Clinical trial NCT05648110: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: COVID-19, SARS-CoV-2
Keywords: Pre-exposure Prophylaxis of COVID-19
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2022-12-13
Enrollment: 3882
Sex: ALL
Minimum age (years): 12
Maximum age (years): 130
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
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).
Primary purpose: PREVENTION

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 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.

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 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).

Primary outcomes:
measure: Parent study - Sentinel Safety Cohort: To evaluate the safety of AZD5156
timeFrame: 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).
measure: Parent study - Main Cohort: To evaluate the safety of AZD3152 and EVUSHELD and/or placebo
timeFrame: 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).
measure: Parent study-Main cohort: To compare the efficacy of AZD3152 to EVUSHELD and/or placebo in the prevention of symptomatic COVID 19 caused by any SARS-CoV-2 variant
timeFrame: Confirmed symptomatic COVID-19 case is evaluated from first dose up to 181 days after last dose. For participants that receive two doses, the evaluation period would be approximately 361 days.
measure: Parent study - Main cohort: To compare the efficacy of AZD3152 to EVUSHELD and/or placebo in the prevention of symptomatic COVID 19 attributable to matched variants (variants that do not contain the F456L mutation)
timeFrame: Confirmed symptomatic COVID-19 case is evaluated from first dose up to 181 days after last dose. For participants that receive two doses, the evaluation period would be approximately 361 days.
measure: Sub-study: To evaluate the safety of AZD3152 and EVUSHELD
timeFrame: SAEs, MAAEs, and AESIs collected throughout the study for the final analysis.
measure: 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
timeFrame: 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.
Secondary outcomes:
measure: Parent study - Sentinel Safety Cohort: To characterize the Pharmacokinetics of AZD5156 (AZD1061 and AZD3152) in serum.
timeFrame: Samples will be collected from Visit 1 (Day 1) up to Visit 11 (Day 361).
measure: Parent study - Sentinel Safety Cohort: To characterize the Pharmacokinetics parameter of maximum concentration (Cmax) of AZD5156 (AZD1061 and AZD3152) in serum
timeFrame: Samples will be collected from Visit 1 (Day 1) up to Visit 11 (Day 361)
measure: Parent study - Sentinel Safety Cohort: To characterize the Pharmacokinetics parameter of time to maximum serum concentration (tmax) of AZD5156 (AZD1061 and AZD3152) in serum
timeFrame: Samples will be collected from Visit 1 (Day 1) up to Visit 11 (Day 361).
measure: Parent study - Sentinel Safety Cohort: To characterize the Pharmacokinetics parameter of terminal half-life (t½) of AZD5156 (AZD1061 and AZD3152) in serum
timeFrame: Samples will be collected from Visit 1 (Day 1) up to Visit 11 (Day 361).
measure: 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
timeFrame: Samples will be collected from Visit 1 (Day 1) up to Visit 11 (Day 361).
measure: 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
timeFrame: Samples will be collected from visit 1 (Day 1) up to visit 11 (Day 361).
measure: Parent study - Sentinel Safety Cohort: To evaluate the ADA responses to AZD5156, AZD3152, and AZD1061 in serum
timeFrame: Samples will be collected from Visit 1 (Day 1) up to Visit 11 (Day 361)
measure: 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
timeFrame: Visit 3 (Day 29)
measure: 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
timeFrame: COVID-19 incidence variables to be evaluated through Visit 9 (Day 361)
measure: Parent study - Main Cohort: To characterize the Pharmacokinetics (PK)of the AZD3152 and AZD7442 (AZD1061 and AZD8865) in serum concentrations at each visit.
timeFrame: Samples will be collected from Visit 1 (Day 1) up to Visit 9 (Day 361)
measure: Parent study - Main Cohort: To evaluate the Anti-drug Antibodies (ADA) responses to AZD3152 and AZD7442 in serum
timeFrame: Samples will be collected from Visit 1 (Day 1) up to Visit 9 (Day 361)
measure: Sub-study: To characterize the Pharmacokinetics of AZD3152 and AZD7442 (EVUSHELD) in serum
timeFrame: Samples will be collected from Visit 1 (Day 1) up to Visit 5 (Day 181).
measure: Sub-study:To evaluate the ADA response to AZD3152 and AZD7442 (EVUSHELD) in serum
timeFrame: Samples will be collected from Visit 1 (Day 1) up to Visit 5 (Day 181).
Other outcomes:
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country: Belgium
facility: Research Site
city: Liège
country: Belgium
facility: Research Site
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Aalborg
country: Denmark
facility: Research Site
city: Aarhus
country: Denmark
facility: Research Site
city: Hvidovre
country: Denmark
facility: Research Site
city: Roskilde
country: Denmark
facility: Research Site
city: Svendborg
country: Denmark
facility: Research Site
city: Dijon
country: France
facility: Research Site
city: La Roche sur Yon
country: France
facility: Research Site
city: Lille
country: France
facility: Research Site
city: Nantes
country: France
facility: Research Site
city: Nîmes Cedex 9
country: France
facility: Research Site
city: Paris cedex 10
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Poitiers
country: France
facility: Research Site
city: Saint-Etienne Cedex 2
country: France
facility: Research Site
city: Strasbourg
country: France
facility: Research Site
city: Toulouse Cedex 9
country: France
facility: Research Site
city: Tours
country: France
facility: Research Site
city: Essen
country: Germany
facility: Research Site
city: Hamburg
country: Germany
facility: Research Site
city: Hannover
country: Germany
facility: Research Site
city: Köln
country: Germany
facility: Research Site
city: Mainz
country: Germany
facility: Research Site
city: Petah Tikva
country: Israel
facility: Research Site
city: Ramat Gan
country: Israel
facility: Research Site
city: Gyeonggi-do
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Bandar Sunway
country: Malaysia
facility: Research Site
city: Kuala Lumpur
country: Malaysia
facility: Research Site
city: Kuala Lumpur
country: Malaysia
facility: Research Site
city: Kuching
country: Malaysia
facility: Research Site
city: Seberang Jaya
country: Malaysia
facility: Research Site
city: Krakow
country: Poland
facility: Research Site
city: Skórzewo
country: Poland
facility: Research Site
city: Singapore
country: Singapore
facility: Research Site
city: Singapore
country: Singapore
facility: Research Site
city: Singapore
country: Singapore
facility: Research Site
city: Badalona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Cordoba
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Marbella (Málaga)
country: Spain
facility: Research Site
city: Mérida
country: Spain
facility: Research Site
city: Pozuelo de Alarcón
country: Spain
facility: Research Site
city: Valladolid
country: Spain
facility: Research Site
city: Vigo
country: Spain
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Khon Kaen
country: Thailand
facility: Research Site
city: Muang
country: Thailand
facility: Research Site
city: Muang
country: Thailand
facility: Research Site
city: Abu Dhabi
country: United Arab Emirates
facility: Research Site
city: Abu Dhabi
country: United Arab Emirates
facility: Research Site
city: Bristol
country: United Kingdom
facility: Research Site
city: Edinburgh
country: United Kingdom
facility: Research Site
city: Harrow
country: United Kingdom
facility: Research Site
city: Leeds
country: United Kingdom
facility: Research Site
city: Liverpool
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Oxford
country: United Kingdom
facility: Research Site
city: Sheffield
country: United Kingdom
facility: Research Site
city: Torpoint
country: United Kingdom
facility: Research Site
city: Truro
country: United Kingdom
facility: Research Site
city: Hanoi
country: Vietnam
facility: Research Site
city: Hochiminh city
country: Vietnam
facility: Research Site
Study officials:
References:
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