Study Understanding Pre-Exposure pRophylaxis of NOVel Antibodies (SUPERNOVA) Sub-study: Study Understanding Pre-Exposure pRophylaxis of NOVel Antibodies (SUPERNOVA) Sub-study (SUPERNOVA)

• ClinicalTrials.gov Identifier: NCT05648110
• Recruitment Status: Recruiting
• First Posted: December 13, 2022
• Last Update Posted: September 6, 2023
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: November 30, 2022
• First Posted Date: December 13, 2022
• Last Update Posted Date: September 6, 2023
• Actual Study Start Date: December 16, 2022
• Estimated Primary Completion Date: September 7, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 29, 2023)

• Parent study - Sentinel Safety Cohort: To evaluate the safety of AZD5156 [ Time Frame: AEs will be collected from IMP administration approximately 90 days following. AESIs will be collected from IMP administration through to Visit 11 (Day 361). SAEs and MAAEs will be collected up to Visit 11 (Day 361). ]
  Occurence of AEs, SAEs, MAAEs, and AESIs will be collected throughout the study
• Parent study - Main Cohort: To evaluate the safety of AZD3152 and EVUSHELD and/or placebo [ Time Frame: Occurrence of AEs collected through approximately 90 days after each IMP administration through to Visit 10 (Day 451). SAEs and MAAEs will be collected up to Visit 10 (Day 451). ]
  Occurrence of AEs, SAEs, MAAEs, and AESIs will be collected throughout the study
• Parent study - Main cohort: To compare the efficacy of AZD3152 to EVUSHELD and/or placebo in the prevention of symptomatic COVID 19 [ Time Frame: Time from the first dose of IMP to the first occurrence of a symptomatic COVID-19 case which is defined as: • Negative RT-PCR at baseline to positive at any time up to Visit 9 (12 months) AND • Satisfying modified WHO definition of symptomatic COVID-19 ]
  Summary measure: Prophylactic efficacy, calculated as 1 - Hazard Ratio (HR) (AZD3152 vs. EVUSHELD and/or placebo) using a hazard regression model. The time-to-event outcome (i.e., SARS-CoV-2 RT-PCR-confirmed COVID-19) will be derived using the participants' COVID-19 symptom occurrence and the timing of symptom onset.
• Sub-study: To evaluate the safety of AZD3152 and EVUSHELD [ Time Frame: SAEs, MAAEs, and AESIs collected throughout the study for the final analysis. ]
  Occurrence of AEs collected through 29 days after IMP administration for the primary analysis.
• Sub-study: To compare the SARS-CoV-2 nAb responses to a current VOC following AZD3152 administration vs SARS-CoV-2 nAb responses to prior variants following EVUSHELD administration [ Time Frame: Predicted GMT ratio of SARS-CoV-2 nAbs between the treatment arms at Visit 3 (Day 29) for the variant that each IMP is intended to neutralize. ]
  SARS-CoV-2 nAb responses to a current VOC following AZD3152 administration vs SARS-CoV-2 nAb responses to prior variants following EVUSHELD administration.

Original Primary Outcome Measures (submitted: December 12, 2022)

• Part A - To evaluate the safety of AZD5156 and AZD7442 [ Time Frame: AEs will be collected through Day 29 and that SAEs and AESIs will be collected throughout the study. ]
  Occurrence of AEs collected through Day 29
• Part A - To compare the nAb responses in serum following AZD5156 and AZD7442 administration to the SARS-CoV-2 Alpha variant in serum [ Time Frame: nAb responses will be collected up to Visit 9 (Day 361). ]
  GMT ratio of SARS CoV 2 nAbs between the treatment arms at Visit 3 (Day 29). Descriptive statistics of SARS-CoV-2 nAb titers will be made by visit.
• Part B - To describe the safety of an open label dose of AZD5156 600 mg IM among participants who received AZD5156 or AZD7442 during Part A Main Cohort [ Time Frame: SAEs and AESIs will be collected up to Visit 9 (Day 361). ]
  Proportions of AEs through 29 days after second dose of study intervention given at 6 months SAEs and AESIs through last visit (Visit 9)

Current Secondary Outcome Measures (submitted: June 29, 2023)

