Tocilizumab in the Treatment of Coronavirus Induced Disease (COVID-19)

SARS-CoV-2 Infection Clinical Trial

— CORON-ACT  

Official title:

CORON-ACT - a Multicenter, Double-blind, Randomized Controlled Phase II Trial on the Efficacy and Safety of Tocilizumab in the Treatment of Coronavirus Induced Disease (COVID-19)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04335071
• Other study ID #: 2020-00691
• Secondary ID: 2020DR2044
• Status: Terminated
• Phase: Phase 2
• Start date: April 26, 2020
• Est. completion date: September 27, 2020

Study information

• Verified date: October 2020
• Source: University Hospital Inselspital, Berne
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The mortality rate of the disease caused by the corona virus induced disease (COVID-19) has been estimated to be 3.7% (WHO), which is more than 10-fold higher than the mortality of influenza. Patients with certain risk factors seem to die by an overwhelming reaction of the immune system to the virus, causing a cytokine storm with features of Cytokine-Release Syndrome (CRS) and Macrophage Activation Syndrome (MAS) and resulting in Acute Respiratory Distress Syndrome (ARDS). Several pro-inflammatory cytokines are elevated in the plasma of patients and features of MAS in COVID-19, include elevated levels of ferritin, d-dimer, and low platelets.

There is increasing data that cytokine-targeted biological therapies can improve outcomes in CRS or MAS and even in sepsis. Tocilizumab (TCZ), an anti-IL-6R biological therapy, has been approved for the treatment of CRS and is used in patients with MAS. Based on these data, it is hypothesized that TCZ can reduce mortality in patients with severe COVID-19 prone to CRS and ARDS.

The overall purpose of this study is to evaluate whether treatment with TCZ reduces the severity and mortality in patients with COVID-19.

Description:

Background and Rationale

The Acute Respiratory Syndrome by Corona Virus 2 (SARS-CoV-2), first discovered in December 2019 in Wuhan/China, is causing a worldwide pandemic with potentially lethal implications on an individual basis, and, on the large scale bringing the health care systems and the economy to its limits. The mortality rate of this COronaVIrus induced Disease, COVID-19, has been estimated by the World Health Organization (WHO) to be 3.7%, which is more than 10-fold higher than the mortality of influenza.

An infection with SARS-CoV-2 may cause an excessive host immune response, leading to an Acute Respiratory Distress Syndrome (ARDS) and death. Reports from China and from Italy describe an overwhelming inflammation which is triggered by the virus, causing a cytokine storm with features of Cytokine-Release Syndrome (CRS) and/or Macrophage Activation Syndrome (MAS). Pro-inflammatory cytokines such as Interleukin-6 (IL-6) are elevated in the plasma of patients and features of MAS in COVID-19 include elevated levels of ferritin, d-dimer and low platelets.

There is increasing evidence, that cytokine-targeted biological therapies can improve outcomes in CRS or MAS and even in sepsis. In recognition of the dramatic development of the COVID-19 pandemic, and in a pragmatic manner, already approved and safe therapies should be evaluated for the use in severe COVID-19.

Tocilizumab (TCZ), an anti-IL-6R biological therapy, has been approved for the treatment of CRS and is used in patients with MAS (and in other rheumatologic conditions like Rheumatoid Arthritis (RA) or Giant Cell Arteritis (GCA), with a good safety profile also in the elderly).

Collectively, the data strongly suggest that neutralization of the inflammatory pathway induced by IL-6 may reduce mortality in patients with severe COVID-19 prone to CRS and ARDS.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 5
• Est. completion date: September 27, 2020
• Est. primary completion date: September 27, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years to 80 Years

Eligibility

Inclusion Criteria:

I (first step):

• Admission to hospital

• Male or non-pregnant female, =60 years of age or =30 years of age plus one or more known risk factors (arterial hypertension, diabetes mellitus, coronary heart disease, heart failure, pre-existing chronic pulmonary disease)

• Confirmed SARS-CoV infection

• Radiographic evidence compatible with Covid-19 pneumonia (X-ray/CT scan, etc.)

• Signed Informed Consent Form

II (second step; indication for intervention):

• CRP =50mg/L plus 3 out of the following 5 criteria need to be fulfilled:

• Respiration Rate =25

• SpO2 <93% (on ambient air)

• PaO2 <65 mmHg

• Persistent or increasing dyspnoea as defined by a one point increase on the mMRC dyspnoea scale (over 1 hour)

• Persistent or increasing oxygen demand (over 1 hour)

Exclusion Criteria:

I (first step):

• Patients >80 years of age

• Patient included in any other interventional trial

• Indication for imminent or immediate transfer to ICU

• Treatment with TCZ (or other anti-IL-6R treatment) within 4 weeks prior to baseline

• Uncontrolled bacterial superinfection according to investigator

• History of severe allergic reaction to TCZ

• History of diverticulitis requiring antibiotic treatment or history of colon perforation

• History of primary immunodeficiency (e.g. CVID) or progressing malignancy

• History of chronic liver disease (>Child-Pugh A, or according to investigator)

II (second step; contraindication for intervention):

• Alanine transaminase/aspartate transaminase (ALT/AST) >5 times of the upper limit of normal

• Hemoglobin <80 g/L

• Leukocytes <2.0 G/L

• Absolute neutrophil count <1.0 G/L

• Platelets <50 G/L

Related Conditions & MeSH terms

• Coronavirus Infections
• SARS-CoV-2 Infection

Intervention

Drug:
• Tocilizumab (TCZ)
Patients get one dose (= 8 mg/kg bodyweight, max. single dose 800 mg) Actemra® (active ingredient: TCZ) intravenously in 100 mL NaCl 0.9% after confirmation of progressive dyspnoea. Infusion time: 60 min. The procedure is repeated once if no clinical improvement in the 8-point WHO scale is observed.
• Placebo
The placebo-controlled intervention is one dose (100 mL) NaCl 0.9% intravenously administered after confirmation of progressive dyspnoea. Infusion time: 60 min. The procedure is repeated once if no clinical improvement in the 8-point WHO scale is observed.

