COVID-19, SARS-CoV-2
Conditions
Keywords
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 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.
Interventions
BIOLOGICALAZD5156 (Parent study Sentinel Safety Cohort)
600 mg AZD5156 consisting of 300 mg AZD1061 at 100 mg/mL and 300 mg AZD3152 at 150 mg/mL 3 mL of AZD1061 2 mL of AZD3152 IM on Visit 1 Day 1
BIOLOGICALPlacebo (Parent study Sentinel Safety Cohort)
single dose of Placebo (3 mL + 2 mL) IM
BIOLOGICALEVUSHELD™ (Parent study Main Cohort)
600 mg EVUSHELD™/AZD7442 consisting of 300 mg AZD1061 and 300 mg AZD8895, both at 100 mg/mL 2 IM injections (thigh) of 3 mL each IM on Visit 1 Day 1 and on Visit 5 Day 181
BIOLOGICALAZD3152 (Parent study Main Cohort)
300 mg AZD3152 at 150 mg/mL 1 IM injection (thigh) of 2 mL of AZD3152 on Visit 1 Day 1 and on Visit 5 Day 181
BIOLOGICALPlacebo (Parent study Main Cohort)
Single doses of 0.9% sodium chloride 2 mL IM for injection on Visit 1 Day 1 and Visit 5 Day 181
BIOLOGICALAZD3152 (Sub-study)
Single dose of 1200 mg IV at Visit 1 Day 1
BIOLOGICALAZD7442 - EVUSHELD™ (Sub-study)
Single dose 300 mg IM administered on Visit 1 Day 1
BIOLOGICALAZD7442 (EVUSHELD™) (Sub-study) Immunocompromised participants offered AZD3152
Single dose of AZD7442 (EVUSHELD™) 300 mg IM
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
For the Sentinel Safety Cohort and Main Cohort, neither the participant nor any of the Investigators or Sponsor staff who are involved in the treatment or clinical evaluation and monitoring of the participants will be aware of the study intervention received. Since AZD5156, AZD3152, and placebo are visually distinct prior to dose preparation (due to differences in vial volumes and container closure), study intervention will be handled by an unblinded pharmacist and administered by an unblinded administrator (or designee, in accordance with local and institutional regulations) at the study site who will be independent of safety evaluations and other trial evaluations. Personnel preparing and administering study intervention may be the same individual. Syringe masking will be required in order to maintain the blind.
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).
Eligibility
Sex/Gender
ALL
Age
12 Years to 130 Years
Healthy volunteers
Yes
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| (Main Cohort) Occurrence of AEs Collected Through Approximately 90 Days After Each IMP Administration; SAEs, MAAEs, and AESIs Collected Through Day 451 | AEs: through 90 days post each IMP administration; SAEs, MAAEs, and AESIs: through Day 451 | Primary: (Main Cohort) Occurrence of AEs collected through approximately 90 days after each IMP administration; SAEs, MAAEs, and AESIs collected through Day 451 |
| (Sub-study) Occurrence of AEs Collected Through 29 Days After IMP Administration. SAEs, MAAEs, and AESIs Collected Through Day 451. | through 29 days post IMP administration (AEs); through Day 451 (SAEs, MAAEs, and AESIs) | (Sub-study) Occurrence of AEs collected through 29 days after IMP administration. SAEs, MAAEs, and AESIs collected through Day 451 (ie, end of study). |
| (Sub-study) Predicted SARS-CoV-2 nAb Titers Derived From Serum PK and in Vitro IC50 for SARS-CoV-2 Variants BA.2.86 Following AZD3152 Administration and Alpha Variant Following EVUSHELD Administration. | at Day 29 | AZD3152 Day 29 predicted nAb titer for BA.2.86 variant = AZD3152 serum PK conc. (ng/mL)/(3.8 ng/mL), where 3.8 ng/mL is AZD3152 BA.2.86 IC50. AZD7442 Day 29 predicted nAb titer for Alpha variant = AZD7442 serum PK conc. (ng/mL)/(2.1 ng/mL), where 2.1 ng/mL is AZD7442 Alpha IC50. This table only shows AZD3152 and AZD7442 concentration at Day 29. |
| (Main Cohort) Confirmed Symptomatic COVID-19 Case | at Primary Analysis: average follow-up time of 170 days | (Main Cohort) Confirmed symptomatic COVID-19 case at Primary Analysis. |
| (Main Cohort) Confirmed Symptomatic COVID-19 Case Attributable to Matched Variants | at Primary Analysis: average follow-up time of 170 days | (Main Cohort) Confirmed symptomatic COVID-19 case attributable to matched variants at Primary Analysis. |
| (Sentinel Cohort) Occurrence of AEs, SAEs, MAAEs, and AESIs Collected Through Day 461 | through Day 461 | Primary: (Sentinel Cohort) Occurrence of AEs, SAEs, MAAEs, and AESIs collected through Day 461 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| (Sub-study) AZD3152 and EVUSHELD (ie, AZD7442) Concentrations in Serum, Over Time | Day 29, Day 91, Day 181 | Secondary: (Sub-study) AZD3152 and EVUSHELD (ie, AZD7442) concentrations in serum, over time. |
| (Sub-study) Incidence of ADA to AZD3152 and EVUSHELD | through Day 181 | AZD3152 recipients were tested for ADA to AZD3152; EVUSHELD recipients were tested for ADA to EVUSHELD. |
| (Sub-study) Cilgavimab and Tixagevimab Concentrations in Serum, Over Time | Day 29, Day 91, Day 181 | AZD7442 (ie EVUSHELD) is composed of cilgavimab and tixagevimab. This summary is only applicable to AZD7442 group. |
| (Sub-study) ADA Titers | Day 1, Day 29, Day 91, Day 181 | ADA titers were only available for ADA positive samples. |
| (Main Cohort) Symptomatic COVID-19 Case (Negative RT-PCR at Baseline to Positive at Any Time up 12 Months With All Observed Events at Final Readout) Caused by Any SARS-CoV-2 Matched Variant | through Day 361 | (Main Cohort) Symptomatic COVID-19 case (negative RT-PCR at baseline to positive at any time up 12 months with all observed events at final readout) caused by any SARS-CoV-2 matched variant. First secondary endpoint to be tested in hierarchical testing after dual-primary endpoint efficacy was demonstrated in hierarchical testing |
| (Main Cohort) Symptomatic COVID-19 Case (Negative RT-PCR at Baseline to Positive at Any Time up to 12 Months With All Observed Events at Final Readout) Caused by Any SARS-CoV-2 Variants | through Day 361 | Secondary: (Main Cohort) Symptomatic COVID-19 case (negative RT-PCR at baseline to positive at any time up to 12 months with all observed events at final readout) caused by any SARS-CoV-2 variants. Second secondary endpoint to be tested in hierarchical testing after dual-primary endpoint efficacy was demonstrated in hierarchical testing |
| (Main Cohort) Severe COVID-19 Caused by Any SARS-CoV-2 Variant Any Time up to 12 Months | through Day 361 | third secondary endpoint to be tested in hierarchical testing after dual-primary endpoint efficacy was demonstrated in hierarchical testing |
| (Main Cohort) Severe COVID-19 Caused by Any SARS-CoV-2 Matched Variants at Any Time up to 12 Months | through Day 361 | Secondary: (Main Cohort) Severe COVID-19 caused by any SARS-CoV-2 matched variants at any time up to 12 months through Day 361. |
| (Main Cohort) Composite of COVID-19-related Hospitalization and/or COVID-19-related Death (WHO COVID-19 Clinical Progression Scale Score ≥ 4) Any Time up to 12 Months | through Day 361 | Secondary: (Main Cohort) Composite of COVID-19-related hospitalization and/or COVID-19-related death (WHO COVID-19 Clinical Progression Scale score ≥ 4) any time up to 12 months. |
| (Main Cohort) COVID-19-related Hospitalization Any Time up to 12 Months | through Day 361 | Secondary: (Main Cohort) COVID-19-related hospitalization any time up to 12 months. |
| (Main Cohort) COVID-19 Related Death | through Day 361 | (Main Cohort) COVID-19 related death - through Day 361 |
| (Main Cohort) GMT of SARS-CoV-2 nAbs at Baseline and Day 29 | at Day 29 | Secondary: (Main Cohort) GMT of SARS-CoV-2 nAbs at baseline and Day 29 |
| (Main Cohort) GMFR of SARS-CoV-2 nAbs at Day 29 | at Day 29 | Secondary: (Main Cohort) GMFR of SARS-CoV-2 nAbs at Day 29 |
| (Main Cohort) AZD3152 and AZD7442 (EVUSHELD) Concentrations Over Time | through Day 361 | (Main Cohort) AZD3152 and AZD7442 (EVUSHELD) concentrations over time - through Day 361 |
| (Main Cohort) Incidence of ADA to AZD3152 and AZD7442 (EVUSHELD) | through Day 361 | AZD3152 recipients were tested for ADA to AZD3152; AZD7442 recipients were tested for ADA to AZD7442. |
