A Multi-Centre 12 Month Parallel-Group Randomized Control Trial of BNT162b2 Versus mRNA( Messenger Ribonucleic Acid) -1273 COVID-19 Vaccine Boosters in Chronic Kidney Disease and Dialysis Patients With Poor Humoral Response Following COVID-19 ( Corona Virus Disease of 2019)Vaccination
Phase: PHASE2
Conditions: Chronic Kidney Diseases, COVID-19
Sponsor: Sunnybrook Health Sciences Centre

(ClinicalTrials.gov COVER PAGE) 
 
BOOST KIDNEY: A Multi-Centre 12 Month Parallel-Group Randomized Control 
Trial of BNT162b2 versus mRNA-1273 COVID-19 Vaccine Boosters in Chronic 
Kidney Disease and Dialysis Patients with Poor Humoral Response following 
COVID-19 Vaccination 
 
 
NCT: 05022329 
 
 
Protocol Dated: 05-Nov-2021 
 

 
 
 
 
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(BOOST KIDNEY) 
 
BOOST KIDNEY: A Multi-Centre 12 Month Parallel-Group Randomized Control 
Trial of BNT162b2 versus mRNA-1273 COVID-19 Vaccine Boosters in Chronic 
Kidney Disease and Dialysis Patients with Poor Humoral Response following 
COVID-19 Vaccination 
 
Protocol Number: 3750 
 
Principal Investigator: Dr. Michelle Hladunewich 
Regulatory Sponsor: Sunnybrook Research Institute 
Funding Agency: COVID-19 Immunity Task Force (CITF)  
Public Health Agency of Canada (PHAC) 
Oreopoulos/Baxter Home Dialysis Grant (Division of Nephrology, 
University of Toronto) 
Coordinating Centre: 
 
 
 
 
 
 
 
 
Centre for Clinical Trial Support (CCTS) 
Sunnybrook Research Institute 
C8-2075 Bayview Avenue 
Toronto, ON M4N 3M5 
Canada 
Email:  covid-ckd@sunnybrook.ca 
Fax:  (416) 480-5633 
 
                                 
 
 
 

 
 
 
 
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SPONSOR STATEMENT OF COMPLIANCE 
This study will comply with the International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human use Good Clinical Practice E6 (ICH-GCP), World Medical 
Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human 
Participants, as well as applicable regulatory and institutional requirements.  
 
Personnel listed below are authorized to sign the protocol and any subsequent protocol 
amendments on behalf of the sponsor:  
Name: 
(Print) 
Dr. Michelle Hladunewich 
Title:  
(Print) 
Principal Investigator 
Signature: 
 
Date of Approval: 
(yyyy-mmm-dd) 
2021-Nov-09 
 
 

 
 
 
 
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PROTOCOL SIGNATURE PAGE 
 
I have read this protocol in its entirety and its appendices.  I agree to comply with the requirements 
of the study protocol and procedures for data recording/reporting and acknowledge my 
responsibility for the well-being of each research participant, and to ensure that all persons 
involved in study activities are adequately informed about the protocol, the investigational product, 
and their trial-related duties.  The signature below constitutes the agreement to conduct this study 
in accordance with the REB approved protocol, GCP and  applicable regulatory requirements, 
including confidentiality, ethical guidelines and regulations regarding the conduct of research in 
humans. 
 
Qualified Investigator: 
Name: 
(Print) 
 
Title & Institution:  
(Print) 
 
Signature: 
 
Date of signature: 
(yyyy-mmm-dd) 
 
 

 
 
 
 
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TABLE OF CONTENTS 
PAGE 
PROTOCOL TITLE                                                                                                                     1 
TABLE OF CONTENTS .................................................................................................. 4 
LIST OF ABBREVIATIONS ............................................................................................. 7 
1   KEY ROLES AND CONTACT INFORMATION ........................................................ 11 
2              INTRODUCTION ........................................................................................... 12 
2.1          BACKGROUND .......................................................................................... 12 
2.2             Clinical Data to Date ................................................................................ 14 
2.3              Rational for Study .................................................................................... 16 
3            STUDY OBJECTIVES ..................................................................................... 20 
3.1             Primary Objectives/Outcomes .................................................................. 20 
3.2             Secondary Objectives/Outcomes ............................................................. 20 
4             STUDY DESIGN ............................................................................................ 22 
4.1           General Design .......................................................................................... 22 
5             PARTICIPANT SELECTION and WITHDRAWAL .......................................... 25 
5.1              Study Population ..................................................................................... 25 
5.2              Inclusion Criteria ..................................................................................... 25 
5.3            Exclusion Criteria ...................................................................................... 26 
5.4            Participant Selection ................................................................................. 26 
5.5            Participant Recruitment ............................................................................. 26 
5.5.1            Randomization Procedures ................................................................. 27 
5.5.2            Blinding and Unblinding ...................................................................... 28 
5.6                  Participant Withdrawal ........................................................................ 28 
5.7                Data Collection and Follow-up for Withdrawn Participants .................... 29 
6           INTERVENTIONS ............................................................................................ 30 
6.1         Investigational Product ................................................................................. 30 
6.1.1           Acquisition, Formulation and Packaging .............................................. 30 
6.1.2              Treatment Assignment Procedures................................................... 31 
6.1.3             Vaccine Allocation and Administration ............................................... 31 

 
 
 
 
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6.1.4 Vaccine Dosage, Preparation and Administration .......................................... 33 
6.1.5            Dose Modification ............................................................................... 36 
6.1.6             Receiving, Storage, Dispensing and Return ...................................... 37 
6.1.7          Prior and Concomitant Medications/Treatments ................................... 38 
6.1.8           Procedures for Intervention Training and Monitoring ........................... 38 
7          STUDY SCHEDULE AND PROCEDURES ....................................................... 39 
7.1            Study Procedure ....................................................................................... 39 
7.2 
Study Assessments .......................................................................................... 40 
8.1.1           Adverse Events .................................................................................... 46 
8.1.2             Serious Adverse Events ..................................................................... 46 
8.1.3            Unexpected Adverse Event ................................................................ 47 
8.1.4         Unexpected Adverse Drug Reaction (ADR) ........................................... 47 
8.2            Assessment of an Adverse Event ............................................................. 47 
8.2.1       Relationship (Causality/Relatedness) ...................................................... 47 
8.3            Adverse Event Recording ......................................................................... 49 
8.4            Reporting of SAEs and Unanticipated Events ........................................... 49 
8.4.1           Investigator reporting: Notifying the REB: ............................................ 49 
8.4.3          Sponsor Reporting of SUADRs: Notifying Health Canada .................... 50 
8.4.4           Sponsor Reporting of SUADRs: Notifying Sites ................................... 50 
8.4.5           Events of Special Interest .................................................................... 51 
8.5             Type and Duration of Follow-up for Adverse Events ................................ 51 
8.6             Reporting and Entry Timelines ................................................................. 51 
9                SITE MONITORING, AUDITING AND INSPECTING .................................. 55 
9.1            Site Monitoring Plan .................................................................................. 55 
11             Data Handling and Record Keeping ............................................................. 62 
11.2              Source Documents ................................................................................ 64 
11.3              Data Management Responsibilities ....................................................... 64 
11.4                    Data Capture ................................................................................... 66 
11.4.1           Case Report Forms ............................................................................ 66 
11.5            Records Retention .................................................................................. 67 

 
 
 
 
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11.6             Clinical Trial Registration ....................................................................... 67 
13                    ETHICS CONSIDERATIONS ................................................................ 70 
13.1               Ethical Standard ................................................................................... 70 
13.2              Research Ethics Board (REB) ............................................................... 70 
13.3               Consent ......................................................................................................................... 70 
14           PUBLICATION/DATA SHARING POLICY........................................................................... 74 
 
 

 
 
 
 
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LIST OF ABBREVIATIONS 
The following abbreviations describe terms, documents and study personnel used in the 
conduct of this study protocol. 
AE 
Adverse Event/Adverse Experience 
AEFI 
Adverse Event Following Immunization 
Anti-NP 
Anti- nucleocapsid Protein 
CC 
Coordinating Centre 
CIOMS 
Council for international Organizations of Medical Sciences 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTO 
Clinical Trial Ontario 
CCTS 
Centre for Clinical Trial Support 
CKD 
Chronic Kidney Disease 
COVID-19 
Coronavirus 19  
EC 
Ethics Committee 
ELISA 
Enzyme Linked Immunosorbent Assay 
HD 
Hemodialysis 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IP 
Investigational Product 
DSMB 
Data Safety Monitoring Committee 
DSPC 
1,2-distearoyl-sn-glycero-3-phosphocholine 
eCRF 
Electronic Case Report Form 
pCRF 
Paper Case Report Form 
EDC 
Electronic Data Capture 

 
 
 
 
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GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
MedDRA 
Medical Dictionary for Regulatory Authorities 
ORN 
Ontario Renal Network 
PD 
Peritoneal Dialysis 
PHI 
Personal Health Information 
PHIPA 
Personal Health Information Protection Act 
PI 
Principal Investigator 
PM 
Product Monograph 
QI 
Qualified Investigator 
RBD 
Receptor-Binding Domain  
REB 
Research Ethics Board 
RCT 
Randomized Controlled Trial 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SC 
Steering Committee 
snELISA 
Surrogate neutralization ELISA 
SOP 
Standard Operating Procedure 
SRI 
Sunnybrook Research Institute 
SUADR 
Serious and Unexpected Adverse Drug Reaction 
TMF 
Trial Master File 
TDL 
Task Delegation Log 
USP 
United States Pharmacopeia 
 

 
 
 
 
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                                                          Protocol Summary 
 
 
 
                Full Title 
 
BOOST KIDNEY: A Multi-Centre 12 Month Parallel-Group 
Randomized Control Trial of BNT162b2 versus mRNA-1273 
COVID-19 Vaccine Boosters in Chronic Kidney Disease and 
Dialysis Patients with Poor Humoral Response following 
COVID-19 Vaccination 
 
               Short Title 
 
BOOST KIDNEY 
 
 
                 Phase  
 
II/III 
 
   
        Protocol Number 
 
3750   
 
 
          Version Date 
 
Version 5.0, Nov 5, 2021 
 
 
         Study Duration 
 
1 year 
 
  
      Principal Investigator 
 
Dr. Michelle Hladunewich 
 
 
                Setting 
 
Multicenter, 5 Dialysis Centres in Ontario and British Columbia, 
Canada  
 
 
   Number of Participants 
 
300 participants 
 
         
 
          Study Design 
 
Four arm parallel randomized controlled trial of BNT162b2 versus 
mRNA-1273, third dose of the COVID-19 vaccine stratified by initial 
two dose vaccine type 
 
 
 
    Main Inclusion Criteria 
 
Dialysis and non-dialysis chronic kidney disease (Stage 3b-5) 
 
 
 
    Primary Outcome(s) 
Evaluate effect of third dose COVID-19 vaccine booster (BNT162b2 
versus mRNA-1273) on serologic SARS-CoV-2 response (Anti-RBD) 
at 1 month following booster dose.  

 
 
 
 
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    Secondary Outcome(s) 
 
1. Evaluate effect of third dose COVID-19 vaccine booster 
(BNT162b2 versus mRNA-1273) on Anti-Spike and SARS-CoV-2 
viral neutralization at 1 month following booster dose. 
2. Anti-Spike and Anti-RBD response at study enrolment, 3 months, 
6 months and 12 months following booster dose. 
3. Flow cytometry on PBMC, single-cell RNA sequencing and 
ELISPOT prior to, 1 month, and 6 months following booster dose 
to evaluate SARS-CoV-2 specific B and T-Cell response. 
4. Evaluate adverse effects related to third dose of vaccine through 
a questionnaire 48 hours -14 days, and 30 days following third 
vaccine dose. 
5. Differences in COVID-19 infections, symptomatic COVID-19 
infections, hospitalization, and death between study groups. 
 
 
 
      Statistical Analysis 
 
Intention to treat analysis for the primary outcome with two Chi-
Squared test or Fisher’s exact test for the primary outcome. Non-
parametric testing for differences in antibody level between study 
groups. Mixed effects models will be used for comparison of 
longitudinal antibody levels. 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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1   KEY ROLES AND CONTACT INFORMATION 
 
Regulatory Sponsor: 
Sunnybrook Research Institute (SRI) 
2075 Bayview Avenue 
Toronto, ON Canada M4N 3M5 
 
Principal Investigator:   
Michelle A. Hladunewich, MD, MSc, Sunnybrook Health 
Sciences Centre, University of Toronto 
 
Academic Research 
Organization: 
Centre for Clinical Trial Support, SRI 
2075 Bayview Avenue 
Toronto, ON Canada M4N 3M5 
 
 
 

 
 
 
 
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2              INTRODUCTION  
 
 
This study document is the protocol for research involving human participants.  This study 
is to be conducted according to Canadian and International standards, and in compliance with 
the protocol, the International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice E6 (GCP), World Medical 
Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human 
Participants, as well as applicable regulatory and institutional requirements and research policies. 
This protocol was developed following the SPIRIT checklist for interventional trials. 
 
2.1          BACKGROUND 
 
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes 
coronavirus disease 2019 (COVID-19), emerged from Wuhan, China in December 2019, and has 
resulted in a devastating global pandemic. In Ontario, there have been nearly 546,000 confirmed 
cases and over 9000 deaths in Ontario as of July 4, 2021.1 Rapid efforts have been untaken by 
the global scientific community to develop effective vaccines against SARS-CoV-2. On December 
9, 2020 the BNT162b2 mRNA Covid-19 Vaccine (COMIRNATY®/Pfizer-BioNTech) was approved 
by Health Canada. This was followed by the approval of the mRNA-1273 SARS-CoV-2 Vaccine 
(SPIKEVAX®/Moderna) on December 23, 2020. Both vaccines are lipid nanoparticle formulated, 
nucleoside-modified mRNA vaccines encoding the SARS-CoV-2 prefusion-stabilized full-length 
spike glycoprotein. Public health efforts are presently underway to quickly vaccinate the general 
population.  

 
 
 
 
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Patients on chronic dialysis have been recognized to be an at-risk population. In Ontario, 
over 15,000 patients require chronic dialysis treatment at over 100 in-centre hemodialysis units.2 
While the general population has been advised to stay at home, dialysis patients must visit dialysis 
treatment facilities minimally three times per week for life sustaining treatment. Shared 
transportation to dialysis, difficulty maintaining social distancing, and interactions with multiple 
healthcare providers, medical comorbidities and impaired immunity place dialysis patients at 
greater risk for acquiring infection nosocomially or in the community. Data from the Ontario Renal 
Network as of July 1, 2021 has demonstrated that 5.73% (1003 out of 176710 dialysis patients) 
have tested positive for COVID-19 compared to 1,545,181 out of 14,747,051 (3.69%) of the 
general Ontario population. Despite close adherence to screening protocols, usage of personal 
protective equipment, and social distancing measures, COVID-19 outbreaks have still occurred 
in Ontario dialysis units.3  
As of July 1, 2021 there have been 1003 patients on chronic dialysis treatment who have 
been infected with COVID-19. Due to their comorbidities, patients on dialysis are at greater risk 
for severe COVID-19 disease. In Ontario, 63% of chronic dialysis patients with COVID-19 have 
required hospitalization, and the case fatality rate has been reported at 28.5%, which is almost 4 
times higher than in the general population.4 This is consistent with a recent meta-analysis of 
3261 hemodialysis patients who contracted COVID-19 and identified an overall mortality rate of 
22.4%.5 Similarly, data from the European Renal Association–European Dialysis and Transplant 
Association Registry identified a COVID-19 attributable mortality of 20% in 3285 receiving 
dialysis.6 
In general, dialysis patients are known to have decreased immune response to 
vaccination, including lower rates of seroconversion, lower antibody titers, and a less sustained 
humoral response after immunization compared with the general population. This is evident from 
routine Hepatitis B vaccination in dialysis patients wherein repeated series and booster doses are 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 14 of 80 
 
required to maintain immunity.7 The rate of seroconversion following the hepatitis B vaccine is 
only 44% in dialysis patients.8 Furthermore, Hepatitis B antibody titers decline more rapidly in 
individuals who receive Hepatitis B immunization compared to individuals who acquire natural 
Hepatitis B infection.  
Predictors of antibody levels against SARS-CoV-2 are under active investigation. A study in 98 
dialysis patients infected with COVID-19 showed that COVID-19 specific antibody titers 
decreased significantly one month following seroconversion,10 which is remarkably shorter than 
the healthy general population wherein durable humoral immunity may last at least 4-8 months.11 
Both the BNT162b2 mRNA Covid-19 Vaccine (COMIRNATY®/Pfizer-BioNTech) and the mRNA-
1273 SARS-CoV-2 Vaccine (SPIKEVAX®/Moderna) randomized placebo-controlled trials, 
included only limited patients with kidney disease and patients receiving immunosuppressive 
treatment were excluded.12,13   
 
2.2             Clinical Data to Date  
Given this significant knowledge gap, we conducted the SMASH-COVID-19 Study (Serial 
Measurement of Quantitative COVID-19 Antibodies in Hemodialysis and Peritoneal Dialysis 
Patients following COVID-19 Vaccination) in hemodialysis patients at Sunnybrook Health 
Sciences Centre to determine their humoral response to vaccination. In this prospective 
observational study, humoral response was compared in 66 hemodialysis patients sampled 28 
days after receipt of one dose of vaccine to 76 patients who received two doses of vaccine 
sampled 14 days after the second dose. Among those receiving one dose, 6% had anti-RBD 
response above the median level of convalescent serum versus 41% who received two doses 
after 28 days. Given this finding, it was concluded that hemodialysis patients exhibit a poor 
humoral response to a single dose of BNT162b2 vaccine and the second dose should not be 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 15 of 80 
 
delayed.14 Furthermore, longitudinal follow-up at 13 weeks of our cohort of vaccinated 
hemodialysis patients has demonstrated that some individuals do not seroconvert and a 
significant proportion of individuals who attained convalescent serum levels of COVID-19 
antibodies (anti-Spike and anti-RBD) exhibit declining antibody levels by 13 weeks as shown in 
Figure 1, which has not been observed in the general population. This single centre pilot study 
has led to a larger multi-centre study in Ontario and British Columbia entitled “Determining the 
Safety and Efficacy of COVID-19 Vaccination in the Chronic Kidney Disease Population” (CTO 
Protocol Number 3604) which  is continuing to recruit patients with chronic kidney disease stage 
3b-5. This study will follow serologic response to COVID-19 vaccination in patients with advanced 
chronic kidney disease including those on dialysis for a one year period to better understand the 
duration of humoral immunity in this patient population. 
 
 
Figure 1: SARS-CoV-2 IgG Anti-RBD Response Following BNT162b2 Vaccine in 
Hemodialysis Patients up to 13 weeks following second dose of vaccine. 
 
 
      Patients have been divided into 5 clusters by k-clustering based on trajectory of anti-RBD 
response over time. Cluster 1 (orange) generally obtained robust response following vaccination 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 16 of 80 
 
and maintains serologic response 13 weeks. Clusters 2 (yellow) had an Anti-RBD response but 
gradually exhibits declining titers, and 3 (green) was characterized by the presence of anti-RBD 
antibodies at the time of the second dose, either due to previous infection, response to the first 
dose, or both; in this group, most individuals retained antibodies at 13 weeks, similar to the Cluster 
1 (orange), but some of the participants had more rapid decline in antibody levels. Cluster 4 (blue) 
generally did not achieve seroconversion following vaccination. Cluster 5 (purple) attained 
seroconversion but did not have an initial robust response defined as reaching convalescent 
serum levels and generally exhibits declining antibody levels over time. Antibody levels are 
reported as relative ratios to synthetic standards. Dots represent individual serum samples 
collected at the indicated times, and the samples from the same patients are connected by lines. 
Seroconversion threshold represents a positive test and is 0.186 and is indicated by the dashed 
line. The median level of antigen in convalescent serum taken 21-115 days post-symptom onset 
is considered a robust antibody response and is 1.25 for anti-RBD. 
2.3              Rationale for Study 
         Given the concern that a proportion of dialysis patients do not reach convalescent serum 
antibody levels following two dose of COVID-19 vaccination, booster doses may represent a 
means of attaining improved humoral immunity analogous to what is currently practiced with 
Hepatitis B vaccines. At this time, there is limited data regarding humoral immunity in dialysis 
patients receiving booster doses and there are no studies examining cellular immunity after a 
booster dose. A study in France of 45 hemodialysis patients receiving a third dose of BNT162b2 
COVID-19 vaccine one month following the second dose found that two out of five patients who 
did not respond to two doses of vaccine had a robust response following the third dose. It was 
also noted that the median increase in antibody titers was >580%  following the third dose.15 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 17 of 80 
 
Early studies of booster doses in other vulnerable patient populations including transplant 
patients on immunosuppression have also emerged. A case series in 30 solid organ transplant 
patients receiving a third dose of vaccine included 24 patients with negative antibody titers, and 
6 with low-positive antibody titers. In this study, the third dose was provided a median of 67 days 
(IQR 59-81 days) following the second dose and different vaccine types were used for the third 
dose: Ad26.COV2.S vaccine (Johnson & Johnson/Janssen) in 15, mRNA-1273 vaccine 
(SPIKEVAX®/Moderna) in 9, and the BNT162b2 (COMIRNATY®/Pfizer-BioNTech) in 6. Antibody 
testing against the spike or RBD protein at 14 days post third dose found that in those with low 
positive antibody levels, all had high positive antibody levels following the third dose. Among those 
with initial negative antibody levels, 6/24 (25%) were able to attain high-positive antibody levels. 
Adverse reactions recorded 7 days following third dose the incidence of severe symptoms was 
low, and the investigators concluded that their finding warranted clinical trials on booster doses in 
this patient population.16  Another recent study from France in solid organ transplant patients, 
including 78 kidney transplant candidates, also confirmed the utility of a third dose of the 
BNT162b2 vaccine in increasing the prevalence of patients with detectable SARS-CoV-2 antibody 
levels from 40% post second dose to 68% 4 weeks after the third dose. In this study, 44% of 
patients who were initially seronegative had seroconversion following the third dose. Notably 
those without antibody response were older and had lower GFR, which is typical of the 
hemodialysis population.17 Limited studies have examined cellular immunity, however a study 
which included 41 hemodialysis patients, 4 peritoneal dialysis patients and 35 healthy controls, 
and 40 kidney transplant patients found impaired memory B cell formation in dialysis patients 
including RBD-specific plasmablasts and post-switch memory B-cells when measured 3-4 weeks 
after second dose of vaccine.18 
Therefore, we propose a multi-site randomized, participant and investigator blinded 
controlled trial with four parallel arms stratified by initial two dose vaccine received in chronic 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 18 of 80 
 
kidney disease stage 3b-5, and patients with end stage kidney disease to determine whether 
vaccine boosters with a third dose of vaccine mRNA-1273 vaccine (SPIKEVAX®/Moderna) or the 
BNT162b2 (Pfizer/BioNTech) will enhance the humoral and cellular immunity in patients with 
kidney disease who have not-responded well to vaccination (defined as levels that are below the 
median convalescent level of anti-RBD). This may mean that a patient never attained 
convalescent serum level of anti-RBD or that they initially obtained convalescent serum levels but 
exhibit declining levels over time.  
The four study arms in this study will be as follows (as shown in Figure 2):  
1. Group 1: First two dose BNT162b2, Third dose BNT162b2  
2. Group 2: First two dose BNT16b2, Third dose mRNA-1273 
3. Group 3: First two dose mRNA-1273, Third dose BNT162b2 
4. Group 4: First two dose mRNA-1273, Third dose mRNA-1273  
        This study will evaluate both the humoral and cellular immune response in these patients. 
Serologic will be collected prior to booster dose, 1 month, 3 months, 6 months and 12 months 
following booster dose.  Based on experience and high patient engagement from our prior pilot 
study measuring humoral response to COVID-19 vaccination, we anticipate >70% of participants 
approached for this study will agree to participate.  
Studies have suggested that heterologous priming COVID-19 vaccination may result in 
improved immunogenicity although reactogenicity may be increased as demonstrated by Com-
COV study from the United Kingdom, which examined heterologous schedules incorporating an 
adenoviral-vectored vaccine (ChAd) and an mRNA vaccine (BNT162b2), randomizing to eight 
groups: ChAd/ChAd, ChAd/BNT, BNT/BNT or BNT/ChAd, administered at 28- or 84-day intervals. 
The trial failed to meet pre-specified  non-inferiority for the BNT/ChAd regimen, but did 
demonstrate that the Geometric Mean Concentration was higher in heterologous combinations 
than the licensed ChAd/ChAd schedule.19,20 Another study from the United Kingdom in 88 health 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 19 of 80 
 
care workers who received ChAd as their first dose and either a homologous boost with 9-12 
weeks later with ChAd (n=37) or mRNA-1273 (n=51) found that 7-10 days following second dose 
Anti-RBD IgG levels were 5 times higher than pre-second dose with ChAd compared to 115 time 
higher with a mRNA-1273 boost. Similarly, this strong serologic response with heterologous 
vaccination was reflected in in vitro neutralizing antibody titers which were 20 times higher with 
heterologous vaccination with mRNA-1273 compared to approximately double following a second 
dose of ChAd compared to pre-second dose titers.21 Therefore in this study, heterologous 
vaccination for the third dose will be explored in comparison to receiving the same vaccine 
(homologous) for all three doses with the hypothesis that the heterologous vaccination will result 
in higher antibody levels. 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 20 of 80 
 
 3            STUDY OBJECTIVES 
  
3.1             Primary Objectives/Outcomes 
Determine the effect of a third dose of COVID-19 vaccine (mRNA-1273 or BNT162b2) on 
humoral immune response in patients with chronic kidney disease stage 3b-5 including 
end stage kidney disease receiving dialysis who did not attain convalescent serum levels 
or exhibiting declining antibody levels below convalescent serum levels of Anti-RBD 
through measurement of Anti-RBD at 1 month (30 days) following third dose of vaccine. 
3.2             Secondary Objectives/Outcomes 
1. Measurement of Anti-Spike, Anti-NP antibodies, and SARS-CoV-2 specific neutralization 
at 1 month (30 days) following third dose of vaccine. 
2. Determine the effect of a third dose of COVID-19 vaccine on humoral immune response 
in hemodialysis patients who did not attain convalescent serum levels or exhibiting 
declining antibody levels below convalescent serum levels of Anti-RBD through 
measurement of Anti-Spike, Anti-RBD, and Anti-NP antibodies at 3 months, 6 months and 
12 months following booster dosage. 
3. In a subset of participants, assess cellular immunity through flow cytometry on PBMC and 
single-cell RNA sequencing prior to, one month, and 6 months following vaccine booster. 
4. Evaluate adverse events related to third dose of vaccine through a questionnaire within 
48 hours to 14 days and 30 days following third vaccine dose. 
5. Differences in COVID-19 infections, symptomatic COVID-19 infections, hospitalization, 
and death between study groups. 
 
