Study setting {9}
Participants will be enrolled at the National Centre for Infectious Diseases (NCID), Singapore.
Eligibility criteria {10}
The key eligibility criterion is individuals who had received a homologous primary vaccines series with BNT162b2 or mRNA-1272 at least six months prior to study enrolment.
Inclusion criteria:
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Willing and able to provide informed consent for participation in this study;
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Aged ≥21years at the time of study enrolment;
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Received the second dose of BNT162b2 or mRNA-1273 vaccines at least 6 months prior to enrolment;
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Willing and able to comply with all scheduled visits, vaccination plan, laboratory tests and other study procedures.
Exclusion criteria:
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Known history of SARS-CoV-2 or SARS-CoV-1 infection;
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Previously received an investigational coronavirus vaccine;
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Previously received a SARS-CoV-2 monoclonal antibody;
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Current or planned simultaneous participation in another interventional study;
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A history of anaphylaxis, urticaria, or other significant adverse reaction requiring medical intervention after receipt of a COVID-19 vaccine, or otherwise have a contraindication to one of the available study vaccines per the approved label;
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Individuals who are immunocompromised (e.g. active leukemia or lymphoma, generalized malignancy, aplastic anemia, solid organ transplant, bone marrow transplant, current radiation therapy congenital immunodeficiency, HIV/AIDS with CD4 lymphocyte count < 200 and patients on immunosuppressant medications);
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Received systemic immunosuppressants or immune-modifying drugs for >14 days in total within 6 months prior to screening (for corticosteroids >/= 20 milligram per day of prednisone equivalent). Topical tacrolimus is allowed if not used within 14 days prior to Day 1;
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Individuals who are pregnant or breast feeding;
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Chronic illness that, in the opinion of the study team, is at a stage where it might interfere with trial conduct or completion;
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Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily;
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Current alcohol abuse or drug addiction that might interfere with the ability to comply with trial procedures in the opinion of the study team;
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Moderate or severe acute illness/infection (according to study team’s judgement) on the day of vaccination, or febrile illness (temperature ≥ 37.5°C). A prospective participant should not be included in the study until the condition has resolved or the febrile event has subsided.
Who will take informed consent?
The principal investigator (PI) or medically qualified co-investigators are responsible for ensuring freely given consent is obtained from each potential participant prior to the conduct of any protocol-specific procedures.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Leftover biological specimen and/or data may be used for future research, subject to participant consent.
Interventions
Explanation for the choice of comparators {6b}
The PRIBIVAC study aims to assess the immunogenicity and safety of heterologous boost COVID-19 vaccine regimens compared with a homologous boost regimen.
Circulating antibody levels wane following vaccination and COVID-19 infection. In our previous study of COVID-19 recovered patients, ~60% of the cohort (n = 164) retained >30% inhibition level of neutralizing antibodies against SARS-CoV-2 at 6 months post infection (5). Data from individuals vaccinated with mRNA-1273 showed gradually declining neutralizing antibody titers by 6 months post inoculation (1).
A third dose of the vaccines developed by Pfizer–BioNTech, Moderna, Oxford–AstraZeneca and Sinovac elicited significant increases in neutralizing antibodies titers when administered several months after the second dose (10). However, there is limited data as to whether a homologous booster regimen can enhance protection against emerging VOC. Due to the large number of potential vaccine combinations, the variation in vaccine types used by programs in different countries, and potentially confounding effects of background infection rates, data relevant to Singapore’s program is not available.
COVAXIN® (Bharat Biotech) was approved by WHO under the EUL procedure on 3 Nov 2021 for use in two doses for primary vaccination and is available in Singapore via the Special Access Route (SAR). A randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial in India has confirmed the safety and efficacy of COVAXIN® against laboratory-confirmed symptomatic COVID-19 disease in adults (21). However, the efficacy of COVAXIN® against emerging VOCs is unknown and is not currently being studied in booster trials.
Intervention description {11a}
The booster vaccine for the control arm will be a homologous mRNA vaccine (e.g. BNT162b2 + BNT162b2 + BNT162b2 or mRNA-1273 + mRNA-1273 + mRNA-1273), while for individuals randomized to intervention group 1 the mRNA booster vaccine administered will be heterologous to the primary series (e.g. BNT162b2 + BNT162b2 + mRNA-1273 or mRNA-1273 + mRNA-1273 + BNT162b2). The booster vaccine candidates for intervention groups 2–4 will be an alternative non-mRNA COVID-19 vaccine. At the time of writing (25-Jan-2022), vaccine candidates for intervention groups 3 and 4 have not been confirmed.
Control group: Homologous mRNA booster vaccine
Intervention group 1: Heterologous mRNA booster vaccine
Intervention group 2: COVAXIN®
Intervention group 3: Non-mRNA booster vaccine B
Intervention group 4: Non-mRNA booster vaccine C
Criteria for discontinuing or modifying allocated interventions {11b}
The participant may be withdrawn prematurely from the trial if he/she withdraws consent to participate in the study. In such instances, the withdrawal will be applicable to both data collection as well as vaccination.
Participants may voluntarily decline the booster vaccination, or they may be withdrawn by their attending physician and/or by the study investigator(s) on the basis of the participant’s best interest. Even if the participant did not receive the booster vaccination, collected samples will still be analysed up until the point the participant withdraws consent.
All participants, including those who declined the booster vaccination, will be followed up until 12 months, unless the subject withdraws informed consent or is lost to follow-up or have died.
Safety and futility will be reviewed by an independent Data and Safety Monitoring Board (DSMB) after the first 10 participants in each of the intervention arms have completed assessments at study day 28. DSMB may recommend discontinuation of a study arm on the basis of safety concerns or futility in immunogenicity.
Strategies to improve adherence to interventions {11c}
Booster dose will be given once only; patient adherence is not applicable.
Relevant concomitant care permitted or prohibited during the trial {11d}
There will be no restrictions on diet, exercise or concomitant medication imposed on participants, except for the restriction of receiving any other COVID-19 vaccines outside of this study.
Provisions for post-trial care {30}
Unless there are any serious adverse events that need to be followed up closely, no post study follow-up and procedures need to be performed after the final study visit. If participant follows the directions of the study team and are physically injured due to the procedure given under the plan for this study, NCID/TTSH will pay the medical expenses for the treatment of that injury.
Outcomes {12}
Objectives
|
Outcome measures
|
Timepoint(s)
|
Primary objective
|
To determine whether heterologous prime-boost-boost COVID-19 vaccine regimens lead to non-inferior humoral immunity compared with homologous prime-boost-boost vaccine regimen against wildtype SARS-CoV-2 and/or 1³ VOC
|
Level of SARS-CoV-2 anti-spike immunoglobulins
|
Day 28
|
Secondary objectives
|
To determine whether heterologous prime-boost-boost COVID-19 vaccine regimens lead to non-inferior humoral and cellular immunity compared with homologous prime-boost-boost vaccine regimen against wildtype SARS-CoV-2 and/or 1³ VOC
|
Level of SARS-CoV-2 anti-spike immunoglobulins
Level of SARS-CoV-2 neutralising antibodies
Quantitative T-cell responses to spike proteins
|
Days 1, 7, 180, 360
Days 1, 7, 28, 180, 360
Days 1, 7, 28, 180, 360
|
To assess the reactogenicity and safety of heterologous and homologous prime-boost-boost COVID-19 vaccine schedules
|
Solicited local and systemic reaction
Changes from baseline in laboratory safety measures
Unsolicited adverse events (AEs)
Serious adverse events (SAEs), AEs of special interest (e.g. myocarditis, pericarditis), medically attended AEs
|
Day 7
Day 7
Day 28
Throughout the study
|
Exploratory objectives
|
To determine whether vaccine efficacy differs between heterologous and homologous prime-boost-boost regimens
|
PCR-confirmed COVID-19 infections as recognised by Ministry of Health, Singapore
|
Throughout the study
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To determine whether the administered mRNA vaccine (control group and intervention group 1 only) can be detected in the blood at ~1 week post vaccination
|
qRT-PCR using primers targeting the sequence of the mRNA for SARS-CoV-2 spike protein
|
Day 7
|
Participant timeline {13}
Footnotes:
1 Screening visit may be performed on the same day as Visit 1
2 Informed consent must be signed prior to initiating any study procedures;
3 Randomization is subjected to vaccine availability;
4 Visit 1: third vaccine shot for participant (only one vaccine booster dose will be administered for the study);
5 Physical examination will be done by a qualified study team member or a treating licensed healthcare provider. The physical examination on visit 1 will be conducted during screening prior to vaccination;
6 Vital signs include pulse, systolic and diastolic blood pressure, respiratory rate and body temperature prior to vaccination and blood collection;
7 For women of child bearing potential, a urine pregnancy test will be conducted;
8 At each study visit, a review for PCR-confirmed COVID-19 infection will be conducted. In most cases, such information will be available in the participant’s HealthHub mobile app;
9 All AEs including a list of solicited and other events will be recorded for 7 days after vaccination. Unsolicited AEs will be recorded up to day 28 after vaccination. SAE will be recorded from study’s vaccination until the end of study period at 12 months. They will be assessed via the listed study procedures, safety laboratory tests, and participant self-recorded diary;
10 Hematology tests include full blood count with differential and platelet counts;
11 Liver panel includes albumin, total bilirubin, alkaline phosphatase (ALP) and alanine transaminase (ALT); Renal panel includes sodium, potassium and creatinine;
12 Cardiology panel include creatine kinase and troponin;
13 Blood samples will be collected at NCID research clinic, de-identified/coded before dispatch to research laboratories such as A*STAR Singapore Immunology Network, Duke-NUS and NCID’s National Public Health Laboratory. The study team based at NCID research clinic will maintain the codes linking the blood samples to its donor. Subjected to participant consent, any de-identified leftover blood samples may also be analyzed for exploratory research to find new scientific information about coronaviruses and related diseases, which may occur locally or overseas;
14 Blood sample for immunogenic studies may be taken at Visit 1 instead of screening visit if blood draw at screening is not possible. The study team will make every effort to complete all blood-taking in one seating to minimize the number of needle pricks.
Sample size {14}
Based on data from our ongoing COVID-19 vaccine immune-monitoring study (SCOPE) (22), the mean level of SARS-CoV-2 anti-spike immunoglobulins was 84% (SD=15%) at 28 days after the second dose. This was determined using a SARS-CoV-2 surrogate virus neutralization test (sVNT) that detects total immuno-dominant neutralizing antibodies targeting the viral spike (S) protein receptor-binding domain in an isotype- and species-independent manner. We expect immunogenicity will be boosted back to the same level after the third booster dose in the control arm. Assuming an immunogenicity level of 81% in an intervention arm and a non-inferiority margin of -10%, a sample size of 87 subjects per arm is needed to conclude non-inferiority of the intervention arm against the control arm with 80% power. The sample size is calculated at a one-sided 2.5% significance level and accounts for an attrition rate of 15%. A sample size of 100 subjects per arm will provide a power of 85.1% based on the above assumptions and calculations.
Since recruitment of subjects to intervention arms may be activated in a staggered way depending on availability of the vaccines, and recruitment to the control arm will continue until the target sample size of 100 is achieved in each intervention arm, we prepare to enroll a double sample size in the control arm for the purpose of study planning. This gives a total sample size of up to 600 subjects.
Recruitment {15}
Recruitment will occur over 6-9 months with one-year follow up period.
Assignment of interventions: allocation
Sequence generation {16a}
Randomization will be performed using randomized permuted blocks and stratified by the following criteria:
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Age (<60 years, ≥60 years)
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Time from 2nd vaccine dose administered (6-9 months, >9 months)
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Primary vaccine series (BNT162b2 or mRNA-1273)
Eligible participants will be randomized in equal proportions to each of the study arms that are open for randomization. Enrolment to a study arm will be discontinued if recommended by DSMB or if the target sample size of 100 in the study arm has been reached. In the scenario where recruitment is discontinued in any of the intervention arms from 1 to 4 at the interim analysis, randomization to the control arm may continue beyond 100 participants until the target sample size of 100 participants has been reached in the remaining intervention arms.
Concealment mechanism {16b}
Randomization will be performed using a web-based randomization system hosted by Singapore Clinical Research Institute (SCRI). Password secured accounts will be assigned to the site personnel responsible for the randomization, where he/she can log into the randomization system using the Internet. Allocation concealment will be maintained until the registration and randomization process have been completed.
Implementation {16c}
The study team from SCRN in charge of participant enrolment will perform the randomization using the web-based randomization system.
Assignment of interventions: Blinding
Who will be blinded {17a}
Vaccine allocation will be single-blind, i.e. only participants will be blinded. This is to reduce the risk of bias in participant-reported adverse events.
Procedure for unblinding if needed {17b}
Blinding will be maintained for the participants until their Day 28 Visit (Visit 3).
Data collection and management
Plans for assessment and collection of outcomes {18a}
All physical examinations will be performed by the investigator or co-investigator. It includes cardiovascular, respiratory, abdomen, neurological, musculoskeletal and skin assessments. Vital signs including pulse rate, systolic and diastolic blood pressure, respiratory rate and body temperature will also be recorded.
The participant will be given a diary to record all the local and general symptoms experienced after receiving the vaccination. Local symptoms may include pain, redness, swelling, bruising, itchiness, muscle ache or movement limitation at the injection site. General symptoms may include headache, fever, nausea, vomiting, sore throat, cough, runny nose, tiredness and red (sore) eyes, as well as symptoms suggestive of COVID-19 infections (e.g. fever, cough and shortness of breath). This diary will cover 7 days post-vaccination and must be returned to the study team when the participant comes for the next visit.
Safety will be assessed via physical examinations, vital sign measurements, medical reviews, AE and SAE evaluation, safety laboratory tests, and participant self-recorded diary. Blood samples will be taken during screening or day 0, and at the follow-up visits at days 7, 28, 180, 360 post-enrollment for evaluation of immunogenicity and/or safety. All adverse events will be entered in the appropriate eCRF (including seriousness, grade, severity, relationship to the intervention procedure and action taken) and in the source documents.
Plans to promote participant retention and complete follow-up {18b}
The study team will remind participants prior to their follow-up visits to minimize any missed appointments. Participants will be reimbursed for their time, inconvenience and transportation costs for every study visit they complete.
Data management {19}
Paper Case Report Forms (CRFs) will be used for initial data collection. These will be transcribed to an eCRF using Research Electronic Data Capture (REDCap). The trial database will include information on demographics, medical history, vaccine arm allocation, vital signs, laboratory investigation tests, as well as AEs and SAEs. Paper documents will be maintained and stored in a locked office, with access restricted to study personnel. All electronic documents with participant information will be password-protected.
Study monitors will visit the study site periodically to assess data quality and study integrity. Study monitors will review the study records on site to directly compare them with source documents, discuss the conduct of the study with the Investigator, and verify that the facilities and workflow are compliant with Good Clinical Practice (GCP). Such visits will be scheduled in advance to allow for logistical arrangements to be made. In addition, the study may be evaluated by government inspectors who must be allowed access to CRFs, source documents and other study files.
Confidentiality {27}
All study findings and documents will be regarded as confidential. The investigators and other study personnel must not disclose such information without prior written approval from the PI. Participant confidentiality will be strictly maintained to the extent possible under the law and local hospital policy. Identifiable information will be removed from any published data.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Blood samples will be collected at NCID research clinic, de-identified/coded before dispatch to collaborating research laboratories such as A*STAR ID Labs and Singapore Immunology Network, Duke-NUS and NCID’s NPHL for immunogenic studies as described below:
Antibody response assays
To determine the presence and levels of anti-SARS-COV-2 in human sera using S-protein flow cytometry-based (SFB) assay. Cells expressing the full S protein in its native configuration will be seeded at 1.5 x 105 cells per well in 96 well V-bottom plates. The cells will be first incubated with human serum (diluted 1:100 in 10% FBS) before a secondary incubation with a double stain, consisting of Alexa Fluor 647-conjugated anti-human IgG (diluted 1:500) and propidium iodide (PI; diluted 1:2500). Cells were read on BD Biosciences LSR4 laser and analyzed using FlowJo (Tree Star). A standard ELISA will also be used with the whole spike-protein, RBD fragment, or peptides encompassing dominant epitopes of the S and N proteins immobilized in the microplate wells. To identify the repertoire of epitopes induced by the vaccines, a peptide library ELISA will be used. This will provide fine resolution of the antibody responses against the S-proteins at different time points and help to determine whether there is a fixation of the antibody response to certain epitopes (antigenic sin).
To examine the neutralizing capacity of the antibodies in the human sera, two different assays will be performed: the sVNT and the pseudovirus or live-virus assay inhibition.
T-cell response assays
Quantitative T-cell responses to the vaccines will be measured using SARS-CoV-2 peptides from spike protein to stimulate the PBMCs isolated from donor’s blood by ELISPOT or flow cytometry. To detect CD8 T-cells, PBMCs will be stimulated with a peptide pool consisting of peptides 8–10 amino acids in length. Negative controls using media and DMSO (~0.5%) will be used as reference. Assays will be performed in duplicates. The cell and peptides will be incubated in ELISpot 96-well plates. After 24 hours, the plates will be washed and assayed for IFNγ. To detect CD4 Th1/2 cells, PBMCs will be stimulated with a peptide pool consisting of peptides that are 15 amino acids in length. After 24 hours, the plates will be washed and assayed for IFNγ (Th1) or IL4/IL5/IL13 (Th2). Spot forming units (SFU) will be measured using IRIS reader (MabTech). SARS-CoV-2 specific T effector subsets will be tested after stimulation with pooled SARS-CoV-2 PepTivator® S, S1, peptides (0.6 nmol/mL each) (Miltenyi Biotec) for 6 hours. Brefeldin A and Monesin (ThermoFisher Scientific) was added at 2 hours post stimulation. Cells were stained with surface stain markers in the dark at room temperature for 20 minutes, followed by fixation and permeabilization for 20 minutes with Foxp3/ Transcription Factor Staining Buffer Set (ThermoFisher Scientific). Permeabilized cells were then stained for intracellular cytokines for 20 minutes. Cells were then acquired with the CytekTM Aurora cytometer running SpectroFlo® Version 2.2.0.3 with automated unmixing. Compensation and analysis of flow cytometry data was performed with FlowJo Version 10.6.1.
The study team based at NCID research clinic will maintain the codes linking the blood samples to its donor. Subjected to participant consent, any de-identified leftover blood samples may also be analyzed for exploratory research to find new scientific information about coronaviruses and related diseases, which may occur locally or overseas.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
a. Safety analyses
Data of AEs, SAEs, Grade 3 and 4 clinical or laboratory AEs will be summarized by study arm with frequency and proportion of participants having the event, as well as the number of events. For SAEs and Grade 3 and 4 AEs, the proportion of participants with the events will be provided together with its 95% confidence interval (CI).
b. Efficacy analyses
Graphical plots will be produced for the various immunity endpoints to depict the change of immunity levels over time. Levels of SAS-CoV-2 anti-spike immunoglobulins will be summarized by study arm and by randomization stratification factors. Mean difference and its 95% confidence interval in levels of SAS-CoV-2 anti-spike immunoglobulins between an intervention arm and the control arm will be estimated from a general linear regression model which adjusts for level of SAS-CoV-2 anti-spike immunoglobulins at baseline, and randomization stratification factors. If the lower bound of the 95% CI falls above -10% (the pre-specified non-inferiority margin), non-inferiority of the intervention arm will be concluded. Analysis of repeated measurements of immunity endpoints will be performed with the use of mixed effects models that adjust for baseline values and randomization stratification factors. Log-transformation of the data may be applied as needed before the analyses.
Interim analyses {21b}
Interim analyses will be performed for DSMB review after 10 participants from each of the intervention arms from 1 to 4 have completed assessments at study day 28. DSMB may recommend discontinuation of participant enrolment to a study arm if any of the following criteria is met:
- Proportion of participants with SAE is at least 25% greater (in absolute difference) in the intervention arm compared with the control arm
- Proportion of participants with Grade 3 and 4 AEs is at least 25% greater (in absolute difference) in the intervention arm compared with the control arm
- Geometric mean ratio of anti-SARS-CoV-2 between the intervention arm and the control arm falls below 0.60.
The above guidelines may be revised in the DSMB charter, which implies the stopping guidelines will take precedence should there be any difference in the guidelines between the protocol and the DSMB charter.
Methods for additional analyses (e.g. subgroup analyses) {20b}
Analysis will be stratified by age (<60 years, ≥60 years), time from 2nd vaccine dose administered (6-9 months, >9 months) and primary vaccine series (BNT162b2 or mRNA-1273).
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Even if the participant did not receive the booster vaccination, collected samples will still be analyzed up until the point the participant withdraws consent. Participants who drop out of the study will not be replaced.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
Datasets analyzed during the study will be available from the corresponding author on reasonable request.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
This study is led by NCID’s Singapore Infectious Disease Clinical Research Network (SCRN) and supported by Singapore Clinical Research Institute (SCRI). SCRN is responsible for project management, subject recruitment and data entry. SCRI is responsible for project and data management, as well as regulatory compliance/ study monitoring.
Composition of the data monitoring committee, its role and reporting structure {21a}
An independent DSMB has been established to monitor the study. The DSMB will evaluate the study design and protocol, and review the accumulative data of safety and immunogenicity, as well as subject enrolment, protocol deviations, and data quality. The DSMB will meet after 10 participants in each intervention group have completed assessments at study day 28. Since participant recruitment may start at different time points for intervention groups 1 to 4 depending on vaccine availability and local regulatory approval, separate DSMB meetings may be needed for data review of intervention groups 1 to 4.
A DSMB Charter will be developed describing the scope of data to be reviewed, memberships of DSMB, terms of reference, decision-making process, and timing and frequency of interim analyses (with specification of stopping guidelines). An interim analysis report will be prepared for each DSMB data review, which will include a summary data on participant enrolment, data quality, demographic and baseline characteristics, protocol deviation, safety data, and immunogenicity data. Following review of interim data, DSMB may recommend discontinuation of participant enrolment to a study arm on the basis of safety concern and/or futility in immunogenicity compared with the control arm. The DSMB may request additional data review if necessary.
Adverse event reporting and harms {22}
Adverse events (AEs)
Safety will be assessed using the FDA Guidance Document (2007): Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trial (http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm074786.htm). Participants will be monitored up to Visit 2 (Day 7) for the occurrence and nature of any AEs.
All AEs will be entered in the appropriate eCRF (including seriousness, grade, severity, relationship to the IP and action taken) and in the source documents. The hospital laboratory will perform investigational tests as specified in the trial schedule, including full blood count (with differential blood count and platelet count), liver panel (total bilirubin, ALP, ALT), renal panel (sodium, potassium and creatinine), creatine kinase, troponin, and pregnancy test if indicated.
For out-of-range values, clinical laboratory reports must be reviewed by a physician within 24 hours of receipt. Out-of-range values will be evaluated as either clinically significant (CS) or not clinically significant (NS). By definition, a value flagged as “CS” must be entered on the AE page in the CRF. The test may be repeated at the Investigator’s discretion. The Investigator may use his own judgment to determine whether the abnormal finding has sufficient reasons to immediately withdraw the participant from the study.
Collecting, Recording and Reporting of “Unanticipated Problems Involving Risk to Subjects or Others” (UPIRTSO) events to the National Healthcare Group (NHG) Domain Specific Review Boards (DSRB)
UPIRTSO events refers to problems, in general, to include any incident, experience, or outcome (including AEs) that meets all of the following criteria:
1. Unexpected, in terms of nature, severity, or frequency of the problem as described in the study documentation (eg: Protocol, Consent documents etc).
2. Related or possibly related to participation in the research. Possibly related means there is a reasonable possibility that the problem may have been caused by the procedures involved in the research; and
3. Risk of harm. This suggests that the research places participants or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.
For urgent reporting, all problems involving local deaths, whether related or not, should be reported immediately – within 24 hours after first knowledge by the NHG investigator. For expedited reporting, all other problems must be reported as soon as possible but not later than 7 calendar days after first knowledge by the NHG investigator.
Collecting, recording and reporting of Serious Adverse Events (SAEs) to the Health Science Authority (HSA)
A SAE is defined as any untoward medical occurrence that: results in death, is life-threatening (immediate risk of death), requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in congenital anomaly/birth defect, or is a medically important event. Medical and scientific judgment should be exercised in determining whether an event is an important medical event. An important medical event may not be immediately life threatening and/or result in death or hospitalization. However, if it is determined that the event may jeopardize the subject and/or may require intervention to prevent one of the other AE outcomes, the important medical event should be reported as serious.
All SAEs that are unexpected and related to the study drug will be reported. The investigator is responsible for informing HSA no later than 15 calendar days after first knowledge that the case qualifies for expedited reporting. Follow-information will be actively sought and submitted as it becomes available. For fatal or life-threatening cases, HSA will be notified as soon as possible but no later than 7 calendar days after first knowledge that a case qualifies, followed by a complete report within 8 additional calendar days.
Frequency and plans for auditing trial conduct {23}
Clinical site monitoring is conducted to ensure that the rights and well-being of trial subjects are protected, that the reported trial data are accurate, complete, and verifiable. Clinical monitoring also ensures conduct of the trial is in compliance with the currently approved protocol/ amendment(s), ICH, GCP, and with applicable regulatory requirement(s) and sponsor requirement(s). Clinical monitoring will also verify that any critical study procedures are completed following specific instructions in the protocol-specific manual of procedures. Details of clinical site monitoring are documented in a clinical monitoring plan (CMP). The CMP describes in detail who will conduct the monitoring, at what frequency monitoring will be done, at what level of detail monitoring will be performed, and the distribution of monitoring reports. Monitoring visits will include, but are not limited to, review of regulatory files, accountability records, CRFs, ICFs, medical and laboratory reports, site study intervention storage records, training records, and protocol and GCP compliance.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
During the trial, any amendments to the protocol or consent materials will be approved by the Ethics Committee (NHG DSRB) before implementation. Participants will be informed in a timely manner of any new information that becomes available during the course of the study that may affect their willingness to continue study participation.
Dissemination plans {31a}
Following completion of the study, results will be published in a medical/scientific journal. Preliminary results may be released by the sponsor to help inform policy-making decisions pertaining to COVID-19 vaccination booster regimens.