key: cord-1047260-u8zxgcrl
authors: Kumar, Princy N; Hernández-Sánchez, Jules; Nagel, Sandra; Feng, Yuning; Cai, Fang; Rabin, Joseph; Morse, Caryn G; Nadig, Nandita R; Ashraf, Obaid; Gotur, Deepa B; McComsey, Grace A; Gafoor, Khalid; Perin, Patrick; Thornton, Sarah C; Stubbings, William; Lin, Celia J F; Tsai, Larry
title: Safety and Efficacy of Tocilizumab 4 or 8 mg/kg in Hospitalized Patients With Moderate to Severe COVID-19 Pneumonia: A Randomized Clinical Trial
date: 2021-12-04
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab608
sha: d7ba3e2639a69755f1029543cce96471a385f14e
doc_id: 1047260
cord_uid: u8zxgcrl

BACKGROUND: Tocilizumab, an interleukin 6 receptor (IL-6R) antagonist monoclonal antibody, has shown efficacy in patients with COVID-19 pneumonia, but the optimal dose is unknown. METHODS: Patients hospitalized for moderate-to-severe COVID-19 pneumonia were randomized 1:1 to receive standard care treatment and 1 to 2 doses of intravenous tocilizumab 4 or 8 mg/kg (open-label). Primary pharmacokinetic and pharmacodynamic end points were serum concentrations of tocilizumab and soluble IL-6R (sIL-6R), IL-6, ferritin, and C-reactive protein (CRP), from baseline to day 60. The secondary end point was safety. Key exploratory efficacy end points included clinical status, time to discharge, mortality rate, and incidence of mechanical ventilation. RESULTS: Of 100 patients randomized, 49 received tocilizumab 4 mg/kg and 48 received 8 mg/kg. In pharmacokinetic and sIL-6R assessments, dose-dependent differences were seen in patients who received 1 or 2 doses of 4 or 8 mg/kg. Serum concentrations of IL-6, ferritin, and CRP and safety outcomes were comparable between groups. Through day 60, serious adverse events were reported in 30.6% and 25.0% of patients in the 4- and 8-mg/kg group, respectively. Eight patients (16.3%) in the 4-mg/kg group and 6 (12.5%) in the 8-mg/kg group died. Exploratory time-to-event outcomes favored 8-mg/kg within the first 2 weeks. CONCLUSIONS: In patients with moderate-to-severe COVID-19 pneumonia who received tocilizumab 4 or 8 mg/kg, pharmacokinetic and sIL-6R assessments showed expected dose-dependent effects; pharmacodynamic assessments and safety were comparable, with no new safety signals. Further study is required before a lower dose of tocilizumab can be recommended in patients with COVID pneumonia.

COVID-19 has taken an immense toll on human health, with >250 million confirmed cases and >5 million deaths globally. 1 Approximately 20% of patients with COVID-19 experience complications related to severe pneumonia, 2 which can progress to acute respiratory distress syndrome and death. [3] [4] [5] [6] Elevated levels of proinflammatory cytokines and mediators, such as interleukin 6 (IL-6), C-reactive protein (CRP), and ferritin are associated with poor clinical outcomes, 5,7-10 which prompted observational studies and clinical trials investigating the safety and efficacy of immunomodulatory treatments early in the pandemic. 11, 12 Tocilizumab is an IL-6 receptor antagonist monoclonal antibody approved for use in inflammatory diseases, including rheumatoid arthritis and cytokine release syndrome associated with chimeric antigen receptor T-cell therapy. [13] [14] [15] Results from randomized controlled trials in patients with rheumatoid arthritis have shown efficacy of tocilizumab at 4and 8-mg/kg doses. [16] [17] [18] [19] Based on resolution of symptoms, tocilizumab was approved at an 8-mg/kg dose for cytokine release syndrome induced by chimeric antigen receptor T-cell therapy, although no formal dose-finding studies were performed. 14, 20 Results from randomized clinical trials of tocilizumab in patients with COVID-19 have been discordant, possibly due to differences in patient populations, co-administered treatments, treatment timing, or the evolving standard of care (SOC). 11 Most randomized trials and observational studies investigating tocilizumab in patients with pneumonia have evaluated the 8-mg/kg dose [21] [22] [23] [24] [25] [26] [27] [28] ; however, other studies have shown potential benefits of doses of ≤4 mg/kg. 29 

This phase 2, open-label, randomized study was conducted at 26 sites in the United States.

We included patients ≥18 years old hospitalized for moderate to severe COVID-19 pneumonia detected by SARS-CoV-2 positive reverse transcriptase polymerase chain reaction (RT-PCR) (within 7 days before randomization) and confirmed by chest x-ray or computed tomography scan. Severe COVID-19 pneumonia was defined as patients having blood oxygen saturation of ≤93% or partial pressure of oxygen to fraction of inspired oxygen ratio of <300 mm Hg. Patients with moderate pneumonia did not meet the oxygen requirements of severe pneumonia but had evidence of inflammation as indicated by CRP levels >2× the upper limit of normal (ULN). All patients received SOC treatment per local practice, which may have included antiviral treatment, low-dose corticosteroids, and supportive care. Patients who were on a mechanical ventilator for >24 hours or ECMO, in shock or with multiorgan failure requiring treatment in an intensive care unit were excluded.

All patients or their legally authorized representative gave written or oral informed consent. This study was conducted in accordance with the International Council for Harmonisation E6 guideline for good clinical practice and the Declaration of Helsinki or local regulations, whichever afforded greater patient protection. This trial was approved by trial sites through a central institutional review board or local institutional review board or ethics committee at the study site.

A c c e p t e d M a n u s c r i p t 7

Patients were randomized 1:1 through permuted-block randomization to receive SOC and 1 dose of tocilizumab 4 or 8 mg/kg (maximum 800 mg) intravenously. An interactive voice or web-based response system provided sites with treatment assignments. Randomization was stratified by pneumonia severity (moderate or severe). An additional infusion (same as initial dose) could be administered 8 to 24 hours after the first if a patient had a sustained fever or clinically significant worsening of signs or symptoms, such as an increased supplemental oxygen requirement.

The pharmacokinetic outcomes were serum concentrations of tocilizumab at baseline and days 1, 2, 3, 7, 14, 21, 28, 35, and 60 following administration of tocilizumab 4 or 8 mg/kg. Key exploratory efficacy outcomes included 1) clinical status, as assessed using an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) (Supplemental Table 1 ) at days 14 and 28; 2) time to hospital discharge or "ready for discharge" (as evidenced by normal body temperature and respiratory rate and stable oxygen saturation on ambient air or ≤2 L of supplemental oxygen) by day 28; 3) mortality rate by day 28; and 4) incidence of mechanical ventilation up to day 28.

In healthy volunteers and patients with rheumatoid arthritis, 20 to 30 individuals per treatment arm was adequate to study between-participant and within-participant pharmacokinetic variability. 33 However, the variability of pharmacokinetic parameters in a heterogeneous population of patients with COVID-19 was unknown; therefore, 50 patients per treatment arm were enrolled. The modified intention-to-treat (mITT) population included all patients who underwent randomization and received either dose of tocilizumab.

The pharmacokinetic analysis population consisted of patients with ≥1 analyzed sample contributing toward the estimation of key parameters. The serum pharmacokinetics of tocilizumab were summarized by estimating the total exposure (area under the curve), maximum concentration, total clearance, and volume of distribution.

Safety assessments were completed for all patients who received any amount of tocilizumab. Efficacy outcomes were exploratory and were evaluated in the mITT population.

Time to hospital discharge was compared between the 2 doses using proportional hazards models stratified by moderate vs severe COVID-19 pneumonia. Cause-specific hazards are reported with death as a competing risk. The Cochran-Mantel-Haenszel test, stratified by COVID-19 severity at baseline, was used to assess the between-group difference in mortality and incidence of mechanical ventilation by day 28. Description of subgroup analysis of mortality is provided in the Supplemental Methods.

A c c e p t e d M a n u s c r i p t 9

A total of 100 patients were randomized; 3 patients did not receive tocilizumab. In the mITT and safety populations, 49 patients received tocilizumab 4 mg/kg plus SOC (1 dose, n=37; 2 doses, n=12) and 48 patients received tocilizumab 8 mg/kg plus SOC (1 dose, n=39, 2 doses, n=9; Figure 1 ). Median time between first and second dose was 18.8 and 19.8 hours in the 4-and 8-mg/kg groups, respectively. (Supplemental Table 2 ). In the 4-and 8-mg/kg groups, 11 patients (22.4%) and 9 (18.8%) had moderate disease, respectively, and 38 (77.6%) and 39 (81.3%) had severe disease.

