Realworld experience of bamlanivimab for COVID-19: a case-control study

Real-world effect of monoclonal antibody treatment in COVID-19 patients in a diverse population in the United States

Casirivimab-Imdevimab treatment is associated with reduced rates of hospitalization among high-risk patients with mild to moderate coronavirus disease-19

Real-world effectiveness and tolerability of monoclonal antibody therapy for ambulatory patients with early COVID-19

Coronavirus disease 2019 (COVID-19) EUA information: drug and biological therapeutic products

European Commission, European Health Union: Commission establishes portfolio of 10 most promising treatments for COVID-19

COVID-19 treatments: under evaluation

A cost-effectiveness framework for COVID-19 treatments for hospitalized patients in the United States

Effectiveness of Regdanvimab Treatment in High-Risk COVID-19 Patients to Prevent Progression to Severe Disease

Count the cost of disability caused by COVID-19

per critically-ill, bill charged on state

Policies and innovations to battle Covid-19 -A case study of South Korea

ICER comments on Gilead's pricing for remdesivir

Treatment of moderate to severe respiratory COVID-19: a cost-utility analysis

Costeffectiveness of remdesivir and dexamethasone for COVID-19 treatment in South Africa

Institute for Clinical and Economic Review, Treatments for COVID-19

CRediT authorship contribution statement SWL: Conception and design of study; acquisition and interpretation of data

SOL: Conception and design of study; acquisition and interpretation of data

JEL: Conception and design of study; acquisition and interpretation of data

Conception and design of study; acquisition and interpretation of data

SHL: Conception and design of study; acquisition and interpretation of data

SYH: Conception and design of study; acquisition and interpretation of data

Conception and design of study; acquisition and interpretation of data

Conception and design of study; acquisition and interpretation of data

YJK: Conception and design of study; acquisition and interpretation of data

SHB: Conception and design of study; acquisition and interpretation of data

Conception and design of study; acquisition and interpretation of data

KTK: Conception and design of study; acquisition and interpretation of data

Statistical analysis and manuscript review were conducted by the sponsor (Celltrion Inc.) Declaration of interest

SHL has been an investigator for clinical trials sponsored by GlaxoSmithKline plc

SYH and KTK have been investigators for clinical trials sponsored by Pfizer, Chong Kun Dang Pharmaceutical

has been an investigators for clinical trials sponsored by Green Cross Corporation, Celltrion, Inc., Shin Poong Parmaceutical Co., Ltd., and Gilead Sciences, outside the scope of the submitted work and also reports consulting fees from Green Cross Corporation

We thank all patients and investigators involved in the study. Medical writing support