COVID-19 Pneumonia
Conditions
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.
Interventions
DRUGTociliuzumab
Participants will receive IV TCZ.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Baseline - Day 60 |
| 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 |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Up to Day 28 | 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. |
| Proportion of Participants With Any Post-Treatment Infection | Up to Day 60 | — |
| Pecentage of Participants With Adverse Events | Up to Day 60 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TCZ 4 mg/kg Participants received intravenous (IV) tocilizumab (TCZ) at a dose of 4 mg/kg in addition to standard-of-care treatment. | 49 |
| TCZ 8 mg/kg Participants received IV tocilizumab (TCZ) at a dose of 8 mg/kg in addition to standard-of-care treatment. | 48 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 8 | 6 |
| Overall Study | Lost to Follow-up | 10 | 7 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | TCZ 8 mg/kg | Total | TCZ 4 mg/kg |
|---|---|---|---|
| Age, Continuous | 59.8 Years STANDARD_DEVIATION 14.6 | 58.3 Years STANDARD_DEVIATION 14.4 | 56.8 Years STANDARD_DEVIATION 14.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants | 26 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 67 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 33 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants | 17 Participants | 8 Participants |
| Race (NIH/OMB) White | 23 Participants | 38 Participants | 15 Participants |
| Sex: Female, Male Female | 18 Participants | 40 Participants | 22 Participants |
| Sex: Female, Male Male | 30 Participants | 57 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 49 | 6 / 48 |
| other Total, other adverse events | 4 / 49 | 3 / 48 |
| serious Total, serious adverse events | 15 / 49 | 12 / 48 |
Outcome results
Primary
Area Under the Curve From Day 0-28 (AUC0-d28) of Tocilizumab)
Time frame: 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.
Population: The PK population consisted of all randomized participants who received any amount of study drug with at least one valid pharmacokinetic (PK) result. Participants were analyzed according to treatment received.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TCZ 4 mg/kg | Area Under the Curve From Day 0-28 (AUC0-d28) of Tocilizumab) | One dose | 371 µg/mL*day |
| TCZ 4 mg/kg | Area Under the Curve From Day 0-28 (AUC0-d28) of Tocilizumab) | Two doses | 837 µg/mL*day |
| TCZ 8 mg/kg | Area Under the Curve From Day 0-28 (AUC0-d28) of Tocilizumab) | One dose | 849 µg/mL*day |
| TCZ 8 mg/kg | Area Under the Curve From Day 0-28 (AUC0-d28) of Tocilizumab) | Two doses | 1330 µg/mL*day |
Primary
Clearance (CL) of Tocilizumab
Time frame: 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.
Population: The PK population consisted of all randomized participants who received any amount of study drug with at least one valid pharmacokinetic (PK) result. Participants were analyzed according to treatment received.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TCZ 4 mg/kg | Clearance (CL) of Tocilizumab | One dose | 0.451 L/day |
| TCZ 4 mg/kg | Clearance (CL) of Tocilizumab | Two doses | 0.468 L/day |
| TCZ 8 mg/kg | Clearance (CL) of Tocilizumab | One dose | 0.487 L/day |
| TCZ 8 mg/kg | Clearance (CL) of Tocilizumab | Two doses | 0.629 L/day |
Primary
Maximum Serum Concentration (Cmax) of Tocilizumab
Time frame: 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.
