AOI 15 Protocol Synopsis.pdf

01 May 2023

NEXT GENERATION COVID-19 BOOSTER VACCINES: PHASE 2B STUDY DESIGN

FOR THE EVALUATION OF NEXT GENERATION VACCINE CANDIDATES

SECTION PAGE

Synopsis 2

Appendix: Schedule of Assessments 7

SYNOPSIS

Name of Sponsor/Company: Pharmaceutical Company(ies) (various)

Name of Investigational Product: Next Generation COVID-19 Booster Vaccines

Name of Active Ingredient: TBD

Title of Study: Next Generation COVID-19 Booster Vaccines: Phase 2b study design for the evaluation of next generation vaccine candidates

Protocol Number: TBD

Version Number: TBD

ClinicalTrials.Gov Number: Pending

Study center(s): Contractor to propose

Studied period (years): 12 months from last participant last dose

Estimated date first participant enrolled: TBD based on product availability

Estimated date last participant completed: TBD

Phase of development: 2b

Study Objectives/Endpoints:

Type Objective Endpoint(s)

Primary

Efficacy

To determine the relative efficacy of the next generation vaccine candidate compared to the currently recommended booster dose for the prevention of symptomatic, PCR confirmed COVID-19

Primary efficacy endpoint: First occurrence of molecularly-confirmed

(PCR positive) symptomatic COVID-19 according to the case definition with onset at least 14 days post-vaccination through 12 months post-booster

Case definition: Virologically confirmed SARS-CoV-2 infection (by

RT-PCR) along with:

• At least TWO of the following systemic symptoms: Fever (≥38ºC), chills, myalgia, headache, sore throat, new olfactory and taste disorder(s), OR

• At least ONE of the following respiratory signs/symptoms: cough, shortness of breath or difficulty breathing, or clinical or radiographical evidence of pneumonia

Secondary

Safety

To assess the safety and tolerability of the next generation vaccine candidate

• Solicited local and systemic reactogenicity through 7 days

• Unsolicited AEs through 30 days

• SAEs/MAAEs/AESIs through 12 months

• Clinical safety laboratory assessments at 7 days post-vaccination

Secondary

Immunogenicity

Humoral Immunogenicity:

To evaluate humoral immunogenicity of the

• GMT of SARS-CoV-2 specific nAb at Day 1 and Month 1, 3, 6, 12 next generation vaccine candidate

• GMFR of SARS-CoV-2 specific nAb relative to Day 1 at Month 1, 3, 6, 12

• GMT of S protein-specific [and/or other product specific antigen] bAb at Day 1 and Month 1, 3, 6, 12

• GMFR of S protein-specific [and/or other product specific antigen] bAb relative to Day 1 at Month 1, 3, 6, 12

Cellular Immunogenicity:

To evaluate cellular immunogenicity of the next generation vaccine candidate

Cellular assays TBD but could include:

• ELISpot assays at Day 1 and Month 1, 3, 6, 12

• Intracellular cytokine and cell surface marker staining at Day 1 and

Month 1, 3, 6, 12

Secondary

Efficacy

To determine the durability of the next generation vaccine candidate compared to the currently recommended booster dose for the prevention of symptomatic, PCR confirmed COVID-19

Estimation of vaccine efficacy over at least 6 months of follow-up and

12 months of follow-up

To determine the relative efficacy of the next generation vaccine candidate compared to the currently recommended booster dose for the prevention of asymptomatic, PCR confirmed COVID-19

Confirmed (PCR positive screening nasal swab) asymptomatic COVID-

19 from 14 days post-vaccination through 12 months post-booster

To determine the relative efficacy of the next generation vaccine candidate compared to the currently recommended booster dose for the prevention of severe PCR confirmed COVID-19

Confirmed (PCR positive) severe COVID-19 from 14 days post-vaccination through 12 months post-booster

Case definition: Virologically confirmed SARS-CoV-2 infection (RT-

PCR) along with:

• Clinical signs at rest indicative of severe systemic illness

(respiratory rate ≥30 per minute, heart rate ≥125 per minute, SpO2

≤93% on room air at sea level or PaO2/FiO2 <300 mm Hg)

• Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation, mechanical ventilation or ECMO)

• Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring vasopressors)

• Significant acute renal, hepatic, or neurologic dysfunction

• Admission to an ICU

• Death

Exploratory

TBD

Efficacy subanalyses

Correlates of Protection analyses

TBD but some potential endpoints could include:

• Efficacy subanalyses by:

o Time period: 0-6 months and 6-12 months o Prior infection o Number of previous boosters o Infecting variant o Previous vaccine(s)

• Immunogenicity against emerging strains/VOCs/VOIs

• Correlation of immune response markers with SARS-CoV-2 infection

Introduction/Background/Scope:

Even though current COVID-19 vaccines are readily available, concerns exist regarding their narrow breadth of coverage against existing and future variants, short duration of protection, limited efficacy in the prevention of illness, and no clear evidence of the prevention of transmission. The evaluation of new COVID-19 vaccine candidates remains important in exploring approaches that provide enhanced and durable protection against ongoing and future SARS-CoV-2 epidemic.

Insert background on vaccine candidate

To respond to the need for ongoing COVID-19 vaccine development, this Phase 2b study is designed to assess the relative efficacy of next generation COVID-19 booster vaccine compared to currently approved/authorized

COVID-19 booster vaccine in the prevention of symptomatic, PCR confirmed SARS-CoV-2 infection. Adult participants who have completed the primary COVID-19 vaccination series and who are eligible to receive a

COVID-19 booster vaccine will be enrolled. Safety and immunogenicity will be collected.

Methodology: Double-blind, active comparator-controlled Phase 2b efficacy, immunogenicity, and safety study in which eligible adult participants will be randomized 1:1 to receive investigational next generation COVID-19 booster vaccine candidate or currently approved/authorized COVID-19 booster vaccine.

For additional details, see Figure 1. Study Design and Appendix 1. Schedule of Assessments.

Number of participants (planned): Approximately 10,000 participants (5,000 per group)

Diagnosis and main criteria for inclusion: Adults ≥18 years of age at time of screening who have completed their primary COVID-19 vaccination series, received their last COVID-19 vaccine ≥3 months prior to study vaccination, eligible to receive a COVID-19 “booster” dose, and willing to receive the investigational next generation COVID-19 booster vaccine

Study Population Considerations:

• Target 25% of participants ≥65 years of age

• Appropriate representation of participants at high risk for severe COVID-19

• Appropriate representation of racially and ethnically diverse populations

Draft eligibility criteria, with additional customization expected based on specific considerations for the investigational next generation COVID-19 booster vaccine

Inclusion Criteria:

1. Adults ≥18 years of age at time of screening.

2. Completed primary approved/authorized COVID-19 vaccination series.

3. Last COVID-19 vaccine received ≥3 months prior to study vaccination.

4. Eligible to receive a COVID-19 “booster” vaccine.

5. Female participants of childbearing potential must agree to consistently use a highly effective method of contraception from at least 30 days prior to enrollment and through 3 months after the last study vaccination.

6. Are medically stable, as determined by the investigator (based on review of health status, vital signs, medical history, and physical examination).

7. Agree to not participate in any other SARS-CoV-2 prevention trial (vaccine, drug, biologic, PReP) during the study follow-up.

8. Willing and able to provide informed consent prior to initiation of study procedures.

9. Able to understand and comply with planned study procedures.

10. Available for all study visits.

Exclusion Criteria:

1. Current participation in any other COVID-19 vaccine or prevention clinical trial.

2. Receipt of products intended to prevent COVID-19.

3. Receipt of blood products or immunoglobulins within 60 days prior to enrollment.

4. Received influenza vaccination within 14 days prior to study vaccination, or any other vaccine within 30 days prior to study vaccination.

5. Participation in research involving an investigational product within 45 days prior to study vaccination.

6. Any autoimmune or immunodeficiency disease/condition (untreated or advanced HIV infection with CD4 counts <200 cells/mm3, history of AIDS defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV).

7. Unstable illness (acute or chronic illness) requiring significant medical monitoring and intervention during the 3 months prior to enrollment.

8. Administration of immunosuppressant, systemic glucocorticoids, or other immune-modifying drugs within

90 days prior to first study vaccination (including history of receiving active treatment with high-dose corticosteroids, e.g., ≥20mg prednisone equivalent per day, antimetabolites, transplant immunosuppressive agents, alkylating agents, cell-depleting agents, cancer chemotherapeutics as some examples).

9. Known contraindication to IM injection or to vaccine candidate route of administration (e.g., bleeding diathesis, acquired coagulopathy).

10. Any known allergies to components contained in the investigational product or comparator or latex allergy

(including PEG allergies).

11. Women who are pregnant, breastfeeding or who plan to become pregnant during the study.

12. Any other condition that, in the opinion of the investigator, would pose a health risk to the participant if enrolled or could interfere with evaluation of the investigational product or interpretation of study results.

13. Study team member or first-degree relative of any study team member (inclusive of sponsor and site personnel involved in the study).

Investigational product, dosage, and mode of administration: Next Generation COVID-19 Booster Vaccines, One dose, Intramuscular (IM) injection or other route of administration depending on vaccine candidate

Duration of treatment: One dose

Reference therapy, dosage, and mode of administration: As per labeling for currently recommended COVID-

19 booster vaccine

Statistical Considerations

This is an event driven study. Based on a 2-sided type 1 error rate of 5%, a total of 255 events will be needed to provide approximately 80% power, to detect a true relative risk reduction (vaccine efficacy) of 30% or greater in the incidence of the primary efficacy endpoint over the 12-month follow-up post-vaccination. The sample size will be approximately 10,000 participants (5,000 per group) with the assumption that the cumulative incidence of the primary efficacy endpoint will be at least 3% over 12-months in the control arm.

Analysis Population(s)

Full Analysis Set (FAS) All randomized participants who received at least one dose of investigational product. Analyses of safety will be performed on the FAS. Vaccine efficacy analyses can be repeated using the FAS.

Per protocol efficacy (PP) set All in FAS who receive planned dose of investigational product per study schedule without major protocol deviations.

Per protocol Immunogenicity (PPI) set All in FAS with valid IG test pre-dose and at least one valid test post-dose.

Efficacy Analyses

The study will have three timepoints for efficacy analyses to evaluate the primary and secondary objectives of this study:

• Primary efficacy analyses will take place as soon as the total number of events (255) has been reached.

• An analysis will be conducted when the last subject completes the visit 6 months post-vaccination or discontinues earlier.

• The end-of-study analysis will be performed when all subjects have completed the visit 12 months post-vaccination or discontinued earlier.

The study is designed to test the primary hypothesis of VE in the PP set: H0: VE<0% vs H1: VE>0%. The primary endpoint will evaluate the first occurrence of molecularly-confirmed (PCR positive) symptomatic

COVID-19 according to the case definition with onset at least from 14 days post-vaccination. The primary efficacy analysis will pool data across populations to evaluate the primary and secondary objectives.

Supplemental analyses of the primary efficacy endpoint will be conducted for pre-specified subgroups such as different age groups, with/without prior infection, number of previous boosters, infecting strains, and previous vaccine(s). In addition, to assess potential time-effects of VE, the Kaplan-Meier method to estimate cumulative

VE over time, defined as [(1 minus ratio (vaccine/placebo) of cumulative incidence by time t) ×100%].

Immunogenicity Analyses

No formal statistical testing of the immunogenicity data is planned. All immunogenicity analyses will be performed on the PPI set.

Safety Analyses

No formal statistical testing of safety data is planned. Safety data will be analyzed descriptively.

Interim Analyses

Interim analyses may be conducted.

APPENDIX: SCHEDULE OF ASSESSMENTS

Phase 2b Study, 7 Visits, 1 Injection, 5 Blood Sample Timepoints, Approximately 12 Months Duration Per Participant

Visit (V) / Contact V00 V01 V02 V03 V04 V05 V06i

U n sc h e d u le d

E a rl y

T er m in a ti o n

Study Timelines (Day [D]) D-3 to -1 D01 D08 D31 D91 D181 D366

Time Interval (days) V01 -3 to -1 days

V01 +

7 days

V01 + 30 days

V01 +

90 days

V01 +

180 days

V01 +

365 days

Time Windows (days) [-3 to -1 days] N/A

[+2 days]

[+3 days]

[+5 days] [+7 days]

[+14 days]

Visit Procedures:

Informed consent X

Inclusion/exclusion criteria X

Collection of demographic data X

Collection of medical history X

Vital signs X

Physical examinationa X X X X X X X X X

Pre-vaccination temperature X

Urine pregnancy test (if applicable)b X X X X X X X X

Contact IRT system for randomization, participant number, and unique dose number allocation

X

Respiratory sample collection Can occur at any time during the study as unscheduled visit(s) X

Clinical safety laboratory assessmentsc (10mL)

(All participants)

X X X X

Serum samples for Ab assays (30mL)

(All participants) X X X X X X

Collection and processing of PBMCs for cellular assaysd (40mL)

(Participants at selected sites)

X X X X X X

SARS-CoV-2 PCR respiratory collection X X

Surveillance (self-swab) sent to central laboratory weekly from 14 days post-vaccination

X

Nasal and/or oral mucosal samples

(Depending on product) X To be collected at up to 6 specified timepoints X

Visit (V) / Contact V00 V01 V02 V03 V04 V05 V06i

U n sc h e d u le d

E a rl y

T er m in a ti o n

Study Timelines (Day [D]) D-3 to -1 D01 D08 D31 D91 D181 D366

Time Interval (days) V01 -3 to -1 days

V01 +

7 days

V01 + 30 days

V01 +

90 days

V01 +

180 days

V01 +

365 days

Time Windows (days) [-3 to -1 days] N/A

[+2 days]

[+3 days]

[+5 days] [+7 days]

[+14 days]

Visit Procedures:

Vaccination (VAC) X

Immediate surveillance (30 minutes) X

Diary Card providede X

Diary Card collected & reviewed X Xf Xf

Collection of solicited injection site

& systemic reactions D01-D08 Xf Xf

Collection of unsolicited AEs D01-D31 X X

Collection of concomitant medications

X

Reportable concomitant medications

All reportable concomitant medications (including influenza vaccination)

X X

Passive surveillance

Participants will be instructed to contact the site if they experience symptoms of a COVID-19-like illness at any time during the study

Active surveillance Participant contact to occur every

2 weeks after D31 until D181g

Collection of SAEs, AESIsh, and

MAAEs

To be reported at any time during the study

Collection of pregnancies

Abbreviations: Ab, Antibody; AE, adverse event; AESI, adverse event of special interest; DC, Diary Card; IRT, interactive response technology; MAAE, medically attended adverse event; S, Spike; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; V, visit; VAC, vaccination

a) Full physical exam at V00. Targeted physical examination based on the participant’s medical history and the examiner’s medical judgment will be performed at all other visits.

b) Urine pregnancy test is applicable to childbearing potential female participant (to be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year or surgically sterile). Urine pregnancy test is to be performed before vaccination.

c) Safety laboratory assessments will include: Serum Chemistries (liver enzymes / Chem 7, lipase, and amylase); hematology (complete blood count with differential); Urinalysis; Microscopy. In cases of abnormal safety laboratory results, unscheduled visits may occur, based on Investigator’s judgment.

d) PBMC collection to be performed at designated sites with capacity to process samples.

e) The Investigator or an authorized designee will interview the participants to collect the information recorded in the DC and will attempt to clarify anything that is incomplete or unclear.

f) Conducted if visit occurs within 7 post-vaccination.

g) Prior to these specified time-points, active surveillance will still occur during the established contacts.

h) AESIs (serious and non-serious) will be collected throughout the study as SAEs to ensure that events are communicated to the Sponsor in an expedited manner and followed-up until the end of the follow-up period or resolution, as per the assigned causal relationship. These include: Anaphylactic reactions, Generalized convulsion, Thrombocytopenia, Lacrimal and salivary disorders (tearing, dry mouth, dry eyes), any new-onset chronic medical conditions, and potential immune-mediated diseases.

i) All participants will be scheduled to attend V06 for blood sampling and 12-Month Safety Follow-up. However, if any participants discontinue the study early, they are still to be followed for safety and are to be contacted with a 12-Month Safety Follow-up call to identify the occurrence of any SAEs and AESIs that had not yet been reported.