TITLE: Study Procedures (Part 6 of Phase 3 study of Vaccine Candidate for COVID-19)
AUTHORS: Chris Ockenhouse, Chris Gast, Renee Holt, Jorge Flores

[DESCRIPTION]
<div class = "text-blocks"><div class = "text-block"><span>This is part 6 of: "Phase 3 randomized, double-blinded, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of </span><span style = "font-weight:bold;">Vaccine Candidate</span><span> against COVID-19 in adults > 18 years of age"</span></div><div class = "text-block">This generic Phase 3 protocol was developed by the PATH team with support of the Bill and Melinda Gates Foundation. The aim of the collection is to share recommended best practices in designing and implementing a Phase 3 study of a COVID-19 vaccine candidate. As Phase 3 trials of different Vaccine Candidates  proceed around the world, following the same protocols will ensure consistency and comparability of the Phase 3 trial results.</div><div class = "text-block"><span style = "font-weight:bold;">Please note</span><span> that this is an evolving document, to be versioned and updated, based on community feedback and new data.</span></div><div class = "text-block"><span style = "font-style:italic;">Note: Study procedures are vaccine-specific and will depend upon vaccine administration days (Day 1 and Day 15 versus Day 1 and Day 29) and serology collection days. The below section assumes that vaccine administrations take place on Days 1 and 15 with procedures as indicated.</span></div></div>

[STEPS]
?. [Screening visit:  to Day 0 (Study procedures and evaluation)]
After the site PI has obtained informed consent from participants, several procedures will be completed during screening to determine study eligibility.  Baseline data will be collected during screening between seven days prior to first vaccination and on Day 1, the day of first vaccination; however, it is anticipated it will generally take no more than a few days to determine eligibility, and participants will be randomized and vaccinated as soon as possible after determination of eligibility. All inclusion/exclusion criteria must be assessed from data obtained within that period, unless otherwise specified in the eligibility criteria. Information gathered during screening (medical history, physical examination, and laboratory analysis) will be recorded in the Source Documents and the CRFs. Laboratory reference values specific to each country will be included in a site-specific addendum. After study information has been provided and the appropriate informed consent has been obtained, the procedures in this "Screening visit" section will be performed before enrollment
?. [Screening visit:  to Day 0 (Study procedures and evaluation)]
Confirm written informed consent has been obtained.
?. [Screening visit:  to Day 0 (Study procedures and evaluation)]
Assign participant ID once study specific consent form has been signed.
?. [Screening visit:  to Day 0 (Study procedures and evaluation)]
Obtain demographic and contact (e.g., address, telephone) information.
?. [Screening visit:  to Day 0 (Study procedures and evaluation)]
Obtain medical history, including:Details of any previous vaccinations in the past 28 days and reaction to vaccinations.Surgery.Previous hospitalization. Allergy to food/drugs.Current medication. History of any chronic or recurrent medical conditions.An interval medical history collected at subsequent clinic visits to assess for any AEs or concomitant medications.
?. [Screening visit:  to Day 0 (Study procedures and evaluation)]
Perform Physical examination, including:Assessment of head, eyes, ears, nose, oropharynx, neck, chest (auscultation), lymph nodes (neck, supraclavicular, axillary, inguinal), abdomen (auscultation and palpation), musculoskeletal, skin, and neurological assessment.
?. [Screening visit:  to Day 0 (Study procedures and evaluation)]
Obtain vaccination history
?. [Screening visit:  to Day 0 (Study procedures and evaluation)]
Obtain details of medication use within the past 30 days.
?. [Screening visit:  to Day 0 (Study procedures and evaluation)]
Measure height and weight.Height should be measured and recorded to the nearest cm.Weight should be measured in kg and recorded to the nearest 0.1 kg.
?. [Screening visit:  to Day 0 (Study procedures and evaluation)]
Collect vital signs, including:Temperature, measured in degrees Celsius (recorded to the nearest 0.1 degree).Respiratory rate, recorded in breaths per minute. Heart rate, measured in beats per minute manually or by automated device.Systolic and diastolic blood pressure, measured in millimeters of mercury (Hg) manually or by automated device.
?. [Screening visit:  to Day 0 (Study procedures and evaluation)]
Collect blood (8 mL) for baseline clinical laboratory testing, including:Complete blood count (CBC) (WBC, hemoglobin, platelet count)Aspartate transaminase (AST or SGOT) Alanine transaminase (ALT or SGPT) Total bilirubin  Creatinine
?. [Screening visit:  to Day 0 (Study procedures and evaluation)]
Perform urine or blood pregnancy test on women of childbearing potential if within one day of vaccine administration.
