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

COVID-19 Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04516746
• Other study ID #: D8110C00001
• Secondary ID: 2020-005226-28
• Status: Completed
• Phase: Phase 3
• Start date: August 28, 2020
• Est. completion date: February 10, 2023

Study information

• Verified date: February 2024
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32450
• Est. completion date: February 10, 2023
• Est. primary completion date: March 5, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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

Related Conditions & MeSH terms

• COVID-19
• SARS-CoV-2

Intervention

Biological:
• AZD1222
AZD1222 is a recombinant replication-defective chimpanzee adenovirus expressing the SARS-CoV-2-5 surface glycoprotein.
• Placebo
Commercially available 0.9% (n/V) saline for injection.

Locations

Country	Name	City	State
Chile	Research Site	Quillota
Chile	Research Site	Santiago
Chile	Research Site	Santiago
Peru	Research Site	Callao
Peru	Research Site	Cercado De Lima
Peru	Research Site	Lima
United States	Research Site	Albuquerque	New Mexico
United States	Research Site	Ankeny	Iowa
United States	Research Site	Ann Arbor	Michigan
United States	Research Site	Austin	Texas
United States	Research Site	Baltimore	Maryland
United States	Research Site	Baltimore	Maryland
United States	Research Site	Berkeley	California
United States	Research Site	Berlin	New Jersey
United States	Research Site	Bethesda	Maryland
United States	Research Site	Boston	Massachusetts
United States	Research Site	Boston	Massachusetts
United States	Research Site	Bronx	New York
United States	Research Site	Brooklyn	New York
United States	Research Site	Burlington	Vermont
United States	Research Site	Butte	Montana
United States	Research Site	Charleston	South Carolina
United States	Research Site	Chicago	Illinois
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Columbus	Ohio
United States	Research Site	Coral Gables	Florida
United States	Research Site	Dallas	Texas
United States	Research Site	Danbury	Connecticut
United States	Research Site	Denver	Colorado
United States	Research Site	Durham	North Carolina
United States	Research Site	El Centro	California
United States	Research Site	Fairway	Kansas
United States	Research Site	Fort Belvoir	Virginia
United States	Research Site	Fort Sam Houston	Texas
United States	Research Site	Gulfport	Mississippi
United States	Research Site	Honolulu	Hawaii
United States	Research Site	Houston	Texas
United States	Research Site	Indianapolis	Indiana
United States	Research Site	Kansas City	Kansas
United States	Research Site	Knoxville	Tennessee
United States	Research Site	Lake Charles	Louisiana
United States	Research Site	Lake Worth	Florida
United States	Research Site	Lexington	Kentucky
United States	Research Site	Little Rock	Arkansas
United States	Research Site	Los Angeles	California
United States	Research Site	Los Angeles	California
United States	Research Site	Madison	Wisconsin
United States	Research Site	McAllen	Texas
United States	Research Site	Meridian	Idaho
United States	Research Site	Miami Lakes	Florida
United States	Research Site	Mineola	New York
United States	Research Site	Minneapolis	Minnesota
United States	Research Site	Monroe	Louisiana
United States	Research Site	Nashville	Tennessee
United States	Research Site	New York	New York
United States	Research Site	New York	New York
United States	Research Site	New York	New York
United States	Research Site	North Charleston	South Carolina
United States	Research Site	Orlando	Florida
United States	Research Site	Phoenix	Arizona
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	Portland	Oregon
United States	Research Site	Portsmouth	New Hampshire
United States	Research Site	Richmond	Virginia
United States	Research Site	Rochester	New York
United States	Research Site	Rochester	New York
United States	Research Site	Royal Oak	Michigan
United States	Research Site	San Antonio	Texas
United States	Research Site	San Diego	California
United States	Research Site	San Diego	California
United States	Research Site	San Francisco	California
United States	Research Site	San Francisco	California
United States	Research Site	Scottsdale	Arizona
United States	Research Site	Seattle	Washington
United States	Research Site	South Charleston	West Virginia
United States	Research Site	Spartanburg	South Carolina
United States	Research Site	Spring	Texas
United States	Research Site	Torrance	California
United States	Research Site	Valhalla	New York
United States	Research Site	Warwick	Rhode Island
United States	Research Site	West Jordan	Utah
United States	Research Site	Wichita	Kansas
United States	Research Site	Wichita	Kansas
United States	Research Site	Yukon	Oklahoma

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Iqvia Pty Ltd

Countries where clinical trial is conducted

United States,  Chile,  Peru, 

References & Publications (12)

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.

Clinical Study Protocol - 1.0 AstraZeneca AZD1222 - D8110C00001 CONFIDENTIAL AND PROPRIETARY 92 of 92

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.