The baseline demographic data were generally comparable between groups, with some differences observed for age and race ( Table 1) Table 4 ). Linear clearance estimates were similar for 1 and 2 doses of tocilizumab 4 mg/kg and for 1 dose of tocilizumab 8 mg/kg but showed a 26% increase in the geometric mean when 8 mg/kg was administered twice compared with a single administration. The volume of the central compartment was similar for all dose groups.

Serum sIL-6R concentrations increased immediately following tocilizumab administration, with a similar rate of sIL-6R-tocilizumab complex production up to day 7 in both groups ( Figure 3A) . Maximum geometric mean serum sIL-6R concentrations were recorded on day 7 for the 4-mg/kg group and on day 14 for the 8-mg/kg group. Geometric mean serum sIL-6R concentrations were lower in the 4-mg/kg group than in the 8-mg/kg group between days 14 and 35. Interpatient variability was low to moderate over time in both dose groups ( Figure   3A ).

Serum IL-6 concentrations increased immediately following the tocilizumab infusion, peaking at day 3 for both doses. No notable differences were observed between the 2 doses in the IL-6 serum concentration-time profiles up to day 60 ( Figure 3B ).

Geometric mean serum CRP concentrations were above the ULN at baseline in both groups. Following tocilizumab administration, the geometric mean concentrations decreased rapidly from baseline to below the ULN at day 7 and remained close to or below the ULN from day 7 to day 60. No notable differences were observed between the 2 doses in the CRP concentration-time profiles up to day 60 ( Figure 3C) .

A c c e p t e d M a n u s c r i p t 11 Geometric mean serum ferritin concentrations were above the ULN at baseline.

Following tocilizumab administration, a marked decrease in serum ferritin concentrations was observed in both groups from approximately day 7 to day 35, with the geometric mean concentrations close to normal range by day 21 (Figure 3D ).

AEs through day 60 occurred in 57.1% of patients in the 4-mg/kg group and 45.8% in the 8mg/kg group ( Table 2) . Serious AEs were reported in 30.6% and 25.0% in the 4-and 8mg/kg groups, respectively. Eight patients (16.3%) in the 4-mg/kg group and 6 (12.5%) in the 8-mg/kg group died ( Table 2 and Supplemental Table 5 ). Infections were the most common AE by System Organ Class and of special interest (Supplemental Table 6 

No formal statistical comparisons between the 4-and 8-mg/kg groups were conducted for exploratory efficacy outcomes because the main objectives were pharmacokinetic and pharmacodynamic outcomes; at the beginning of the pandemic, there was insufficient information to design a noninferiority trial to compare efficacy of 4 and 8 mg/kg. In the analysis of clinical status, the 7-category ordinal scale distribution favored the 8-mg/kg group from day 2 until day 7, but there were no differences between the groups at day 28 (Supplemental Table 7 and Supplemental Figure 1) . A trend for increased progression A c c e p t e d M a n u s c r i p t 12 toward worse clinical status (categories 5 and 6) and death (category 7) was seen up to day 14 for the 4-mg/kg vs 8-mg/kg group, followed by no notable difference between groups at days 21 and 28.

Overall, 39 patients (79.6%) in the 4-mg/kg group and 38 (79.2%) in the 8-mg/kg group were discharged or ready to be discharged by day 28, as assessed by hospital records (Supplemental Table 7 The mortality rate at day 28 was higher in the 4-vs 8-mg/kg group (7 patients [14.3%] vs 5 [10.4%], respectively); the weighted difference between the treatment groups was −4.5% (95% CI, −18.2% to 9.2%) (Supplemental Table 7 ). None of the subgroups showed a clear difference between the 2 treatment groups in the odds ratio for mortality at day 28 (Supplemental Figure 3) .

increased from baseline until day 7 and then declined due to clinical improvement. The incidence of mechanical ventilation to day 28, including mechanical ventilation ongoing at baseline, was 14 patients (28.6%) in the 4-mg/kg group and 15 (31.3%) in the 8-mg/kg group (Supplemental Table 7 ); the weighted difference was 1.5% (95% CI, −16.4% to 19.5%). In the patients who were not on mechanical ventilation at baseline, the incidence of new mechanical ventilation events to day 28 was 10 patients (22.2%) in the 4-mg/kg group and 8 (19.5%) in the 8-mg/kg group (Supplemental Table 7 ); the weighted difference was −3.2% (95% CI, −20.6% to 14.1%).

A c c e p t e d M a n u s c r i p t 13

In this randomized phase 2 trial of hospitalized patients with moderate to severe COVID-19 pneumonia who received tocilizumab 4 or 8 mg/kg, pharmacokinetic and sIL-6R assessments showed expected dose-dependent effects. Serum sIL-6R concentrations were lower between days 14 and 35 in the 4-mg/kg group compared with the 8-mg/kg group.

Similarly, there was a higher clearance of TCZ serum concentrations observed in the 8mg/kg than 4-mg/kg group. This difference between the 2 doses is possibly related to an unbalanced distribution of covariates known to have a positive impact on tocilizumab clearance, including body weight 33 , with a higher mean body weight in 8-mg/kg group than the 4-mg/kg group.

Serum sIL-6R concentrations were lower between days 14 and 35 in the 4-mg/kg group than in the 8-mg/kg group; as expected, the duration of target engagement was longer for the 8-mg/kg dose than the 4-mg/kg dose. Otherwise, pharmacodynamic assessments revealed no clear differences between the tocilizumab doses in serum IL-6, CRP, or ferritin concentrations up to day 60.

The safety of tocilizumab 4 mg/kg was comparable to that of 8 mg/kg. No new safety signals were identified. Results of the present MARIPOSA trial are consistent with those of other randomized trials of tocilizumab in COVID-19. [21] [22] [23] [24] [25] [26] [27] 34 Overall mortality rates and frequency of serious AEs in this trial were lower than those in the COVACTA trial 23 but higher than those in the EMPACTA trial, 24 

The open-label design is a limitation; however, pharmacokinetic and pharmacodynamic end points were unlikely to be affected by awareness of tocilizumab dose. The trial was not powered to evaluate efficacy and did not have a placebo arm.

In this randomized clinical trial of hospitalized patients with moderate to severe pneumonia who received 1 to 2 doses of tocilizumab 4 or 8 mg/kg, pharmacokinetic assessments and sIL-6R levels showed expected dose-dependent effects, whereas other pharmacodynamic assessments revealed no clear differences between the 2 dose regimens. Safety outcomes were comparable between groups, and no new safety signals were identified. Exploratory efficacy results indicated that further study is required before a lower tocilizumab dose can be recommended in patients with moderate to severe COVID-19 pneumonia.

A c c e p t e d M a n u s c r i p t 15

The authors would like to thank Christophe Dhalluin and Teresa Gleissl who assisted with medical data review during the study.

Medical Writing, Editorial, and Other Assistance: Support for third-party writing assistance, provided by Sarah Nordquist, PhD, and Nicola Gillespie, DVM, of Health Interactions, Inc, was provided by Genentech, Inc.

Financial Support: This study was funded by F. Hoffmann-La Roche Ltd, which was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. A c c e p t e d M a n u s c r i p t 

World Health Organization. Coronavirus (COVID-19) Dashboard

Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. Interim guidance

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Factors associated with death in critically ill patients with coronavirus disease 2019 in the US

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a

prognostic value of C-reactive protein in patients with coronavirus 2019

Ferritin levels and COVID-19. Rev Panam Salud 136

Covid-19 controversies: the tocilizumab chapter

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome

Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial

IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebocontrolled trial

Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year

Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double

Applied clinical pharmacology in a crisis: interleukin-6 axis blockade and COVID-19

Interleukin-6 receptor antagonists in critically ill patients with Covid-19

Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial

Tocilizumab in hospitalized patients with severe Covid-19 pneumonia

Tocilizumab in Patients Hospitalized with Covid-19

Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial

Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial

SD, standard deviation; sIL-6R, soluble interleukin 6 receptor. a Self-reported

b Seven-category ordinal scale: 1, discharged (or ready for discharge as evidenced by normal body temperature and respiratory rate and stable oxygen saturation on ambient air or