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- Title
Safety and Efficacy of Combined Tixagevimab and Cilgavimab Administered Intramuscularly or Intravenously in Nonhospitalized Patients With COVID-19: 2 Randomized Clinical Trials.
- Authors
Bender Ignacio, Rachel A.; Chew, Kara W.; Moser, Carlee; Currier, Judith S.; Eron, Joseph J.; Javan, Arzhang Cyrus; Giganti, Mark J.; Aga, Evgenia; Gibbs, Michael; Tchouakam Kouekam, Hervé; Johnsson, Eva; Esser, Mark T.; Hoover, Keila; Neytman, Gene; Newell, Matthew; Daar, Eric S.; Fischer, William; Fletcher, Courtney V.; Li, Jonathan Z.; Greninger, Alexander L.
- Abstract
Key Points: Question: Do tixagevimab and cilgavimab, 2 long-acting anti–SARS-CoV-2 monoclonal antibodies given in combination, improve symptoms and viral shedding when administered intramuscularly in the thigh or intravenously in persons with early COVID-19? Findings: In these 2 phase 2 randomized clinical trials within the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)–2/A5401 platform, tixagevimab-cilgavimab given intramuscularly or intravenously was safe but did not shorten symptom duration. Fewer participants who received intramuscular treatment vs placebo had quantifiable SARS-CoV-2 RNA in nasopharyngeal swabs at day 7. Meaning: Tixagevimab-cilgavimab produced modest antiviral effects, suggesting potential clinical activity for treatment of SARS-CoV-2 infection, but had no effect on symptom duration. These 2 phase 2 randomized clinical trials evaluated the safety and efficacy of single-dose combination tixagevimab and cilgavimab administered intramuscularly and intravenously, each compared with placebo, for treatment of symptomatic nonhospitalized adults with early COVID-19. 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 Measures: Coprimary 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. Trial Registration: ClinicalTrials.gov Identifier: NCT04518410
- Subjects
UNITED States; DRUG efficacy; RESEARCH; RELATIVE medical risk; COVID-19; COMBINATION drug therapy; INTRAVENOUS therapy; CONFIDENCE intervals; VIRAL load; MONOCLONAL antibodies; MANN Whitney U Test; INTRAMUSCULAR injections; RANDOMIZED controlled trials; TREATMENT effectiveness; QUALITY assurance; DESCRIPTIVE statistics; RESEARCH funding; STATISTICAL sampling; DATA analysis software; PATIENT safety; POISSON distribution
- Publication
JAMA Network Open, 2023, Vol 6, Issue 4, pe2310039
- ISSN
2574-3805
- Publication type
Article
- DOI
10.1001/jamanetworkopen.2023.10039