Locations

Country	Name	City	State
Switzerland	University Hospital Bern (Inselspital)	Bern
Switzerland	Centre Hospitalier Universitaire Vaudois (CHUV)	Lausanne
Switzerland	Ospedale Regionale di Lugano (EOC)	Viganello
Switzerland	University Hospital Zurich	Zurich

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Inselspital, Berne	Roche Pharma AG

Country where clinical trial is conducted

Switzerland, 

References & Publications (15)

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Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, Siri DA, Tomsic M, Alecock E, Woodworth T, Genovese MC. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010 Jan;69(1):88-96. doi: 10.1136/ard.2008.105197. — View Citation

Khanna D, Denton CP, Jahreis A, van Laar JM, Frech TM, Anderson ME, Baron M, Chung L, Fierlbeck G, Lakshminarayanan S, Allanore Y, Pope JE, Riemekasten G, Steen V, Müller-Ladner U, Lafyatis R, Stifano G, Spotswood H, Chen-Harris H, Dziadek S, Morimoto A, Sornasse T, Siegel J, Furst DE. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016 Jun 25;387(10038):2630-2640. doi: 10.1016/S0140-6736(16)00232-4. Epub 2016 May 5. Erratum in: Lancet. 2018 Apr 7;391(10128):1356. — View Citation

Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, Przepiorka D, Farrell AT, Pazdur R. FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome. Oncologist. 2018 Aug;23(8):943-947. doi: 10.1634/theoncologist.2018-0028. Epub 2018 Apr 5. — View Citation

Morrondo CD, Zarza LP, Gil JG, Pinto Tasende JA, Diez PD, López JM. Benefit of Tocilizumab Therapy for Adult-Onset Still Disease Complicated With Acute Respiratory Distress Syndrome. J Clin Rheumatol. 2016 Aug;22(5):291-3. doi: 10.1097/RHU.0000000000000374. — View Citation

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Richter A, Listing J, Schneider M, Klopsch T, Kapelle A, Kaufmann J, Zink A, Strangfeld A. Impact of treatment with biologic DMARDs on the risk of sepsis or mortality after serious infection in patients with rheumatoid arthritis. Ann Rheum Dis. 2016 Sep;75(9):1667-73. doi: 10.1136/annrheumdis-2015-207838. Epub 2015 Nov 13. — View Citation

Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 May;46(5):846-848. doi: 10.1007/s00134-020-05991-x. Epub 2020 Mar 3. Erratum in: Intensive Care Med. 2020 Apr 6;:. — View Citation

Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, Cron RQ, Opal SM. Interleukin-1 Receptor Blockade Is Associated With Reduced Mortality in Sepsis Patients With Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial. Crit Care Med. 2016 Feb;44(2):275-81. doi: 10.1097/CCM.0000000000001402. — View Citation

Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, Brouwer E, Cid MC, Dasgupta B, Rech J, Salvarani C, Schett G, Schulze-Koops H, Spiera R, Unizony SH, Collinson N. Trial of Tocilizumab in Giant-Cell Arteritis. N Engl J Med. 2017 Jul 27;377(4):317-328. doi: 10.1056/NEJMoa1613849. — View Citation

Villiger PM, Adler S, Kuchen S, Wermelinger F, Dan D, Fiege V, Bütikofer L, Seitz M, Reichenbach S. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2016 May 7;387(10031):1921-7. doi: 10.1016/S0140-6736(16)00560-2. Epub 2016 Mar 4. — View Citation

Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, Huang H, Zhang L, Zhou X, Du C, Zhang Y, Song J, Wang S, Chao Y, Yang Z, Xu J, Zhou X, Chen D, Xiong W, Xu L, Zhou F, Jiang J, Bai C, Zheng J, Song Y. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020 Jul 1;180(7):934-943. doi: 10.1001/jamainternmed.2020.0994. — View Citation

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* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of deaths		Within 28 days after randomisation
Other	Number of patients with ICU admission		Within 28 days after randomisation
Other	Number of patients with intubation		Within 28 days after randomisation
Other	Number of patients with events of special interest	Events of special interest are defined as secondary infections, acute kidney failure, hepatic, and cardiac failure	Within 28 days after randomisation
Other	Number of patients with SAEs considered by the investigator to be at least probably related to the IMP		Within 28 days after randomisation
Primary	Number of patients with ICU admission		7 days after randomisation
Primary	Number of patients with intubation		14 days after randomisation
Primary	Number of patients with death		28 days after randomisation
Secondary	Illness severity	Assessed by the 8-point WHO scale	At days 2, 7, 14, 28 after randomisation
Secondary	Number of patients with clinical improvement	Clinical improvement is defined as a = 2-point improvement in the 8-point WHO scale	At days 2, 7, 14, 28 after randomisation
Secondary	Time to clinical improvement (days)	Clinical improvement is defined as a = 2-point improvement in the 8-point WHO scale	Up to day 28 after randomisation
Secondary	Duration of hospitalization (days)		Up to day 28 after randomisation
Secondary	Time to ICU admission (days)		Up to day 28 after randomisation
Secondary	Duration of ICU stay		Up to day 28 after randomisation
Secondary	Time to intubation		Up to day 28 after randomisation
Secondary	Duration of mechanical ventilation (days)		Up to day 28 after randomisation