Tocilizumab for treatment of patients with severe COVID-19: A retrospective cohort study

Design

Retrospective cohort

N=51

Objective

To assess the clinical benefit of tcocilizumab for selected COVID-19 patients with high inflammatory markers

Study Groups

Study group: Tocilizumab 8mg/kg intravenously (Max: 400mg per dose)

Control: No tocilizumab

Methods

Inclusion criteria: 18 years of age or older, diagnosed with severe COVID-19 defined as requiring supplemental oxygen for saturation of less than 94% on room air

Exclusion criteria: Not requiring supplemental oxygen during hospitalization

Charts for all patients who were diagnosed with COVID-19 admitted to Cleveland Clinic Fairview Hospital between March 13 and April 19, 2020 were retrospectively reviewed. Tocilizumab was given to patients with evident hypoxia, lung infiltrates on chest x-ray, elevated C-reactive protein, concern for clinical deterioration, and if none of the following contraindications existed; confirmed or suspected bacterial infection, platelet count <100,000/mm³, neutrophil count <2000/mm³, and ALT/AST >5x ULN.

Outcome Measures

Primary outcomes: Time to clinical improvement, duration of invasive ventilation, and duration of circulatory shock requiring vasopressor support in tocilizumab vs. no tocilizumab cohorts.

Secondary outcomes: Oxygen-support categories. change in oxygen requirement, clinical improvement, discharge, required mechanical ventilation, duration of vassopressr support

Baseline Characteristics

Tocilizumab n=28

No Tocilizumab n=23

Median age, years (range)

62 (53-71)

70 (55-75)

Women

8

13

White

22

14

Invasive mechanical ventilation

21

11

High-flow oxygen

1

1

Low-flow oxygen

6

11

Medical intensive care unit

24

16

Regular nursing floor

4

7

Systemic steroid

20

11

Hydroxychloroquine and azithromycin

26

22

Results

Endpoint

Tocilizumab

No tocilizumab

Improvement in oxygen-support category

18

13

Discharged from hospital

11

13

Clinical improvement

76.5% (95% CI:57.3-95.6)

79.4% (95% CI: 56.0-100)

Time to clinical improvement

6.5 days (IQR:4-9 days)

7 days (IQR: 5-10 days)

Required mechanical ventilation

67.9% (95% CI: 43.2-92.7)

61.9% (95% CI: 21.9-100)

Duration of vasopressor support

2 days (IQR: 1.75-4.25 days)

5 days (IQR: 4-8 days)

Duration of invasive mechanical ventilation

7 days (IQR: 4-14 days)

10 days (IQR: 5-15 days)

Died

3

2

Adverse Events

Common Adverse Events: Not disclosed

Serious Adverse Events: Not disclosed

Percentage that Discontinued due to Adverse Events: Not disclosed

Study Author Conclusions

The study indicated that the tocilizumab cohort had a higher rate of improvement in oxygen-support category for those requiring invasive and non-invasive oxygen support. Those requiring intubation in the tocilizumab cohort had 5 days shorter median time to clinical improvement. Duration of vasopressor support and invasive mechanical ventilation was 3 days shorter in the tocilizumab cohort

InpharmD Researcher

Critique

This study is limited in regards to the study design being retrospective with a non-randomized control group and the concomitant use of other medication may have influenced the outcomes. The study included a small sample size and had a short follow up duration.

Tocilizumab treatment in COVID‐19: A single center experience

Design

Retrospective observational

N=15

Objective

To present treatment responses of tocilizumab in COVID-19 patients to provide guidance for clinical use.

Study Groups

Tocilizumab (n=15)

Methods

Patients infected with COVID-19 at Tongji Hospital in Wuhan, China were identified and treated with tocilizumab with doses ranging from 80 to 600mg.

Patients were classified as mildly, moderately, seriously, or critically ill. Serum levels of C-reactive protein and IL-6 were observed before and after administration of tocilizumab. Data included all comorbidities, treatments, laboratory results, and clinical outcomes from the medical records.

Clinical outcome was evaluated within 1 week after tocilizumab treatment.

Duration

January 27, 2020 to March 5, 2020

Outcome Measures

Primary outcome: Not provided

Secondary outcomes: Decrease in C-reactive protein level, decrease in IL-6 level, clinical outcome (i.e., death, stabilization, aggrevation)

Baseline Characteristics

Value

Median Age, years

73

Women

3

Moderately ill

2

Seriously ill

6

Critically ill

7

Tocilizumab dose range

80mg – 600mg

One or more co-morbidities

10

Received methylprednisolone

8

Received tocilizumab twice or more

5

Results

Endpoint

Before

After

C-reactive protein

126.9 (10.7-257.9) mg/L

11.2 (0.02-113.7)

IL-6

16.4-112.8 pg/mL

12.4-5000 pg/mL

Death

 -

3

Clinical stabilization

 -

9

Clinical improvement

 -

1

Disease aggravation

 -

2

Adverse Events

Common Adverse Events: Not disclosed

Serious Adverse Events: Not disclosed

Percentage that Discontinued due to Adverse Events: Not disclosed

Study Author Conclusions

The study suggest that a single dose fails to improved disease in critically ill patients. However, lower repeated doses might improve the condition of critically ill patients.

InpharmD Researcher

Critique

This study is limited by several factors: it is non-controlled, and done using a small sample size of patients with variable risks for poor outcomes, and utilizes inconsistent treatment techniques. Results should be interpreted with caution due to use of lab parameters.

Tocilizumab in patients with severe COVID-19: a retrospective cohort study

Design

Retrospective, observational cohort

N=544

Objective

To assess the role of tocilizumab in reducing the risk of invasive mechanical ventilation and death in patients with severe COVID-19 pneumonia who received standard of care treatment.

Study Groups

Tocilizumab plus standard of care (N=179) 

Sstandard of care only (N=365)

Methods

Inclusion criteria: 18 years of age or older,  diagnosed with severe COVID-19 pneumonia,

Exclusion: coexisting infection other than COVID-19, ratio of arterial oxygen partial pressure to fractional inspired oxygen of >300mmHg, chronic or current glucocorticoid use, history of severe allergic reactions to monoclonal antibodies, neutrophil count <500/microliter, active GI tract condition, or severe hematological, renal or liver function impairment.

 All patients receive standard of care which included supplemental oxygen, hydroxychloroquine, azithromycin, antiretrovirals, and low molecular weight heparin. A non-random subset of patients also received tocilizumab intravenously at 8mg/kg in two infusions, 12h apart, or subcutaneously at 162mg in two doses, one in each thigh, when the intravenous options was unavailable.

Duration

February 21st 2020 to April 30th 2020

Outcome Measures

Primary outcome: Composite of invasive mechanical ventilation or death

Secondary outcomes: Mechanical ventilation, death, death after mechanical ventilation

Baseline Characteristics

Tocilizumab plus standard of care (n=179)

Standard of care (n=365)

Median Age, years (range)

64 (54-72)

69 (57-78)

Women

52

133

Men

127

232

Baseline PaO₂/FiO₂ (mm Hg)

169 (106-246)

277 (191-345)

Duration of symptoms

7 (4-10)

5 (2-9)

Results

Endpoint

Tocilizumab plus standard of care (n=179)

Standard of care (n=365)

p-value

Follow-up (days)

12 (6-17)

8 (4-14)

-

Mechanical ventilation

33

57

-

Deaths after mechanical ventilation

5

14

-

Death

13

73

-

Composite of ventilation or death; unadjusted HR

Standard Cox: 0.6
Weighted Cox: 0.54

1
1

0.0030

0.0009

Composite of ventilation or death; adjusted HR

Standard Cox: 0.61
Weighed Cox: 0.53

1
1

0.020
0.016

All-cause mortality; unadjusted HR

0.28

1

<0.0001

All-cause mortality; adjusted HR

0.38

 1

0.015

Adverse Events

Common Adverse Events: Not disclosed

Serious Adverse Events: higher prevalence of infection in the tocilizumab group

Percentage that Discontinued due to Adverse Events: Not disclosed

Study Author Conclusions

The study indicated that those receiving tocilizumab, intravenously or subcutaneously, showed significant reduction in risk of invasive mechanical ventilation or death when compared to those receiving standard of care only. There was no marked difference between the intravenous and subcutaneous groups.

InpharmD Researcher

Critique

This study is limited in regards to the study design being retrospective and unmeasured confounding could not be ruled out. There was a shortage of tocilizumab which determined how many participants received treatment and those receiving standard of care only were older and had higher baseline risk of the composite endpoint.