Efficacy and safety of intramuscular administration of tixagevimab-cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial

Abstract

Background: Early intramuscular administration of SARS-CoV-2-neutralising monoclonal antibody combination, tixagevimab-cilgavimab, to non-hospitalised adults with mild to moderate COVID-19 has potential to prevent disease progression. We aimed to evaluate the safety and efficacy of tixagevimab-cilgavimab in preventing progression to severe COVID-19 or death.

Methods: TACKLE is an ongoing, phase 3, randomised, double-blind, placebo-controlled study conducted at 95 sites in the USA, Latin America, Europe, and Japan. Eligible participants were non-hospitalised adults aged 18 years or older with a laboratory-confirmed SARS-CoV-2 infection (determined by RT-PCR or an antigen test) from any respiratory tract specimen collected 3 days or less before enrolment and who had not received a COVID-19 vaccination. A WHO Clinical Progression Scale score from more than 1 to less than 4 was required for inclusion and participants had to receive the study drug 7 days or less from self-reported onset of mild to moderate COVID-19 symptoms or measured fever. Participants were randomly assigned (1:1) to receive either a single tixagevimab-cilgavimab 600 mg dose (two consecutive 3 mL intramuscular injections, one each of 300 mg tixagevimab and 300 mg cilgavimab) or placebo. Randomisation was stratified (using central blocked randomisation with randomly varying block sizes) by time from symptom onset, and high-risk versus low-risk of progression to severe COVID-19. Participants, investigators, and sponsor staff involved in the treatment or clinical evaluation and monitoring of the participants were masked to treatment-group assignments. The primary endpoints were severe COVID-19 or death from any cause through to day 29, and safety. This study is registered with ClinicalTrials.gov, NCT04723394.

Findings: Between Jan 28, 2021, and July 22, 2021, 1014 participants were enrolled, of whom 910 were randomly assigned to a treatment group (456 to receive tixagevimab-cilgavimab and 454 to receive placebo). The mean age of participants was 46·1 years (SD 15·2). Severe COVID-19 or death occurred in 18 (4%) of 407 participants in the tixagevimab-cilgavimab group versus 37 (9%) of 415 participants in the placebo group (relative risk reduction 50·5% [95% CI 14·6-71·3]; p=0·0096). The absolute risk reduction was 4·5% (95% CI 1·1-8·0; p<0·0001). Adverse events occurred in 132 (29%) of 452 participants in the tixagevimab-cilgavimab group and 163 (36%) of 451 participants in the placebo group, and were mostly of mild or moderate severity. There were three COVID-19-reported deaths in the tixagevimab-cilgavimab group and six in the placebo group.

Interpretation: A single intramuscular tixagevimab-cilgavimab dose provided statistically and clinically significant protection against progression to severe COVID-19 or death versus placebo in unvaccinated individuals and safety was favourable. Treating mild to moderate COVID-19 earlier in the disease course with tixagevimab-cilgavimab might lead to more favourable outcomes.

Funding: AstraZeneca.

Figure 1

Trial profile *Informed consent received. †This differs from the initial number of deaths shown in table 3 because one death occurred after the data cutoff, but the adverse event began before the data cutoff, thus the outcome was recorded. This death is excluded from the figure because the record itself is after the data cutoff. ‡Participants excluded from the primary analysis modified full analysis set comprised those hospitalised at baseline for isolation purposes (in Japan and Russia) or those randomly assigned after 7 days of symptom onset.

Figure 2

Analysis of the composite primary endpoint of severe COVID-19 or death from any cause up to day 29 after receiving study drug (A) Kaplan-Meier plot of time to severe COVID-19 or death from any cause through to day 29 in the modified full analysis set. p value is based on log-rank test stratified by time from symptom onset (≤5 days vs >5 days), when applicable, and risk of progression to severe COVID-19 (high risk vs low risk). Total number of patients censored: tixagevimab–cilgavimab group n=389, placebo group n=378. (B) Forest plot of RR reduction estimates for severe COVID-19 or death from any cause through to day 29 by time from symptom onset at random assignment. Day 1 symptom count started from the first day of symptoms. RR reductions represent the percentage reduction in incidence of severe COVID-19 or death from any cause in the tixagevimab–cilgavimab group relative to placebo. A RR reduction >0 represents favourable efficacy in the tixagevimab–cilgavimab group. (C) Forest plot of RR reduction estimates for severe COVID-19 or death from any cause through to day 29 by participant subgroup in the modified full analysis set. Arrows denote 95% CI bounds that are lower than the scale shown. Results in panel C were from a Cochran-Mantel-Haenszel test with stratification factors used in the primary analysis. For the subgroups of age, risk of progression was not a stratification factor. If there was no stratification factor, a χ² test was used. HR=hazard ratio. NE=not evaluable. RR=relative risk.

Figure 2

Analysis of the composite primary endpoint of severe COVID-19 or death from any cause up to day 29 after receiving study drug (A) Kaplan-Meier plot of time to severe COVID-19 or death from any cause through to day 29 in the modified full analysis set. p value is based on log-rank test stratified by time from symptom onset (≤5 days vs >5 days), when applicable, and risk of progression to severe COVID-19 (high risk vs low risk). Total number of patients censored: tixagevimab–cilgavimab group n=389, placebo group n=378. (B) Forest plot of RR reduction estimates for severe COVID-19 or death from any cause through to day 29 by time from symptom onset at random assignment. Day 1 symptom count started from the first day of symptoms. RR reductions represent the percentage reduction in incidence of severe COVID-19 or death from any cause in the tixagevimab–cilgavimab group relative to placebo. A RR reduction >0 represents favourable efficacy in the tixagevimab–cilgavimab group. (C) Forest plot of RR reduction estimates for severe COVID-19 or death from any cause through to day 29 by participant subgroup in the modified full analysis set. Arrows denote 95% CI bounds that are lower than the scale shown. Results in panel C were from a Cochran-Mantel-Haenszel test with stratification factors used in the primary analysis. For the subgroups of age, risk of progression was not a stratification factor. If there was no stratification factor, a χ² test was used. HR=hazard ratio. NE=not evaluable. RR=relative risk.