 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 22 of 80 
 
4             STUDY DESIGN 
4.1           General Design  
The BOOST-KIDNEY study is a prospective, investigator and participant blinded 
randomized four parallel arm controlled study for CKD stage 3b-5 patients to evaluate the effect 
of a booster dose of vaccine on immunogenicity among those who did not respond defined as not 
reaching convalescent serum levels of Anti-RBD, or who exhibit declining antibody titers below 
the convalescent serum level of Anti-RBD. Enrolment will prioritize patients on dialysis but 
inclusion criteria will also include non-dialysis CKD stage 3b-5. Patients who are already 
participating in the study “Determining the Safety and Efficacy of COVID-19 Vaccination in the 
Chronic Kidney Disease Population” (CTO Protocol Number 3604) and have been found to have 
poor humoral response to COVID-19 vaccination will prioritized for recruitment. However, if a 
booster dose of COVID-19 vaccine is approved for the study population during the study period, 
patients will be eligible without serologic evaluation. 
Patients 
will 
be 
randomized 
to 
mRNA-1273 
SARS-CoV-2 
Vaccine 
(SPIKEVAX®/Moderna), or BNT162b2 mRNA Covid-19 Vaccine (COMIRNATY®/Pfizer-
BioNTech) administered by a trained vaccine administrator. Information on prior vaccines 
received will be recorded, and patients may have received either mRNA-1273 SARS-CoV-2 
Vaccine (SPIKEVAX®/Moderna), or BNT162b2 mRNA Covid-19 Vaccine (COMIRNATY®/Pfizer-
BioNTech) for their initial two doses of vaccine. Patients will be stratified by their initial vaccine 
type (BNT162b2 or mRNA-1273) prior to randomization, which will result in four study groups as 
shown in Figure 2.  
A placebo arm is not included in this study as it was not felt to be ethically justififed, but 
comparison will be made to participants not receiving a booster vaccine enrolled in CTO Protocol 
Number 3604 who choose not to participate. Similarly a primary outcome of COVID-19 infection 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 23 of 80 
 
or hospitalizations was not chosen given the low incidence of COVID-19 infections in Canada due 
to high vaccination rates in the country. 
Prior to receiving a third vaccine dose, quantitative SARS-CoV-2 IgG antibody levels 
against the full-length spike protein S1 domain, and Receptor Binding Domain (RBD) to assess 
humoral response will be measured and Anti-SARS-CoV-2 nucleocapsid protein to measure 
evidence of prior COVID-19 infection. In addition, we will isolate peripheral blood mononuclear 
cells in a subset to evaluate cellular immune response, however this will only be performed at 
University Health Network and Sunnybrook Health Sciences Centre as only these centres have 
the capacity for processing these samples. A neutralization antibody assay developed by the 
Gingras lab will also be used to assess for viral neutralization prior to booster dose at 1 month 
(30 days) post third dose of vaccine. 
 
 
 

 
 
 
 
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Figure 2: Four study groups in the BOOST KIDNEY study. Study participants will be 
randomized 1:1 after stratification by initial vaccine type. 
 
Following the intervention, SARS-CoV-2 antibodies will be measured 1 month, 3 months, 
6 months and 12 months post booster vaccination. Neutralizing antibodies will be measured at 
baseline and 1 month post third dose of booster vaccine. Cellular immunity in a subset will be 
evaluated at baseline, 1 month and 6 months post third dose of booster vaccine. Adverse events 
related to third dose of vaccination will be surveyed in the 14 day period following third dose of 
vaccine, and again 1 month following third dose. The study protocol may be altered if booster 
doses become available that are intended to target new SARS-CoV-2 variants.                
Furthermore, the study design will be adaptive, as if patients do not response to a third dose of 
vaccine the study protocol may be amended to consider other vaccine booster interventions. All 
study practices will follow social distancing measures currently recommended by Public Health 
authorities. 
Participant 
Enrolled
BNT162b2 Two 
Doses
Third Dose 
mRNA-1273
Third Dose 
BNT162b2
mRNA-1273 
Two Doses
Third Dose 
mRNA-1273
Third Dose 
BNT162b2

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 25 of 80 
 
5             PARTICIPANT SELECTION and WITHDRAWAL   
  
5.1              Study Population 
Chronic kidney disease (CKD) patients including those on dialysis (in-centre hemodialysis, 
nocturnal hemodialysis, home hemodialysis, peritoneal dialysis) at the Toronto Academic Health 
Science Network (Sunnybrook Health Sciences Centre, University Health Network, and Unity 
Health Toronto), Scarborough General Hospital and University of British Columbia will be eligible. 
 
5.2              Inclusion Criteria 
 
         Each participant must meet all of the following inclusion criteria to participate in this study: 
1. Patients with CKD stage 3b-5 defined as an eGFR of less than 45ml/min/1.73m2 or less 
will be eligible. Stage 5 CKD will include patients receiving in-centre hemodialysis, home 
dialysis (home hemodialysis or peritoneal dialysis), at Sunnybrook Health Sciences 
Centre, Unity Health Toronto, University Health Network, Scarborough General Hospital, 
or the University of British Columbia vaccinated with two doses of the COVID-19 vaccine 
will be eligible for a third dose to be given 2-12 months following the second dose. Patients 
may have participated in another COVID-19 study (CTO Protocol Number 3604) to assess 
humoral response .Patient not currently in CTO Study Number 3604 who are interested in 
the study are also eligible for recruitment into that trial. 
2. All participants will be age ≥18 at the time of study enrolment.  
3. The participants informed consent is obtained. 
 

 
 
 
 
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5.3            Exclusion Criteria 
 
            All participants meeting any of the following exclusion criteria at baseline will be excluded 
from participation in this study: 
1. Patients not vaccinated against COVID-19 vaccination. 
2. Patients who received heterologous first two doses of vaccine (expected to be a minimal 
number in this population as almost all patients received the same vaccine for both doses 
due to vaccination in dialysis units).  
3. Patients with severe allergic reaction to prior COVID-19 vaccination or any of the 
ingredients. 
4. New COVID-19 infection following study enrolment as determined by Anti-NP (drawn upon 
study enrolment) or new positive RT-PCR. 
 
 
5.4            Participant Selection  
         Approximately 300 patients on dialysis, CKD stage 3b-5, will be recruited for the study. 
Serologic eligibility criteria for the study must be met following the screening period in the study. 
 
5.5            Participant Recruitment 
          Participants will be recruited from participating renal centers within Canada from patients 
who have received two doses of COVID-19 vaccine. Eligible patients already participating in 
“Determining the Safety and Efficacy of COVID-19 Vaccination in the Chronic Kidney Disease 
Population” (CTO Protocol No. 3604) will be approached, but patients not in CTO Protocol No. 
3604 will also be screened for eligibility and participation. Patients with known poor humoral 
response based upon their serum Anti-RBD levels will be prioritized for recruitment into the trial, 

 
 
 
 
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but if a booster dose of COVID-19 vaccine is approved for the study population during the study 
period, all participants meeting the inclusion and exclusion criteria will be approached.  
 
5.5.1            Randomization Procedures 
Stratified randomization will be performed centrally upon study enrolment with 1:1 
receiving BNT162b2 mRNA COVID-19 Vaccine (COMIRNATY®/Pfizer-BioNTech), and mRNA-
1273 SARS-CoV-2 Vaccine (SPIKEVAX®/Moderna) with stratification by baseline vaccine type 
BNT162b2 or mRNA-1273 given possible differences in vaccine immunogenicity in this population 
and heterologous priming. 
The Participant whose  written informed or preliminary verbal consent was obtained and 
eligible for the study will be randomized. Allocation will occur through identical, sequentially 
numbered, opaque, sealed envelopes. The two interventions will be the two COVID-19 vaccines 
which have been used predominantly in the dialysis population: the BNT162b2 mRNA COVID-19 
Vaccine 
(COMIRNATY®/Pfizer-BioNTech) 
and 
mRNA-1273 
SARS-CoV-2 
Vaccine 
(SPIKEVAX®/Moderna). The BNT162b2 mRNA Covid-19 Vaccine (COMIRNATY®/Pfizer-
BioNTech), is administered in 30 μg per dose while the mRNA-1273 SARS-CoV-2 Vaccine 
(SPIKEVAX®/Moderna) is administered as 100 μg. Vaccines will be released from participating 
hospital pharmacies. Approval has been granted by the respective government agencies in in 
Ontario and British Columbia.  
 
 
 

 
 
 
 
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5.5.2            Blinding and Unblinding 
Trial participants, study investigators, research team member, outcome assessors, and 
data analysts will be blinded to the intervention randomization. The individual dispensing and 
administering the vaccine will be aware of the vaccine being dispensed and administered but the 
patient will be blinded. Patients will be un-blinded to the vaccine they received following 
completing of adverse events following immunization reporting (30 days) and at that point will be 
provided with a vaccine receipt.  
Un-blinding will only occur under exceptional circumstances where knowledge of the 
vaccine received is essential for further management of the study participant. Physicians are 
encouraged to discuss with the Qualified Investigator if un-blinding is necessary. If un-blinding is 
considered necessary, the Qualified Investigator will contact the randomization centre, who will 
do the code break as deemed necessary and communicate it directly to the attending physician. 
The Qualified Investigator will report all code breaks as they occur on the case report form. 
 
5.6                  Participant Withdrawal  
At their own discretion, participants may withdraw from the study at any time and for any 
reason. Participants withdrawing from the study should be contacted by the study research team 
requesting a final visit and to follow up with any unresolved adverse events. 
The participant may also be withdrawn from the study for the following reasons: 
 
Death: The participant died 
 
Protocol Deviation: The participant’s findings or conduct failed to meet the protocol entry 
criteria or failed to adhere to the protocol requirements (e.g., failure to return for defined 
number of visits). The deviation must be discussed with Principal Investigator prior to the 
participant study withdrawal. 

 
 
 
 
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 
Lost to Follow-up: The participant fails to attend study visits and study personnel are 
unable to contact the participant after repeated attempts. 
 
Physician Decision: The participant was terminated for a reason other than those listed 
above by the physician caring for the participant. 
 
Other: The participant was terminated for a reason other than those listed above and the 
reason will be recorded. 
 
5.7                Data Collection and Follow-up for Withdrawn Participants 
Once withdrawn from the study, no further study procedures or evaluations should be 
performed, or additional study data collected. Any data collected prior to the withdrawal of consent 
may be retained and used by the sponsor. However, every effort should be made to obtain 
permission to document the reason for withdrawal and to collect participant outcomes, such as 
survival data up to the protocol-described end of participant follow up period, where possible. Any 
data collected prior to the withdrawal of consent may be retained and used by the sponsor. 
 
 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 30 of 80 
 
6           INTERVENTIONS  
 
6.1         Investigational Product  
The study exposure will be COVID-19 vaccination with a third dose (booster) of the 
BNT162b2 mRNA COVID-19 Vaccine (COMIRNATY®/Pfizer-BioNTech) or mRNA-1273 SARS-
CoV-2 Vaccine (SPIKEVAX®/Moderna).  
 
6.1.1           Acquisition, Formulation and Packaging 
 
 6.1.1.1               Acquisition and formulation 
 
The vaccine doses utilized in this study will be obtained at each site through the hospital 
supply of vaccine. Release of the vaccine for this research study has been approved by the 
Ontario and British Columbia Ministries of Health. The BNT162b2 mRNA Covid-19 Vaccine 
(COMIRNATY®/Pfizer-BioNTech) is a suspension for intramuscular injection which must be 
diluted prior to administration. After preparation, a single dose is 0.3 mL, while the mRNA-1273 
SARS-CoV-2 Vaccine (SPIKEVAX®/Moderna) is administered as 0.5mL intramuscularly.  
 
