ANZCTR - Registration

Registration number

ACTRN12621001202853

Ethics application status

Approved

Date submitted

31/08/2021

Date registered

9/09/2021

Date last updated

9/09/2021

Date data sharing statement initially provided

9/09/2021

Type of registration

Retrospectively registered

Titles & IDs

Public title

Efficacy of COVID-19 Vaccination in People with Follicular Lymphoma and Waldenström Macroglobulinaemia – A Prospective Cohort Study

Scientific title

Efficacy of COVID-19 Vaccination in People with Follicular Lymphoma and Waldenström Macroglobulinaemia – A Prospective Cohort Study

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Follicular Lymphoma

Waldenstrom Macroglobulinaemia

Condition category

Condition code

Blood

Haematological diseases

Cancer

Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure

Study type

Observational

Description of intervention(s) / exposure

Patients with haematological malignancies such as Follicular Lymphoma (FL) and Waldenstrom's Macroglobulinaemia (WM) may have reduced response to the COVID-19 vaccine. This is due to changes in the immune system, either due to the disease itself and their disease treatments (such as chemotherapy). This study aims to assess the immune responses of patients with FL and WM to the COVID-19 vaccine. This study does this by collecting blood samples at defined timepoints:
T1 Baseline (Day of 1st vaccine dose or up to 2 weeks prior).
T2 Post 1st vaccine dose (Day of 2nd dose, or any day a minimum of 21 days post 1st dose).
T3 Post 2nd vaccine dose (28 days +/- 14 days post 2nd dose)
T4 6 months (180 days +/- 30 days post 2nd dose)
T5 12 months following 2nd vaccination (+/- 30 days): this time point is not yet confirmed and will depend on data analysed following T4 and appropriateness for collection.

Intervention code [1]

Not applicable

Comparator / control treatment

The comparator/control group are healthy controls that do not have a haematological malignancy.

Control group

Active

Outcomes

Primary outcome [1]

Levels of blood IgG anti-spike titres for FL/WM patients treated with immunochemotherapy/BTKi compared to treatment-naïve FL/WM patients and healthy controls.

Timepoint [1]

T1. Baseline (Day of 1st vaccine dose or up to 2 weeks prior).
T2. Post 1st vaccine dose (Day of 2nd dose, or any day a minimum of 21 days post 1st dose).
T3. Post 2nd vaccine dose (28 days +/- 14 days post 2nd dose)
T4. 6 months (180 days +/- 30 days post 2nd dose).
T5. 12 months following 2nd vaccination (+/- 30 days): this time point is not yet confirmed and will depend on data analysed following T4 and appropriateness for collection.

Primary outcome [2]

Levels of blood antigen-specific T-cell responses for FL patients treated with immunochemotherapy compared to treatment-naïve FL patients and healthy controls.

Timepoint [2]

T1. Baseline (Day of 1st vaccine dose or up to 2 weeks prior).
T2. Post 1st vaccine dose (Day of 2nd dose, or any day a minimum of 21 days post 1st dose).
T3. Post 2nd vaccine dose (28 days +/- 14 days post 2nd dose)
T4. 6 months (180 days +/- 30 days post 2nd dose).
T5. 12 months following 2nd vaccination (+/- 30 days): this time point is not yet confirmed and will depend on data analysed following T4 and appropriateness for collection.

Primary outcome [3]

Phenotype of blood T-cell response by multi-parameter flow-cytometry for FL/WM patients treated with immunochemotherapy/BTKi compared to treatment-naïve FL/WM patients and healthy controls.

Timepoint [3]

T1. Baseline (Day of 1st vaccine dose or up to 2 weeks prior).
T2. Post 1st vaccine dose (Day of 2nd dose, or any day a minimum of 21 days post 1st dose).
T3. Post 2nd vaccine dose (28 days +/- 14 days post 2nd dose)
T4. 6 months (180 days +/- 30 days post 2nd dose).
T5. 12 months following 2nd vaccination (+/- 30 days): this time point is not yet confirmed and will depend on data analysed following T4 and appropriateness for collection.

