A Study to Investigate Intravenous Tocilizumab in Participants With Moderate to Severe COVID-19 Pneumonia

Study Overview
=================
Brief Summary
-----------------
This study will assess the pharmacodynamics, pharmacokinetics, safety and efficacy of two different doses of tocilizumab (TCZ) in combination with standard-of-care (SOC) in hospitalized adult participants with moderate to severe COVID-19 pneumonia.

Official Title
-----------------
A Phase-II, Open-Label, Randomized, Multicenter Study to Investigate the Pharmacodynamics, Pharmacokinetics, Safety, and Efficacy of 8 mg/kg or 4mg/kg Intravenous Tocilizumab in Patients With Moderate to Severe COVID-19 Pneumonia

Conditions
-----------------
COVID-19 Pneumonia

Intervention / Treatment
-----------------
* Drug: Tociliuzumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Hospitalization with COVID-19 pneumonia confirmed by a positive polymerase chain reaction (PCR) of any specimen [e.g., respiratory, blood, urine, stool, and other bodily fluids]) and evidence of pneumonia on chest X-ray or computed tomography scan For severe patients, SpO2 </= 93% or PaO2/FiO2 < 300 mmHg. If a participant is on supplemental oxygen with SpO2 > 93%, but desaturation </= to 93% on lower supplemental oxygen or ambient air is documented during screening, the inclusion criterion is met For moderate patients (those who do not qualify as severe based oxygen requirements), CRP > 2 x upper limit of normal (ULN) is required For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, as defined by the protocol For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined by the protocol Exclusion Criteria Known severe allergic reactions to TCZ or other monoclonal antibodies Active tuberculosis (TB) infection Suspected active bacterial, fungal, viral, or other infection (besides SARS-CoV-2) Participants who are on a mechanical ventilator > 24 hours or extracorporeal membrane oxygenation (ECMO), in shock, or combination thereof with other organ failure requiring treatment in an ICU In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments Receipt of oral anti-rejection or immunomodulatory drugs (including TCZ) within the past 3 months Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 10 x ULN detected within 24 hours at screening or at baseline (according to local laboratory reference ranges) Absolute neutrophil count (ANC) < 1000/uL at screening and baseline (according to local laboratory reference ranges) Platelet count < 50,000/uL at screening and baseline (according to local laboratory reference ranges) Pregnancy or breastfeeding, or positive pregnancy test at a predose examination Treatment with an investigational drug within 5 drug-elimination half-lives or 30 days (whichever is longer) of randomization

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: TCZ 8 mg/kg<br>Participants will receive intravenous (IV) tocilizumab (TCZ) at a dose of 8 mg/kg in addition to standard-of-care treatment. | Drug: Tociliuzumab<br>* Participants will receive IV TCZ.<br>|
| Experimental: TCZ 4 mg/kg<br>Participants will receive IV tocilizumab (TCZ) at a dose of 4 mg/kg in addition to standard-of-care treatment. | Drug: Tociliuzumab<br>* Participants will receive IV TCZ.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve From Day 0-28 (AUC0-d28) of Tocilizumab) |  | Days 0-28. Participants received a second dose within 8-24 hours after the initial infusion of TCZ at the discretion of the investigator upon clinically significant demonstration of worsening signs or symptoms. | 
| Maximum Serum Concentration (Cmax) of Tocilizumab |  | Baseline - Day 60. Participants received a second dose within 8-24 hours after the initial infusion of TCZ at the discretion of the investigator upon clinically significant demonstration of worsening signs or symptoms. | 
| Clearance (CL) of Tocilizumab |  | Baseline - Day 60. Participants received a second dose within 8-24 hours after the initial infusion of TCZ at the discretion of the investigator upon clinically significant demonstration of worsening signs or symptoms. | 
| Volume of the Central Compartment (Vc) of Tocilizumab |  | Baseline - Day 60. Participants received a second dose within 8-24 hours after the initial infusion of TCZ at the discretion of the investigator upon clinically significant demonstration of worsening signs or symptoms. | 
| Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ |  | Baseline - Day 60 | 
| Serum Concentration of Ferritin Following Administration of IV TCZ |  | Baseline - Day 60 | 
| Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ |  | Baseline - Day 60 | 
| Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ |  | Baseline - Day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pecentage of Participants With Adverse Events | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. | Up to Day 60 | 
| Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time |  | Baseline - Day 60 | 
| Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | Time to Real-Time Polymerase Chain Reaction (RT-PCR) virus negativity was defined as the number of days from the first dose of study drug to when a negative RT-PCR SARS-CoV-2 assessment result was observed. Results are presented as a cumulative incidence function (CIF) with death as a competing risk. | Up to Day 28 | 
| Proportion of Participants With Any Post-Treatment Infection |  | Up to Day 60 |