The BNT162b2 vaccine includes the following ingredients: messenger ribonucleic acid 
(mRNA),  ALC-0315 = ((4-hydroxybutyl)  azanediyl), bis(hexane-6,1-diyl),bis (2-hexyldecanoate), 
ALC-0159 = 2-[(polyethylene glycol)-2000]-N, N-ditetradecylacetamide, 1,2-distearoyl-sn-
glycero-3-phosphocholine, cholesterol, dibasic sodium phosphate dehydrate, monobasic 
potassium phosphate, potassium chloride, sodium chloride, sucrose, and water for injection. The 
mRNA-1273 vaccine contains the following ingredients: messenger ribonucleic acid (mRNA), 1,2-
distearoyl-sn-glycero-3-phosphocholine (DSPC), Acetic acid, Cholesterol, Lipid SM-102, 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 31 of 80 
 
PEG2000, DMG 1,2-dimyristoyl-racglycerol,methoxy-polyethyleneglycol, Sodium acetate tri-
hydrate, Sucrose, Trometamol, Trometamol hydrochloride, and water for injection. Individuals 
with severe allergies to any of the components or who had a severe reaction to a previous dose 
of COVID-19 vaccine will be excluded from this study. 
6.1.1.2               Packaging  
 
The BNT162b2 Pfizer-BioNTech COVID-19 Vaccine is packaged in a clear glass 2 mL vial with 
a rubber stopper (not made with natural rubber latex), aluminum overseal, and flip-off cap.  The 
mRNA-1273 vaccine (SPIKEVAX®/Moderna) is supplied in a multi-dose 10R type I glass vial 
(each of 5 mL) with a 20 mm Fluro Tec-coated chlorobutyl elastomer stopper, 20 mm flip-off 
aluminum seal. The vial stopper does not contain natural rubber latex. Vials are packaged in a 
secondary carton containing a total of ten (10) mRNA-1273 vaccine vials per carton. 
6.1.2              Treatment Assignment Procedures 
 
        All patients eligible for the study will receive a booster vaccine dose. Randomization will be 
stratified by initial two vaccines received (BNT162b2 versus mRNA-1273) with 1:1 randomization 
to a third dose of BNT162b2 or mRNA-1273. 
 
6.1.3             Vaccine Allocation and Administration 
The third dose of vaccine will be administered between 2 months to 12 months following 
second dose of vaccine to allow a reasonable window for eligibility, and to allow for the appropriate 
screening of study participants with suboptimal initial humoral serologic response for this study. 
Vaccine will be dispensed by the central pharmacies through concealed allocation prior to planned 
administration of the study intervention. The vaccine will be administered by an individual who 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 32 of 80 
 
has been trained in COVID-19 vaccine administration. The individual administering the vaccine 
will not be blinded to the vaccine type. Vaccine receipt will be entered in the COVAX database, 
and receipt of a booster vaccine dose will be recorded in the Ontario Renal Network COVID-19 
vaccine tracker after unblinding following reporting of the adverse events at 30 days. 
  
Participants will be provided with documentation indicating that they have received a third 
booster dose and the date that this was received after unblinding following the completion of 
adverse event following immunization. As with standard vaccine administration, participants will 
sign additional informed consent to receive the vaccine and confirm that they do not have allergies 
to the components of either vaccine type. Participants will be monitored for 15 minutes following 
vaccine administration prior to being allowed to return home. For in-centre hemodialysis 
participants, the vaccine administration will occur during maintenance hemodialysis. 
 
6.1.3.1        Identification of Individuals with Suboptimal Humoral 
Response 
Patients enrolled in the pilot study “Determining the Safety and Efficacy of COVID-19 
Vaccination in the Chronic Kidney Disease Population” (with Protocol CTO number 3604) or who 
are interested in the study who are found to have poor humoral response will be determined to 
be eligible for the trial by assessing their most recent antibody levels drawn at a minimum 1 month 
following their second dose of COVID-19 vaccine. Upon study enrolment SARS-CoV-2 antibodies 
against anti-Spike, anti-RBD, and anti-NP will be performed to exclude evidence of recent COVID-
19 infection and confirm anti-RBD levels below convalescent serum levels. 
Antibodies targeting the full-length spike protein (anti-spike) and its Receptor Binding 
Domain (anti-RBD) measured humoral response to SARS-CoV-2 vaccination and/or natural 
infection while antibodies to the nucleocapsid protein (anti-NP) detected natural SARS-CoV-2 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 33 of 80 
 
infection, as this antigen is not targeted by the BNT162b2 vaccine. Antibody levels are reported 
as relative ratios to a synthetic standard included as a calibration curve on each assay plate.  
Thresholds for positivity (seroconversion) were determined by aggregating data from 
negative controls and calculating the mean + 3 standard deviations. The median level of 
convalescent serum is determined by comparison to the median levels of convalescent serum 
taken 21-115 days post symptom onset in patients with COVID 19. The convalescent serum 
patients (n=211) were obtained from the Toronto Invasive Bacterial Diseases Network (REB 
studies #20-044 Unity Health, #02-0118-U/05-0016-C, Mount Sinai Hospital).  had a median age 
of 59 years, 115/211 (55%) were male and included patients with mild (defined as not requiring 
hospitalization), moderate, and severe disease severity. 
Seroconversion thresholds represent a positive serology test and are 0.19, 0.186, and 
0.396 for anti-spike, anti-RDB, anti-NP antibodies respectively at a dilution of 0.0625.  The median 
level of antibody in convalescent serum taken 21-115 days post-symptom onset in those infected 
with COVID-19 is considered a robust antibody response and is 1.38, 1.25, and 1.13 for anti-
spike, anti-RBD, and anti-NP antibodies, respectively. All patients with anti-RBD below the level 
of convalescent serum at last serologic sampling will be eligible for the study which will be 
confirmed by serology taken upon enrolment in the study or already available due to registration 
in “Determining the Safety and Efficacy of COVID-19 Vaccination in the Chronic Kidney Disease 
Population” (CTO Protocol No. 3604). 
6.1.4 Vaccine Dosage, Preparation and Administration 
         The following dosage, preparation and administration are summarized from the product 
monographs of the investigational products: 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 34 of 80 
 
6.1.4.1               mRNA-1273 (SPIKEVAX®/Moderna) 
           COVID-19 Vaccine SPIKEVAX®/Moderna must not be reconstituted, mixed with other 
medicinal products, or diluted. The COVID-19 Vaccine Moderna should be administered 
intramuscularly as a 0.5mL dose. COVID-19 Vaccine Moderna is a white to off-white dispersion. 
It may contain white or translucent product-related particulates. Inspect COVID-19 Vaccine 
Moderna vials visually for foreign particulate matter and/or discoloration prior to administration. If 
either of these conditions exists, the vaccine should not be administered. COVID-19 Vaccine 
SPIKEVAX®/Moderna should be administered by the intramuscular (IM) route only. Do not inject 
the vaccine intravascularly, subcutaneously or intra-dermally. The preferred site is the deltoid 
muscle of the upper arm. A needle length of ≥1 inch should be used as needles <1 inch may be 
of insufficient length to penetrate muscle tissue in some adults. 
          Using aseptic technique, cleanse the vial stopper with a single-use antiseptic swab. 
Withdraw each 0.5 mL dose of vaccine from the vial using a new sterile needle and syringe for 
each injection. Pierce the stopper preferably at a different site each time. The dose in the syringe 
should be used as soon as feasible, and no later than 24 hours after the vial was first entered 
(needle-punctured). COVID-19 Vaccine Moderna is preservative free. Once the vial has been 
entered, it should be discarded after 24 hours. Do not refreeze. Thawed vials and filled syringes 
can be handled in room light conditions. Any unused vaccine or waste material should be 
disposed of in accordance with local requirements. To help ensure the traceability of vaccines for 
patient immunization record-keeping as well as safety monitoring, health professionals should 
record the time and date of administration, quantity of administered dose (if applicable), 
anatomical site and route of administration, brand name and generic name of the vaccine, the 
product lot number and expiry date. 
 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 35 of 80 
 
6.1.4.2              BNT162b2 (COMIRNATY®/Pfizer) 
         COMIRNATY®/Pfizer-BioNTech COVID-19 Vaccine is a suspension for intramuscular 
injection which must be diluted prior to administration. After preparation, a single dose is 0.3 mL.  
           Dilution: Obtain sterile 0.9% Sodium Chloride Injection, USP,use only this as the diluent. 
Using aseptic technique, withdraw 1.8 mL of 0.9% Sodium Chloride Injection, USP into a transfer 
syringe (21-gauge or narrower needle), cleanse the vaccine vial stopper with a single-use 
antiseptic swab, add 1.8 mL of 0.9% Sodium Chloride Injection, USP into the vaccine vial.         
Equalize vial pressure before removing the needle from the vial by withdrawing 1.8 mL air into 
the empty diluent syringe, gently invert the vial containing the COMIRNATY®/Pfizer-BioNTech 
COVID-19 Vaccine 10 times to mix. Do not shake and inspect the vaccine in the vial.The vaccine 
will be an off-white suspension. Do not use if vaccine is discoloured or contains particulate matter. 
          Administration: Preparation of Individual 0.3mL doses of Pfizer-Biontech COVID-19 
Vaccine: Using aseptic technique, cleanse the vial stopper with a single-use antiseptic swab, and 
withdraw 0.3 mL of the PfizerBioNTech COVID-19 Vaccine, preferentially using low dead-volume 
syringes and/or needles. Each dose must contain 0.3 mL of vaccine. If the amount of vaccine 
remaining in the vial cannot provide a full dose of 0.3 mL, discard the vial and any excess volume. 
Administer immediately, and no later than 6 hours after dilution. Low dead-volume syringes and/or 
needles can be used to extract 6 doses from a single vial. In order to ensure consistent withdrawal 
of 6 doses of 0.3mL, it is important to adhere to minimizing volume loss during dose extraction. 
Visually inspect each dose in the dosing syringe prior to administration. The diluted vaccine will 
be an off-white suspension.  During the visual inspection: verify the final dosing volume of 0.3 mL, 
confirm there are no particulates and that no discolouration is observed, do not administer if 
vaccine is discoloured or contains particulate matter. 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 36 of 80 
 
          Administer COMIRNATY®/Pfizer-BioNTech COVID-19 Vaccine intramuscularly, preferably 
in the deltoid muscle. Do not inject the vaccine intravascularly, subcutaneously or intra-dermally. 
After dilution, vials of Pfizer-BioNTech COVID-19 Vaccine contain 6 doses of 0.3 mL of vaccine. 
Low dead-volume syringes and/or needles can be used to extract 6 doses from a single vial. In 
order to ensure consistent withdrawal of 6 doses of 0.3 mL, it is important to adhere to minimizing 
volume loss during dose extraction. If standard syringes and needles are used, there may not be 
sufficient volume to extract a 6th dose from a single vial. Irrespective of the type of syringe and 
needle: each dose must contain 0.3 mL of vaccine, if the amount of vaccine remaining in the vial 
cannot provide a full dose of 0.3 mL, discard the vial and any excess volume, do not pool excess 
vaccine from multiple vials. 
6.1.5            Dose Modification  
No modification will be made to the vaccine doses in the study. 
 
 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 37 of 80 
 
6.1.6             Receiving, Storage, Dispensing and Return 
 
6.1.6.1                 Receipt of Investigational Product 
        Upon receipt of the investigational product and/or study supplies, an inventory must be 
performed and a receipt log filled out and signed by the research team member accepting the 
shipment.  It is important that the designated study staff counts and verifies that the shipment 
contains all the items noted in the shipment inventory.  Any damaged or unusable product in a 
given shipment will be documented in the study files.  The site must notify the study sponsor of 
any damaged or unusable product that was supplied to the site. 
6.1.6.2              Vaccine Storage and Stability 
        All the sites involved in this study have resources and capacity for the storage of both 
vaccines. The BNT162b2 vaccine is stored -80°C and must be thawed prior to dilution. Vials must 
reach room temperature before dilution. Undiluted vials may be stored at room temperature for 
no more than 2 hours. After dilution, the vials are stored between 2°C to 25°C (35°F to 77°F) and 
used within 6 hours from the time of dilution. The mRNA-1273 multi-dose vials are stored frozen 
between -25º to -15ºC (-13º to 5ºF). Once thawed, unpunctured vials may be kept at 2 º C to 8 ºC 
in a refrigerator for up to 30 days, or at 8º C to25ºC for up to 24 hours. After thawing, the vial is 
allowed to stand at room temperature for 15 minutes before administering. Alternatively, thaw at 
room temperature between 15°C to 25°C (59°F to 77°F) for 1 hour. Once the vial has been 
entered (needle-punctured), it can be stored at room temperature or refrigerated, but must be 
discarded after 24 hours. 
 
 

 
 
 
 
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6.1.7          Prior and Concomitant Medications/Treatments 
 
         Information regarding receipt of COVID-19 vaccination will be documented to determine 
study eligibility with stratification determined by receipt of BNT162b2 and mRNA-1273. In addition, 
a booster dose of vaccine will not be administered within 14 days of another vaccine (e.g. Hepatitis 
B or Shingle vaccination). 
 
6.1.8           Procedures for Intervention Training and Monitoring  
 
        Individuals providing the COVID-19 vaccine will have undergone standardized training for 
administration of both the BNT162b2 and mRNA-1273 vaccines. 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 39 of 80 
 
7          STUDY SCHEDULE AND PROCEDURES 
 
7.1            Study Procedure 
Participants who meet study eligibility criteria and consent to participate will be enrolled in 
the study. At study enrolment baseline, serum will be collected for SARS-CoV-2 serology, 
neutralizing antibodies and in a subset determined by the Investigator, PBMC will be collected for 
assessment of cellular immunity at Sunnybrook Health Sciences Centre or University Health 
Network prior to receiving the booster dose. Patients who are already participating in the study 
“Determining the Safety and Efficacy of COVID-19 Vaccination in the Chronic Kidney Disease 
Population” (CTO Protocol Number 3604) and have been found to have poor humoral response 
to COVID-19 vaccination will prioritized for recruitment. However, if a booster dose of COVID-19 
vaccine is approved for subsets of the study population or the study population at large during the 
study period, patients remain eligible for randomization without serological confirmation of low 
antibody titres.   
 Vaccine will be administered by an individual trained in vaccine administration at the site.  
Following vaccination, participants will be asked about adverse symptoms related to 
COVID-19 vaccination through a questionnaire at 48 hours -14 days either in person in the dialysis 
unit or by telephone and at 1 month post third dose.  
Following the intervention with either third dose of booster vaccine, the participant will 
have blood collection for Anti-SARS-CoV-2 IgG antibodies targeting the full length spike protein, 
RBD, nucleocapsid protein at 1 month, 3 months, 6 months, and 12 months following receipt of 
the booster dose. For feasibility, neutralizing antibodies will only be performed at 1 month 
following third dose. Non-dialysis participants may have bloodwork testing as part of routine 

 
 
 
 
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clinical care at each time point to determine if the booster vaccine dose has impacted kidney 
function including a serum creatinine and a spot urine micro-albumin creatinine ratio. 
 
 7.2 
Study Assessments 
 
7.2.1        Anti-SARS-CoV-2 IgG Antibody Assays 
Anti-SARS-CoV-2 IgG antibodies targeting the full-length spike protein trimer and its 
receptor binding domain will be measured to assess humoral response to vaccination. Anti-SARS-
CoV-2 IgG antibodies to the nucleocapsid protein will indicate likely prior SARS-CoV-2 infection 
as this is the antigen with the strongest immune-dominance in the coronavirus family, and this 
antigen is not targeted by the current COVID-19 vaccines available in Canada. 
Dr. Anne-Claude Gingras has developed in-house SARS-CoV-2 Receptor Binding 
Domain (RBD) and nucleocapsid protein ELISA test on a robotic platform that can be scaled up 
to test up to 10,000 samples/day. She currently is performing highly reproducible, in-house, 
quantitative and highly specific assays of serum IgG, IgA, and IgM to SARS-CoV-2 Spike, 
nucleoprotein, and RBD domain. She has also developed a surrogate assay that can predict 
neutralization ability of serum to SARS-CoV-2.22,24 These tests have been validated on cohorts of 
laboratory confirmed positive and negative specimens. Levels of antibodies to each of the 
antigens will be normalized to reference standards included on each plate (in collaboration with 
the National Research Council of Canada), and expressed as relative ratios. All assays are also 
calibrated to the international standard from the National Institute for Biological Standards and 
Control (NIBSC). 
Assessment of viral neutralization will be performed using a viral neutralization assay 
developed by the Gingras laboratory and may be adapted to test neutralization against novel 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 41 of 80 
 
variants of concern. The Gingras laboratory has a surrogate neutralization assay which is 
performed on the same platform as the ELISA for the antibody testing and was well correlated 
with the gold standard plaque reduction neutralization test.22All testing on serum will be performed 
by the Gingras Lab at Mount Sinai Hospital.    
 
7.2.2              Cellular Immunity Testing 
 
To assess cellular immunity flow cytometry will be performed in peripheral blood 
mononuclear cells (PBMC) in a subset of participants to examine SARS-CoV-2 specific B and T-
cell lymphocyte subsets prior to and following booster dosage of vaccine. Based upon baseline 
serologic levels individuals will be categorized as non-responders (who never attained 
convalescent level of anti-RBD) or those with waning antibody levels. In total approximately 50 
participants at University Health Network and Sunnybrook Health Sciences Centre are anticipated 
to have samples drawn for this sub-study. PBMC will be collected prior to third dose booster, 1 
month, and 6 months following booster dose. ELISpot (enzyme-linked immunospot) assays to 
evaluate SARS-CoV-2 specific cellular immunity will be harmonized with protocols with other CITF 
studies.   
 
7.2.3          Evaluation for COVID-19 Infection 
 
To avoid potential contamination of the study result by participants who develop COVID-
19 during the study period , natural COVID-19 infection will be detected by serologic assessments 
with Anti-NP which has a sensitivity of approximately 79%.  Participants who present with any 
signs or symptoms of COVID-19 will be swabbed with SARS-CoV-2 nasopharyngeal swabs as 
per current screening protocols. Participants who develop COVID-19 infection during the study 
will be excluded from the analysis. 

 
 
 
 
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7.2.4            SARS-CoV-2 Variants of Concern 
Given the emergence of novel SARS-CoV-2 variants of concern, additional neutralization 
assays may be considered to evaluate effectiveness against variants of concern including the 
B.1.1.7, B.1.351, P.1, and B.1.617.2 (Delta) variant. Additionally, if any breakthrough infections 
are reported in patients in this study, whole genome sequencing will be performed in order to 
identify the viral lineage. Table 1 provides summary of study assessments. 
 
 
 
            Table 1: Schedule of Study Assessments for BOOST KIDNEY Protocol 
 
Study Visit 
 
Screenin
g for 
Eligibility 
and 
Informed 
Consent  
 
Baseline 
Study 
Assessm
ent  
 
Adverse 
Event 
Question
naire 
 
Serum SARS-
CoV-2 
Antibodies 
(Spike, RBD, 
NP)  
(5mL SST 
Tube) 
 
SARS-
CoV-2 
Neutra
lizing 
Antibo
dies  
(5mL 
SST 
Tube) 
 
PBMC 
(20mL Na 
Heparin 
blood) 
(n=50) 
 
Vaccine 
Receipt and 
Participant 
Unblinding 
Study 
Enrolment 
 
X 
 
X 
 
 
X 
 
 
 
Prior to 
Booster 
 
 
 
 
 
X 
 
X 
 
Booster 
Vaccine  
Administratio
n 
 
X 
 
 
 
 
 
48 hours -14 
days post-
booster 
 
 
 
X 
 
 
 
 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 43 of 80 
 
 
 
 
 
 
7.3            Specimen Collection, Transportation, Bio-banking 
For serum, blood will be collected in a single SST tube, and allowed to clot for 30 minutes 
and centrifuged for 10 minutes at 3000 x g at room temperature. Aliquots are made in 1 or 2 mL 
-80°C stable cryo-vials each with a volume of 300µL. Testing for three antigens (Anti-NP, Anti-
Spike, and Anti-RBD) and surrogate SARS-CoV-2 pseudo-neutralization assay requires a 
minimum volume of 200µL. Tubes are labelled with the study code, participant ID, date of 
collection, and appropriate time point.  Samples are transferred on dry-ice to the Gingras Lab. A 
paper copy of list of samples sent is emailed using the template for data collection including 
labelled information in addition to vaccine type received and vaccination dates.  Samples will not 
be collected if a participant has active COVID-19 as determined by Infection Control and 
Prevention but may resume when precautions have been discontinued. If a study participant has 
active COVID-19, clinical surplus if available at Sunnybrook may be processed into serum as part 
 
1 month 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
3 months 
 
 
 
 
X 
 
 
 
 
6 months 
 
 
 
 
X 
 
 
X 
 
 
12 months 
 
 
 
 
X 
 
 
 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 44 of 80 
 
of the Sunnybrook COVID-19 Biobank REB2109 and released to this study for serological 
analysis. 
All study procedures will be in compliance with current Public Health guidelines for COVID-
19 including the use of personal protective equipment, masking, and social distancing by all study 
personnel. If a study participant becomes infected with SARS-CoV-2, confirmed by RT-PCR 
during the course of the study, a study sample will not be collected from the participant with active 
COVID-19, but the participant will resume in the study once deemed safe by Public Health and 
their quarantine period is complete.   
All infected patients will be referred for appropriate clinical care. Policies and procedures 
are already in place for in-center dialysis patients at each participating site to manage patients 
who have COVID-19 including ensuring appropriate isolation, droplet/contact precaution 
procedures, and informing Public Health authorities as well as local hospital Infection Prevention 
and Control. Non dialysis patients that become infected will also be referred for appropriate clinical 
follow-up and will be reported to Public Health Authorities per provincial mandates. All 
participating sites are experienced managing infected patients with established services to follow 
remotely and recommend admission when necessary. These services will be involved in each 
case to provide symptom assessment, develop an appropriate monitoring plan with regular 
severity assessments, and treatment plan for the patients. 
 
For PBMC, 20 ml of heparinized blood will be separated into a mononuclear fraction by 
Ficoll-Paque or SepMate tube methodology. Blood samples will be separated into peripheral 
blood mononuclear cells and plasma within four hours of collection. Mononuclear cells will be 
viably frozen and plasma samples will be frozen for future use. Mononuclear cells with be frozen 
in 10% DMSO in alpha-MEM with 50% fetal bovine serum.  Storage concentration is 1-10 x 107 
cells/aliquot. Viable PBMC will be cryopreserved in vapor-phase liquid nitrogen. 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 45 of 80 
 
 
 
7.4          Baseline Data Collection   
The Ontario Renal Reporting System (ORRS) and British Columbia’s PROMISE databases 
will be used to obtain demographic information on all participants enrolled in the study. The 
Ontario Renal Network has already mandated provincial data collection regarding 
symptoms/adverse events related to vaccination and COVID-19 infection confirmed by SARS-
CoV-2 RT-PCR in hemodialysis and peritoneal dialysis patients. Specifically the following 
variables will be collected in all participants: age, sex, prior COVID-19 (NP Swab), vascular 
access, cause of kidney disease, current immunosuppressive medications (defined as taking 
any of the following: antimetabolite agent, calcineurin inhibitor, cytotoxic medications, 
rituximab in prior 6 months, tumor necrosis factor alpha monoclonal antibodies, or 
glucocorticoids greater than prednisone 5 mg daily), autoimmune disease, diabetes mellitus, 
cancer, coronary artery disease, congestive heart failure, chronic obstructive lung disease, 
hypertension, obesity, hepatitis B non-responder status (defined as <10mIU/mL), and ABO 
blood type. In non-dialysis patients serum creatinine and proteinuria will be recorded. 
 
 
 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 46 of 80 
 
 
8              ASSESMENT OF SAFETY 
           The safety of research participants is foremost and should always be considered 
throughout the conduct of research.  
 
8.1         Definitions  
 
8.1.1           Adverse Events 
           An adverse event (AE) means any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment, and includes an adverse drug reaction 
(ADR).An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
 
8.1.2             Serious Adverse Events 
      A serious adverse event (SAE) or reaction is any untoward occurrence that at any dose: 
Results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or in significant disability/incapacity, is a congenital 
abnormality or a birth defect. The term "life-threatening" in the definition of "serious" refers to an 
event in which the participant was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe.  
 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 47 of 80 
 
8.1.3            Unexpected Adverse Event 
          An unexpected adverse event is any AE that is not identified in nature, severity or frequency 
in the current Investigator’s Brochure or Product Monograph. 
 
8.1.4         Unexpected Adverse Drug Reaction (ADR) 
         An ADR is an adverse reaction, the severity of which is not consistent with the applicable 
Investigator’s Brochure or Product Monograph.   All noxious and unintended responses to a 
medicinal product related to any dose should be considered an ADR. The phrase "responses to 
a medicinal product" means that a causal relationship between a medicinal product and an 
adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out.         The 
expression “causal relationship” is meant to convey that in general there are facts, evidence or 
arguments to suggest a reasonable causal relationship.  All serious and unexpected ADRs will 
have expedited reporting to regulatory agencies following ICH-GCP and local regulatory 
requirements. 
8.2            Assessment of an Adverse Event 
8.2.1       Relationship (Causality/Relatedness) 
         The causality assessment is the determination, according to the investigator’s clinical 
judgment, of the existence of a reasonable possibility that the study drug (IP) caused or 
contributed to an adverse event. If the investigator or delegated sub-investigator is unsure about 
whether or not the study drug caused or is related to the event, then the event will be handled as 
“related” to the study drug for reporting purposes of the trial.  If the causality assessment is 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 48 of 80 
 
"unknown but not related” to the study drug, this should be clearly documented in the source 
documents.  
 
         8.2.2         Expectedness 
              Events are classified as unforeseen or unexpected if the nature, severity or frequency is 
not consistent with the risk information set out in the Product Monograph (PM) or label.     
 
          8.2.3        Seriousness 
            Events are classified as serious if associated with effects threatening the life or 
physiological functions of a participant. 
 