Population: The PK population consisted of all randomized participants who received any amount of study drug with at least one valid pharmacokinetic (PK) result. Participants were analyzed according to treatment received.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TCZ 4 mg/kg | Maximum Serum Concentration (Cmax) of Tocilizumab | One dose | 82.2 µg/mL |
| TCZ 4 mg/kg | Maximum Serum Concentration (Cmax) of Tocilizumab | Two doses | 150 µg/mL |
| TCZ 8 mg/kg | Maximum Serum Concentration (Cmax) of Tocilizumab | One dose | 159 µg/mL |
| TCZ 8 mg/kg | Maximum Serum Concentration (Cmax) of Tocilizumab | Two doses | 228 µg/mL |
Primary
Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ
Time frame: Baseline - Day 60
Population: Modified intent-to-treat population (mITT): All randomized participants who received any amount of study drug. Participants are analyzed according to the treatment assigned at randomization.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TCZ 4 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Baseline | 125.04 mg/L | Geometric Coefficient of Variation 121.5 |
| TCZ 4 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 1 - 15 min post-dose | 124.67 mg/L | Geometric Coefficient of Variation 118.8 |
| TCZ 4 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 1 - pre-dose 2nd infusion | 123.49 mg/L | Geometric Coefficient of Variation 68 |
| TCZ 4 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 1 - 15 min post-dose 2nd infusion | 116.89 mg/L | Geometric Coefficient of Variation 62.4 |
| TCZ 4 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 2 - 24 hours post-dose | 85.75 mg/L | Geometric Coefficient of Variation 133.1 |
| TCZ 4 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 3 | 41.56 mg/L | Geometric Coefficient of Variation 129.6 |
| TCZ 4 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 7 | 7.27 mg/L | Geometric Coefficient of Variation 145.1 |
| TCZ 4 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 14 | 4.42 mg/L | Geometric Coefficient of Variation 554.8 |
| TCZ 4 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 21 | 3.73 mg/L | Geometric Coefficient of Variation 552.5 |
| TCZ 4 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 28 | 3.01 mg/L | Geometric Coefficient of Variation 483 |
| TCZ 4 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 35 | 2.12 mg/L | Geometric Coefficient of Variation 234.5 |
| TCZ 4 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 60 | 2.41 mg/L | Geometric Coefficient of Variation 256 |
| TCZ 8 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 35 | 11.25 mg/L | Geometric Coefficient of Variation 1543.9 |
| TCZ 8 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Baseline | 115.77 mg/L | Geometric Coefficient of Variation 128.7 |
| TCZ 8 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 7 | 5.62 mg/L | Geometric Coefficient of Variation 188.3 |
| TCZ 8 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 1 - 15 min post-dose | 109.19 mg/L | Geometric Coefficient of Variation 134.4 |
| TCZ 8 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 28 | 2.57 mg/L | Geometric Coefficient of Variation 2251.1 |
| TCZ 8 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 1 - pre-dose 2nd infusion | 118.83 mg/L | Geometric Coefficient of Variation 45.1 |
| TCZ 8 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 14 | 0.87 mg/L | Geometric Coefficient of Variation 95 |
| TCZ 8 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 1 - 15 min post-dose 2nd infusion | 112.97 mg/L | Geometric Coefficient of Variation 53.4 |
| TCZ 8 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 60 | 1.61 mg/L | Geometric Coefficient of Variation 154.1 |
| TCZ 8 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 2 - 24 hours post-dose | 86.01 mg/L | Geometric Coefficient of Variation 124.2 |
| TCZ 8 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 21 | 1.75 mg/L | Geometric Coefficient of Variation 1681.6 |
| TCZ 8 mg/kg | Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ | Day 3 | 39.17 mg/L | Geometric Coefficient of Variation 134.8 |
Primary
Serum Concentration of Ferritin Following Administration of IV TCZ
Time frame: Baseline - Day 60
Population: Modified intent-to-treat population (mITT): All randomized participants who received any amount of study drug. Participants are analyzed according to the treatment assigned at randomization.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TCZ 4 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Day 60 | 282.85 pmol/L | Geometric Coefficient of Variation 148.7 |
| TCZ 4 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Baseline | 2081.46 pmol/L | Geometric Coefficient of Variation 162.4 |
| TCZ 4 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Day 2 - 24 hours post-dose | 2282.62 pmol/L | Geometric Coefficient of Variation 191.3 |
| TCZ 4 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Day 3 | 2016.10 pmol/L | Geometric Coefficient of Variation 128 |
| TCZ 4 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Day 7 | 1760.82 pmol/L | Geometric Coefficient of Variation 170.3 |
| TCZ 4 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Day 14 | 1108.34 pmol/L | Geometric Coefficient of Variation 127.2 |
| TCZ 4 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Day 21 | 754.24 pmol/L | Geometric Coefficient of Variation 138.4 |
