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Phase III Double-blind, Placebo-controlled Study of AZD1222 for the Prevention of COVID-19 in Adults

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04516746
Recruitment Status : Completed
First Posted : August 18, 2020
Results First Posted : April 1, 2022
Last Update Posted : February 5, 2024
Sponsor:
Collaborator:
Iqvia Pty Ltd
Information provided by (Responsible Party):
AstraZeneca

Study Description
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Brief Summary:
The aim of the study is to assess the safety, efficacy, and immunogenicity of AZD1222 for the prevention of COVID-19.

Condition or disease Intervention/treatment Phase
COVID-19 SARS-CoV-2 Biological: AZD1222 Biological: Placebo Phase 3

Detailed Description:
The COVID-19 pandemic has caused major disruption to healthcare systems with significant socioeconomic impacts. Currently, there are no specific treatments available against COVID-19 and accelerated vaccine development is urgently needed. A safe and effective vaccine for COVID-19 prevention would have significant public health impact.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32450 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Participants are assigned to one of two or more groups in parallel for the duration of the study.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double Blind: two or more parties are unaware of the intervention assignment.
Primary Purpose: Treatment
Official Title: A Phase III Randomized, Double-blind, Placebo-controlled Multicenter Study in Adults, to Determine the Safety, Efficacy, and Immunogenicity of AZD1222, a Non-replicating ChAdOx1 Vector Vaccine, for the Prevention of COVID-19
Actual Study Start Date : August 28, 2020
Actual Primary Completion Date : March 5, 2021
Actual Study Completion Date : February 10, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: AZD-1222

Arms and Interventions
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Arm Intervention/treatment
Experimental: AZD1222
Approximately 20,000 participants randomized to the AZD1222 arm
 Biological: AZD1222
AZD1222 is a recombinant replication-defective chimpanzee adenovirus expressing the SARS-CoV-2-5 surface glycoprotein.
Placebo Comparator: Placebo
Approximately 10,000 participants randomized to the saline placebo arm
 Biological: Placebo
Commercially available 0.9% (n/V) saline for injection.


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants With Binary Response [ Time Frame: From 15 days post second dose up to data cut-off date (DCO) of 05 March 2021 or study discontinuation or unblinding or receipt of non-study COVID-19 vaccination, up to a maximum of 17 weeks ]
    A binary response, whereby a participant with negative serostatus at baseline is defined as a COVID-19 case if their first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurs ≥ 15 days post second dose of study intervention. Otherwise, a participant is not defined as a COVID-19 case. The primary efficacy analysis was performed once approximately 150 events meeting the primary efficacy outcome measure definition had occurred across the AZD1222 and placebo groups.

  2. Number of Participants With Adverse Events (AEs) Post Each Dose of Study Intervention [ Time Frame: From Day 1 up to 28 days post second dose of study intervention, approximately 57 days ]
    An AE is the development of any untoward medical occurrence in a clinical study participant administered medicinal product and which does not necessarily have a causal relationship with this medicinal product. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

  3. Number of Participants With Serious Adverse Events (SAE), Medically Attended Adverse Events (MAAE), and Adverse Event of Special Interest (AESI) Prior to Non-study COVID-19 Vaccination [ Time Frame: From Day 1 up to receipt of non-study COVID-19 vaccination or a maximum of Day 760 for participants without non-study COVID-19 vaccination. ]
    An SAE is an AE occurring during any study phase that fulfils 1 or more of the following criteria: death; immediately life-threatening; in-participant hospitalization or prolongation of existing hospitalization; persistent or significant disability or incapacity; congenital abnormality or birth defect; an important medical event. AESIs were events of scientific and medical interest specific to the further understanding of the study intervention safety profile and required close monitoring and rapid communication by the investigators to the sponsor. MAAEs are defined as AEs leading to medically-attended visits that were not routine visits for physical examination or vaccination, such as an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. Different follow-up time between AZD1222 and Placebo groups (20223 versus 3893 participant years).

  4. Number of Participants With Local and Systemic Solicited AEs in the Substudy Only [ Time Frame: From Day 1 up to 7 days post each dose of study intervention, approximately 14 days ]
    Solicited AEs are local or systemic predefined events for assessment of reactogenicity. Solicited AEs were collected in a e-Diary only for participants in the substudy.


Secondary Outcome Measures :
  1. Number of Participants With First Post-intervention Response for SARS-CoV-2 Nucleocapsid Antibodies Post Second Dose of Study Intervention [ Time Frame: From 15 days post second dose up to DCO of 05 March 2021 or study discontinuation or unblinding or receipt of non-study COVID-19 vaccination, up to a maximum of 17 weeks ]
    The incidence of the first post-intervention response (negative at baseline to positive post intervention with study intervention) for SARS-CoV-2 nucleocapsid antibodies occurring ≥ 15 days post second dose of study intervention (key secondary endpoint).