Secondary outcome [1]

Clinical failure of COVID-19 vaccination. Measured as a patient-reported PCR-confirmed SARS-CoV-2 infection and/or clinical diagnosis of COVID-19. Assessment of degree of severity (i.e. managed as: outpatient, non-ICU inpatient care; ICU care; death). Diagnosis will be assessed through patient reported infection and from medical records.

Timepoint [1]

T1. Baseline (Day of 1st vaccine dose or up to 2 weeks prior).
T2. Post 1st vaccine dose (Day of 2nd dose, or any day a minimum of 21 days post 1st dose).
T3. Post 2nd vaccine dose (28 days +/- 14 days post 2nd dose)
T4. 6 months (180 days +/- 30 days post 2nd dose).
T5. 12 months following 2nd vaccination (+/- 30 days): this time point is not yet confirmed and will depend on data analysed following T4 and appropriateness for collection.

Secondary outcome [2]

Blood baseline antibody and T-cell responses to SARS-CoV-2 coronaviruses.

Timepoint [2]

T1. Baseline (Day of 1st vaccine dose or up to 2 weeks prior).
T2. Post 1st vaccine dose (Day of 2nd dose, or any day a minimum of 21 days post 1st dose).
T3. Post 2nd vaccine dose (28 days +/- 14 days post 2nd dose)
T4. 6 months (180 days +/- 30 days post 2nd dose).
T5. 12 months following 2nd vaccination (+/- 30 days): this time point is not yet confirmed and will depend on data analysed following T4 and appropriateness for collection.

Secondary outcome [3]

Rates of COVID-19 infection within the FL treated cohort to Pfizer vaccines and Astra Zeneca vaccine or if a mix of both vaccines is delivered to this cohort.

Timepoint [3]

T1. Baseline (Day of 1st vaccine dose or up to 2 weeks prior).
T2. Post 1st vaccine dose (Day of 2nd dose, or any day a minimum of 21 days post 1st dose).
T3. Post 2nd vaccine dose (28 days +/- 14 days post 2nd dose)
T4. 6 months (180 days +/- 30 days post 2nd dose).
T5. 12 months following 2nd vaccination (+/- 30 days): this time point is not yet confirmed and will depend on data analysed following T4 and appropriateness for collection.

Secondary outcome [4]

Difference in response within the "Phase 3 evaluation of PET-guided, Response-Adapted therapy in patients with previously untreated, high tumour burden follicular lymphoma" (PETReA) treated FL cohorts from the UK to the FL treated cohorts in Australia with our study acting as a validation cohort for the PETReA consortium.

Timepoint [4]

T1. Baseline (Day of 1st vaccine dose or up to 2 weeks prior).
T2. Post 1st vaccine dose (Day of 2nd dose, or any day a minimum of 21 days post 1st dose).
T3. Post 2nd vaccine dose (28 days +/- 14 days post 2nd dose)
T4. 6 months (180 days +/- 30 days post 2nd dose).
T5. 12 months following 2nd vaccination (+/- 30 days): this time point is not yet confirmed and will depend on data analysed following T4 and appropriateness for collection.

Secondary outcome [5]

Rates of COVID-19 infection within patients with WM cohort to Pfizer vaccines and AstraZeneca vaccine or if a mix of both vaccines is delivered to this cohort.

Timepoint [5]

T1. Baseline (Day of 1st vaccine dose or up to 2 weeks prior).
T2. Post 1st vaccine dose (Day of 2nd dose, or any day a minimum of 21 days post 1st dose).
T3. Post 2nd vaccine dose (28 days +/- 14 days post 2nd dose)
T4. 6 months (180 days +/- 30 days post 2nd dose).
T5. 12 months following 2nd vaccination (+/- 30 days): this time point is not yet confirmed and will depend on data analysed following T4 and appropriateness for collection.

Secondary outcome [6]

Patient reported differences in any adverse reactions/side effects reported between FL treated and FL treatment-naïve groups.

Timepoint [6]

T1. Baseline (Day of 1st vaccine dose or up to 2 weeks prior).
T2. Post 1st vaccine dose (Day of 2nd dose, or any day a minimum of 21 days post 1st dose).
T3. Post 2nd vaccine dose (28 days +/- 14 days post 2nd dose)
T4. 6 months (180 days +/- 30 days post 2nd dose).
T5. 12 months following 2nd vaccination (+/- 30 days): this time point is not yet confirmed and will depend on data analysed following T4 and appropriateness for collection.

Secondary outcome [7]

Patient reported differences in any adverse reactions/side effects reported between WM treated and WM treatment-naïve groups.

Timepoint [7]

T1. Baseline (Day of 1st vaccine dose or up to 2 weeks prior).
T2. Post 1st vaccine dose (Day of 2nd dose, or any day a minimum of 21 days post 1st dose).
T3. Post 2nd vaccine dose (28 days +/- 14 days post 2nd dose)
T4. 6 months (180 days +/- 30 days post 2nd dose).
T5. 12 months following 2nd vaccination (+/- 30 days): this time point is not yet confirmed and will depend on data analysed following T4 and appropriateness for collection.

Secondary outcome [8]

Blood baseline antibody and T-cell responses to seasonal “common cold” coronaviruses.

Timepoint [8]

T1. Baseline (Day of 1st vaccine dose or up to 2 weeks prior).
T2. Post 1st vaccine dose (Day of 2nd dose, or any day a minimum of 21 days post 1st dose).
T3. Post 2nd vaccine dose (28 days +/- 14 days post 2nd dose)
T4. 6 months (180 days +/- 30 days post 2nd dose).
T5. 12 months following 2nd vaccination (+/- 30 days): this time point is not yet confirmed and will depend on data analysed following T4 and appropriateness for collection.

Secondary outcome [9]

Rates of hospitalisation and death within the FL treated cohort to Pfizer vaccines and Astra Zeneca vaccine or if a mix of both vaccines is delivered to this cohort.

Timepoint [9]

T1. Baseline (Day of 1st vaccine dose or up to 2 weeks prior).
T2. Post 1st vaccine dose (Day of 2nd dose, or any day a minimum of 21 days post 1st dose).
T3. Post 2nd vaccine dose (28 days +/- 14 days post 2nd dose)
T4. 6 months (180 days +/- 30 days post 2nd dose).
T5. 12 months following 2nd vaccination (+/- 30 days): this time point is not yet confirmed and will depend on data analysed following T4 and appropriateness for collection.

Secondary outcome [10]

Rates of hospitalisation and death within the WM treated cohort to Pfizer vaccines and Astra Zeneca vaccine or if a mix of both vaccines is delivered to this cohort.

Timepoint [10]

T1. Baseline (Day of 1st vaccine dose or up to 2 weeks prior).
T2. Post 1st vaccine dose (Day of 2nd dose, or any day a minimum of 21 days post 1st dose).
T3. Post 2nd vaccine dose (28 days +/- 14 days post 2nd dose)
T4. 6 months (180 days +/- 30 days post 2nd dose).
T5. 12 months following 2nd vaccination (+/- 30 days): this time point is not yet confirmed and will depend on data analysed following T4 and appropriateness for collection.

Eligibility

Key inclusion criteria

1. Patient with low grade FL treated with immunochemotherapy
2. Patients with FL who are treatment-naïve.
3. Patients with WM currently on treatment with a BTKi
4. Patients with WM during or following treatment with standard immunochemotherapy
5. Patients with WM who are treatment-naïve.
6. A group of healthy volunteers who are controls

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

1. Patients with additional medical co-morbidities and/or medications that compromise their immune function (e.g. inflammatory bowel disease, rheumatoid arthritis, SLE, HIV, high dose prednisolone for reasons other than lymphoma treatment). If there is any doubt, the final decision will rest with the PI.
2. Those not wishing to consent

Study design

Statistical methods / analysis

The Head of Biostatistics at the Kirby Institute, Prof Matthew Law, has determined the minimum numbers needed to detect a 4 fold decreased in anti-spike Ab (compared with healthy volunteers) following COVID-19 vaccinations. These data are based on the original published licensing data for both the Pfizer and AstraZeneca vaccines. For the Pfizer vaccine the estimate is n=4 for both cohort and healthy controls to determine a 4-fold decreased with 80% power. For the AstraZeneca vaccine it is n=7 for both cohort group and healthy controls. Therefore given the robustness of the published data we are confident of detecting significantly lower Ab titres as proposed.

Descriptive statistics of continuous data will be based on means (standard deviation) or median (interquartile range) depending on data normality. Categorical data will be summarised using frequency distributions. Differences between groups (anti-SARS-CoV-2 antibodies, Neutralising Ab test and Antigen-specific T cell responses) will be determined by the non-parametric Mann-Whitney tests.

Analyses of the outcomes will adhere to the Intention to Treat (ITT) principle, where all participants will be included unless specified otherwise. Analysis of endpoints will be according to cohort. p-values will be considered significant if <0.05.

Recruitment

Recruitment status

Active, not recruiting

Date of first participant enrolment

Anticipated

Actual

18/05/2021

Date of last participant enrolment

Anticipated

Actual

16/06/2021

Date of last data collection

Anticipated

30/06/2022

Actual

Sample size

Target

80

Accrual to date

Final

85

Recruitment in Australia

Recruitment state(s)

NSW

Recruitment hospital [1]

Concord Repatriation Hospital - Concord

Recruitment postcode(s) [1]

2139 - Concord

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Department of Haematology, Concord Repatriation General Hospital

Country [1]

Australia

Funding source category [2]

Charities/Societies/Foundations

Name [2]

International Waldenstrom's Macroglobulinaemia Foundation (IWMF)

Country [2]

United States of America

Primary sponsor type

Hospital

Name

Concord Repatriation General Hospital

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Country [1]

Other collaborator category [1]

University

Name [1]

The Kirby Institute, The University of New South Wales

Country [1]

Australia

Other collaborator category [2]

Charities/Societies/Foundations

Name [2]

WMozzies

Country [2]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Sydney Local Health District HREC

Ethics committee address [1]

Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

01/05/2021

Approval date [1]

07/05/2021

Ethics approval number [1]

X21-0120

Summary

Brief summary

People with haematological malignancies are at increased risk of severe disease and death from COVID-19. New vaccines from Pfizer and AstraZeneca are reporting high immunogenicity and efficacy in clinical trials, but there is lack of data regarding how well people with haematological cancers respond to vaccines, to what extent and how durable responses may be.

It seems reasonable that responses will differ in patients with haematological malignancy, based on both disease factors and factors related to specific anti-cancer treatments. Follicular lymphoma (FL) and Waldenstrom Macroglobulinaemia (WM) are two low grade non-Hodgkin lymphomas that offer potential models to study the impact of immunocompromisation on the immunogenicity of the COVID-19 vaccines.

This study, combined with our evolving understanding of which types of vaccine responses are most important in conferring long-term protection against COVID-19, will allow people with FL and WM to make better informed decisions about treatment induction and maintenance options when indicated. It will also provide patients who have already completed treatment a better idea of how much protection to expect and what additional precautions might be required (e.g. preventative pharmacological agents in development, ongoing isolation if necessary, or additional vaccination if evidence emerges to support that).

Trial website

Public notes

Contacts

Principal investigator

Name

Dr Brendan Beaton

Address

Department of Haematology,
Ground East, Main Building
Concord Hospital
1 Hospital Road, Concord, NSW, Australia, 2139

Country

Australia

Phone

+61 2 9767 5765

Email

[email protected]

Contact person for public queries

Name

Judith Trotman

Address

Department of Haematology,
Ground East, Main Building
Concord Hospital
1 Hospital Road, Concord, NSW, Australia, 2139

Country

Australia

Phone

+61 2 9767 7243

Email

[email protected]

Contact person for scientific queries

Name

Judith Trotman

Address

Department of Haematology,
Ground East, Main Building
Concord Hospital
1 Hospital Road, Concord, NSW, Australia, 2139

Country

Australia

Phone

+61 2 9767 7243

Email

[email protected]

Trial Review

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