          8.2.4          Severity  
           The term "severe" is often used to describe the intensity (severity) of a specific event (e.g. 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively 
minor medical significance (such as severe headache). This is not the same as "serious," which 
is based on participant/event outcome or action criteria usually associated with events that pose 
a threat to a participant's life or functioning. The terms “serious” and “severe” are not synonymous.  
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 49 of 80 
 
8.3            Adverse Event Recording 
        Investigations into potential adverse events should be done during each contact with a 
participant.  Investigations may be done through specific questioning and, as appropriate, by 
examination.  Information on all adverse events should be recorded promptly in the source 
document, and assessed by an investigator in a timely manner allowing sufficient time to meet 
required reporting timelines for SAEs and SUADRs if needed.  Adverse event CRFs should be 
completed using source documents by a delegated research team member in a timely 
manner/within 15 days of site awareness.  All clearly related signs, symptoms, and abnormal 
diagnostic procedures should be recorded in the source document, though should be grouped 
under one diagnosis.  
            The following are not considered AEs and therefore do not require recording: Pre-existing 
diseases or conditions identified and recorded at screening/baseline unless, at the discretion of 
the investigator, the disease or condition worsens in severity or frequency, at the discretion of the 
investigator; events considered likely manifestations of the underlying disease or that commonly 
occur in the study population independent of IP exposure, and elective medical or surgical 
procedures.   
8.4            Reporting of SAEs and Unanticipated Events 
8.4.1           Investigator reporting: Notifying the REB: 
        Serious adverse events and unanticipated events should be recorded and reported to the 
REB in accordance with local reporting requirements and timelines.   
 8.4.2         Investigator reporting: Notifying the Sponsor 
            The investigator is responsible for reporting serious adverse events and serious and 
unexpected adverse drug reactions (SUADRs) to the sponsor in accordance with applicable 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 50 of 80 
 
regulations and reporting requirements and timelines. Events that are assessed to be serious and 
unexpected and related or cannot be ruled out as related to the investigational product are 
considered SUADRs.  Reporting for SUADRs should include a description of the event in sufficient 
detail to allow for a complete medical assessment of the case and independent determination of 
possible causality.  The minimum information required includes at least one identifiable 
participant, one identifiable reporter, one serious reaction, and one suspect product.  
            Additionally, a Suspect Adverse Reaction Report – CIOMS I Form (see appendix B) must 
be completed by the investigator and forwarded to the Sponsor within 24 hours of site awareness.  
Information on other possible causes of the event, such as concomitant medications and illnesses 
should also be provided as soon as is made available. 
 
8.4.3          Sponsor Reporting of SUADRs: Notifying Health Canada 
         The regulatory sponsor is responsible for reporting SUADRs to regulatory authorities in 
accordance with local expedited reporting requirements and timelines.  In addition, the Sponsor 
will complete the ADR Expedited Reporting Summary Form and submit this form in conjunction 
with the completed CIOMS Form to the appropriate Health Canada directorate.   
  
8.4.4           Sponsor Reporting of SUADRs: Notifying Sites 
         The regulatory sponsor is responsible for distributing blinded expedited reports of SUADRs 
to each investigator for submission to local Ethics Committees within 15 days of sponsor 
awareness. 
 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 51 of 80 
 
8.4.5           Events of Special Interest  
      Events of Special Interest in relation to COVID-19 are derived from the Public Health 
Ontario Report of Adverse Event Following Immunization (AEFI): Vaccine-associated enhanced 
disease, acute respiratory distress syndrome, acute cardiovascular injury, coagulation disorder, 
acute kidney injury, acute liver injury, anosmia and / or ageusia, chilblain-like lesions, single 
organ cutaneous vasculitis, erythema multiforme. 
 
8.5             Type and Duration of Follow-up for Adverse Events  
            AEs occurring as of the first administered dose of the investigational product and 30-days 
after the last administered dose, will be collected.  AEs recorded during this period will be followed 
through to resolution, or until the event is assessed as chronic or stable. 
 
8.6             Reporting and Entry Timelines 
          Study investigators will report SAEs to the sponsor within the following timelines:  All deaths 
and immediately life-threatening events, whether related or unrelated, will be recorded and reported to 
the sponsor within 24 hours of site awareness. Serious adverse events other than death and 
immediately life-threatening events, regardless of relationship, will be reported to the sponsor 
within 72 hours of site awareness. Adverse event information will be entered into the CRF in a 
timely manner and no later than 15 days from the time the investigator becomes aware of the 
event. Serious adverse event information will be entered into the CRF in a timely manner/within 
72 hours from the time the investigator becomes aware of the event. 
 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 52 of 80 
 
8.7            Evaluation of Adverse Events and Safety Questionnaires 
Local and systemic AE will be evaluated within 48 hours to 14 days and 1 month post third 
dose. Local adverse events include pain at the injection site, redness, and swelling. Systemic 
adverse events include fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened 
muscle pain, and new or worsened joint pain. Serious adverse events (SAE) will be recorded and 
investigated and questions will be adapted from the report of Adverse Event Following 
Immunization (AEFI) from Public Health Ontario, including local reactions at the injection site, 
symptoms (fever, chills, fatigue, nausea/vomiting, diarrhea, muscle pain, joint pains and other 
adverse events). Participants will be advised that acetaminophen may reduce vaccine side-effects 
but will not actively be counselled to medicate, but usage will be recorded. Due to kidney disease, 
anti-inflammatory medication will be discouraged. A recent study of heterologous prime-boost 
found increased adverse events with heterologous vaccination but no hospitalizations were 
recorded, and most adverse events occurred within 48 hours of vaccination.20 
 
      In Ontario, all chronic dialysis patients are currently being tracked for serious adverse events 
using the COVID-19 vaccine tracker although this had not detected any serious adverse events 
to date. This customized Excel spreadsheet is pre-populated by the Ontario Renal Network (ORN) 
and completed by renal programs monthly (submitted securely via Tumbleweed systems). 
Adverse events related to vaccination are also tracked in PROMIS (BC) which has detailed clinical 
records on their patients. Coordinators will conduct a questionnaire to inquire about local and 
systemic symptoms related to the vaccine. Other rare adverse events will be captured using 
detailed descriptions. Questionnaires will be conducted 48 hours -14 days, and 1 month after the 
booster vaccination dose. Individuals participating in the pilot study have had side effects after 
the first two doses of vaccine recorded. SAEs are defined using the Health Canada definition as 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 53 of 80 
 
those resulting in hospitalization admission or prolongation of existing hospitalization, resulting in 
persistent or significant disability or incapacity, is life-threatening, or resulting in death and 
definitely or probably associated with vaccination in the opinion of their nephrologist. The 
provincial data collection includes reasons for vaccine hesitancy or refusal which could inform 
education for specific groups. In addition, renal programs in Ontario are currently tracking all 
infections, including the 3 reported variants (B117, B1351, P1, and others). 
 
 
8.8           Data Safety Monitoring Committee (DSMB) 
The data safety monitoring committee will include Nephrologists, an infectious disease 
specialist, Public Health Specialist, and experts in clinical trials. The DSMC will review summary 
data and adverse events several times early in the trial and subsequently will meet at 
approximately 6 months and 12 months following the third dose.  The purpose of the DSMC will 
be to review safety concerns and review external data that may have bearing on the design of or 
decision to continue the trial.  
 
 
8.9           General Trial Conduct Considerations 
 
8.9.1            Protocol Deviation 
We will allow a 7 day window for collection of blood samples for the primary outcome at 1 
month. During the later blood collection period, we will allow a 15 day window for collection of 
blood samples or the blood collection will be deferred until the next scheduled time point. It is the 
responsibility of the investigator to ensure that only investigative procedures, as outlined in this 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 54 of 80 
 
protocol are performed on study participants; the occurrence of deviations from the protocol or 
SOPs are limited; and compliance with the regulations is maintained.  Planned deviations from 
the protocol must not be implemented without prior agreement from the sponsor and approval 
from the local REB/ethics committee (EC), as required, unless to eliminate an immediate hazard 
to a participant. Planned or unplanned deviations may occur on the part of the participant, the 
investigator, or study research team. In resolution to a deviation, corrective/preventative actions 
are to be developed and implemented in a timely manner. Protocol deviations will be documented 
and reported as required and assessed where necessary during analysis. 
 
 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 55 of 80 
 
9                SITE MONITORING, AUDITING AND INSPECTING 
 
9.1            Site Monitoring Plan 
 
       Site monitoring is conducted to ensure the safety of human study participants and the 
protection of their rights and well-being.  Monitoring also verifies that collected study data is 
accurate, complete and verifiable by source documentation and that the study is conducted in 
accordance with the protocol and operating procedures. 
       Monitoring for this study is the responsibility of the sponsor.  The delegated monitor will 
evaluate study processes and documentation based on the approved protocol/amendment(s), 
Part C, Division 5 of the Food and Drug Regulations, the International  Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (ICH), E6: Good Clinical Practice 
guidelines (GCP) and institutional policies. 
       The extent and nature of monitoring is outlined in the Monitoring Plan. The monitoring plan 
specifies the frequency of monitoring, monitoring procedures, the level of site monitoring activities 
(e.g., the percentage of participant data to be reviewed), and the distribution of monitoring reports.  
Monitoring activities will be performed both in person and remotely.  Reports of findings identified 
during monitoring activities will be provided to sites detailing any required actions.  Documentation 
of monitoring activities and findings will be provided to the site study team and the study QI. The 
institution and/or local REB reserves the right to conduct independent audits as necessary. 
       The Investigator is responsible for ensuring monitors and/or quality assurance reviewers are 
given access to all study-related documents noted above and study related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.), and have adequate space to conduct the monitoring visit 
or audit. 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 56 of 80 
 
 
9.2            Auditing and Inspecting 
       The investigator will provide direct access to source data/documents for the purposes of 
study-related monitoring, audits, and inspections by the REB, the sponsor, and applicable 
regulatory bodies.  The investigator will permit the review of all study related documents (e.g. 
source documents, regulatory documents, data collection instruments, study data etc.) and will 
ensure access to applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 57 of 80 
 
10           STATISTICAL CONSIDERATIONS 
 
10.1         Study Hypotheses 
Based on evidence from the transplant population, we hypothesize that patients who did 
not initially attain an initial robust immune response to two dose COVID-19 vaccination, a 
substantial proportion may attain improved humoral and cellular immunity against COVID-19 
following a third vaccine booster with acceptable tolerability. We hypothesize that heterologous 
vaccination (e.g. a different vaccine from the first two doses) for the third dose may result in 
increased serologic response. 
 
10.2         Sample Size Considerations 
Approximately 500 patients with chronic kidney disease are presently enrolled in the study 
entitled “Determining the Safety and Efficacy of COVID-19 Vaccination in the Chronic Kidney 
Disease Population”, but this number is rapidly increasing. We have limited information to guide 
our sample size, but in the case series published in transplant patients 25% of patient who were 
seronegative responded to a booster vaccine, while 100% of those with “low positive” antibody 
levels responded to a booster vaccine. Similarly in a study from France the prevalence of positive 
SARS-CoV-2 antibodies increased 28% after the third dose. 
        Our sample size is based on serologic response for Anti-RBD as this measure may be a 
better correlate with neutralizing antibodies than Anti-Spike.22,23 In our pilot study we found that 
60% of patients had attained convalescent serum levels of Anti-RBD by two weeks after post-
second dose and therefore we expect no issues with finding eligible participants. For our sample 
size calculation, to achieve 80% power to detect 25% difference in individuals reaching 
convalescent serum levels of Anti-RBD receiving a COVID-19 from mRNA-1273 versus 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 58 of 80 
 
BTN162b2 at a two sided alpha of 0.05 assuming 25% response in the BNT162b2 group based 
on the limited studies to date, we would require 58 participants in each study group. The 25% 
difference was determined by consensus by the Principal Investigators to represent a clinically 
important difference. Given the stratification by baseline vaccination received, there will be four 
study groups, requiring a sample size of 232 participants as shown in Table 2. A Bonferroni 
adjustment for the alpha will not be used. A similar sample size calculation is obtained if the 
nested (two) chi-squared tests for the primary outcome of this study are considered the equivalent 
of a logistic regression equation with the baseline initial vaccine received as the two covariates. 
Assuming approximately 25% response to a booster dose, and the general rule that 10 outcome 
events are required per covariate, and 10% drop out during the one month period of the primary 
outcome, a total sample size of 89 would be required. Capacity to enroll is higher, therefore the 
target sample size will be 300 participants to avoid under-powering the study, and will account for 
up to 10% participant loss to follow-up due to death or new COVID-19 infection during the 1 month 
follow-up period for the primary outcome.  
 
 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 59 of 80 
 
Table 2: Potential sample size calculations based upon differences in Anti-RBD response 
observed between BNT162b2 and mRNA-1273 vaccines at a Power (1-β) of 80% and ∞ 0.05 
 
Clinically 
Significant 
Difference 
BNT162b2 
Responsea 
mRNA-1273 
Responsea 
Power 
(1-β) 
Alpha 
(∞) 
Required 
Sample Size 
Per Group 
Required Total Sample 
Size (4 Groups) 
30% 
25% 
55% 
80% 
0.05 
41 
164 
30% 
50% 
80% 
80% 
0.05 
39 
156 
30% 
65% 
95% 
80% 
0.05 
27 
108 
25% 
25% 
50% 
80% 
0.05 
58 
232 
25% 
50% 
75% 
80% 
0.05 
58 
232 
25% 
65% 
90% 
80% 
0.05 
43 
172 
20% 
25% 
45% 
80% 
0.05 
82 
328 
20% 
50% 
70% 
80% 
0.05 
93 
372 
20% 
65% 
85% 
80% 
0.05 
73 
292 
15% 
25% 
40% 
80% 
0.05 
152 
608 
15% 
50% 
65% 
80% 
0.05 
170 
680 
15% 
65% 
80% 
80% 
0.05 
138 
552 
aDefined as reaching median convalescent serum levels of anti-RBD.  
 
10.3               Planned Analyses 
The primary outcome will be evaluated at 30 days (1 month ) following the study intervention. 
Subsequent analyzes will be planned at other time points in the study (3 months, 6 months, and 
12 months) following study intervention. 
 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 60 of 80 
 
10.3.1              Safety Review 
Adverse event questionnaires completed following the study intervention will be reviewed 
continuously with planned safety reviews at 30 days by the Data Safety Monitoring Board. 
 
 
10.4                Stopping Rules 
       This study will be stopped prior to its completion if: (1) the intervention is associated with 
adverse events that call into question the safety of the intervention; (2) difficulty in study 
recruitment or retention will significantly impact the ability to evaluate the study endpoints; (3) any 
new information becomes available during the trial that necessitates stopping the trial; or (4) other 
situations occur that might warrant stopping the trial. 
 
10.5                Final Analysis Plan  
        The final analysis plan will be developed by the biostatistician in conjunction with the 
Principal Investigator. The targeted sample size for this study will be 300 due to feasibility, 
although a lower number are estimated to be required based upon sample size calculations 
above, and the final sample size may be adjusted by the Principal Investigator dependent upon 
study recruitment. If the final sample size is adjusted, a Clinical Trial Amendment will be filed. The 
proportion of patients receiving BNT162b2 and mRNA-1273 will be reported.  
 
         Quantitative Anti-SARS-CoV-2 IgG targeting the spike protein, RBD, nucleocapsid, and 
neutralizing antibodies will be reported at each time point as relative levels. Descriptive statistics 
will be used to describe baseline characteristics of patients in all four arms of the study. Mean 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 61 of 80 
 
and median timing between first, second, and third (booster) vaccine dosage will be reported.  
Differences in the cell-mediated immunity as measured through flow cytometry on PBMC will be 
exploratory. Pre-specified clinical outcomes will include COVID-19 infections, COVID-19 related 
hospitalizations, and death.  
 
10.5.1           Statistical Analysis of the Primary Outcome 
 An intention-to-treat analysis will be followed for the primary outcome. The primary 
outcome will be the proportion of patients who attain convalescent serum levels of Anti-RBD at 1 
month (30 days) following third dose of vaccine.  Two Chi-Squared test or Fisher’s exact test will 
be used, one for those who received first two doses of BNT162b2 and the second for those who 
received mRNA-1273 for the first two doses. This study is powered to determine differences 
between the use of mRNA-1273 vaccine and BNT16b2 vaccine as the booster dose on the 
primary outcome based on a clinically significant difference of 25% as described above in the 
sample size considerations. An adjusted analysis with logistic regression modelling will be 
performed if imbalance in baseline characteristics is found to between study groups following 
stratified randomization. Individuals who develop new COVID-19 infection as determined by a 
positive Anti-NP serologic test or positive SARS-CoV-2 RT-PCR nasopharyngeal swab during the 
study will be excluded from analysis of the primary outcome.  
  
10.5.2                Statistical Analysis of Secondary Outcomes  
 Secondary outcomes will include the proportion of patients who attain Anti-Spike median 
convalescent serum at 1 month (30 days) following third dose of vaccine. Differences in relative 
antibody levels (Anti-Spike and Anti-RBD) and neutralizing antibodies between study groups will 
be assessed through the Mann-Whitney test. The relative levels of antibodies will be tracked 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 62 of 80 
 
longitudinally for each patient permitting analysis of SARS-CoV-2 antibody kinetics following 
vaccination and will be assessed through a mixed-effects repeated measures model with random 
intercepts and fixed covariates following log transformation of relative ratios, which will be 
exploratory. Differences in serial levels in relative antibody levels will be compared through a 
mixed effects model as above. Similar to the primary outcome, those with a new positive Anti-NP 
serologic test or COVID-19 nasopharygneal swab during the study will be excluded from analysis. 
An intention to treat analysis will be followed, although an exploratory per protocol analysis may 
also be reported. 
 
10.5.3               Subgroup Analyses 
Pre-specified subgroup analyses will be exploratory and are not included in the sample 
size calculation and are as follows: 
1. Hemodialysis versus peritoneal dialysis patients. 
2. Non-dialysis CKD patients. 
3. Participants who do not seroconvert following two doses of vaccine. 
4. Patients who initially obtain convalescent serum levels but exhibit declining titers. 
5. Patients who never attained convalescent serum levels. 
 
11             Data Handling and Record Keeping 
 
11.1             Confidentiality  
        Information about study participants will be kept confidential and managed according to the 
requirements of the Personal Health Information Protection Act of 2004 (PHIPA) and the 
Research Ethics Board.  PHIPA outlines the rules for the collection, use and disclosure of personal 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 63 of 80 
 
health information.  The Act requires each participant to consent to the collection, use and access 
of personal health information (PHI), unless consent is waived by the REB.  Where consent is 
required, each participant must be informed of the following:  
 What PHI will be collected during this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research participant to revoke their authorization for use of their PHI.  
In the event that a participant revokes authorization to collect or use PHI, the investigator may 
use all information collected prior to the revocation of participant authorization.  For participants 
that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the participant is alive) at the end of their 
scheduled study period. The study staff may communicate with participants via E-mail. No PHI 
(Personal Health Information will be communicated via E-mail. E-mail transmission cannot be 
guaranteed to be secure or error-free as information could be intercepted, corrupted, lost, 
destroyed, or incomplete. To the best of our abilities, the research team will take the necessary 
precautions to transmit emails in a secure manner, by using a secure network. To ensure 
participant confidentiality and safety, all transmitted emails will include the following disclaimer: 
This email and any attachments are confidential and may contain privileged or confidential 
information. If you are not the intended recipient, any transmission, distribution, replicating, or 
disclosure by you is prohibited and may be illegal and you must not use or rely on this email for 
any purpose. 

 
 
 
 
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Protocol Version 5.0 date 5 Nov 2021                                                                                           Page 64 of 80 
 
11.2              Source Documents 
           Source data/documents are original documents, data and records in a clinical study that 
are necessary for the reconstruction and evaluation of the study.  Examples of these original 
documents and data records include, but are not limited to worksheets, hospital records, medical 
records, memorandum, participants’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments (i.e. ECGs), copies or transcriptions certified 
after verification as being accurate and complete, participant files and records kept at the 
pharmacy, entries entered directly into the printed CRF. 
The following data points will be recorded directly on the CRFs, and will be considered source 
data as no prior written or electronic record of data is available: SARS-CoV-2 Antibody Levels, 
neutralizing antibodies, adverse event questionnaires. 
        Each participating site will maintain appropriate medical and research records for this study, 
in addition to regulatory and institutional requirements for the protection of confidentiality of 
participants.  If electronic source data documents are printed it should be signed and dated by 
the investigator to confirm content and filed with other source documents.  
        The investigator(s) and research team members listed on the Task Delegation Log (TDL) 
will have access to participant medical records and will collect only the information needed for the 
study.  Sponsor delegated monitors, representatives of institutional committees and regulatory 
authority representatives of the country in which the study is being conducted will also have 
access to examine records for the purposes of quality assurance reviews, audits and evaluation 
of study safety and progress. 
 
11.3              Data Management Responsibilities 
 

 
 
 
 
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         Data collection and accurate documentation are the responsibility of the study personnel 
under the supervision of the investigator.  All source documents and applicable laboratory reports 
should be reviewed as needed and used to ensure that data collected for the purposes of the 
study are accurate and complete.  Contemporaneous review of laboratory results and the 
assessment of clinical significance for those results considered out of range should be 
documented by means of dated signature by the reviewing investigator. Study personnel, 
including data entry team members, should use source documents to complete case report forms 
(CRFs).  
         As part of the safety plan for this study, the investigator will review individual study 
participant records to ensure that appropriate mechanisms to protect the safety of study 
participants are being followed, that protocol requirements are being adhered to, and that data is 
accurate, complete, and secure. Participant records include, but are not limited to: consent forms, 
case report forms, data forms, laboratory specimen records, inclusion/exclusion forms, and 
medical charts. All study data will be collected by a member of the study research team and 
recorded in accordance with applicable procedures. 
         Data in the (COVID-19 Immunity Task Force ) CITF Database may be used by researchers 
in Canada or in other countries following Data Access Committee (DAC) approval. These 
transfers will also be made in compliance with Canadian law and research ethics. A DAC will be 
responsible for reviewing applications for access to data and for approving applications that 
respect the privacy and access policies of the CITF. The data will be used to perform research 
concerning COVID-19 and related health outcomes. Data may be used alone or in combination 
with other data, including other health data. The DAC will ask researchers to confirm that their 
intended research activities have received necessary ethics approvals. Data may also be shared 

 
 
 
 
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with other COVID-19 research databases that follow similar protections and procedures as the 
CITF Database.  
  
  
         Participation in the CITF Database is not likely to provide a direct benefit to participants’ 
health or well-being. Participation in the CITF will help collect accurate data about COVID-19 
immunization that will potentially help in the creation of treatments or otherwise improve the 
quality of COVID-19 healthcare delivery.  No directly identifying information will be provided to the 
CITF, nor included in the CITF Database. Participants’ identifiers, such as name and civic 
address, will be replaced with a code. By agreeing to participate in this research, patients do not 
give up any legal rights against the CITF. 
 
11.4                    Data Capture 
11.4.1           Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  
Electronic/Paper case report forms (eCRFs/pCRFs) will be used to collect data for this study. 
CRFs are to be completed by data capture personnel and signed off by the investigator in a timely 
manner.  Good documentation practices should be implemented according to standard operating 
procedures.  All data requested on the CRF must be recorded and verifiable by source document.   
 

 
 
 
 
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11.5            Records Retention 
         It is the responsibility of the REB, investigator and regulatory sponsor to retain study 
essential documents as per local regulatory requirements and GCP Guidelines. Study essential 
documents must be maintained in a secure and confidential manner for participating Canadian 
sites for a period of 25 years.  For the purposes of this study, the start date of the retention period 
is the date of the final report of the trial.  Exceptions may be made for sites which close 
prematurely, wherein the start date for the retention period will be the date of notification to Health 
Canada of the sites closure. Sites conducting this study outside of Canada must maintain study 
records for the required retention period as stipulated by local regulatory authorities. All study 
records are then to be destroyed according to local and national policy and requirements. It is the 
investigator’s responsibility to request authorization for destruction at the completion of the 
retention period and/or for the sponsor to inform the investigator/institution when these documents 
may be destroyed.  
 
11.6             Clinical Trial Registration 
         In accordance with Health Canada’s Notice “Registration and Disclosure of Clinical Trial 
Information, November 30, 2007”, the sponsor will be responsible for registering the study on 
Clinicaltrials.gov (www.clinicaltrials.gov), a publically available registry that conforms to 
international standards for registries. 
 
 

 
 
 
 
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12               QUALITY CONTROL AND QUALITY ASSURANCE 
        As per ICH-GCP and local regulations, the sponsor is responsible for ensuring the 
implementation and maintenance of systems that support quality assurance and quality 
control. The study must be conducted in compliance with the study protocol and all data collected 
must be accurate and verifiable by source document(s). For the purpose of monitoring and 
auditing by the Sponsor, and inspection by regulatory authorities, the site will provide direct 
access to all study related source data/documents. The sponsor will verify that the study is 
conducted and data has been collected, documented (recorded), and reported in compliance with 
the protocol, GCP, and applicable regulatory requirements.  
         Data for the study will be centrally stored and managed by the Centre for Clinical Trial 
Support (CCTS). To ensure the quality of study data, quality assurance and control systems will 
be implemented using validated electronic quality control checks within the electronic data capture 
system.  These verification measures will identify missing data, inconsistencies and/or data 
anomalies.  Both electronic and manual queries will be generated for resolution and review by 
sites. Access to secure and validated electronic systems used for the purposes of this study will 
be controlled by the sponsor.  Access will only be granted to individual research team members 
upon review of training and qualification and authorization by delegation of the investigator.   
        Quality assurance and control measures will be implemented to ensure training for specific 
trial–related tasks beyond the usual scope of practice.  Only administration of the booster vaccine 
is considered potentially a study specific procedures requiring additional training, and will be 
reviewed for documentation of training and/or qualification.  
 

 
 
 
 
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12.1               Steering Committee 
The steering committee (SC) will include: Dr. Hladunewich, Dr. Yau, Dr. Levin, Dr. Leis, 
Dr. Bolotin, Dr. Perl and Dr. Chan. The SC will meet once monthly to discuss and emerging 
scientific or logistical issues related to the conduct of the study. 
 
