Study on Clinical Use of EVUSHELD (AZD7442) in the Real-world Setting – A Multi‑centre, Single-arm, Observational Study to Determine the Utilisation and Clinical Outcomes of EVUSHELD in China - CLEAR

Rationale Despite the increase in COVID-19 vaccine roll-out, many individuals still remain at high risk of breakthrough infection and many of these individuals are also at higher risk of poor COVID-19 outcomes. Although the PROVENT trial was invaluable in demonstrating AZD7442’s ability to prevent symptomatic infection, it was conducted in highly controlled environments using a rigorous protocol, which does not accurately reflect the patient experience in clinical practice. Furthermore, the sample size of Asian population in phase 3 clinical trials is small (110 subjects in AZD7442 group and 60 subjects in placebo group), and there is very limited clinical trial/real-world data in Chinese population is reported. Studies are therefore needed to understand who is being administered AZD7442 in the real world, the frequency of COVID-19 related events, and healthcare resource utilisation (HCRU). Also, important to understand is the potential impact that AZD7442 administration may have on COVID-19 risk behaviours (particularly shielding and other preventive measures), which may in turn influence interpretation of AZD7442 effectiveness results. Such information is imperative to inform clinical decision-making for the care of this relatively vulnerable population. Therefore, this current study aims to describe the utilisation and clinical outcomes of AZD7442 in Chinese population for pre-exposure prophylaxis. Although this study will not evaluate the effectiveness of AZD7442, the descriptive results may guide further development of studies to assess real world effectiveness of AZD7442. The study is planned to be conducted in approximately 100 sites in China.

1.1 Primary Objectives • To describe the baseline demographic and clinical characteristics of individuals receiving AZD7442 for pre-exposure prophylaxis 1.2 Secondary Objectives • To describe the baseline demographic and clinical characteristics of individuals receiving AZD7442 for pre-exposure prophylaxis by population subgroup of key basic disease, including hematological malignancies, solid organ transplant, autoimmune diseases, solid tumor, respiratory disease, chronic kidney disease (CKD; including dialysis) and others • To describe the incidence of SARS-CoV-2 infection (asymptomatic or symptomatic), medically attended COVID-19, and COVID-19 related hospitalization and death up to 12 months after first administration of AZD7442 for pre-exposure prophylaxis • To describe the incidence of all-cause hospitalization and mortality during the 12 months after first administration of AZD7442 for pre-exposure prophylaxis • To describe COVID-19 risk behaviours at the time of AZD7442 injection and during the 12 months after first administration of AZD7442 for pre-exposure prophylaxis • To describe COVID-19-related healthcare resource utilisation (HCRU) during the 12 months after first administration of AZD7442 for pre-exposure prophylaxis • To describe the safety of AZD7442 during the 12 months after first administration of AZD7442 1.3 Exploratory Objectives • To describe the demographic and clinical characteristics of SARS-CoV-2 infection (asymptomatic or symptomatic), medically attended COVID-19, and COVID-19 related hospitalized cases occurring up to 12 months following AZD7442 first administration for pre-exposure prophylaxis in comparison to non-cases • To describe the incidence of long COVID syndrome following AZD7442 first administration for pre-exposure prophylaxis • To describe the baseline and repeat administration(s) of AZD7442 • To describe the usage purpose of AZD7442 2. METHODOLOGY 2.1 Study Design – General Aspects This will be a multi centre, single arm, observational study using primary data collection to describe the demographic and clinical characteristics of subjects who received AZD7442. The study is planned to be conducted in approximately 100 sites in China. The study will be conducted in the hospital centres that are authorized to administer AZD7442, agree to participate in the study, and wherein investigators have access to all medical records (electronic or paper) for individual patients. The physicians at the hospital centres will make a decision to administer AZD7442 to patients according to the local regulations (including the prescribing information) and such a decision to use AZD7442 is independent of the study. The investigators will recruit subjects who meet the study eligibility criteria. The date of first administration of AZD7442 to individual patients will be the index date (Day 0 for the individual patient). Enrolment visit (subjects are recruited into the study at this visit) could be at/after the index date. The informed consent will be obtained from subjects before data are collected. Prospective data collection will commence immediately after enrolment into the study. Subjects will be contacted remotely (by phone/text message) or return to site every 30 days to enquire about COVID-19 risk behaviours, any positive test result for SARS-CoV-2 infection for themselves and any household/direct contacts and, if they report a positive test result, their COVID-19 symptoms, hospitalization, and HCRU. Data will be collected at study enrolment and every 30 days, until Month 12 after the index date, or discontinuation, loss to follow up, entry into an interventional study, or death, whichever occurs first. In addition, prospective data can be collected from subjects as part of their routine clinical visits, from participating centre personnel, patient medical records as a referred source data. If the subject administrated AZD7442 before enrolment, the data from the index date to enrolment date will be collected retrospectively. Baseline data (data prior to the index date/Day 0) including demographics and baseline clinical characteristics, history of SARS CoV 2 infection causing COVID 19, underlying co morbidities from up to 12 months before first administration of AZD7442, history of hospitalization, and other HCRU will be collected from patients’ medical records. If baseline data couldn’t be collected completely due to subjects’ clinical condition, it still can be collected in the following visits. Data will be prospectively entered into an electronic case report form (CRF) by the investigator or designee. All retrospective data will be entered in the database within 7 days from the date of enrolment. The total duration of participation in the study for each subject will be up to 12 months. 2.1.1 Data Source Hospital centres that are authorized to administer AZD7442 and where investigators have access to all medical records (electronic or paper) for individual patients will be selected for participation in this study. Baseline data and prospective data during the follow up period will be collected by the treating physicians from patients’ medical records and through direct contact with subjects using a pre approved and validated electronic CRF and risk behaviour questionnaire. The study will be approved by Institutional Review Board (IRB)/Independent Ethics Committee (IEC) before the commencement of subject recruitment at any centre. 2.1.2 Data Management Data management will be performed by AstraZeneca/designee according to the Data Management Plan. An electronic data capture system will be used to manage data collection during this study. The electronic data capture system is a software tool designed to ensure quality assurance and facilitate data capture during clinical trials. The data will be extracted by the investigator or designee from the patient’s medical records and from the subjects during the follow up period and transcribed into the electronic data capture system. The investigator will ensure the accuracy, completeness, and timeliness of the data reported to AstraZeneca. Data collection processes and procedures will be reviewed for completeness, accuracy, reliability, and consistency by the investigator or a designee. The investigator or designee will cooperate with AstraZeneca representative(s) for the periodic review of study documents to ensure the accuracy and completeness of the data capture system in accordance with the study monitoring plan. Electronic consistency checks and manual review will be used to identify any errors or inconsistencies in the data. This information will be provided to the study sites by means of electronic or manual queries. 2.2 Study Population Participants included in this study are all individuals who have received AZD7442 since AZD7442 will be on market in China. 2.3 Inclusion Criteria Patients who fulfil all the following inclusion criteria will be eligible to participate in the study: • Individuals receiving AZD7442 before enrolment date or have been prescribed have planned to administrate at enrolment date • Informed consent signed. 2.4 Exclusion Criteria Patients who fulfil any of the following exclusion criteria will not be eligible to participate in the study: • Patients currently participating in interventional clinical trials of SARS-CoV-2 prophylactic or treatments 2.5 Participant Follow-up If the subject administrated AZD7442 before enrolment, the data from the index date and enrolment date will be collected retrospectively. Subjects will be contacted remotely or return to site to enquire about COVID-19 risk behaviours, any positive test result for SARS-CoV-2 infection for themselves and any household/direct contacts and, if they report a positive test result, their COVID-19 symptoms, hospitalization, and HCRU. Data will be collected at study enrolment and every 30 days until Month 12 after the index date. 3. VARIABLES AND EPIDEMIOLOGICAL MEASUREMENTS Definitions for clinical outcomes: • SARS-CoV-2 infection: SARS-CoV-2 infection confirmed by either molecular or antigen test. • Symptomatic COVID-19 disease: SARS-CoV-2 infection confirmed by either molecular or antigen test and at least one of the following symptoms at the time of testing with any of the following symptoms: • Fever • Shortness of breath • Difficulty breathing • New onset confusion (only for participants ≥ 60 years) • Appetite loss or decrease food intake (only for participants ≥ 60 years) • Increased supplemental oxygen requirement (only for participants ≥ 60 years on baseline supplemental oxygen) • Cough • Fatigue • Muscle aches • Body aches • Headache • New loss of taste or smell • Sore throat • Congestion • Runny nose • Nausea • Vomiting • Diarrhea • Medically attended COVID-19: An inpatient record, emergency department visit, outpatient clinic, or general practitioner encounter with a recorded diagnosis of COVID-19; can be with or without a documented SARS-CoV-2 infection, confirmed by either molecular or antigen test. • COVID-19 related hospitalization: Inpatient record with an admission or discharge diagnosis of COVID-19; can be with or without a documented SARS-CoV-2 infection, confirmed by either molecular or antigen test. • Intensive care unit (ICU) Admission for COVID-19: Inpatient record with an admission or discharge diagnosis consisting of COVID-19 with a specific notation of ICU as the setting of care. • COVID-19 related death: • A recorded death with COVID-19 listed as an underlying cause of death on cause-of-death registers, or • Death during hospitalization, with COVID-19 as a listed diagnosis, or • Death within 28 days after a diagnosis or hospitalization for COVID-19 • COVID-19 severity as per WHO Clinical Progression Scale: (Marshall et al., 2020; WHO, 2021) Long COVID syndrome: signs and symptoms that develop during or after an infection consistent with COVID-19, continue for more than 12 weeks and are not explained by an alternative diagnosis (WHO, 2021). 3.1 Exposures First dose of AZD7442 should be administrated before the enrolment or AZD7442 have been prescribed or have planned to be administrated at the enrolment. The date of administration of AZD7442 to subjects will be the index date. 4. STATISTICAL ANALYSIS PLAN 4.1 Statistical Methods – General Aspects All analyses will be descriptive in nature. Continuous variables will be summarized by providing the number of observations (n), mean, standard deviation, median, quartiles (Q1 and Q3), minimum and maximum. Categorical variables will be summarized by providing frequency and proportions. Event rates and the associated exact Poisson 95% confidence intervals (CIs) will be calculated. Time-to-event data will be summarized using Kaplan-Meier estimates of the median event time and quartiles together with their 95% CIs. Analysis will be executed via SAS 9.4 or above. Data will be analysed based on observed cases only without imputing of missing values. The level of missingness of each of the study variables will be reported. For continuous variables, numbers of subjects with missing values will be reported. For categorical variables, missing will be reported as one of categories. The study design and conduct will be planned so as to minimise loss to follow up and missing data. At the completion of data collection, if missingness of key variables and loss to follow up is seen to be greater than 20%, we will examine the mechanism of the missingness and discuss the implications on the study findings. The full analysis set (FAS) will include all patients who received at least one dose of AZD7442. All analyses will be performed on the FAS. Further specification on planned analyses will be provided in a separate statistical analysis plan (SAP). 4.1.1 Primary Objectives Baseline demographic and clinical characteristics (Section 4.2, Primary Outcomes) of individuals receiving AZD7442 for pre-exposure prophylaxis, along with the total number of sites, and number of subjects per site will be described for the entire study population using descriptive statistics (Section 5.1). 4.1.2 Secondary Objectives The incidence rate of laboratory confirmed and/or healthcare attended SARS-CoV-2 infection (up to 12 months after first administration of AZD7442) will be calculated as the number of such events in the population divided by the total person-time follow-up (from index date until the earliest of: event, death or loss to follow-up). The associated exact Poisson 95% CI will also be presented. Sensitivity analyses will be conducted excluding those with active SARS-CoV-2 infections detected within the first two weeks after AZD7442 administration and also stratifying by known contact with a SARS-CoV-2 positive person within the two weeks prior to AZD7442 administration. The incidence rate of COVID-19 related hospitalisation, as well as other events, (up to 12 months after first administration of AZD7442) will be calculated as the number of such events in the population divided by the total person-time follow-up (from index date until the earliest of: event, death or loss to follow-up). The associated exact Poisson 95% CI will also be presented. The incidence rate of SAE/AESI/ADR will be summarized by numbers and percentages of subjects with events, as well as numbers of events. The 95% CI of even rate will also be presented. Given the different follow up we may have in the study, exposure adjusted SAE/AESI/ADR will also be summarized if appropriate. COVID-related hospitalization and days hospitalized will be described using descriptive statistics (Section 5.1). COVID-19 risk behaviours at the time of AZD7442 injection and during the 12 months after first administration of AZD7442, as well as COVID-19-related HCRU during the 12 months after first administration of AZD7442 for pre-exposure prophylaxis will be described using descriptive statistics (Section 5.1). Description and analysis will be executed for each of six cohorts (including: haematological malignancies, solid organ transplant, autoimmune disease, solid tumour, respiratory disease and CKD). If there are disease type(s) other than the six diseases above, similar description and analysis will be executed also. If sufficient events are observed, time to medically attended COVID-19, time to SARS-CoV-2 infection (asymptomatic or symptomatic), time to COVID-19 death, time to COVID-19-related hospitalization, time to COVID-19 ICU admission will be summarized using Kaplan-Meier estimates of the median event time and quartiles together with their 95% CIs. Given the immortal time bias we may have, the details of the statistical method to eliminate immortal time bias will be described in the SAP. 4.1.3 Exploratory Objectives The baseline demographic and clinical characteristics among subjects with SARS- CoV-2 confirmed infections up to 12 months after first administration of AZD7442 will be presented as well as ones among those subjects without infection using descriptive statistics (Section 5.1). The incidence of long COVID-19 syndrome (Section 4.2) will be calculated as the number of such events in the population divided by the total person-time follow-up (from index date until the earliest of: event, death or loss to follow-up). The associated exact Poisson 95% CI will also be presented. The baseline and repeat administrations of AZD7442 (Section 4.2, Exploratory Outcomes) will also be described using descriptive statistics (Section 5.1). The usage purpose of AZD7442 will be described by numbers and percentages of subjects using descriptive statistics. 4.2 Bias 4.2.1 Methods to Minimize Bias Not applicable as this is a single arm study. 4.3 Interim Analyses Interim analyses will be conducted approximately at 1000, 2500 and 6000 subjects enrolled in the study, and 6-month after last subject in (LSI). 4.4 Precision Calculations As this study will be a descriptive observational study, without any formal comparisons, no power calculation will be required. All subjects using AZD7442 meeting the inclusion/exclusion criteria are eligible for inclusion in the study, subject to site agreement and subject consent to participate. The study plans to enroll 6000 subjects from almost 100 sites. Based on clinical unmet needs, subjects with haematological malignancies, solid organ transplant, autoimmune disease, solid tumour, respiratory disease and CKD will be the population of interest. Assuming the expected prevalence of the 6 predefined subgroups would be ranging from 1% to 50%, the sample size of 6000 could provide the 95% CI estimation as listed in below table, using Clopper-Pearson exact method. As listed below, the precision estimate is ranging from 0.3% to 1.3%, which complies with general clinical requirement for precision estimation. 5. STUDY PLAN Prospective data will be collected remotely or return to site every 30 days, until Month 12 after the index date, or discontinuation, lost to follow up, entry into an interventional study, or death, whichever occurs first. In addition, prospective data can be collected from subjects as part of their routine clinical visits, from participating centre personnel, patient medical records as a referred source data. Adverse event (AE) data will be collected at 24 hours after injection (if subject is enrolled in the study on the day of first administration of AZD7442) and thereafter during the study period. Thereafter, AEs will be collected as part of routine clinical visits along with other prospective data collection. If the subject administrated AZD7442 before enrolment, the data from the index date and enrolment date will be collected retrospectively. Baseline data (data prior to the index date) will be collected from patients’ medical records. 5.1.1 Procedures Procedure for Subject Discontinuation/Withdrawal from Study A subject may withdraw from the study at any time at his/her own request, or may be withdrawn from the study at any time at the discretion of the investigator for behavioural, compliance, or administrative reasons. The investigator should inquire with the subject about the reason for withdrawal and follow up with the subject regarding any unresolved AEs. Information regarding the reason for not completing the study will be recorded on the appropriate electronic CRF. Specific reasons for subject discontinuation may include the following: • Withdrawal of consent by the subject • Violation of eligibility criteria The extracted data for the subject, if any, will not be used in the analyses for such subjects. Discontinued subjects will not be replaced. Procedure for Early Termination Should AZ decide to discontinue the study prior to what is established in this protocol, the investigator and relevant authorities will receive written notice describing the rationale supporting the decision of terminating the study. 5.1.2 Quality Control Monitoring Before the first subject is recruited into the study, the AZ affiliate or contract research organisation (CRO) representative will: • Establish the adequacy of the facilities and the investigator’s capability to appropriately select the sample • Discuss with the investigators (and other personnel involved with the study) their responsibilities with regards to protocol compliance, and the responsibilities of AZ or its representatives. This will be documented in an Observational Study Primary Agreement between AZ/delegate and the investigator. During the study, the local CRO representative or delegate can implement different activities to assure compliance with AZ standards of quality. These activities could include but are not limited to the following: Contacts with the sites to: • Provide information and support to the investigators • Confirm that the research team is complying with the protocol and that data are being accurately recorded in electronic CRFs • Ensure that the subject informed consent forms (ICFs) are signed and stored at the investigator’s site • Ensure that the CRFs are completed properly and with adequate quality. Monitoring activities for: • Checking of ICFs • Checking that subjects exist in medical records The extent and nature of monitoring will be decided during the study planning based on design, complexity, number of subjects, number of centres, etc. Observational Research Centre (multi country) will give some recommendations that could be locally adapted. Different signals (e.g., high rejection rate in a centre) should be used as potential identification of low protocol compliance by investigators. If these or any other signal occurs or if the local coordinator is suspicious of a potential non optimal level of protocol compliance by the site investigator, specific measures should be adopted to evaluate the situation, identify the issue, and implement specific action plans to correct the situation. Training of Study Site Personnel The principal investigator will ensure that appropriate training relevant to the Observational Study is given to investigational staff, and that any new information relevant to the performance of this Observational Study is forwarded to the staff involved. 5.2 Protection of Human Subjects The Observational Study will be performed in accordance with ethical principles that are consistent with the Declaration of Helsinki, International Committee on Harmonization of Good Clinical Practice (ICH GCPs), Good Pharmacoepidemiology Practices and the applicable legislation on Observational Studies. The investigator will perform the Observational Study in accordance with the regulations and guidelines governing medical practice and ethics in the country of the Observational Study and in accordance with currently acceptable techniques and know how. The final protocol of the Observational Study, including the final version of the subject ICF, must be approved or given a favourable opinion in writing by the Ethics Committee/IRB/IEC. The Ethics Committee/IRB/IEC must also approve any amendment to the protocol and all advertising used to recruit subjects for the study, according to local regulations. 5.2.1 Subject Informed Consent The investigator at each centre will ensure that the subject is given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the Observational Study. Subjects must also be notified that they are free to discontinue from the Observational Study at any time. Subjects should be given the opportunity to ask questions and allowed time to consider the information provided. For participants aged ≥12 years but <18 years, written informed consent must be obtained from both the participant and his/her guardian. Subjects who voluntarily consented to participate in this study and provided written informed consent unless informed consent could be exempted after the approval by IRB/ECs. The signed and dated subject informed consent must be obtained before any specific procedure for the Observational Study is performed, including the following: • Interview with the investigator • Fulfil the questionnaires • CRFs completion. The investigator must store the original, signed subject ICF. A copy of the signed ICF must be given to the subject. 5.2.2 Confidentiality of Study/Subject Data The subject ICF will incorporate wording that complies with relevant data protection and privacy legislation. Pursuant to this wording, subjects will authorise the collection, use, and disclosure of their personal data by the investigator and by those persons who need that information for the purposes of the Observational Study. The subject ICF will explain that Observational Study data will be stored in a computer database, maintaining confidentiality in accordance with the local law for Data Protection. The subject ICF will also explain that for quality check purposes, a monitor of AZ or a monitor of company representing AZ, will require direct access to the signed subject ICFs. In case source data verification will be planned as quality check, the ICF will explain that for data verification purposes, monitor of AZ or a monitor of company representing AZ may require direct access to source documents that are part of the hospital or practice records relevant to the Observational Study. 5.3 Collection and Reporting of Adverse Events/Adverse Drug Reactions 5.3.1 Definition of Adverse Events An AE is any untoward medical occurrence in a subject or clinical study subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The term AE is used to include both serious and non serious AEs. 5.3.2 Definition of Serious Adverse Event A SAE is an AE occurring during any study phase, that fulfil one or more of the following criteria: • Results in death • Is life threatening (life threatening in this context refers to a reaction in which the was at risk of death at the time of the reaction; it does not refer to a reaction that hypothetically might have caused death if more severe) • Requires in patient hospitalisation or prolongation of existing hospitalisation • Results in persistent or significant disability or incapacity • Is a congenital abnormality/birth defect • Is an important medical event that may jeopardise the patient or may require intervention to prevent one of the outcomes listed above. Medical and scientific judgement should be exercised in deciding whether other situations should be considered an SAE. Any suspected transmission via a medicinal product of an infectious agent is also considered an SAE and may be subject to expedited reporting requirements in some countries. Any organism, virus, or infectious particle, pathogenic or non pathogenic, is considered an infectious agent. 5.3.3 Definition of Adverse Events of Special Interest • AESIs are events of scientific and medical interest specific to the further understanding of AZD7442’s safety profile and require close monitoring and rapid communication by the investigators to AstraZeneca. An AESI may be serious or non-serious. All AESIs will be recorded in the eCRF. Serious AESIs will be recorded and reported as per Section 6.3.6. • The AESIs for AZD7442 are anaphylaxis and other serious hypersensitivity reactions, including immune complex disease, and injection site reactions. 5.3.4 Definition of Adverse Drug Reactions An Adverse drug reaction (ADR) is an AE suspected to be causally related to the medicinal product. An ADR is a response to a medicinal product which is noxious and unintended. Adverse reactions may arise from use of the product within or outside the terms of the marketing authorization or from occupational exposure. 5.3.5 Collection of Adverse Events In this study, all SAEs, AESIs and ADRs will be recorded in the electronic CRF. Serious events will be collected from patient charts. Non-serious ADR events (suspected to be related to the product per reporter) will be reported based on physician assessment of causality of events. Any collected SAE (including serious ADRs) and non-serious ADRs will be reported to the AZ PS Data Entry Site (DES) for recording in global safety database. The following variables will be collected: • AE term • The date when the SAE started and stopped • Intensity or changes in intensity • Common Terminology Criteria for Adverse Events (CTCAE) grade and changes in CTCAE grade • Seriousness criteria • Investigator causality rating against the medicinal product (yes or no) • Action taken with regard to medicinal product • Outcome It is important to distinguish between serious and severe AEs. Severity is a measure of intensity whereas seriousness is defined by the criteria in Sections 6.3.2. An AE of severe intensity need not necessarily be considered serious. For example, nausea that persists for several hours may be considered severe nausea, but not a SAE unless it meets one of the criteria shown in Section 6.3.2. On the other hand, a stroke that results in only a limited degree of disability may be considered a mild stroke but would be a SAE if it satisfies one of the criteria shown in Section 6.3.2. Causality collection The investigator will assess the causal relationship between the studied medicinal product and each AE, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may have been caused by the medicinal product?’ Time period for collection of adverse events Adverse Events will be collected from the time of signing the ICF and during any follow up period specified in the protocol. 5.3.6 Reporting of Adverse Events The investigators or other site personnel will inform the appropriate AZ representatives within 1-day i.e., immediately but no later than 24 hours of when he or she becomes aware of: • All SAEs • All non serious ADRs The designated AZ representative works with the investigator to ensure that all the necessary information is provided to the AZ Patient Safety data entry site within 1 calendar day of initial receipt for fatal and life threatening events and within 5 calendar days of initial receipt for all SAEs and non-serious ADRs. For all collected events, where important or relevant information is missing, active follow up is undertaken immediately. Investigators or other site personnel inform AZ representatives of any follow up information within the same timeframe as the original report. All collected AEs will be summarised in an interim safety analysis and the final study report. 5.3.7 Special Situations All special situations must be reported to AstraZeneca as per list below: • Exposure to product during pregnancy • Exposure to product whilst breastfeeding • Overdose • Medication error • Off label use/product use issue • Drug abuse • Drug misuse • Occupational exposure • Product quality complaint/issues including counterfeit/falsified product • Lack of efficacy and disease progression • Medical device/device constituent part malfunction or deficiency For special situations associated with safety events, standard reporting timelines apply. Special situations not associated with safety events should be reported to AstraZeneca within 5 calendar days. Additional details on the collection and reporting of adverse events will be provided in AstraZeneca safety data handling plan for non-interventional studies.