?. [Screening visit:  to Day 0 (Study procedures and evaluation)]
Screening procedure timelines for any single subject will include a 7-day window before randomization. Data collection will be by eCRF. The in-person visit days and procedures that include permissible window intervals are described in a Schedule of Events Table (Appendix A).
?. [Randomization]
Enrollment will take place online using EDC System. Randomization will occur on the day participants receive their first study vaccination (Day 1), after confirmation of eligibility and immediately prior to vaccine administration.
?. [Randomization]
The participant will be randomized to one of two study groups, determined by block randomization (
?. [Randomization]
Participants will receive a coded treatment assignment after demographic and eligibility data have been entered into the system and eligibility has been confirmed. The unblinded research pharmacist will receive the treatment assignment codes to prepare the vaccine to be given to each participant. The unblinded research pharmacist will maintain the treatment code list in a secure place.
?. [First vaccination visit (Day 1)]
Day 1 procedures:
Appendix A shows the study day, window periods, blood sampling tests, and volumes for all study procedures.
?. [First vaccination visit (Day 1)]
Verify demographic data.
?. [First vaccination visit (Day 1)]
Measure vital signs prior to immunization.
?. [First vaccination visit (Day 1)]
Measure axillary temperature in degrees Celsius (recorded to the nearest 0.1 degree).
?. [First vaccination visit (Day 1)]
Record respiratory rate in breaths per minute.
?. [First vaccination visit (Day 1)]
Measure heart rate in beats per minute manually or by automated device.
?. [First vaccination visit (Day 1)]
Measure systolic and diastolic blood pressure in millimeters of mercury (Hg) manually or by automated device.
?. [First vaccination visit (Day 1)]
Verify medical history.
?. [First vaccination visit (Day 1)]
Conduct targeted physical examination if indicated.
?. [First vaccination visit (Day 1)]
Perform urine pregnancy test for women of reproductive age.
?. [First vaccination visit (Day 1)]
Update information on concomitant medications.
?. [First vaccination visit (Day 1)]
Collect nasopharyngeal swabs for SARS-CoV-2 virus detection.
?. [First vaccination visit (Day 1)]
Obtain blood (serum) for antibody ELISA and neutralizing antibody titers (X mL).
?. [First vaccination visit (Day 1)]
Clean the prospective deltoid muscle injection site with an alcohol swab and allow it to dry completely.
?. [First vaccination visit (Day 1)]
Administer vaccine/placebo in the deltoid region, with clear documentation regarding the arm in which the vaccine is administered.
?. [First vaccination visit (Day 1)]
Observe participants for at least 30 minutes post-vaccination. Address and document any immediate reactions to vaccination.
?. [First vaccination visit (Day 1)]
Take vital signs and assess the injection site after at least 30 minutes. Measure and record any redness and/or induration. Document any complaints or reactogenicity signs or symptoms.
The site investigator (PI) (or designee) may determine that a participant requires further on-site observation.
?. [First vaccination visit (Day 1)]
Discharge participant from the study clinic once all study related procedures are complete and the site investigator determines that a participant’s condition is acceptable.
?. [First vaccination visit (Day 1)]
Provide diary card/memory aid to participants selected to assess reactogenicity (reactogenicity cohort, e.g., 1,000 per country) to record local and systemic adverse reactions. Review with participants what they should record and how to record it.  The following parameters for reactogenicity will be assessed during the seven days after each study injection:  AB1Local ReactogenicitySystemic Reactogenicity2PainFever3TendernessHeadache4Erythema (redness)Vomiting5IndurationNausea6PruritusFatigue7Chills8Myalgia9ArthralgiaParticipants in the reactogenicity cohort will be given a thermometer and measuring tape and will be instructed on entering signs and symptoms daily for seven days. All participants will be given an emergency telephone number to contact a special 24/7 study call center if in need of urgent medical attention. Staff will follow up with phone interviews, email, and SMS text to enter data electronically into the CRF. Participants will be instructed on how to enter and self-assess the severity of these AEs. Participants will also be asked to document unsolicited AEs on the programmed diary card, and whether medication was taken to relieve symptoms for seven days after each immunization.
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AB1Local ReactogenicitySystemic Reactogenicity2PainFever3TendernessHeadache4Erythema (redness)Vomiting5IndurationNausea6PruritusFatigue7Chills8Myalgia9Arthralgia
?. [Second vaccination visit (Day 15 + 7-day window)]
Check inclusion and exclusion criteria.
?. [Second vaccination visit (Day 15 + 7-day window)]
Collect the diary card/memory aid and have investigator review it with the participant.
?. [Second vaccination visit (Day 15 + 7-day window)]
Update demographic data.
?. [Second vaccination visit (Day 15 + 7-day window)]
Measure vital signs prior to second vaccination.
?. [Second vaccination visit (Day 15 + 7-day window)]
Update the medical history with any new information.
?. [Second vaccination visit (Day 15 + 7-day window)]
Perform a targeted physical examination (if indicated).
?. [Second vaccination visit (Day 15 + 7-day window)]
Complete a urine pregnancy test for women of reproductive age.
?. [Second vaccination visit (Day 15 + 7-day window)]
Obtain information on concomitant medication use.
?. [Second vaccination visit (Day 15 + 7-day window)]
Obtain blood samples for serological testing (5 mL).
?. [Second vaccination visit (Day 15 + 7-day window)]
Clean the prospective deltoid muscle injection site with an alcohol swab and allow to dry completely.
?. [Second vaccination visit (Day 15 + 7-day window)]
Administer the vaccine/placebo in the deltoid region and clearly document in which arm the vaccine was administered.
?. [Second vaccination visit (Day 15 + 7-day window)]
Observe participants at the site for at least 30 minutes following vaccination.
?. [Second vaccination visit (Day 15 + 7-day window)]
Measure and record vital signs after at least 30 minutes. Assess injection site for redness and/or induration. Assess and document any complaints or reactogenicity signs or symptoms.
?. [Second vaccination visit (Day 15 + 7-day window)]
Determine whether a participant requires further on-site observation (responsibility of investigator); additional site or clinical assessments may be completed as needed.
?. [Second vaccination visit (Day 15 + 7-day window)]
Discharge participant from study clinic when all study related procedures are complete and the site investigator determines a participant’s condition is acceptable.
?. [Second vaccination visit (Day 15 + 7-day window)]
Provide participants in the reactogenicity cohort with a diary card/memory aid to record local and systemic adverse reactions over the seven following days. Participants should also be given an axillary thermometer and measuring tape, and be instructed on entering signs and symptoms daily for seven days. All participants will be given an emergency telephone number to contact a special 24/7 study call center if urgent medical attention is needed. Staff will follow up with phone interviews, email, and SMS text to enter data electronically into the CRF. Participants will be instructed on how to enter and self-assess the severity of AEs. Participants will also be instructed to document unsolicited AEs on the diary card, and whether medication was taken to relieve symptoms for seven days after each immunization.
?. [Day 28 ( window)]
The investigator reviews the diary card/memory aid with the participant
?. [Day 28 ( window)]
Review unsolicited AEs.
?. [Day 28 ( window)]
Obtain blood samples for serological testing (5 mL).
?. [Day  (42-56; two-to-four weeks after final vaccination, depending on vaccine)]
The investigator reviews the diary card/memory aid with the participant for unsolicited AEs.
?. [Day  (42-56; two-to-four weeks after final vaccination, depending on vaccine)]
Update interim medical history.
?. [Day  (42-56; two-to-four weeks after final vaccination, depending on vaccine)]
Update concomitant medications.
?. [Day  (42-56 to study end)]
Investigators will contact participants approximately every two weeks (or more frequently without restriction) to remind them of COVID-19 symptoms and the need to seek medical attention and COVID-19 testing as soon as possible.
?. [Day 180]
Study staff will collect serum from participants to assess seroresponse to both vaccine and non-vaccine antigens in the vaccine that may indicate asymptomatic infection occurring in the interval after vaccine administration.
?. [Day 365/730]
Study end procedures include end of study serum collection and inquiries about any major medical events (SAEs, AESIs, etc.) in the interim between preceding visits.
?. [Interim contacts and visits]
Interim contacts and visits (those between regularly scheduled follow-up visits) may be performed at participant request or as deemed necessary by the investigator or designee at any time during the study. All interim contacts and visits will be documented in participants’ study records and on applicable case report forms.
?. [Withdrawal from study]
Participants can leave the study at any time for any reason without any penalty or loss of benefits to which they are otherwise entitled. Participants can also be withdrawn from the study at the discretion of the investigator. The following reasons may lead to withdrawal of individual participants:Withdrawal of informed consent by volunteer. Any SAE.Any AE that, according to clinical judgment of the investigator, is considered as a definite contraindication to continuing in the study.Completely lost to follow-up (after three unsuccessful attempts to establish contact).Pregnancy during immunization phase. Women found to be pregnant after the final immunization will not be withdrawn but followed through study end.Ineligibility (arising during the study or retrospectively, having been overlooked at screening).If the investigator believes that continuation would be detrimental to the subject’s well-being. Non-compliance with study procedures.Any other protocol deviation that results in a significant risk to the subject’s safety.The reason for withdrawal will be recorded in the CRF. If withdrawal is due to an AE or accidental pregnancy after vaccination, appropriate follow-up visits or medical care will be arranged, with the agreement of the participant, until the AE has resolved. If a participant withdraws from the study, data, serum, and RNA collected from nasopharyngeal samples prior to withdrawal may still be used for analysis. Storage of serum/ RNA collected from nasopharyngeal samples will continue unless the participant specifically requests otherwise.