 
 
 
 

 
 
 
 
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13                    ETHICS CONSIDERATIONS 
 
13.1               Ethical Standard 
         The investigator will ensure that this study is conducted in accordance with the principles 
set forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Participants of Research, and codified in the Tri-Council Policy Statement and/or the ICH E6. The 
Principal Investigator will be responsible for ensuring that this trial will be conducted in accordance 
with the protocol, the applicable regulations and guidelines for Good Clinical Practice (GCP), 
Health Canada’s regulations, the Tri-Council Policy Statement: Ethical Conduct for Research 
Involving Humans (TCPS 2.0) and the principles in the Declaration of Helsinki.   
13.2              Research Ethics Board (REB)  
         The protocol, informed consent form(s), recruitment materials, and all participant materials 
will be submitted to the REB for review and approval.  Approval of both the protocol and the 
consent form must be obtained before any participant is enrolled.  Any amendment to the protocol 
will require review and approval by the REB before the changes are implemented in the study, 
unless to eliminate an immediate hazard  
13.3               Consent  
          Informed consent is a process that is initiated prior to the individual agreeing to participate 
in the study and continues throughout study participation. Informed consent will be obtained from 
in-centre hemodialysis patients to participate in this study while they are attending maintenance 
hemodialysis or via telephone. CKD and home dialysis patients will be consented during clinic 
appointments or via telephone. A consent form describing in detail the study procedures and risks 

 
 
 
 
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will be reviewed with and given to each participant.  Consent forms will be REB-approved, and 
the participant is required to read and review the document or have the document read to him or 
her.  The investigator or designee will explain the research study to the participant and answer 
any questions that may arise.  The informed consent process could be over the phone or initially 
verbally obtained, then when the participants present for their first study related visit, they will sign 
the informed consent form (ICF). Participants will be given the opportunity to discuss the study 
with their surrogates or think about it prior to agreeing to participate.  They may withdraw consent 
at any time throughout the course of the study.  A copy of the signed informed consent document 
will be given to participants for their records.   
          Prior to involvement in any study-related activities, consent must be obtained in writing for 
each participant using the current REB approved informed consent from.  It is the responsibility 
of the investigator to ensure that all advertisements and written information, including the informed 
consent form, disseminated to participants has been approved by the local REB prior to use. The 
ethics approved Informed Consent Form (ICF) and any other written information, must be 
provided to each participant, allowing ample time to ask and have answered any questions prior 
to making a decision regarding participation.  Neither the investigator nor study staff should unduly 
influence or coerce a participant to participate in the study.   
          The ICF will be signed and dated by the participant and individual obtaining consent.  The 
consent process will be documented in the clinical or research record.  The original ICF, in its 
entirety, will be maintained by the site, and a complete copy of the signed ICF provided 
to the participant.  The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their clinical care will not be adversely affected if 
they decline to participate in this study. The provision of consent is an ongoing process 

 
 
 
 
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and should be maintained throughout the duration of the study.   Participants may 
withdraw consent at any time throughout the course of the study. Patients may request 
access to their study results from their primary nephrologist or the study coordinator. Results will 
not appear on their electronic medical record. Risks and benefits to participations in the study are 
outlined below.  
13.3.1                 Benefits 
 
Benefits to participants include the potential for increased immunity following a booster 
dose of vaccine. Results from this study will provide evidence to help determine whether a booster 
vaccination may be beneficial in this patient population, if a specific vaccine is more beneficial for 
boosting, and may inform policy change at the provincial and/or national level for patients with 
chronic kidney disease.  
 
 
13.3.2                  Risks 
 
All potential risks will be explained to the participants. The greatest risks to this study 
include the possibility for increased reactogenicity or adverse effects following a booster dose of 
vaccine that may make the patient feel unwell. Larger studies on safety of a third dose are not 
widely available, but early studies in solid organ transplant patient have demonstrated acceptable 
tolerability and generally low incidence of severe adverse effects, therefore we expect that this 
risk will be present but not high. The risk of phlebotomy is low as the blood volume obtained from 
patients is minimal, and does not require additional blood draws from hemodialysis patients as 
these blood samples will be collected during routine hemodialysis care through pre-existing 
vascular access. Peritoneal dialysis and CKD patients have a small risk of bruising due to blood 
draws.  
 

 
 
 
 
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14           PUBLICATION/DATA SHARING POLICY 
Given the urgency for timely knowledge dissemination, findings of study will be rapidly 
submitted for peer reviewed publication. Authorship on study publications will adhere to the 
Uniform Requirements for Manuscripts Submitted to Biomedical Journals of the International 
Committee of Medical Journal Editors. These requirements state “Authorship credit should be 
based on: 
 1) Substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data;  
2) Drafting the article or revising it critically for important intellectual content; and  
3) Final approval of the version to be published. 
 
 

 
 
 
 
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15               CONFLICT OF INTEREST 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial. The Oreopoulos/Baxter Home Dialysis Grant is an unrestricted research grant from 
the Division of Nephrology, University of Toronto and Baxter has no role in the design or conduct 
of the study. 
 
 

 
 
 
 
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16           LITERATURE REFERENCES  
1.  
Daily Epidemiological Summary - COVID-19 in Ontario: January 15, 2020 to July 4, 2021. 
Public Health Ontario. Accessed July 4, 2021. https://files.ontario.ca/moh-covid-19-report-
en-2021-07-05.pdf 
2.  
Ontario Renal Network COVID-19 Weekly Report - Renal Patients in Ontario as of July 1, 
2021. 
3.  
Yau K, Muller MP, Lin M, et al. COVID-19 Outbreak in an Urban Hemodialysis Unit. Am J 
Kidney Dis. 2020;76(5):690-695.e1. doi:10.1053/j.ajkd.2020.07.001 
4.  
Taji L, Doneal T, Oliver MJ, et al. SARS-CoV-2 Infection and COVID-19 Disease in Patients 
Treated with Chronic Dialysis in Ontario, Canada: A Prospective Analysis of Risk Factors 
and Outcomes. Cmaj. 2021;In Press. 
5.  
Chen C-Y, Shao S-C, Chen Y-T, et al. Incidence and Clinical Impacts of COVID-19 
Infection in Patients with Hemodialysis: Systematic Review and Meta-Analysis of 396,062 
Hemodialysis Patients. Healthc . 2021;9(1). doi:10.3390/healthcare9010047 
6.  
Jager KJ, Kramer A, Chesnaye NC, et al. Results from the ERA-EDTA Registry indicate a 
high mortality due to COVID-19 in dialysis patients and kidney transplant recipients across 
Europe. Kidney Int. 2020;98(6):1540-1548. doi:10.1016/j.kint.2020.09.006 
7.  
Buti M, Viladomiu L, Jardi R, et al. Long-Term Immunogenicity and Efficacy of Hepatitis B 
Vaccine 
in 
Hemodialysis 
Patients. 
Am 
J 
Nephrol. 
1992;12(3):144-147. 
doi:10.1159/000168436 
8.  
Krueger KM, Ison MG, Ghossein C. Practical Guide to Vaccination in All Stages of CKD, 
Including Patients Treated by Dialysis or Kidney Transplantation. Am J Kidney Dis. 
2020;75(3):417-425. doi:10.1053/j.ajkd.2019.06.014 
9.  
Eleftheriadis T, Pissas G, Antoniadi G, Liakopoulos V, Stefanidis I. Factors affecting 
effectiveness of vaccination against hepatitis B virus in hemodialysis patients. World J 
Gastroenterol. 2014;20(34):12018-12025. doi:10.3748/wjg.v20.i34.12018 
10.  
Labriola L, Scohy A, Seghers F, et al. A Longitudinal, 3-Month Serologic Assessment of 
SARS-CoV-2 Infections in a Belgian Hemodialysis Facility. Clin J Am Soc Nephrol. 
Published online November 18, 2020:CJN.12490720. doi:10.2215/CJN.12490720 
11.  
Hartley GE, Edwards ESJ, Aui PM, et al. Rapid generation of durable B cell memory to 
SARS-CoV-2 spike and nucleocapsid proteins in COVID-19 and convalescence. Sci 
Immunol. 2020;5(54):eabf8891. doi:10.1126/sciimmunol.abf8891 

 
 
 
 
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12.  
Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-
CoV-2 
Vaccine. 
N 
Engl 
J 
Med. 
Published 
online 
December 
30, 
2020. 
doi:10.1056/NEJMoa2035389 
13.  
Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-
19 Vaccine. N Engl J Med. 2020;383(27):2603-2615.doi:10.1056/NEJMoa2034577 
14.  
Yau K, Abe KT, Naimark D, et al. Evaluation of the SARS-CoV-2 Antibody Response to 
the BNT162b2 Vaccine in Patients Undergoing Dialysis. JAMA Netw Open. 2021;In Press. 
doi:10.1101/2021.05.24.21257425 
15.  
Ducloux D, Colladant M, Chabannes M, Yannaraki M, Courivaud C. Humoral response 
after three doses of BNT162b2 mRNA COVID-19 vaccine in patients on hemodialysis. 
Kidney Int. Published online 2021. doi:https://doi.org/10.1016/j.kint.2021.06.025 
16.  
Werbel WA, Boyarsky BJ, Ou MT, et al. Safety and Immunogenicity of a Third Dose of 
SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case Series. Ann Intern 
Med. Published online June 15, 2021. doi:10.7326/L21-0282 
17.  
Kamar N, Abravanel F, Marion O, Couat C, Izopet J, Del Bello A. Three Doses of an mRNA 
Covid-19 Vaccine in Solid-Organ Transplant Recipients. N Engl J Med. Published online 
June 23, 2021. doi:10.1056/NEJMc2108861 
18.  
Rincon-Arevalo H, Choi M, Stefanski A-L, et al. Impaired humoral immunity to SARS-CoV-
2 BNT162b2 vaccine in kidney transplant recipients and dialysis patients. Sci Immunol. 
2021;6(60):eabj1031. doi:10.1126/sciimmunol.abj1031 
19.  
Liu, Xinxue, Shaw R. Safety and Immunogenicity Report from the Com-COV Study – a 
Single-Blind Randomised Non-Inferiority Trial Comparing Heterologous And Homologous 
Prime-Boost Schedules with An Adenoviral Vectored and mRNA COVID-19 Vaccine. 
Lancet. 2021;Preprint. 
20.  
Shaw RH, Stuart A, Greenland M, Liu X, Van-Tam JSN, Snape MD. Heterologous prime-
boost COVID-19 vaccination: initial reactogenicity data. Lancet. 2021;397(10289):2043-
2046. doi:https://doi.org/10.1016/S0140-6736(21)01115-6 
21.  
Normark J, Vikström L, Gwon Y-D, et al. Heterologous ChAdOx1 nCoV-19 and mRNA-
1273 
Vaccination. 
N 
Engl 
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Published 
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14, 
2021. 
doi:10.1056/NEJMc2110716 
22.  
Abe KT, Li Z, Samson R, et al. A simple protein-based surrogate neutralization assay for 
SARS-CoV-2. JCI Insight. 2020;5(19). doi:10.1172/jci.insight.142362 
23.  
Iyer AS, Jones FK, Nodoushani A, et al. Persistence and decay of human antibody 

 
 
 
 
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responses to the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 
patients. Sci Immunol. 2020;5(52):eabe0367. doi:10.1126/sciimmunol.abe0367 
24.  
Isho B, Abe KT, Zuo M, et al. Persistence of serum and saliva antibody responses to SARS-
CoV-2 spike antigens in COVID-19 patients. Sci Immunol. 2020;5(52):eabe5511. 
doi:10.1126/sciimmunol.abe5511 
 

 
 
 
 
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APPENDICES: 
Appendix A: Schedule of Study Assessments for BOOST KIDNEY Protocol 
 
 
 
 
 
Study Visit 
 
Screenin
g for 
Eligibility 
and 
Informed 
Consent  
 
Baseline 
Study 
Assessm
ent  
 
Adverse 
Event 
Question
naire 
 
Serum SARS-
CoV-2 
Antibodies 
(Spike, RBD, 
NP)  
(5mL SST 
Tube) 
 
SARS-
CoV-2 
Neutra
lizing 
Antibo
dies 
(5mL 
SST 
Tube) 
 
PBMC(20mL 
Na Heparin 
blood) 
(n=50) 
 
Vaccine 
Receipt and 
Participant 
Unblinding 
Study 
Enrolment 
 
X 
 
X 
 
 
X 
 
 
 
Prior to 
Booster 
 
 
 
 
 
X 
 
X 
 
Booster 
Vaccine  
Administratio
n 
 
X 
 
 
 
 
 
48 hours-14 
days post-
booster 
 
 
 
X 
 
 
 
 
 
1 month 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
3 months 
 
 
 
 
X 
 
 
 
 
6 months 
 
 
 
 
X 
 
 
X 
 
 
12 months 
 
 
 
 
X 
 
 
 

 
 
 
 
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Appendix B : CIOMS  FORM