Janssen’s companion pivotal Phase 3 trial of Ad26.COV2.S in adults ≥18 years, evaluating a two-dose regimen (vs. single-dose in ENSEMBLE / VAC31518COV3001) to assess whether a homologous booster two months after the primary dose improved efficacy and duration of protection. Run in parallel with ENSEMBLE and funded by the same Janssen + BARDA contract. The source is Janssen’s Amendment 7 (27 April 2022) hosted on clinicaltrials.gov, with an Appendix carrying full Section / Description / Rationale tables for every prior amendment.
Latest protocol we have: jj-ensemble2-NCT04614948-protocol.pdf
| Category | Count | Amendments |
|---|---|---|
| Total documents in the history (Original + Amendments 1–7) | 8 | |
| Direct PDFs available | 2 | Amendments 3, 7 |
| Summary-only (date and rationale recorded here, no full PDF available) | 6 | Amendments 1, 2, 4, 5, 6; Original Protocol |
| Document | Date | Available documents | Main rationale for the amendment |
|---|---|---|---|
| Original Protocol | 22 August 2020 | Summary only — no full PDF of this version available | (no main-rationale paragraph in source) |
| Amendment 1 | 25 September 2020 | Summary only — no full PDF of this version available | The amendment is written to adjust the dose level of Ad26.COV2.S from 1×1011 virus particle (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. 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 VAC31518COV3009 are listed below, including the rationale of each change and a list of all applicable sections. |
| Amendment 2 | 27 November 2020 | Summary only — no full PDF of this version available | The 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. In addition, text in relation to biomarker evaluation of RNAseq analyses (PAXgene tube) is deleted, and based on Health Authority request, text in exclusion criterion #7 was corrected and text regarding United Kingdom (UK) specific self-swabbing test was deleted. Finally, text was added to introduce the utilization of tokenization and matching procedures, for United States (US) participants only, to obtain participant's medical data 5 years prior to enrollment of the participant until 5 years after study completion from consenting participants. The changes made to the clinical protocol of study VAC31518COV3009 are listed below, including the rationale of each change and a list of all applicable sections. |
| Amendment 3 | 18 December 2020 | jj-ensemble2-amendment-3-2020-12-18.pdfWayback Machine — jnj.com | The main purpose of this amendment is to outline the procedures to be followed in the event that an investigator receives a request to unblind study participants who may become eligible to receive an authorized/licensed COVID-19 vaccine if/when these become available. The purpose is to ensure (1) that the participants are informed that there is no data on the safety of receiving two different COVID-19 vaccines, (2) that in the event the participant is unblinded, no further study vaccination will be permitted, (3) that unblinded participants will continue to be followed in this study in line with the Schedules of Activities, and that safety, efficacy, and immunogenicity evaluations will continue to be performed, although the data will be analyzed separately from the point of unblinding. The changes made to the clinical protocol of study VAC31518COV3009 are listed below, including the rationale of each change and a list of all applicable sections. |
| Amendment 4 | 12 March 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 Ad26.COV2.S Emergency Use Authorization (EUA) in the United States (US) and approval of Protocol Amendment 4 by the local Health Authority and the Independent Ethics Committee/Institutional Review Board (IEC/IRB). A single dose of Ad26.COV2.S vaccine will be offered to enrolled participants who initially received placebo, resulting in de facto unblinding of all participants and investigators. In addition, the study design has been updated to replace the 2-dose placebo arm with a 1-dose active vaccination arm to allow assessment of the level of efficacy and duration of protection of a 2-dose schedule of Ad26.COV2.S compared to the 1-dose schedule, as well as a direct comparison of the immunogenicity of the 2 schedules, whereby the single dose is introduced at different time points. All participants will be encouraged to remain in the study and continue to be followed for efficacy/effectiveness, safety and immunogenicity. The changes made to the clinical protocol of study VAC31518COV3009 are listed below, including the rationale of each change and a list of all applicable sections. [[PAGE 214]] VAC31518 (JNJ-78436735) Clinical Protocol VAC31518COV3009Amendment 7 CONFIDENTIAL –FOIA Exemptions Apply in U.S. 215 Status: Approved, Date: 27 April 2022 |
| Amendment 5 | 6 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 in the 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 adverse event of special interest (AESI) that needs to be reported to the sponsor within 24 hours of awareness. In addition, the protocol has been adjusted to align with the latest vaccine risk language. |
| Amendment 6 | 15 October 2021 | Summary only — no full PDF of this version available | This amendment has been created to offer a 1-dose booster vaccination with Ad26.COV2.S at the 5x1010 vp dose level to all ongoing participants who received only a single vaccination with Ad26.COV2.S in the study. Participants who already received 2 vaccinations with Ad26.COV2.S at the 5x1010 vp dose level or any COVID-19 vaccinations outside of the study (including the Janssen vaccine) at the time of local approval of Protocol Amendment 6 are not eligible to receive a booster vaccination with Ad26.COV2.S. The booster vaccination will be administered in the open-label phase of the study, preferably within 6 to 12 months after the participant’s first Ad26.COV2.S vaccination in the study. If this is not possible, the booster vaccination should not occur earlier than 3 months after the participant’s first Ad26.COV2.S vaccination. All participants (whether they consent to the booster vaccination or not) will be encouraged to remain in the study and will be monitored for safety, immunogenicity, and efficacy according to their original schedule. 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. Furthermore, while protection against variants of concern (such as the Beta and Mu variants in study COV3001 and the Delta variant in the Sisonke study) remains high against severe/critical disease, hospitalization, and death, this protection is lower against, eg, the Gamma variant compared to the reference Wuhan strain. Protection against severe/critical disease caused by different variants of concern (such as Gamma, Lambda and Mu variants) was shown to be reduced in the final analysis of study COV3001 compared to the reference Wuhan strain and the Alpha variant, for example. Giving a second dose of Ad26.COV2.S results in marked increases of immune responses and those higher immune responses correlate with better protection against COVID-19, as shown in the primary analysis of study COV3009. Some national vaccination recommendation bodies (eg, CDC) have recently advised to give a booster vaccination. Therefore, this amendment will permit boosting of all eligible ongoing participants in this study who received only a single vaccination with Ad26.COV2.S in the study. As the Janssen vaccine is approved as a single dose vaccine, participants who received two doses of Ad26COV2.S are considered to already have received the booster dose. Given that the sponsor has no safety information on mixed schedule vaccinations, participants that received a COVID-19 vaccination outside of the study will not be offered the booster dose in this study. |
| Amendment 7 | 27 April 2022 | jj-ensemble2-NCT04614948-protocol.pdfclinicaltrials.gov (NCT04614948) | Vaccine Ad26.COV2.S has received emergency use authorization (EUA) by the United States (US) Food and Drug Administration (FDA) and conditional marketing authorization by the European Commission. Vaccine Ad26.COV2.S has also been authorized in several other countries/territories worldwide. The epidemic continued and new variants of concern emerged, and national recommendations introduced booster vaccinations. The primary analysis of the study that described the double-blind phase has been completed, the primary objectives of the double-blind phase have been met, and the CSR has been finalized for this part of the study. Further efficacy evaluations of the open-label data have limitations, due to the unblinding and the loss of the placebo group. 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 new 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 COVID-19 events) and a second end of study analysis is planned (using a passive follow-up of COVID-19 events). These and other changes made to the clinical protocol of Study VAC31518COV3009 as part of Protocol Amendment 7 are listed below, including the rationale for each change and a list of all applicable sections. Changes made as part of Protocol Amendments 1 to 6 are listed in Section 10.15. VAC31518 (JNJ-78436735) Clinical Protocol VAC31518COV3009Amendment 7 CONFIDENTIAL –FOIA Exemptions Apply in U.S. 3 Status: Approved, Date: 27 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 |
|---|---|---|
| distinguishing dosing across both studies. | ||
| 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. Minor clarifications are made. |
| 1.1 Synopsis 2.1 Study Rationale 2.2 Background 4.1 Overall Design 4.3 Justification for Dose 4.4 End-of-study Definition 6.1 Study Vaccines Administered 8.1.4 Immunogenicity Assessments | The Ad26.COV2.S dose level has been changed 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 (28days 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 were met by the 5x1010 vp dose, the sponsor decided to use this dose for further evaluation in the Phase 3 study VAC31518COV3009. | ||
| 1.1 Synopsis 9.5.1 Primary Endpoint Evaluation 9.5.1.1 Study Monitoring | The trigger for the evaluation of the primary endpoint has been modified, adding one condition related to the number of COVID- 19 cases (6) meeting the primary endpoint definition of moderate to severe/critical COVID-19 in the elderly population, that needs 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. |
| 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. | To clarify that antipyretics are recommended post- vaccination for symptom relief, as needed. Prophylactic antipyretic use is not encouraged. |
| 5.2 Exclusion Criteria 6.6 Continued Access to Study Vaccine After the End of the Study 6.8 Prestudy and Concomitant Therapy | Guidance has been added on the use of licensed COVID-19 vaccines, when one might become available, during the study. | Clarification purposes |
| 1.1 Synopsis 1.3.1 All Participants 2.3.1 Risks Related to Study Participation | It has been clarified that the post- vaccination observation period at the study site will be at least 30 minutes for the first 1,000 | To align with the number of participants included in Stage 1 since the decision to reduce the post- |
| 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 | participants (and not 2,000 participants) and may be decreased to at least 15 minutes for the remaining participants, if no acute reactions are observed. | vaccination follow-up time at the site will be based on the planned Day 3 safety evaluation. |
| 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. |
| 9.2.1 Efficacy (Total Sample Size) | The time to signal has been modified in the sample size section. | To present time to signal corresponding to the assumed VE for powering the study (VE=65%). |
| 1.1 Synopsis 1.3.1 All Participants 4.1 Overall Design 8.7 Baseline and Longitudinal Risk Factor Assessment 9.4 Participant Information 9.5.3 Exploratory Endpoints 10.12 Appendix 12: Risk Factor Assessment | It has been added that additional 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. |
| 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. |
| 1.1 Synopsis 2.1 Study Rationale 4.1 Overall Design 4.3 Justification for Dose | Additional rationale for the assessment of the 2-dose regimen has been added. | Even though a single-dose regimen in study VAC31518COV1001 showed good immunogenicity, evaluation of the 2-dose regimen is still valuable as this |
| regimen may show a higher and more durable immune response. | ||
| 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 is clarified that at the time of study entry, each participant will need to indicate to the study site, 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. | To ensure optimal follow up of participants with COVID-19. |
| 10.3.3 Informed Consent Process | Information about the caregiver’s consent form has been added. | For clarification purposes. |
| 10.3.8 Data Quality Assurance 10.3.11 Monitoring | Source data verification has been replaced by review of the source data. | To clarify that source data verification will not be done on most of the data. |
| 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. |
| 3 OBJECTIVES AND ENDPOINTS | A secondary endpoint looking at the first occurrence of molecularly confirmed, moderate to severe/critical COVID-19 with onset 14 days after the 1st vaccination has been added. | To allow for a pooled analysis on this timepoint across studies. |
| 9.5.1 Primary Endpoint Evaluation | It has been clarified that the data from this study may be pooled with data from other ongoing efficacy studies. | To have a more robust data package in support of health authority interactions. |
| Throughout the protocol | Minor errors and inconsistencies were corrected, and minor clarifications were added throughout the protocol | Correction of minor errors and inconsistencies. Minor clarifications are made. |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| SARS-CoV-2 infection, regardless of symptomatic or asymptomatic. | ||
| 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. |
| 5.1 Inclusion Criteria | Inclusion criterion 4 was updated to include a timeframe for criteria a and b for stable/well-controlled HIV infection. In addition, 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 |
| 5.2 Exclusion Criteria | Exclusion criterion 4 updated for clarification. | Clarification |
| Throughout the protocol | Minor errors and inconsistencies were corrected, and minor clarifications were added throughout the protocol. | Correction of minor errors and inconsistencies. Minor clarifications are made. |
| 1.1 Synopsis 1.3.2 Participants With (Suspected) COVID-19 4.1 Overall Design | Clarified that all participants that have a RT-PCR positive finding for SARS-CoV-2 from outside the study, even if asymptomatic, will | To ensure safety of staff and other persons coming in contact with the infected participant. |
| 8 Study Assessments and Procedures and associated subsections 10.3.10 Source Documents | be followed until there are two consecutive negative PCRs. | |
| 1.1 Synopsis 1.3.1 All Participants 1.3.2 Participants With (Suspected) COVID-19 3 Objectives and Endpoints 4.1 Overall Design 4.2 Scientific Rationale for Study Design 6.3 Measures to Minimize Bias: Randomization and Blinding 8 Study Assessments and Procedures and associated subsections 9.5.4 Other Analyses 10.2 Appendix 2: Clinical Laboratory Tests 10.3.4 Data Protection | Text in relation to the evaluation of biomarker RNAseq analyses (PAXgene tube) is deleted and subsequently, the total amount of blood drawn from the participants has been adjusted. | Deletion. Collection of biomarker data from participants in Study VAC31518COV3001 is deemed sufficient, hereby the assessment was taken out from this study. |
| 1.1 Synopsis 2.1 Study Rationale 2.3.3 Benefit-Risk Assessment of Study Participation 4.1 Overall Design 8.1.4 Immunogenicity Assessments 9.2.2 Immunogenicity Subset | It has been clarified that Stage 2 will enroll participants with and without comorbidities and immunogenicity subset will be enrolled in Stage 2 only. | Clarification |
| 5.2 Exclusion Criteria 6.8 Prestudy and Concomitant Therapy 7.1 Discontinuation of Study Vaccination | The specification of ‘(>10 days)’ when referring to the chronic use of systemic corticosteroids has been removed from the exclusion criterion 3 and aligned throughout. | To remove ambiguity as within the same exclusion criterion 3 b substantial immunosuppressive steroid dose is defined as ≥2 weeks of daily receipt of 20 mg of prednisone or equivalent |
| 6.9 Study Vaccination Pausing Rules for Stage 1 10.3.6 Committees Structure | Text was added to clarify that if there will be any study pause, the Sponsor will submit a request to restart the study with pertinent data to the Health Authorities as a request for a substantial amendment, as required by the local regulations. | Upon Health Authority feedback |
| 1.3.1 All Participants 1.3.2 Participants With (Suspected) COVID-19 8.1.2 Procedures in the Event of (Suspected) COVID-19 8.5 Medical Resource Utilization 10.8 Appendix 8: Medically-attended COVID-19 (MA-COV) Form | The MA-COV form has been updated to also capture additional individual signs and symptoms, including clinical or radiological evidence of pneumonia, hyperinflammatory syndrome, and if the oxygen 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 | To ensure collection of all necessary information in order to determine the severity of COVID- 19 per the case definitions and clarification purposes. |
| completed by the study site personnel. | ||
| 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 VAC31518COV3009 as pregnant women are not allowed to participate in the study. |
| 1.1 Synopsis 1.3.1 All Participants 1.3.2 Participants With (Suspected) COVID-19 4.1 Overall Design 8.1.2 Procedures in the Event of (Suspected) COVID-19 8.6 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 post- vaccination 1 followed by 6 months and 1 year post-vaccination 2, and at COVID-19 Day 3-5. In addition, it was also 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 on when participants will be interviewed on additional characteristics that will be used for risk factor analysis. |
| 5.2 Exclusion Criteria | Chronic kidney disease has been removed and participant 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 6.8 Prestudy and Concomitant Therapy | Exclusion criterion 7 and text for Prestudy therapy was updated to remove remdesivir and to clarify that the use of investigational Immunoglobulin (Ig), investigational monoclonal antibodies or convalescent serum are not allowed during the study. | Upon Health Authority feedback and alignment across Ad26.COV2.S study protocols |
| 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 VAC31518COV3009. |
| 1.1 Synopsis 1.3.1 All Participants 3 Objectives and Endpoints 4.1 Overall Design 8 Study Assessments and Procedures | Text was deleted related to UK- specific self-swabbing test as these will not be performed. | Upon National Institute for Health Research (NIHR), UK feedback |
| 8.1.3 Efficacy Assessments and related subsections 10.2 Clinical Laboratory Tests | ||
| 1.1 Synopsis 5.2 Exclusion Criteria | Clarification has been added that the history of Parkinson’s disease, seizures, ischemic strokes, intercranial hemorrhage encephalopathy, meningoencephalitis is exclusionary from Stage 1. | Clarification. |
| 5.2 Exclusion Criteria | It is clarified that participants with Guillain-Barré syndrome (Exclusion criterion 16) and participants requiring hospitalization as indicated in exclusion criterion 17 are excluded from the study altogether and not only in Stage 1 of the study. | Correction |
| 5.1 Inclusion Criteria | Clarifications have been made to the inclusion criterion 4, indicating that Stage 1 participants can have a condition that is stable and well- controlled except the ones listed in exclusion criterion 14 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 2.1 Study Rationale 4.1 Overall Study Design 9.8 Interim Analyses and Committees 10.3.6 Committees Structure | Reference to a possible sample size adjustment has been deleted and sample size considerations has been added. | Correction: per the VAC31518COV3009 Amendment 1, the sample size of approximately 30,000 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 SpO criteria is per the 2 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. |
| 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 1.3.1 All Participants 1.3.2 Participants With (Suspected) COVID-19 4.1 Overall Design 8 Study Assessments and Procedures and associated subsections | Term "COVID-19 signs and symptoms surveillance" is changed to "(Suspected) COVID-19 surveillance (symptom check)" and additional clarification is provided by adding this to the procedures followed for participants with (suspected) COVID-19. | Clarification |
| 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 | 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 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 |
| 8.7 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 | 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 8Study Assessments and Procedures 9.3 Populations for Analysis Sets | Clarified that when the study pause has been lifted, efforts will be made to still vaccinate a participant if the vaccination window is missed due to the study pause. Clarified that these participants will not be excluded from the per protocol efficacy (PP) and per protocol immunogenicity (PPI) population by default for this reason. | Mitigation in case of study pause: Clarification on out of window vaccination. |
| 1.1 Synopsis 1.3.1 All Participants 6.8 Prestudy and Concomitant Therapy 8.3.1 Time Period and Frequency for Collecting Adverse Event, Medically-attended Adverse Event, and Serious Adverse Event Information 8.3.2 Method of Detecting Adverse Events, Medically-attended Adverse Events, and Serious Adverse Events | Clarified that if solicited signs and symptoms are not resolved within 7 days post-vaccination, the participant will continue to complete the e-Diary until Day 29 post-vaccination or until they are resolved, whichever comes first. Similarly, the concomitant therapies will also be collected by the participants and recorded in the eCRF until Day 29 post-vaccination or until they are resolved, whichever comes first. | Clarification |
| 9.5.2 Secondary Endpoints | The text about the endpoint of molecularly confirmed COVID-19 cases requiring medical intervention has been added. | Addition: to align the secondary endpoints described with the secondary endpoints that are part of the hypothesis testing. |
| 1.1 Synopsis 9.3 Populations for Analysis Sets | PP population has been corrected to include seronegative test at Day 71 sample. | Correction |
| 5.2 Exclusion Criteria | Text has been added to restrict the proportion of seropositive participants in the study. | Clarification |
| 8Study Assessments and Procedures | Clarification has been added that visits apart from screening and vaccination can be performed at participant's home by the study staff or designee | Clarification |
| 8Study Assessments and Procedures | Clarification has been added that in case of home visit, assessments that cannot be delegated to a designee must be performed by an appropriate Site staff member via a phone call or telemedicine. | Clarification |
| 1.3.2 Participants With (Suspected) COVID-19 8.1.2 Procedures in the Event of (Suspected) COVID-19 | Further clarifications are made to the procedures to be followed in case of (suspected) COVID-19. | Clarification |
| 6.9 Study Vaccination Pausing Rules for Stage 1 8.2 Safety Assessments 10.1 Appendix 1 Abbreviations 10.3.6 Committees Structure | Text has been corrected to remove the reference to collaboration partners, PI and PSRT, as there will be no collaboration partners involved and PI review is not planned. The safety data will be reviewed by Sponsor/Sponsor committee, as applicable and not PSRT. | Correction |
| 1.1 Synopsis 1.3.1 All Participants 2.1 Study Rationale 2.3.1 Risks Related to Study Participation 2.3.3 Benefit-Risk Assessment of Study Participation 4.1 Overall Study Design 8.3.2 Method of Detecting Adverse Events, Medically-attended Adverse Events, and Serious Adverse Events | Text about the equal distribution of participants in 2 age groups (≥18 to <60 years and ≥60 years of age) in Stage 1 and equal distribution of first 1000 participants has been deleted. | Based on accumulating safety data from study VAC31518COV3001, safety evaluation of approximately 1000 participants without comorbidities will trigger the enrolment of participants with and without comorbidities. |
| 7.1 Discontinuation of Study Vaccination 7.2 Participant Discontinuation/Withdrawal From the Study | Further clarification was added on the consent withdrawal by the participants. | Clarification |
| 1.1 Synopsis 2.1 Study Rationale 4.1 Overall Design | Clarification has been added that the enrollment might be stopped if the primary endpoint will be reached. | Clarification |
| 2.3.1 Risks Related to Study Participation 5.1 Inclusion Criteria 11 REFERENCES | It has been clarified that the use of condoms is not considered as an acceptable contraceptive barrier method due to the failure rate of female and male condoms. | Clarification |
| Title Page | Study Title has been changed from "HORIZON" to "ENSEMBLE 2". | To clarify that this study is strongly linked to study VAC31518COV3001, which is referred to as the ENSEMBLE study. To allow harmonization across our Ad26.COV2.S program and to assist the public with associating both studies and, assisting the public with identifying an appropriate study site, and |
| distinguishing dosing across both studies. | ||
| 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. Minor clarifications are made. |
| 1.1 Synopsis 2.1 Study Rationale 2.2 Background 4.1 Overall Design 4.3 Justification for Dose 4.4 End-of-study Definition 6.1 Study Vaccines Administered 8.1.4 Immunogenicity Assessments | The Ad26.COV2.S dose level has been changed 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 (28days 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 |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| Throughout the protocol | Minor errors and inconsistencies were corrected, and minor clarifications were added throughout the protocol. Reference to “double-blind”/ “double-blind phase” and “open- label”/ “open-label phase” were made as applicable. “PCR” was clarified to “RT-PCR,” where applicable. | Correction of minor errors and inconsistencies. Minor clarifications are made. Alignment across sections in the protocol Ensure clarity where timing or procedures are specific to one phase of the study. |
| 1.1 Synopsis 6.3 Measures to Minimize Bias: Randomization and Blinding 6.6 Continued Access to Study Vaccine After the End of the Study 7.1 Discontinuation of Study vaccination 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 in participants that have received a 1-dose or 2-dose Ad26.COV2.S vaccine, and that no further study vaccination will be permitted; that unblinded participants will continue to be followed throughout the study for safety, efficacy and immunogenicity assessments, although the data will be analyzed separately from the point of unblinding. |
| 7.1 Discontinuation of Study vaccination | Clarification that study vaccination will be discontinued in participants with molecularly confirmed | Clarification |
| SARS-CoV-2 infection, regardless of symptomatic or asymptomatic. | ||
| 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. |
| 5.1 Inclusion Criteria | Inclusion criterion 4 was updated to include a timeframe for criteria a and b for stable/well-controlled HIV infection. In addition, 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 |
| 5.2 Exclusion Criteria | Exclusion criterion 4 updated for clarification. | Clarification |
| Throughout the protocol | Minor errors and inconsistencies were corrected, and minor clarifications were added throughout the protocol. | Correction of minor errors and inconsistencies. Minor clarifications are made. |
| 1.1 Synopsis 1.3.2 Participants With (Suspected) COVID-19 4.1 Overall Design | Clarified that all participants that have a RT-PCR positive finding for SARS-CoV-2 from outside the study, even if asymptomatic, will | To ensure safety of staff and other persons coming in contact with the infected participant. |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| 1.1 Synopsis 1.2 Schema 1.3.2 Open-label Unblinding Visit (added) 2.1 Study Rationale (added) 2.3.3 Benefit-Risk Assessment of Study Participation 4.1 Overall Design4.2 Scientific Rationale for Study Design 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 8.1.3 Efficacy Assessments 8.1.4 Immunogenicity Assessments 8.3.1 Time Period and Frequency for Collecting Adverse Event, Medically-attended Adverse Event, and Serious Adverse Event Information 8.3.2 Method of Detecting Adverse Events, Medically-attended Adverse Events, and Serious Adverse Events 8.8Assessment and Procedures After Emergency Use Authorization and Implementation of Protocol Amendment 4 9.5.1 Primary Endpoint Evaluation 9.9Analyses for cohort unblinded due to administration of an authorized/licensed COVID-19 vaccine (Double-blind Phase) 10.2 Appendix 2: Clinical Laboratory tests 10.3.3 Informed Consent Process 10.3.8Data Quality Assurance | An unblinding visit will be introduced for all participants who have already received Ad26.COV2.S or placebo. At the unblinding visit, participants who initially received placebo will be offered a single dose of Ad26.COV2.S vaccine. Upon unblinding, all participants will enter the open-label phase of the study. Before the actual participant unblinding, all of the previously available data should be complete and accurate in the participant’s eCRF. Relevant sections were updated regarding the open-label phase. | As 1 dose of the vaccine is highly efficacious against severe disease, hospitalization, and death, it is considered ethical to offer 1 dose of the active vaccine to the placebo controls in this study. Investigators will be encouraged to follow health authority guidelines on prioritization of immunization. All participants will be counselled to continue practicing other public health/preventive 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. |
| Schedule of Activities 1.3.1 All participants 1.3.2 Open-label Unblinding Visit (added) 8.1.2 Procedures in the Event of (Suspected) COVID-19 8.1.3 Efficacy Assessments 8.1.4 Immunogenicity Assessments 8.3.2 Pregnancy Testing 8.8Assessment and Procedures After Emergency Use Authorization and Implementation of Protocol Amendment 4 10.2 Appendix 2: Clinical Laboratory Test | The unblinding visit should be scheduled as soon as reasonably practicable and preferably no later than 2 months following EUA in the US and approval of Protocol Amendment 4 by the local Health Authority and the Independent Ethics Committee/Institutional Review Board (IEC/IRB). At the unblinding visit, participants will have a blood draw, nasal swab, body temperature and urine pregnancy test (for participants of childbearing potential who will receive vaccination). A Schedule of Activities 1.3.2 was added for the unscheduled unblinding visit, which can be combined with the next scheduled visit, if possible, without duplicating any procedures. | The unblinding visit will be scheduled to inform all participants about their study vaccine allocation as well as to offer placebo recipients Ad26.COV2.S after EUA in the US and approval of Protocol Amendment 4 by the local Health Authority and the IEC/IRB. 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 unblinding visits, as well as having a new baseline read-out for the remainder of the study. The additional pregnancy test is to rule out pregnancy prior to vaccinating any participant at unblinding visit. Participants who are pregnant and previously received placebo during the double- blind phase may be vaccinated, if allowed by local regulations for emergency use of the vaccine. |
| 1.1 Synopsis 1.2 Schema 4.1 Overall Design 4.2 Scientific Rationale for Study Design 5.5 Criteria for Temporarily Delaying Administration of Study Vaccination 6.1 Study Vaccines Administered 6.3 Measures to Minimize Bias: Randomization and Blinding 6.4 Unblinding and Open-label phase (added) 9.3 Populations for Analysis | A single-dose active vaccination regimen was introduced in the study to replace the 2-dose placebo regimen. Newly enrolled participants will be randomized 1:1 to the 1- or 2-dose regimen. | To ensure the direct comparison of the immunogenicity of the 2 Ad26.COV2.S dosing schedules (1 dose vs. 2 dose) in the open-label phase of the study. To ensure completion of target sample size. |
| 1.1 Synopsis 3 OBJECTIVES AND ENDPOINTS 9.8 Interim Analysis and Committees | For double-blind phase, following changes were made:
| This change will allow for formal testing and reporting of the secondary endpoint counting cases from 28 days post-vaccination as an additional condition for success. Clarification To gather information regarding efficacy against variants. |
| 1.1 Synopsis 3 Objectives and Endpoints 4.1 Overall Design 6.3 Measures to Minimize Bias: Randomization and Blinding 6.4 Unblinding and Open-label phase (added) 9.1 Statistical Hypotheses 9.2.1 Efficacy (Total Sample Size) 9.2.2 Immunogenicity Subset 9.3 Populations for Analysis Sets 9.5.1 Primary Endpoint Evaluation for the Double-Blind Phase 9.5.2 Secondary Endpoints for the Double-blind Phase 9.5.3 Analyses for the Open-label Phase 9.6 Immunogenicity Analyses 9.8Interim Analysis and Committees | Objectives were added for the open-label phase of the study. All data will be analyzed separately from the point of unblinding. Text was added to indicate that the SAP for the open-label part, including the detailed objectives, and endpoints, and inferential analyses, will be provided to regulatory authorities prior to the primary analysis of efficacy of the 2-dose schedule versus placebo in the double-blind phase. Text was added to clarify that a superiority evaluation will be done for the primary objective of the open-label phase using a null hypothesis of relative VE=0%. An interim analysis may be performed using group sequential methodology. All details regarding the analysis will be specified in the SAP. Text was added to indicate that the final analysis of the open-label phase will occur when all active participants have completed Visit 8 or discontinued earlier. Immunogenicity analyses for the open-label phase were added. | The study design changed from double-blind placebo-controlled to open-label 1-dose versus 2-dose regimen. |
| 1.1 Synopsis 4.1 Overall Design 9.5.1 Primary Endpoint Evaluation for Double-blind Phase | Added text to clarify that for any case definition to be considered for classification of COVID-19 cases, there needs to be at least one SARS- CoV-2 positive RT-PCR or molecular test result from any available respiratory tract sample (eg, nasal swab sample, sputum sample, throat swab sample, saliva sample) that is confirmed by the central laboratory. If there will be delay in availability of the results, a sensitivity analysis may be performed using all RT-PCR or molecular test result, regardless of the confirmation by the central laboratory. | Clarification |
| 1.1 Synopsis 2.3.1 Risks Related to Study Participation 3 Objectives and Endpoints 8.1.3 Efficacy Assessments 8.1.3.1 Case Definition for Moderate to Severe/Critical COVID-19 8.1.3.6 Clinical Severity Adjudication Committee 10.3.6 Committees Structure | The Clinical Evaluation Committee is replaced by the Clinical Severity Adjudication Committee. Text related to Clinical Severity Adjudication Committee was updated. Deletion of the exploratory endpoint relating to evaluation of the occurrence, severity, and duration of COVID-19 episodes by Clinical Evaluation Committee. | To align with study VAC31518COV3001, the Clinical Evaluation Committee is replaced by the Clinical Severity Adjudication Committee which will evaluate and adjudicate COVID-19 cases. |
| 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 | Additional changes made to allow unblinding 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 or Phase 3B study for Ad26.COV2.S, to continue to be followed in VAC31518COV3009. |
| 1.3.2 Open-label Unblinding Visit (added) 8.2.3 Pregnancy Testing 8.8Assessment and Procedures After Emergency Use Authorization and Implementation of Protocol Amendment 4 10.2 Appendix 2: Clinical Laboratory Test | Added an additional urine pregnancy test for participants of childbearing potential who will receive active vaccination at the time of unblinding visit. Participants who are pregnant and previously received placebo during the double-blind phase may be vaccinated, if allowed by local regulations for emergency use of the vaccine. | To rule out pregnancy prior to vaccinating any participant at unblinding visit. |
| 1.3 Schedule of Activities 5.2 Exclusion Criteria 6.4 Unblinding and Open-label Phase (added) | Exclusion criterion 3 has been modified to allow
| Clarification that injectable corticosteroids for local use are allowed as they are not systemic corticosteroids Clarification that non- immunomodulating monoclonal antibodies are allowed. |
| 1.1 Synopsis 1.3.1 All Participants 1.3.2 Open-label Unblinding Visit (added) 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 8.8Assessment and Procedures After Emergency Use Authorization and Implementation of Protocol Amendment 4 | Changes previously implemented in a local amendment are now included in the global amendment. | To align the Global version of the protocol with a local protocol version. |
| 1.3 Schedule of Activities 8STUDY ASSESSMENTS AND PROCEDURES | Note was added that the baseline SIC should be completed prior to the first vaccine administration and further if a participant is unable to complete the SIC, the reason for missing should be recorded in the eCRF. | If the baseline SIC is not completed, no eCOA scales will be triggered. |
| 1.3 Schedule of Activities 8STUDY ASSESSMENTS AND PROCEDURES | Clarifications have been added to the "Closure of the COVID-19 episode" regarding collection of nasal swabs, saliva samples and SIC. | Clarification |
| 6.3 Measures to Minimize Bias: Randomization and Blinding 6.4 Unblinding and Open-label Phase 7.1 Discontinuation of Study Vaccination | Wording was added to differentiate between the general unblinding after EUA in the US and approval of Protocol Amendment 4 by the local Health Authority and IEC/IRB of Ad26.COV2.S and the unblinding requested previously by participants in order to receive a licensed COVID-19 vaccine. | Clarification and alignment. |
| 6.9Prestudy and Concomitant Therapy | It was added that receipt of any COVID-19 vaccination (outside the study) should be recorded at any timepoint during the study. | Clarification and alignment. |
| 1.3 Schedule of Activities 6.9Prestudy and Concomitant Therapy | Clarification has been added that prestudy therapies linked to inclusion and exclusion criteria (eg, flu vaccine) should be recorded. | Clarification. |
| 1.3 Schedule of Activities | Window period of Visit 7 was modified to Day -106 to Day +28. Visit Timing references were changed from Vaccination 2 to Visit 4 and Visit day/week references were also changed from Vaccination 2 to Day 57. Text was added to the schedule of activities 1.3.1 to accommodate the changes for participants who will be administered a single-dose in the open-label phase. | To unblind a majority of the participants at a scheduled visit and enable the unblinding as soon as possible. To clarify the timing of visits in the open-label phase of the study. |
| 1.1 Synopsis 1.3 Schedule of Activities 4.1 Overall Design 8 Study Assessments and Procedures | Updated the twice weekly eCOA assessments to occur until completion of Visit 8 (triggering of final analysis of the open-label phase). | To ensure that all participants have 1 year of eCOA assessments. |
| 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 |
| 1.1 Synopsis 4.1 Overall Design 9.1Statistical Hypotheses 9.2.1 Efficacy (Total Sample Size) 9.2.4 Safety (Safety Subset) 9.5 Efficacy Analyses 9.5.1 Primary Endpoint Evaluation for the Double-blind Phase 9.5.1.1 Study Monitoring 9.6 Immunogenicity Analyses 9.6.1 Immunogenicity Subset 9.8Interim Analysis and Committees 10.1 Appendix 1: Abbreviations | The assumptions for sample size were modified to delete reference to target number of events (TNE). The sequential probability ratio test (SPRT) was removed. Target enrollment was updated to “approximately” 30,000 and text was added that up to 10% of additional participants may be recruited to partially compensate for increased fraction unblinded prior to unblinding visit and/or increased seroprevalence rates and/or drop-outs. Text was added/deleted to indicate that interim testing would not be conducted on double-blind data, and that the primary analysis of the double-blind data would occur when at least 90% of participants have reached the unblinding visit. Monitoring for non-efficacy and efficacy was removed from the double-blind phase. Text was added to clarify that every effort will be made to reach a target of 6,000 participants in the safety subset before unblinding. A 1-dose vs 2-dose immunogenicity assessment was added. | To update the analysis as appropriate for the change to an open-label design. |
| 9.8Interim Analysis and Committees | The role ofthe IDMC was modified. | To clarify that IDMC will oversee safety and perform harm monitoring during double-blind and open-label phase. Also, to clarify that IDMC will no longer perform efficacy monitoring, as the analysis of the double-blind phase is no longer event driven but will occur when at least 90% of the participants have completed their unblinding visit. |
| 10.2 Appendix 12: Risk Factor Assessment | Updated the assessment form to change any references to 2020 to “the near future.” Deletion of Questionnaire 2. | To extend the data collection period, as the study is still ongoing. Questionnaire 2 is not applicable; the baseline version is repeated at post-baseline timepoints. |
| Throughout the protocol | Minor errors and inconsistencies were corrected, and minor clarifications were added throughout the protocol. Reference to “double-blind”/ “double-blind phase” and “open- label”/ “open-label phase” were made as applicable. “PCR” was clarified to “RT-PCR,” where applicable. | Correction of minor errors and inconsistencies. Minor clarifications are made. Alignment across sections in the protocol Ensure clarity where timing or procedures are specific to one phase of the study. |
| 1.1 Synopsis 6.3 Measures to Minimize Bias: Randomization and Blinding 6.6 Continued Access to Study Vaccine After the End of the Study 7.1 Discontinuation of Study vaccination 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 in participants that have received a 1-dose or 2-dose Ad26.COV2.S vaccine, and that no further study vaccination will be permitted; that unblinded participants will continue to be followed throughout the study for safety, efficacy and immunogenicity assessments, although the data will be analyzed separately from the point of unblinding. |
| 7.1 Discontinuation of Study vaccination | Clarification that study vaccination will be discontinued in participants with molecularly confirmed | Clarification |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| per country based on national recommendation | amongst countries based on national recommendations. | |
| 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. |
| 1.1 Synopsis 1.3.1 All Participants 1.3.2 Open-label Unblinding Visit 1.3.5 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 6.10 Prestudy and Concomitant Therapy 7.1 Discontinuation of Study Vaccination 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 Event of Special Interest, | TTS will be considered an AESI. Follow-up assessments will be performed in the event of a suspected AESI. In addition, blood samples will be collected for a baseline assessments of platelet count and storage for future coagulation-related testing. | Emerging data following use of the Ad26.COV2.S vaccine under emergency use authorization in the US suggest an increased risk of thrombosis combined with thrombocytopenia, with onset of symptoms approximately 1-2 weeks after vaccination. Therefore, additional reporting and data collection procedures are implemented to follow-up thrombotic events and thrombocytopenia and identify cases of TTS. |
| 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 8.3.7 Adverse Events of Special Interest 8.3.7.1 Thrombosis with Thrombocytopenia Syndrome 9.2.4 Safety (Safety Subset) 9.7 Safety 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 Suspected AESIs | ||
| 1.1 Synopsis 1.3.2 Open-label Unblinding Visit 4.1 Overall Design 4.2 Scientific Rationale for Study Design 6.4 Unblinding and Open-label Phase 8.1.4 Immunogenicity Assessments 10.2 Appendix 2: Clinical Laboratory Tests | A blood sample for humoral immunogenicity and sero- confirmation of SARS-CoV-2 infection should be taken at the unblinding visit except when the previous sample was taken within 5 days of the visit. | To decrease the blood sampling burden for participants. |
| 1.3.1 All Participants | The Day 57 visit will be a phone call visit except for participants who will be vaccinated on this day or who are part of the immunogenicity subset. | To decrease the visit burden for participants. |
| 1.1 Synopsis 1.3.2 Open-label Unblinding Visit 4.1 Overall Design 6.1 Study Vaccines Administered 6.4 Unblinding and Open-label Phase 8.8 Assessment and Procedures After Emergency Use Authorization and Implementation of Protocol Amendment 4 10.3.3 Informed Consent Process | The schedule for the unblinding visit was updated to clarify the procedures to be performed when vaccination takes place at a later date than unblinding. | Although it is recommended that the unblinding and vaccination occur at the same time, due to the study vaccination pause, there may be a delay between the date of unblinding and date of vaccination of some participants in the open- label phase. |
| 2.3.1 Risks Related to Study Participation | Side effects were updated to include injection site pain and nausea. It has been clarified that anaphylaxis is considered an important identified risk. | To align with the vaccine’s risk language. Added anaphylaxis as identified risk. |
| 6.1 Study Vaccines Administered | Placebo is now correctly classified as an Investigational Medicinal Product instead of a Non- Investigational Medicinal Product. | Correction of an error |
| 1.3.1 All Participants 1.3.2 Open-label Unblinding Visit 2.3.1 Risks Related to Study Participation 6.4 Unblinding and Open-label Phase 7.1 Discontinuation of Study Vaccination 8.3.5 Pregnancy | It has been further clarified that participants who become pregnant during the open-label phase and previously received placebo during the double-blind phase may be vaccinated with Ad26.COV2.S (single-dose regimen), if the investigator considers that the potential benefits outweigh the potential risks. | For clarification purposes. |
| 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 | A diagram on the safety reporting process is added for clarity. | Additional clarification per health authority request. |
| Throughout the protocol | Minor grammatical, formatting and spelling changes or clarifications were made. | Minor errors and unclarities were noted. |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| 1.1 Synopsis 1.2 Schema 1.3.1 All Participants 1.3.2 Open-label Unblinding Visit 1.3.3 Booster Vaccination 2.1 Study Rationale | All ongoing participants who received only a single vaccination with Ad26.COV2.S in the study will be offered a booster vaccination with Ad26.COV2.S at the same dose level of 5×1010 vp. Participants who already received | See overall rationale for amendment. |
| 2.3.1 Risks Related to Study Participation 2.3.2 Benefits of Study Participation 2.3.3 Benefit-Risk Assessment of Study Participation 3 OBJECTIVES AND ENDPOINTS 4.1 Overall Design 4.2.1 Study-Specific Ethical Design Considerations 4.4 End-of-study Definition 5 STUDY POPULATION 5.5 Criteria for Temporarily Delaying Administration of Study Vaccination 6.1 Study Vaccines Administered 6.4 Unblinding and Open-label Phase 6.5 Booster Vaccination 6.8 Continued Access to Study Vaccine After the End of the Study 6.10 Prestudy and Concomitant Therapy 7.1 Discontinuation of Study Vaccination 8 STUDY ASSESSMENTS AND PROCEDURES 8.1.3 Efficacy Assessments 8.1.3.5 SARS-CoV-2 Seroconversion Assessment 8.1.4 Immunogenicity Assessments 8.3.1 Time Period and Frequency for Collecting Adverse Event, Medically-attended Adverse Event, Adverse Event of Special Interest, and Serious Adverse Event Information 8.3.5 Pregnancy 8.9 Assessment and Procedures for Booster Vaccination and Follow-up After Implementation of Protocol Amendment 6 9.1 Statistical Hypotheses 9.2.1 Efficacy (Total Sample Size) 9.2.2 Immunogenicity Subset 9.2.4 Safety (Safety Subset) 9.5.3 Analyses for the Open-label Phase 9.6.1 Immunogenicity Subset 9.7 Safety Analysis 10.1 Appendix 1: Abbreviations 10.2 Appendix 2: Clinical Laboratory Tests 10.3.3 Informed Consent Process | 2 vaccinations with Ad26.COV2.S at the 5x1010 vp dose level or any COVID-19 vaccinations outside of the study (including the Janssen vaccine) are not eligible to receive a booster vaccination with Ad26.COV2.S. Booster vaccination should preferably be within 6-12 months after first vaccination and should not occur earlier than 3 months after first vaccination. The booster vaccination should preferably coincide with the next scheduled visit (ie, Visit 7 or Visit 8 for the majority of participants). Follow-up after the booster vaccination will be minimally 6 months. Objectives of the open-label phase are updated accordingly. The open- label phase will include 3 study cohorts (2-dose schedule cohort, 1-dose schedule cohort, and booster schedule cohort). Updates to statistical analysis was made: - comparison of the 2-dose cohort with the 1-dose cohort will be performed when all active participants have completed their Visit 8 or discontinued earlier. - Comparison of the 2-dose cohort with the booster cohort will be performed at the time of the end-of- study analysis. | |
| 6.4 Unblinding and Open-label Phase 7.1 Discontinuation of Study Vaccination 10.1 Appendix 1: Abbreviations | Capillary leak syndrome (CLS) was added to the list of reasons for the discontinuation of the Ad26.COV2.S vaccine. | Based on the emerging data following use of the Ad26.COV2.S vaccine, CLS has been identified as a contraindication for the use of Ad26.COV2.S vaccine. |
| 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 | Figure 4 was corrected by adding AEs and SAEs that are related to study procedures or that are related to non-investigational sponsor products and the corresponding footnote was corrected: deleted section of footnote (a) and added this as new footnote (b). | Correction |
| 5.1 Inclusion Criteria for the Double-Blind Phase and for Newly Enrolled Participants in the Open- Label Phase 5.2 Exclusion Criteria for the Double-Blind Phase and for Newly Enrolled Participants in the Open- Label Phase | Added that the eligibility criteria in Section 5 are specific for the double-blind phase and the newly enrolled participants in the open-label phase and that eligibility criteria for open-label and booster vaccination are described in Section 6.4 and 6.5, respectively. | Clarification on eligibility criteria for pregnant women throughout the different phases of the study, on request of PEI (Paul-Ehrlich- Institut, Germany) |
| 1.3.5 Participants with a Suspected AESI 8 STUDY ASSESSMENTS AND PROCEDURES | The volume of the clinical laboratory blood sample (whole blood) taken at AESI Day 1 and Day 29 has been corrected; 15 mL instead of 12 mL of blood will be collected at each of the visits. | Correction |
| 10.2 Appendix 2: Clinical Laboratory Tests | For the clinical evaluation of suspected AESIs, added that it is upon discretion of the sponsor that all or some of the coagulation- related assays may be conducted on the stored pre-vaccination sample and on the AESI samples. Added that, as part of investigation of any AESI, samples from appropriate controls (from vaccinated participants who did not experience an AESI) within the study could be used for coagulation- related assays. | Clarification |
| 1.3.4 Participants With (Suspected) COVID-19 8.1.2 Procedures in the Event of (Suspected) COVID-19 | Clarification was added that for participants with a positive test result for SARS-CoV-2 infection, a study visit will be conducted 28 days after symptom onset (ie, at the COVID-19 Day 29 visit) to assess the clinical course of the infection. | Clarification |
| 1.3.5 Participants with a Suspected AESI | Clarification was added that if an AESI is reported to the investigator, more than 28 days after the onset of the event, the AESI Day 29 visit will therefore become redundant and does not need to be performed. | Clarification |
| 1.3.5 Participants with a Suspected AESI 2.3.1 Risks Related to Study Participation | The naming ‘Janssen Adjudication Committee’ was corrected to ‘AESI Adjudication Committee’, in alignment with other places in the protocol. | Consistency throughout protocol |
| 1.3.5 Participants with a Suspected AESI 8.2.4 Clinical Laboratory Assessments | It is clarified that also in the event of thrombocytopenia, laboratory assessments (to be performed locally) are required to facilitate diagnosis and determine treatment options, including but not limited to platelet count and anti-PF4 tests. It is clarified that all local laboratory results need to be encoded in the electronic case report form (eCRF), including platelet counts. Low platelet counts are to be recorded as suspected AESI (thrombocytopenia). | Clarification |
| 1.1 Synopsis 11 REFERENCES | The reference to the Brighton Collaboration case definition of thrombotic events and thrombocytopenia was updated. | Update |
| 1.3.1 All Participants | Added a dot in the Early Exit column of the Schedule of Activities for recording of MAAEs, (S)AEs and concomitant therapies, for consistency with Section 8.3.1 | Correction |
| 5.1 Inclusion Criteria for the Double-Blind Phase and for Newly Enrolled Participants in the Open- Label Phase | Participant is ≥18 to <60 years or ≥60 years of age on the day of signing the ICF. Vaccine allocation in each age group may be different | Age limit for individuals that receive the authorized Ad26.COV2.S vaccine varies |
| per country based on national recommendation | amongst countries based on national recommendations. | |
| 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. |
| 1.1 Synopsis 1.3.1 All Participants 1.3.2 Open-label Unblinding Visit 1.3.5 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 6.10 Prestudy and Concomitant Therapy 7.1 Discontinuation of Study Vaccination 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 Event of Special Interest, | TTS will be considered an AESI. Follow-up assessments will be performed in the event of a suspected AESI. In addition, blood samples will be collected for a baseline assessments of platelet count and storage for future coagulation-related testing. | Emerging data following use of the Ad26.COV2.S vaccine under emergency use authorization in the US suggest an increased risk of thrombosis combined with thrombocytopenia, with onset of symptoms approximately 1-2 weeks after vaccination. Therefore, additional reporting and data collection procedures are implemented to follow-up thrombotic events and thrombocytopenia and identify cases of TTS. |
| Section # and Name | Description of Change | Brief Rationale |
|---|---|---|
| 1.1 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 Definitionµ 5.5 Criteria for Temporarily Delaying Administration of Study Vaccination 6.5 Booster Vaccination 6.10 Prestudy and Concomitant Therapy 8STUDY 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 8.1.4 Immunogenicity Assessments 8.2 Safety Assessments 8.2.1 Physical Examinations (Up to Amendment 7) 8.2.2 Vital Signs 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 8.9Assessment and Procedures for Booster Vaccination and Follow-up After Implementation of Protocol Amendment 6 9.7 Analyses of the Open-label Phase 10.2 Appendix 2: Clinical Laboratory Tests 10.3.6 Committees Structure 10.4.1 Adverse Event Definitions and Classifications 10.6 Appendix 6: Symptoms of Infection with Coronavirus-19 (SIC) 10.7 Appendix 7: MRU Questionnaire 10.8Appendix 8: Medically- attended COVID-19 (MA-COV) Form | The number of on-site study visits has been reduced and management of new suspected COVID-19 episodes has been changed from active to passive follow-up, defined as safety follow-up phone call visits by the site instead of on-site visits to document COVID-19 events as (S)AEs and MAAEs and to record concomitant therapies associated with COVID-19. eCOA has been decommissioned. | The primary analysis of the study that described the double-blind phase has been completed. Further efficacy evaluations of the open-label data have limitations, due to the unblinding and the loss of the placebo group. Moreover, constant evolution of the COVID-19 pandemic has impacted the practical implementation of a strict follow-up of new suspected COVID-19 episodes. |
| 1.1 Synopsis 3 OBJECTIVES AND ENDPOINTS 9.1 Statistical Hypotheses 9.7 Analyses of the Open-label Phase | The endpoints of the open-label phase and passive follow-up phase have been adapted and/or added and more clarification on the open- label phase has been provided. The scope and endpoints of the end of study analysis have been added. | To more clearly describe the endpoints of the open-label phase, related to the different cohorts that are evaluated (one dose, two dose, and booster cohorts). In addition, the changes in the follow-up of new suspected COVID-19 episodes come with endpoints specific to the follow-up phase. |
| 10.4.3 Severity Criteria | Instructions were added on grading severity of thrombocytopenia AEs with platelet counts between >140,000/µL and <150,000/µL. | Due to a discrepancy in what the FDA toxicity grading scale and the Brighton collaboration case definitions define as abnormal in terms of platelet counts. |
| 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. |