Bringing Optimised COVID-19 Vaccine Schedules To ImmunoCompromised Populations (BOOST-IC): an Adaptive Randomised Controlled Clinical Trial

Study Overview
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Brief Summary
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Despite the greater risk of adverse COVID-19 outcomes, antibody and cell-mediated immune responses to COVID-19 vaccines vary amongst immunocompromised (IC) people and are poorly defined. IC hosts were largely excluded from the COVID-19 vaccine registration trials, though many countries recommend additional and booster doses of vaccination in this group. BOOST-IC is an adaptive randomised clinical trial (RCT) to assess the immunogenicity and safety of additional COVID-19 vaccine doses in immunocompromised (IC) people, including people with HIV, solid organ transplants (SOT) recipients or those with haematological malignancies. Briefly, the study aims to generate high-quality evidence on the immunogenicity and safety of alternative COVID-19 booster strategies against SARS-CoV-2 for IC people in Australia.

Detailed Description
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Despite the greater risk of adverse COVID-19 outcomes, antibody and cell-mediated immune responses to COVID-19 vaccines vary amongst immunocompromised (IC) people and are poorly defined. IC hosts were largely excluded from the COVID-19 vaccine registration trials, though many countries recommend additional and booster doses of vaccination in this group. However, data are heterogeneous, in part due the variable nature of immunodeficiencies in IC groups and non-standardised outcome measures used in studies. BOOST-IC is an adaptive randomised clinical trial (RCT) to assess the immunogenicity and safety of additional bivalent COVID-19 vaccine doses in immunocompromised (IC) people, including people with HIV, solid organ transplants (SOT) recipients or those with haematological malignancies. Briefly, the study aims to generate high-quality evidence on the immunogenicity and safety of alternative COVID-19 booster strategies against SARS-CoV-2 for IC people in Australia. To do this, participants who have previously completed 3- to 6-doses of Australian TGA approved COVID-19 vaccines (BA.4/5 Moderna and Pfizer vaccines) will be randomised 1:1 to receive either one or two doses of a bivalent COVID-19 vaccine, as these become available in Australia. And additional arm can be added if an additional suitable vaccine becomes available. Namely, patients will be randomised to receive either one or two doses of bivalent Moderna or Pfizer COVID-19 vaccine. As additional bivalent vaccines become available in Australia, these will be included in the trial, as additional arms. The trial can incorporate up to three arms at one time. Patients will be followed up for 455 days post randomisation. Specific study questions pertain to: examining how additional doses of COVID-19 vaccine/s affect correlates of protective immunity examining the safety of additional doses of COVID-19 vaccine/s characterising the humoral and cellular immune responses to COVID-19 vaccination receiving 1 or 2 booster doses of COVID-19 vaccine/s

Official Title
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Bringing Optimised COVID-19 Vaccine Schedules To ImmunoCompromised Populations (BOOST-IC): an Adaptive Randomised Controlled Clinical Trial

Conditions
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HIV, Organ Transplantation, Lymphoma, Non-Hodgkin, Chronic Lymphocytic Leukemia, Multiple Myeloma, COVID-19 Vaccines

Intervention / Treatment
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* Biological: Pfizer Bivalent COVID-19 Vaccine
* Biological: Moderna Bivalent mRNA vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to give informed consent and undertake study procedures Age ≥16 years old Have completed at least 3 months prior, 3- to 6-doses of an Australian TGA approved SARS-CoV-2 vaccine (including mRNA [Pfizer or Moderna], ChAdOx1 [Oxford/Astra Zeneca] or protein [Novavax]) Fit the criteria to be included in one of the following 3 populations: Infected with HIV; Current recipient of a solid organ transplant including: kidney, pancreas, liver, malignancy episodes of severe rejection requiring T- or B-cell depleting agents in the prior 3 months; Undergoing chemotherapy, immunotherapy and/or targeted therapy, or completed in the last 2 years for: chronic lymphocytic leukemia, multiple myeloma or non-Hodgkin lymphoma. Exclusion Criteria: Are contraindicated to receive a COVID-19 booster vaccination, e.g. history of anaphylaxis to a vaccine component or myocarditis attributed to previous receipt of an mRNA vaccine. Has had led less than 3 or more than 6 doses of COVID-19 vaccine Is on another clinical trial investigating alternate COVID-19 vaccination schedules or investigational drugs to prevent or treat COVID-19 Life expectancy < 12 months, or enrolment deemed not in the best interest of the patient Unable to provide informed consent Receipt of SARS-CoV-2 specific monoclonal antibodies in the 3 months prior to receiving the first dose of study vaccine Acute respiratory tract infection and/or temperature > 38 degrees centigrade on day of receiving first dose of study vaccine History of autologous stem cell transplant in the prior 6 months or history of ever having an allogeneic stem cell transplant or CAR T-cell therapy

Ages Eligible for Study
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Minimum Age: 16 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Study participants who have received three to six doses of Australian TGA approved COVID-19 vaccine will be randomised into one of up to three groups, who will be administered either one or two homologous doses of bivalent COVID-19 vaccines, e.g. bivalent Moderna mRNA vaccine OR bivalent Pfizer mRNA vaccine, using a central computer-generated random allocation algorithm, with random block sizes of 3 or 6. Randomisation will be stratified by: - Study subgroup (HIV, solid organ transplant, haematological malignancy)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: People living with Human Immunodeficiency Virus (HIV)<br>Eligible participants living with HIV will be randomised 1:1:1 to receive a one or two doses of bivalent COVID-19 vaccine: Moderna bivalent COVID-19 vaccine, SPIKEVAX BIVALENT ORIGINAL/OMICRON BA.4-5 (elasomeran/davesomeran); 25 micrograms of imelasomeran that targets the Omicron variant BA.4-5, and 25 micrograms of elasomeran that targets the ancestral strain of SARSCoV-2. Pfizer bivalent COVID-19 vaccine, COMIRNATY ORIGINAL/OMICRON BA.4-5 (tozinameran/famtozinameran); 15 µg of tozinameran and 15 µg of famtozinameran. TBC | Biological: Pfizer Bivalent COVID-19 Vaccine<br>* One or Two doses three months apart, per manufacturer's recommendations.<br>* Other names: COMIRNATY Original/Omicron BA.1;Biological: Moderna Bivalent mRNA vaccine<br>* One or Two doses three months apart, per manufacturer's recommendations.<br>* Other names: Spikevax;|
| Experimental: Solid Organ Transplant recipients<br>Eligible participants who have previously received at least one solid organ transplant, including kidney, pancreas, liver, heart, lung, or any combination of these organs at least 6 weeks prior and without episodes of severe rejection requiring T- or B-cell depleting agents in the prior 3 months, will be randomised 1:1:1 to receive a one or two doses of bivalent COVID-19 vaccine: Moderna bivalent COVID-19 vaccine, SPIKEVAX BIVALENT ORIGINAL/OMICRON BA.4-5 (elasomeran/davesomeran); 25 micrograms of imelasomeran that targets the Omicron variant BA.4-5, and 25 micrograms of elasomeran that targets the ancestral strain of SARSCoV-2. Pfizer bivalent COVID-19 vaccine, COMIRNATY ORIGINAL/OMICRON BA.4-5 (tozinameran/famtozinameran); 15 µg of tozinameran and 15 µg of famtozinameran. TBC | Biological: Pfizer Bivalent COVID-19 Vaccine<br>* One or Two doses three months apart, per manufacturer's recommendations.<br>* Other names: COMIRNATY Original/Omicron BA.1;Biological: Moderna Bivalent mRNA vaccine<br>* One or Two doses three months apart, per manufacturer's recommendations.<br>* Other names: Spikevax;|
| Experimental: People with Haematological Neoplasms (CLL, NHL, MM)<br>Undergoing chemotherapy, immunotherapy and/or targeted therapy, or completed in the last 2 years for chronic lymphocytic leukemia, multiple myeloma or non-Hodgkin lymphoma will be randomised 1:1:1 to receive a one or two doses of bivalent COVID-19 vaccine: Moderna bivalent COVID-19 vaccine, SPIKEVAX BIVALENT ORIGINAL/OMICRON BA.4-5 (elasomeran/davesomeran); 25 micrograms of imelasomeran that targets the Omicron variant BA.4-5, and 25 micrograms of elasomeran that targets the ancestral strain of SARSCoV-2. Pfizer bivalent COVID-19 vaccine, COMIRNATY ORIGINAL/OMICRON BA.4-5 (tozinameran/famtozinameran); 15 µg of tozinameran and 15 µg of famtozinameran. TBC | Biological: Pfizer Bivalent COVID-19 Vaccine<br>* One or Two doses three months apart, per manufacturer's recommendations.<br>* Other names: COMIRNATY Original/Omicron BA.1;Biological: Moderna Bivalent mRNA vaccine<br>* One or Two doses three months apart, per manufacturer's recommendations.<br>* Other names: Spikevax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The geometric mean concentration (GMC) of anti-spike SARS-CoV-2 IgG antibody against SARS-CoV-2 | geometric mean concentration (GMC) of anti-spike SARS-CoV-2 IgG (AU/ml) | 28 days after completion of trial vaccine/s | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| anti-Spike IgG antibody geometric mean concentration | The geometric mean concentration (GMC) (AU/ml) of anti-spike SARS-CoV-2 IgG antibody against SARS-CoV-2 6- and 12-months after completion of trial vaccine/s | Up to 12 months post completion of trial vaccine/s | 
| Seroconversion | The proportion of participants seronegative to SARS-CoV-2 IgG becoming seropositive 1-, 6- and 12-months after completion of trial vaccine/s | 1-, 6- and 12-months after completion of trial vaccine/s | 
| Neutralisation responses | Proportion of participants with SARS-CoV-2 neutralising antibody response in each group after 1-, 6- and 12-months post completion of trial vaccine/s, with response defined as either 4-fold rise in the neutralising antibody titre for those with detectable neutralising antibodies at baseline, OR Detectable neutralisation in those with no detectable neutralising antibodies at baseline | Up to 12 months post completion of trial vaccine/s | 
| T cell polyfunctionality | Subset analysis and polyfunctionality (number, and concentration of effector cytokines) of SARS-CoV-2 specific T-cell responses at 1-, 6- and 12-months post completion of trial vaccine/s in a subset of participants. | Up to 12 months post completion of trial vaccine/s | 
| T lymphocyte responses | Magnitude of SARS-CoV-2 specific T-cell responses at 1-, 6- and 12-months post completion of trial vaccine/s in a subset of participants | Up to 12 months post completion of trial vaccine/s | 
| Early local and systemic reactions | Local and systemic reactions assessed by questionnaire on Day 1,2,3,4,5,6 and 7 after randomisation. Solicited and unsolicited adverse events following immunisation (AEFI) up to Day 28. Hospitalisation resulting from adverse events following immunisation (AEFI) up to Day 28. | Up to 7 days post completion of trial vaccine/s | 
| Adverse Events Following Immunisation | Proportion with solicited and unsolicited adverse events following immunisation (AEFI) up to Day 28. | Up to 28 days post completion of trial vaccine/s | 
| Hospitalisation due to Immunisation | Proportion of participants with hospitalisation resulting from adverse events following immunisation (AEFI) up to Day 28. | Up to 28 days post completion of trial vaccine/s | 
| Clinical outcomes - COVID-19 infection | Proportion of patients with PCR-confirmed OR rapid antigen test (RAT) positive SARS-CoV-2 infection in participants up to 12-months post completion of trial vaccine/s | Up to 12 months post completion of trial vaccine/s | 
| Clinical outcomes - Healthcare Attendance Due to COVID-19 infection | Proportion of participants with PCR-confirmed OR rapid antigen test (RAT) positive SARS-CoV-2 infection requiring attendance at a medical facility for assessment and/or hospital admission up to 12-months post completion of trial vaccine/s | Up to 12 months post completion of trial vaccine/s | 
| Clinical outcomes - All Cause and SARS-CoV-2 Related Mortality | Proportion of participants experiencing mortality due to i) any cause and ii) SARS-CoV-2 infection up to 12-months post completion of trial vaccine/s | Up to 12 months post completion of trial vaccine/s | 
| Clinical outcomes - Severity | Proportion of participants needing oxygen therapy and/or ventilatory support due to SARS-CoV-2 infection up to 12-months post completion of trial vaccine/s Need for ICU care due to SARS-CoV-2 infection up to 12-months post completion of trial vaccine/s | Up to 12 months post completion of trial vaccine/s | 
| Clinical outcomes - Severe COVID-19 | Proportion of Participants with need for ICU care due to SARS-CoV-2 infection up to 12-months post completion of trial vaccine/s | Up to 12 months post completion of trial vaccine/s | 
| Clinical outcomes - Quality of Life | Quality of life estimates (using EQ-5D-5L survey) at 1-, 6- and 12-months post completion of trial vaccine/s | Up to 12 months post completion of trial vaccine/s | 
| Clinical outcomes - Healthcare utilisation | Proportion of participants with healthcare utilisation including outpatient pharmaceutical and medical service use and inpatient hospital admissions related to COVID-19 or study vaccines up to 12-months post completion of trial vaccine/s | Up to 12 months post completion of trial vaccine/s | 
| Clinical outcomes - All cause healthcare utilisation | Proportion of participants with healthcare utilisation including outpatient pharmaceutical and medical service use and inpatient hospital admissions | Up to 12 months post completion of trial vaccine/s |