Tocilizumab vs CRRT in Management of Cytokine Release Syndrome (CRS) in COVID-19 (TACOS)

A Retrospective Study of Evaluating Safety and Efficacy of Tocilizumab Compared to Continuous Renal Replacement Therapy in Controlling CRS Triggered by COVID-19

Some patients infected with the COVID-19 can develop uncontrolled immune response, leading to potentially life-threatening damage to lung tissue. Tocilizumab was first approved by the U.S. FDA in 2010 for rheumatoid arthritis and might now be used to treat serious COVID-19 patients with lung damage, according to China's National Health Commission updated its treatment guidelines in 7th version.Continuous Renal Replacement Therapy (CRRT) was recommended by China's National Health Commission treatment guidelines in 1st-7th version to control sever COVID-19 patients.

Study Overview

• Status: Unknown
• Conditions: Covid-19; Cytokine Storm; Cytokine Release Syndrome; SARS; Tocilizumab
• Intervention / Treatment: Drug: Tocilizumab; Other: Standard of care; Procedure: Continuous renal replacement therapy

Detailed Description

Tocilizumab doesn't directly kill the novel coronavirus. It's known as an inhibitor of the receptor of interleukin 6 (IL-6), a pro-inflammatory cytokine. In the disease COVID-19, the body may respond to the pathogen by overproducing immune cells and their signaling molecules in a dangerous phenomenon called cytokine release storm.It has been recently speculated that IL-6 as a main culprit in that immune over activation among COVID-19 patients, hence the Tocilizumab clinical trial was initiated. In 2017, the FDA also approved Tocilizumab to treat cytokine release syndrome (CRS), a form of cytokine storm caused by CAR-T treatment. The investigator's hypothesis was that Tocilizumab would be associated with better clinical outcomes, such as decreased systemic inflammation, improved survival rate, better hemodynamic and improved of respiratory distress.Systemic inflammatory response syndrome was one of the main indications for treatment with CRRT. So it is clinically significant to compare the efficacy and safety of Tocilizumab and CRRT in management of CRS triggered by COVID-19.

• Study Type: Observational
• Enrollment (Anticipated): 120

Contacts and Locations

• Study Contact: Name: YIKAI YU, M.D; Phone Number: +1 (484) 995-5917; Email: yuyikai@163.com
• Study Contact Backup: Name: WEI TU, M.D; Phone Number: +86 15671678920

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430030
      • Recruiting
      • Tongji Hospital
      • Contact: AIHUA DU, M.D; Phone Number: +86 2783662886
      • Principal Investigator: YIKAI YU, M.D
      • Sub-Investigator: SHAOXIAN HU, M.D
      • Sub-Investigator: YIHAN YU, M.D
      • Sub-Investigator: LINGLI DONG, M.D
      • Sub-Investigator: WEI TU, M.D
      • Sub-Investigator: RUI XING, M.D
      • Sub-Investigator: ZHENG WANG, M.D
      • Sub-Investigator: CONG YE, M.D
      • Sub-Investigator: FEI YU, M.D
      • Sub-Investigator: GUIFEN SHEN, M.D
      • Sub-Investigator: YUJIE DAI, M.D

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Laboratory (RT-PCR) confirmed infection with 2019-nCoV. Lung involvement confirmed with chest imaging Hospitalized with a SaO2/SPO2≤93% on room air or Pa02/Fi02 ratio <300mmHg and ≤14 days since illness onset.

Description

Inclusion Criteria:

1. Agrees to the collection of oropharyngeal or anal swabs and venous blood per protocol.
2. Male or non-pregnant female adult ≥18 years of age at time of enrollment.
3. Has laboratory-confirmed novel coronavirus infection as determined by polymerase chain reaction (PCR), or other commercial or public health assay in oropharyngeal or anal specimen within 72 hours prior to hospitalization.