Folegatti PM, Bittaye M, Flaxman A, Lopez FR, Bellamy D, Kupke A, Mair C, Makinson R, Sheridan J, Rohde C, Halwe S, Jeong Y, Park YS, Kim JO, Song M, Boyd A, Tran N, Silman D, Poulton I, Datoo M, Marshall J, Themistocleous Y, Lawrie A, Roberts R, Berrie E, Becker S, Lambe T, Hill A, Ewer K, Gilbert S. Safety and immunogenicity of a candidate Middle East respiratory syndrome coronavirus viral-vectored vaccine: a dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial. Lancet Infect Dis. 2020 Jul;20(7):816-826. doi: 10.1016/S1473-3099(20)30160-2. Epub 2020 Apr 21. Erratum In: Lancet Infect Dis. 2020 May 12;: Lancet Infect Dis. 2020 Jun 8;: — View Citation

Li F. Structure, Function, and Evolution of Coronavirus Spike Proteins. Annu Rev Virol. 2016 Sep 29;3(1):237-261. doi: 10.1146/annurev-virology-110615-042301. Epub 2016 Aug 25. — View Citation

Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Wang W, Song H, Huang B, Zhu N, Bi Y, Ma X, Zhan F, Wang L, Hu T, Zhou H, Hu Z, Zhou W, Zhao L, Chen J, Meng Y, Wang J, Lin Y, Yuan J, Xie Z, Ma J, Liu WJ, Wang D, Xu W, Holmes EC, Gao GF, Wu G, Chen W, Shi W, Tan W. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020 Feb 22;395(10224):565-574. doi: 10.1016/S0140-6736(20)30251-8. Epub 2020 Jan 30. — View Citation

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.

Waldrop G, Doherty M, Vitoria M, Ford N. Stable patients and patients with advanced disease: consensus definitions to support sustained scale up of antiretroviral therapy. Trop Med Int Health. 2016 Sep;21(9):1124-30. doi: 10.1111/tmi.12746. Epub 2016 Jul 22. — View Citation

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.

Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020 Mar;579(7798):270-273. doi: 10.1038/s41586-020-2012-7. Epub 2020 Feb 3. Erratum In: Nature. 2020 Dec;588(7836):E6. — View Citation

Zou G. A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004 Apr 1;159(7):702-6. doi: 10.1093/aje/kwh090. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Binary Response	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.	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
Primary	Number of Participants With Adverse Events (AEs) Post Each Dose of Study Intervention	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.	From Day 1 up to 28 days post second dose of study intervention, approximately 57 days
Primary	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	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).	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.
Primary	Number of Participants With Local and Systemic Solicited AEs in the Substudy Only	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.	From Day 1 up to 7 days post each dose of study intervention, approximately 14 days
Secondary	Number of Participants With First Post-intervention Response for SARS-CoV-2 Nucleocapsid Antibodies Post Second Dose of Study Intervention	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).	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
Secondary	Number of Participants With First COVID-19 Symptomatic Illness Using Centers for Disease Control and Prevention (CDC) Criteria Post Second Dose of Study Intervention	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.	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
Secondary	Number of Participants With First COVID-19 Symptomatic Illness Using University of Oxford-Defined Symptom Criteria Post Second Dose of Study Intervention	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.	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
Secondary	Number of Participants With First Symptomatic COVID-19 Regardless of Evidence of Prior SARS-CoV-2 Infection Post Second Dose of Study Intervention	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).	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
Secondary	Number of Participants With COVID-19 Severe or Critical Symptomatic Illness Post Second Dose of Study Intervention	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).	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
Secondary	Number of Participants With COVID-19 Severe or Critical Symptomatic Illness Post First Dose of Study Intervention	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.	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
Secondary	Number of Participants With COVID-19-Related Emergency Department Visits Post Second Dose of Study Intervention	The incidence of COVID-19-related emergency department visits occurring = 15 days post second dose of study intervention (key secondary endpoint).	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
Secondary	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	The GMT was calculated as the antilogarithm of S(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.	Baseline (Day 1) and Days 15, 29, 43, 57, 90, 180, 360, and 730
Secondary	Geometric Mean Fold Rise (GMFR) for SARS-CoV-2 S and RBD Antibodies as Measured by MSD Serology Assay	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 S (log base 2 transformed (post-vaccination titer/ pre-vaccination titer)/n). Where 'n' is the number of participants with titer information.	Days 15, 29, 43, 57, 90, 180, 360, and 730
Secondary	Percentage of Participants With Seroresponse to the S and RBD Antigens of AZD1222 as Measured by MSD Serology Assay	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.	Days 15, 29, 43, 57, 90, 180, 360, and 730
Secondary	GMTs for SARS-CoV-2 Neutralizing Antibodies as Measured by Pseudo-neutralization Assay	The GMT was calculated as the antilogarithm of S(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.	Baseline (Day 1) and Days 15, 29, 43, 57, 90, 180, and 360
Secondary	GMFR for SARS-CoV-2 Neutralizing Antibodies as Measured by Pseudo-neutralization Assay	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 S (log base 2 transformed (post-vaccination titer/ pre-vaccination titer)/n). Where 'n' is the number of participants with titer information.	Days 15, 29, 43, 57, 90, 180, and 360
Secondary	Percentage of Participants With Seroresponse to SARS-CoV-2 Neutralizing Antibodies of AZD1222 as Measured by Pseudo-neutralization Assay	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.	Days 15, 29, 43, 57, 90, 180, and 360
Secondary	Number of Participants With COVID-19 Symptomatic Illness Post First Dose of Study Intervention	The incidence of SARS-CoV-2 RT-PCR-positive symptomatic illness occurring post first dose of study intervention.	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

External Links

•   CSR Synopsis
•   D8110C00001-CSP-amendment-6_Redacted.pdf
•   Statistical Analysis Plan (SAP)