| TCZ 4 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Day 28 | 393.46 pmol/L | Geometric Coefficient of Variation 139.3 |
| TCZ 4 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Day 35 | 309.23 pmol/L | Geometric Coefficient of Variation 105.5 |
| TCZ 8 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Day 28 | 519.51 pmol/L | Geometric Coefficient of Variation 139 |
| TCZ 8 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Day 14 | 720.66 pmol/L | Geometric Coefficient of Variation 102.3 |
| TCZ 8 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Baseline | 1821.19 pmol/L | Geometric Coefficient of Variation 174 |
| TCZ 8 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Day 60 | 246.17 pmol/L | Geometric Coefficient of Variation 171.4 |
| TCZ 8 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Day 2 - 24 hours post-dose | 1938.19 pmol/L | Geometric Coefficient of Variation 154.6 |
| TCZ 8 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Day 21 | 558.57 pmol/L | Geometric Coefficient of Variation 119 |
| TCZ 8 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Day 3 | 2060.41 pmol/L | Geometric Coefficient of Variation 131.2 |
| TCZ 8 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Day 35 | 291.24 pmol/L | Geometric Coefficient of Variation 66.5 |
| TCZ 8 mg/kg | Serum Concentration of Ferritin Following Administration of IV TCZ | Day 7 | 1494.76 pmol/L | Geometric Coefficient of Variation 86.7 |
Primary
Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ
Time frame: Baseline - Day 60
Population: Modified intent-to-treat population (mITT): All randomized participants who received any amount of study drug. Participants are analyzed according to the treatment assigned at randomization.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TCZ 4 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 1 - 15 min post-dose | 336.99 ng/L | Geometric Coefficient of Variation 248.8 |
| TCZ 4 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 2 - 15 min post-dose | 292.69 ng/L | Geometric Coefficient of Variation 159.8 |
| TCZ 4 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 2 - 24 hours post-dose | 733.99 ng/L | Geometric Coefficient of Variation 226.5 |
| TCZ 4 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 3 | 748.82 ng/L | Geometric Coefficient of Variation 394.2 |
| TCZ 4 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 7 | 545.44 ng/L | Geometric Coefficient of Variation 315.9 |
| TCZ 4 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 14 | 234.88 ng/L | Geometric Coefficient of Variation 332.2 |
| TCZ 4 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 21 | 49.16 ng/L | Geometric Coefficient of Variation 482.7 |
| TCZ 4 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 28 | 5.73 ng/L | — |
| TCZ 4 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 35 | 7.68 ng/L | Geometric Coefficient of Variation 361.9 |
| TCZ 4 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 60 | 2.52 ng/L | — |
| TCZ 8 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 28 | 28.66 ng/L | Geometric Coefficient of Variation 371.7 |
| TCZ 8 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 1 - 15 min post-dose | 325.96 ng/L | Geometric Coefficient of Variation 236.4 |
| TCZ 8 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 14 | 125.64 ng/L | Geometric Coefficient of Variation 345.9 |
| TCZ 8 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 2 - 15 min post-dose | 638.00 ng/L | — |
| TCZ 8 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 60 | 2.28 ng/L | — |
| TCZ 8 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 2 - 24 hours post-dose | 757.17 ng/L | Geometric Coefficient of Variation 172.4 |
| TCZ 8 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 21 | 91.86 ng/L | Geometric Coefficient of Variation 465.9 |
| TCZ 8 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 3 | 743.84 ng/L | Geometric Coefficient of Variation 263 |
| TCZ 8 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 35 | 39.79 ng/L | Geometric Coefficient of Variation 503 |
| TCZ 8 mg/kg | Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ | Day 7 | 589.21 ng/L | Geometric Coefficient of Variation 429 |
Primary
Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ
Time frame: Baseline - Day 60
Population: Modified intent-to-treat population (mITT): All randomized participants who received any amount of study drug. Participants are analyzed according to the treatment assigned at randomization. Participants at Day 2 15-min post-dose were those that received a second dose of TCZ and had PK taken after that second dose.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TCZ 4 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 2 - 24 hours post-dose | 97280.14 ng/L | Geometric Coefficient of Variation 31.3 |
| TCZ 4 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 14 | 258484.08 ng/L | Geometric Coefficient of Variation 52.3 |
| TCZ 4 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 2 - 15 min post-dose | 80880.16 ng/L | Geometric Coefficient of Variation 24.9 |
| TCZ 4 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 21 | 162025.68 ng/L | Geometric Coefficient of Variation 73.1 |
| TCZ 4 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 3 | 139128.70 ng/L | Geometric Coefficient of Variation 26.5 |
| TCZ 4 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 28 | 82508.76 ng/L | Geometric Coefficient of Variation 102.6 |
| TCZ 4 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 1 - 15 min post-dose | 47037.59 ng/L | Geometric Coefficient of Variation 56.1 |
| TCZ 4 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 35 | 80425.91 ng/L | Geometric Coefficient of Variation 138.7 |
| TCZ 4 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 7 | 261637.28 ng/L | Geometric Coefficient of Variation 30.2 |
| TCZ 4 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 60 | 36049.91 ng/L | Geometric Coefficient of Variation 21.7 |
| TCZ 4 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Baseline | 35869.87 ng/L | Geometric Coefficient of Variation 29.1 |
| TCZ 8 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 60 | 34258.34 ng/L | Geometric Coefficient of Variation 22.2 |
| TCZ 8 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Baseline | 35331.04 ng/L | Geometric Coefficient of Variation 31.3 |
| TCZ 8 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 1 - 15 min post-dose | 40928.43 ng/L | Geometric Coefficient of Variation 46.4 |
| TCZ 8 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 2 - 15 min post-dose | 44300.00 ng/L | — |
| TCZ 8 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 2 - 24 hours post-dose | 90057.53 ng/L | Geometric Coefficient of Variation 28.8 |
| TCZ 8 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 3 | 139528.82 ng/L | Geometric Coefficient of Variation 30.3 |
| TCZ 8 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 7 | 263899.86 ng/L | Geometric Coefficient of Variation 26.7 |
| TCZ 8 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 14 | 339661.18 ng/L | Geometric Coefficient of Variation 19.6 |
| TCZ 8 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 21 | 265981.84 ng/L | Geometric Coefficient of Variation 49.1 |
| TCZ 8 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 28 | 162795.31 ng/L | Geometric Coefficient of Variation 106 |
| TCZ 8 mg/kg | Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ | Day 35 | 144868.00 ng/L | Geometric Coefficient of Variation 105.4 |
Primary
Volume of the Central Compartment (Vc) of Tocilizumab
Time frame: 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.
Population: The PK population consisted of all randomized participants who received any amount of study drug with at least one valid pharmacokinetic (PK) result. Participants were analyzed according to treatment received.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TCZ 4 mg/kg | Volume of the Central Compartment (Vc) of Tocilizumab | One dose | 4.14 L |
| TCZ 4 mg/kg | Volume of the Central Compartment (Vc) of Tocilizumab | Two doses | 4.2 L |
| TCZ 8 mg/kg | Volume of the Central Compartment (Vc) of Tocilizumab | One dose | 4.34 L |
| TCZ 8 mg/kg | Volume of the Central Compartment (Vc) of Tocilizumab | Two doses | 4.57 L |
Secondary
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.
Time frame: Up to Day 60
Population: The safety population included all randomized participants who received any amount of study drug, with participants analyzed according to the treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TCZ 4 mg/kg | Pecentage of Participants With Adverse Events | 57.1 Percentage of Participants |
| TCZ 8 mg/kg | Pecentage of Participants With Adverse Events | 45.8 Percentage of Participants |
Secondary
Proportion of Participants With Any Post-Treatment Infection
Time frame: Up to Day 60
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TCZ 4 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Pneumonia | 2.0 Percentage of Participants |
| TCZ 4 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Atypical pneumonia | 2.0 Percentage of Participants |
| TCZ 4 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Septic shock | 2.0 Percentage of Participants |
| TCZ 4 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Pneumonia bacterial | 2.0 Percentage of Participants |
| TCZ 4 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Urinary tract infection | 2.0 Percentage of Participants |
| TCZ 4 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Pneumonia klebsiella | 2.0 Percentage of Participants |
| TCZ 4 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Sepsis | 2.0 Percentage of Participants |
| TCZ 4 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Pneumonia streptococcal | 2.0 Percentage of Participants |
| TCZ 4 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Abscess limb | 2.0 Percentage of Participants |
| TCZ 4 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Staphylococcal infection | 2.0 Percentage of Participants |
| TCZ 4 mg/kg | Proportion of Participants With Any Post-Treatment Infection | COVID-19 pneumonia | 6.1 Percentage of Participants |
| TCZ 8 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Staphylococcal infection | 0 Percentage of Participants |
| TCZ 8 mg/kg | Proportion of Participants With Any Post-Treatment Infection | COVID-19 pneumonia | 2.1 Percentage of Participants |
| TCZ 8 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Sepsis | 4.2 Percentage of Participants |
| TCZ 8 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Septic shock | 4.2 Percentage of Participants |
| TCZ 8 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Pneumonia | 2.1 Percentage of Participants |
| TCZ 8 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Urinary tract infection | 2.1 Percentage of Participants |
| TCZ 8 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Abscess limb | 0 Percentage of Participants |
| TCZ 8 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Atypical pneumonia | 0 Percentage of Participants |
| TCZ 8 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Pneumonia bacterial | 0 Percentage of Participants |
| TCZ 8 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Pneumonia klebsiella | 0 Percentage of Participants |
| TCZ 8 mg/kg | Proportion of Participants With Any Post-Treatment Infection | Pneumonia streptococcal | 0 Percentage of Participants |
Secondary
Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time
Time frame: Baseline - Day 60
Population: The safety population included all randomized participants who received any amount of study drug, with participants analyzed according to the treatment received.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TCZ 4 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Baseline | 30.56 copies/µL |
| TCZ 4 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 2 | 8.38 copies/µL |
| TCZ 4 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 3 | 3.82 copies/µL |
| TCZ 4 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 4 | 2.44 copies/µL |
| TCZ 4 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 5 | 8.74 copies/µL |
| TCZ 4 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 6 | 0.91 copies/µL |
| TCZ 4 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 7 | 0.49 copies/µL |
| TCZ 4 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 10 | 2.56 copies/µL |
| TCZ 4 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 14 | 0.14 copies/µL |
| TCZ 4 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 21 | 0.1 copies/µL |
| TCZ 4 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 28 | 0.16 copies/µL |
| TCZ 4 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 35 | 0.1 copies/µL |
| TCZ 4 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 45 | 0.1 copies/µL |
| TCZ 4 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 60 | 0.1 copies/µL |
| TCZ 8 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Early withdrawal | 0.1 copies/µL |
| TCZ 8 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 10 | 0.59 copies/µL |
| TCZ 8 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Baseline | 8.51 copies/µL |
| TCZ 8 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 3 | 4.46 copies/µL |
| TCZ 8 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 35 | 0.12 copies/µL |
| TCZ 8 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 2 | 7.90 copies/µL |
| TCZ 8 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 14 | 0.18 copies/µL |
| TCZ 8 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 60 | 0.1 copies/µL |
| TCZ 8 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 4 | 2.73 copies/µL |
| TCZ 8 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 21 | 0.12 copies/µL |
| TCZ 8 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 5 | 5.39 copies/µL |
| TCZ 8 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 45 | 0.1 copies/µL |
| TCZ 8 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 6 | 2.56 copies/µL |
| TCZ 8 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 28 | 0.12 copies/µL |
| TCZ 8 mg/kg | Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time | Day 7 | 1.47 copies/µL |
Secondary
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.
Time frame: Up to Day 28
Population: Only participants with at least one virology assessment were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TCZ 4 mg/kg | Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | CIF for event on Day 7 | 0.3389 Probability |
| TCZ 4 mg/kg | Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | CIF for death on Day 7 | 0.0665 Probability |
| TCZ 4 mg/kg | Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | CIF for event on Day 14 | 0.5068 Probability |
| TCZ 4 mg/kg | Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | CIF for death on Day 14 | 0.1024 Probability |
| TCZ 4 mg/kg | Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | CIF for event on Day 21 | 0.5068 Probability |
| TCZ 4 mg/kg | Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | CIF for death on Day 21 | 0.1497 Probability |
| TCZ 4 mg/kg | Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | CIF for event on Day 28 | 0.5730 Probability |
| TCZ 4 mg/kg | Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | CIF for death on Day 28 | 0.3420 Probability |
| TCZ 8 mg/kg | Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | CIF for death on Day 28 | 0.1793 Probability |
| TCZ 8 mg/kg | Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | CIF for event on Day 7 | 0.2874 Probability |
| TCZ 8 mg/kg | Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | CIF for event on Day 21 | 0.5727 Probability |
| TCZ 8 mg/kg | Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | CIF for death on Day 7 | 0.0000 Probability |
| TCZ 8 mg/kg | Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | CIF for event on Day 28 | 0.6327 Probability |
| TCZ 8 mg/kg | Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | CIF for event on Day 14 | 0.5727 Probability |
| TCZ 8 mg/kg | Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | CIF for death on Day 21 | 0.1280 Probability |
| TCZ 8 mg/kg | Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity | CIF for death on Day 14 | 0.0884 Probability |