Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001509752
Ethics application status
Approved
Date submitted
6/10/2022
Date registered
5/12/2022
Date last updated
5/12/2022
Date data sharing statement initially provided
5/12/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
SARS-CoV-2 (COVID-19) vaccination and the immune responses in patients with haematological malignancy and other immune deficiency.
Scientific title
COVAXI - 2: SARS-CoV-2 vaccination and the immune responses in patients with haematological malignancy and other immune deficiency.
Secondary ID [1] 308149 0
PBI-101
Universal Trial Number (UTN)
Trial acronym
COVAXI-2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Haematological malignancy 327750 0
Immunosuppression 327869 0
COVID-19 327870 0
Condition category
Condition code
Blood 324822 324822 0 0
Haematological diseases
Cancer 324949 324949 0 0
Leukaemia - Chronic leukaemia
Cancer 324950 324950 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 324951 324951 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 324952 324952 0 0
Myeloma
Inflammatory and Immune System 324953 324953 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This is an observational Cohort study to assess the immune response to the SARS-CoV-2 vaccination and the prevalence of clotting related antibodies in hematology and other immunosuppressed patients.
Participants in this study will be assigned to one of the following groups:
- Group A: Patients with haematology and other immunosuppressed conditions who have received at least 3 doses of SARS-COV-2 vaccination according to Australian Government Vaccine Guidelines.
- Subgroup 1a: Immuno-suppressed haematology patients in Group A who have received or eligible to receive standard of care Australian Government Therapeutic Goods Administration approved COVID prevention subcutaneous injection (Evusheld - Cilgavimab and Tixagevimab) according to the WA Health Department Guidelines.
- Group B: General Population patients without haematological disorders who have received at least 3 doses of SARS-COV-2 vaccination according to Australian Government Vaccine Guidelines.
After informed consent, demographic and clinical information (Disease history for immunocompromised patients only, general medical history, concomitant medications, COVID-19 vaccination status/virus positivity status and vital signs) will be collected at registration and blood taken Day 30 to 120 post 3 or 4th vaccine for initial measurement of established protective antibody response. At 6 months or before further additional booster vaccination further clinical review (Disease history for immunocompromised patients only, concomitant medications, COVID-19 vaccination status/virus positivity status and vital signs) and blood draw to measure of the duration of the protective antibody response. A third blood sample will be taken Day 30 to 120 post 4 or 5th vaccine to measure of protective antibody response after next vaccination. In the eligible immunosuppressive haematology patients receiving Evusheld (Cilgavimab and Tixagevimab), a pre vaccination blood test and a day 30 post injection blood test in addition will be taken.
Frequency of Blood sample collection-
For Group A and B:
- A single blood sample will be collected between Day 30 to 120 post 3 or 4th vaccine
-A single blood sample will be collected up to 6 months before further additional booster vaccination
- A single blood sample will be collected between Day 30 to 120 post 4 or 5th vaccine

For sub group 1a
- A single pre-vaccination sample will be collected up to 7 days prior to Evusheld administration.
- A single blood sample will be collected between Day 20-30 post Evusheld

As of the current guidelines, the participants will receive 4 vaccinations; but this may change according to the standard COVID-19 vaccination guidelines in the future.
Intervention code [1] 324507 0
Early Detection / Screening
Comparator / control treatment
- Subgroup 1a: Immuno-suppressed haematology patients in Group A who have received or eligible to receive standard of care Australian Government Therapeutic Goods Administration approved COVID prevention subcutaneous injection (Evusheld - Cilgavimab and Tixagevimab) according to the WA Health Department Guidelines.

- Group B: General Population patients without haematological disorders who have received at least 3 doses of SARS-COV-2 vaccination according to Australian Government Vaccine Guidelines. Group B will serve as the comparator group
Control group
Active

Outcomes
Primary outcome [1] 332641 0
-Determine the strength of the IgG response to receptor binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2 from blood samples collected in immunocompromised haematology patients overtime and compare to matched controls.
Timepoint [1] 332641 0
For Group A and B:
- A single blood sample will be collected between Day 30 to 120 post 3 or 4th vaccine
-A single blood sample will be collected up to 6 months before further additional booster vaccination
- A single blood sample will be collected between Day 30 to 120 post 4 or 5th vaccine

For sub group 1a
- A single pre-vaccination sample will be collected up to 7 days prior to Evusheld administration.
- A single blood sample will be collected between Day 20-30 post Evusheld
Secondary outcome [1] 414184 0
We will assess nucleocapsid protein antibody concentration of the spike protein of SARS-CoV-2 bound IgG concentration.
Timepoint [1] 414184 0
For Group A and B:
- A single blood sample will be collected between Day 30 to 120 post 3 or 4th vaccine
-A single blood sample will be collected up to 6 months before further additional booster vaccination
- A single blood sample will be collected between Day 30 to 120 post 4 or 5th vaccine

For sub group 1a
- A single pre-vaccination sample will be collected up to 7 days prior to Evusheld administration.
- A single blood sample will be collected between Day 20-30 post Evusheld
Secondary outcome [2] 414994 0
We will assess SARS-CoV-2 antibody titre concentration.
Timepoint [2] 414994 0
For Group A and B:
- A single blood sample will be collected between Day 30 to 120 post 3 or 4th vaccine
-A single blood sample will be collected up to 6 months before further additional booster vaccination
- A single blood sample will be collected between Day 30 to 120 post 4 or 5th vaccine

For sub group 1a
- A single pre-vaccination sample will be collected up to 7 days prior to Evusheld administration.
- A single blood sample will be collected between Day 20-30 post Evusheld
Secondary outcome [3] 414995 0
We will determine the SARS-CoV-2 antibody assay validity coefficient based on WHO International Standard.
Timepoint [3] 414995 0
For Group A and B:
- A single blood sample will be collected between Day 30 to 120 post 3 or 4th vaccine
-A single blood sample will be collected up to 6 months before further additional booster vaccination
- A single blood sample will be collected between Day 30 to 120 post 4 or 5th vaccine

For sub group 1a
- A single pre-vaccination sample will be collected up to 7 days prior to Evusheld administration.
- A single blood sample will be collected between Day 20-30 post Evusheld
Secondary outcome [4] 414996 0
We will assess a single secondary outcome- full blood count prior to additional vaccination.
Timepoint [4] 414996 0
For Group A and B:
- A single blood sample will be collected between Day 30 to 120 post 3 or 4th vaccine
-A single blood sample will be collected up to 6 months before further additional booster vaccination
- A single blood sample will be collected between Day 30 to 120 post 4 or 5th vaccine

For sub group 1a
- A single pre-vaccination sample will be collected up to 7 days prior to Evusheld administration.
- A single blood sample will be collected between Day 20-30 post Evusheld
Secondary outcome [5] 414997 0
We will assess coagulation markers including PF4 antibodies concentrations
Timepoint [5] 414997 0
For Group A and B:
- A single blood sample will be collected between Day 30 to 120 post 3 or 4th vaccine
-A single blood sample will be collected up to 6 months before further additional booster vaccination
- A single blood sample will be collected between Day 30 to 120 post 4 or 5th vaccine

For sub group 1a
- A single pre-vaccination sample will be collected up to 7 days prior to Evusheld administration.
- A single blood sample will be collected between Day 20-30 post Evusheld
Secondary outcome [6] 414998 0
We will assess the incidence of patients testing positive for SARS-CoV-2 infection by rapid antigen test, PCR test, etc.
Timepoint [6] 414998 0
By doing rapid antigen test or PCR test
Secondary outcome [7] 416342 0
We will assess the receptor-binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2 bound IgG concentration.
Timepoint [7] 416342 0
For Group A and B:
- A single blood sample will be collected between Day 30 to 120 post 3 or 4th vaccine
-A single blood sample will be collected up to 6 months before further additional booster vaccination
- A single blood sample will be collected between Day 30 to 120 post 4 or 5th vaccine

For sub group 1a
- A single pre-vaccination sample will be collected up to 7 days prior to Evusheld administration.
- A single blood sample will be collected between Day 20-30 post Evusheld
Secondary outcome [8] 416343 0
We will assess coagulation markers including platelet glycoprotein VI
Timepoint [8] 416343 0
For Group A and B:
- A single blood sample will be collected between Day 30 to 120 post 3 or 4th vaccine
-A single blood sample will be collected up to 6 months before further additional booster vaccination
- A single blood sample will be collected between Day 30 to 120 post 4 or 5th vaccine

For sub group 1a
- A single pre-vaccination sample will be collected up to 7 days prior to Evusheld administration.
- A single blood sample will be collected between Day 20-30 post Evusheld
Secondary outcome [9] 416344 0
We will assess coagulation markers including thrombin generation.
Timepoint [9] 416344 0
For Group A and B:
- A single blood sample will be collected between Day 30 to 120 post 3 or 4th vaccine
-A single blood sample will be collected up to 6 months before further additional booster vaccination
- A single blood sample will be collected between Day 30 to 120 post 4 or 5th vaccine

For sub group 1a
- A single pre-vaccination sample will be collected up to 7 days prior to Evusheld administration.
- A single blood sample will be collected between Day 20-30 post Evusheld