• Parent study - Sentinel Safety Cohort: To characterize the Pharmacokinetics of AZD5156 (AZD1061 and AZD3152) in serum. [ Time Frame: Samples will be collected from Visit 1 (Day 1) up to Visit 11 (Day 361). ]
  AZD5156 (AZD1061 and AZD3152) serum concentrations at each visit.
• Parent study - Sentinel Safety Cohort: To characterize the Pharmacokinetics parameter of maximum concentration (Cmax) of AZD5156 (AZD1061 and AZD3152) in serum [ Time Frame: Samples will be collected from Visit 1 (Day 1) up to Visit 11 (Day 361) ]
  To describe maximum concentration (Cmax) for AZD5156 (AZD1061 and AZD3152).
• Parent study - Sentinel Safety Cohort: To characterize the Pharmacokinetics parameter of time to maximum serum concentration (tmax) of AZD5156 (AZD1061 and AZD3152) in serum [ Time Frame: Samples will be collected from Visit 1 (Day 1) up to Visit 11 (Day 361). ]
  To describe time to maximum serum concentration (tmax) for AZD5156 (AZD1061 and AZD3152).
• Parent study - Sentinel Safety Cohort: To characterize the Pharmacokinetics parameter of terminal half-life (t½) of AZD5156 (AZD1061 and AZD3152) in serum [ Time Frame: Samples will be collected from Visit 1 (Day 1) up to Visit 11 (Day 361). ]
  To describe terminal half-life (t½) for AZD5156 (AZD1061 and AZD3152).
• Parent study - Sentinel Safety Cohort: To characterize the Pharmacokinetics parameter of area under the concentration-time curve at the last measured time point (AUClast) of AZD5156 (AZD1061 and AZD3152) in serum [ Time Frame: Samples will be collected from Visit 1 (Day 1) up to Visit 11 (Day 361). ]
  To describe area under the concentration-time curve at the last measured time point (AUClast) for AZD5156 (AZD1061 and AZD3152).
• Parent study - Sentinel Safety Cohort: To characterize the Pharmacokinetics parameter of area under the concentration-time curve from time zero extrapolated to infinity (AUCinf) of AZD5156 (AZD1061 and AZD3152) in serum [ Time Frame: Samples will be collected from visit 1 (Day 1) up to visit 11 (Day 361). ]
  To describe area under the concentration-time curve from time zero extrapolated to infinity (AUCinf) for AZD5156 (AZD1061 and AZD3152).
• Parent study - Sentinel Safety Cohort: To evaluate the ADA responses to AZD5156, AZD3152, and AZD1061 in serum [ Time Frame: Samples will be collected from Visit 1 (Day 1) up to Visit 11 (Day 361) ]
  Incidence of ADA to AZD5156, AZD3152, and AZD1061, ADA titers
• Parent study - Main Cohort: To compare the nAb responses to the SARS-CoV-2 variants Alpha, Omicron BA.2, Omicron BA.4/5 and/or Omicron XBB.1.5 in serum following AZD3152 and EVUSHELD and/or placebo administration [ Time Frame: Visit 3 (Day 29) ]
  GMT and GMFR ratio of SARS-CoV-2 nAbs between the treatment arms at Visit 3 (Day 29). Descriptive statistics for GMTs and GMFRs will be provided.
• Parent study - Main Cohort: To describe the incidence of symptomatic COVID-19, severe COVID-19, COVID-19 related hospitalization, and COVID-19 related death in participants receiving study intervention [ Time Frame: COVID-19 incidence variables to be evaluated through Visit 9 (Day 361) ]
  Incidence post treatment:

  • Symptomatic COVID-19 case (negative RT-PCR at baseline to positive at any time up to 6 and 12 months)
  • Severe COVID-19
  • Composite of COVID-19 related hospitalization and/or COVID-19 related death (WHO COVID-19 Clinical Progression Scale score ≥ 4)
  • COVID-19 related hospitalization (separately)
  • COVID-19 related death (separately)
• Parent study - Main Cohort: To characterize the Pharmacokinetics (PK)of the AZD3152 and AZD7442 (AZD1061 and AZD8865) in serum concentrations at each visit. [ Time Frame: Samples will be collected from Visit 1 (Day 1) up to Visit 9 (Day 361) ]
  AZD3152 and AZD7442 (AZD1061 and AZD8895) serum concentrations at each visit.
• Parent study - Main Cohort: To evaluate the Anti-drug Antibodies (ADA) responses to AZD3152 and AZD7442 in serum [ Time Frame: Samples will be collected from Visit 1 (Day 1) up to Visit 9 (Day 361) ]
  Incidence of Anti-drug Antibodies (ADA) to AZD3152, AZD7442, AZD1061, and AZD8895, ADA titers
• Sub-study: To characterize the Pharmacokinetics of AZD3152 and AZD7442 (EVUSHELD) in serum [ Time Frame: Samples will be collected from Visit 1 (Day 1) up to Visit 5 (Day 181). ]
  AZD3152, AZD7442 (EVUSHELD), cilgavimab, and tixagevimab concentrations in serum, over time
• Sub-study:To evaluate the ADA response to AZD3152 and AZD7442 (EVUSHELD) in serum [ Time Frame: Samples will be collected from Visit 1 (Day 1) up to Visit 5 (Day 181). ]
  Incidence of ADA to AZD3152, AZD7442 (EVUSHELD), cilgavimab, and tixagevimab; ADA titers

Original Secondary Outcome Measures (submitted: December 12, 2022)

• Part A - To compare the nAb responses in serum following AZD5156 and AZD7442 admin to the SARS-CoV-2 Omicron variant BA.4/5 and the emerging dominant variant of concern circulating during the course of the study in serum following AZD5156 & AZD7442 admin [ Time Frame: Visit 3 (Day 29) ]
  GMT and GMFR ratio of SARS-CoV-2 nAbs between the treatment arms at Visit 3 (Day 29). Descriptive statistics for GMTs and GMFRs will include the number of participants, geometric mean, GSD, 95% CI, minimum, and maximum and summarized by treatment arm and visit
• Part A - To describe the efficacy of a single dose of AZD5156 and AZD7442 for the prevention of COVID-19, severe COVID-19, COVID-19 related hospitalization, and COVID-19 related death [ Time Frame: Covid-19 Efficacy variables to be evaluated through Day 181 in Part A Main cohort and Day 361 (sentinel and Part B). ]
  Incidence of a post treatment:

  • Symptomatic COVID 19 case
  • COVID-19 case (negative RT PCR at baseline to positive at any time up to 6 and 12 months)
  • Severe COVID-19
  • Composite of COVID-19 related hospitalization and/or COVID-19 related death (WHO COVID 19 Clinical Progression Scale score ≥ 4)
  • COVID-19 related hospitalization (separately)
  • COVID 19 related death (separately)
• Part A - To characterize the PK of AZD5156 and AZD7442 in serum [ Time Frame: PK will be collected up to Visit 9 (Day 361). ]
  In the Sentinel Safety Cohort: AZD5156 concentrations over time and PK parameters (eg, Cmax, tmax, t½, AUClast, and AUCinf) In the Main Cohort: AZD5156 and AZD7442 concentrations over time
• Part A - To evaluate the ADA responses to AZD5156 and AZD7442 in serum [ Time Frame: ADA will be collected up to Visit 9 (Day 361). ]
  Incidence of ADA
• Part B - To describe the safety of an open label dose of AZD5156 IM among participants who received AZD5156 or AZD7442 during Part A Main Cohort [ Time Frame: SAEs and AESIs will be collected up to Visit 9 (Day 361). ]
  Proportions of AEs through 29 days after second dose of study intervention given at 6 months SAEs and AESIs through last visit (Visit 9)
• Part B - Serum AZD5156, AZD1061, and AZD3152 concentrations [ Time Frame: Serum samples will be collected up to Visit 9 (Day 361). ]
  To characterize the PK of an open label dose of AZD5156 IM among participants who received AZD5156 during Part A Main Cohort
• Part B - Serum AZD1061, AZD3152, and AZD8895 concentrations [ Time Frame: Serum samples will be collected up to Visit 9 (Day 361). ]
  To characterize the PK of AZD1061, AZD3152, and AZD8895 during Part B among participants who received AZD7442 during Part A Main Cohort
• Part B - Incidence of ADA following a dose of AZD5156 given at 6 months [ Time Frame: ADA will be collected up to Visit 9 (Day 361). ]
  To describe ADA responses to an open-label dose of AZD5156 IM among participants who received AZD5156 or AZD7442 during Part A Main Cohort
• Part B - Post treatment GMTs and GMFRs from Visit 5 [ Time Frame: GMTs and GMFRs will be collected up to Visit 9 (Day 361) ]
  To evaluate SARS-CoV-2 nAb levels in serum following an open-label dose of AZD5156 IM among participants who received AZD5156 or AZD7442 during Part A Main Cohort

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study Understanding Pre-Exposure pRophylaxis of NOVel Antibodies (SUPERNOVA) Sub-study: Study Understanding Pre-Exposure pRophylaxis of NOVel Antibodies (SUPERNOVA) Sub-study
• Official Title: A Phase I/III Randomized, Double Blind Study to Evaluate the Safety, Efficacy and Neutralizing Activity of AZD5156/AZD3152 for Pre Exposure Prophylaxis of COVID 19 in Participants With Conditions Causing Immune Impairment. Sub-study: Phase II Open Label Sub-study to Evaluate the Safety, PK, and Neutralizing Activity of AZD3152 for Pre-exposure Prophylaxis of COVID-19

Brief Summary

AZD3152, a single mAb, is being developed to have broad neutralizing activity across known SARS-CoV-2 variants of concern for pre-exposure prophylaxis of COVID-19.

The aim of the Phase I/III study (Parent Study) will be to evaluate the safety, efficacy and neutralizing activity of AZD3152 compared with comparator for pre exposure prophylaxis of COVID-19, and separately evaluate the safety and PK of AZD5156, a combination of AZD3152 and AZD1061.

Sub-study:

This Phase II sub-study of SUPERNOVA will assess the safety, PK, and predicted neutralizing activity of AZD3152 compared with EVUSHELD for pre-exposure prophylaxis of COVID-19.

Detailed Description

In the Parent study, the Phase I Sentinel Safety Cohort will assess the safety of AZD5156 (a combination of 2 mAbs, AZD1061 [cilgavimab, a component of AZD7442 (EVUSHELD)] and AZD3152) in healthy adults and the Phase III Main Cohort will assess the safety, efficacy, PK, and neutralizing activity of two doses of AZD3152 compared with two doses of comparator given at a 6-month interval in adults and adolescents 12 years of age or older (weighing at least 40 kg) with conditions causing immune impairment, who are less likely to mount an adequate protective immune response after vaccination and thus are at higher risk of developing severe COVID-19 in approximately 20 countries..

Sub-study:

This Phase II sub-study of SUPERNOVA is operating in USA only, and it will assess the safety, PK, and predicted neutralizing activity of AZD3152 in adults 18 years of age or older (weighing at least 40 kg) with conditions causing immune impairment who are less likely to mount an adequate protective immune response after vaccination as well as individuals who are immunocompetent (including healthy participants) with all degrees of SARS-CoV-2 infection risk.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

D7000C00001 is a Phase I/III study (Parent study) being conducted in conjunction with a Phase II sub study that will be conducted in approximately 3706 participants (approximately 3256 in the Parent study and 450 in the sub study) to evaluate the safety, efficacy, PK, and neutralizing activity of AZD3152 compared with comparator for pre exposure prophylaxis of COVID-19, and separately evaluate the safety and PK of AZD5156, a combination of AZD3152 and AZD1061.

The Parent study will consist of 2 cohorts: a Sentinel Safety Cohort and a Main Cohort. The Sentinel Safety Cohort will compare AZD5156 with placebo, while the Main Cohort will compare AZD3152 with placebo.

