COVID-19 Response
During the COVID-19 pandemic, the PETAL Network directed its entire efforts to studying COVID-19. Below is a compilation of the network’s participating efforts to better understand the acute and long-term effects and to find treatments for COVID-19.
Completed studies:
The Network’s first study funded by the NHLBI was a randomized placebo-controlled trial of hydroxychloroquine named ORCHID. The study stopped after enrolling 479 participants in June 2020 based on the fourth scheduled interim analysis showing no evidence of benefit or harm. ORCHID was published in the Journal of the American Medical Association (JAMA. 2020;324(21):2165-76. doi:10.1001/jama.2020.22240. PMID:33165621.) and the study rationale and methods were published in the Annals of the American Thoracic Society (Ann Am Thorac Soc. 2020 Sep;17(9):1144-1153. doi:10.1513/AnnalsATS.202005-478SD. PMID:32492354.). Data from this study is now available through NHLBI’s BioLINCC.
The RED CORAL study is an NHLBI funded study was launched soon after ORCHID and is now complete. RED CORAL was an observational study of retrospective review of data collected on hospitalized patients with COVID-19. The primary manuscript was published in the American Journal of Critical Care (Am J Crit Care. 2022 Mar 1; 31(2): 146–157. doi:10.4037/ajcc2022549. PMID:34709373. ). Two sub studies have been published in Critical Care Medicine (Crit Care Med. 2021 Jul 1;49(7):1038-1048. doi:10.1097/CCM.0000000000005013. PMID:33826584. ) and Chest (Chest. 2022 Jun; 161(6): 1485–1489. doi:10.1016/j.chest.2022.01.034. PMID:35108571. ).
BLUE CORAL is an NHLBI funded multicenter prospective observational study designed to collect comprehensive data on hospitalized patients with COVID-19. This study completed enrollment in July 2021. This study gathered images, biospecimens, and long-term outcomes. Data analysis is ongoing. Two long-term outcome papers have been published with the data from BLUE CORAL: Journal of Hospital Medicine (J Hosp Med. 2021 Aug 18;16: 531-537. doi:10.12788/jhm.3660. PMID:34424190. ) and JAMA (JAMA Netw Open. 2023 Feb; 6(2):e2255795. doi:10.1001/jamanetworkopen.2022.55795. PMID:36787143. ).
FIRE CORAL is an ancillary study to BLUE CORAL that aims to describe post-hospital outcomes for patients previously hospitalized with COVID-19. This study looks at lung function, recovery trajectories, and biospecimens to better understand clinical and biologic factors associated with persistent impairment of the lungs. This study recruited subjects from June 2021 through February 2022. A manuscript was published in Pilot Feasibility Studies (Pilot Feasibility Stud 8, 212 (2022). doi:10.1186/s40814-022-01151-8. PMID:36123599. ) describing the protocol.
Collaboration studies with other groups:
In response to the global COVID-19 pandemic, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private initiative was organized by NIH and the Foundation for the NIH (FNIH). ACTIV developed an international strategy for an integrated research response to COVID-19. The strategy involves streamlining human clinical trials, tapping into existing trial networks such as the NHLBI's Prevention and Early treatment of Acute Lung Injury (PETAL) network, coordinating regulatory processes, and prioritization of therapeutic and vaccine candidates. The following studies are funded by the NIH.
ACTIV-3/TICO is a global multi-center randomized placebo-controlled study of antiviral treatments in patients hospitalized with COVID-19. ACTIV-3 was launched in August 2020 and completed recruitment in December 2021, after evaluating several agents through its master protocol design. Several manuscripts have been published relating to TICO, including: Tixagevimab–cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial (Lancet Respir Med. 2022 Oct;10(10):972-984. doi:10.1016/S2213-2600(22)00215-6. PMID:35817072. ), Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial (Lancet Infect Dis. 2022 May;22(5):622-635. doi:10.1016/S1473-3099(21)00751-9. PMID:34953520. ), A Neutralizing Monoclonal Antibody for Hospitalized Patients with COVID-19 (Engl J Med. 2021 Mar 11;384(10):905-914. doi:10.1056/NEJMoa2033130. PMID:33356051. ), Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19 (Ann Intern Med. 2022 Sep;175(9):1266-1274. doi:10.7326/M22-1503. PMID:35939810. ), and The Association of Baseline Plasma SARS-CoV-2 Nucleocapsid Antigen Level and Outcomes in Patients Hospitalized With COVID-19 (Ann Intern Med. 2022 Oct;175(10):1401-1410. doi:10.7326/M22-0924. PMID:36037469. ).
ACTIV-3b/TESICO is a master protocol similar in structure to ACTIV-3 designed to evaluate safety and efficacy of investigational agents aimed at improving outcomes for patients with acute respiratory failure related to COVID-19. Patients with respiratory failure, which in COVID-19 is likely best termed Acute Respiratory Distress Syndrome (ARDS), have extremely high morbidity and mortality. TESICO recruited subjects from April 2021 through May 2022, and is led by PETAL's Dr. Sam Brown of Intermountain Medical Center.
ACTIV-4a is a multi-center clinical trial looking at agents that decrease coagulation of the blood in patients hospitalized for COVID-19. Many patients hospitalized with COVID-19 develop blood clots and signs of coagulation in multiple organs in autopsy findings. These signs of increase coagulation correlate with worse organ failure and mortality. The PETAL Network is collaborating with several other networks nationally and internationally to determine the effectiveness of antithrombotic strategies for prevention of adverse outcomes and organ failure in COVID-19 positive inpatients. This study enrolled subjects from September 2020 through March 2023. Several manuscripts have been published with the results of the first two agents study: Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with COVID-19 (N Engl J Med. 2021 Aug 26;385(9):790-802. doi:10.1056/NEJMoa2105911. PMID:34351721. ), Therapeutic Anticoagulation with Heparin in Critically Ill Patients with COVID-19 (N Engl J Med. 2021 Aug 26;385(9):777-789. doi:10.1056/NEJMoa2103417. PMID:34351722. ), Effect of P2Y12 Inhibitors on Survival Free of Organ Support Among Non–Critically Ill Hospitalized Patients With COVID-19 (JAMA. 2022 Jan 18;327(3):227-236. doi:10.1001/jama.2021.23605. PMID:35040887. ), and Effect of P2Y12 Inhibitors on Organ Support-Free Survival in Critically Ill Patients Hospitalized for COVID-19: A Randomized Clinical Trial (JAMA Netw Open. 2023 May 1;6(5):e2314428. doi:10.1001/jamanetworkopen.2023.14428. PMID:37227729. ). Data collection and analysis is ongoing for the third and fourth agents studied.
ACTIV-4 Host Tissue is a multi-center clinical trial testing agents that target the host-tissue response to SARS-CoV-2 infection. The initial agents on the platform will target the Renin-Angiotensin-Aldosterone System (RAAS). The goal of this platform is to determine if these host-tissue targeted agents hasten recovery and prevent illness progression in patients hospitalized with COVID-19. This study started enrolling subjects in July 2021 and is still recruiting. A manuscript has been published in JAMA (JAMA. 2023 Apr 11;329(14):1170-1182. doi:10.1001/jama.2023.3546. PMID:37039791. ) describing the outcomes of the first two agents studied.