Phase III Study of AZD7442 for Treatment of COVID-19 in Outpatient Adults

Conditions

COVID-19

Keywords

Treatment of COVID-19

Brief summary

This Phase III study will assess whether AZD7442 (a combination of 2 mAbs) can safely treat outpatient adults with COVID-19 and prevent either severe COVID-19 or death.

Detailed description

A novel coronavirus, SARS-CoV-2, first emerged in China in November 2019 causing cases of atypical pneumonia. As of 6 October 2020, the virus has spread to all corners of the globe, with over 35 million confirmed cases reported and more than one million associated deaths according to the WHO. The COVID-19 pandemic is causing major disruption to global healthcare systems with significant socioeconomic impacts. Effective interventions to prevent or treat COVID-19 remain few in number and clinical experience is limited. There is an urgent need to rapidly evaluate treatments in the non-hospitalized setting to prevent progression and reduce serious complications of COVID-19, as well as its transmission. As a response to the ongoing pandemic, AstraZeneca is developing mAbs to the SARS-CoV-2 spike protein. The SARS-CoV-2 spike protein contains the virus's RBD, which enables the virus to bind to receptors on human cells. By targeting this region of the virus's spike protein, antibodies can block the virus's attachment to human cells, and, therefore, is expected to block infection. Amino acid substitutions have been introduced into the antibodies to both extend their half-lives, which should prolong their potential prophylactic benefit, and decrease Fc effector function in order to decrease the potential risk of antibody-dependent enhancement of disease. AZD7442, a combination of 2 of these mAbs (AZD8895 and AZD1061), is being evaluated for administration to treat or prevent COVID-19. There are currently one ongoing Phase I study and two ongoing Phase III studies with AZD7442, in addition to this treatment study. Enrollment of up to approximately 1700 participants is planned.

Hobbs FDR, Montgomery H, Padilla F, Simón-Campos JA, Arbetter D, Seegobin S, Kiazand A, Streicher K, Martinez-Alier N, Cohen TS, Esser MT.

2024-02-253 citations

10.1007/s40121-024-00931-4

Serum AZD7442 (tixagevimab–cilgavimab) concentrations and <i>in vitro</i><scp>IC<sub>50</sub></scp> values predict SARS‐CoV‐2 neutralising antibody titres

Lindsay E. Clegg, Oleg Stepanov, Samuel A. Matthews, Tom White, Seth Seegobin et al. (12 authors)

Clinical & Translational Immunology2024-01-014 citations

10.1002/cti2.1517

529. Safety of AZD7442 (Tixagevimab/Cilgavimab) for Treatment of Mild-to-Moderate COVID-19: 15-Month Final Analysis of the TACKLE Phase 3 Study

Richard Hobbs, Hugh Montgomery, Francisco Padilla, Jesus Abraham Simón Campos, Douglas Arbetter et al. (11 authors)

Open Forum Infectious Diseases2023-11-27

10.1093/ofid/ofad500.598

Analysis of SARS-CoV-2 Emergent Variants Following AZD7442 (Tixagevimab/Cilgavimab) for Early Outpatient Treatment of COVID-19 (TACKLE Trial).

Kijak GH, Ahani B, Arbetter D, Chuecos F, Gopalakrishnan V, Beloor J, Brady T, Nguyen A, Roe TL, Schuko N, Zhang T, Hobbs FDR, Padilla F, Kelly EJ, Montgomery H, Streicher K.

2023-11-022 citations

10.1007/s40121-023-00882-2

Outpatient Treatment with AZD7442 (Tixagevimab/Cilgavimab) Prevented COVID-19 Hospitalizations over 6 Months and Reduced Symptom Progression in the TACKLE Randomized Trial.

Hobbs FDR, Montgomery H, Padilla F, Simón-Campos JA, Kim K, Arbetter D, Padilla KW, Reddy VP, Seegobin S, Streicher K, Templeton A, Viani RM, Johnsson E, Koh GCKW, Esser MT.

2023-09-266 citations

10.1007/s40121-023-00861-7

1924. Outpatient Treatment With the SARS-CoV-2–Neutralizing Antibody Combination AZD7442 (Tixagevimab/Cilgavimab) for Preventing COVID-19 Hospitalizations in the Phase 3 TACKLE Trial

Richard Hobbs, Hugh Montgomery, Francisco Padilla, Kenneth Kim, Jesus Abraham Simón Campos et al. (13 authors)

Open Forum Infectious Diseases2022-12-01

10.1093/ofid/ofac492.1551

1160. Treatment-Emergent Viral Variants in the Phase 3 TACKLE Trial Investigating Efficacy and Safety of AZD7442 (Tixagevimab/Cilgavimab) for the Treatment of Mild to Moderate COVID-19 in Adults

Gustavo H. Kijak, Bahar Ahani, Douglas Arbetter, Tyler Brady, Fernando Chuecos et al. (13 authors)

Open Forum Infectious Diseases2022-12-01

10.1093/ofid/ofac492.997

1918. Impact of the SARS-CoV-2–Neutralizing Antibody Combination AZD7442 (Tixagevimab/Cilgavimab) on the Severity and Progression of COVID-19 Symptoms in the Phase 3 TACKLE Trial

Jesus Abraham Simón Campos, Douglas Arbetter, Hugh Montgomery, Richard Hobbs, Francisco Padilla et al. (10 authors)

Open Forum Infectious Diseases2022-12-01

10.1093/ofid/ofac492.1545

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.

Montgomery H, Hobbs FDR, Padilla F, Arbetter D, Templeton A, Seegobin S, Kim K, Campos JAS, Arends RH, Brodek BH, Brooks D, Garbes P, Jimenez J, Koh GCKW, Padilla KW, Streicher K, Viani RM, Alagappan V, Pangalos MN, Esser MT, TACKLE study group.

2022-06-07173 citations

10.1016/s2213-2600(22)00180-1

The SARS-CoV-2 monoclonal antibody combination, AZD7442, is protective in nonhuman primates and has an extended half-life in humans

Yueh–Ming Loo, Patrick M. McTamney, Rosalinda H. Arends, Michael E. Abram, Anastasia A. Aksyuk et al. (31 authors)

Science Translational Medicine2022-01-25208 citations

10.1126/scitranslmed.abl8124

Interventions

DRUGAZD7442

Single dose (× 2 separate IM injections) of 600 mg of AZD7442 or saline placebo on Day 1.

DRUGPlacebo

Single dose (× 2 separate IM injections) of 600 mg of AZD7442 or saline placebo on Day 1.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

1. Participant has a documented laboratory-confirmed SARS-CoV-2 infection, as determined by a molecular test (antigen or nucleic acid) from any respiratory tract specimen (eg, oropharyngeal, NP, or nasal swab, or saliva) collected ≤ 3 days prior to Day 1. 2. WHO Clinical Progression Scale score \> 1 and \< 4. 3. Participant must be dosed with IMP no more than 7 days from self-reported onset of COVID-19-related symptoms (mild to moderate COVID-19) or measured fever, defined as the self-reported date of first reported sign/symptom. 4. One or more of the following signs/symptoms must be present within 24 hours prior to Day1: Cough, Sore throat, Shortness of breath or difficulty breathing at rest or with activity, Body pain or muscle pain/aches, Fatigue, Headache, Chills, Nasal obstruction or congestion, Nasal discharge, Nausea or vomiting, Diarrhea, New loss of taste or smell. 5. Oxygenation saturation of ≥ 92% obtained at rest by study staff within 24 hours prior to Day 1 (unless participant regularly receives chronic supplementary oxygen for an underlying lung condition). 6. Participant agrees not to participate in another clinical trial for the treatment of COVID-19 or SARS-CoV-2 during the study period until reaching hospitalization or 28 days after entry into the study (whichever is earliest). 7. Participant must be ≥ 18 years of age, provide informed consent and is able to comply with study requirements/procedures. 8. Male participants: Contraception for male participants is not required; however, to avoid the transfer of any fluids, all male participants must use a condom from Day 1 and agree to continue through 90 days following administration of IMP. 9. Women of childbearing potential must use one highly effective form of birth control.

Exclusion criteria

1. History or current hospitalization for COVID-19. 2. Current need for hospitalization/immediate medical attention in a clinic/emergency room service 3. Previous hypersensitivity, infusion related reaction, or adverse reaction to any monoclonal antibodies or known allergy to components of the IMP or placebo. 4. Receipt of any investigational or licensed vaccine for prevention of COVID-19 at any time prior to entry into this study or expected administration immediately after enrollment. 5. Current requirement or anticipated impending need for mechanical ventilation. 6. Any significant disease, disorder or finding that may increase risk to the participant that might affect his/her ability to participate in this study. 7. Received convalescent COVID-19 plasma treatment any time prior to entry into this study. 8. Receipt of systemic steroids (e.g., prednisone, dexamethasone) or inhaled steroids within 30 days prior to study entry, unless a stable dose is used for a chronic condition. 9. Receipt of any IMP in the previous 90 days or 5 half lives (whichever is longer), or expected receipt of IMP during the study follow-up period, or concurrent participation in another interventional study. 10. Pregnant or breastfeeding women.

Design outcomes

Primary

Measure	Time frame	Description
A Composite of Either Severe COVID-19 or Death From Any Cause Through Day 29	Baseline (Day 1) and Day 29	Severe COVID-19 is characterized by a minimum of either pneumonia (fever, cough, tachypnea, or dyspnea, and lung infiltrates) or hypoxemia (SpO2 \< 90% in room air and/or severe respiratory distress) and a WHO Clinical Progression Scale score of 5 or higher.

Secondary

Measure	Time frame	Description
A Composite of Death From Any Cause or Hospitalization for COVID-19 Complications or Sequelae Through Day 169	Baseline (Day 1) and Day 169	Death from Any Cause or Hospitalization for COVID-19 Complications or Sequelae through Day 169

Countries

Argentina, Brazil, Czechia, Germany, Hungary, Italy, Japan, Mexico, Peru, Poland, Russia, Spain, Ukraine, United Kingdom, United States

Participant flow

Recruitment details

910 participants were randomized to receive treatment in study D8851C00001 (TACKLE) with AZD7442 (AZD8895 + AZD1061) or placebo. Of the 910 participants randomized, 903 (99.2%) received treatment with study drug. Of the 903 dosed, 452 (50.1%) participants received AZD7442 and 451 (49.9%) participants received placebo.

Pre-assignment details

In TACKLE, at the first visit, ie, the enrollment visit 1, participants were evaluated regarding the protocol mandated inclusion and exclusion criteria. After enrolment, eligible participants were randomized at a 1: 1 ratio to receive a single dose of study provided AZD7442 (AZD8895 + AZD1061) or placebo.

Participants by arm

Arm	Count
AZD7442 Single dose of 600 mg of AZD7442 (2 separate IM injections) on Day 1	452
Placebo Single dose of Placebo (2 separate IM injections) on Day 1	451
Total	903

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	0	3
Overall Study	Death	8	8
Overall Study	Lost to Follow-up	20	17
Overall Study	Participants withdrawn due to eligibility, eligibility, moving, and being randomized in error.	0	2
Overall Study	Physician Decision	1	0
Overall Study	Withdrawal by Subject	20	34