4. Illness of any duration, and at least one of the following:

   1. Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR
   2. Clinical assessment (evidence of rales/crackles on physical examination) AND SpO2 ≤93% on room air, OR
   3. Requiring mechanical ventilation and/or supplemental oxygen, OR
   4. Sustained fever in the past 24 hours and unresponsive to NSAID or steroid
5. Serum IL-6 ≥3 times the upper limit of normal

Exclusion Criteria:

1. Alanine transaminase/aspartate transaminase (ALT/AST) > 5 times the upper limit of normal.
2. Stage 4 severe chronic kidney disease or requiring dialysis (i.e. estimated glomerular filtration rate (eGFR) < 30 ml /min/1.73 m^2)
3. Hemoglobin<80 g/L
4. Leukocytes<2.0×10^9
5. Platelets<50×10^9
6. Pregnancy or breast feeding.
7. Anticipated transfer to another hospital which is not a study site within 72 hours.
8. Expected life span does not exceed 7 days.
9. Allergy to any study medication.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Tocilizumab; Subjects received 8 mg/kg (body weight) Tocilizumab once in 100 ml 0.9% saline solution and administered intravenously within no less than 60 minutes. Tocilizumab was administered according to the local label.	Drug: Tocilizumab; Administered as an intravenous infusion.; Other Names: Actemra; Other: Standard of care; Standard of care therapy per local written policies or guidelines and includes balancing of electrolytes and acid-base, the provision of enteral or parenteral nutrients support, antibiotics therapy, oxygen therapy and noninvasive ventilation.
Continuous Renal Replacement Therapy; Femoral vein catheterization was performed to complete continuous renal replacement therapy for consecutive 3 times or more.	Other: Standard of care; Standard of care therapy per local written policies or guidelines and includes balancing of electrolytes and acid-base, the provision of enteral or parenteral nutrients support, antibiotics therapy, oxygen therapy and noninvasive ventilation.; Procedure: Continuous renal replacement therapy; Catheter insertion site is femoral vein.
Standard care; Standard of care therapy per local written policies or guidelines.	Other: Standard of care; Standard of care therapy per local written policies or guidelines and includes balancing of electrolytes and acid-base, the provision of enteral or parenteral nutrients support, antibiotics therapy, oxygen therapy and noninvasive ventilation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants With Normalization of Fever and Oxygen Saturation Through Day 14	This is a composite outcome measure. Criteria for fever normalization: Temperature < 36.6 °C armpit, < 37.2 °C oral sustained for at least 72 hours and criteria for oxygen normalization: peripheral capillary oxygen saturation (Sp02) > 94% sustained for at least 72 hours.	First dose date up to 14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of hospitalization	Measured in days	Up to 28 days
Proportion of Participants With Normalization of Fever Through Day 14	Criteria for: Temperature < 36.6 °C armpit, < 37.2 °C oral, or < 37.8 °C rectal sustained for at least 72 hours.	First dose date up to 14 days
Change from baseline in white blood cell and differential count	Blood routine test	Day 1 through Day 28
Time to first negative in 2019 novel Corona virus RT-PCR test	Oropharyngeal or anal swabs	Up to 28 days
All-cause mortality	Date and cause of death (if applicable).	up to 12 weeks
Change from baseline in hsCRP	Serum hsCRP	Day 1 through Day 28
Change from baseline in cytokines IL-1β, IL-10, sIL-2R, IL-6, IL-8 and TNF-α	Serum inflammatory cytokines	Day 1 through Day 28
Change from baseline in proportion of CD4+CD3/CD8+CD3 T cells	Flow cytometry for peripheral whole blood	Day 1 through Day 28 (if applicable)

Collaborators and Investigators

• Sponsor: Tongji Hospital
• Collaborators: Wuhan Central Hospital; Wuhan No.1 Hospital; Hubei Xinhua Hospital
• Investigators: Study Director: SHAOXIAN HU, M.D, Tongji Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2020
• Primary Completion (Anticipated): May 30, 2020
• Study Completion (Anticipated): June 20, 2020

Study Registration Dates

• First Submitted: March 8, 2020
• First Submitted That Met QC Criteria: March 12, 2020
• First Posted (Actual): March 13, 2020

Study Record Updates

• Last Update Posted (Actual): March 17, 2020
• Last Update Submitted That Met QC Criteria: March 16, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Disease; Shock; COVID-19; Syndrome; Cytokine Release Syndrome
• Other Study ID Numbers: WHTJCOVID-19

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes