Tags

Type your tag names separated by a space and hit enter

Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial.
Lancet Respir Med. 2021 05; 9(5):511-521.LR

Abstract

BACKGROUND

Global randomised controlled trials of the anti-IL-6 receptor antibody tocilizumab in patients admitted to hospital with COVID-19 have shown conflicting results but potential decreases in time to discharge and burden on intensive care. Tocilizumab reduced progression to mechanical ventilation and death in a trial population enriched for racial and ethnic minorities. We aimed to investigate whether tocilizumab treatment could prevent COVID-19 progression in the first multicentre randomised controlled trial of tocilizumab done entirely in a lower-middle-income country.

METHODS

COVINTOC is an open-label, multicentre, randomised, controlled, phase 3 trial done at 12 public and private hospitals across India. Adults (aged ≥18 years) admitted to hospital with moderate to severe COVID-19 (Indian Ministry of Health grading) confirmed by positive SARS-CoV-2 PCR result were randomly assigned (1:1 block randomisation) to receive tocilizumab 6 mg/kg plus standard care (the tocilizumab group) or standard care alone (the standard care group). The primary endpoint was progression of COVID-19 (from moderate to severe or from severe to death) up to day 14 in the modified intention-to-treat population of all participants who had at least one post-baseline assessment for the primary endpoint. Safety was assessed in all randomly assigned patients. The trial is completed and registered with the Clinical Trials Registry India (CTRI/2020/05/025369).

FINDINGS

180 patients were recruited between May 30, 2020, and Aug 31, 2020, and randomly assigned to the tocilizumab group (n=90) or the standard care group (n=90). One patient randomly assigned to the standard care group inadvertently received tocilizumab at baseline and was included in the tocilizumab group for all analyses. One patient randomly assigned to the standard care group withdrew consent after the baseline visit and did not receive any study medication and was not included in the modified intention-to-treat population but was still included in safety analyses. 75 (82%) of 91 in the tocilizumab group and 68 (76%) of 89 in the standard care group completed 28 days of follow-up. Progression of COVID-19 up to day 14 occurred in eight (9%) of 91 patients in the tocilizumab group and 11 (13%) of 88 in the standard care group (difference -3·71 [95% CI -18·23 to 11·19]; p=0·42). 33 (36%) of 91 patients in the tocilizumab group and 22 (25%) of 89 patients in the standard care group had adverse events; 18 (20%) and 15 (17%) had serious adverse events. The most common adverse event was acute respiratory distress syndrome, reported in seven (8%) patients in each group. Grade 3 adverse events were reported in two (2%) patients in the tocilizumab group and five (6%) patients in the standard care group. There were no grade 4 adverse events. Serious adverse events were reported in 18 (20%) patients in the tocilizumab group and 15 (17%) in the standard care group; 13 (14%) and 15 (17%) patients died during the study.

INTERPRETATION

Routine use of tocilizumab in patients admitted to hospital with moderate to severe COVID-19 is not supported. However, post-hoc evidence from this study suggests tocilizumab might still be effective in patients with severe COVID-19 and so should be investigated further in future studies.

FUNDING

Medanta Institute of Education and Research, Roche India, Cipla India, and Action COVID-19 India.

Authors+Show Affiliations

Medanta Institute of Education and Research, Medanta-The Medicity Hospital, Gurugram, Haryana, India. Electronic address: avisoin1@gmail.com.Medanta Institute of Education and Research, Medanta-The Medicity Hospital, Gurugram, Haryana, India.Medanta Institute of Education and Research, Medanta-The Medicity Hospital, Gurugram, Haryana, India.Medanta Institute of Education and Research, Medanta-The Medicity Hospital, Gurugram, Haryana, India.Medanta-The Medicity Hospital, Gurugram, Haryana, India.Medanta-The Medicity Hospital, Gurugram, Haryana, India.Medanta-The Medicity Hospital, Gurugram, Haryana, India.Medanta-The Medicity Hospital, Gurugram, Haryana, India.Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India.Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India.Medeor Hospital, Manesar, Haryana, India.Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.Apollo Hospitals Chennai, Tamil Nadu, India.BJ Medical College, Pune, Maharashtra, India.Indraprastha Apollo Hospital, New Delhi, India.Apollo Hospital Hyderabad, Telangana, India.Fortis Mulund, Mumbai, Maharashtra, India.Nayati Hospitals, Agra, Uttar Pradesh, India.Fortis Memorial Research Institute, Gurugram, Haryana, India.University Hospitals Bristol NHS Foundation Trust and Translational Health Sciences, Bristol Medical School, Bristol, UK.

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33676589

Citation

Soin, Arvinder S., et al. "Tocilizumab Plus Standard Care Versus Standard Care in Patients in India With Moderate to Severe COVID-19-associated Cytokine Release Syndrome (COVINTOC): an Open-label, Multicentre, Randomised, Controlled, Phase 3 Trial." The Lancet. Respiratory Medicine, vol. 9, no. 5, 2021, pp. 511-521.
Soin AS, Kumar K, Choudhary NS, et al. Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial. Lancet Respir Med. 2021;9(5):511-521.
Soin, A. S., Kumar, K., Choudhary, N. S., Sharma, P., Mehta, Y., Kataria, S., Govil, D., Deswal, V., Chaudhry, D., Singh, P. K., Gupta, A., Agarwal, V., Kumar, S., Sangle, S. A., Chawla, R., Narreddy, S., Pandit, R., Mishra, V., Goel, M., & Ramanan, A. V. (2021). Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial. The Lancet. Respiratory Medicine, 9(5), 511-521. https://doi.org/10.1016/S2213-2600(21)00081-3
Soin AS, et al. Tocilizumab Plus Standard Care Versus Standard Care in Patients in India With Moderate to Severe COVID-19-associated Cytokine Release Syndrome (COVINTOC): an Open-label, Multicentre, Randomised, Controlled, Phase 3 Trial. Lancet Respir Med. 2021;9(5):511-521. PubMed PMID: 33676589.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial. AU - Soin,Arvinder S, AU - Kumar,Kuldeep, AU - Choudhary,Narendra S, AU - Sharma,Pooja, AU - Mehta,Yatin, AU - Kataria,Sushila, AU - Govil,Deepak, AU - Deswal,Vikas, AU - Chaudhry,Dhruva, AU - Singh,Pawan Kumar, AU - Gupta,Ashish, AU - Agarwal,Vikas, AU - Kumar,Suresh, AU - Sangle,Shashikala A, AU - Chawla,Rajesh, AU - Narreddy,Suneetha, AU - Pandit,Rahul, AU - Mishra,Vipul, AU - Goel,Manoj, AU - Ramanan,Athimalaipet V, Y1 - 2021/03/04/ PY - 2021/01/12/received PY - 2021/01/27/revised PY - 2021/01/28/accepted PY - 2021/3/8/pubmed PY - 2021/5/14/medline PY - 2021/3/7/entrez SP - 511 EP - 521 JF - The Lancet. Respiratory medicine JO - Lancet Respir Med VL - 9 IS - 5 N2 - BACKGROUND: Global randomised controlled trials of the anti-IL-6 receptor antibody tocilizumab in patients admitted to hospital with COVID-19 have shown conflicting results but potential decreases in time to discharge and burden on intensive care. Tocilizumab reduced progression to mechanical ventilation and death in a trial population enriched for racial and ethnic minorities. We aimed to investigate whether tocilizumab treatment could prevent COVID-19 progression in the first multicentre randomised controlled trial of tocilizumab done entirely in a lower-middle-income country. METHODS: COVINTOC is an open-label, multicentre, randomised, controlled, phase 3 trial done at 12 public and private hospitals across India. Adults (aged ≥18 years) admitted to hospital with moderate to severe COVID-19 (Indian Ministry of Health grading) confirmed by positive SARS-CoV-2 PCR result were randomly assigned (1:1 block randomisation) to receive tocilizumab 6 mg/kg plus standard care (the tocilizumab group) or standard care alone (the standard care group). The primary endpoint was progression of COVID-19 (from moderate to severe or from severe to death) up to day 14 in the modified intention-to-treat population of all participants who had at least one post-baseline assessment for the primary endpoint. Safety was assessed in all randomly assigned patients. The trial is completed and registered with the Clinical Trials Registry India (CTRI/2020/05/025369). FINDINGS: 180 patients were recruited between May 30, 2020, and Aug 31, 2020, and randomly assigned to the tocilizumab group (n=90) or the standard care group (n=90). One patient randomly assigned to the standard care group inadvertently received tocilizumab at baseline and was included in the tocilizumab group for all analyses. One patient randomly assigned to the standard care group withdrew consent after the baseline visit and did not receive any study medication and was not included in the modified intention-to-treat population but was still included in safety analyses. 75 (82%) of 91 in the tocilizumab group and 68 (76%) of 89 in the standard care group completed 28 days of follow-up. Progression of COVID-19 up to day 14 occurred in eight (9%) of 91 patients in the tocilizumab group and 11 (13%) of 88 in the standard care group (difference -3·71 [95% CI -18·23 to 11·19]; p=0·42). 33 (36%) of 91 patients in the tocilizumab group and 22 (25%) of 89 patients in the standard care group had adverse events; 18 (20%) and 15 (17%) had serious adverse events. The most common adverse event was acute respiratory distress syndrome, reported in seven (8%) patients in each group. Grade 3 adverse events were reported in two (2%) patients in the tocilizumab group and five (6%) patients in the standard care group. There were no grade 4 adverse events. Serious adverse events were reported in 18 (20%) patients in the tocilizumab group and 15 (17%) in the standard care group; 13 (14%) and 15 (17%) patients died during the study. INTERPRETATION: Routine use of tocilizumab in patients admitted to hospital with moderate to severe COVID-19 is not supported. However, post-hoc evidence from this study suggests tocilizumab might still be effective in patients with severe COVID-19 and so should be investigated further in future studies. FUNDING: Medanta Institute of Education and Research, Roche India, Cipla India, and Action COVID-19 India. SN - 2213-2619 UR - https://www.unboundmedicine.com/medline/citation/33676589/Tocilizumab_plus_standard_care_versus_standard_care_in_patients_in_India_with_moderate_to_severe_COVID_19_associated_cytokine_release_syndrome__COVINTOC_:_an_open_label_multicentre_randomised_controlled_phase_3_trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2213-2600(21)00081-3 DB - PRIME DP - Unbound Medicine ER -