Baseline characteristics

Characteristic	AZD7442	Total	Placebo
Age, Continuous	46.3 Years STANDARD_DEVIATION 15.42	46.0 Years	45.9 Years STANDARD_DEVIATION 14.99
BMI (kg/m^2)	28.9 kg/m^2 STANDARD_DEVIATION 5.46	29.0 kg/m^2 STANDARD_DEVIATION 6.03	29.2 kg/m^2 STANDARD_DEVIATION 6.56
Country Argentina	29 Participants	57 Participants	28 Participants
Country Brazil	7 Participants	19 Participants	12 Participants
Country Czech Republic	3 Participants	5 Participants	2 Participants
Country Germany	33 Participants	71 Participants	38 Participants
Country Hungary	2 Participants	3 Participants	1 Participants
Country Italy	37 Participants	70 Participants	33 Participants
Country Japan	26 Participants	40 Participants	14 Participants
Country Mexico	139 Participants	305 Participants	166 Participants
Country Poland	1 Participants	2 Participants	1 Participants
Country Russian Federation	55 Participants	106 Participants	51 Participants
Country Spain	31 Participants	68 Participants	37 Participants
Country Ukraine	5 Participants	15 Participants	10 Participants
Country United Kingdom	20 Participants	38 Participants	18 Participants
Country United States	64 Participants	104 Participants	40 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	100 Participants	215 Participants	115 Participants
Race/Ethnicity, Customized Asian	30 Participants	51 Participants	21 Participants
Race/Ethnicity, Customized Black or African American	16 Participants	36 Participants	20 Participants
Race/Ethnicity, Customized Hispanic or Latino	230 Participants	468 Participants	238 Participants
Race/Ethnicity, Customized Multiple	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	222 Participants	435 Participants	213 Participants
Race/Ethnicity, Customized Not reported	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Unknown	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized White	285 Participants	559 Participants	274 Participants
Risk of Progression to Severe COVID-19 High	405 Participants	811 Participants	406 Participants
Risk of Progression to Severe COVID-19 Low	47 Participants	92 Participants	45 Participants
Sex: Female, Male Female	239 Participants	455 Participants	216 Participants
Sex: Female, Male Male	213 Participants	448 Participants	235 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	8 / 452	8 / 451
other Total, other adverse events	230 / 452	224 / 451
serious Total, serious adverse events	46 / 452	65 / 451

Outcome results

Primary

A Composite of Either Severe COVID-19 or Death From Any Cause Through Day 29

Severe COVID-19 is characterized by a minimum of either pneumonia (fever, cough, tachypnea, or dyspnea, and lung infiltrates) or hypoxemia (SpO2 \< 90% in room air and/or severe respiratory distress) and a WHO Clinical Progression Scale score of 5 or higher.

Time frame: Baseline (Day 1) and Day 29

Population: Modified Full Analysis Set (mFAS) - All randomized participants who received IMP ≤ 7 days from symptom onset and were not hospitalized at baseline (≤ Day 1) for isolation purpose. For AZD7442, N = 413; Placebo, N = 421. For the analysis of the primary endpoint, only participants within this population who were assessed for the primary endpoint were included in the analysis.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
AZD7442	A Composite of Either Severe COVID-19 or Death From Any Cause Through Day 29	18 Participants
Placebo	A Composite of Either Severe COVID-19 or Death From Any Cause Through Day 29	37 Participants

Comparison: AZD7442 vs Placebop-value: 0.0195% CI: [14.38, 71.25]Cochran-Mantel-Haenszel

Secondary

A Composite of Death From Any Cause or Hospitalization for COVID-19 Complications or Sequelae Through Day 169

Death from Any Cause or Hospitalization for COVID-19 Complications or Sequelae through Day 169

Time frame: Baseline (Day 1) and Day 169

Population: Modified Full Analysis Set (mFAS) - All randomized participants who received IMP \<= 7 days from symptom onset and were not hospitalized at baseline (\<= Day 1) for isolation purpose. For AZD7442, N = 413; Placebo, N = 421. For the analysis of the Key Secondary Endpoint, only participants within this population who were assessed for the primary endpoint were included in the analysis.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
AZD7442	A Composite of Death From Any Cause or Hospitalization for COVID-19 Complications or Sequelae Through Day 169	20 Participants
Placebo	A Composite of Death From Any Cause or Hospitalization for COVID-19 Complications or Sequelae Through Day 169	40 Participants

Comparison: AZD7442 vs Placebop-value: 0.00995% CI: [14.72, 69.79]Cochran-Mantel-Haenszel

Phase III Study of AZD7442 for Treatment of COVID-19 in Outpatient Adults

Conditions

Keywords

Brief summary

Detailed description

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

A Composite of Either Severe COVID-19 or Death From Any Cause Through Day 29

A Composite of Death From Any Cause or Hospitalization for COVID-19 Complications or Sequelae Through Day 169