Parent Study: Study Understanding Pre-Exposure pRophylaxis of NOvel Anitbodies (SUPERNOVA) Sub-study: Study Understanding Pre-Exposure pRophylaxis of NOvel Anitbodies (SUPERNOVA Sub-study)

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 18 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.

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:

• Have had a solid organ transplant within 2 years and / or
• Had a hematopoietic stem cell transplant within 2 years and / or
• Who have chronic graft-versus-host disease
• 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 CV 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 or 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).