Efficacy and safety of baricitinib or ravulizumab in adult patients with severe COVID-19 (TACTIC-R) : a randomised, parallel-arm, open-label, phase 4 trial
Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved..
BACKGROUND: From early in the COVID-19 pandemic, evidence suggested a role for cytokine dysregulation and complement activation in severe disease. In the TACTIC-R trial, we evaluated the efficacy and safety of baricitinib, an inhibitor of Janus kinase 1 (JAK1) and JAK2, and ravulizumab, a monoclonal inhibitor of complement C5 activation, as an adjunct to standard of care for the treatment of adult patients hospitalised with COVID-19.
METHODS: TACTIC-R was a phase 4, randomised, parallel-arm, open-label platform trial that was undertaken in the UK with urgent public health designation to assess the potential of repurposing immunosuppressants for the treatment of severe COVID-19, stratified by a risk score. Adult participants (aged ≥18 years) were enrolled from 22 hospitals across the UK. Patients with a risk score indicating a 40% risk of admission to an intensive care unit or death were randomly assigned 1:1:1 to standard of care alone, standard of care with baricitinib, or standard of care with ravulizumab. The composite primary outcome was the time from randomisation to incidence (up to and including day 14) of the first event of death, invasive mechanical ventilation, extracorporeal membrane oxygenation, cardiovascular organ support, or renal failure. The primary interim analysis was triggered when 125 patient datasets were available up to day 14 in each study group and we included in the analysis all participants who were randomly assigned. The trial was registered on ClinicalTrials.gov (NCT04390464).
FINDINGS: Between May 8, 2020, and May 7, 2021, 417 participants were recruited and randomly assigned to standard of care alone (145 patients), baricitinib (137 patients), or ravulizumab (135 patients). Only 54 (39%) of 137 patients in the baricitinib group received the maximum 14-day course, whereas 132 (98%) of 135 patients in the ravulizumab group received the intended dose. The trial was stopped after the primary interim analysis on grounds of futility. The estimated hazard ratio (HR) for reaching the composite primary endpoint was 1·11 (95% CI 0·62-1·99) for patients on baricitinib compared with standard of care alone, and 1·53 (0·88-2·67) for ravulizumab compared with standard of care alone. 45 serious adverse events (21 deaths) were reported in the standard-of-care group, 57 (24 deaths) in the baricitinib group, and 60 (18 deaths) in the ravulizumab group.
INTERPRETATION: Neither baricitinib nor ravulizumab, as administered in this study, was effective in reducing disease severity in patients selected for severe COVID-19. Safety was similar between treatments and standard of care. The short period of dosing with baricitinib might explain the discrepancy between our findings and those of other trials. The therapeutic potential of targeting complement C5 activation product C5a, rather than the cleavage of C5, warrants further evaluation.
FUNDING: UK Medical Research Council, UK National Institute for Health Research Cambridge Biomedical Research Centre, Eli Lilly and Company, Alexion Pharmaceuticals, and Addenbrooke's Charitable Trust.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
|---|---|
| Enthalten in: |
The Lancet. Respiratory medicine - 11(2023), 12 vom: 14. Dez., Seite 1064-1074 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Hall, Frances C [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Baricitinib |
|---|
| Anmerkungen: |
Date Completed 01.12.2023 Date Revised 02.12.2023 published: Print-Electronic ClinicalTrials.gov: NCT04390464 Citation Status MEDLINE |
|---|
| doi: |
10.1016/S2213-2600(23)00376-4 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM364687010 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM364687010 | ||
| 003 | DE-627 | ||
| 005 | 20231226095939.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/S2213-2600(23)00376-4 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1215.xml |
| 035 | |a (DE-627)NLM364687010 | ||
| 035 | |a (NLM)37977159 | ||
| 035 | |a (PII)S2213-2600(23)00376-4 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Hall, Frances C |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Efficacy and safety of baricitinib or ravulizumab in adult patients with severe COVID-19 (TACTIC-R) |b a randomised, parallel-arm, open-label, phase 4 trial |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 01.12.2023 | ||
| 500 | |a Date Revised 02.12.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT04390464 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved. | ||
| 520 | |a BACKGROUND: From early in the COVID-19 pandemic, evidence suggested a role for cytokine dysregulation and complement activation in severe disease. In the TACTIC-R trial, we evaluated the efficacy and safety of baricitinib, an inhibitor of Janus kinase 1 (JAK1) and JAK2, and ravulizumab, a monoclonal inhibitor of complement C5 activation, as an adjunct to standard of care for the treatment of adult patients hospitalised with COVID-19 | ||
| 520 | |a METHODS: TACTIC-R was a phase 4, randomised, parallel-arm, open-label platform trial that was undertaken in the UK with urgent public health designation to assess the potential of repurposing immunosuppressants for the treatment of severe COVID-19, stratified by a risk score. Adult participants (aged ≥18 years) were enrolled from 22 hospitals across the UK. Patients with a risk score indicating a 40% risk of admission to an intensive care unit or death were randomly assigned 1:1:1 to standard of care alone, standard of care with baricitinib, or standard of care with ravulizumab. The composite primary outcome was the time from randomisation to incidence (up to and including day 14) of the first event of death, invasive mechanical ventilation, extracorporeal membrane oxygenation, cardiovascular organ support, or renal failure. The primary interim analysis was triggered when 125 patient datasets were available up to day 14 in each study group and we included in the analysis all participants who were randomly assigned. The trial was registered on ClinicalTrials.gov (NCT04390464) | ||
| 520 | |a FINDINGS: Between May 8, 2020, and May 7, 2021, 417 participants were recruited and randomly assigned to standard of care alone (145 patients), baricitinib (137 patients), or ravulizumab (135 patients). Only 54 (39%) of 137 patients in the baricitinib group received the maximum 14-day course, whereas 132 (98%) of 135 patients in the ravulizumab group received the intended dose. The trial was stopped after the primary interim analysis on grounds of futility. The estimated hazard ratio (HR) for reaching the composite primary endpoint was 1·11 (95% CI 0·62-1·99) for patients on baricitinib compared with standard of care alone, and 1·53 (0·88-2·67) for ravulizumab compared with standard of care alone. 45 serious adverse events (21 deaths) were reported in the standard-of-care group, 57 (24 deaths) in the baricitinib group, and 60 (18 deaths) in the ravulizumab group | ||
| 520 | |a INTERPRETATION: Neither baricitinib nor ravulizumab, as administered in this study, was effective in reducing disease severity in patients selected for severe COVID-19. Safety was similar between treatments and standard of care. The short period of dosing with baricitinib might explain the discrepancy between our findings and those of other trials. The therapeutic potential of targeting complement C5 activation product C5a, rather than the cleavage of C5, warrants further evaluation | ||
