Evaluation of AZD3152 and Cilgavimab for Pre-exposure Prophylaxis of COVID-19 in Immunocompromised Patients: A Randomized, Double-blind, Phase I/III Study
- Trial ID
- 2024-512554-15-00
- Protocol
- D7000C00001
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and **efficacy** of AZD3152 and EVUSHELD, as well as a placebo, in the prevention of symptomatic **COVID-19** in individuals with conditions causing immune impairment. This is clinically relevant as it aims to provide insights into effective prophylactic measures for a vulnerable population against various **SARS-CoV-2** variants. Additionally, the study seeks to assess the safety of AZD5156 in a sentinel safety cohort.
Secondary objectives include:
- Comparing the neutralizing antibody (nAb) responses to SARS-CoV-2 variants such as Alpha, Omicron BA.2, Omicron BA.4/5, and Omicron XBB.1.5 following administration of AZD3152, EVUSHELD, and/or placebo.
- Describing the incidence of symptomatic COVID-19, severe COVID-19, COVID-19-related hospitalization, and COVID-19-related death in participants receiving the study intervention.
- Characterizing the pharmacokinetics (PK) of AZD3152, AZD7442, and AZD5156 in serum.
- Evaluating the anti-drug antibody (ADA) responses to AZD3152, AZD7442, AZD5156, and AZD1061 in serum.
Participants
The clinical trial involves a total of **2816 participants** who are being evaluated for the safety and efficacy of AZD3152 and EVUSHELD in the prevention of symptomatic **COVID-19**. The study population includes both male and female subjects, with age ranges spanning from 12 years and older. Participants in the Main Cohort must weigh at least 40 kg, while those in the Sentinel Safety Cohort must weigh between 45 kg and 110 kg. The trial includes individuals with specific risk factors such as those with solid tumor cancer on active immunosuppressive treatment, hematologic malignancies, or those who have undergone solid organ or hematopoietic stem cell transplants. Additionally, participants may be actively taking immunosuppressive medications or have conditions like advanced HIV infection. The trial population was selected based on their ability to understand and comply with study requirements, with informed consent obtained from all participants or their legal representatives. The study also includes a vulnerable population, ensuring a comprehensive evaluation of the investigational treatments across diverse health statuses.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the safety, efficacy, and neutralizing activity of AZD3152 and EVUSHELD for pre-exposure prophylaxis of **COVID-19** in participants with conditions causing immune impairment. The trial is structured to include both a main cohort and a sentinel safety cohort, with the main cohort focusing on participants with specific risk factors such as solid tumor cancer, hematologic malignancy, or those undergoing immunosuppressive treatment. The trial is expected to run from December 19, 2022, to February 7, 2025, with participant involvement lasting up to 15 days for the treatment period, followed by additional follow-up visits.
Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to assess eligibility based on medical history, physical examination, and baseline safety laboratory tests. The main cohort requires participants to be medically stable and able to comply with study requirements. The sentinel safety cohort includes healthy participants aged 18 to 55 years. Following the screening, eligible participants will receive the investigational medicinal product (IMP) through **intramuscular injection**. The primary endpoints include the occurrence of adverse events (AEs) and the prophylactic efficacy of AZD3152 compared to EVUSHELD and/or placebo in preventing symptomatic COVID-19.
Follow-up visits will be conducted to monitor the occurrence of AEs, serious adverse events (SAEs), medically attended adverse events (MAAEs), and adverse events of special interest (AESIs) through approximately 90 days after each IMP administration. The end-of-study visit will assess the overall safety and efficacy outcomes, including the incidence of symptomatic COVID-19 cases and the geometric mean titer (GMT) of SARS-CoV-2 neutralizing antibodies. Participants may be terminated early from the study if they experience significant adverse reactions or fail to comply with study protocols. The trial aims to provide valuable insights into the prophylactic potential of AZD3152 and EVUSHELD in a population at increased risk for COVID-19 due to immune impairment.
Treatment
The clinical trial involves the administration of **Sipavibart**, an experimental medication formulated as a **solution for injection/infusion**. The active substance, **sipavibart**, is a protein-based compound, specifically a Human IgG1 gamma TM-YTE monoclonal antibody targeting the SARS-CoV-2 spike protein receptor binding domain. The pharmaceutical form is a solution intended for **intramuscular injection**. The maximum daily dose is 300 mg, with a total maximum dose of 600 mg over a treatment period of 15 days. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.
**Sodium Chloride** is utilized as a non-experimental treatment in the study, serving as a placebo or comparator. It is provided as a **solution for injection** and is administered via **intramuscular injection**. The maximum daily dose is 18 mg, with a total maximum dose of 36 mg over a 15-day treatment period. This treatment is used to maintain the study's double-blind design and to evaluate the efficacy of the experimental medication against a standard comparator.
**EVUSHELD**, containing the active substance **cilgavimab**, is another comparator treatment in the trial. It is formulated as a **solution for injection** and is administered through **intramuscular injection**. The maximum daily dose is 300 mg, with a total maximum dose of 600 mg over a 15-day treatment period. EVUSHELD is a Human IgG1λ monoclonal antibody and is used to compare the efficacy and safety of the experimental medication, Sipavibart, in preventing symptomatic COVID-19.
Efficacy
The efficacy of the investigational product AZD3152 will be assessed in a Phase I/III randomized, double-blind clinical trial aimed at evaluating its use for pre-exposure prophylaxis of COVID-19 in participants with conditions causing immune impairment. The primary efficacy endpoints include the occurrence of confirmed symptomatic COVID-19 cases, both overall and attributable to matched variants, in participants who are SARS-CoV-2 negative at baseline. These endpoints will be classified as binary outcomes, incorporating the time from the first dose of the investigational medicinal product (IMP) until the development of COVID-19 symptoms. Prophylactic efficacy will be calculated using a hazard regression model, comparing AZD3152 to EVUSHELD and/or placebo.
Secondary efficacy endpoints will include the geometric mean titer (GMT) and geometric mean fold rise (GMFR) ratio of SARS-CoV-2 neutralizing antibodies (nAbs) between treatment arms at Visit 3 (Day 29). Additionally, the incidence of post-treatment symptomatic COVID-19 cases, severe COVID-19 cases, COVID-19-related hospitalizations, and COVID-19-related deaths will be evaluated. Pharmacokinetic parameters and the incidence of anti-drug antibodies (ADA) to AZD3152 and other related compounds will also be assessed. These efficacy parameters will be measured and analyzed at specified timepoints throughout the study, ensuring a comprehensive evaluation of the investigational product's efficacy in preventing COVID-19 in the target population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Sentinel Safety Cohort: 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)
- Sentinel Safety Cohort: Age 18 to 55 years at the time of signing the informed consent
- Sentinel Safety Cohort: 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.
- Sentinel Safety Cohort: Negative rapid antigen test at Visit 1
- Sentinel Safety Cohort: Weight ≥ 45 kg and ≤ 110 kg at screening.
- Sentinel Safety Cohort: 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.
- Main Cohort: Participant must be 12 years of age or older at the time of signing the informed consent.
- Main Cohort: 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. For participants from 12 to < 18 years of age, their parents or legal guardians must give their signed written informed consent, as appropriate, and participants will sign an assent form.
- Main Cohort: Negative rapid antigen test prior to dosing at Visit 1.
- Main Cohort: Weight ≥ 40 kg at screening
- Main Cohort: 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], 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 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 AIDSdefining illness without immune reconstitution, or clinical manifestations of symptomatic HIV)
- Main Cohort: 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.
- Main Cohort: 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.
Exclusion Criteria
- Sentinel Safety Cohort: 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, (see details in CSP).
- Sentinel Safety Cohort: Known hypersensitivity to any component of the study intervention.
- Sentinel Safety Cohort: Previous hypersensitivity or severe adverse reaction following administration of a mAb.
- Sentinel Safety Cohort: Acute (time-limited) or febrile (temperature ≥ 38.0°C 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.
- Sentinel Safety Cohort: Blood drawn in excess of a total of 450 mL (1 unit) for any reason within 30 days prior to Visit 1.
- Sentinel Safety Cohort: Clinically significant bleeding disorder (eg, factor deficiency, coagulopathy, or platelet disorder), or prior history of significant bleeding or bruising following IM injections or venipuncture.
- Sentinel Safety Cohort: Receipt of immunoglobulin (non-COVID related) or blood products within 6 months prior to Visit 1
- Sentinel Safety Cohort: Previous receipt of a mAb against SARS-CoV-2
- Sentinel Safety Cohort: Receipt of a COVID-19 vaccine within 3 months prior to Visit 1
- Sentinel Safety Cohort: Receipt of a COVID-19 antiviral for prophylaxis within at least 2 weeks prior to Visit 1
- Sentinel Safety Cohort: COVID-19 within 3 months prior to Visit 1 (confirmed either by laboratory testing or a rapid test [including at home testing])
- Sentinel Safety Cohort: 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.
- Main Cohort: 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 (see details in CSP).
- Main Cohort: Known hypersensitivity to any component of the study intervention.
- Main Cohort: Previous hypersensitivity or severe adverse reaction following administration of a mAb
- Main Cohort: Acute (time-limited) or febrile (temperature ≥ 38.0°C 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.
- Main Cohort: Blood drawn in excess of a total of 450 mL (1 unit) for any reason within 30 days prior to Visit 1.
- Main Cohort: Clinically significant bleeding disorder (eg, factor deficiency, coagulopathy, or platelet disorder), or prior history of significant bleeding or bruising following IM injections or venipuncture.
- Main Cohort: 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.
- Main Cohort: Receipt of convalescent COVID-19 plasma treatment within 6 months prior to Visit 1.
- Main Cohort: Previous receipt of a mAb against SARS-CoV-2 within 6 months prior to Visit 1.
- Main Cohort: Receipt of a COVID-19 vaccine within 3 months prior to Visit 1.
- Main Cohort: Receipt of a COVID-19 antiviral for prophylaxis within at least 2 weeks prior to Visit 1.
- Main Cohort: COVID-19 within 3 months prior to Visit 1 (confirmed either by laboratory testing or a rapid test [including at-home testing]).
- Main Cohort: 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).
- Main Cohort: Alcohol or substance abuse that, in the opinion of the Investigator, might interfere with the trial conduct or completion.
- Main Cohort: Deprived of freedom by an administrative or court order, or in emergency setting, or hospitalized involuntarily.
- Main Cohort: Any condition that, in the opinion of the Investigator, might compromise participant safety or interfere with evaluation of the study intervention or interpretation of participant safety or study results.
- Main Cohort: Employees of AstraZeneca involved in planning, executing, supervising, or reviewing the AZD5156/AZD3152 program, clinical study site staff, or any other individuals involved with the conduct of the study, or family members of such individuals.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 19 Dec 2022 | 27 |
 Denmark | Not Recruiting | 19 Dec 2022 | 73 |
 France | Not Recruiting | 19 Dec 2022 | 81 |
 Germany | Not Recruiting | 19 Dec 2022 | 148 |
 Poland | Not Recruiting | 19 Dec 2022 | 18 |
 Spain | Not Recruiting | 19 Dec 2022 | 186 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Sipavibart | Test | SOLUTION FOR INJECTION/INFUSION | INTRAMUSCULAR INJECTION | 300 | 15 | PRD11323393 |
SODIUM CHLORIDE | Placebo | — | INTRAMUSCULAR INJECTION | 18 | 15 | SUB12581MIG |
EVUSHELD 150 mg + 150 mg solution for injection | Comparator | SOLUTION FOR INJECTION | INTRAMUSCULAR INJECTION | 300 | 15 | PRD9606390 |
EVUSHELD 150 mg + 150 mg solution for injection | Comparator | SOLUTION FOR INJECTION | INTRAMUSCULAR INJECTION | 300 | 15 | PRD9606398 |