The sub-study will have an initial Sentinel Safety Cohort that will include 12 healthy volunteers; all other participants in the study will be either immunocompromised or immunocompetent with all degrees of SARS-CoV-2 infection risk. Participants will be randomized 2:1 to receive AZD3152 or AZD7442 (EVUSHELD).

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention

• Condition: COVID-19, SARS-CoV-2

Intervention

• Biological: AZD5156 (Parent study Sentinel Safety Cohort)
  600 mg single dose of AZD5156 IM (300 mg of AZD1061 and 300 mg of AZD3152) on Visit 1 Day 1
• Biological: Placebo (Parent study Sentinel Safety Cohort)
  single dose of Placebo IM
• Biological: EVUSHELD™ (Parent study Main Cohort)
  600 mg single doses of EVUSHELD™ IM on Visit 1 Day 1 and on Visit 5 Day 181
  Other Name: EVUSHELD™
• Biological: AZD3152 (Parent study Main Cohort)
  300 mg single doses of AZD3152 IM on Visit 1 Day 1 and on Visit 5 Day 181
• Biological: Placebo (Parent study Main Cohort)
  Single doses of 0.9% sodium chloride IM for injection on Visit 1 Day 1 and Visit 5 Day 181
• Biological: AZD3152 (Sub-study)
  Single dose of 1200 mg IV at Visit 1 Day 1
• Biological: AZD7442 - EVUSHELD™ (Sub-study)
  Single dose 300 mg IM administered on Visit 1 Day 1
• Biological: AZD7442 (EVUSHELD™) (Sub-study) Immunocompromised participants offered AZD3152
  Single dose of AZD7442 (EVUSHELD™) 300 mg IM

Study Arms

• Experimental: Parent study Sentinel Safety Cohort - Subcohort 1a Gluteal - AZD5156
  The Sentinel Safety Cohort of the Parent Study will enroll 56 healthy adults, 18 to 55 years of age, who will be randomized to receive AZD5156 (40 participants) or placebo (16 participants). Participants will be randomized to receive study intervention IM either in the gluteal or the anterolateral thigh. Dosing within the Sentinel Safety Cohort will be staggered, with participants allocated sequentially to 4 subcohorts (1a, 1b, 2a, and 2b).
  Intervention: Biological: AZD5156 (Parent study Sentinel Safety Cohort)
• Placebo Comparator: Parent study Sentinel Safety Cohort - Subcohort 1a Gluteal - Placebo
  The Sentinel Safety Cohort of the Parent study will enroll 56 healthy adults, 18 to 55 years of age, who will be randomized to receive AZD5156 (40 participants) or placebo (16 participants). Participants will be randomized to receive study intervention IM either in the gluteal or the anterolateral thigh. Dosing within the Sentinel Safety Cohort will be staggered, with participants allocated sequentially to 4 subcohorts (1a, 1b, 2a, and 2b).
  Intervention: Biological: Placebo (Parent study Sentinel Safety Cohort)
• Experimental: Parent study Sentinel Safety Cohort - Subcohort 1b Thigh - AZD5156
  The Sentinel Safety Cohort of the Parent study will enroll 56 healthy adults, 18 to 55 years of age, who will be randomized to receive AZD5156 (40 participants) or placebo (16 participants). Participants will be randomized to receive study intervention IM either in the gluteal or the anterolateral thigh. Dosing within the Sentinel Safety Cohort will be staggered, with participants allocated sequentially to 4 subcohorts (1a, 1b, 2a, and 2b).
  Intervention: Biological: AZD5156 (Parent study Sentinel Safety Cohort)
• Placebo Comparator: Parent study Sentinel Safety Cohort - Subcohort 1b Thigh - Placebo
  The Sentinel Safety Cohort of the Parent study will enroll 56 healthy adults, 18 to 55 years of age, who will be randomized to receive AZD5156 (40 participants) or placebo (16 participants). Participants will be randomized to receive study intervention IM either in the gluteal or the anterolateral thigh. Dosing within the Sentinel Safety Cohort will be staggered, with participants allocated sequentially to 4 subcohorts (1a, 1b, 2a, and 2b).
  Intervention: Biological: Placebo (Parent study Sentinel Safety Cohort)
• Experimental: Parent study Sentinel Safety Cohort - Subcohort 2a Gluteal- AZD5156
  The Sentinel Safety Cohort of the Parent study will enroll 56 healthy adults, 18 to 55 years of age, who will be randomized to receive AZD5156 (40 participants) or placebo (16 participants). Participants will be randomized to receive study intervention IM either in the gluteal or the anterolateral thigh. Dosing within the Sentinel Safety Cohort will be staggered, with participants allocated sequentially to 4 subcohorts (1a, 1b, 2a, and 2b).
  Intervention: Biological: AZD5156 (Parent study Sentinel Safety Cohort)
• Placebo Comparator: Parent study Sentinel Safety Cohort - Subcohort 2a Gluteal - Placebo
  The Sentinel Safety Cohort of the Parent study will enroll 56 healthy adults, 18 to 55 years of age, who will be randomized to receive AZD5156 (40 participants) or placebo (16 participants). Participants will be randomized to receive study intervention IM either in the gluteal or the anterolateral thigh. Dosing within the Sentinel Safety Cohort will be staggered, with participants allocated sequentially to 4 subcohorts (1a, 1b, 2a, and 2b).
  Intervention: Biological: Placebo (Parent study Sentinel Safety Cohort)
• Experimental: Parent study Sentinel Safety Cohort - Subcohort 2b Thigh - AZD5156
  The Sentinel Safety Cohort of the Parent study will enroll 56 healthy adults, 18 to 55 years of age, who will be randomized to receive AZD5156 (40 participants) or placebo (16 participants). Participants will be randomized to receive study intervention IM either in the gluteal or the anterolateral thigh. Dosing within the Sentinel Safety Cohort will be staggered, with participants allocated sequentially to 4 subcohorts (1a, 1b, 2a, and 2b).
  Intervention: Biological: AZD5156 (Parent study Sentinel Safety Cohort)
• Placebo Comparator: Parent study Sentinel Safety Cohort - Subcohort 2b Thigh - Placebo
  The Sentinel Safety Cohort of the Parent study will enroll 56 healthy adults, 18 to 55 years of age, who will be randomized to receive AZD5156 (40 participants) or placebo (16 participants). Participants will be randomized to receive study intervention IM either in the gluteal or the anterolateral thigh. Dosing within the Sentinel Safety Cohort will be staggered, with participants allocated sequentially to 4 subcohorts (1a, 1b, 2a, and 2b).
  Intervention: Biological: Placebo (Parent study Sentinel Safety Cohort)
• Experimental: Parent study Main Cohort - AZD3152
  The Main Cohort of the Parent study will enroll approximately 3200 participants. Dosing in the Main Cohort will be staggered, so that it starts with adult participants aged 18 years and older, with no adolescent participants dosed in the Main Cohort until safety data from Visit 2a (Day 8) and Visit 2b (Day 15) have been reviewed by the DSMB for at least 80 adult Main Cohort participants (which will include at least 40 participants who have received AZD3152). Participants in the Main Cohort will be randomized 1:1 to receive AZD3152 300 mg or comparator administered IM in the anterolateral thigh on Day 1. Participants will receive a second dose of their original randomized study intervention (ie, active treatment or comparator) 6 months after Visit 1.
  Interventions:

  • Biological: Placebo (Parent study Sentinel Safety Cohort)
  • Biological: AZD3152 (Parent study Main Cohort)
• Active Comparator: Parent study Main Cohort - EVUSHELD™

  Participants in the Main Cohort of the Parent study will be randomized 1:1 to receive AZD3152 300 mg or comparator administered IM in the anterolateral thigh on Day 1. Participants will receive a second dose of their original randomized study intervention (ie, active treatment or comparator) 6 months after Visit 1.

  At the request of regulatory authorities the active comparator will be changed to placebo. As the comparator is given on two occasions, this means that a participant randomized to the comparator arm may receive (a) two doses of EVUSHELD, (b) a dose of EVUSHELD and a dose of placebo, or (c) two doses of placebo.

  Intervention: Biological: EVUSHELD™ (Parent study Main Cohort)
• Placebo Comparator: Parent study Main Cohort - Placebo

  Participants in the Main Cohort of the Parent study will be randomized 1:1 to receive AZD3152 300 mg or comparator administered IM in the anterolateral thigh on Day 1. Participants will receive a second dose of their original randomized study intervention (ie, active treatment or comparator) 6 months after Visit 1.

  At the request of regulatory authorities the active comparator will be changed to placebo. As the comparator is given on two occasions, this means that a participant randomized to the comparator arm may receive (a) two doses of EVUSHELD, (b) a dose of EVUSHELD and a dose of placebo, or (c) two doses of placebo.

  Intervention: Biological: Placebo (Parent study Main Cohort)
• Experimental: Sub-study - AZD3152
  This sub-study will enroll approximately 450 participants, ≥ 18 years of age with a minimum weight of 40 kg. An initial Sentinel Safety Cohort will include 12 healthy volunteers; all other participants in the study will be either immunocompromised or immunocompetent (including healthy participants) with all degrees of SARS-CoV-2 infection risk.
  Intervention: Biological: AZD3152 (Sub-study)
• Active Comparator: Sub-study - AZD7442 (EVUSHELD™)
  This sub-study will enroll approximately 450 participants, ≥ 18 years of age with a minimum weight of 40 kg. An initial Sentinel Safety Cohort will include 12 healthy volunteers; all other participants in the study will be either immunocompromised or immunocompetent (including healthy participants) with all degrees of SARS-CoV-2 infection risk.
  Intervention: Biological: AZD7442 - EVUSHELD™ (Sub-study)
• Experimental: Sub-study - AZD7442 (EVUSHELD™) Immunocompromised participants offered AZD3152 1200mg IV
  This sub-study will enroll approximately 450 participants, ≥ 18 years of age with a minimum weight of 40 kg. An initial Sentinel Safety Cohort will include 12 healthy volunteers; all other participants in the study will be either immunocompromised or immunocompetent (including healthy participants) with all degrees of SARS-CoV-2 infection risk.
  Intervention: Biological: AZD7442 (EVUSHELD™) (Sub-study) Immunocompromised participants offered AZD3152