  2. Number of Participants With First COVID-19 Symptomatic Illness Using Centers for Disease Control and Prevention (CDC) Criteria Post Second Dose of Study Intervention [ Time Frame: From 15 days post second dose up to DCO of 05 March 2021 or study discontinuation or unblinding or receipt of non-study COVID-19 vaccination, up to a maximum of 17 weeks ]
    The incidence of the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurring ≥ 15 days post second dose of study intervention using CDC criteria. Participant must present with at least 1 of the following symptoms per CDC criteria: fever, shortness of breath, difficulty breathing, chills, cough, fatigue, muscle aches, body aches, headache, new loss of taste, new loss of smell, sore throat, congestion, runny nose, nausea, vomiting, or diarrhea.

  3. Number of Participants With First COVID-19 Symptomatic Illness Using University of Oxford-Defined Symptom Criteria Post Second Dose of Study Intervention [ Time Frame: From 15 days post second dose up to DCO of 05 March 2021 or study discontinuation or unblinding or receipt of non-study COVID-19 vaccination, up to a maximum of 17 weeks ]
    The incidence of the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurring ≥ 15 days post second dose of study intervention using University of Oxford-defined symptom criteria: new onset of fever (> 100 °Fahrenheit [> 37.8 °Celsius]), cough, shortness of breath, or anosmia/ageusia.

  4. Number of Participants With First Symptomatic COVID-19 Regardless of Evidence of Prior SARS-CoV-2 Infection Post Second Dose of Study Intervention [ Time Frame: From 15 days post second dose up to DCO of 05 March 2021 or study discontinuation or unblinding or receipt of non-study COVID-19 vaccination, up to a maximum of 17 weeks ]
    The incidence of the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurring ≥ 15 days post second dose of study intervention regardless of evidence of prior SARS-CoV-2 infection (key secondary endpoint).

  5. Number of Participants With COVID-19 Severe or Critical Symptomatic Illness Post Second Dose of Study Intervention [ Time Frame: From 15 days post second dose up to DCO of 05 March 2021 or study discontinuation or unblinding or receipt of non-study COVID-19 vaccination, up to a maximum of 17 weeks ]
    The incidence of SARS-CoV-2 RT-PCR-positive severe or critical symptomatic illness occurring ≥ 15 days post second dose of study intervention. The severity of COVID-19 was evaluated in participants with symptoms of COVID-19. Following are the findings regarding severe of critical symptomatic COVID-19: clinical signs at rest indicative of severe systemic illness; respiratory failure; evidence of shock; significant acute renal, hepatic, or neurologic dysfunction; admission to an intensive care unit; and death (key secondary endpoint).

  6. Number of Participants With COVID-19 Severe or Critical Symptomatic Illness Post First Dose of Study Intervention [ Time Frame: From 15 days post second dose up to DCO of 05 March 2021 or study discontinuation or unblinding or receipt of non-study COVID-19 vaccination, up to a maximum of 17 weeks ]
    The incidence of SARS-CoV-2 RT-PCR-positive severe or critical symptomatic illness occurring post first dose of study intervention. The severity of COVID-19 was evaluated in participants with symptoms of COVID-19. Following are the findings regarding severe of critical symptomatic COVID-19: clinical signs at rest indicative of severe systemic illness; respiratory failure; evidence of shock; significant acute renal, hepatic, or neurologic dysfunction; admission to an intensive care unit; and death.

  7. Number of Participants With COVID-19-Related Emergency Department Visits Post Second Dose of Study Intervention [ Time Frame: From 15 days post second dose up to DCO of 05 March 2021 or study discontinuation or unblinding or receipt of non-study COVID-19 vaccination, up to a maximum of 17 weeks ]
    The incidence of COVID-19-related emergency department visits occurring ≥ 15 days post second dose of study intervention (key secondary endpoint).

  8. Geometric Mean Titers (GMTs) for SARS-CoV-2 Spike (S) and Receptor Binding Domain (RBD) Antibodies as Measured by Meso Scale Discovery (MSD) Serology Assay [ Time Frame: Baseline (Day 1) and Days 15, 29, 43, 57, 90, 180, 360, and 730 ]
    The GMT was calculated as the antilogarithm of Σ(log base 2 transformed titer/n), i.e. as the anti-logarithm transformation of the mean of the log-transformed titer, where 'n' is the number of participants with titer information.

  9. Geometric Mean Fold Rise (GMFR) for SARS-CoV-2 S and RBD Antibodies as Measured by MSD Serology Assay [ Time Frame: Days 15, 29, 43, 57, 90, 180, 360, and 730 ]
    The fold rise was calculated as the ratio of the post-vaccination titer level to the pre-vaccination titer level. GMFR was calculated as anti-logarithm of Σ (log base 2 transformed (post-vaccination titer/ pre-vaccination titer)/n). Where 'n' is the number of participants with titer information.

  10. Percentage of Participants With Seroresponse to the S and RBD Antigens of AZD1222 as Measured by MSD Serology Assay [ Time Frame: Days 15, 29, 43, 57, 90, 180, 360, and 730 ]
    The fold rise was calculated as the ratio of the post-vaccination titer level to the pre-vaccination titer level. The percentage of participants with a post-intervention seroresponse (≥ 4-fold rise in titers from baseline value to 28 days post each dose) to the S and RBD antigens of AZD1222 as measured by MSD serology assay is reported.

  11. GMTs for SARS-CoV-2 Neutralizing Antibodies as Measured by Pseudo-neutralization Assay [ Time Frame: Baseline (Day 1) and Days 15, 29, 43, 57, 90, 180, and 360 ]
    The GMT was calculated as the antilogarithm of Σ(log base 2 transformed titer/n), i.e. as the anti-logarithm transformation of the mean of the log-transformed titer, where 'n' is the number of participants with titer information.

  12. GMFR for SARS-CoV-2 Neutralizing Antibodies as Measured by Pseudo-neutralization Assay [ Time Frame: Days 15, 29, 43, 57, 90, 180, and 360 ]
    The fold rise was calculated as the ratio of the post-vaccination titer level to the pre-vaccination titer level. GMFR was calculated as anti-logarithm of Σ (log base 2 transformed (post-vaccination titer/ pre-vaccination titer)/n). Where 'n' is the number of participants with titer information.

  13. Percentage of Participants With Seroresponse to SARS-CoV-2 Neutralizing Antibodies of AZD1222 as Measured by Pseudo-neutralization Assay [ Time Frame: Days 15, 29, 43, 57, 90, 180, and 360 ]
    The fold rise was calculated as the ratio of the post-vaccination titer level to the pre-vaccination titer level. The percentage of participants with a post-intervention seroresponse (≥ 4-fold rise in titers from baseline value to 28 days post each dose) to SARS-CoV-2 neutralizing antibodies of AZD1222 as measured by pseudo-neutralization assay is reported.

  14. Number of Participants With COVID-19 Symptomatic Illness Post First Dose of Study Intervention [ Time Frame: From Day 1 up to DCO of 05 March 2021 or study discontinuation or unblinding or receipt of non-study COVID-19 vaccination, up to a maximum of approximately 27 weeks ]
    The incidence of SARS-CoV-2 RT-PCR-positive symptomatic illness occurring post first dose of study intervention.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Increased risk of SARS-CoV-2 infection
  • Medically stable

Exclusion Criteria:

  • confirmed or suspected immunosuppressive or immunodeficient state
  • significant disease, disorder, or finding
  • Prior or concomitant vaccine therapy for COVID-19
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04516746


Locations
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Sponsors and Collaborators
AstraZeneca
Iqvia Pty Ltd
Investigators
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Principal Investigator: Ann Falsey, MD University of Rochester
Principal Investigator: Magda Sobieszczyk, MD Columbia University
  Study Documents (Full-Text)

Documents provided by AstraZeneca:
Study Protocol  [PDF] February 19, 2021
Statistical Analysis Plan  [PDF] February 28, 2021

More Information
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Additional Information:

Publications:
CDC. (Centers for Disease Control and Prevention). Coronavirus Disease 2019 (COVID-19), Symptoms of Coronavrus. https://www.cdc.gov/coronavirus/2019-ncov/symptomstesting/ symptoms.html. Published 2020. Accessed 01 July 2020.
FDA. (Food and Drug Administration). Guidance for Industry. Toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials. . https://www.fda.gov/media/73679/download. Published 2007. Accessed 20 June 2020.
SPEAC. (Safety Platform for Emergency Vaccines) D2.3 Priority list of adverse events of special interest: COVID-19. Work Package: WP2 Standards and Tools. v1.1. 05 March 2020. https://media.tghn.org/articles/COVID-19_AESIs_SPEAC_V1.1_5Mar2020.pdf. Published 2020. Accessed 14 June 2020.
van Doremalen N, Lambe T, Spencer A, Belij-Rammerstorfer S, Purushotham JN, Port JR et al. ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques. bioRxiv. 2020;2020.05.13.093195.
WHO. (World Health Organization) Coronavirus disease (COVID-19) situation report-175. 13 July 2020. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200713- covid-19-sitrep-175.pdf?sfvrsn=d6acef25_2. Published 2020. Accessed 13 July 2020.
Clinical Study Protocol - 1.0 AstraZeneca AZD1222 - D8110C00001 CONFIDENTIAL AND PROPRIETARY 92 of 92

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04516746    
Other Study ID Numbers: D8110C00001
2020-005226-28 ( EudraCT Number )
First Posted: August 18, 2020    Key Record Dates
Results First Posted: April 1, 2022
Last Update Posted: February 5, 2024
Last Verified: February 2024
Individual Participant Data (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
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
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 de-identified 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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
COVID-19 Vaccine
Additional relevant MeSH terms:
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COVID-19
Pneumonia, Viral
Pneumonia
Respiratory Tract Infections
Infections
Virus Diseases
 Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases