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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 : Active, not recruiting
First Posted : August 18, 2020
Results First Posted : April 1, 2022
Last Update Posted : July 21, 2022
Sponsor:
Collaborator:
Iqvia Pty Ltd
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE August 17, 2020
First Posted Date  ICMJE August 18, 2020
Results First Submitted Date  ICMJE March 3, 2022
Results First Posted Date  ICMJE April 1, 2022
Last Update Posted Date July 21, 2022
Actual Study Start Date  ICMJE August 28, 2020
Actual Primary Completion Date March 5, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 3, 2022)
  • Number of Participants Achieving Binary Response [ 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 ]
    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.
  • Number of Participants With Adverse Events (AEs) Occurring 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.
  • Number of Participants With Serious Adverse Events (SAE), Medically Attended Adverse Events (MAAE), and Adverse Event of Special Interest (AESI) Occurring Throughout the Study [ 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 ]
    An SAE is an AE occurring during any study phase that fulfils one 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 17, 2020)
  • To estimate the efficacy of 2 IM doses of AZD1222 compared to placebo for the prevention of COVID-19 in adults ≥ 18 years of age [ Time Frame: 1 year ]
    A binary response, whereby a participant 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.
  • To assess the safety and tolerability of 2 IM doses of AZD1222 compared to placebo in adults ≥ 18 years of age [ Time Frame: a: 28 days post each dose of study Intervention. / b: from Day 1 post-treatment through Day 730. ]
    1. Incidence of adverse events.
    2. Incidence of serious adverse events, medically attended adverse events, and adverse events of special interest.
  • To assess the reactogenicity of 2 IM doses of AZD1222 compared to placebo in adults ≥ 18 years of age (Substudy only) [ Time Frame: 7 days post each dose of study intervention. ]
    Incidence of local and systemic solicited adverse events.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 3, 2022)
  • Number of Participants With First Post-intervention Response for SARS-CoV-2 Nucleocapsid Antibodies Occurring 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).
  • Number of Participants With First COVID-19 Symptomatic Illness Using Centers for Disease Control and Prevention (CDC) Criteria Occurring 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 one 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.
  • Number of Participants With First COVID-19 Symptomatic Illness Using University of Oxford-Defined Symptom Criteria Occurring 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.
  • Number of Participants With First Symptomatic COVID-19 Regardless of Evidence of Prior SARS-CoV-2 Infection Occurring 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).
  • Number of Participants With COVID-19 Severe or Critical Symptomatic Illness Occurring 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).
  • Number of Participants With COVID-19 Severe or Critical Symptomatic Illness Occurring 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 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.
  • Number of Participants With COVID-19-Related Emergency Department Visits Occurring 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).
  • 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, and 57 ]
    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.
  • Geometric Mean Fold Rise (GMFR) for SARS-CoV-2 S and RBD Antibodies as Measured by MSD Serology Assay [ Time Frame: Baseline (Day 1) and Days 15, 29, 43, and 57 ]
    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.
  • Percentage of Participants With Seroresponse to the S and RBD Antigens of AZD1222 as Measured by MSD Serology Assay [ Time Frame: Baseline (Day 1) and Days 15, 29, 43, and 57 ]
    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.
  • GMTs for SARS-CoV-2 Neutralizing Antibodies as Measured by Pseudo-neutralization Assay [ Time Frame: Baseline (Day 1) and Days 15, 29, 43, and 57 ]
    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.
  • GMFR for SARS-CoV-2 Neutralizing Antibodies as Measured by Pseudo-neutralization Assay [ Time Frame: Baseline (Day 1) and Days 15, 29, 43, and 57 ]
    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.
  • Percentage of Participants With Seroresponse to SARS-CoV-2 Neutralizing Antibodies of AZD1222 as Measured by Pseudo-neutralization Assay [ Time Frame: Baseline (Day 1) and Days 15, 29, 43, and 57 ]
    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.