Eligibility
Key inclusion criteria
• Age > or = 18.
• Are eligible to receive or have received at least 3 doses of the standard of care SARS-COV-2 vaccine as per current Australian Government Therapeutic Goods Administration Vaccine Guidelines. Currently in Australia vaccines choices include Astra Zeneca (ChAdOx1), Pfizer (BNT162b2) Moderna (mRNA -1273) and Novavax.
• Patients with haematology disorders including CLL (Chronic lymphocytic leukemia), lymphoma, other B cell lymphoproliferative disorders, myeloma, MGUS (Monoclonal gammopathy of undetermined significance), myeloproliferative disorders and other immunosuppressed patients.
• Patients who present to primary care without haematological disorders who have received at least 3 doses of SARS-COV-2 vaccination according to Australian Government Vaccine Guidelines.
• Able and willing to provide Written and Informed Consent.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• People with vaccine allergies.
• Pregnant or breast-feeding woman.

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Both
Statistical methods / analysis
IgG titres to the RBD of the S1 subunit of the spike protein of SARS-CoV-2 will be the primary data point to be used in estimating sample size and our data analysis. We use the following assumptions and principles in our sample size calculation and data analyses. Haematological patients will have a lower rate of seroconversion compared to controls (e.g., up to 40% vs over 90%). Haematological patients will have a much faster pace to reduce their antibody titres over a 12 to 24-month period. Two time points are available for antibody titres (up to 120 days, 6 months). We use repeated measures of ANOVA (one-way in assessing changes over time and two-way interaction in determining differences between 2 groups: haematological, control over time). We assume up to about 20% of the individuals may not have a complete set of data at all two time-points. Because of multiple testing for changes in titres over time for each of the three groups of participants, and, we are interested to compared between groups, in their differences in titres over time, we assume the alpha-value to be <0.01 as significant and 95% power as acceptable.

Any Response to COVID Vaccination (>50BAU/ml): We are planning a study of independent cases and controls with 1 control(s) per case. Prior data indicate that the probability of exposure among controls is 0.95. If the actual probability of exposure among cases is 0.3, we will need to study 9 case patients and 9 control patients to be able to reject the null hypothesis that the exposure rates for case and controls are equal with probability (power) 0.9. The Type I error probability associated with this test of this null hypothesis is 0.05. We will use an uncorrected chi-squared statistic to evaluate this null hypothesis.

Protective Response to COVID Vaccination (>600 BAU/ml): We are planning a study of independent cases and controls with 1 control(s) per case. Prior data indicate that the probability of exposure among controls is 0.98. If the actual probability of exposure among cases is 0.15, we will need to study 5 case patients and 5 control patients to be able to reject the null hypothesis that the exposure rates for case and controls are equal with probability (power) 0.9. The Type I error probability associated with this test of this null hypothesis is 0.05. We will use an uncorrected chi-squared statistic to evaluate this null hypothesis.
Assuming those 15% responding over 600 BAU/ml median was 800 immediately after the 4th dose vaccination which dropped to 200 BAU/ml at 6 months. Assuming the reduction in the titre is linear then T50 will be 3 months which means that immunosuppressed patients had their reduction in protection twice as fast as the control (healthy) patients.
If we assume the decline in antibody titre is proportional to the antibody titre at any time point, as in a typical exponential decay curve, then the rate of decay in antibody titre for the immunosuppressive group was about 7.8 faster than the control (given they had a lower titre to start with, the decline should be slower than half within the same time frame).

We have three groups of patients (Haematology Patients with no Evusheld, Haematology patients with Evusheld and age and matched controls).
Data will be analysed through 2-way ANOVA and assessing the treatment groups interacting with time remains a valid sample size calculation method. However, to avoid the dropout of cases with missing blood test data, a linear mixed model will be better to analyse and include patients who might have missing blood tests.

If we assume a titre of 600 BAU or more is protective. The mean titre of the control is 540 (90% of the 600 BU/ml), the mean titre for the group: haem + Evusheld is 480 (80% of 600 BU/ml), and the mean titre of the haem group only group is 420 BU/ml, data at three-time points are available, alpha error = 5% and power 95% acceptable, a correlation between measurements are 0.5, then the total sample size is 177 (or 59 per group). If we scale up to allow a 20% lost to follow-up or due to incomplete data, we will need at least 212 patients. If we have 150 patients in each group, we will have confidence in terms of power if our assumptions are valid.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
24/08/2022
Date of last participant enrolment
Anticipated
1/09/2023
Actual
Date of last data collection
Anticipated
1/09/2024
Actual
Sample size
Target
450
Accrual to date
65
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 23326 0
Perth Blood Institute - West Perth
Recruitment postcode(s) [1] 38698 0
6005 - West Perth

Funding & Sponsors
Funding source category [1] 312315 0
Other Collaborative groups
Name [1] 312315 0
The Perth Blood Institute
Country [1] 312315 0
Australia
Primary sponsor type
Other Collaborative groups
Name
The Perth Blood Institute
Address
18 prowse Street, West Perth-6005, Western Australia
Country
Australia
Secondary sponsor category [1] 313868 0
None
Name [1] 313868 0
Address [1] 313868 0
Country [1] 313868 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311683 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 311683 0
123 Glen Osmond Road Eastwood, South Australia 5063
Ethics committee country [1] 311683 0
Australia
Date submitted for ethics approval [1] 311683 0
20/05/2022
Approval date [1] 311683 0
29/06/2022
Ethics approval number [1] 311683 0
HREC_2022-05-451

Summary
Brief summary
The aim of this study is to assess the immune response to the SARS-CoV-2 vaccines and the prevalence of antibodies (anti-PF4) associated with development of a rare complication of SARS-CoV-2 vaccination, thrombotic thrombocytopaenia syndrome, in patients with blood cancers compared to an elderly control population from primary care.

Who is it for?
You may be eligible for this study if you are aged 18 years or older, have a haematological disorder (including chronic lymphocytic leukaemia, lymphoma, other B cell lymphoproliferative disorders, myeloma, monoclonal gammopathy of undetermined significance, and myeloproliferative disorders) or are immunosuppressed, and are eligible to receive or have received at least 3 doses of an intramuscular SARS-CoV-2 vaccine (including Astra Zeneca (ChAdOx1), Pfizer (BNT162b2) Moderna (mRNA -1273) and Novavax) or the subcutaneous vaccine (Evusheld) as per current Australian Government Vaccine Guidelines. You may also be eligible for this study if you are aged 18 years or older, presenting to primary care without haematological disorders and have received at least 3 doses of SARS-COV-2 vaccination according to Australian Government Vaccine Guidelines.

Study details
All participants will undergo SARS-CoV-2 vaccination in accordance with Australian Government Vaccine Guidelines. For those receiving intramuscular vaccination, a single blood sample for the assessment of immune response and antibody formation will be collected between Days 30 to 120 post 3rd or 4th vaccination, 6 months post 3rd or 4th vaccination (or immediately prior to additional booster vaccination), and between Days 30 to 120 post 4th or 5th vaccination.
For those receiving subcutaneous vaccination, a single blood sample will be collected up to 7 days prior to vaccination and at Days 20 and 30 post-vaccination.
At these timepoints, clinical reviews will also be undertaken to determine haematological malignancy diagnosis, baseline characteristics of independent variables (e.g., previous treatments) and blood parameters (e.g., full blood count).

It is hoped that this study may help to determine the immune response to the SARS-CoV-2 vaccination in this vulnerable group of patients, and will inform formulation of guidelines and treatment protocols for SARS-CoV-2 infection in the general population and immunosuppressed haematology patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 121982 0
Prof Ross Baker
Address 121982 0
Prof. Ross Baker
The Perth Blood Institute
18 Prowse Street,
West Perth-6005
Western Australia
Country 121982 0
Australia
Phone 121982 0
+610892005300
Fax 121982 0
Email 121982 0
rbaker@whoc.com.au
Contact person for public queries
Name 121983 0
Dr Jarod Horobin
Address 121983 0
Dr. Jarod Horobin
The Perth Blood Institute
18 Prowse Street,
West Perth-6005
Western Australia
Country 121983 0
Australia
Phone 121983 0
+610892005300
Fax 121983 0
Email 121983 0
jarod@pbi.org.au
Contact person for scientific queries
Name 121984 0
Prof Ross Baker
Address 121984 0
Prof. Ross Baker
The Perth Blood Institute
18 Prowse Street,
West Perth-6005
Western Australia
Country 121984 0
Australia
Phone 121984 0
+610892005300
Fax 121984 0
Email 121984 0
info@pbi.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified participant data including clinical data and demographics.
When will data be available (start and end dates)?
IPD availability at the conclusion of the study up to 31/12/2024. Anticipated study conclusion date is 2023.
Available to whom?
data is only available to researchers upon written request and approval by the research study team of investigators.
Available for what types of analyses?
meta-analysis
How or where can data be obtained?
data is available upon written request and approval by the research study team of investigators. Upon approval, data requests can be made by contacting the Principal Investigator, Prof Ross Baker (email: info@pbi.org.au)


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.