Intramuscular AZD7442 (Tixagevimab-Cilgavimab) for Prevention of Covid-19

Design

Multicenter, double-blind, parallel-group, randomized, placebo-controlled, phase 3 trial

N= 5,197

Objective

To assess the safety and efficacy of a single dose of AZD7442 (Evusheld^®; tixagevimab-cilgavimab) for preexposure prophylaxis against Covid-19 in adults who had an increased risk of an inadequate response to Covid-19 vaccination, an increased risk of exposure to SARS-CoV-2, or both

Study Groups

Tixagevimab-cilgavimab (n= 3,460)

Placebo (n= 1,737)

Inclusion Criteria

Age ≥ 18 years, increased risk for inadequate response to Covid-19 vaccination or exposure to SARS-CoV-2, negative SARS-CoV-2 serological test result at screening

Exclusion Criteria

History of SARS-CoV-2 infection, a positive SARS-CoV-2 result at screening, previous receipt of a vaccine or biologic agent indicated for the prevention of SARS-CoV-2 infection or Covid-19, or an allergy to any component in treatment or placebo

Methods

Participants were randomized 2:1 to receive a 300 mg dose of tixagevimab-cilgavimab (one 1.5-mL intramuscular injection of each antibody administered consecutively) or saline placebo (two 1.5-mL intramuscular injections administered consecutively) on day 1. Patients were monitored for adverse events for 1-4 hours after the injections, after which they were followed up weekly to monitor for Covid-19 symptoms.  

Participants considered to be at increased risk for an inadequate response to Covid-19 vaccination were ≥ 60 years old, obese, immunocompromised, or unable to receive vaccines without adverse effects or as having congestive heart failure, chronic obstructive pulmonary disease, chronic kidney disease, or chronic liver disease.

Participants at increased risk for exposure to SARS-CoV-2 included health care workers (including staff working in long-term care facilities), workers in industrial settings such as meatpacking plants, military personnel, students living in dormitories, and individuals living together in close or high-density proximity.

Duration

Randomization: November 21, 2020 to March 22, 2021

Safety and assessment period: 366 days + 91 day additional safety assessment period

Outcome Measures

Safety: incidence of adverse events

Efficacy: first episode of symptomatic Covid-19, confirmed with reverse-transcriptase–polymerase-chain-reaction (RT-PCR) testing

Baseline Characteristics

Tixagevimab-cilgavimab (n= 3,460)

Placebo (n= 1,737)

Age, years

≥ 60

≥ 65

≥ 75

53.6 ± 15.0

43.4%

23.6%

4.3%

53.3 ± 14.9

43.6%

23.5%

4.0%

Female

Race

White

Black

Asian

73.6%

17.3%

3.2% 

71.9%

17.4%

3.5%

Obesity (bod-mass index ≥ 30 kg/m²)

42.1%

41%

Baseline comorbidities

Hypertension

Smoking

Diabetes

Cardiovascular disease

35.5%

20.8%

14.2%

7.9%

36.7%

21.3%

13.9%

8.7%

Results

Endpoint

Tixagevimab-cilgavimab (n= 3,460)

Placebo (n= 1,737)

Adverse events

Mild

Moderate

Severe

761 (22.0%)

387 (11.2%)

64 (1.8%)

369 (21.3%)

191 (11.0%)

27 (1.6%)

Serious adverse events

Cardiac disorders*

Any serious adverse event

Related to treatment

Leading to trial discontinuation

Medically attended

23 (0.7%) 

50 (1.4%)

1 (< 0.1%)

1 (< 0.1%)

360 (10.4%)

5 (0.3%)

23 (1.3%)

0

0

157 (9.0%)

Adverse events of special interest

Injection-site reaction

Anaphylaxis

Immune complex disease

Other

Related to treatment

93 (2.7%)

82 (2.4%)

1 (< 0.1%)

1 (< 0.1%)

9 (0.3%)

87 (2.5%) 

37 (2.1%)

36 (2.1%)

0

0

2 (0.1%)

36 (2.1%)

Adverse events leading to death

All adverse events

Illicit-drug overdose

Myocardial infarction

Renal failure

Covid-19

Covid-19 related ARDS

4 (0.1%)

2 (0.1%)

1 (< 0.1%)

1 (< 0.1%)

0

0 

4 (0.2%)

2 (0.1%)

0

0

1 (0.1%)

1 (0.1%)

RRR (95% CI)

First episode of symptomatic Covid-19

Primary analysis

Median 6-month follow-up

8 (0.2%)

11 (0.3%) 

17 (1.0%)

31 (1.8%)

76.7% (46.0–90.0); p< 0.001

82.8% (65.8–91.4); p-value N/A

*Includes acute left ventricular failure, angina pectoris, arrhythmia, arteriosclerosis coronary artery, atrial fibrillation, cardiac failure, cardiomegaly, cardiomyopathy, cardio-respiratory arrest, congestive cardiac failure, coronary artery disease, myocardial infarction, and paroxysmal atrioventricular block.

ARDS, acute respiratory distress syndrome; RRR, relative risk reduction; CI, confidence interval

Adverse Events

Study Author Conclusions

A single dose of tixagevimab-cilgavimab had efficacy for the prevention of Covid-19, without evident safety concerns.

InpharmD Researcher Critique

While incidences of serious cardiovascular events were reported in study participants, a statistical comparison of rates with tixagevimab-cilgavimab versus placebo was not provided. Additionally, one patient in the tixagevimab-cilgavimab group died due to a myocardial infarction, however, this event was not considered to be related to tixagevimab-cilgavimab treatment. This trial is currently ongoing. 

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

Design

Ongoing, phase 3, randomized, double-blind, placebo-controlled study

N= 903

Objective

Study Groups

Tixagevimab-cilgavimab (n= 452)

Placebo (n= 451)

Inclusion Criteria

Exclusion Criteria

Did not receive study drug 7 days or less from self-reported onset of mild to moderate COVID-19 symptoms or measured fever, participating in another COVID-19 clinical trial, history of hospitalization or currently hospitalized for COVID-19, current need for hospitalization or immediate medical attention

Patients that were required to be isolated in certain countries (e.g., Japan and Russia) were excluded from the primary analysis, but not subsequent analyses. 

Methods

Patients were randomized (1:1) to receive either tixagevimab-cilgavimab as two consecutive 3 mL intramuscular (IM) injections consisting of 300 mg tixagevimab and 300 mg cilgavimab or matching placebo containing 0.9% NaCl. Patients were monitored up to 456 days after treatment which presents a safety assessment of over 5 half-lives of the study drug. Complete physical examinations were performed on day 366 and adverse events were reported by patients. 

The table will focus on reporting the safety outcomes of cardiovascular adverse events

Duration

Efficacy endpoints up to 29 days

Safety endpoints up to 456 days

Outcome Measures

Cardiovascular outcomes

Baseline Characteristics

Tixagevimab-cilgavimab (n= 452)

Placebo (n= 451)

Age, years

Female

White

Body mass index, kg/m²

Time from symptom onset, days

One or more risk factors for severe COVID-19

Cardiovascular disease

89%

9%

89%

8%

Results

Endpoint

Tixagevimab-cilgavimab (n= 452)

Placebo (n= 451)

Total deaths

Acute myocardial infarction or acute left ventricular failure

Sudden cardiac death

6 (1%)

1 (<1%)

1 (<1%)

6 (1%)

0

0

Study Author Conclusions

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 favorable. Treating mild to moderate COVID-19 earlier in the disease course with tixagevimab–cilgavimab might lead to more favorable outcomes.

InpharmD Researcher Critique