Safety and Efficacy of Combined Tixagevimab and Cilgavimab Administered Intramuscularly or Intravenously in Nonhospitalized Patients With COVID-19: 2 Randomized Clinical Trials

被引:7
|
作者
Ignacio, Rachel A. Bender [1 ,2 ]
Chew, Kara W. [3 ]
Moser, Carlee [4 ]
Currier, Judith S. [3 ]
Eron, Joseph J. [5 ]
Javan, Arzhang Cyrus [6 ]
Giganti, Mark J. [4 ]
Aga, Evgenia [4 ]
Gibbs, Michael [7 ]
Kouekam, Herve Tchouakam [8 ]
Johnsson, Eva [9 ]
Esser, Mark T. [10 ]
Hoover, Keila [11 ]
Neytman, Gene [12 ]
Newell, Matthew [5 ]
Daar, Eric S. [13 ]
Fischer, William [14 ]
Fletcher, Courtney V. [15 ]
Li, Jonathan Z. [16 ]
Greninger, Alexander L. [17 ]
Coombs, Robert W. [17 ]
Hughes, Michael D. [4 ]
Smith, Davey [18 ]
Wohl, David Alain [5 ]
机构
[1] Univ Washington, Div Allergy & Infect Dis, Dept Med, Seattle, WA USA
[2] Fred Hutchinson Canc Ctr, Vaccine & Infect Dis Div, Seattle, WA USA
[3] UCLA, David Geffen Sch Med, Div Infect Dis, Dept Med, Los Angeles, CA USA
[4] Harvard T H Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA
[5] Univ N Carolina, Sch Med, Dept Med, Div Infect Dis, Chapel Hill, NC USA
[6] Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Bethesda, MD USA
[7] AstraZeneca, Vaccines Immune Therapies, BioPharmaceut R&D, Cambridge, England
[8] AstraZeneca, Vaccines Immune Therapies, BioPharmaceut R&D, Toronto, ON, Canada
[9] AstraZeneca, Vaccines Immune Therapies, BioPharmaceut R&D, Gothenburg, Sweden
[10] AstraZeneca, Vaccines Immune Therapies, BioPharmaceut R&D, Gaithersburg, MD USA
[11] Miami Clin Res & Baptist Hlth South Florida, Miami, FL USA
[12] Quantum Clin Trials, Miami Beach, FL USA
[13] Harbor UCLA Med Ctr, Lundquist Inst, Div HIV Med, Los Angeles, CA USA
[14] Univ N Carolina, Sch Med, Div Pulm Dis & Crit Care Med, Chapel Hill, NC USA
[15] Univ Nebraska Med Ctr, UNMC Ctr Drug Discovery, Omaha, NE USA
[16] Harvard Med Sch, Div Infect Dis, Dept Med, Boston, MA USA
[17] Univ Washington, Med Ctr, Dept Lab Med & Pathol, Seattle, WA USA
[18] Univ Calif San Diego, Div Infect Dis & Global Publ Hlth, Dept Med, San Diego, CA USA
基金
美国国家卫生研究院;
关键词
MONOCLONAL-ANTIBODY;
D O I
10.1001/jamanetworkopen.2023.10039
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Importance Development of effective, scalable therapeutics for SARS-CoV-2 is a priority. Objective To test the efficacy of combined tixagevimab and cilgavimab monoclonal antibodies for early COVID-19 treatment. Design, Setting, and Participants Two phase 2 randomized blinded placebo-controlled clinical trials within the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-2/A5401 platform were performed at US ambulatory sites. Nonhospitalized adults 18 years or older within 10 days of positive SARS-CoV-2 test and symptom onset were eligible and were enrolled from February 1 to May 31, 2021. Interventions Tixagevimab-cilgavimab, 300 mg (150 mg of each component) given intravenously (IV) or 600 mg (300 mg of each component) given intramuscularly (IM) in the lateral thigh, or pooled placebo. Main Outcomes and MeasuresCoprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLOQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events through 28 days. Results A total of 229 participants were randomized for the IM study and 119 were randomized for the IV study. The primary modified intention-to-treat population included 223 participants who initiated IM tixagevimab-cilgavimab (n=106) or placebo treatment (n=117) (median age, 39 [IQR, 30-48] years; 113 [50.7%] were men) and 114 who initiated IV tixagevimab-cilgavimab (n=58) or placebo treatment (n=56) (median age, 44 [IQR, 35-54] years; 67 [58.8%] were women). Enrollment in the IV study was stopped early based on a decision to focus on IM product development. Participants were enrolled at a median of 6 (IQR, 4-7) days from COVID-19 symptom onset. Significant differences in time to symptom improvement were not observed for IM tixagevimab-cilgavimab vs placebo or IV tixagevimab-cilgavimab vs placebo. A greater proportion in the IM tixagevimab-cilgavimab arm (69 of 86 [80.2%]) than placebo (62 of 96 [64.6%]) had nasopharyngeal SARS-CoV-2 RNA below LLOQ at day 7 (adjusted risk ratio, 1.33 [95% CI, 1.12-1.57]) but not days 3 and 14; the joint test across time points favored treatment (P=.003). Differences in the proportion below LLOQ were not observed for IV tixagevimab-cilgavimab vs placebo at any of the specified time points. There were no safety signals with either administration route. Conclusions In these 2 phase 2 randomized clinical trials, IM or IV tixagevimab-cilgavimab was safe but did not change time to symptom improvement. Antiviral activity was more evident in the larger IM trial.
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页数:15
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