Immunocompromised Swiss Cohorts Based Trial Platform

Study Overview
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Brief Summary
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This study is to set up a flexible trial platform using two existing national cohorts of immunocompromised patients (i.e. Swiss HIV Cohort Study [SHCS] and Swiss Transplant Cohort Study [STCS]) to assess the comparative effectiveness and safety of approved SARS-CoV-2 vaccines in immunocompromised patients. This platform will be tested in the frame of an exploratory pilot trial and a framework will be set up to conduct a larger, flexible, randomized controlled trial (RCT) to test approved SARS-CoV-2 vaccines to prevent SARS-CoV-2 infections. The first sub-protocol for a pilot trial is to investigate the operability of a platform trial that is nested into two existing cohort studies and compare immune response, safety and clinical efficacy of the first two mRNA vaccines (Comirnaty® by Pfizer / BioNTech and COVID-19 mRNA Vaccine Moderna®, by Moderna) in immune compromised patients in the Swiss HIV and Swiss Transplant Cohort studies. The second sub-protocol (observational study) is to collect a blood sample before the third vaccination and 8 weeks after vaccination to analyze an additional benefit of a third SARS-CoV-2 vaccine in these immunocompromised patients. In the third sub-protocol (substudy-3; observational) we will recruit patients who have received m-RNA-1273.214 by Moderna in the frame of clinical routine. We will start a second arm of our observational study as soon as another bivalent mRNA vaccine (from Pfizer-BioNTech) has been approved by Swissmedic. We aim to compare the immunologic response and safety of the bivalent mRNA-1273.214 vaccine from Moderna among immunocompromised persons (persons living with HIV or kidney or lung transplant recipients) to the immunologic response of immunocompromised persons who received the bivalent mRNA vaccine from Pfizer-BioNTech.

Detailed Description
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The aim of this study is to set up a flexible trial platform using two existing national cohorts of immunocompromised patients (i.e. Swiss HIV Cohort Study [SHCS] and Swiss Transplant Cohort Study [STCS]) to assess the comparative effectiveness and safety of approved SARS-CoV-2 vaccines in immunocompromised patients. Nesting this trial into cohorts with highly standardized data collection allows for a rapid, efficient and cost-saving trial conduct. This platform will be tested in the frame of a pilot trial and a framework will be set up to conduct a larger, flexible, randomized controlled trial (RCT) to test approved SARS-CoV-2 vaccines to prevent SARS-CoV-2 infections. The pilot study will primarily assess the functionality of the trial platform and early immunogenicity, efficacy and safety data. At a later stage, the platform might also be used to enlarge the pilot trial or to develop sub-protocols to deal with patients with no or insufficient immune response to Sars-CoV-2 vaccines. Since January 12, 2021 two mRNA vaccines against Sars-CoV-2 by Pfizer / BioNTech (Comirnaty®) and COVID-19 mRNA Vaccine Moderna® by Moderna have been licensed in Switzerland and roll-out of vaccines has started The first sub-protocol for a pilot trial is to investigate the operability of a platform trial that is nested into two existing cohort studies and compare immune response, safety and clinical efficacy of the first two mRNA vaccines (Comirnaty® by Pfizer / BioNTech and COVID-19 mRNA Vaccine Moderna®, by Moderna) in immune compromised patients in the Swiss HIV and Swiss Transplant Cohort studies. In Switzerland, since October 2021 severely immunodeficient persons ≥ 12 years of age who have received two doses of an mRNA vaccine should receive a third dose of Comirnaty® or Spikevax® as part of the basic immunization, regardless of any antibody titer. Among all other immunocompromised patients a booster vaccination with an mRNA vaccine is recommended. These vaccines will be administered to patients from the SHCS and the STCS in the frame of clinical routine. This second sub-protocol (observational study) is to collect a blood sample before the third vaccination and 8 weeks after vaccination to analyze an additional benefit of a third SARS-CoV-2 vaccine in these immunocompromised patients. In the third sub-protocol (substudy-3; observational) we will recruit patients who have received m-RNA-1273.214 by Moderna in the frame of clinical routine. We will start a second arm of our observational study as soon as another bivalent mRNA vaccine (from Pfizer-BioNTech) has been approved by Swissmedic. We aim to compare the immunologic response and safety of the bivalent mRNA-1273.214 vaccine from Moderna (n=160) among immunocompromised persons (persons living with HIV or kidney or lung transplant recipients) to the immunologic response of immunocompromised persons who received the bivalent mRNA vaccine from Pfizer-BioNTech (n=80). Patients will be asked to provide blood sample at baseline (before receiving bivalent mRNA SARS-CoV-2 vaccine) and 4 weeks, 8 weeks, and 6 months after vaccination (see details in original study protocol below).

Official Title
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Randomised Controlled Trials to Assess Approved SARS-CoV-2 Vaccines in Immunocompromised Patients: A Master Protocol for the Set-up of a Swiss Cohorts Based Trial Platform

Conditions
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Immunocompromised Patients

Intervention / Treatment
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* Biological: Moderna COVID-19 Vaccine, mRNA-1273 (100 μg)
* Biological: Pfizer-BioNTech COVID-19 Vaccine BNT162b2 (30 µg)( Comirnaty®)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: All patients registered with informed consent from participating cohorts aged ≥18 years Additional consent for participation in the specific sub-protocol trial Inclusion criteria for pilot trial: All patients with either a chronic HIV infection or recipients of solid organs registered with informed consent from the SHCS and STCS cohorts aged ≥18 years Patients with solid organ transplantation of lungs or kidneys at least one month post-transplantation with a prednisone dose of 20mg or less. Covid-19 vaccination recommended by treating physician Inclusion criteria for 2. sub protocol (observational study): Third covid-19 vaccination recommended by treating physician and administered in the frame of clinical routine Inclusion criteria for 3. substudy. - Patients receiving a new bivalent (Wuhan/Omicron BA.1) mRNA SARS-CoV-2 vaccine in the frame of clinical routine, according to the treating physician Exclusion criteria: Acute symptomatic SARS-CoV-2 infection, influenza or other acute respiratory tract infection Known allergy or contra-indications for vaccines or any vaccine components Any emergency condition requiring immediate hospitalization for any condition Patients with previous PCR documented SARS-CoV-2 infection and, or documented antibodies less than 3 months prior to screening visit (day 0) Exclusion criteria for pilot trial: Pregnancy Acute symptomatic SARS-CoV-2 infection, influenza or other acute respiratory tract infection Known allergy or contra-indications for vaccines or any vaccine components Any emergency condition requiring immediate hospitalization for any condition Patients with previous PCR documented SARS-CoV-2 infection and, or documented antibodies less than 3 months prior to randomisation Patients with solid organ transplantation (lung or kidney) with the following conditions: Solid organ transplant recipients less than one month post-transplantation Solid organ transplant recipients with the use of T-cell/B-cell depleting agents in the last 3 months (i. e induction treatment in standard risk or high-risk immunological situation or rejection treatment). Solid organ transplant recipients with the need of pulse corticosteroids (>100mg prednisone or equivalent) in the last 1 month or who have received ATG or rituximab in the last 6 months Solid organ transplant recipients with the need of any kind of chemotherapy treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Cohort embedded platform with a first sub-study pilot trial of two arms comparing licensed vaccines against SARS-CoV-2. The platform design allows to expand the pilot trial into a larger trial by sub-protocols to add or drop vaccine arms or to add further sub-protocols for re-randomization of patients with no immune response to a vaccine booster or new vaccines A parallel two-arm open-label randomized controlled exploratory pilot trial comparing the first in Switzerland approved SARS-CoV-2 vaccines (based on a trial platform that is integrated into the ongoing routine prospective data collection of two national cohorts, the SHCS and STCS). Within substudy-2 and substudy-3 observational studies were added to the platform trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Moderna mRNA COVID-19 vaccine<br>The Moderna COVID-19 Vaccine, mRNA-1273 (100 μg) is administered intramuscularly as a series of two doses (0.5 mL each), given 28 days apart. ARM CLOSED | Biological: Moderna COVID-19 Vaccine, mRNA-1273 (100 μg)<br>* intramuscular injection, proposed as a series of two doses (0.5 mL each), dosing is 100 microgram on day 0 and day 28<br>|
| Active Comparator: Comirnaty® (Pfizer / BioNTech) mRNA COVID-19 vaccine<br>Active: The comparator product is the first licensed vaccine against SARS-CoV-2 in Switzerland. Pfizer-BioNTech COVID-19 Vaccine, BNT162b2 (30 µg) Comirnaty®, is administered intramuscularly (IM) as a series of two 30 µg doses of the diluted vaccine solution (0.3 mL each) according to the following schedule: a single dose followed by a second dose 21 days later. ARM CLOSED | Biological: Pfizer-BioNTech COVID-19 Vaccine BNT162b2 (30 µg)( Comirnaty®)<br>* intramuscular injection, proposed dosing is 30 microgram of the diluted vaccine solution (0.3 mL each) on day 0 and day 21<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| immunological outcome: change in pan-Ig antibody response (pan-Ig anti-S1-RBD) | A commercial immunoassay Elecsys® Anti-SARS-CoV-2 S for the in vitro quantitative determination of antibodies to the SARS-CoV-2 spike (S) protein receptor binding domain (RBD) in human serum and plasma is used. This assay detects pan-Ig antibody response (pan-Ig anti-S1-RBD) and allows for a quantitative assessment of the serological response of the participants. | at baseline (day of vaccination) and three months after vaccination | 
| immunological outcome: change in anti-Nucleocapsid (N) response | Qualitative measurement of anti-Nucleocapsid (N) responses with Elecsys® Anti-SARS-CoV-2 N assay | at baseline (day of vaccination) and three months after vaccination | 
| immunological outcome: change in SARS-CoV-2-binding antibodies | SARS-CoV-2-binding antibody responses of the participants are assessed by analyzing the IgM, IgA and IgG responses to a wider range of SARS-CoV-2 proteins (S1, S2, RBD and N) using an in-house method (ABCORA). The ABCORA test allows a parallel assessment of IgG, IgM and IgA reactivity. | at baseline (day of vaccination) and three months after vaccination | 
| Number of participants with newly polymerase chain reaction (PCR)-confirmed asymptomatic COVID-19 infection | Number of participants with newly PCR-confirmed asymptomatic COVID-19 infection (identified by the presence of anti-SARS-CoV-2 nucleocapsid antibodies or Sars-Cov-2 PCR or rapid antigen test) and no related symptoms [(i.e. fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose nausea or vomiting, and diarrhea]) | at any time point in within 48 weeks following randomisation (day of vaccination) | 
| Number of participants with newly PCR-confirmed symptomatic COVID-19 infection | Number of participants with newly PCR-confirmed symptomatic COVID-19 infection with at least one of the following symptoms (i.e. fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose nausea or vomiting, and diarrhea | at any time point in within 48 weeks following randomisation (day of vaccination) | 
| Number of participants with severe COVID-19 infection | Number of participants with severe COVID-19 infection with respiratory failure, evidence of shock (as diagnosed by a treating physician), clinically significant acute renal, hepatic, or neurologic dysfunction; admission to an intensive care unit; or death | at any time point in within 48 weeks following randomisation (day of vaccination) | 
| Clinical Outcome: COVID-19 burden of diseases (BOD) | COVID-19 burden of diseases (BOD), a composite, will be scored as by using 0 for no COVID-19, 1 for non-severe COVID-19, and 2 for severe COVID-19. | within 48 weeks following randomisation (day of vaccination) | 
| Duration of RCT set up (specific endpoint related to trial conduct feasibility) | Duration of RCT set up (i.e. time from deciding which interventions will be tested until the first patient is randomised). | one time assessment at baseline (from deciding which interventions will be tested until the first patient is randomised) | 
| Time of patient recruitment from activation of first study site until 40 patients are randomised | Time of patient recruitment from activation of first study site until 40 patients are randomised | one time assessment after approx. 3 months (from activation of first study site until 40 patients are randomised) | 
| Time of patient recruitment from activation of first study site until 380 patients are randomised | Time of patient recruitment from activation of first study site until 380 patients are randomised | one time assessment after approx. 3 months (from activation of first study site until 380 patients are randomised) | 
| Patient consent rate | Patient consent rate (i.e. proportion of patients giving informed consent out of approached eligible patients) | approx. 3 months | 
