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

• ClinicalTrials.gov Identifier: NCT04306705
• Recruitment Status: Unknown
• First Posted: March 13, 2020
• Last Update Posted: March 17, 2020
• Sponsor: Tongji Hospital
• Collaborators: Hubei Xinhua Hospital; Wuhan No.1 Hospital; Wuhan Central Hospital
• Information provided by (Responsible Party): YIKAI YU, Tongji Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment
Covid-19; SARS; Cytokine Storm; Cytokine Release Syndrome; Tocilizumab	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 Design

• Study Type: Observational
• Estimated Enrollment: 120 participants
• Observational Model: Cohort
• Time Perspective: Retrospective
• Official Title: A Retrospective Study of Evaluating Safety and Efficacy of Tocilizumab Compared to Continuous Renal Replacement Therapy in Controlling CRS Triggered by COVID-19
• Actual Study Start Date: February 20, 2020
• Estimated Primary Completion Date: May 30, 2020
• Estimated Study Completion Date: June 20, 2020

Groups and Cohorts

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 Name: 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.

Outcome Measures

Primary Outcome Measures :

1. Proportion of Participants With Normalization of Fever and Oxygen Saturation Through Day 14 [ Time Frame: First dose date up to 14 days ]
   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.

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• 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.

Criteria

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.

Contacts and Locations

Contacts

Contact: YIKAI YU, M.D; +1 (484) 995-5917; yuyikai@163.com

Contact: WEI TU, M.D; +86 15671678920

Locations

China, Hubei

Tongji Hospital; Recruiting

Wuhan, Hubei, China, 430030

Contact: AIHUA DU, M.D +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

Sponsors and Collaborators

Tongji Hospital

Hubei Xinhua Hospital

Wuhan No.1 Hospital

Wuhan Central Hospital

Investigators

• Study Director: SHAOXIAN HU, M.D; Tongji Hospital

More Information

• Responsible Party: YIKAI YU, Clinical professor, Tongji Hospital
• ClinicalTrials.gov Identifier: NCT04306705
• Other Study ID Numbers: WHTJCOVID-19
• First Posted: March 13, 2020
• Last Update Posted: March 17, 2020
• Last Verified: March 2020

• Studies a U.S. FDA-regulated Drug Product: Yes

Additional relevant MeSH terms:

COVID-19; Syndrome; Cytokine Release Syndrome; Disease; Pathologic Processes; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Shock