| (Sentinel Cohort) AZD5156, AZD1061, and AZD3152 Concentrations Over Time | Day 29, Day 181, Day 361 | AZD5156 is a combination of AZD3152 and AZD1061. This summary is only eligible for AZD5156 group. |
| (Sentinel Cohort) Incidence of ADA to AZD5156, AZD3152, and AZD1061 | through Day 361 | (Sentinel Cohort) Incidence of ADA to AZD5156, AZD3152, and AZD1061 - through Day 361 |
| (Main Cohort) ADA Titers | through Day 361 | ADA titers were only available for ADA positive samples. |
| (Main Cohort) AZD1061 and AZD8895 Concentrations Over Time | through Day 361 | AZD7442 (ie EVUSHELD) is composed of AZD1061 (ie, cilgavimab) and AZD8895 (ie, tixagevimab). This summary is only applicable to AZD7442 group. |
Countries
Australia, Belgium, Canada, Denmark, France, Germany, Israel, Malaysia, Poland, Singapore, South Korea, Spain, Taiwan, Thailand, United Arab Emirates, United Kingdom, United States, Vietnam
Participant flow
Recruitment details
In Main Cohort, 3348 participants 12 years of age or older were randomized 1:1 to receive AZD3152 or comparator. In Sentinel Cohort, 57 participants were randomized 5:2 to receive AZD5156 (41 participants) or Placebo (16 participants). In Sub-study, 476 participants, 18 years of age or older, were randomized 2:1 to receive AZD3152 or AZD7442.
Pre-assignment details
Overall 3713 participants were screened in the Main Study; 87 screened for the Sentinel Cohort; 576 participants were screened in the Sub-study.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 56.7 years STANDARD_DEVIATION 14.6 |
| Age, Customized 85 years and over | 29 Participants |
| Age, Customized Adolescents (12-17 years) | 7 Participants |
| Age, Customized Adults (18-64 years) | 2543 Participants |
| Age, Customized Children (2-11 years) | 0 Participants |
| Age, Customized From 65-84 years | 597 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants |
| Age, Customized In utero | 0 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants |
| Age, Customized Preterm newborn infants (gestational age < 37 wks) | 0 Participants |
| Ethnicity Hispanic or Latino | 356 Participants |
| Ethnicity Not Hispanic or Latino | 841 Participants |
| Ethnicity Not reported | 26 Participants |
| EVUSHELD use within 12 months prior to randomization Missing | 0 Participants |
| EVUSHELD use within 12 months prior to randomization No EVUSHELD use | 954 Participants |
| EVUSHELD use within 12 months prior to randomization Yes EVUSHELD use | 378 Participants |
| Prior SARS-CoV-2 infection within 6 months prior to randomization No prior SARS-CoV-2 infection | 1044 Participants |
| Prior SARS-CoV-2 infection within 6 months prior to randomization Yes prior SARS-CoV-2 infection | 135 Participants |
| Race Asian | 94 Participants |
| Race Black or African American | 516 Participants |
| Race Missing | 12 Participants |
| Race Multiple | 78 Participants |
| Race Not reported | 8 Participants |
| Race Other | 2 Participants |
| Race White | 814 Participants |
| Race/Ethnicity, Customized Asian | 111 Participants |
| Race/Ethnicity, Customized Black or African American | 33 Participants |
| Race/Ethnicity, Customized More than one race | 78 Participants |
| Race/Ethnicity, Customized Other | 82 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized White | 814 Participants |
| SARS-CoV-2 vaccination status within 6 months prior to randomization No SARS-CoV-2 vaccination | 511 Participants |
| SARS-CoV-2 vaccination status within 6 months prior to randomization Yes SARS-CoV-2 vaccination | 147 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 717 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 40 / 1,671 | 24 / 1,102 | 6 / 561 | 1 / 41 | 0 / 16 | 2 / 310 | 0 / 156 | 0 / 2 |
| other Total, other adverse events | 892 / 1,671 | 624 / 1,102 | 292 / 561 | 19 / 41 | 12 / 16 | 38 / 310 | 17 / 156 | 1 / 2 |
| serious Total, serious adverse events | 315 / 1,671 | 222 / 1,102 | 90 / 561 | 2 / 41 | 0 / 16 | 15 / 310 | 11 / 156 | 1 / 2 |
Outcome results
None listed