| Proportion of missing data for all baseline variables from routinely collected cohort data | Proportion of missing data for all baseline variables from routinely collected cohort data | one time assessment at baseline | 
| Proportion of missing data for all clinical outcomes | Proportion of missing data for all clinical outcomes from routinely collected cohort data and outcome data that is collected in the trial platform | one time assessment after approx. 3 months | 
| SARS-CoV-2-specific antibodies | SARS-CoV-2-specific antibodies (using a pan-IgG antibody assay against the receptor binding domain (RBD) against the nP and spike 1 subunits) | three months after vaccination | 
| SARS-CoV-2-specific titers | SARS-CoV-2-specific titers (using an in-house assay developed by the Institute of Medical Virology, University of Zurich which can detect multiple viral epitopes) | three months after vaccination | 
| The proportion of patients with a positive antibody response to SARS-CoV-2 spike (S1) protein receptor binding domain in human serum or plasma assessed in the observational second sub- protocol | The proportion of patients with a positive antibody response to SARS-CoV-2 spike (S1) protein receptor binding domain in human serum or plasma assessed or plasma assessed in the observational second sub- protocol by the commercial immunoassay Elecsys Anti-SARS-CoV-2 S (Elecsys S) from Roche Diagnostics. An antibody response will be considered as positive using the threshold ≥ 100 units/ml, predicting a protective immune response. | 8 weeks (¨+/- 2 weeks) after 3. vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients with a positive antibody response using SARS-CoV-2 spike (S1) Elecsys S by Roche in the observational second sub- protocol, using a threshold of ≥0.8 units/ml as defined by the manufacturer | The proportion of patients with a positive antibody response using SARS-CoV-2 spike (S1) Elecsys S by Roche in the observational second sub- protocol, using a threshold of ≥0.8 units/ml as defined by the manufacturer | 8 weeks (¨+/- 2 weeks) after 3. vaccination | 
| The proportion of patients with a positive antibody response using antibody response using the Antibody CORonavirus Assay (ABCORA) 2 in the observational second sub- protocol | The proportion of patients with a positive antibody response using antibody response using the Antibody CORonavirus Assay (ABCORA) 2 in the observational second sub- protocol that assesses seropositivity by measuring specific IgG, IgA and IgM responses to SARS-CoV-2 receptor binding domains, S1, S2 and N16 | 8 weeks (¨+/- 2 weeks) after 3. vaccination | 
| The proportion of patients with neutralizing neutralization activity against the vaccine strain Wuhan-Hu-1 in the observational second sub- protocol | The proportion of patients with neutralizing neutralization activity against the vaccine strain Wuhan-Hu-1 in sera in the observational second sub- protocol defined as having an ABCORA sum S1 (sum of S1 signal over cut-off values of IgG, IgA, IgM) above the threshold of 17. | 8 weeks (¨+/- 2 weeks) after 3. vaccination | 
| Immune response (pan-Ig antibodies against the receptor binding domain (RBD) in the S1 subunit of the spike protein (pan-Ig anti-S1-RBD) of SARS-CoV-2 in the observational second sub- protocol | Immune response (pan-Ig antibodies against the receptor binding domain (RBD) in the S1 subunit of the spike protein (pan-Ig anti-S1-RBD) of SARS-CoV-2 in the observational second sub- protocol | 8 weeks (¨+/- 2 weeks) after 3. vaccination | 
| Mean immune response of IgM, IgA and IgG to the subunit S1 using ABCORA in the observational second sub- protocol | Mean immune response of IgM, IgA and IgG to the subunit S1 using ABCORA in the observational second sub- protocol | 8 weeks (¨+/- 2 weeks) after 3. vaccination | 
| Number of newly PCR-confirmed asymptomatic SARS-CoV-2 infection in the observational second sub- protocol | Number of newly PCR-confirmed asymptomatic SARS-CoV-2 infection in the observational second sub- protocol | 8 weeks (¨+/- 2 weeks) after 3. vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Covid-19 infection, SARS-CoV-2-specific antibodies, Sars-CoV-2 vaccine, vector based messenger ribonucleic acid (mRNA) vaccines, SARS-CoV-2 infection, Swiss HIV Cohort Study [SHCS], Swiss Transplant Cohort Study [STCS], BNT162b2, mRNA-1273, bivalent SARS-CoV-2 vaccine, mRNA-1273.214