| 520 | |a FUNDING: UK Medical Research Council, UK National Institute for Health Research Cambridge Biomedical Research Centre, Eli Lilly and Company, Alexion Pharmaceuticals, and Addenbrooke's Charitable Trust | ||
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Clinical Trial, Phase IV | |
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a ravulizumab |2 NLM | |
| 650 | 7 | |a C3VX249T6L |2 NLM | |
| 650 | 7 | |a baricitinib |2 NLM | |
| 650 | 7 | |a ISP4442I3Y |2 NLM | |
| 650 | 7 | |a Complement C5 |2 NLM | |
| 700 | 1 | |a Cheriyan, Joseph |e verfasserin |4 aut | |
| 700 | 1 | |a Cope, Andrew P |e verfasserin |4 aut | |
| 700 | 1 | |a Galloway, James |e verfasserin |4 aut | |
| 700 | 1 | |a Wilkinson, Ian |e verfasserin |4 aut | |
| 700 | 1 | |a Bond, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Norton, Sam |e verfasserin |4 aut | |
| 700 | 1 | |a Banham-Hall, Edward |e verfasserin |4 aut | |
| 700 | 1 | |a Bayes, Hannah |e verfasserin |4 aut | |
| 700 | 1 | |a Kostapanos, Michalis |e verfasserin |4 aut | |
| 700 | 1 | |a Nodale, Marianna |e verfasserin |4 aut | |
| 700 | 1 | |a Petchey, William G |e verfasserin |4 aut | |
| 700 | 1 | |a Sheeran, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Underwood, Jonathan |e verfasserin |4 aut | |
| 700 | 1 | |a Jayne, David R |e verfasserin |4 aut | |
| 700 | 0 | |a TACTIC-R Investigators Group |e verfasserin |4 aut | |
| 700 | 1 | |a Hall, Frances C |e investigator |4 oth | |
| 700 | 1 | |a Cheriyan, Joseph |e investigator |4 oth | |
| 700 | 1 | |a Cope, Andrew P |e investigator |4 oth | |
| 700 | 1 | |a Galloway, James |e investigator |4 oth | |
| 700 | 1 | |a Wilkinson, Ian |e investigator |4 oth | |
| 700 | 1 | |a Bond, Simon |e investigator |4 oth | |
| 700 | 1 | |a Norton, Sam |e investigator |4 oth | |
| 700 | 1 | |a Banham-Hall, Edward |e investigator |4 oth | |
| 700 | 1 | |a Bayes, Hannah |e investigator |4 oth | |
| 700 | 1 | |a Kostapanos, Michalis |e investigator |4 oth | |
| 700 | 1 | |a Nodale, Marianna |e investigator |4 oth | |
| 700 | 1 | |a Petchey, William |e investigator |4 oth | |
| 700 | 1 | |a Sheeran, Thomas |e investigator |4 oth | |
| 700 | 1 | |a Underwood, Jonathan |e investigator |4 oth | |
| 700 | 1 | |a Jayne, David R |e investigator |4 oth | |
| 700 | 1 | |a Galloway, James |e investigator |4 oth | |
| 700 | 1 | |a Nagra, Deepak |e investigator |4 oth | |
| 700 | 1 | |a Norton, Sam |e investigator |4 oth | |
| 700 | 1 | |a Bird, Georgina |e investigator |4 oth | |
| 700 | 1 | |a Underwood, Jonathan |e investigator |4 oth | |
| 700 | 1 | |a Davies, Rhys John |e investigator |4 oth | |
| 700 | 1 | |a Forde, Donall |e investigator |4 oth | |
| 700 | 1 | |a Nye, Clemency |e investigator |4 oth | |
| 700 | 1 | |a Balan, Andrea |e investigator |4 oth | |
| 700 | 1 | |a Bird, Sam |e investigator |4 oth | |
| 700 | 1 | |a Britten, Vianne |e investigator |4 oth | |
| 700 | 1 | |a Broad, Lauren |e investigator |4 oth | |
| 700 | 1 | |a Evans, Teriann |e investigator |4 oth | |
| 700 | 1 | |a Frayling, Sharon |e investigator |4 oth | |
| 700 | 1 | |a Gray, Laura |e investigator |4 oth | |
| 700 | 1 | |a Haynes, Matthew |e investigator |4 oth | |
| 700 | 1 | |a Oliver, Catherine |e investigator |4 oth | |
| 700 | 1 | |a Rahilly, Karen |e investigator |4 oth | |
| 700 | 1 | |a Williams, Gail |e investigator |4 oth | |
| 700 | 1 | |a Ahmed, Tanwir |e investigator |4 oth | |
| 700 | 1 | |a Bayliss, Carrie |e investigator |4 oth | |
| 700 | 1 | |a Byrne, Natalie |e investigator |4 oth | |
| 700 | 1 | |a Hernan-Sancho, Elena |e investigator |4 oth | |
| 700 | 1 | |a Kasanicki, Mary |e investigator |4 oth | |
| 700 | 1 | |a Stockley, Louise |e investigator |4 oth | |
| 700 | 1 | |a Templin, Heike |e investigator |4 oth | |
| 700 | 1 | |a Kostapanos, Michalis |e investigator |4 oth | |
| 700 | 1 | |a Cheriyan, Joseph |e investigator |4 oth | |
| 700 | 1 | |a Banham-Hall, Edward |e investigator |4 oth | |
| 700 | 1 | |a Fisk, Marie |e investigator |4 oth | |
| 700 | 1 | |a Goodman, James |e investigator |4 oth | |
| 700 | 1 | |a Graggaber, Johann |e investigator |4 oth | |
| 700 | 1 | |a Gray, Joanna |e investigator |4 oth | |
| 700 | 1 | |a Gudu, Tania |e investigator |4 oth | |
| 700 | 1 | |a Kulkarni, Spoorthy |e investigator |4 oth | |
| 700 | 1 | |a Ni Lu, Ing |e investigator |4 oth | |
| 700 | 1 | |a Masters, Peta |e investigator |4 oth | |
| 700 | 1 | |a Mir, Fraz |e investigator |4 oth | |
| 700 | 1 | |a Stober, Carmel |e investigator |4 oth | |
| 700 | 1 | |a Abercrombie, Donna |e investigator |4 oth | |
| 700 | 1 | |a Bermperi, Areti |e investigator |4 oth | |
| 700 | 1 | |a Burns, Stella |e investigator |4 oth | |
| 700 | 1 | |a Canna, Laura |e investigator |4 oth | |
| 700 | 1 | |a Domingo, Jason |e investigator |4 oth | |
| 700 | 1 | |a Hodges, Kathy |e investigator |4 oth | |
| 700 | 1 | |a Jose, Sherly |e investigator |4 oth | |
| 700 | 1 | |a Kourampa, Evgenia |e investigator |4 oth | |
| 700 | 1 | |a Meadows, Anne |e investigator |4 oth | |
| 700 | 1 | |a Mendoza, Vivien |e investigator |4 oth | |
| 700 | 1 | |a Mushapaizdi, Thelma |e investigator |4 oth | |
| 700 | 1 | |a Nacorda, Aileen |e investigator |4 oth | |
| 700 | 1 | |a Pasquale, Ciro |e investigator |4 oth | |
| 700 | 1 | |a Read, Debbie |e investigator |4 oth | |
| 700 | 1 | |a Rowlands, Jane |e investigator |4 oth | |
| 700 | 1 | |a Ruffulo, Valentina |e investigator |4 oth | |
| 700 | 1 | |a Soave, Carlotta |e investigator |4 oth | |
| 700 | 1 | |a Titti, Lissamma |e investigator |4 oth | |
| 700 | 1 | |a Tordesillas, Hugo |e investigator |4 oth | |
| 700 | 1 | |a Wright, Samantha |e investigator |4 oth | |
| 700 | 1 | |a Bayes, Hannah |e investigator |4 oth | |
| 700 | 1 | |a Scott, Kathryn |e investigator |4 oth | |
| 700 | 1 | |a Sharma, Varun |e investigator |4 oth | |
| 700 | 1 | |a Cathcart, Susanne |e investigator |4 oth | |
| 700 | 1 | |a Rimmer, Dominic |e investigator |4 oth | |
| 700 | 1 | |a Semple, Gary |e investigator |4 oth | |
| 700 | 1 | |a Sheeran, Tom |e investigator |4 oth | |
| 700 | 1 | |a Phiri, Laurence |e investigator |4 oth | |
| 700 | 1 | |a Plumbe, Ann |e investigator |4 oth | |
| 700 | 1 | |a Petchey, William |e investigator |4 oth | |
| 700 | 1 | |a Bhagat, Shweta |e investigator |4 oth | |
| 700 | 1 | |a Moody, Anne Margaret |e investigator |4 oth | |
| 700 | 1 | |a Kellett, Jo |e investigator |4 oth | |
| 700 | 1 | |a Bukhari, Marwan |e investigator |4 oth | |
| 700 | 1 | |a Burns, Karen |e investigator |4 oth | |
| 700 | 1 | |a Crayton, Susanna |e investigator |4 oth | |
| 700 | 1 | |a Fielding, Andra |e investigator |4 oth | |
| 700 | 1 | |a Simpson, Kerry |e investigator |4 oth | |
| 700 | 1 | |a Shah, Andrew |e investigator |4 oth | |
| 700 | 1 | |a Thatcher, Hilary |e investigator |4 oth | |
| 700 | 1 | |a Makkuni, Damodar |e investigator |4 oth | |
| 700 | 1 | |a Harrison, Wendy |e investigator |4 oth | |
| 700 | 1 | |a Jain, Thrusha |e investigator |4 oth | |
| 700 | 1 | |a Patrick, Jean |e investigator |4 oth | |
| 700 | 1 | |a Pratt, Arthur |e investigator |4 oth | |
| 700 | 1 | |a Sheerin, Neil S |e investigator |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |t The Lancet. Respiratory medicine |d 2013 |g 11(2023), 12 vom: 14. Dez., Seite 1064-1074 |w (DE-627)NLM232005109 |x 2213-2619 |7 nnns |
| 773 | 1 | 8 | |g volume:11 |g year:2023 |g number:12 |g day:14 |g month:12 |g pages:1064-1074 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/S2213-2600(23)00376-4 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 11 |j 2023 |e 12 |b 14 |c 12 |h 1064-1074 | ||