Efficacy and Safety of Pacritinib vs Placebo for Patients With Severe COVID-19
MD John Cafardi, MD Carole Miller, DO; Howard Terebelo, MD Chad Tewell, MD Sadia Benzaquen, MD David Park, MD Pamela Egan, MD Daniel Lebovic, MD Kristen Pettit, MD Eric Whitman, MD Douglas Tremblay, MD Jonathan Feld, MD Sarah Buckley, MS Karisse Roman-Torres, PhD Jennifer Smith, MD; Adam Craig, MD John Mascarenhas
JAMA Network Open, doi:10.1001/jamanetworkopen.2022.42918
IMPORTANCE The morbidity and mortality associated with COVID-19 remain high despite advances in standard of care therapy, and the role of anti-inflammatory agents that inhibit the interleukin 6/JAK2 pathway is still being elucidated.
OBJECTIVE To evaluate the efficacy and safety of the oral JAK2/IRAK1 inhibitor pacritinib vs placebo in the treatment of adults with severe COVID-19. DESIGN, SETTING, AND PARTICIPANTS This phase 2, double-blind, placebo-controlled, randomized clinical trial enrolled hospitalized adult patients with severe COVID-19 at 21 centers across the US between June 2020 and February 2021, with approximately 1.5 months of safety follow-up per patient. Data analysis was performed from September 2021 to July 2022. INTERVENTIONS Patients were randomized 1:1 to standard of care plus pacritinib (400 mg per os on day 1 followed by 200 mg twice daily on days 2-14) vs placebo, for 14 days.
MAIN OUTCOMES AND MEASURES The primary end point was death or need for invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) by day 28. All-cause mortality and safety were also assessed.
RESULTS A total of 200 patients were randomized to pacritinib (99 patients; 56 men [56.6%]; median [range] age, 60 [19-87] years) or placebo (101 patients; 64 men [63.4%]; median [range] age 59 [28-94] years). The percentage requiring supplementary oxygen was 99.0% (98 patients) in the pacritinib group vs 98.0% (99 patients) in the placebo group. The percentage who progressed to IMV, ECMO, or death was 17.2% (17 patients) in the pacritinib group vs 22.8% (23 patients) in the placebo group (odds ratio, 0.62; 95% CI, 0.28-1.35; P = .23). Among patients with elevated interleukin 6, the rate was 17.5% (11 of 63 patients) in the pacritinib group vs 30.4% (21 of 96 patients) in the placebo group. The adverse event rate was similar for pacritinib vs placebo (78.1% [75 patients] vs 80.2% [81 patients]), with no excess in infection (14.6% [14 patients] vs 19.8% [20 patients]), bleeding (8.3% [8 patients] vs 10.9% [11 patients]), or thrombosis (8.3% [8 patients] vs 7.9% [8 patients]). Rates of grade 3 or higher adverse events were lower with pacritinib than placebo (29.2% [28 patients] vs 40.6% [41 patients]).
CONCLUSIONS AND RELEVANCE The study did not meet its primary end point in patients with severe COVID-19. Subgroup analyses may indicate specific populations with hyperinflammation that could benefit from pacritinib, although further clinical trials would be needed to confirm these effects.
The effect size of pacritinib compared with placebo in prevention of IMV, ECMO, or death in the overall population (OR, 0.62) was comparable to the effect size for baricitinib plus remdesivir in prevention of IMV or ECMO in the ACTT-2 (A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults) study (OR, 0.61) 21 or baricitinib in prevention of high-flow oxygen, noninvasive positive pressure ventilation, IMV, ECMO, or death in the COV-BARRIER (A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 3 Study of Baricitinib in Patients With COVID-19 Infection) study (OR, 0.85). 22 Both ACTT-2 and COV-BARRIER were adequately powered phase 3 confirmatory trials, with a total sample size of more than 1000 patients. PRE-VENT, by contrast, was designed as a phase 2 study, and although the results are encouraging, the study was not powered to detect the observed effect size. Since April 2020, when PRE-VENT was designed, standard of care therapy for severe COVID-19 has evolved rapidly. Almost all patients enrolled in the PRE-VENT trial received corticosteroids and prophylactic-dose or intermediate-dose anticoagulation as part of standard therapy. In November 2020, approximately 4 months before study closure, the JAK1/2 inhibitor baricitinib was approved, in combination with remdesivir, under EUA in the US. In June 2021, approximately 4 months after study..
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doi:10.1186/s13054-015-0811-2{ 'indexed': {'date-parts': [[2024, 7, 6]], 'date-time': '2024-07-06T00:14:47Z', 'timestamp': 1720224887896},
'reference-count': 29,
'publisher': 'American Medical Association (AMA)',
'issue': '12',
'content-domain': {'domain': [], 'crossmark-restriction': False},
'abstract': '<jats:sec><jats:title>Importance</jats:title><jats:p>The morbidity and mortality associated '
'with COVID-19 remain high despite advances in standard of care therapy, and the role of '
'anti-inflammatory agents that inhibit the interleukin 6/JAK2 pathway is still being '
'elucidated.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To '
'evaluate the efficacy and safety of the oral JAK2/IRAK1 inhibitor pacritinib vs placebo in '
'the treatment of adults with severe '
'COVID-19.</jats:p></jats:sec><jats:sec><jats:title>Design, Setting, and '
'Participants</jats:title><jats:p>This phase 2, double-blind, placebo-controlled, randomized '
'clinical trial enrolled hospitalized adult patients with severe COVID-19 at 21 centers across '
'the US between June 2020 and February 2021, with approximately 1.5 months of safety follow-up '
'per patient. Data analysis was performed from September 2021 to July '
'2022.</jats:p></jats:sec><jats:sec><jats:title>Interventions</jats:title><jats:p>Patients '
'were randomized 1:1 to standard of care plus pacritinib (400 mg per os on day 1 followed by '
'200 mg twice daily on days 2-14) vs placebo, for 14 '
'days.</jats:p></jats:sec><jats:sec><jats:title>Main Outcomes and '
'Measures</jats:title><jats:p>The primary end point was death or need for invasive mechanical '
'ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) by day 28. All-cause '
'mortality and safety were also '
'assessed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A total of 200 '
'patients were randomized to pacritinib (99 patients; 56 men [56.6%]; median [range] age, 60 '
'[19-87] years) or placebo (101 patients; 64 men [63.4%]; median [range] age 59 [28-94] '
'years). The percentage requiring supplementary oxygen was 99.0% (98 patients) in the '
'pacritinib group vs 98.0% (99 patients) in the placebo group. The percentage who progressed '
'to IMV, ECMO, or death was 17.2% (17 patients) in the pacritinib group vs 22.8% (23 patients) '
'in the placebo group (odds ratio,\u20090.62; 95% CI, 0.28-1.35; '
'<jats:italic>P</jats:italic>\u2009=\u2009.23). Among patients with elevated interleukin 6, '
'the rate was 17.5% (11 of 63 patients) in the pacritinib group vs 30.4% (21 of 96 patients) '
'in the placebo group. The adverse event rate was similar for pacritinib vs placebo (78.1% [75 '
'patients] vs 80.2% [81 patients]), with no excess in infection (14.6% [14 patients] vs 19.8% '
'[20 patients]), bleeding (8.3% [8 patients] vs 10.9% [11 patients]), or thrombosis (8.3% [8 '
'patients] vs 7.9% [8 patients]). Rates of grade 3 or higher adverse events were lower with '
'pacritinib than placebo (29.2% [28 patients] vs 40.6% [41 '
'patients]).</jats:p></jats:sec><jats:sec><jats:title>Conclusions and '
'Relevance</jats:title><jats:p>The study did not meet its primary end point in patients with '
'severe COVID-19. Subgroup analyses may indicate specific populations with hyperinflammation '
'that could benefit from pacritinib, although further clinical trials would be needed to '
'confirm these effects.</jats:p></jats:sec><jats:sec><jats:title>Trial '
'Registration</jats:title><jats:p>ClinicalTrials.gov Identifier: <jats:ext-link '
'xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" '
'xlink:href="https://clinicaltrials.gov/ct2/show/NCT04404361">NCT04404361</jats:ext-link></jats:p></jats:sec>',
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