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Efficacy and Safety of Pacritinib vs Placebo for Patients With Severe COVID-19

Cafardi et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2022.42918, NCT04404361

Dec 2022

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RCT 200 hospitalized patients with severe COVID-19 showing no significant differences with pacritinib.

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risk of death, 27.5% higher, RR 1.28, p = 0.63, treatment 10 of 99 (10.1%), control 8 of 101 (7.9%), day 28.

risk of death, 27.5% higher, RR 1.28, p = 0.75, treatment 5 of 99 (5.1%), control 4 of 101 (4.0%), day 15.

mechanical ventilation or ECMO or death, post-hoc, 24.6% lower, RR 0.75, p = 0.38, treatment 17 of 99 (17.2%), control 23 of 101 (22.8%), NNT 18, day 28, primary outcome.

mechanical ventilation or ECMO or death, prespecified, 6.1% higher, RR 1.06, p = 0.87, treatment 26 of 99 (26.3%), control 25 of 101 (24.8%), day 28, primary outcome.

risk of no improvement by 2+ points, 17.1% higher, RR 1.17, p = 0.53, treatment 31 of 99 (31.3%), control 27 of 101 (26.7%).

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

Cafardi et al., 5 Dec 2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, median age 59.0, 17 authors, study period June 2020 - February 2021, trial NCT04404361 (history).

This Paper Pacritinib All

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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Data analysis was performed from September 2021 to July ' '2022.InterventionsPatients ' '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 ' 'MeasuresThe 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.ResultsA 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; ' 'P\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]).Conclusions and ' 'RelevanceThe 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.Trial ' 'RegistrationClinicalTrials.gov Identifier: NCT04404361', 'DOI': '10.1001/jamanetworkopen.2022.42918', 'type': 'journal-article', 'created': {'date-parts': [[2022, 12, 5]], 'date-time': '2022-12-05T16:03:03Z', 'timestamp': 1670256183000}, 'page': 'e2242918', 'source': 'Crossref', 'is-referenced-by-count': 3, 'title': 'Efficacy and Safety of Pacritinib vs Placebo for Patients With Severe COVID-19', 'prefix': '10.1001', 'volume': '5', 'author': [ { 'given': 'John', 'family': 'Cafardi', 'sequence': 'first', 'affiliation': [ { 'name': 'The Carl and Edyth Lindner Center for Research and Education at ' 'The Christ Hospital, Cincinnati, Ohio'}]}, { 'given': 'Carole', 'family': 'Miller', 'sequence': 'additional', 'affiliation': [{'name': 'Ascension St Agnes Cancer Institute, Baltimore, Maryland'}]}, { 'given': 'Howard', 'family': 'Terebelo', 'sequence': 'additional', 'affiliation': [ { 'name': 'Ascension St John Newland Medical Associates, Southfield, ' 'Michigan'}]}, { 'given': 'Chad', 'family': 'Tewell', 'sequence': 'additional', 'affiliation': [ { 'name': 'Ascension Medical Group St Vincent Carmel Infectious Disease, ' 'Carmel, Indiana'}]}, { 'given': 'Sadia', 'family': 'Benzaquen', 'sequence': 'additional', 'affiliation': [{'name': 'Albert Einstein Medical Center, Philadelphia, Pennsylvania'}]}, { 'given': 'David', 'family': 'Park', 'sequence': 'additional', 'affiliation': [ { 'name': 'Providence St Jude Medical Center, Providence Medical ' 'Foundation, Fullerton, California'}]}, { 'given': 'Pamela', 'family': 'Egan', 'sequence': 'additional', 'affiliation': [{'name': 'Lifespan Cancer Institute, Rhode Island Hospital, Providence'}]}, { 'given': 'Daniel', 'family': 'Lebovic', 'sequence': 'additional', 'affiliation': [{'name': 'Ascension St John Hospital, Detroit, Michigan'}]}, { 'given': 'Kristen', 'family': 'Pettit', 'sequence': 'additional', 'affiliation': [ { 'name': 'Bone Marrow Transplant & Leukemia Clinic, C. 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'family': 'Craig', 'sequence': 'additional', 'affiliation': [{'name': 'CTI BioPharma, Seattle, Washington'}]}, { 'given': 'John', 'family': 'Mascarenhas', 'sequence': 'additional', 'affiliation': [ { 'name': 'Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, ' 'New York, New York'}]}], 'member': '10', 'published-online': {'date-parts': [[2022, 12, 5]]}, 'reference': [ { 'issue': '3', 'key': 'zoi221209r1', 'doi-asserted-by': 'publisher', 'first-page': '251', 'DOI': '10.1016/S2213-2600(20)30527-0', 'article-title': 'Comparison of the characteristics, morbidity, and mortality of COVID-19 ' 'and seasonal influenza: a nationwide, population-based retrospective ' 'cohort study.', 'volume': '9', 'author': 'Piroth', 'year': '2021', 'journal-title': 'Lancet Respir Med'}, { 'issue': '12', 'key': 'zoi221209r2', 'doi-asserted-by': 'publisher', 'first-page': '1700', 'DOI': '10.7326/M21-2239', 'article-title': 'Measuring the COVID-19 mortality burden in the United States: a ' 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Collection of ' 'race and ethnicity data in clinical trials: guidance for industry and ' 'Food and Drug Administration staff. October 26, 2016. Accessed October ' '12, 2022. https://www.fda.gov/media/75453/download'}], 'container-title': 'JAMA Network Open', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://jamanetwork.com/journals/jamanetworkopen/articlepdf/2799198/cafardi_2022_oi_221209_1669647622.34377.pdf', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 12, 5]], 'date-time': '2022-12-05T16:03:07Z', 'timestamp': 1670256187000}, 'score': 1, 'resource': {'primary': {'URL': 'https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2799198'}}, 'subtitle': ['A Phase 2 Randomized Clinical Trial'], 'short-title': [], 'issued': {'date-parts': [[2022, 12, 5]]}, 'references-count': 29, 'journal-issue': {'issue': '12', 'published-print': {'date-parts': [[2022, 12, 1]]}}, 'URL': 'http://dx.doi.org/10.1001/jamanetworkopen.2022.42918', 'relation': {}, 'ISSN': ['2574-3805'], 'subject': [], 'container-title-short': 'JAMA Netw Open', 'published': {'date-parts': [[2022, 12, 5]]}}

Late treatment
is less effective

Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.

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