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Clinical Trial
. 2022 Dec 1;5(12):e2242918.
doi: 10.1001/jamanetworkopen.2022.42918.

Efficacy and Safety of Pacritinib vs Placebo for Patients With Severe COVID-19: A Phase 2 Randomized Clinical Trial

John Cafardi  1 , Carole Miller  2 , Howard Terebelo  3 , Chad Tewell  4 , Sadia Benzaquen  5 , David Park  6 , Pamela Egan  7 , Daniel Lebovic  8 , Kristen Pettit  9 , Eric Whitman  10 , Douglas Tremblay  11 , Jonathan Feld  11 , Sarah Buckley  12 , Karisse Roman-Torres  12 , Jennifer Smith  12 , Adam Craig  12 , John Mascarenhas  11
Affiliations
Clinical Trial

Efficacy and Safety of Pacritinib vs Placebo for Patients With Severe COVID-19: A Phase 2 Randomized Clinical Trial

John Cafardi et al. JAMA Netw Open. .

Abstract

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.

Trial registration: ClinicalTrials.gov Identifier: NCT04404361.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cafardi reported receiving support from Ansun Biopharma Financial for a separate clinical trial in COVID-19; receiving personal fees from Gilead Sciences, West Virginia Rural Health Association, Integritas Health, and Keating Muething & Klekamp, PLL; and participating on a Gilead Sciences Advisory Board and receiving drug samples from Gilead Sciences; in addition, his institution receives grants from Gilead Sciences, Merck, and AbbVie. Dr Miller reported receiving grants from CTI BioPharma Corp, Incyte, and Bristol Myers Squibb paid to their institution; and personal fees from CTI BioPharma Corp, Inyte, and Bristol Myers Squibb outside the submitted work. Dr Lebovic reported receiving payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AbbVie, Sanofi, and Takeda; and participating in data safety monitoring boards or advisory boards for AbbVie and Sanofi. Dr Pettit reported receiving grants or contracts from CTI BioPharma Corp, AbbVie, Imago Biosciences, and Incyte Corp; receiving personal fees from CTI Biopharma Corp and AbbVie outside the submitted work; and participating on an AbbVie Advisory Board. Dr Tremblay reported receiving personal fees from AbbVie and grants from Astellas Research paid to his institution outside the submitted work. Dr Mascarenhas reported that his institution received grants or contracts from Incyte, Novartis, Roche, Merck, Geron, CTI BioPharma, Bristol Myers Squibb, AbbVie, Celgene, Kartos, and PharmaEssentia; and receiving consulting fees from Incyte, CTI BioPharma Corp, Constellation, Geron, Kartos, Bristol Myers Squibb, Celgene, Novartis, Karyopharm, Sierra Oncology, AbbVie, PharmaEssentia, and Galecto. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flow Diagram
Diagram shows the flow of patients from screening through study completion, defined as 30 days after the last dose of study drug. The number of patients evaluable for the primary end point (with a day 28 Ordinal Scale Score) are also shown. There were 15 patients randomized to pacritinib and 8 randomized to placebo who did not have an Ordinal Scale Score documented at day 28. The safety population included 197 patients (by actual treatment group, distribution was 96 in the pacritinib group and 101 in the placebo group since 1 patient randomized to pacritinib received placebo). ITT indicates intention to treat; LAR, legal authorized representative.
Figure 2.
Figure 2.. Subgroup Analyses of Primary End Point
Odds ratios for invasive mechanical ventilation, extracorporeal membrane oxygenation, or death by day 28 in the intention-to-treat population are shown. Odds ratios are the Cochran-Mantel Haenszel odds ratios of the end point in the pacritinib (PAC) compared with the placebo (PBO) group. Ordinal Scale Score is represented as clinical status. CRP indicates C-reactive protein; IL-6, interleukin 6; LDH, lactate dehydrogenase; NE, not evaluable; SOC, standard of care; ULN, upper limit of normal.
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