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Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.

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Official Title

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

Double Blind: two or more parties are unaware of the intervention assignment.

Approximately 20,000 participants randomized to the AZD1222 arm

Approximately 10,000 participants randomized to the saline placebo arm

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

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

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.

CTIS Number

EudraCT Number

NCT ID

Patient Level Data

Therapeutic Area

AZD1222 is a recombinant replication-defective chimpanzee adenovirus expressing the SARS-CoV-2-5 surface glycoprotein.

Commercially available 0.9% (n/V) saline for injection.

Research Site

Participants are assigned to one of two or more groups in parallel for the duration of the study.

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

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.

a. Incidence of adverse events.
b. Incidence of serious adverse events, medically attended adverse events, and adverse events of special interest.

Incidence of local and systemic solicited adverse events.

Age Continuous

Sex: Female, Male

Race/Ethnicity, Customized

All randomized participants analysis set included all participants who enrolled into the study.

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.

The 95% confidence interval (CI) and p-value were estimated based on Poisson regression with robust variance (including study arm and stratification factor [age group at informed consent] as covariates, and log of the follow up time as an offset).

The fully vaccinated analysis set (FVS) included all participants in the full analysis set (FAS) who were seronegative at baseline, received 2 doses of study intervention, and who remained on-study 15 days after their second dose without having had a prior SARS-CoV-2 RT-PCR-positive confirmed COVID-19 infection.

Number of Participants With Binary Response

After first dose

After second dose

After any dose

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.

The safety analysis set included all participants who received at least 1 dose of study intervention from primary analysis data cut which is 1 participant less in placebo group than that from the final data cut.

Number of Participants With Adverse Events (AEs) Post Each Dose of Study Intervention

SAEs

MAAEs

AESIs

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).

The safety analysis set included all participants who received at least 1 dose of study intervention.

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

Solicited local AEs: After first dose

Solicited local AEs: After second dose

Solicited local AEs: After any dose

Solicited systemic AEs: After first dose

Solicited systemic AEs: After second dose

Solicited systemic AEs: After any dose

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.

The safety analysis set included all participants who received at least 1 dose of study intervention. Only participants included in the substudy were analyzed.

Number of Participants With Local and Systemic Solicited AEs in the Substudy Only

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).

The 95% CI and p-value were estimated based on Poisson regression with robust variance (including study arm and stratification factor [age group at informed consent] as covariates, and log of the follow up time as an offset).

The FVS included all participants in the FAS who were seronegative at baseline, received 2 doses of study intervention, and who remained on-study 15 days after their second dose without having had a prior SARS-CoV-2 RT-PCR-positive confirmed COVID-19 infection.

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 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.

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 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 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 regardless of evidence of prior SARS-CoV-2 infection (key secondary endpoint).

The FVS regardless of prior SARS-COV-2 infection included all participants in the FAS who were seronegative at baseline, received 2 doses of study intervention, and who remained on-study 15 days after their second dose.

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 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).

The exact 1-sided 97.5% CI and p-value were estimated based on stratified Poisson regression with exact conditional method (including study arm and stratification factor [age group at informed consent] as strata factor and log of total number of participants for each combination of study arm and strata as an offset).

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 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.

The 95% CI were estimated based on Poisson regression with robust variance (including study arm and age group at screening (18-65 years, ≥ 65 years) as covariates and log of the follow-up time as an offset).

The FAS included all randomized participants who received at least 1 dose of study intervention, irrespective of their protocol adherence and continued participation in the study. Only participants who are seronegative at baseline were analyzed.

Number of Participants With COVID-19 Severe or Critical Symptomatic Illness Post First 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).

Number of Participants With COVID-19-Related Emergency Department Visits Post Second Dose of Study Intervention

S Antibody Titer: Baseline (Day 1)

S Antibody Titer: Day 15

S Antibody Titer: Day 29

S Antibody Titer: Day 43

S Antibody Titer: Day 57

S Antibody Titer: Day 90

S Antibody Titer: Day 180

S Antibody Titer: Day 360

S Antibody Titer: Day 730

RBD Antibody Titer: Baseline (Day 1)

RBD Antibody Titer: Day 15

RBD Antibody Titer: Day 29

RBD Antibody Titer: Day 43

RBD Antibody Titer: Day 57

RBD Antibody Titer: Day 90

RBD Antibody Titer: Day 180

RBD Antibody Titer: Day 360

RBD Antibody Titer: Day 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.

The immunogenicity analysis population included all participants in the safety analysis set who had no protocol deviations judged to have the potential to interfere with the generation or interpretation of an immune response. Only participants included in the substudy were analyzed.

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 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.

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. 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.

Percentage of Participants With Seroresponse to the S and RBD Antigens of AZD1222 as Measured by MSD Serology Assay

Baseline (Day 1)

Day 15

Day 29

Day 43

Day 57

Day 90

Day 180

Day 360

GMTs for SARS-CoV-2 Neutralizing Antibodies as Measured by Pseudo-neutralization Assay

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. 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.

Percentage of Participants With Seroresponse to SARS-CoV-2 Neutralizing Antibodies of AZD1222 as Measured by Pseudo-neutralization Assay

The incidence of SARS-CoV-2 RT-PCR-positive symptomatic illness occurring post first dose of study intervention.

Number of Participants With COVID-19 Symptomatic Illness Post First Dose of Study Intervention

Overall Study

The study had a screening period (14 days), followed by a treatment and follow-up period (up to 760 days). A total of 32450 participants were randomized in a 2:1 ratio to receive AZD1222 or placebo. One participant was enrolled at 2 sites and excluded from all analysis sets. The first participants randomized in each age group in the United States of America participated in a substudy to assess immunogenicity and reactogenicity.

Global Clinical Lead

The incidence of the first post-treatment response (negative at baseline to positive post treatment with study intervention) for SARS-CoV-2 Nucleocapsid antibodies occurring greater than or equal to 15 days post second dose of study intervention.

The incidence of the first case of SARS-CoV-2 RT-PCR-positive symptomatic illness for a participant occurring at or after 15 days post second dose of study intervention using criteria from the CDC.

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.

The incidence of SARS-CoV-RT-PCR-positive severe or critical symptomatic illness occurring 15 days or more post second 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 incidence of COVID-19-related Emergency Department visits occurring ≥ 15 days post second dose of study intervention

Post-treatment GMTs and GMFRs in SARS-CoV-2 S, 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)

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)

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

The incidence of SARS-CoV-2 RT-PCR-positive symptomatic illness occurring post first dose of study intervention

Arms	Assigned Interventions
Experimental: AZD1222 Approximately 20,000 participants randomized to the AZD1222 arm	Biological/Vaccine: 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/Vaccine: Placebo Commercially available 0.9% (n/V) saline for injection.

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

Official Title

Medical condition

Phase

Healthy volunteers

Study drug

Sex

Actual Enrollment

Study type

Age

Date

Study design

Verification:

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Documents available

Statistical Analysis Plan (SAP)

D8110C00001-CSP-amendment-6_Redacted.pdf

CSR Synopsis

Trial Results Summaries

Contacts

Contact

Investigators

Principal Investigator