  • Number of Participants With COVID-19 Symptomatic Illness Occurring 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 17, 2020)
  • To estimate the efficacy of 2 IM doses of AZD1222 compared to placebo for the prevention of SARS-CoV-2 asymptomatic infection [ Time Frame: 1 year ]
    Proportion of participants positive for SARS-CoV-2 Nucleocapsid antibodies over time.
  • To estimate the efficacy of 2 IM doses of AZD1222 compared to placebo for the prevention of symptomatic COVID-19 using CDC criteria [ Time Frame: 1 year ]
    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
  • To estimate the efficacy of 2 IM doses of AZD1222 compared to placebo for the prevention of University of Oxford defined symptomatic COVID-19 [ Time Frame: 1 year ]
    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
  • To estimate the efficacy of 2 IM doses of AZD1222 compared to placebo for the prevention of severe or critical symptomatic COVID-19 [ Time Frame: 1 year ]
    The incidence of SARS-CoV-2 RT-PCR-positive severe or critical symptomatic illness occurring ≥ 15 days post second dose of study intervention.
  • To estimate the efficacy of 2 IM doses of AZD1222 compared to placebo for the prevention of COVID-19-related Emergency Department visits [ Time Frame: 1 year ]
    The incidence of COVID-19-related Emergency Department visits occurring ≥ 15 days post second dose of study intervention
  • To assess antibody responses to AZD1222 S antigen following 2 IM doses of AZD1222 or placebo (Substudy and Illness Visits only) [ Time Frame: 28 days post each dose ]
    Post-treatment GMTs and GMFRs in SARS-CoV-2S, RBD antibodies (MSD serology assay); The proportion of participants who have a post-treatment seroresponse (≥ 4-fold rise in titers) to the S, RBD antigens of AZD1222 (MSD serology assay)
  • To determine anti-SARS-CoV-2 neutralizing antibody levels in serum following 2 IM doses of AZD1222 or placebo (Sub-study and Illness Visits only) [ Time Frame: 28 days post each dose ]
    Post-treatment GMTs and GMFRs in SARS-CoV-2 neutralizing antibodies (wild-type assay or pseudo-neutralization assay); Proportion of participants who have a post-treatment seroresponse (≥ 4-fold rise in titers) to AZD1222 as measured by SARS-CoV-2 neutralizing antibodies (wild-type assay or pseudo-neutralization assay)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase III Double-blind, Placebo-controlled Study of AZD1222 for the Prevention of COVID-19 in Adults
Official Title  ICMJE 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
Brief Summary The aim of the study is to assess the safety, efficacy, and immunogenicity of AZD1222 for the prevention of COVID-19.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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
Condition  ICMJE
  • COVID-19
  • SARS-CoV-2
Intervention  ICMJE
  • Biological: AZD1222
    AZD1222 is a recombinant replication-defective chimpanzee adenovirus expressing the SARS-CoV-2-5 surface glycoprotein.
  • Biological: Placebo
    Commercially available 0.9% (n/V) saline for injection.
Study Arms  ICMJE
  • Experimental: AZD1222
    Approximately 20,000 participants randomized to the AZD1222 arm
    Intervention: Biological: AZD1222
  • Placebo Comparator: Placebo
    Approximately 10,000 participants randomized to the saline placebo arm
    Intervention: Biological: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 22, 2021)
32459
Original Estimated Enrollment  ICMJE
 (submitted: August 17, 2020)
30000
Estimated Study Completion Date  ICMJE February 24, 2023
Actual Primary Completion Date March 5, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 130 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Chile,   Peru,   United States
Removed Location Countries Argentina,   Colombia,   France
 
Administrative Information
NCT Number  ICMJE NCT04516746
Other Study ID Numbers  ICMJE D8110C00001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Supporting Materials: 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
Current Responsible Party AstraZeneca
Original Responsible Party Same as current
Current Study Sponsor  ICMJE AstraZeneca
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Iqvia Pty Ltd
Investigators  ICMJE
Principal Investigator: Ann Falsey, MD University of Rochester
Principal Investigator: Magda Sobieszczyk, MD Columbia University
PRS Account AstraZeneca
Verification Date July 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP