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Efficacy and Safety of Intramuscular Administration of Tixagevimab–Cilgavimab for Early Outpatient Treatment of COVID-19
TAKE-HOME MESSAGE
- This international, randomized, double-blind, placebo-controlled trial evaluated the safety and efficacy of tixagevimab–cilgavimab for the treatment of mild to moderate COVID-19 in non-hospitalized unvaccinated adults from January 2021 to July 2021. The primary outcome of severe COVID-19 infection or death occurred in significantly fewer individuals in the intervention cohort, with an absolute risk reduction of 4.5%. The rate of adverse events were comparable between the two study arms.
- Tixagevimab–cilgavimab is a combination of intramuscular long-acting monoclonal antibodies directed against COVID-19, currently under emergency use authorization for pre-exposure prophylaxis. The current study supports its use for the treatment of patients with active COVID-19, although additional assessment in vaccinated individuals with the Omicron variant infection is warranted.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
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.
Additional Info
Disclosure statements are available on the authors' profiles:
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
Lancet Respir Med 2022 Jun 07;[EPub Ahead of Print], H Montgomery, FDR Hobbs, F Padilla, D Arbetter, A Templeton, S Seegobin, K Kim, JAS Campos, RH Arends, BH Brodek, D Brooks, P Garbes, J Jimenez, GCKW Koh, KW Padilla, K Streicher, RM Viani, V Alagappan, MN Pangalos, MT EsserFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Monoclonal antibodies – “Rent an army” to fight COVID-19
Monoclonal antibodies are an attractive way to protect vulnerable patients. Essentially we can lend an army to our patients right at the time when they need it the most. Of course, vaccination to generate your army is still the best strategy. However, a “rent an army” would be beneficial to patients who are not vaccinated or who did not respond to vaccines.
This particular monoclonal antibody treatment is made up of two antibodies, tixagevimab and cilgavimab. These antibodies are fully human antibodies that bind onto different areas of the spike protein of SARS-CoV-2. If one site mutates, then the other antibody would still be able to attach. These antibodies have an extended half-life, and, in the PROVENT study, the combination of these antibodies when given prophylactically was able to prevent patients from getting infected for at least 6 months.
This current study, called TACKLE, was conducted to see if this combination could be used to treat patients after they are infected. The authors looked at 910 patients who tested positive for COVID-19 using the RT-PCR test, with mild to moderate COVID-19, and were not vaccinated. They stratified them based on high or low risk of progression to severe COVID-19 and also by the time from the onset of symptoms. The monoclonal antibodies were administered as two separate intramuscular injections, and those shots had to be administered within 7 days of symptom onset.
The results showed that the combination of monoclonal antibodies reduced severe COVID-19 or death by 50% (RRR, 50.5% [95% CI, 14.6–71.3]; P = ·0096). The absolute risk reduction was 4·5% (95% CI, 1.1–8.0; P < ·0001). This translates into an NNT of 22 patients to prevent one severe COVID-19 case or death.
As expected, the earlier the treatment was started, the better the outcomes. Patients who got the injections within 3 days of symptom onset had 88% protection. Interestingly, both high- and low-risk patients had benefits. The side-effect profile was very similar to that of placebo.
One caveat to point out is that this study was conducted between Jan 28, 2021, and July 22, 2021, which means that the data do not include the omicron variant. In laboratory testing, this combination has been shown to work against the omicron variant and, most recently, against the BA.4 and BA.5 versions. However, there are no clinical outcome studies yet for the omicron family of viruses.
This is a phase III study, and the regulatory agencies will still need to review it; however, two simple intramuscular injections would be very useful in our fight against COVID-19. “Rent an army” is a good option. If approved, this combination can be used to prevent infection and treat patients who are at risk of developing severe COVID-19.
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