?. [Handling of participant withdrawals or termination]
Investigators or designees will follow participants who are withdrawn as result of an SAE/AE until resolution of the event. Study staff will make an attempt to contact those participants who do not return for scheduled visits or follow-up. Information relative to the withdrawal will be documented in the CRF. The investigator will document whether the decision to withdraw from the study was made by the subject or the investigator and which of the following possible reasons was responsible for withdrawal:SAE.Non-serious AE.protocol violation (specify).Consent withdrawal, not due to an AE.Moved from the study area.Lost to follow-up.If a subject withdraws or is terminated from the study after enrollment, including lost to follow-up, they may be replaced. If the reason for withdrawal is pregnancy during the immunization phase of the study, the participant won’t receive further immunizations but will be followed for safety until delivery or termination of the pregnancy.
?. [Premature termination or suspensions of study]
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause as determined by Sponsor. Written notification, documenting the reason for study suspension or termination, will be provided to the investigator, ERC/IRBs, and to regulatory authorities. If the study is prematurely terminated or suspended, the PI will promptly inform the ERC/IRB and will provide the reason(s) for the termination or suspension.The Sponsor reserves the right to terminate or curtail this clinical study for any reason, including but not limited to the following:Risk to participant safety. The scientific question is no longer relevant or the objectives will not be met (e.g., slow accrual). Failure to comply with good clinical practice (GCP) or terms of Clinical Trial Agreement.Risks that cannot be adequately quantified. Ethical concerns raised by the local community or local medical care/health care authorities. Failure to remedy deficiencies identified through site monitoring (e.g., data recording is inaccurate and/or incomplete on a chronic basis, or failure to meet other identified Sponsor performance standards).Sponsor decides to discontinue development of the study vaccine.Unsatisfactory participant enrollment with respect to quality and/or quantity. If at any time a decision is made to permanently discontinue administration of study product in all participants, the PI will notify the ERC/IRB and the regulatory agency in a timely manner. In addition, the DSMB may recommend Sponsor terminate the study based on a review of the safety data or interim safety analysis. If the study is prematurely discontinued by Sponsor for any reason, a summary report will be submitted to regulatory authorities. The summary report will provide a brief description of the study, the number of participants exposed to the vaccine, dose and duration of exposure, details of adverse drug reactions (if any), and the reason for discontinuation of the study or non-pursuit of the new drug application.
?. [Blinding]
Sufficient measures will be taken to assure that blinding of participants and evaluation staff is maintained. Study product assignments will be accessible to the data coordinating center staff and others who are required to know this information to ensure proper trial conduct. The DSMB members may also be unblinded to treatment assignment as required to review vaccine safety and efficacy. Emergency unblinding decisions are expected to be rare and justified only when that information is needed for the future clinical management of that participant. If, in the opinion of the investigator, the event the health and safety of the participant will benefit from knowing the treatment code, efforts will be made to contact the medical monitor as long as patient safety is not at imminent risk. If the subject is at imminent risk, the investigator should have the ability to unblind although should notify the Medical Monitor (MM) and Sponsor as soon as possible thereafter.
?. [Management of birth control and pregnancy during study]
Contraception status should be assessed and documented prior to enrollment and study vaccination for female participants of childbearing potential. Adequate methods of contraception include barrier contraception, hormonal birth control, intrauterine device (IUD), surgical sterility, and abstinence from sexual activity that can lead to pregnancy. If a female participant becomes pregnant following randomization, she will be encouraged to complete remaining visits and study procedures (except for any remaining investigational product dosing) unless medically contraindicated. The investigator is required to notify the contract research organization (CR)O within 24 hours of knowledge of a pregnancy. Any participant who becomes pregnant during the period between vaccination and the last study visit will continue to be followed for pregnancy outcome, even if birth occurs after the scheduled end of the study for the subject.  The pregnancy and its outcome will be reported on the Pregnancy CRF.
?. [First vaccination visit (Day 1)]
Check inclusion and exclusion criteria.