Publications *

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• CDC 2021 CDC (Centers for Disease Control and Prevention). General Best Practice Guidelines for Immunization: Altered Immunocompetence. Available from: https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html. Accessed 23 May 2022.
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• Dall'Acqua WF, Kiener PA, Wu H. Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn). J Biol Chem. 2006 Aug 18;281(33):23514-24. doi: 10.1074/jbc.M604292200. Epub 2006 Jun 21.
• Fact Sheet EUA Bebtelovimab 2022 US Food and Drug Administration. Fact Sheet For Healthcare Providers: Emergency Use Authorization for Bebtelovimab, March 2022. Available at: https://www.fda.gov/media/156152/download. Accessed 23 May 2022.
• Gupta A, Gonzalez-Rojas Y, Juarez E, Crespo Casal M, Moya J, Falci DR, Sarkis E, Solis J, Zheng H, Scott N, Cathcart AL, Hebner CM, Sager J, Mogalian E, Tipple C, Peppercorn A, Alexander E, Pang PS, Free A, Brinson C, Aldinger M, Shapiro AE; COMET-ICE Investigators. Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab. N Engl J Med. 2021 Nov 18;385(21):1941-1950. doi: 10.1056/NEJMoa2107934. Epub 2021 Oct 27.
• Harpaz R, Dahl RM, Dooling KL. Prevalence of Immunosuppression Among US Adults, 2013. JAMA. 2016 Dec 20;316(23):2547-2548. doi: 10.1001/jama.2016.16477. No abstract available.
• Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020 Mar 5.
• Levin MJ, Ustianowski A, De Wit S, Launay O, Avila M, Templeton A, Yuan Y, Seegobin S, Ellery A, Levinson DJ, Ambery P, Arends RH, Beavon R, Dey K, Garbes P, Kelly EJ, Koh GCKW, Near KA, Padilla KW, Psachoulia K, Sharbaugh A, Streicher K, Pangalos MN, Esser MT; PROVENT Study Group. Intramuscular AZD7442 (Tixagevimab-Cilgavimab) for Prevention of Covid-19. N Engl J Med. 2022 Jun 9;386(23):2188-2200. doi: 10.1056/NEJMoa2116620. Epub 2022 Apr 20.
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• Loo YM, McTamney PM, Arends RH, Abram ME, Aksyuk AA, Diallo S, Flores DJ, Kelly EJ, Ren K, Roque R, Rosenthal K, Streicher K, Tuffy KM, Bond NJ, Cornwell O, Bouquet J, Cheng LI, Dunyak J, Huang Y, Rosenbaum AI, Pilla Reddy V, Andersen H, Carnahan RH, Crowe JE Jr, Kuehne AI, Herbert AS, Dye JM, Bright H, Kallewaard NL, Pangalos MN, Esser MT. The SARS-CoV-2 monoclonal antibody combination, AZD7442, is protective in nonhuman primates and has an extended half-life in humans. Sci Transl Med. 2022 Mar 9;14(635):eabl8124. doi: 10.1126/scitranslmed.abl8124. Epub 2022 Mar 9.
• Lusvarghi S, Pollett SD, Neerukonda SN, Wang W, Wang R, Vassell R, Epsi NJ, Fries AC, Agan BK, Lindholm DA, Colombo CJ, Mody R, Ewers EC, Lalani T, Ganesan A, Goguet E, Hollis-Perry M, Coggins SA, Simons MP, Katzelnick LC, Wang G, Tribble DR, Bentley L, Eakin AE, Broder CC, Erlandson KJ, Laing ED, Burgess TH, Mitre E, Weiss CD. SARS-CoV-2 BA.1 variant is neutralized by vaccine booster-elicited serum but evades most convalescent serum and therapeutic antibodies. Sci Transl Med. 2022 May 18;14(645):eabn8543. doi: 10.1126/scitranslmed.abn8543. Epub 2022 May 18.
• Maltezou HC, Anastassopoulou C, Hatziantoniou S, Poland GA, Tsakris A. Anaphylaxis rates associated with COVID-19 vaccines are comparable to those of other vaccines. Vaccine. 2022 Jan 21;40(2):183-186. doi: 10.1016/j.vaccine.2021.11.066. Epub 2021 Nov 27.
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• Oganesyan V, Gao C, Shirinian L, Wu H, Dall'Acqua WF. Structural characterization of a human Fc fragment engineered for lack of effector functions. Acta Crystallogr D Biol Crystallogr. 2008 Jun;64(Pt 6):700-4. doi: 10.1107/S0907444908007877. Epub 2008 May 14.
• Parker EPK, Desai S, Marti M, Nohynek H, Kaslow DC, Kochhar S, O'Brien KL, Hombach J, Wilder-Smith A. Response to additional COVID-19 vaccine doses in people who are immunocompromised: a rapid review. Lancet Glob Health. 2022 Mar;10(3):e326-e328. doi: 10.1016/S2214-109X(21)00593-3. No abstract available.
• Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, Brown SG, Camargo CA Jr, Cydulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor AD Jr, Hepner DL, Lewis LM, Lieberman PL, Metcalfe DD, O'Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW. Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006 Feb;117(2):391-7. doi: 10.1016/j.jaci.2005.12.1303.
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Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 29, 2023): 3706
• Original Estimated Enrollment (submitted: December 12, 2022): 1244
• Estimated Study Completion Date: January 21, 2025
• Estimated Primary Completion Date: September 7, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Parent study - Sentinel Safety Cohort Participants (Phase I):

Parent study - Sentinel Cohort Inclusion Criteria:

• Healthy participants according to medical history, physical examination, baseline safety laboratory tests, and screening parameters, according to the judgment of the investigator, with no concomitant disease or concomitant medication (except for medication specifically permitted by the protocol).
• Age 18 to 55 years at the time of signing the informed consent.
• Negative rapid antigen test at Visit 1.
• Weight ≥ 45 kg and ≤ 110 kg at screening.

Parent study - Sentinel Cohort Exclusion Criteria:

• Women who are pregnant, lactating, or of childbearing potential and not using a highly effective method of contraception or abstinence from at least 4 weeks prior to study intervention administration and until at least 6 months after study intervention administration.
• Known hypersensitivity to any component of the study intervention.
• Previous hypersensitivity or severe adverse reaction following administration of a mAb.
• Acute (time-limited) or febrile (temperature ≥ 38.0°C [100.4ºF]) illness/infection on day prior to or day of planned dosing; participants excluded for transient acute illness may be dosed if illness resolves within the screening period or may be rescreened once.
• Blood drawn in excess of a total of 450 mL (1 unit) for any reason within 30 days prior to Visit 1.
• Clinically significant bleeding disorder (eg, factor deficiency, coagulopathy, or platelet disorder), or prior history of significant bleeding or bruising following IM injections or venipuncture.
• Receipt of immunoglobulin (non-COVID related) or blood products within 6 months prior to Visit 1.
• Previous receipt of a mAb against SARS-CoV-2.
• Receipt of a COVID-19 vaccine within 3 months prior to Visit 1.
• Receipt of a COVID-19 antiviral for prophylaxis within 3 months prior to Visit 1
• COVID-19 within 3 months prior to Visit 1 (confirmed either by laboratory testing or a rapid test [including at home testing]).
• Receipt of any IMP in the preceding 90 days or expected receipt of IMP during the period of study follow-up, or concurrent participation in another interventional study.
• Known or suspected congenital or acquired immunodeficiency, or receipt of immunosuppressive therapy, including any course of glucocorticoid therapy exceeding 2 weeks of prednisone or equivalent at a dose of 20 mg daily or every other day within 6 months prior to screening.
• Active infection with hepatitis B or C.
• Serum creatinine, AST, or ALT above 1.5 × ULN at screening
• History of malignancy other than treated non-melanoma skin cancers or locally-treated cervical cancer in previous 5 years.

Parent study - Main Cohort Participants (Phase III):

Parent study - Main Cohort Inclusion Criteria:

• Participant must be 12 years of age or older at the time of signing the informed consent.
• Negative rapid antigen test prior to dosing at Visit 1.
• Weight ≥ 40 kg at screening.

• Participants must satisfy at least 1 of the following risk factors at enrollment:

  • Have solid tumor cancer and be on active immunosuppressive treatment
  • Have hematologic malignancy

  • Transplant participants must satisfy at least one of the following:

    1. Have had a solid organ transplant within 2 years and / or
    2. Had a hematopoietic stem cell transplant within 2 years and / or
    3. Who have chronic graft-versus-host disease
    4. Participants who previously had a solid organ transplant or hematopoietic stem cell transplant more than 2 years prior to Visit 1 may also be eligible based on the inclusion criterion for immunosuppressive treatment
  • Are actively taking immunosuppressive medicines (eg, are using corticosteroids [ie, ≥ 20 mg prednisone or equivalent per day when administered for ≥ 2 weeks], high dose alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive [eg, Bruton's tyrosine kinase inhibitors], tumor-necrosis blockers, or other immunosuppressive or immunomodulatory biologic agents (eg, for rheumatic diseases)
  • Received chimeric antigen receptor T cell therapy
  • Within 1 year of receiving B-cell depleting therapies (eg, rituximab, ocrelizumab, ofatumumab, alemtuzumab)
  • Have a moderate or severe primary (eg, DiGeorge syndrome) or secondary (eg, hemodialysis) immunodeficiency
  • Advanced or untreated HIV infection (people with HIV and CD4 cell counts < 200/mm3 within 6 months of Visit 1, history of an AIDS-defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV)
• Medically stable defined as disease not requiring significant change in maintenance therapy or hospitalization for worsening disease or any recent cardiovascular event (eg, acute myocardial infarction, thromboembolic event) during the 1 month prior to enrollment, with no acute change in condition at the time of study enrollment as judged by the Investigator and no expected changes at the time of the enrollment.
• Able to understand and comply with all study requirements/procedures (if applicable, with assistance by caregiver, surrogate, or legally authorized representative or equivalent representative as locally defined), including those at Illness Visits, based on the assessment of the Investigator.

Parent study - Main Cohort Exclusion Criteria:

• Women who are pregnant, lactating, or of childbearing potential and not using a highly effective method of contraception or abstinence from at least 4 weeks prior to study intervention administration and until at least 6 months after study intervention administration. Note: female participants aged > 12 years will be considered to be a woman of childbearing potential.
• Known hypersensitivity to any component of the study intervention.
• Previous hypersensitivity or severe adverse reaction following administration of a mAb.
• Acute (time-limited) or febrile (temperature ≥ 38.0°C [100.4ºF]) illness/infection on day prior to or day of planned dosing; participants excluded for transient acute illness may be dosed if illness resolves and may be rescreened for enrollment once.
• Blood drawn in excess of a total of 450 mL (1 unit) for any reason within 30 days prior to Visit 1.
• Clinically significant bleeding disorder (eg, factor deficiency, coagulopathy, or platelet disorder), or prior history of significant bleeding or bruising following IM injections or venipuncture.
• Receipt of IV or SC immunoglobulin within 6 months prior to Visit 1 or expected to receive IV and SC immunoglobulin 6 months after dosing.
• Receipt of convalescent COVID-19 plasma treatment within 6 months prior to Visit 1.
• Previous receipt of a mAb against SARS-CoV-2 within 6 months prior to Visit 1.
• Receipt of a COVID-19 vaccine within 3 months prior to Visit 1.
• Receipt of a COVID-19 antiviral for prophylaxis within at least 2 weeks prior to Visit 1.
• COVID-19 within 3 months prior to Visit 1 (confirmed either by laboratory testing or a rapid test [including at home testing]).
• Receipt of any IMP in the preceding 90 days or expected receipt of IMP during the period of study follow-up, or concurrent participation in another interventional study except where the participant ceased IMP treatment >90 days and is in the follow-up period of the study and not expected to receive further IMP).

Sub-study - Inclusion Criteria (Phase II):

Sub-study - Sentinel Safety Cohort Inclusion Criteria:

• Healthy, defined according to medical history, physical examination, baseline safety laboratory tests, and screening parameters, according to the judgment of the Investigator.
• Participants must be 18 to 55 years at the time of signing the informed consent.
• Weight ≥ 45 kg and ≤ 110 kg at screening.

Sub-study - Full Sub-study Cohort Inclusion Criteria:

• Immunocompromised or immunocompetent, including healthy participants, with all degrees of SARS-CoV-2 infection risk, will be enrolled following completion of Sentinel Safety Cohort enrolment.
• Participants must be 18 years of age or older at the time of signing the informed consent.
• Weight ≥ 40 kg at screening.

Sub-study - Sub-study Sentinel Safety Cohort and Full Sub-study Cohort Inclusion Criteria:

• Written informed consent and any locally required authorization (eg, HIPAA in the US) obtained from the participant prior to performing any protocol-related procedures, including screening evaluations.
• Negative rapid antigen test for SARS-CoV-2 prior to dosing at Visit 1.
• Medically stable defined as disease not requiring significant change in maintenance therapy or hospitalization for worsening disease or any recent cardiovascular event (eg, acute myocardial infarction, thromboembolic event) during the 1 month prior to enrollment, with no acute change in condition at the time of study enrollment as judged by the Investigator and no expected changes at the time of the enrollment.
• Able to understand and comply with all study requirements/procedures (if applicable, with assistance by caregiver, surrogate, or legally authorized representative or equivalent representative as locally defined), based on the assessment of the Investigator.

Sub-study - Exclusion Criteria (Phase II):

Sub-study - Sentinel Safety Cohort Exclusion Criteria:

• Active infection with hepatitis B or C.
• Serum creatinine, AST, or ALT above 1.5 × ULN at screening.
• History of malignancy other than treated non-melanoma skin cancers or locally-treated cervical cancer in previous 5 years.

Sub-study - Sentinel Safety Cohort and Full Sub-study Cohort Exclusion Criteria:

• Receipt of EVUSHELD (AZD7442) within 12 months prior to Visit 1.
• Women who are pregnant, lactating, or of childbearing potential and not using a highly effective method of contraception or abstinence from at least 4 weeks prior to study intervention administration and until at least 6 months after study intervention administration. Note: female participants aged > 12 years will be considered to be a woman of childbearing potential.
• Known hypersensitivity to any component of the study intervention.
• Previous hypersensitivity or severe adverse reaction following administration of a mAb.
• Acute (time-limited) or febrile (temperature ≥ 38.0°C [100.4ºF]) illness/infection on day prior to or day of planned dosing; participants excluded for transient acute illness may be dosed if illness resolves and may be rescreened for enrollment once.
• Blood drawn in excess of a total of 450 mL (1 unit) for any reason within 30 days prior to Visit 1.
• Clinically significant bleeding disorder (eg, factor deficiency, coagulopathy, or platelet disorder), or prior history of significant bleeding or bruising following IM injections or venipuncture.
• Has human immunodeficiency virus infection.
• Receipt of IV or SC immunoglobulin or blood products within 6 months prior to Visit 1 and expected to receive IV or SC immunoglobulin or blood products 6 months after dosing.
• Receipt of a COVID-19 vaccine within 3 months prior to Visit 1.
• Receipt of a COVID-19 antiviral for prophylaxis within at least 2 weeks prior to Visit 1.
• COVID-19 within 3 months prior to Visit 1 (confirmed either by laboratory RT-PCR testing or a rapid antigen test [including at-home testing]).
• Receipt of any IMP in the preceding 90 days or expected receipt of IMP during the period of study follow-up, or concurrent participation in another interventional study (except where the participant ceased IMP treatment > 90 days and is in the follow-up period of the study and not expected to receive further IMP).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: AstraZeneca Clinical Study Information Center; 1-877-240-9479; information.center@astrazeneca.com

• Listed Location Countries: Argentina, Australia, Belgium, Canada, Denmark, France, Germany, Israel, Korea, Republic of, Malaysia, Mexico, Poland, Singapore, South Africa, Spain, Taiwan, Thailand, Turkey, United Arab Emirates, United Kingdom, United States, Vietnam

Administrative Information

• NCT Number: NCT05648110
• Other Study ID Numbers: D7000C00001; 2022-002378-95 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• Supporting Materials: Study Protocol
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: AstraZeneca
• Verification Date: September 2023