Safety and Immunogenicity of RNA-based Vaccines Against SARS-CoV-2 Variants in Healthy Participants

Study Overview
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Brief Summary
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This trial consists of three parts, Part A, Part B, and Part C, and will evaluate the safety and immunogenicity of a third booster injection of the multivalent vaccine BNT162b2 (B.1.1.7 + B.1.617.2), and the safety and immunogenicity of a third booster injection of the monovalent vaccine BNT162b2 (B.1.617.2) or BNT162b2 (B.1.1.7), in participants who have received two doses of the parent vaccine BNT162b2 at 30 µg, at least 6 months after the second dose of BNT162b2. It will also evaluate the safety and immunogenicity of a three-dose regimen of BNT162b2 (B.1.1.7 + B.1.617.2) in participants who have not received prior Coronavirus Disease 2019 (COVID-19) vaccination. In addition, the safety and immunogenicity of BNT162b2 (B.1.1.529.1) or BNT162b2 given as a third or fourth vaccine dose to RNA COVID-19 vaccine-experienced participants with history of SARS-CoV-2 infection will be evaluated and contrasted with the natural immune response reached after infection with the SARS-CoV-2 Omicron variant.

Detailed Description
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Trial participants in Part A will be assigned to one of 6 cohorts (Cohort 1-6). Trial participants in Part B will be assigned to one of 3 cohorts (Cohort 1, 4, and 6). Trial participants in Part C will be randomized in a 2:2:1 ratio into 3 cohorts (Cohort 7-9).

Official Title
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A Phase II Trial to Evaluate the Safety and Immunogenicity of SARS-CoV-2 Monovalent and Multivalent RNA-based Vaccines in Healthy Subjects

Conditions
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SARS-CoV2 Infection, COVID-19, SARS-CoV-2 Acute Respiratory Disease, SARS (Disease)

Intervention / Treatment
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* Biological: BNT162b2
* Biological: BNT162b2 (B.1.1.7 + B.1.617.2)
* Biological: BNT162b2 (B.1.1.7)
* Biological: BNT162b2 (B.1.617.2)
* Biological: BNT162b2 (B.1.1.529.1)
* Other: Observational


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have given informed consent by signing the informed consent form (ICF) before initiation of any trial-specific procedures. Volunteers who at the time of consent are: Part A: 18 to 55 years old. Part B and Part C: 18 to 85 years old ( 60% should be 18 to 55 years old and  40% 56 to 85 years old). For Cohorts 1 to 5: In Part A, who have received BNT162b2 vaccine (30 µg, two-dose regimen) in either a clinical trial or as part of the governmental vaccination programs at least 6 months before Visit 0. Participants who are currently enrolled in the Phase III BNT162-02 / C4591001 trial, have already been unblinded, and have previously received two doses of BNT162b2 at least 6 months earlier can be included (for Cohorts 1 and 4 in Part B, prior enrollment and dosing in the BNT162-02 / C4591001 trial is mandatory). At enrollment into Part B of this trial, their participation in the BNT162-02 / C4591001 trial will be terminated. Participants should have not experienced COVID-19 based on medical history. For Cohort 6: Are COVID-19 vaccine-naïve and have not experienced COVID-19 based on their medical history. Are willing and able to comply with all scheduled visits, vaccination plan, laboratory tests, lifestyle considerations, and other trial procedures. Are overall healthy at Visit 0 in the clinical judgment of the investigator based on the medical history, clinical assessment (including physical examination, vital signs, blood and urine clinical laboratory tests, 12-lead electrocardiogram (ECG), and oral swab for Nucleic Acid Amplification-based Test (NAAT)-based Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) testing). Note: Healthy volunteers with pre-existing stable disease, defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 12 weeks before Visit 0, can be included. Note: Volunteers who had hepatitis C (HCV) infection, but have completed curative treatment based on the medical history can be included. Volunteers who had or have hepatitis B (HBV) or human immunodeficiency virus (HIV) based on the medical history cannot be included. Agree not to enroll in another trial of an Investigational Medicinal Product (IMP), starting after Visit 0 and continuously until the last planned visit in this trial. Women of childbearing potential (WOCBP) must test negative in a urine beta-human chorionic gonadotropin (β-HCG) test at Visits 0 and 1. WOCBP must agree to practice a highly effective form of contraception starting at Visit 0 and continuously until 28 days after their last IMP administration in this trial. WOCBP must confirm that they practiced an acceptable form of contraception for the 14 days prior to Visit 0. WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction starting after Visit 0 and continuously until 28 days after their last IMP injection in this trial. Men who are sexually active with a WOCBP and have not had a vasectomy must agree to use a highly effective form of contraception with their female partner of childbearing potential starting after Visit 0 and continuously until 28 days after their last IMP injection in this trial. Men must be willing to refrain from sperm donation, starting after Visit 0 and continuously until 28 days after their last vaccination. For Part C, Cohorts 7, 8, and 9: have received two or three documented doses of any authorized COVID-19 RNA-based vaccine (e.g., BNT162b2 [Comirnaty] or the Moderna vaccine [Spikevax]) prior to being diagnosed with SARS-CoV-2 infection from January 2022 onwards (and limited to a period when there was a high prevalence of SARS-CoV-2 Omicron infections). Note: The interval between the last COVID-19 RNA-based vaccine administered and randomization should be >4 months. The latest prior diagnosed SARS-CoV-2 infection should be at least 2 months before randomization. The latest SARS-CoV-2 infection should be documented with a result from a NAAT (as a preferable option). In case no historic NAAT result is available proving prior SARS-CoV-2 infection, the local positive result of SARS-CoV-2 N-binding antibodies done at screening will be sufficient. Exclusion Criteria: Any existing condition which may affect vaccine injection and/or assessment of local reactions assessment, e.g., tattoos, severe scars, etc. Any bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection. Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that, in the investigator's judgment, make the participant inappropriate for the trial. Any current febrile illness (body temperature ≥38.0°C/≥100.4°F) or other acute illness within 48 h prior to Day 1/IMP injection in this trial. Any current or history of cardiovascular diseases, e.g., myocarditis, pericarditis, myocardial infarction, congestive heart failure, cardiomyopathy or clinically significant arrhythmias, unless such disease is not considered relevant for participation in this trial in the investigator's judgment. History of COVID-19 and/or clinical (based on COVID-19 symptoms/signs alone, if a SARS CoV 2 NAAT result was not available) or microbiological (based on COVID-19 symptoms/signs and a positive SARS CoV 2 NAAT result) evidence of prior infection with SARS CoV 2 at screening (Visit 0). Note: not applicable for Part C. History of Guillain-Barré syndrome. Known or suspected immunodeficiency. History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g., anaphylaxis) to any component of the trial IMPs. History or known allergy, hypersensitivity, or intolerance to the trial IMP including any excipients of the IMPs in this trial. Have received any SARS CoV 2 vaccination other than BNT162b2 (30 µg BNT162b2 given as a course of two doses approximately 21 days apart). Note: not applicable for Part C. Have received a live or live attenuated vaccine within 28 days prior to Day 1/IMP injection. Have received any other vaccines within 14 days before or after any IMP injection, e.g., influenza, tetanus, pneumococcal, hepatitis A or B. When possible standard or care vaccinations should be planned with the trial IMP administrations in mind. Individuals who receive treatment with radiotherapy or immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids (if systemic corticosteroids are administered for ≥14 days at a dose of ≥20 mg/day of prednisone or equivalent), e.g., for cancer or an autoimmune disease, or planned receipt throughout this trial. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or eyes) corticosteroids are permitted. Receipt of blood/plasma products or immunoglobulin, from 60 days before IMP administration or planned receipt throughout this trial. Participation in other trials involving IMP within 28 days or 5 half-lives (whichever is longer) prior to Visit 1 and/or during trial participation, besides participation in trials with BNT162b2. Are pregnant or breastfeeding or are planning pregnancy within 28 days after last IMP treatment. Are vulnerable individuals as per International Conference on Harmonisation (ICH) E6 definition, i.e., are individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. For Part C, Cohorts 7, 8, and 9: Vaccination with other non-RNA or unauthorized COVID-19 vaccines. For Part C, Cohorts 7, 8, and 9: Vaccination with any COVID-19 vaccine after SARS-CoV-2 infection from January 2022 onwards (and limited to a period when there was a high prevalence of SARS-CoV-2 Omicron infections).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A - Cohort 1: 18 to 55 years of age<br>Participants will receive 1 dose of BNT162b2 (B.1.1.7 + B.1.617.2) of 30 µg. | Biological: BNT162b2 (B.1.1.7 + B.1.617.2)<br>* Intramuscular (IM)<br>|
| Experimental: Part A - Cohort 2: 18 to 55 years of age<br>Participants will receive 2 doses of BNT162b2 (B.1.1.7 + B.1.617.2) of 30 µg. | Biological: BNT162b2 (B.1.1.7 + B.1.617.2)<br>* Intramuscular (IM)<br>|
| Experimental: Part A - Cohort 3: 18 to 55 years of age<br>Participants will receive 1 dose of BNT162b2 (B.1.1.7) of 30 µg. | Biological: BNT162b2 (B.1.1.7)<br>* Intramuscular (IM)<br>|
| Experimental: Part A - Cohort 4: 18 to 55 years of age<br>Participants will receive 1 dose of BNT162b2 (B.1.617.2) of 30 µg. | Biological: BNT162b2 (B.1.617.2)<br>* Intramuscular (IM)<br>|
| Experimental: Part A - Cohort 5: 18 to 55 years of age<br>Participants will receive 1 dose of BNT162b2 of 30 µg. | Biological: BNT162b2<br>* Intramuscular (IM)<br>|
| Experimental: Part A - Cohort 6: 18 to 55 years of age<br>Participants will receive 3 doses of BNT162b2 (B.1.1.7 + B.1.617.2) of 30 µg. | Biological: BNT162b2 (B.1.1.7 + B.1.617.2)<br>* Intramuscular (IM)<br>|
| Experimental: Part B - Cohort 1: 18 to 85 years of age<br>Participants will receive 1 dose of BNT162b2 (B.1.1.7 + B.1.617.2) of 30 µg. | Biological: BNT162b2 (B.1.1.7 + B.1.617.2)<br>* Intramuscular (IM)<br>|
| Experimental: Part B - Cohort 4: 18 to 85 years of age<br>Participants will receive 1 dose of BNT162b2 (B.1.617.2) of 30 µg. | Biological: BNT162b2 (B.1.617.2)<br>* Intramuscular (IM)<br>|
| Experimental: Part B - Cohort 6: 18 to 85 years of age<br>Participants will receive 3 doses of BNT162b2 (B.1.1.7 + B.1.617.2) of 30 µg. | Biological: BNT162b2 (B.1.1.7 + B.1.617.2)<br>* Intramuscular (IM)<br>|
| Experimental: Part C - Cohort 7: 18 to 85 years of age<br>Participants will receive 1 dose of BNT162b2 (B.1.1.529.1) of 30 µg. | Biological: BNT162b2 (B.1.1.529.1)<br>* Intramuscular (IM)<br>|
| Experimental: Part C - Cohort 8: 18 to 85 years of age<br>Participants will receive 1 dose of BNT162b2 of 30 µg. | Biological: BNT162b2<br>* Intramuscular (IM)<br>|
| Other: Part C - Cohort 9: 18 to 85 years of age<br>Participants will receive no vaccination within 3 months after Visit 1. | Other: Observational<br>* No vaccination within 3 months after Visit 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All parts - Percentage of participants reporting local reactions at the injection site | Local reactions (pain, tenderness, erythema/redness, induration/swelling). | up to 7 days after each dose | 
| All parts - Percentage of participants reporting systemic events | Systemic events (fever, fatigue, headache, chills, vomiting, nausea, diarrhea, new or worsened muscle pain, and new or worsened joint pain). | up to 7 days after each dose | 
| All parts - Percentage of participants reporting adverse events (AEs) |  | Part A and B: Dose 1 up to 1 month after each dose; Part C: Dose 1 up to 1 month after the last dose | 
| All parts - Percentage of participants reporting serious adverse events (SAEs) |  | Dose 1 up to 6 months after the last dose | 
| Part B - GMR of B.1.1.7 NT 1 month after 1 dose of BNT162b2 (B.1.1.7 + B.1.617.2) in BNT162b2-experienced participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III C4591001 trial. | GMR = Geometric mean ratio; NT = neutralizing titers | 1 month | 
| Part B - GMR of B.1.617.2 NT 1 month after 1 dose of BNT162b2 (B.1.1.7 + B.1.617.2) on BNT162b2-experienced participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III BNT162-02 / C4591001 trial |  | 1 month | 
| Part B - GMR of B.1.617.2 NT 1 month after 1 dose of BNT162b2 (B.1.617.2) on BNT162b2-experienced participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III BNT162-02 / C4591001 trial |  | 1 month | 
| Part B - The difference in Seroresponse (SR) to B.1.1.7 | The difference in SR to B.1.1.7 NT 1 month after 1 dose of BNT162b2 (B.1.1.7 + B.1.617.2) in BNT162b2-experienced participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III BNT162-02 / C4591001 trial. | 1 month | 
| Part B - The difference in SR to B.1.617.2 | The difference in SR to B.1.617.2 NT 1 month after 1 dose of BNT162b2 (B.1.1.7 + B.1.617.2) on BNT162b2-experienced participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III BNT162-02 / C4591001 trial. | 1 month | 
| Part B - The difference in SR to B.1.617.2 NT 1 month after 1 dose of BNT162b2 (B.1.617.2) on BNT162b2-experienced participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III BNT162-02 / C4591001 trial |  | 1 month | 
| Part B - GMR of B.1.1.7 NT 1 month after 2 doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III BNT162-02 / C4591001 trial |  | 1 month | 
| Part B - GMR of B.1.617.2 NT 1 month after 2 doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III BNT162-02 / C4591001 trial |  | 1 month | 
| Part B - The difference in SR to B.1.1.7 NT 1 month after 2 doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III C4591001 trial |  | 1 month | 
| Part B - The difference in SR to B.1.617.2 NT 1 month after 2 doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III C4591001 trial |  | 1 month | 
| Part B - GMR of reference strain NT in participants with evidence of prior infection to the reference strain NT in participants without evidence of infection (COVID-19 vaccine-naïve participants) | GMR of reference strain NT 3 weeks after one dose of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants with evidence of prior infection to the reference strain NT 1 month after two doses of BNT162b2 in participants without evidence of infection from the Phase III trial BNT162-02 / C4591001. | 1 month | 
| Part B - The difference in SRs to the reference strain NT in subjects with evidence of prior infection and to the reference strain NT in participants without evidence of infection (COVID-19 vaccine-naïve participants) | The difference in SRs to the reference strain NT 3 weeks after one dose of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants with evidence of prior infection and to the reference strain NT 1 month after two doses of BNT162b2 in participants without evidence of infection from the Phase III trial BNT162-02 / C4591001. | 1 month | 
| Part C - GMR of B.1.1.529.1 NT 1 month after one dose of BNT162b2 (B.1.1.529.1) in RNA-based COVID-19 vaccine-experienced participants with history of SARS-CoV-2 infection to those at 1 month after one dose of BNT162b2 for Cohorts 7 and 8. |  | 1 month | 
| Part C - The difference in SR of B.1.1.529.1 NT 1 month after one dose of BNT162b2 (B.1.1.529.1) in RNA-based COVID-19 vaccine-experienced participants with history of SARS-CoV-2 infection to those at 1 month after one dose of BNT162b2 for Cohorts 7 & 8. |  | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A - Geometric mean titer (GMT) at each timepoint | For BNT162b2-experienced participants (defined as participants who have previously received two injections of 30 μg BNT162b2). Reference and variant(s) of concern (VOC) specific NT. | Day 1 up to Day 421 | 
| Part A - Geometric mean fold rises (GMFR) from before vaccination to each subsequent time point after vaccination | For BNT162b2-experienced participants (defined as participants who have previously received two injections of 30 μg BNT162b2). Reference and VOC specific NT. | Day 1 to Day 421 | 
| Part A - SR in terms of NT at each post vaccination time point | For BNT162b2-experienced participants (defined as participants who have previously received two injections of 30 μg BNT162b2). Reference and VOC specific NT. | Day 1 to Day 421 | 
| Part B Cohort B1 - GMT - B.1.1.7 + B.1.617.2 vs BNT162b2 | VOC and reference strain-specific NTs in participants from the BNT162-17 trial (BNT162b2-experienced participants) and reference strain NTs in participants from the Phase III BNT162-02 / C4591001 trial. GMTs and SRs of VOCs and reference strain NT 1 month after 1 dose of BNT162b2 (B.1.1.7 + B.1.617.2) and dose 2 of BNT162b2. | Day 1 to Day 360 | 
| Part B Cohort B4 - GMT - B.1.617.2 vs BNT162b2 | VOC and reference strain-specific NTs in participants from the BNT162-17 trial (BNT162b2-experienced participants) and reference strain NTs in participants from the Phase III BNT162-02 / C4591001 trial (BNT162b2-experienced participants). GMTs and SRs of VOCs and reference strain NT 1 month after 1 dose of BNT162b2 (B.1.617.2) and dose 2 of BNT162b2. | Day 1 to Day 360 | 
| Part B Cohort B6 - GMT - B.1.1.7 + B.1.617.2 to the reference strain | VOC and reference strain NTs in participants from the BNT162-17 trial and reference strain NTs in participants from the Phase III BNT162-02 / C4591001 trial (COVID-19 vaccine-naïve participants). GMTs and SRs of VOCs and reference strain NT 1 month after dose 2 and dose 3 of BNT162b2 (B.1.1.7 + B.1.617.2). | Day 1 to Day 386 | 
| Part B - GMTs - VOC in COVID-19 vaccine-naïve participants with evidence of prior infection (one primary dose) and in BNT162b2- experienced participants without evidence of infection (one booster dose) | GMTs and SRs of VOC specific NTs (B.1.1.7, B.1.617.2, B.1.1.529.5 [Omicron BA.5]) 3 weeks after one dose of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants with evidence of prior infection and 1 month after one booster dose of BNT162b2 (B.1.1.7 + B.1.617.2) in BNT162b2-experienced participants without evidence of infection. | Day 1 to Day 29 | 
| Part B - GMR - VOC in COVID-19 vaccine-naïve participants with evidence of prior infection (one primary dose) to in BNT162b2- experienced participants without evidence of infection (one booster dose) | GMR of VOC specific NTs (B.1.1.7, B.1.617.2, B.1.1.529.5 [Omicron BA.5]) 3 weeks after one dose of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants with evidence of prior infection to the VOCs NT 1 month after one booster dose of BNT162b2 (B.1.1.7 + B.1.617.2) in BNT162b2-experienced participants without evidence of infection. | Day 1 to Day 29 | 
| Part B - Difference in SRs to VOCs in COVID-19 vaccine-naïve participants with evidence of prior infection (one primary dose) to VOCs in BNT162b2- experienced participants without evidence of infection (one booster dose) | The difference in SRs to VOC specific NTs (B.1.1.7, B.1.617.2, B.1.1.529.5 [Omicron BA.5]) 3 weeks after one dose of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants with evidence of prior infection and to the VOCs NT 1 month after one booster dose of BNT162b2 (B.1.1.7 + B.1.617.2) in BNT162b2- experienced participants without evidence of infection. | Day 1 to Day 29 | 
| Part B - GMTs - VOC in COVID-19 vaccine-naïve participants with evidence of prior infection (one primary dose) and in COVID-19 vaccine-naïve participants without evidence of infection (two primary doses) | GMTs and SRs of VOC specific NTs (B.1.1.7, B.1.617.2, B.1.1.529.5 [Omicron BA.5]) 3 weeks after one dose of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants with evidence of prior infection and 1 month after two doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants without evidence of infection. | Day 1 to Day 50 | 
| Part B - GMR - VOC in COVID-19 vaccine-naïve participants with evidence of prior infection (one primary dose) to in COVID-19 vaccine-naïve participants without evidence of infection (two primary doses) | GMR of VOC specific NTs (B.1.1.7, B.1.617.2, B.1.1.529.5 [Omicron BA.5]) 3 weeks after one dose of BNT162b2 (B.1.1.7 + B.1.617.2) in participants with evidence of prior infection to the VOCs NT 1 month after two doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants without evidence of infection. | Day 1 to Day 50 | 
| Part B - Difference in SRs to VOCs in COVID-19 vaccine-naïve participants with evidence of prior infection (one primary dose) to in COVID-19 vaccine-naïve participants without evidence of infection (two primary doses) | The difference in SRs to VOC specific NTs (B.1.1.7, B.1.617.2, B.1.1.529.5 [Omicron BA.5]) 3 weeks after one dose of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants with evidence of prior infection (one primary dose) and to the VOCs NT 1 month after two doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants without evidence of infection. | Day 1 to Day 50 | 
| Part C - GMT - B.1.1.529.1 in RNA based COVID-19 vaccine-experienced participants with history of SARS-CoV-2 infection | VOC NT in RNA-based COVID-19 vaccine-experienced participants with history of SARS-CoV-2 infection at baseline and 7 days, 1 month, and 3 months after the trial start for Cohorts 7, 8, and 9, and 6 and 12 months after the trial start for Cohorts 7 and 8. | Day 1 to Day 360 |