TOCILIZUMAB - An Option for Patients With COVID-19 Associated Cytokine Release Syndrome; A Single Center Experience
Phase: PHASE4
Conditions: Covid19
Sponsor: FMH College of Medicine and Dentistry

 
 
 
 TOCILIZUMAB – An option for 
Patients with COVID-19 associated 
Cytokine release syndrome; A single 
Center experience 
IRB# FMH-05-2020-IRB-758-M 
Study Protocols, Statistical analysis plan 
 
 
 
2020 
 
12th, May, 
2020 
 
 
 
 
 
 
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Methodology: 
Study Design: It was a Quasi-experimental study where participants were allocated using 
predefined protocol who met the inclusion criteria of study after signing a written & informed 
consent either by the patient or the person legally authorized to sign. 
 Study Settings: The study was conducted in Fatima Memorial Hospital, Lahore among in-house 
patients of COVID-19. 
Sample size and technique: our sample size was 93, out of which 33 patients were kept in the 
experimental group who were offered Tocilizumab and 60 patients were offered Corticosteroids 
for comparing the efficacy of both modalities of treatment. The sampling technique was 
consecutive sampling as per the inclusion and exclusion criteria 
Data Collection and analysis Procedure: All admitted patients who had moderate to severe 
disease or who were in a cytokine storm, were studied and data related to Epidemiological, 
demographic, clinical, laboratory, radiological, and treatment were collected and analyzed. 
Outcomes were noted and compared. 
The response of the patient after Tocilizumab or Corticosteroid administration was recorded. The 
response was recorded based on clinical parameters (Oxygen requirement, Fever, Need for 
invasive positive pressure ventilation), biochemical parameters (D-dimers, C-reactive protein 
(CRP), Ferritin, Lactate dehydrogenase (LDH) levels), Chest X-ray findings, and Repeated PCR 
 test for COVID-19. Any side effects noted after administration of TCZ/ Corticosteroid were 
recorded. 
Tocilizumab administration protocol: Patients received an initial dose calculated as per the 
body weight (8mg/kg) maximum 800mg/dose) over 1 hour, followed by up to three additional 
doses if required as per the response after the first dose with 8 hours intervals. Predefined 

Parameters of disease severity were assessed 12 to 24 hourly. Injection Paracetamol 1g was 
administered before infusion. 
Corticosteroid administration protocol: Patients received methylprednisolone 80mg/day in 
two divided doses as per national/local guidelines and predefined parameters of disease severity 
were assessed on each day. 
Data was entered and analyzed using SPSS 25.0. Frequency and percentages were calculated for 
the qualitative variables like gender, comorbidity, symptoms, radiological findings, response to 
treatment. Quantitative variables of the study like age, laboratory parameters were expressed as 
Median (IQR).  
Ethical Considerations: Patients were included in the study after written and informed consent 
Institutional review board IRB approval was taken from the ethical committee. IRB# FMH-05-
2020-IRB-758-M 
 
 
 
 
 
 
 
 
 
 
 
 

Table.1: Baseline characteristics of the participants along with Comorbidities, Initial workup and their 
Outcomes  
Characteristics 
All patients         
( N=93 ) 
        Tocilizumab     
group  ( N=33 ) 
                   Steroid group 
                        ( N=60 ) 
Median age(IQR)-
years 
58 (21) 
60(14) 
56(23) 
Age category N (%) 
< 50 years 
50-70 years  
>70 years 
 
 
 
30(32.3) 
48 (51.6) 
15 (16.1) 
 
 
7 (7.5) 
20 (21.5) 
6 (6.5) 
 
 
23 (24.7) 
28 (30.1) 
9 ( 9.7) 
Male Sex _no(%) 
67(72) 
22(23.7) 
45(48.4) 
Female 
26( 28) 
11( 11.8) 
15(16.1) 
Comorbidities 
 
 
 
Diabetes Mellitus 
37( 39.8) 
11(11.8) 
26(28) 
Hypertension 
45(48.5) 
17(18.3) 
28( 30.1) 
Chronic kidney 
disease  
9( 9.7) 
5(5.4) 
4(4.3) 
Ischemic heart 
disease  
16(17.2) 
5(5.4) 
11(11.8) 
Lung disease  
7(7.5) 
7(7.5) 
0 (0) 
Smoker 
48(51.6) 
16(17.2) 
32(34.4) 
Malignancy 
5(5.4) 
2(2.2) 
3(3.2) 
Symptoms at 
presentation  
 
 
 
Fever 
80(86.0%) 
32(34.4%) 
48(51.6%) 
Cough  
75(80.6%) 
29(31.1%) 
46(49.4%) 
Shortness of breath 
86(92.4%) 
32(34.4%) 
54(58.06%) 
Vitals on admission 
 
 
 
Respiratory rate_ 
IQR 
26(9) 
26(9) 
26(9) 
Heart rate_IQR  
110(19) 
109(11) 
112(10) 
Temperature_IQR 
100(99) 
101(99) 
100(99) 
Oxygen saturation 
at presentation  
90(13) 
90(13) 
90(12) 
Highest level of 
Care 
 
 
 
Intensive care unit 
67(72.04) 
33(35.5) 
34(36.5) 
Regular Medical 
floor 
26(28) 
0(0) 
26(28) 
PCR +VE 
 
89(95.7) 
33(35.5) 
56(60.2) p-value 
PCR –VE 
 
4(4.3) 
0(0) 
4(4.3) 
Chest x ray findings  
 
 
 

 
IQR, interquartile range;  length of hospital stay 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilateral patchy 
ground glass 
appearance  
22(23.7) 
22(23.7) 
0(0) 
Bilateral 
Consolidation with 
peripheral 
infiltrates   
71(76.3) 
11(11.8) 
60(64.5) 
 Renal replacement 
therapy (RRT) 
5(5.4) 
1(1.1) 
4(4.3) 
Median hospital 
stay days(IQR)  
7(4) 
5(3.5) 
9(5) 
Outcomes 
 
 
 
Mechanical 
Ventilation 
days(IQR) 
5(5.4) 
3(3.2) 
2(2.2) 
Death 
10(10.8) 
6(6.5) 
4(4.3) 
Recovery  
83(89.2) 
27(29) 
56(60) 

 
 
 
 
 
 
Table.2: Comparative analysis, Pre and Post therapy biochemical markers of Tocilizumab group & 
Steroids group 
 
Variables 
Tocilizumab 
group  (N=33  
Steroid group     
(N=60 ) 
Total  
N93=) 
p-Value 
between 
groups  
Before  
Oxygen requirement in 
liters_ Median(IQR) 
18(5) 
18(5) 
8(9) 
0.911 
Lymphocytes in 109 
cells/liter_ Median(IQR) 
1.9(9.90) 
4.6(4.1) 
3.9(4.0) 
0.711 
D-dimers                  micro 
gram/mL    Median(IQR)  
2.1(4.4) 
2.0(3.60) 
2.0(3.75) 
0.844 
CRP mg/dl         Median_ 
(IQR) 
200(190 
202(177) 
200(189) 
0.800 
Ferritin    ng/ml 
Median(IQR) 
1525(1255) 
2000(1002) 
2000(1200) 
0.424 
Trop I ng/ml 
_Median(IQR) 
16(17) 
12(11) 
13.7(12.85 
0.496 
Serum Creatinine mg/dl_ 
Median(IQR) 
1.27(1.34) 
1.31(1.9) 
1.19(1.1) 
0.012 
After  
Oxygen requirement in 
liters_ Median(IQR) 
8(9) 
8(9) 
8(9) 
0.714 
Lymphocytes in 109 
cells/liter_ Median(IQR) 
2.9(2.7) 
4(4.1) 
4.8(4.7) 
0.941 
D-dimers                  micro 
gram/mL    Median(IQR)  
1.0(0.89) 
1.0(1.16) 
1.0(1.16) 
0.433 
CRP mg/dl         Median_ 
(IQR) 
145(130) 
139(90) 
145(90) 
0.942 
Ferritin    ng/ml 
Median(IQR) 
1000(1266) 
1000(1000) 
1000(1091) 
0.884 
Trop I ng/ml 
_Median(IQR) 
16(18) 
11(11.0) 
18(13) 
0.827 
Serum Creatinine mg/dl_ 
Median(IQR) 
1.1(1.2) 
1.20(1.6) 
1.4(1.3) 
0.021 
 
 
 
 

 
 
 
 
 
Results: Table 1 summarizes the baseline characteristics of the patients and few important vital signs but 
few of the important determinants are discussed here. A total of 93 patients were enrolled in our study, 
two groups were made according to the treatment modality offered and named as Tocilizumab (TCZ) 
group (case) and Corticosteroid (CS) group (Control), and 33 patients were kept in the TCZ group and 60 
patients were enrolled in the corticosteroid group. The median age of all participants was 58 years (IQR-
21), TCZ group participants’ median age was 60 years (IQR-14) whereas, in the steroid group, it was 56 
years (IQR-23). there were 67(72%) male participants and 26(28%) were female. The male predilection 
of covid-19 was noted down in this study. Regarding age categories, most of the patients 48(51.6%) 
were falling in the age range of 50 to 70 years, followed by 30(32.3%) and 15(16.1%) in the age 
categories of < 50 years and > 70 years respectively. Regarding the comorbidities in the participants, 
there were 37(39.8%) patients with diabetes mellitus, 11(11.8%) in the TCZ group, and 26(28%) in the CS 
group. There were 45(48.5%) patients having hypertension, 17(18.3%) in the TCZ group, and 28(30.1%) 
in the CS group. There were 9(9.7%) patients who had chronic kidney disease, 5(5.4%) and 4 (4.3%) in 
TCZ and CS group respectively. There were 16(17.2%) patients who had Ischemic heart disease, 5(5.4%) 
and 11(11.8%) in TCZ and CS group respectively. Discussing lung disease, there were a total of 7(7.5%) 
patients and all belonged to the TCZ group only. 48(51.6%) patients were smokers and 32(34.4%) in the 
TCZ group and 16(17.2%) in the CS group. Patients who had malignancy were 5(5.40%), 2(2.2%), and 
3(3.2%) in the TCZ group and CS group respectively. 

Regarding symptoms on presentation, Shortness of breath was the commonest symptom in both the 
groups, out of 93 patients, 86(92.4%) had it, TCZ group and CS group (34.4% vs 58.06%), Fever was 
observed in 80(86%), (34.4% vs 51.6%) and cough was seen in 75(80.6%), (34.4 vs 58.06). 
Regarding vitals on admission, the median respiratory rate with IQR was 26(9) breaths per minute and 
the same values were seen in both the groups i-e 26(9) breaths per minute. 
The median heart rate was 110(19) beats per minute, 109(11) in the TCZ group, and 112(10) in the CS 
group. 
The median temperature was 100(2) degrees Fahrenheit. 
The Median Oxygen saturation (SPO2 %) in liters with the Interquartile range (IQR) at presentation was 
90 (13), the same value observed in the TCZ group whereas it was 90(12) in the CS group. 
The highest level of care (Intensive care unit, ICU stay) was offered to a total of 67(72%) patients 
according to their severity of the clinical condition, (35.5% vs 34%) in TCZ and CS group respectively. 
26(28%) patients were managed on the medical floor and all these patients belonged to the CS group. 
Laboratory & Radiologic Findings: 
 There were 89 (95.7%) PCR positive patients from their nasopharyngeal swab and only 4(4.3%) had 
negative PCR reports but radiologically and clinically they were labeled as PCR negative Covid-19 
patients as per decisions of senior consultant radiologists of the hospital and senior physicians. 
All patients included in the study underwent a chest radiograph on admission, 22(23.7%) patients had 
the bilateral patchy ground-glass appearance and all belonged to the TCZ group and 71(76.3%) patients 
had bilateral pulmonary opacities with peripheral infiltrates, 11(11.8%) vs 60(64.5%) patients were in 
TCZ group CS group respectively. 
Total 5(5.4%) patients needed renal replacement therapy (RRT), 1(1.1%) in TCZ vs 4 (4.3%) in the CS 
group. 

On the whole, the total median hospital stay in days was 7 with IQR (4), there was a shorter hospital stay 
in the TCZ group, 5 with IQR (3.5) days and a longer hospital stay in CS group 9 with IQR (5) days. 
The median time in days of patients who remained on invasive positive pressure ventilation (IPPV), was 
5(5.4) days with a shorter duration in CS group 2(2.2) and 3(3.20) in the TCZ group. 
Total 83(89.2%) patients recovered successfully and discharged, 27(29%) in the TCZ group and 56(60.2%) 
in the CS group. 
Total 10(10.8%) patients died, out of which 6(6.5%) belonged to the TCZ group and 4(4.3%) belonged to 
the CS group. 
Table.2: showing the comparison between the two groups’ pre and post-treatment 
Important parameters like Oxygen requirement, Lymphocytes count, biochemical markers like d-dimers, 
C reactive protein(CRP), serum ferritin levels, Troponin-I, and serum creatinine were measured before 
and after the treatment was offered to both the group. 
Before treatment: The median Oxygen requirement with IQR was 18(5) in both the groups and in total it 
was 8(9).p-value(0.911).The median Lymphocyte count 109 cells/liter 3.9(4.0), TCZ vs CS group 1.9(9.9) 
vs 4.6(4.1), p-value (0.711), median D-dimers levels microgram/L 2.0(3.75), 2.1(4.4) vs 2.0 (3.60), p-
value(0.844), median CRP levels mg/l 200(189), 200(190) vs 202(177),p-value(0.844), median Ferritin 
levels ng/ml 2000(1200),1525(1255) vs 2000(1002),p-value(0.424), median Trop-I levels ng/ml were 
13.7(12.85), 16(17) vs 12(11),p-value(0.496), median Serum creatinine mg/dl was 1.27(1.34), 1.31(1.9) 
vs 1.19(1.12), p-value(0.012). 
 After treatment: The median Oxygen requirement with IQR was 8(9) in both the groups and in total as 
well, p-value(0.714).The median Lymphocyte count 109 cells/liter was 4.8(4.7),TCZ vs CS group 2.9(2.7) 
vs 4(4.1), p-value (0.941), median D-dimers levels microgram/L were 1.0(1.16), 1.0(0.89) vs 1.0(1.16), p-
value(0.433), median CRP levels mg/l was 145(90), 145(130) vs 139(90),p-value(0.942), median Ferritin 
levels ng/ml was 1000(1091), 1000(1000) vs 1000(1091),p-value(0.884), median Trop-I levels ng/ml was 

18(13), 16(18) vs 11(11.0), p-value(0.827), median Serum creatinine mg/dl was 1.4(1.34), 1.1(1.2) vs 
1.20(1.3), p-value(0.021).