Janssen’s pivotal Phase 3 randomized, double-blind, placebo-controlled efficacy trial of single-dose Ad26.COV2.S (JNJ-78436735, the Janssen/J&J COVID-19 vaccine) in adults ≥18 years. Funded by Janssen and BARDA under contract HHS0100201700018C. The trial supported the February 2021 FDA Emergency Use Authorization of the single-dose Ad26.COV2.S vaccine in the US (later constrained, then ultimately withdrawn from US distribution in May 2023). The source is Janssen’s Amendment 7 (15 April 2022) hosted on clinicaltrials.gov, with an Appendix 15 (Protocol Amendment History) carrying full Section / Description / Rationale tables for every prior amendment.
Latest protocol we have: jj-ensemble-NCT04505722-protocol.pdf
| Category | Count | Amendments |
|---|---|---|
| Total documents in the history (Original + Amendments 1–7) | 8 | |
| Direct PDFs available | 3 | Amendments 1, 3, 7 |
| Summary-only (date and rationale recorded here, no full PDF available) | 5 | Amendments 2, 4, 5, 6; Original Protocol |
| Document | Date | Available documents | Main rationale for the amendment |
|---|---|---|---|
| Original Protocol | 22 July 2020 | Summary only — no full PDF of this version available | (no main-rationale paragraph in source) |
| Amendment 1 | 15 September 2020 | jj-ensemble-amendment-1-2020-09-15.pdfWayback Machine — jnj.com | The amendment is written to adjust the dose level for Ad26.COV2.S from 1×1011 virus particles (vp) to 5×1010 vp based on data from the first-in-human (FIH) study VAC31518COV1001, including safety and immunogenicity data from Cohort 1a, safety data from Cohort 3 and immunogenicity data from the sentinel group of Cohort 3. Additional changes such as the determination of the sample size, further fine tuning of the case definitions for COVID-19, and the addition of target percentages (min/max) for enrollment of certain age groups are made based on emerging epidemiology information and advancing insights. Furthermore, throughout the protocol changes are made in response to the feedback received from Health Authorities, partners, and the community. Finally, minor errors and inconsistencies were corrected throughout the protocol. The changes made to the clinical protocol of study VAC31518COV3001 are listed below, including the rationale of each change and a list of all applicable sections. |
| Amendment 2 | 29 October 2020 | Summary only — no full PDF of this version available | This amendment is written to clarify that all participants that have a reverse-transcriptase polymerase chain reaction (RT-PCR) positive finding for SARS- CoV-2 from any source, even if asymptomatic, will be followed until there are two consecutive negative PCRs. Also, some errors, have been corrected, including the clarification that blood will be drawn on Day 29 for biomarker RNAseq analyses (PAXgene tube), which is needed in order to assess the current objectives. Finally, some minor errors have been corrected. The changes made to the clinical protocol of study VAC31518COV3001 are listed below, including the rationale of each change and a list of all applicable sections. |
| Amendment 3 | 14 December 2020 | jj-ensemble-amendment-3-2020-12-14.pdfWayback Machine — jnj.com | The main purpose of this amendment is to add first occurrence of molecularly confirmed, moderate to severe/critical COVID-19, with onset at least 28 days post double-blind vaccination as a co-primary endpoint in addition to the current primary endpoint counting as of 14 days post double-blind vaccination. The applicable secondary and exploratory endpoints were updated similarly to also include COVID-19 cases with onset at least 28 days post double-blind vaccination. In addition, the total sample size was reduced from 60,000 to approximately 40,000 participants. The protocol is further amended to change the conditions for monitoring whether efficacy greater than 30% is achieved using the sequential monitoring algorithm: (1) The minimum number of COVID-19 cases meeting the primary case definition needed to start the efficacy monitoring was modified to at least 42 instead of 20, (2) The need for a follow-up of 8 weeks for 50% of the participants prior to an initial look at an efficacy signal if the other conditions are met was removed. These and other changes made to the clinical protocol of study VAC31518COV3001 are listed below, including the rationale of each change and a list of all applicable sections. |
| Amendment 4 | 22 February 2021 | Summary only — no full PDF of this version available | The main purpose of this amendment is to outline the procedures to be followed after Emergency Use Authorization (EUA), conditional licensure, or approval in any country and approval of the protocol Amendment 4 by both Health Authority and Independent Ethics Committee (IEC)/Institutional Review Board (IRB) where a single dose of Ad26.COV2.S vaccine will be offered to enrolled participants who initially received placebo, resulting in de facto unblinding of participants and investigators. All participants will be encouraged to remain in the study and continue to be followed for efficacy/effectiveness, safety and immunogenicity as originally planned for up to 2 years post-vaccination on Day 1. This will allow assessment of the duration of protection and immunogenicity of a single dose of Ad26.COV2.S by comparing 2 groups vaccinated approximately 4 to 6 months apart. In addition, clarification is provided that RT-PCR test results obtained from any source (including local laboratories) may be used for analyses and that confirmation by the central laboratory will no longer be required as part of the case definitions. NCT04505722 [[PAGE 233]] VAC31518 (JNJ-78436735) Clinical Protocol VAC31518COV3001 Amendment 7 CONFIDENTIAL –FOIA Exemptions Apply in U.S. 234 Status: Approved, Date: 15 April 2022 These and other changes made to the clinical protocol of study VAC31518COV3001 are listed below, including the rationale of each change and a list of all applicable sections. |
| Amendment 5 | 07 May 2021 | Summary only — no full PDF of this version available | This amendment has been created to include additional safety measures due to reports of adverse events following use of the Ad26.COV2.S vaccine under Emergency Use Authorization (EUA) in the United States (US), suggesting an increased risk of thrombosis combined with thrombocytopenia. Based on this, thrombosis with thrombocytopenia syndrome (TTS), which is a very rare event, will be followed in this protocol as an adverse event of special interest (AESI) that needs to be reported to the sponsor within 24 hours of awareness. In addition, anaphylaxis has been added as an important identified risk. In addition, this amendment has been created to reinstate the use of a central laboratory for RT- PCR tests or other molecular diagnostic test to confirm cases of SARS-CoV-2 infection upon health authority (HA) request. These and other changes made to the clinical protocol of study VAC31518COV3001 are listed below, including the rationale for each change and a list of all applicable sections. |
| Amendment 6 | 04 September 2021 | Summary only — no full PDF of this version available | The main purpose of this amendment is to offer a 1-dose booster vaccination with Ad26.COV2.S at the 5x1010 vp dose level to all ongoing participants in the study, regardless of their primary vaccination regimen (Ad26.COV2.S vaccine or a single or two dose regimen of an mRNA vaccine or another authorized COVID-19 vaccine including protein, inactivated, and adenovector based vaccines). The booster vaccination will be administered in the open-label phase of the study. The combination of homologous or heterologous prime/boost vaccination will not be randomized, but depend on what participants received during the double-blind phase of the study as described in this protocol. Booster vaccination should occur preferably 6 months but at least 3 months after the primary vaccination regimen. Participants in the study who have already received an additional COVID-19 vaccination after the primary regimen outside the study with any vaccine as described above will also be eligible for the Ad26.COV2.S booster in this study preferably 6 months but at least 3 months after their last COVID-19 vaccination. Participants are free to choose when to receive the booster vaccination within the window of the booster vaccination visit, to receive booster vaccination outside the study, or not to receive booster vaccination. Participants who choose to receive a booster vaccination with the Ad26.COV2.S vaccine (if recommended and available) or another authorized COVID-19 vaccine outside the study or choose not to receive a booster vaccination will not be withdrawn from the study and will be encouraged to remain in the study. All participants who received a booster vaccination within the study or received a booster vaccination outside the study and remained in the study will be monitored for safety, immunogenicity, and efficacy. Immunogenicity will be assessed with blood draws on the day of booster vaccination (prior to booster vaccination, if feasible), and 28 days, 72 days, and 6 months post booster vaccination. In addition, immunogenicity subsets with more extensive blood draws for immunogenicity assessments will be included. Safety blood draws will include a platelet count at Baseline (prior to booster vaccination, if feasible), and 28 days after booster vaccination and extra blood, aside from that required for immunogenicity and N serology for determination of infection, to assess relevant parameters in case of an adverse event of interest. With implementation of this amendment, the start date of the first cross-over unblinding visit (implemented with Amendment 4) and the date of first booster vaccine administration until 1-year follow-up of the last booster vaccination define the open-label booster vaccination phase of the study. This phase will be utilized to describe safety, immunogenicity, and efficacy during the time participants have and have not been boosted. Rationale: A single dose of Ad26.COV2.S vaccine is immunogenic and highly efficacious against severe COVID-19 disease and COVID-19 related hospitalization and death for at least 8 months. Despite this durability, signs of waning immunity in terms of the numbers of participants with undetectable antibody have been observed, especially in the older population, where as many as 28% have no detectable neutralizing antibody at 6 months post vaccination. Furthermore, while protection against variants of concern such as the Beta variant, the Gamma variant, and the B.1.621 NCT04505722 [[PAGE 227]] VAC31518 (JNJ-78436735) Clinical Protocol VAC31518COV3001 Amendment 7 CONFIDENTIAL –FOIA Exemptions Apply in U.S. 228 Status: Approved, Date: 15 April 2022 variant in this study24 and the Delta variant in the Sisonke study remains high against serious disease, hospitalization, and death, this protection is somewhat lower against, for example, the Delta variant compared to the reference Wuhan strain.38 Protection against mild to moderate disease against the Delta variant is very low at the late time points when measured in the Sisonke study, although it is unknown if this is due to waning immunity or biologic factors related to the Delta variant. Waning immune responses and less protection against moderate to severe disease against the Delta variant has also been observed for mRNA vaccines. Based on these findings, regulatory and advisory bodies including the FDA are planning to recommend booster doses for vaccines when data supports such recommendations. Therefore, based on this recommendation for a booster vaccination and the availability of booster vaccinations outside the study, this amendment will permit boosting of all ongoing participants in this study who have previously received any COVID-19 vaccine(s) (either as part of a primary regimen or as an additional dose administered after the primary regimen). All participants who received vaccination with Ad26.COV2.S, an mRNA vaccine and/or another COVID-19 vaccine authorized for primary vaccination, if the last vaccination was preferably 6 months but at least 3 months ago, and who subsequently remained in the study will be eligible to receive the booster. These and other changes made to the clinical protocol of study VAC31518COV3001 are listed below, including the rationale for each change and a list of all applicable sections. |
| Amendment 7 | 15 April 2022 | jj-ensemble-NCT04505722-protocol.pdfclinicaltrials.gov (NCT04505722) | Following emergency use authorization (EUA) by the United States (US) Food and Drug Administration (FDA), the conditional marketing authorization by the European Commission, all participants were gradually unblinded and a single dose of Ad26.COV2.S was offered to enrolled participants who initially received placebo. Also, the epidemic continued, and new variants of concern emerged, national recommendations introduced booster vaccinations. The final analyses of the study that described the double-blind phase has been completed and the primary and secondary objectives have been met. Further efficacy evaluations of the open-label data have limitations, due to the loss of the placebo group, due to the loss of randomization, as many participants in the placebo groups in the studies did not cross over to Ad26.COV2.S (eg, they received another vaccine), and unblinding (eg, the participants’ knowledge of the number and type of doses received or the timing since vaccination), which could have led to behavioral changes impacting the results. Operational challenges have impacted the feasibility of a strict follow-up of any COVID-19 episode and active follow-up cannot be sustained. Because of these reasons, the protocol has been amended to reduce the number of on-site visits and to change the requirements for COVID-19 episode reporting by applying a passive follow-up approach. Participants in the Immunogenicity Subset will continue with the on-site study visits. There are no changes to follow-up of safety endpoints, including the reporting of adverse events of special interest (AESIs). Two analyses are still planned for the study, a first analysis will be conducted for the open-label phase of the study (using the initially designed “active” follow-up of COVD-19 events) and a second end of study analysis is planned (using passive follow-up of COVID-19 events).The changes made to the clinical protocol VAC31518COV3001 as part of Protocol Amendment 7 are listed below, including the rationale of each change and a list of all applicable sections. NCT04505722 VAC31518 (JNJ-78436735) Clinical Protocol VAC31518COV3001 Amendment 7 CONFIDENTIAL –FOIA Exemptions Apply in U.S. 3 Status: Approved, Date: 15 April 2022 |
For each amendment that ships a ‘Summary of Major Changes’ table in the source PDF, the full Section / Description / Rationale rows are reproduced below. The Original protocol typically has no change-table (nothing to compare against).
(no detailed Section / Description / Rationale table for this amendment in the source PDF)
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| 1.1 Synopsis 2.1 Study Rationale 2.2 Background 4.1 Overall Design 4.4 End-of-study Definition 4.3 Justification for Dose 6.1 Study Vaccines Administered 8.1.4 Immunogenicity Assessments | The Ad26.COV2.S dose level has been lowered from 1×1011 vp to 5×1010 vp. | Immunogenicity data from Cohort 1a and a sentinel group of Cohort 3 of study VAC31518COV1001 have become available. The data demonstrated that a single dose of Ad26.COV2.S at a dose level of 5×1010 vp is sufficient to induce an acceptable immune response that meets prespecified minimum criteria: (1) wild-type virus neutralization assay (wtVNA)a response rate (28 days post-Dose 1): lower limit of 95% confidence interval (CI) ≥65%; (2) T-helper cell type 1 (Th1)/T-helper cell type 2 (Th2) response magnitude ratio: Th1>Th2 within responder population and (3) pseudovirus (ps)VNA magnitude associated with protection in non-human primate (NHP) studies is induced by vaccination in humans: estimated population mean protection probability ≥40% and lower limit of 95% CI of estimated population mean protection probability ≥20%. This finding was |
| supplemented with several sensitivity analyses utilizing ELISA, a more sensitive psVNA, and statistical evaluation of attributed values below the level of sensitivity of the original psVNA. The safety data from Cohort 1a and Cohort 3 of the FIH study with the Ad26.COV2.S 5×1010 vp dose level were deemed acceptable. Since all criteria for proceeding to Phase 3 were met by the 5x1010 vp dose, the sponsor decided to use this dose for further evaluation in the Phase 3 study VAC31518COV3001. | ||
| 1.1 Synopsis 2.1 Study Rationale 4.1 Overall Design 9.2.1 Efficacy (Total Sample Size) 9.2.4 Safety (Safety Subset) | The protocol has been adjusted to reflect the selected sample size of approximately 60,000 participants. A detailed rationale for the sample size selection has been added to Section 9.2 Sample Size Determination of the protocol. | Based on epidemiological modeling and currently available data (further explained in Section 9.2.1), the maximum sample size of 60,000 participants was selected. |
| 1.1 Synopsis 9.5.1 Primary Endpoint Evaluation | The trigger for the evaluation of the primary endpoint has been modified, adding 3 conditions, one related to available follow-up information, one related to the number of severe/critical COVID-19 cases and one related to the number of cases meeting the primary endpoint definition of moderate to severe/critical COVID-19 in the elderly population, that need to be met. | In order to ensure the evaluation of the primary endpoint provides sufficient information to assess the benefit/risk and potentially support an Emergency Use Authorization. |
| 1.1 Synopsis 1.3.1 All Participants 3 OBJECTIVES AND ENDPOINTS 8 STUDY ASSESSMENTS AND PROCEDURES 8.1.4 Immunogenicity Assessments 9.2.1 Efficacy (Total Sample Size) 9.5.1 Primary Endpoint Evaluation 9.5.2 Secondary Endpoints 9.5.1.1 Study Monitoring 10.2 Appendix 2: Clinical Laboratory Tests | The time to begin counting COVID-19 cases after vaccination with Ad26.COV2.S has been decreased from at least 28 days post-vaccination to at least 14 days post-vaccination (Day 15). | Based on preliminary data from Cohort 1b of study VAC31518COV1001, showing robust immunology data 14 days after vaccination that are similar to the data seen 28 days after vaccination. |
| 1.1 Synopsis 2.1 Study Rationale 4.1 Overall Design 9.2.1 Efficacy (Total Sample Size) 9.5.1 Primary Endpoint Evaluation | The assumed vaccine efficacy (VE) has been adjusted from a VE=65% VE to a 60%=VE. The target number of events (TNE) has been adjusted accordingly from 104 to 154 events | The study power was adjusted to have approximately 90% power to detect an assumed vaccine efficacy as low as 60%, in line with Health Authority guidance. The target number of events has been adjusted accordingly. |
| 1.1 Synopsis 1.2 Schema 2.1 Study Rationale 2.3.3 Benefit-Risk Assessment of Study Participation 4.1 Overall Design 9.2.2 Immunogenicity Subset | It has been clarified that Stage 2a (adults ≥60 years of age) can start in parallel to Stage 1a (adults ≥18 to <60 years of age) unless this is not allowed per local Health Authority guidance. | After a review of the currently available safety and immunogenicity data from Cohort 1a and Cohort 3 of study VAC31518COV1001 (see above), staggered enrollment of Stage 2 is no longer deemed necessary. |
| 5.1 Inclusion Criteria 5.2 Exclusion Criteria | A clarification was added to the eligibility criteria on blood pressure for Stage 1a and Stage 2a. | Following discussion with the agency on the VAC31518COV1001 protocol, it was agreed that the blood pressure criteria from the CDC list of comorbidities associated with COVID-19 progression could be modified. The VAC31518COV3001 protocol has been harmonized with the VAC31518COV1001 protocol. |
| 1.1 Synopsis 5.1 Inclusion Criteria 5.2 Exclusion Criteria 10.10 Appendix 10: Symptoms of Coronavirus (US Centers for Disease Control and Prevention) | It has been clarified that the current list of CDC comorbidities applicable to the in- and exclusion criteria will not be adjusted during the conduct of the study even if the source CDC list is updated. | Changing the CDC list of comorbidities during the study would be operationally very difficult and should not be required since they are only used in the initial part of the study, ie, in enrollment of the first 2,000 participants in each of the age groups, which will occur only a few weeks apart. |
| 1.3.1 All Participants 5.1 Inclusion Criteria 5.2 Exclusion Criteria 8.4 Virology Assessments 9.7Safety Analysis | The eligibility criteria, HIV RNA viral load and CD4 cell count assessment and subanalyses of the data related to HIV positive participants in this study has been updated. | To provide objective criteria for stable/well-controlled HIV infection and details regarding this subpopulation on various other study aspects. |
| 1.1 Synopsis 3 OBJECTIVES AND ENDPOINTS 9.2.3 Immunogenicity Correlates (Correlates Subset) 9.5.2 Secondary Endpoints | The endpoint used to assess the effect of Ad26.COV2.S on all molecularly confirmed symptomatic COVID-19, as compared to placebo was adjusted to the Burden of Disease endpoint. | Following a Health Authority question on how the different groups of mild, moderate and severe COVID-19 cases will be analyzed, the Burden of Disease (BOD) secondary endpoint has been added to the protocol. The BOD endpoint will be evaluated based on the first occurrence of molecularly confirmed COVID- 19, including mild, moderate and severe/critical case definitions. |
| 1.1 Synopsis 9.5.1 Primary Endpoint Evaluation 9.5.1.1 Study Monitoring 9.8 Interim Analysis and Committee(s) | The severe harm monitoring rule has been modified to indicate that monitoring will start from the 5th severe event onwards instead of the 8th severe event and monitoring will be done until the primary analysis is triggered instead of until the end of the study. In addition, monitoring for efficacy will start from the 20th event onward at least once a week instead of after each event. | Based on Health Authority request to start monitoring earlier. |
| 1.1 Synopsis 3 OBJECTIVES AND ENDPOINTS 9.5.2 Secondary Endpoints | It has been clarified that all secondary endpoint analyses will occur in the per protocol analysis set, in seronegative participants unless otherwise indicated. | To clarify the analysis set used to evaluate the secondary endpoints. |
| 1.1 Synopsis 8.1.3.1 Case Definition for Moderate to Severe/Critical COVID-19 8.1.3.2 Case Definition for Mild COVID-19 | The case definitions of both mild and moderate COVID-19 have been modified and terminology has been aligned across case definitions. | To incorporate additional key conditions in the case definition of mild disease and for clarification purposes. |
| 1.1 Synopsis 1.3.2 Participants With COVID-19-like Signs and Symptoms 4.1 Overall Design 8.1.1 Prespecified Criteria for Suspected COVID-19 8.1.2 Procedures in the Event of COVID-19- like Signs and Symptoms | It has been clarified that because several of the prespecified criteria for suspected COVID-19 overlap with vaccine-related reactogenicity, investigators' clinical judgement is required to exclude vaccine-related events. | To ensure that vaccine-related events do not trigger the COVID-19 related follow-up procedures for mild disease, to be able to include cases of moderate disease that were not classifiable by the definition and for simplification and clarification purposes. |
| 4.2.1 Study-Specific Ethical Design Considerations 6.6 Continued Access to Study Vaccine After the End of the Study | It has been clarified that the sponsor will also look into the possibility of offering placebo recipients the study vaccine, if this vaccine is determined to be efficacious, considering country-specific conditions and ethical considerations. | Based on a partner request to clarify the plans of providing vaccine, if it is determined to be efficacious, to participants who received placebo. |
| 5.2 Exclusion Criteria | It has been clarified that every effort will be made to avoid inclusion of participants who have been previously enrolled in coronavirus studies and to prevent subsequent enrollment of a participant in other coronavirus studies during their participation in this study. | To ensure that co-enrollment in other efficacy studies is avoided. |
| 1.1 Synopsis 8.1.3.4 Case Definition for Asymptomatic or Undetected COVID 19 8.1.3.5 SARS-CoV-2 Seroconversion Assessment | A subsection on case definition of asymptomatic or undetected COVID-19 and SARS-CoV-2 seroconversion assessment has been added to the Efficacy Assessment section. | To clarify what is considered an asymptomatic infection. |
| 5.2 Exclusion Criteria | It has been clarified that planning to become pregnant within 3 months after study vaccine administration will lead to exclusion from participation in the study. | For clarification purposes. |
| 1.1 Synopsis 8.1.4 Immunogenicity Assessments | It has been added that serology testing outside the study is discouraged and if testing would be needed, the site will guide the participant to an appropriate assay. | Vaccination with Ad26.COV2.S may interfere with some serologic assays utilized at local community health clinics/commercial laboratories and may result in unblinding the participant. |
| 2.3.1 Risks Related to Study Participation 6.8 Prestudy and Concomitant Therapy | Guidance on the use of antipyretics during the study has been added in the prestudy and concomitant therapy section of the protocol. | To clarify that antipyretics are recommended post-vaccination for symptom relief, as needed. Prophylactic antipyretic use is not encouraged. |
| 1.1 Synopsis 1.3.1 All Participants 2.3.1 Risks Related to Study Participation 2.3.3 Benefit-Risk Assessment of Study Participation 4.1 Overall Design 8.3.2 Method of Detecting Adverse Events, Medically-attended Adverse Events, and Serious Adverse Events | It has been clarified that the post-vaccination observation period at the study site will be at least 30 minutes for the first 2,000 participants in each of the 2 age groups and may be decreased to 15 minutes for the remaining participants, if no acute reactions are observed. | To decrease the burden for the participant and for clarification purposes. |
| 1.1 Synopsis 4.1 Overall Design 8.1.4 Immunogenicity Assessments | It has been clarified that the participant will be notified of a confirmed positive SARS- CoV-2 infection and positive serology test. | For clarification purposes. |
| 6.2 Preparation/Handling/Storage/Accountability 6.4 Study Vaccine Compliance | It has been clarified that the unblinded pharmacist cannot vaccinate participants. | Administration of the vaccine by an unblinded pharmacist is not permitted. |
| 8.1.2 Procedures in the Event of COVID-19- like Signs and Symptoms | It has been clarified that the study staff visiting participants at home will use personal protective equipment according to local regulations. | Based on partner recommendations to include protective measures for site staff visiting participants at home. |
| 8.2.2 Vital Signs | It has been clarified that any vital signs measures taken at home that may trigger the severe/critical case definition will be confirmed as soon as possible by qualified medical staff and participants will be referred for care, if needed. | Based on a partner request to clarify if a participant with a positive test will be referred to a health care provider. |
| 1.1 Synopsis 1.3.1 All Participants 4.1 Overall Design 8.7Baseline and Longitudinal Risk Factor Assessment 9.4 Participant Information 9.5.3 Exploratory Endpoints 10.12 Appendix 12: Baseline Risk Factor Assessment | It has been added that additional baseline and longitudinal characteristics related to current work situation, living situation, and community interactions, from participants who consent to this, will be collected for risk factor analysis, if allowed per local regulations. | To assess baseline and longitudinal characteristics that are potentially useful to identify the risk of acquiring COVID-19 which will be used for the correlates of protection analysis. |
| 5.2 Exclusion Criteria | Exclusion of participants with drug or alcohol abuse has been removed from exclusion criterion 12. | To avoid redundancy as this is also covered in exclusion criterion 14. |
| 1.1 Synopsis 9.1 Statistical Hypotheses | It has been clarified that additional analyses after the primary analysis can be planned, if deemed appropriate. | For clarification purposes. |
| 1.1 Synopsis 3 Objectives and Endpoints 8.1.4 Immunogenicity Assessments | An exploratory immunogenicity objective/endpoint and respective assays have been added to assess other coronavirus immune responses at baseline. | To assess the impact of pre- existing humoral immunity against coronaviruses other than SARS-CoV-2 at baseline on Ad26.COV2.S vaccine immunogenicity. |
| 2.3.1 Risks Related to Study Participation 5.2 Exclusion Criteria | It has been clarified that breastfeeding women can participate in the study. | To allow the enrollment of breastfeeding women in the study, as the risk of getting infected outweighs the risk of exposing the child to vaccine induced antibodies. |
| 1.1 Synopsis 1.2 Schema 2.1 Study Rationale 4.1 Overall Design | In Stages 1a and 1b combined, the enrollment of participants aged ≥18 to <40 years will be limited to approximately 20% of the total study population. The aim of having a minimum of approximately 25% of recruited participants ≥60 years of age has been adjusted to 30%. | The sponsor believes that Ad26.COV2.S is more likely to protect against more severe disease and progression of infection is age related with twice the level of severity in 50-year-olds compared to 20-year-olds. The cap of approximately 20% of participants 18-40 years and the aim to enroll a minimum of approximately 30% elderly participants, will allow to enroll a more representative population at highest risk of severe disease per the protocol case definition. |
| 5.2 Exclusion Criteria 6.8 Prestudy and Concomitant Therapy | In the exclusion criteria and the concomitant medication section, it has been further clarified that the use of any investigational or approved COVID-19 vaccine (other than Ad26.COV2.S) is disallowed at any time prior to and during the study. | Clarification of an inconsistency and alignment across sections within the protocol. |
| 1.1 Synopsis 1.3.1 All Participants 3 OBJECTIVES AND ENDPOINTS 8 STUDY ASSESSMENTS AND PROCEDURES 8.1.3 Efficacy Assessments 8.1.4 Immunogenicity Assessments 10.2 Appendix 2: Clinical laboratory Tests | Blood draws for immunologic testing for SARS-CoV-2 seroconversion (ELISA and/or SARS-CoV-2 immunoglobulin assay) based on SARS-CoV-2 N protein, have been added on Day 71 and 6 months in order to identify cases of asymptomatic infection. Visit 4 has therefore become a mandatory visit for all participants. | To allow for the identification of a possible signal for the prevention of asymptomatic infection at earlier timepoints. |
| 1.3.1 All Participants 1.3.2 Participants With COVID-19-like Signs and Symptoms 2.3.1 Risks Related to Study Participation 8 Study Assessments and Procedures 8.1.2 Procedures in the Event of COVID-19- like Signs and Symptoms 10.2 Appendix 2: Clinical Laboratory Tests 10.8 Medically-attended COVID-19 (MA- COV) Form | The term "mid-turbinate" in relation to the nasal swabs collection has been removed throughout the protocol. | To remove any confusion around the type of swabs used during the study as the swabs currently used are not mid turbinate swabs but their performance can be considered equivalent. |
| 1.3.2 Participants With COVID-19-like Signs and Symptoms 8.1.2 Procedures in the Event of COVID-19- like Signs and Symptoms 10.2 Appendix 2: Clinical Laboratory Tests | The sample for sero- confirmation of SARS-CoV-2 infection to be collected on Day 3-5 in participants with COVID-19 like signs and symptoms has been removed | It is unlikely to detect antibodies 3-5 days post signs and symptoms or a positive PCR for SARS-COV-2 infection. Antibodies will likely be observed from 7 days post signs and symptoms onwards. |
| 1.1 Synopsis 1.3.1 All Participants 4.1 Overall Design | It has been clarified that enrolled participants will be counselled on SARS-COV-2 infection prevention. In addition, it is clarified that at the time of study entry, each participant will need to indicate to the study site where, in case they would get infected with SARS-CoV-2 the identity and location of their routine medical care physician and/or facility and the identity and location of where they would obtain emergency care and hospitalization if necessary. If this information is not available, a plan for where such care could be obtained should be developed. | For clarification purposes. |
| 1.3.2 Participants With COVID-19-like Signs and Symptoms 8.1.2 Procedures in the Event of COVID19- like Signs and Symptoms 10.3.3 Informed Consent Process | It has been clarified that the caregiver can only assist with the eCOA. | To provide clarity on the roles and responsibilities of the caregiver. |
| 1.3.2 Participants With COVID-19-like Signs and Symptoms 8.1.2 Procedures in the Event of COVID19- like Signs and Symptoms | Term "episode" was added to include all aspects of the COVID-19 illness. | For clarification purposes. |
| 5.1 Inclusion Criteria 8.3 Adverse Events, Serious Adverse Events, Medically-attended Adverse Events, and Other Safety Reporting 10.3.3 Informed Consent Process 10.3.4 Data Protection | References to a legally Acceptable Representative being allowed to provide consent instead of the potential participant has been removed from the protocol. | A participant needs to fully understand and be able to provide consent themselves given there may be no benefit to participation. Participants unable to consent for themselves should not be enrolled in the study. |
| 1.1 Synopsis 2.1 Study Rationale 2.3.3 Benefit-Risk Assessment of Study Participation 4.1 Overall Design 9.8 Interim Analysis and Committee(s) 10.3.6 Committees Structure | Reference to Grade 4 AEs and SAEs in the context of Day 3 safety review by the DSMB has been deleted from the protocol. | The DSMB review of the Day 3 safety data from Stage 1a and 2a prior to enrollment of Stage 1b and 2b, respectively, will not be limited to Grade 4 AEs and SAEs. All available safety data will be reviewed. |
| 1.1 Synopsis 2.1 Study Rationale 4.1 Overall Design 9.5.1 Primary Endpoint Evaluation 9.8 Interim Analysis and Committee(s) 10.3.6 Committees Structure | The role of the Sponsor Committee has been replaced either by the role of the Oversight Group (as described in the Oversight Group Charter) or the role of the sponsor. | For clarification purposes. |
| 2.3.1 Risks Related to Study Participation | Influenza will not be used as a control in the surveillance system for detection of COVID-19. | Influenza may not serve as a good positive control due to social distancing measures and the need for significant sampling to have a valid comparison. |
| 6.10 Study Vaccination Pausing Rules for Stages 1a and 2a | It has been clarified that based on the pausing criteria, the sponsor’s medical monitor or designee decides whether a study pause is warranted and informs the DSMB of the decision, instead of the PSRT deciding whether a pausing rule is warranted. | For clarification purposes. |
| 9.5.2 Secondary Endpoints | It has been clarified that among participants with SARS-CoV-2 infection, the effect of vaccination on the viral load levels at and after diagnosis as well as on the duration of SARS-CoV-2 viral load positivity will be evaluated. | For clarification purposes. |
| 1.1 Synopsis 3 OBJECTIVES AND ENDPOINTS | The exploratory efficacy objective assessing both symptomatic and asymptomatic infections combined, (that are serologically and/or molecularly confirmed) compared to placebo has been moved to the secondary objectives. | This endpoint was moved to secondary as it will be included in the inferential testing strategy. |
| 3 OBJECTIVES AND ENDPOINTS | An exploratory objective to assess the impact of the vaccine on other respiratory diseases has been added. | To obtain epidemiology data of other important respiratory infections that may be affected by COVID-19 circulation. |
| 1.1 Synopsis 8.1.4 Immunogenicity Assessments | Analysis of neutralizing antibodies to SARS-CoV-2 using a reporter SARS-CoV-2 virus has been added. | To add a new assay that may become available. |
| 10.7Appendix 7: MRU Questionnaire | Clarifications were made in the MRU Questionnaire. | For clarification purposes |
| Throughout the protocol | Minor errors and inconsistencies were corrected, and minor clarifications were added throughout the protocol. | Correction of minor errors and inconsistencies. Addition of minor clarifications. |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| 1.1 Synopsis 1.3.2 Participants With (Suspected) COVID- 19 4.1 Overall Design 8 STUDY ASSESSMENTS AND PROCEDURES 8.1.1 Prespecified Criteria for Suspected COVID-19 8.1.2 Procedures in the Event of (Suspected) COVID-19 8.1.3.4 Case Definition for Asymptomatic or Undetected COVID-19 10.3.10 Source Documents | Clarified that all participants that have a RT-PCR positive finding for SARS-CoV-2 from outside the study, even if asymptomatic, will be followed until there are two consecutive negative PCRs. | To ensure safety of staff and other persons coming in contact with the infected participant. |
| 1.3.1 All Participants 8 STUDY ASSESSMENTS AND PROCEDURES 10.2 Appendix 2: Clinical Laboratory Tests | It has been clarified that at Day 29 2.5 mL blood will be collected from participants for biomarker RNAseq analyses (PAXgene tube). | Correction. In order to assess the objectives as currently stated in the protocol, a blood sampling for biomarker RNAseq (PAXgene)performed after the participants have received the vaccination is required. |
| 1.1 Synopsis 2.1 Study Rationale 2.3.3 Benefit-Risk Assessment of Study Participation 4.1 Overall Design 9.2.2 Immunogenicity Subset | It has been clarified that Stage 1b and Stage 2b will enroll participants with and without comorbidities. However, participants in the Immunogenicity Subset 1b and 2b will be participants with comorbidities. | Clarification |
| 5.2 Exclusion Criteria 6.8 Prestudy and Concomitant Therapy | The specification of ‘(>10 days)’ when referring to the chronic use of systemic corticosteroids has been removed from the exclusion criterion 3. | To remove ambiguity as within the same exclusion criterion 3 a substantial immunosuppressive steroid dose is defined as ≥2 weeks of daily receipt of 20 mg of prednisone or equivalent |
| 1.3.1 All Participants 1.3.2 Participants With (Suspected) COVID- 19 8.6 Medical Resource Utilization | The MA-COV form has been updated to also capture if a participant has clinical or radiological evidence of pneumonia and if the oxygen | To ensure collection of all necessary information in order to determine the severity of COVID-19 per the case |
| 10.8 Appendix 8: Medically-attended COVID-19 (MA-COV) Form | saturation for a participant is considered clinically abnormal but >93% (corrected for altitude). In addition, some clarifications were added to the form and it is clarified that the form may also be completed by the study site personnel. | definitions and clarification purposes. |
| 10.3.11 Monitoring | Source data verification has been replaced by review of the source data. | Source document review will be done instead of source document data verification. |
| 2.3.1 Risks Related to Study Participation 10.4.4 Special Reporting Situations | It is stated more clearly that breastfeeding women are allowed to participate in the study. In alignment with this, exposure to a sponsor study vaccine from breastfeeding has been removed from the list of special reporting situations. | Breastfeeding is allowed in the current study VAC31518COV3001. |
| 1.1 Synopsis 5.1 Inclusion Criteria 5.2 Exclusion Criteria | Gestational diabetes has been removed from the list of comorbidities (or risk factors) that might be associated with increased risk of progression to severe COVID-19. | Gestational diabetes is not applicable in the current study VAC31518COV3001 as pregnant women are not allowed to participate in the study. |
| 9.5.1.1 Study Monitoring | Clarified that there will be no adjustment for multiple testing for the potential harm monitoring of severe cases, ie, an exact 1-sided binomial test of the fraction of infections assigned to who receive the vaccine will be used with an unadjusted p-value ⍺at 5%. | Adjusted in line with HA feedback to start monitoring of severe events as soon as 5 events and subsequently after every new event without adjustment for multiple testing |
| 1.1 Synopsis 1.3.1 All Participants 1.3.2 Participants With (Suspected) COVID- 19 4.1 Overall Design 8.7 Risk Factor Assessment 9.4 Participant Information 10.12 Appendix 12: Risk Factor Assessment | It is clarified that, besides being interviewed on characteristics related to current work situation, living situation, and community interactions, as specified in Appendix 12, prior to vaccination on Day 1, they will be asked about any changes related to these characteristics at Day 71 and 6 months and 1 year post vaccination and at COVID-19 Day 3-5. | Clarification on when participants will be interviewed on additional characteristics that will be used for risk factor analysis. |
| 5.2 Exclusion Criteria 6.8 Prestudy and Concomitant Therapy | Exclusion criterion 7 was adjusted to exclude participants who received investigational | Alignment across Ad26.COV2.S Phase 3 study protocols |
| immunoglobulin or monoclonal antibodies within 3 months, or received convalescent serum for COVID-19 treatment within 4 months. | ||
| 5.2 Exclusion Criteria | Chronic kidney disease (with dialysis) has been removed from the examples of clinical conditions expected to have an impact on the immune response of the study vaccine. | There is no evidence that dialysis has an impact on antibody concentration in the blood. |
| 1.1 Synopsis 5.2 Exclusion Criteria | It is clarified Parkinson’s disease, seizures, ischemic strokes, intercranial hemorrhage encephalopathy, meningoencephalitis are not part of the CDC list of comorbidities that are associated with increased risk of progression to severe COVID-19. | Clarification |
| 5.2 Exclusion Criteria | It is clarified that participants with Guillain-Barré syndrome are excluded from the study altogether and not only in Stage 1a and Stage 2a of the study. | Correction |
| 5.1 Inclusion Criteria | Clarifications have been made to the inclusion criterion 4, indicating that for Stages 1a and 2a participants can have a condition that is stable and well controlled except the ones listed in exclusion criterion 15 which are associated with increased risk of progression to severe COVID-19. In addition, medication dose for allowed stable conditions (in all stages of the study) cannot have been increased within 12 weeks prior to vaccination. | Clarification |
| 5.4 Screen Failures | It has been clarified that participants can be rescreened once, also when they meet all in- and exclusion criteria but the 28-day screening period was exceeded. | To allow participants who were found eligible to be enrolled in the study but were not randomized within the 28-day screening window to still participate in the study. |
| 1.1 Synopsis 9.8 Interim Analysis and Committees | Reference to a possible sample size adjustment has been deleted. | Correction; per the VAC31518COV3001 Amendment 1, the sample size of approximately 60,000 participants was selected based |
| on available epidemiology data at the time of Amendment 1 writing. | ||
| 1.3.1 All Participants | It is clarified that the diagnostic molecular RT-PCR test for SARS-CoV-2 infection (from nasal swab taken at baseline) will be performed at a central laboratory on a retrospective basis. These baseline results are not available in real time, and thus cannot be used to inform participants at time of enrollment. | Clarification |
| 1.1 Synopsis 3 OBJECTIVES AND ENDPOINTS 4.1 Overall Design | It is clarified that molecularly confirmed COVID-19 is defined as a positive SARS- CoV-2 viral RNA result by a central laboratory using a PCR-based or other molecular diagnostic test. | For clarification purposes and to align information included in Section 8.1.3 which states that molecular confirmation of SARS-CoV-2 infection by a central laboratory will be used for the analysis of the case definition. |
| 10.3.10 Source Documents | It has been clarified that source documents for any relevant medical history and prestudy therapies determining eligibility (ie, as specified in the footnotes to the Schedule of Activities) of the participants needs to be collected | To ensure that all necessary information to properly assess SAEs (relatedness) is collected. |
| 1.1 Synopsis 5.2 Exclusion Criteria | The list of comorbidities (or risk factors) that are or might be associated with an increased risk of progression to severe COVID-19 has been corrected from ‘uncontrolled human immunodeficiency virus (HIV) infection’ to ‘HIV infection’ | Correction |
| 1.1 Synopsis 8.1.3.1 Case Definition for Moderate to Severe/Critical COVID-19 10.8 Appendix 8: Medically-attended COVID-19 (MA-COV) Form | It has been clarified that the adjustment according to altitude for the SpO2 criteria is per the investigator judgement. | Clarification |
| 8.3.6 Disease-related Events and Disease- related Outcomes Not Qualifying as Adverse Events or Serious Adverse Events | It has been clarified that (S)AEs caused by molecularly confirmed SARS-CoV-2 infection will be removed at the analysis level from the (S)AE listings and tables and presented separately. | Alignment across different sections of the protocol. |
| Title page | Prepared by line removed | To align with internal guidelines on legal entity to be mentioned on title page |
| Throughout the protocol | Minor errors and inconsistencies were corrected, and minor clarifications were added throughout the protocol. | Correction of minor errors and inconsistencies. Addition of minor clarifications. Alignment across sections in the protocol. |
| 1.1 Synopsis 2.1 Study Rationale 2.2 Background 4.1 Overall Design 4.4 End-of-study Definition 4.3 Justification for Dose 6.1 Study Vaccines Administered 8.1.4 Immunogenicity Assessments | The Ad26.COV2.S dose level has been lowered from 1×1011 vp to 5×1010 vp. | Immunogenicity data from Cohort 1a and a sentinel group of Cohort 3 of study VAC31518COV1001 have become available. The data demonstrated that a single dose of Ad26.COV2.S at a dose level of 5×1010 vp is sufficient to induce an acceptable immune response that meets prespecified minimum criteria: (1) wild-type virus neutralization assay (wtVNA)a response rate (28 days post-Dose 1): lower limit of 95% confidence interval (CI) ≥65%; (2) T-helper cell type 1 (Th1)/T-helper cell type 2 (Th2) response magnitude ratio: Th1>Th2 within responder population and (3) pseudovirus (ps)VNA magnitude associated with protection in non-human primate (NHP) studies is induced by vaccination in humans: estimated population mean protection probability ≥40% and lower limit of 95% CI of estimated population mean protection probability ≥20%. This finding was |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| 1.1 Synopsis 3 OBJECTIVES AND ENDPOINTS 4.1 Overall Design 8.1.3.1 Case Definition for Moderate to Severe/Critical COVID-19 8.1.3.6 Clinical Severity Adjudication Committee 9.1 Statistical Hypotheses 9.2.1 Efficacy (Total Sample Size) 9.5.1 Primary Endpoints Evaluation 9.5.1.1 Study Monitoring 9.5.2 Secondary Endpoints 9.8 Interim Analysis and Committees 10.3.6 Committees Structure | A co-primary endpoint was added counting COVID-19 cases from 28 days post-vaccination (Day 29), in addition to from 14 days post- vaccination (Day 15). The applicable secondary and exploratory endpoints were updated to also include COVID-19 cases with onset at least 28 days post- vaccination, in addition to from 14 days post-vaccination. | This change will allow for formal testing and reporting of the primary endpoint counting cases from 28 days post-vaccination as an additional condition for success along with the 14 days post- vaccination endpoint results. Maintaining the original primary endpoint will preserve trial integrity. This approach will allow to provide the most accurate description of the vaccine efficacy and to assess vaccine efficacy as early as 14 days post-vaccination. |
| 3 OBJECTIVES AND ENDPOINTS | Deletion of the exploratory endpoint relating to evaluation of the occurrence, severity and duration of COVID-19 episodes in participants who received Ad26.COV2.S, as compared to placebo, by the Clinical Severity Adjudication Committee, previously known as the Clinical Evaluation Committee. | The Clinical Severity Adjudication Committee only exists to determine severe/critical cases of COVID-19. |
| 9.2.1 Efficacy (Total Sample Size) 9.2.4 Safety Subset | The total sample size was reduced from 60,000 to approximately 40,000. The paragraph on the operational futility was removed. | The incidence of moderate to severe COVID-19 seen in the US and reported in other COVID-19 vaccine studies is significantly higher than assumed at the time of protocol planning. Furthermore, based on that incidence and modeling, there is a high degree of probability that an efficacy signal meeting the prespecified criteria in this amendment will be reached at, or prior to, the time when 50% of participants will have been followed for 8 weeks from the time of vaccination. |
| 1.1 Synopsis 9.5.1 Primary Endpoints Evaluation | The conditions for monitoring whether efficacy greater than 30% is achieved using the sequential monitoring algorithm were changed: (1) The minimum number of COVID-19 cases with onset at least 28 days after vaccination meeting the primary case definition needed to start the efficacy monitoring was modified to at least 42 instead of 20. (2) The need for a follow-up of 8 weeks for 50% of participants prior to an initial look at an efficacy signal if the other conditions are met, was removed. In addition, text was added to clarify the timing of primary and interim analyses. | (1) The minimum number of COVID-19 cases was increased to have a more robust signal at the time of the efficacy declaration. (2) This change was made to expedite submissions to ensure the vaccine is made available to the public as soon as possible. Following 50% of participants for 8 weeks from the day of vaccination meets the sponsor’s understanding of the requirement for 8 weeks median follow-up for a 40,000-participant study. |
| 1.1 Synopsis 3 OBJECTIVES AND ENDPOINTS 9.5.2 Secondary Endpoints | A secondary objective and endpoint were added assessing the efficacy of the vaccine in the prevention of molecularly confirmed, severe/critical COVID-19 with onset at least 14 days post-vaccination and 28 days post- vaccination. | With the increased incidence of disease that is being observed, the likelihood of having enough severe cases of COVID-19 to examine vaccine efficacy against this endpoint has increased. Vaccine efficacy against severe disease is considered an important endpoint for a 1-dose vaccine. |
| 1.1 Synopsis 1.3.1 All Participants 3 OBJECTIVES AND ENDPOINTS 8.1.3 Efficacy Assessments 8.1.3.5 SARS-CoV-2 Seroconversion Assessment 8.1.4 Immunogenicity Assessments 10.2 Appendix 2: Clinical Laboratory Tests | An exploratory objective and endpoint were added assessing the effect of the vaccine on confirmed asymptomatic or undetected infections by testing serologic conversion between baseline and 28 days post-vaccination. | This change allows the evaluation of the effect of the vaccine on asymptomatic infections up to Day 29, in line with other efficacy endpoints. |
| 3 Objectives and Endpoints OBJECTIVES AND ENDPOINTS | An exploratory objective and endpoint to examine the degree of frailty were added. | The vaccine will be especially useful in the elderly population with co-morbidities. The frailty index has been utilized as a tool to summarize the degree of frailty that a participant has. |
| 1.1 Synopsis 2.3.1. Risks Related to Study Participation 3 OBJECTIVES AND ENDPOINTS 8.1.3 Efficacy Assessments 8.1.3.6 Clinical Severity Adjudication Committee 10.3.6 Committees Structure | The Clinical Evaluation Committee was replaced by the Clinical Severity Adjudication Committee. | The standard case definition of severe/critical disease may not cover all situations where clinical judgement would disagree with the classification on clinical grounds. |
| 1.1 Synopsis 8.1.3.1 Case Definition for Moderate to Severe/Critical COVID-19 | Addition of text defining the definitive role of the Clinical Severity Adjudication Committee in determining whether cases are severe/critical cases of COVID-19. | Clarification of the definitive role of the Clinical Severity Adjudication Committee in defining the severity of cases of COVID-19. |
| 1.1 Synopsis 1.3.1 All Participants 3 OBJECTIVES AND ENDPOINTS 4.1 Overall Design 4.2 Scientific Rationale for Study Design 4.2.1 Study-Specific Ethical Design Considerations 8.8 Participant Medical Information Prior to, During and After the Study (Real-world Data) 9.5.4 Other Analyses 10.1 Appendix 1: Abbreviations 11 References | Addition of the utilization of tokenization and matching procedures to obtain medical data 5 years prior to enrollment of the participant until 5 years after the participant completed the study from consenting participants in the United States (US). | Participant medical data (electronic health records, claims, laboratory data from other care settings) prior to, during and following participation in the study (real- world data) is important to obtain in order to better understand the impact of prior medical history on the response to immunization and the impact of immunization on efficacy and duration of efficacy as well as adverse events that may occur during and after completion of the study. The technique proposed to obtain this data, ie, tokenization and matching procedures, allows for such data to be obtained without violation of participant confidentiality. This collection of real-world data will only be conducted for consenting participants from the US where this technique is feasible. |
| 1.1 Synopsis 3 OBJECTIVES AND ENDPOINTS 8.1.4 Immunogenicity Assessments | psVNA was removed from the protocol. wtVNA will be used to support the exploratory immunogenicity endpoint. | Due to lack of sensitivity of the evaluated psVNA, the assay has been removed from the protocol wtVNA is currently only qualified and not validated and can therefore not be used to support a secondary immunogenicity endpoint unless validated. |
| 1.3.1 All Participants 1.3.2 Participants With (Suspected) COVID-19 | Further clarifications are made to the procedures to be followed in case of (suspected) COVID-19. | Alignment across the protocol and clarifications on the procedures to |
| 4.1 Overall Design 8.1.2 Procedures in the Event of (Suspected) COVID-19 | be followed in case of (suspected) COVID-19. | |
| 5.1 Inclusion Criteria | Inclusion criterion 4 was updated to clarify that all comorbidities need to be stable and well-controlled, those that are associated with severe COVID-19 AND those that are not associated with severe COVID-19. In addition, a time frame was added for criteria a and b for stable/well-controlled HIV infection. | Clarification |
| 5.1 Inclusion Criteria | In inclusion criterion 4, it was clarified that participants with stable/well-controlled HIV infection that are on stable ART are included if nationwide guidelines require transition from one ART regimen to another, within a period of less than 6 months. | Clarification |
| 5.1 Inclusion Criteria | It was clarified in inclusion criterion 9 that participants with visual impairment are eligible and may have caregiver assistance in completing the eCOA questionnaires. | Clarification |
| 5.2 Exclusion Criteria | In exclusion criterion 3, “Patients on hemodialysis” has been added to the examples of clinical conditions expected to have an impact on the immune response of the study vaccine. | There is evidence that hemodialysis has a negative impact on the immune response elicited by the vaccination. |
| 5.2 Exclusion Criteria | In exclusion criterion 4, it was clarified that autologous blood transfusions are not excluded. | Clarification |
| 1.1 Synopsis 8.1.4 Immunogenicity Assessments | The list of immunoassays used in support of exploratory endpoints has been completed. | Addition of missing assay. |
| 1.1 Synopsis 6.3 Measures to Minimize Bias: Randomization and Blinding 6.7Continued Access to Study Vaccine After the End of the Study 9.9 Analyses for Cohort Unblinded Due to Administration of an Authorized/Licensed COVID-19 Vaccine | Clarification of procedures for unblinding of study participants who may become eligible to receive an authorized/licensed COVID-19 vaccine during the course of the study. | To ensure that if participants become eligible to receive an authorized/licensed COVID-19 vaccine, they are aware of the potential options and ramifications, including the lack of safety data of the authorized/licensed vaccine. |
| 10.8 Appendix 8: Medically- attended COVID-19 (MA-COV) Form | The MA-COV form has been updated to also capture hyperinflammatory syndrome. | To ensure collection of all necessary information in order to determine the severity of COVID-19 per the case definitions and clarification purposes. |
| 2.3.1 Risks Related to Study Participation | It was clarified that the use of condoms is not considered an | Clarification |
| 5.1 Inclusion Criteria | acceptable contraceptive barrier method due to the failure rate of female and male condoms. | |
| 8 STUDY ASSESSMENTS AND PROCEDURES | It was clarified that in case of home visits, assessments that cannot be delegated to a designee must be performed by an appropriate site staff member via a phone call or telemedicine. | Clarification |
| 8.7Risk Factor Assessment 9.4 Participant Information | It was clarified that the risk factor data initially collected at screening from the participants, before the implementation of this amendment will also be used for the planned risk factor analysis. | Clarification |
| 6.3 Measures to Minimize Bias: Randomization and Blinding 9.5.1 Primary Endpoints Evaluation | The timepoints of analyses at which the sponsor will be unblinded were clarified. | Clarification |
| Throughout the protocol | Minor errors and inconsistencies were corrected, and minor clarifications were added throughout the protocol. | Correction of minor errors and inconsistencies. Addition of minor clarifications. Alignment across sections in the protocol. |
| 1.1 Synopsis 1.3.2 Participants With (Suspected) COVID- 19 4.1 Overall Design 8 STUDY ASSESSMENTS AND PROCEDURES 8.1.1 Prespecified Criteria for Suspected COVID-19 8.1.2 Procedures in the Event of (Suspected) COVID-19 8.1.3.4 Case Definition for Asymptomatic or Undetected COVID-19 10.3.10 Source Documents | Clarified that all participants that have a RT-PCR positive finding for SARS-CoV-2 from outside the study, even if asymptomatic, will be followed until there are two consecutive negative PCRs. | To ensure safety of staff and other persons coming in contact with the infected participant. |
| 1.3.1 All Participants 8 STUDY ASSESSMENTS AND PROCEDURES 10.2 Appendix 2: Clinical Laboratory Tests | It has been clarified that at Day 29 2.5 mL blood will be collected from participants for biomarker RNAseq analyses (PAXgene tube). | Correction. In order to assess the objectives as currently stated in the protocol, a blood sampling for biomarker RNAseq (PAXgene)performed after the participants have received the vaccination is required. |
| 1.1 Synopsis 2.1 Study Rationale 2.3.3 Benefit-Risk Assessment of Study Participation 4.1 Overall Design 9.2.2 Immunogenicity Subset | It has been clarified that Stage 1b and Stage 2b will enroll participants with and without comorbidities. However, participants in the Immunogenicity Subset 1b and 2b will be participants with comorbidities. | Clarification |
| 5.2 Exclusion Criteria 6.8 Prestudy and Concomitant Therapy | The specification of ‘(>10 days)’ when referring to the chronic use of systemic corticosteroids has been removed from the exclusion criterion 3. | To remove ambiguity as within the same exclusion criterion 3 a substantial immunosuppressive steroid dose is defined as ≥2 weeks of daily receipt of 20 mg of prednisone or equivalent |
| 1.3.1 All Participants 1.3.2 Participants With (Suspected) COVID- 19 8.6 Medical Resource Utilization | The MA-COV form has been updated to also capture if a participant has clinical or radiological evidence of pneumonia and if the oxygen | To ensure collection of all necessary information in order to determine the severity of COVID-19 per the case |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| and Name | ||
| 8.2.3 Pregnancy Testing 8.3.5 Pregnancy | 8.2.3 Pregnancy Testing | |
| 8.3.5 Pregnancy | ||
| 6.1 Study Vaccines Administered | ||
| 8.3.1 Time Period and Frequency for | ||
| Collecting Adverse Event, Medically- | ||
| attended Adverse Event, Adverse | ||
| Event of Special Interest, and Serious | ||
| Adverse Event Information | ||
| 1.1 Synopsis | ||
| 4.1 Overall Design | ||
| 8.9 Assessment and Procedures after | ||
| EUA or Approval/Licensure and | ||
| Implementation of Protocol | ||
| Amendment 4 | ||
| 9.1 Statistical Hypotheses | ||
| 9.8 Interim Analysis and Committees | ||
| Throughout the protocol | Throughout the protocol | |
| 1.1 Synopsis 1.2 Study Schema 1.3.1 Schedule of Activities 2 Introduction 2.1 Study Rationale 2.3.3 Benefit-Risk Assessment of Study Participation 3 Objectives and endpoints 4.1 Overall Design 4.2 Scientific Rationale for Study Design 5. Study Population 5.5 Criteria for Temporarily Delaying Administration of Study Vaccination 6.1 Study Vaccines Administered 6.2 Preparation/Handling/Storage/ Accountability 6.3 Measures to Minimize Bias: Randomization and Blinding 6.4 Unblinding and Open-label Phase (added) 6.7 Continued Access to Study Vaccine After the End of the Study 8.9 Assessment and Procedures After EUA or Approval/Licensure and Implementation of protocol Amendment 4 10.2 Appendix 2: Clinical Laboratory Test 10.3.3 Informed Consent Process | At the 6 Month/unblinding visit, all participants who initially received placebo will be offered a single dose of Ad26.COV2.S vaccine (5×1010 vp), starting an open-label phase of the study. This is to occur as soon as possible after the Day 71 visit. All participants at the Month 6/unblinding visit will have a blood draw and nasal swab. Relevant sections were updated regarding the open-label phase. Participants to be reminded there is no data on the safety of receiving 2 different COVID-19 vaccines. Removed the following sentence at the end of Section 6.6: "At such time, an amendment will be submitted to permit individual unblinding and to determine the approach to this situation in the Statistical Analysis Plan." | As the vaccine is highly efficacious against severe disease, hospitalization and death, it is considered ethical to offer the active vaccine to the placebo controls in this study. Hereby, an unblinding visit will be scheduled to inform all participants about their study vaccine allocation as well as to offer all placebo recipients Ad26.COV2.S after EUA, conditional licensure or approval in any country. Taking blood samples and nasal swabs from all participants will allow the comparison of efficacy and immunogenicity results in a placebo-controlled manner up to the point of the Month 6/unblinding visit, as well as having a new baseline read-out for the remainder of the study. The 6 Month visit with a broadened visit window will be used as an unblinding visit to allow for rapid cross-over in the context of logistic issues. Investigators will be encouraged to follow health authority guidelines on prioritization of immunization when feasible. All participants will be counselled to continue practicing other public health/preventative measures that were introduced at the start of this pandemic (eg, social distancing, face masks, frequent hand washing), in compliance with local and national guidelines. |
| 1.1 Synopsis 6.3 Measures to Minimize Bias: Randomization and Blinding 6.7 Continued Access to Study Vaccine After the End of the Study | Additional changes needed to allow unblinding prior to authorization/licensure and simultaneous participation in an Expanded Access Program or a Phase 3B study (eg, Sisonke/TOGETHER in South Africa). | To allow participants in an Expanded Access Program for Ad26.COV2.S prior to EUA, conditional licensure or approval in any country to continue to be followed in VAC31518COV3001. |
| 6.4 Unblinding and Open-label Phase (added) | Describes the conditions under which participants who received placebo initially may be vaccinated with Ad26.COV2.S. | To provide guidance on the appropriate vaccination of participants at the start of the open- label phase. |
| 1.1 Synopsis 9.5.1 Primary Endpoint Evaluation | Text has been added describing a final analysis of the double-blind phase which will be performed when all participants will have completed the Month 6/unblinding visit and will provide an analysis of all endpoints for the blinded portion of the study. | To provide an analysis on all data that can be considered part of the double-blind phase of the study. |
| 3 Objectives and endpoints | Reference to "post-vaccination" in objectives and endpoints has been updated to "after double-blind." | To clarify changes required by adding the open-label phase of the study. |
| 3 Objectives and endpoints 9.5.1 Primary Endpoint Evaluation | The following secondary endpoint was added: - Asymptomatic infection detected by RT-PCR at the time of the Month 6/unblinding visit. The following exploratory objectives were added: - To evaluate the long term durability of the efficacy of Ad26.COV2.S in the prevention of molecularly confirmed, moderate to severe/critical COVID-19, in adults by comparing 2 groups of participants vaccinated approximately 4 to 6 months apart. - To examine efficacy for moderate/severe and severe disease as well as medical utilization or death in the vaccine and placebo groups for variant strains that have been identified. | To gather information regarding long term efficacy and efficacy against variants. |
| 1.1 Synopsis 9 Statistical Considerations | Added text describing analysis of the data once EUA, conditional licensure or approval in any country is obtained and all participants are unblinded. | To ensure assessment of the duration of protection and immunogenicity of a single dose of Ad26.COV2.S by comparing 2 groups vaccinated approximately 4 to 6 months apart. |
| 1.1 Synopsis 1.3.1 Schedule of Activities 3 Objectives and Endpoints 4.1 Overall Design 8.1.3 Efficacy Assessments 9.5.1 Primary Endpoint Evaluation 10.2 Appendix 2: Clinical Laboratory Test | Added text to clarify that a RT-PCR test obtained from any source will be used for all analyses. These include RT-PCR tests performed by local laboratories that have utilized RT-PCR testing devices approved by the COVID-19 Response Team (formerly known as OWS), laboratories that are designated as substitutes for local laboratories within the context of the study or any PCR test utilized for a hospitalized study participant for diagnosis and treatment of COVID- 19. In addition, any RT-PCR test not meeting the above criteria can only be used for determination of an asymptomatic case. Confirmation by the central laboratory will not be required as part of any of the case definitions. | Based on data seen thus far, there was a high concordance of results between the central and local laboratories, therefore it is deemed reasonable to use RT-PCR results from local laboratories to confirm cases of SARS-CoV-2 infection. |
| 1.1 Synopsis 8.1.3.6 Clinical Severity Adjudication Committee 10.3.6 Committees Structure | Added text describing adjudication of asymptomatic, mild, moderate, severe, and cases requiring hospitalization, ICU, ventilator support or ECMO and death including date of onset and reasons for the classification. As new information becomes available, cases may be readjudicated. | The role of the Clinical Severity Adjudication Committee is being expanded to improve the classification of the cases. The SAP will be amended to include the new adjudication process in the efficacy assessment of the vaccine (endpoint selection for the analysis). |
| 1.1 Synopsis 8.1.3.4 Case Definition for Asymptomatic or Undetected COVID-19 9.5.1 Primary Endpoints Evaluation | Clarification about the definition of asymptomatic infection. | The current definition does not clearly eliminate cases that are SARS-CoV-2 N antibody sero- converters but RT-PCR negative and have symptoms consistent with COVID-19. |
| 1.1 Synopsis 1.3.1 Schedule of Activities 4.1 Overall Design 8 Study Assessments and Procedures | Updated the twice weekly eCOA assessments to occur 1 year following the Month 6/unblinding visit. | To ensure that all participants have 1 year of eCOA assessments following the Month 6/unblinding visit. |
| 6.9 Prestudy and Concomitant Therapy | A statement was added that receipt of another COVID-19 vaccine by a study participant at any time during the study should be recorded along with the name and date(s) of the vaccine. | This was added so receipt of another COVID-19 vaccine can be accounted for in determining efficacy, duration of efficacy calculations and safety evaluations. Participants that have received another COVID-19 vaccine will not be allowed to receive a single dose of Ad26.COV2.S |
| 1.1 Synopsis 9.5.1 Primary Endpoints Evaluation | Include the study success criterion of the point estimate of VE being >50% for both co-primary endpoints. | A consequence of using a VE of 30% in the hypothesis testing is that the null hypothesis could be rejected with a result for either co-primary VE of less than 50%. It is specified that this would not be considered a successful study. |
| 6.3 Measures to Minimize Bias: Randomization and Blinding 9.9 Analyses for Cohort Unblinded Due to Administration of an Authorized/Licensed COVID-19 Vaccine | Changed SARS-COV-2 to Ad26.COV2.S | Consistency |
| 1.3.1 Schedule of Activities 8.1.4 Immunogenicity Assessments | Blood draw at the 1-Year visit will be replaced by Month 18 visit for non-immunogenicity subset participants (10 mL). | To evaluate the levels of immunogenicity 1 year after beginning of the open label phase of the study. |
| 1.3.1 Schedule of Activities 2.3.1 Risks Related to Study Participation 6.3 Measures to Minimize Bias: Randomization and Blinding 8.2.3 Pregnancy Testing | Added an additional urine pregnancy test at the time of Month 6/unblinding visit for cross-over participants who initially received placebo. | In order to be aware of potential pregnancy before administering Ad26 vaccine. Vaccination of pregnant may be allowed depending on local guidelines. |
| 1.1 Synopsis 8.1.4 Immunogenicity Assessments 8.2 Safety Assessments 8.3.1 Time Period and Frequency for Collecting Adverse Event, Medically-attended AdverseEvent, and Serious Adverse Event Information 8.3.2 Method of Detecting Adverse Events, Medically-attended Adverse Events, and Serious Adverse Events 9.2.4 Safety | Clarified that the Safety and Immunogenicity Subsets are applicable for the double-blind phase only, but special reporting situations will be recorded until 28 days as well as MAAEs will be reported until 6 months after (double-blind or open-label) vaccination with Ad26.COV2.S and SAEs will be reported until end-of-study. | To be consistent with the safety reporting requirements following administration of an investigational vaccine. |
| 1.1 Synopsis 9 Statistical Considerations | Added statement to indicate that samples from open-label phase will be analyzed separately. | The double-blind and the open- label phases will be analyzed separately and will be described in separate SAPs. |
| Synopsis 9.8Interim Analysis and Committees | Text was added to describe the final analysis of the double-blind data and the open-label data, supplemented by real-world data. | The double-blind and the open- label phases will be analyzed separately. Interpretation of the open-label data may be supplemented by real-world data from other studies if applicable. |
| 8.1.2 Procedures in Event of (Suspected) COVID-19 | Clarified procedures around suspected COVID-19 cases. | Clarification |
| 2.3.2 Benefits of Study Participation | Added statement about recent data suggesting efficacy/safety of Ad26.COV2.S from primary analysis of COV3001. | Updated text |
| 10.12 Appendix 12: Risk Factor Assessment | Updated the assessment form to change any references to “2020” to “the near future.” | To extend the data collection period, as the study is still ongoing. |
| Throughout the protocol | Specified “double-blind” vaccination throughout as applicable Updated terminology from “COVID-19 infection” to “SARS- CoV-2 infection” Minor errors and inconsistencies were corrected, and minor clarifications were added throughout the protocol. | This was done to clarify that the timing of follow-up (except for MAAEs and special reporting situations) is relative to the first vaccination for participants who cross-over to open-label active vaccine. To differentiate the disease from its causative agent. Correction of minor errors and inconsistencies. Addition of minor clarifications. Alignment across sections in the protocol. |
| 1.1 Synopsis 3 OBJECTIVES AND ENDPOINTS 4.1 Overall Design 8.1.3.1 Case Definition for Moderate to Severe/Critical COVID-19 8.1.3.6 Clinical Severity Adjudication Committee 9.1 Statistical Hypotheses 9.2.1 Efficacy (Total Sample Size) 9.5.1 Primary Endpoints Evaluation 9.5.1.1 Study Monitoring 9.5.2 Secondary Endpoints 9.8 Interim Analysis and Committees 10.3.6 Committees Structure | A co-primary endpoint was added counting COVID-19 cases from 28 days post-vaccination (Day 29), in addition to from 14 days post- vaccination (Day 15). The applicable secondary and exploratory endpoints were updated to also include COVID-19 cases with onset at least 28 days post- vaccination, in addition to from 14 days post-vaccination. | This change will allow for formal testing and reporting of the primary endpoint counting cases from 28 days post-vaccination as an additional condition for success along with the 14 days post- vaccination endpoint results. Maintaining the original primary endpoint will preserve trial integrity. This approach will allow to provide the most accurate description of the vaccine efficacy and to assess vaccine efficacy as early as 14 days post-vaccination. |
| 3 OBJECTIVES AND ENDPOINTS | Deletion of the exploratory endpoint relating to evaluation of the occurrence, severity and duration of COVID-19 episodes in participants who received Ad26.COV2.S, as compared to placebo, by the Clinical Severity Adjudication Committee, previously known as the Clinical Evaluation Committee. | The Clinical Severity Adjudication Committee only exists to determine severe/critical cases of COVID-19. |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| and Name | ||
| 10.2 Appendix 2: Clinical Laboratory Test | 10.2 Appendix 2: Clinical Laboratory | |
| Test | ||
| Throughout the protocol | ||
| and Name | ||
| 1.1 Synopsis | ||
| 1.3.1 All Participants | ||
| 1.3.3 Participants with a Suspected | ||
| AESI | ||
| 2.3.1 Risks Related to Study | ||
| Participation | ||
| 2.3.3 Benefit-Risk Assessment of | ||
| Study Participation | ||
| 3. OBJECTIVES AND ENDPOINTS | ||
| 4.1 Overall Design | ||
| 6.4 Unblinding and Open-label Phase | ||
| 6.9 Prestudy and Concomitant Therapy | ||
| 8. STUDY ASSESSMENTS AND | ||
| PROCEDURES | ||
| 8.2.4 Clinical Laboratory Assessments | ||
| 8.3 Adverse Events, Serious Adverse | ||
| Events, Medically-attended Adverse | ||
| Events, Adverse Events of Special | ||
| Interest, and Other Safety Reporting | ||
| 8.3.1 Time Period and Frequency for | ||
| Collecting Adverse Event, Medically- | ||
| attended Adverse Event, Adverse | ||
| and Name | ||
| Event of Special Interest, and Serious | ||
| Adverse Event Information | ||
| 8.3.2 Method of Detecting Adverse | ||
| Events, Medically-attended Adverse | ||
| Events, Adverse Events of Special | ||
| Interest, and Serious Adverse Events | ||
| 8.3.3 Follow-up of Adverse Events, | ||
| Medically-attended Adverse Events, | ||
| Adverse Events of Special Interest, and | ||
| Serious Adverse Events | ||
| 8.3.7Adverse Events of Special | ||
| Interest | ||
| 8.3.7.1 Thrombosis with | ||
| Thrombocytopenia Syndrome | ||
| 9.2.4.2 All Participants | ||
| 9.7Safety Analysis | ||
| 10.2 Appendix 2: Clinical Laboratory | ||
| Tests | ||
| 10.3.6 Committees Structure | ||
| 10.4 Appendix 4: Adverse Events, | ||
| Serious Adverse Events, Adverse | ||
| Events of Special Interest, Medically- | ||
| attended Adverse Events, Product | ||
| Quality Complaints, and Other Safety | ||
| Reporting: Definitions and Procedures | ||
| for Recording, Evaluating, Follow-up, | ||
| and Reporting | ||
| 10.4.5 Procedures | ||
| 10.13 Appendix 13: TTS AESI Form | ||
| 10.14 Appendix 14: Thrombotic | ||
| Events to be Reported as AESIs | ||
| 11 REFERENCES | ||
| 1.1 Synopsis | ||
| 1.3.1 Schedule of Activities “All | ||
| Participants” | ||
| 1.3.2 Schedule of Activities | ||
| “Participants With (Suspected) | ||
| COVID-19” | ||
| 3 OBJECTIVES AND ENDPOINTS | ||
| 4.1 Overall Design | ||
| 8.1.3 Efficacy Assessments | ||
| 9.5.1 Primary Endpoint Evaluation | ||
| 10.2 Appendix 2: Clinical Laboratory | ||
| Test | ||
| 2.3.1 Risks Related to Study Participation | 2.3.1 Risks Related to Study | |
| Participation | ||
| 1.3.1 All Participants | ||
| 2.3.1 Risks Related to Study | ||
| Participation | ||
| 5.5 Criteria for Temporarily Delaying | ||
| Administration of Study Vaccination | ||
| 6.4 Unblinding and Open-label Phase | ||
| and Name | ||
| 8.2.3 Pregnancy Testing 8.3.5 Pregnancy | 8.2.3 Pregnancy Testing | |
| 8.3.5 Pregnancy | ||
| 6.1 Study Vaccines Administered | ||
| 8.3.1 Time Period and Frequency for | ||
| Collecting Adverse Event, Medically- | ||
| attended Adverse Event, Adverse | ||
| Event of Special Interest, and Serious | ||
| Adverse Event Information | ||
| 1.1 Synopsis | ||
| 4.1 Overall Design | ||
| 8.9 Assessment and Procedures after | ||
| EUA or Approval/Licensure and | ||
| Implementation of Protocol | ||
| Amendment 4 | ||
| 9.1 Statistical Hypotheses | ||
| 9.8 Interim Analysis and Committees | ||
| Throughout the protocol | Throughout the protocol |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| and Name | ||
| 1.1 Synopsis | ||
| 1.2 Schema | ||
| 1.3.1 Schedule of Activities “All | ||
| Participants” | ||
| 2.1 Study Rationale | ||
| 2.3.3 Benefit-Risk Assessment of | ||
| Study Participation | ||
| 4.1 Overall Design | ||
| 5 STUDY POPULATION | ||
| 5.5 Criteria for Temporarily Delaying | ||
| Administration of Study Vaccination | ||
| 6.1 Study Vaccines Administered | ||
| 6.2 Preparation/Handling/Storage/ | ||
| Accountability | ||
| 6.8 Continued Access to Study Vaccine | ||
| After the End of the Study | ||
| 8 STUDY ASSESSMENTS AND | ||
| PROCEDURES | ||
| 8.1.3 Efficacy Assessments | ||
| 8.1.3.5 SARS-CoV-2 Seroconversion | ||
| Assessment | ||
| 8.1.4 Immunogenicity Assessments | ||
| 8.2.3 Pregnancy Testing | ||
| 8.3.1 Time Period and Frequency for | ||
| Collecting Adverse Event, Medically- | ||
| attended Adverse Event, Adverse | ||
| Events of Special Interest, and Serious | ||
| Adverse Event Information | ||
| 8.3.5 Pregnancy | ||
| and Name | ||
| 8.10 Assessments and Procedures Related to Booster Vaccination 9.2.2 Immunogenicity Subset (Double- blind Phase and Booster Vaccination 10.1 Appendix 1: Abbreviations 10.2 Appendix 2: Clinical Laboratory Test 10.3.3 Informed Consent Process | 8.10 Assessments and Procedures | |
| Related to Booster Vaccination | ||
| 9.2.2 Immunogenicity Subset (Double- | ||
| blind Phase and Booster Vaccination | ||
| 10.1 Appendix 1: Abbreviations | ||
| 10.2 Appendix 2: Clinical Laboratory | ||
| Test | ||
| 10.3.3 Informed Consent Process | ||
| 1.1 Synopsis 3.2 Booster Vaccination | ||
| 6.5 Booster Vaccination | ||
| 1.1 Synopsis 1.3.1 Schedule of Activities “All Participants” 8.1.4 Immunogenicity Assessments 9.8.1 Immunogenicity Subset (Open- label Booster Vaccination Phase) | ||
| 1.1 Synopsis | ||
| 9 STATISTICAL | ||
| CONSIDERATIONS | ||
| 9.2.1 Efficacy (Total Sample Size) | ||
| 9.8 Analysis of the Open-label Booster | ||
| Vaccination Phase | ||
| 9.8.1 Immunogenicity Subset (Open- | ||
| label Booster Vaccination Phase) | ||
| 9.8.2 Immunogenicity Correlates | ||
| (Correlates Subset) | ||
| 9.8.3 Efficacy Analyses | ||
| and Name | ||
| 2.3.1 Risks Related to Study Participation | ||
| 1.3.1 Schedule of Activities “All | ||
| Participants” | ||
| 8 STUDY ASSESSMENTS AND | ||
| PROCEDURES | ||
| 1.3.3 Participants with a Suspected AESI 8 STUDY ASSESSMENTS AND PROCEDURES | 1.3.3 Participants with a Suspected | |
| AESI | ||
| 8 STUDY ASSESSMENTS AND | ||
| PROCEDURES | ||
| 1.1 Synopsis 11 REFERENCES | ||
| 6.4 Unblinding and Open-label Phase | ||
| and Name | ||
| 10.2 Appendix 2: Clinical Laboratory Test | 10.2 Appendix 2: Clinical Laboratory | |
| Test | ||
| Throughout the protocol | ||
| and Name | ||
| 1.1 Synopsis | ||
| 1.3.1 All Participants | ||
| 1.3.3 Participants with a Suspected | ||
| AESI | ||
| 2.3.1 Risks Related to Study | ||
| Participation | ||
| 2.3.3 Benefit-Risk Assessment of | ||
| Study Participation | ||
| 3. OBJECTIVES AND ENDPOINTS | ||
| 4.1 Overall Design | ||
| 6.4 Unblinding and Open-label Phase | ||
| 6.9 Prestudy and Concomitant Therapy | ||
| 8. STUDY ASSESSMENTS AND | ||
| PROCEDURES | ||
| 8.2.4 Clinical Laboratory Assessments | ||
| 8.3 Adverse Events, Serious Adverse | ||
| Events, Medically-attended Adverse | ||
| Events, Adverse Events of Special | ||
| Interest, and Other Safety Reporting | ||
| 8.3.1 Time Period and Frequency for | ||
| Collecting Adverse Event, Medically- | ||
| attended Adverse Event, Adverse |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| and Name | ||
| Synopsis | ||
| 1.2 Schema | ||
| 1.3 Schedules of Activities | ||
| 2.1 Study Rationale | ||
| 3 OBJECTIVES AND ENDPOINTS | ||
| 4.1 Overall Design | ||
| 4.4 End-of-study Definition | ||
| 5.5 Criteria for Temporarily Delaying | ||
| Administration of Study Vaccination | ||
| 6.5 Booster Vaccination | ||
| 6.10 Prestudy and Concomitant | ||
| Therapy | ||
| 8 STUDY ASSESSMENTS AND | ||
| PROCEDURES | ||
| 8.1.2 Procedures in the Event of | ||
| (Suspected) COVID-19 | ||
| 8.1.3.4 Case Definition for | ||
| Asymptomatic or Undetected COVID- | ||
| 19 | ||
| 8.1.3.6 Clinical Severity Adjudication | ||
| Committee | ||
| 8.2 Safety Assessments | ||
| 8.2.1 Physical Examinations | ||
| 8.2.2 Vital Signs | ||
| 8.3.1 Time Period and Frequency for | ||
| Collecting Adverse Event, Medically- | ||
| attended Adverse Event, Adverse | ||
| Events of Special Interest, and Serious | ||
| Adverse Event Information | ||
| 8.10 Assessment and Procedures | ||
| Related to Booster Vaccination | ||
| 9.2.4.2 All Participants | ||
| 10.2 Appendix 2: Clinical Laboratory | ||
| Tests | ||
| 10.3.6 Committees Structure | ||
| 10.4.1 Adverse Event Definitions and | ||
| Classifications | ||
| 10.7Appendix 7: MRU Questionnaire | ||
| 10.8 Appendix 8: Medically-attended | ||
| COVID-19 (MA-COV)Form | ||
| Synopsis 3 OBJECTIVES AND ENDPOINTS 9.1 Statistical Hypotheses 9.7Safety Analysis 9.8 Analysis of the Open-label Cross- over Phase, Open-label Booster Vaccination Phase | Synopsis | |
| 3 OBJECTIVES AND ENDPOINTS | ||
| 9.1 Statistical Hypotheses | ||
| 9.7Safety Analysis | ||
| 9.8 Analysis of the Open-label Cross- | ||
| over Phase, Open-label Booster | ||
| Vaccination Phase | ||
| 10.4.3 Severity Criteria | ||
| and Name | ||
| Throughout the protocol | Throughout the protocol |