Clinical trial NCT04805125: Immunocompromised Swiss Cohorts Based Trial Platform
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Immunocompromised Patients
Keywords: 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
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
Collaborators: name: Swiss National Science Foundation
name: ModernaTX, Inc.
First posted: 2021-03-18
Enrollment: 610
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: OTHER

Brief summary: 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: 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).

Eligibility criteria: 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:

  1. Solid organ transplant recipients less than one month post-transplantation
  2. 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).
  3. 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
  4. Solid organ transplant recipients with the need of any kind of chemotherapy treatment

Primary outcomes:
measure: immunological outcome: change in pan-Ig antibody response (pan-Ig anti-S1-RBD)
timeFrame: at baseline (day of vaccination) and three months after vaccination
measure: immunological outcome: change in anti-Nucleocapsid (N) response
timeFrame: at baseline (day of vaccination) and three months after vaccination
measure: immunological outcome: change in SARS-CoV-2-binding antibodies
timeFrame: at baseline (day of vaccination) and three months after vaccination
measure: Number of participants with newly polymerase chain reaction (PCR)-confirmed asymptomatic COVID-19 infection
timeFrame: at any time point in within 48 weeks following randomisation (day of vaccination)
measure: Number of participants with newly PCR-confirmed symptomatic COVID-19 infection
timeFrame: at any time point in within 48 weeks following randomisation (day of vaccination)
measure: Number of participants with severe COVID-19 infection
timeFrame: at any time point in within 48 weeks following randomisation (day of vaccination)
measure: Clinical Outcome: COVID-19 burden of diseases (BOD)
timeFrame: within 48 weeks following randomisation (day of vaccination)
measure: Duration of RCT set up (specific endpoint related to trial conduct feasibility)
timeFrame: one time assessment at baseline (from deciding which interventions will be tested until the first patient is randomised)
measure: Time of patient recruitment from activation of first study site until 40 patients are randomised
timeFrame: one time assessment after approx. 3 months (from activation of first study site until 40 patients are randomised)
measure: Time of patient recruitment from activation of first study site until 380 patients are randomised
timeFrame: one time assessment after approx. 3 months (from activation of first study site until 380 patients are randomised)
measure: Patient consent rate
timeFrame: approx. 3 months
measure: Proportion of missing data for all baseline variables from routinely collected cohort data
timeFrame: one time assessment at baseline
measure: Proportion of missing data for all clinical outcomes
timeFrame: one time assessment after approx. 3 months
measure: SARS-CoV-2-specific antibodies
timeFrame: three months after vaccination
measure: SARS-CoV-2-specific titers
timeFrame: three months after vaccination
measure: 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
timeFrame: 8 weeks (¨+/- 2 weeks) after 3. vaccination
Secondary outcomes:
measure: 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
timeFrame: 8 weeks (¨+/- 2 weeks) after 3. vaccination
measure: 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
timeFrame: 8 weeks (¨+/- 2 weeks) after 3. vaccination
measure: The proportion of patients with neutralizing neutralization activity against the vaccine strain Wuhan-Hu-1 in the observational second sub- protocol
timeFrame: 8 weeks (¨+/- 2 weeks) after 3. vaccination
measure: 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
timeFrame: 8 weeks (¨+/- 2 weeks) after 3. vaccination
measure: Mean immune response of IgM, IgA and IgG to the subunit S1 using ABCORA in the observational second sub- protocol
timeFrame: 8 weeks (¨+/- 2 weeks) after 3. vaccination
measure: Number of newly PCR-confirmed asymptomatic SARS-CoV-2 infection in the observational second sub- protocol
timeFrame: 8 weeks (¨+/- 2 weeks) after 3. vaccination
Other outcomes:
measure: Safety Outcome: number of local symptoms
timeFrame: during the first 7 days after vaccination
measure: Safety Outcome: number of systemic symptoms
timeFrame: during the first 7 days after vaccination
measure: Safety Outcome: number of vaccine related symptoms
timeFrame: during the first 7 days after vaccination
measure: Number of participants with newly PCR-confirmed asymptomatic Covid-19 infection (clinical effectiveness endpoint according to FDA recommendations for phase III Covid-19 vaccine licensing trials)
timeFrame: at any time points within 48 weeks follow-up
measure: Newly PCR-confirmed symptomatic Covid-19 infection (clinical effectiveness endpoint according to FDA recommendations for phase III Covid-19 vaccine licensing trials)
timeFrame: at any time points within 48 week follow-up
measure: Number of participants with severe COVID-19 infection (clinical effectiveness endpoint according to FDA recommendations for phase III Covid-19 vaccine licensing trials)
timeFrame: at any time points within 48 week follow-up
measure: Covid-19 burden of diseases (BOD) (clinical effectiveness endpoint according to FDA recommendations for phase III Covid-19 vaccine licensing trials)
timeFrame: within 48 week follow-up
Locations:
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Bern
country: Switzerland
facility: University Hospital Bern
city: Lausanne
country: Switzerland
facility: University Hospital Lausanne CHUV
city: Zurich
country: Switzerland
facility: University Hospital Zurich
Study officials:
affiliation: Basel Institute for Clinical Epidemiology & Biostatistics, University Hospital Basel
name: Heiner C. Bucher, Prof. Dr. med.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Speich B, Chammartin F, Abela IA, Amico P, Stoeckle MP, Eichenberger AL, Hasse B, Braun DL, Schuurmans MM, Muller TF, Tamm M, Audige A, Mueller NJ, Rauch A, Gunthard HF, Koller MT, Trkola A, Briel M, Kusejko K, Bucher HC; Swiss HIV Cohort Study and the Swiss Transplant Cohort Study. Antibody Response in Immunocompromised Patients After the Administration of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine BNT162b2 or mRNA-1273: A Randomized Controlled Trial. Clin Infect Dis. 2022 Aug 24;75(1):e585-e593. doi: 10.1093/cid/ciac169.
citation: Kusejko K, Chammartin F, Smith D, Odermatt M, Schuhmacher J, Koller M, Gunthard HF, Briel M, Bucher HC, Speich B; Swiss HIV Cohort Study; Swiss Transplant Cohort Study. Developing and testing a Corona VaccinE tRiAL pLatform (COVERALL) to study Covid-19 vaccine response in immunocompromised patients. BMC Infect Dis. 2022 Jul 28;22(1):654. doi: 10.1186/s12879-022-07621-x.
citation: Chammartin F, Kusejko K, Pasin C, Trkola A, Briel M, Amico P, Stoekle MP, Eichenberger AL, Hasse B, Braun DL, Schuurmans MM, Muller TF, Tamm M, Mueller NJ, Rauch A, Koller MT, Gunthard HF, Bucher HC, Speich B, Abela IA; and the Swiss HIV Cohort Study. Determinants of antibody response to severe acute respiratory syndrome coronavirus 2 mRNA vaccines in people with HIV. AIDS. 2022 Aug 1;36(10):1465-1468. doi: 10.1097/QAD.0000000000003246. Epub 2022 Jul 9.
citation: Speich B, Chammartin F, Smith D, Stoeckle MP, Amico P, Eichenberger AL, Hasse B, Schuurmans MM, Muller T, Tamm M, Dickenmann M, Abela IA, Trkola A, Hirsch HH, Manuel O, Cavassini M, Hemkens LG, Briel M, Mueller NJ, Rauch A, Gunthard HF, Koller MT, Bucher HC, Kusejko K; study groups from the Swiss HIV Cohort Study and the Swiss Transplant Cohort Study. A trial platform to assess approved SARS-CoV-2 vaccines in immunocompromised patients: first sub-protocol for a pilot trial comparing the mRNA vaccines Comirnaty(R) and COVID-19 mRNA Vaccine Moderna(R). Trials. 2021 Oct 21;22(1):724. doi: 10.1186/s13063-021-05664-0.