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SARS-CoV-2 InfectionPhase 2CORON-ACTNCT04335071

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

A Phase 2 study testing Tocilizumab (TCZ) in people with SARS-CoV-2 Infection, run by Insel Gruppe AG, University Hospital Bern at 4 sites in Switzerland.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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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. Read more about this study

Who is it for?
Ages 30 to 80 years
Conditions the study is for
SARS-CoV-2 Infection
What is being tested?
Tocilizumab (TCZ)
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
5 participants
Where
4 sitesSwitzerland
Study dates
26 Apr 2020to 27 Sep 2020
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 30 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 13Show fewer
  • 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)

Who cannot join

  • 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
Show all 16Show fewer
  • 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

Trial locations and contacts

4 sites in 1 country.

Switzerland4 sites

  • University Hospital Bern (Inselspital)

    Bern, 3010

  • Centre Hospitalier Universitaire Vaudois (CHUV)

    Lausanne, 1011

  • Ospedale Regionale di Lugano (EOC)

    Viganello, 6962

  • University Hospital Zurich

    Zurich, 8091

Other trials in Switzerland

About this study

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)

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.

Read the detailed 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.

Being tested
Tocilizumab (TCZ), Placebo
Keywords
Covid-19, Pneumonia, Tocilizumab
Medical subject headings
COVID-19, Pneumonia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Tocilizumab (TCZ)Drug

    Also called Actemra

    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.

  • PlaceboDrug

    Also called NaCl 0.9%

    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.

Study groups in NCT04335071
Study groupRoleWhat they receive
ActemraExperimentalPatients 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 improvement in the 8-point WHO scale is observed.
Receives: Drug: Tocilizumab (TCZ)
PlaceboPlacebo comparatorThe 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 improvement in the 8-point WHO scale is observed.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of patients with ICU admission

    Measured: 7 days after randomisation

  2. Number of patients with intubation

    Measured: 14 days after randomisation

  3. Number of patients with death

    Measured: 28 days after randomisation

Secondary outcomes (8)

  1. Illness severity

    Assessed by the 8-point WHO scale

    Measured: At days 2, 7, 14, 28 after randomisation

  2. Number of patients with clinical improvement

    Clinical improvement is defined as a ≥ 2-point improvement in the 8-point WHO scale

    Measured: At days 2, 7, 14, 28 after randomisation

  3. Time to clinical improvement (days)

    Clinical improvement is defined as a ≥ 2-point improvement in the 8-point WHO scale

    Measured: Up to day 28 after randomisation

  4. Duration of hospitalization (days)

    Measured: Up to day 28 after randomisation

  5. Time to ICU admission (days)

    Measured: Up to day 28 after randomisation

  6. Duration of ICU stay

    Measured: Up to day 28 after randomisation

  7. Time to intubation

    Measured: Up to day 28 after randomisation

  8. Duration of mechanical ventilation (days)

    Measured: Up to day 28 after randomisation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Apr 2020
  2. Study start26 Apr 2020
  3. Primary completion27 Sep 2020
  4. Study completion27 Sep 2020

Why it stopped: 1.) Not possible to recruit the planned number of patients during the planned study period; 2.) "Dexamethason" was included in the standard of care for the study population during the course of the study and inclusion criteria could no longer be met.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
A multicenter, double-blind, randomized controlled phase II trial
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
5 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04335071
Sponsor's protocol ID
2020-00691
Other IDs
2020DR2044
Acronym
CORON-ACT
Status last verified
Oct 2020
First submitted
2 Apr 2020
Last updated
14 Oct 2020
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24.

    PubMed 31986264

  • 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.

    PubMed 32167524

  • Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11.

    PubMed 32171076

  • 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.

    PubMed 29622697

  • Morrondo CD, Zarza LP, Gil JG, Pinto Tasende JA, Diez PD, Lopez 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. No abstract available.

    PubMed 27464783

  • 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.

    PubMed 26567181

  • 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.

    PubMed 26584195

  • Neuenschwander B, Capkun-Niggli G, Branson M, Spiegelhalter DJ. Summarizing historical information on controls in clinical trials. Clin Trials. 2010 Feb;7(1):5-18. doi: 10.1177/1740774509356002.

    PubMed 20156954

  • 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.

    PubMed 19297346

  • 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.

    PubMed 28745999

  • Villiger PM, Adler S, Kuchen S, Wermelinger F, Dan D, Fiege V, Butikofer 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.

    PubMed 26952547

  • Yang S, Cao P, Du P, Wu Z, Zhuang Z, Yang L, Yu X, Zhou Q, Feng X, Wang X, Li W, Liu E, Chen J, Chen Y, He D. Early estimation of the case fatality rate of COVID-19 in mainland China: a data-driven analysis. Ann Transl Med. 2020 Feb;8(4):128. doi: 10.21037/atm.2020.02.66.

    PubMed 32175421

  • 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, Muller-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.

    PubMed 27156934

  • Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7. Epub 2020 Jan 30.

    PubMed 32007143

  • 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. No abstract available.

    PubMed 32125452

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Tocilizumab (TCZ) in people with SARS-CoV-2 Infection, run by Insel Gruppe AG, University Hospital Bern at 4 sites in Switzerland.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 14 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: 1.) Not possible to recruit the planned number of patients during the planned study period; 2.) "Dexamethason" was included in the standard of care for the study population during the course of the study and inclusion criteria could no longer be met.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of patients with ICU admission (time frame: 7 days after randomisation). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04335071, which also lists 15 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Oct 2020.

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