The impact of pausing BTKi therapy and responsiveness of vaccination in blood cancer patients: A randomised controlled study – the IMPROVE study
| ISRCTN | ISRCTN14197181 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN14197181 |
| IRAS number | 319057 |
| Secondary identifying numbers | IRAS 319057, CPMS 53957 |
- Submission date
- 03/09/2022
- Registration date
- 20/09/2022
- Last edited
- 03/04/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Plain English summary of protocol
Background and study aims
Chronic lymphocytic leukaemia (CLL) is a blood cancer that affects the white blood cells called lymphocytes. It is the commonest adult leukaemia, with 3,800 people diagnosed each year in the UK. It is more common in people aged over 60 years. Currently some 31,900 people have CLL in the UK.
CLL develops slowly and there is no cure. People with CLL have a weakened immune system and are susceptible to infections. These infections can be severe and life-threatening. New drugs called Bruton Tyrosine Kinase inhibitors (BTKi) have transformed the outlook for CLL patients, however they stop the immune response to vaccination. They need to be taken daily and continuously. They are sometimes paused if a patient needs an operation. In the UK, they are used at all stages of treatment. The IMPROVE study aims to find out:
Does pausing BTKi inhibitor drugs for a total of three weeks before and after having the COVID vaccine improve the antibody response and is this well tolerated?
Who can participate?
Adults with well-controlled CLL who have been taking a BTKi inhibitor for at least a year, and are due to have a COVID vaccine
What does the study involve?
The study aims to recruit 120 people at up to 10 NHS hospital sites. Half (60) will be asked to pause their treatment for three weeks: one week before their vaccine, and two weeks after. The other half (60) will continue their treatment as usual. Blood samples will be taken to check everyone’s vaccine response three weeks and 12 weeks after vaccination. The participant's CLL will also be monitored and participants will be asked to complete questionnaires about their quality of life.
What are the possible benefits and risks of participating?
In March 2020 everyone with CLL was advised to shield. To date, most people with CLL continue to shield as best they can. Advice from haematologists is to be as careful as possible. This means they are largely trapped in their homes, feeling increasingly left behind as the rest of society moves on. It is now COVID-19 that is restricting life for people with CLL and their families, rather than their CLL. The problem is people with CLL have very poor responses to COVID-19 vaccines in comparison to the general population. For those on BTKi inhibitor drugs, it is a double whammy as the drugs make it even more unlikely that patient will respond to COVID-19 vaccination. As COVID-19 is here to stay, further vaccine doses are likely to be recommended for clinically vulnerable patients. The IMPROVE study aims to see if this 3 week's pausing of BTKi therapy would help protect people with CLL and allow them to resume a more normal life.
With regards to risks, to participate in the study, 3 blood samples need to be taken – so there are the risks that come with a blood sample being taken. The questions/questionnaires used in this study are not mandatory and do not ask questions that might embarrass a participant.
Improving vaccination responses has been a hot topic between clinicians and the CLL community for many years. COVID-19 has made this a priority. People with CLL co-designed the IMPROVE study and are partners in governing, managing and advising throughout the study.
Where is the study run from?
The study is overseen by the University of Birmingham, and the Chief Investigator, Dr Helen Parry is based there. Researchers and those experienced in running clinical studies are managing the study at the University of Oxford. The researchers in Oxford are specifically based in the Oxford Clinical Trials Research Unit (OCTRU). Participants are aimed to be recruited from NHS hospitals across the UK that have the permissions to approach participants to consider taking part in the IMPROVE study.
When is the study starting and how long is it expected to run for?
August 2022 to January 2024
Who is funding the study?
National Institute for Health and Social Care Research (NIHR), Efficacy and efficiency mechanism (EME) programme (UK)
Who is the main contact?
improve@ndorms.ox.ac.uk
Contact information
Public
OCTRU
Botnar Research Centre
University of Oxford
Windmill Road
Oxford
OX3 7LF
United Kingdom
 ORCID ID |
0000-0001-9631-3666 |
|---|---|
| Phone | +44 (0)1865223469 |
| improve@ndorms.ox.ac.uk |
Study information
| Study design | Multicentre parallel-group two-arm superiority open-label randomized controlled study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Other |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | A multi-centre randomised controlled trial examining the effects of temporarily pausing Bruton Tyrosine Kinase inhibitor therapy to coincide with SARS-CoV-2 vaccination and its impact on immune responses in patients with Chronic Lymphocytic Leukaemia |
| Study acronym | IMPROVE |
| Study objectives | The aim of this study is to assess whether a temporary three-week pause of daily Bruton tyrosine kinase inhibitor (BTKi) treatment around SARS-CoV-2 vaccination improves the immune response in people with chronic lymphocytic leukaemia (CLL) whilst maintaining disease control. |
| Ethics approval(s) | Approved 09/09/2022, Leeds East Research Ethics Committee (Yorkshire and the Humber – Leeds East, NHSBT Newcastle Blood Donor Centre, Holland Drive, Newcastle upon Tyne, NE2 4NQ, UK; +44 (0)207 104 8105, +44 (0)2071048170; leedseast.rec@hra.nhs.uk), ref: 22YH0226 |
| Health condition(s) or problem(s) studied | Chronic lymphocytic leukaemia |
| Intervention | The intervention is a 3-week temporary pause (suspension) of existing ongoing BTKi therapy. The 3-week temporary pause starts 1 week before vaccination 6 days of no BTKi administration, then on day 7 of no BTKi – COVID vaccination is received and then another 14 days of no BTKi administration – in total 21 days of tablets are omitted). The BTKi therapy being paused will either be Acalabrutinib or Ibrutinib at any dose, and those participating in the study will have been on a BTKi for at least 12 months prior to study enrolment. The control group will not have any pausing in the BTKi administration for the purpose of COVID vaccination. All participants will have data collection at Baseline (pre-vaccination), 3 weeks post-COVID vaccination and 12 weeks post-COVID vaccination. Blood sampling will occur at each of these timepoints. Participants will be invited into clinics for blood sampling, and data collection. Participants will also have the option to answer some of the questionnaires at 3 and 12 weeks electronically before attending the clinic visit. Participants are randomised when they know they have a confirmed COVID vaccination date and are randomised using an online tool by researchers in IMPROVE. Randomisation allocations will be including stratification and participants will equally (1:1) to intervention and control arms based on the stratification factor of the BTKi therapy the participant is taking – their first line or subsequent therapy for CLL. |
| Intervention type | Other |
| Primary outcome measure | Anti-SARS-CoV-2 spike (S) protein receptor binding domain (RBD) antibody levels measured using Roche Elecsys® electrochemiluminescence assay (Roche S) at baseline and at 3 weeks post-SARS-CoV-2 vaccination |
| Secondary outcome measures | 1. Anti-spike (IgG, IgA and IgM) RBD antibody levels measured using Roche Elecsys® electrochemiluminescence assay (Roche S) at baseline and at 12 weeks post-SARS-CoV-2 vaccination 2. Neutralising antibody titre levels at 50% and 90% against Wuhan D614G (B.1) and the current variant of concern (VOC) ) will be assessed using validated laboratory methods at baseline, 3 and 12 weeks post SARS-CoV-2 vaccination 3. Antigen-specific T-cell response for ancestral Wuhan and 1 x VOC spike, and combined nucleocapsid and membrane response measured using the enzyme-linked immunosorbent spot (ELISpot) assay at baseline and 3 weeks post-SARS-CoV-2 vaccination 4. Antibody response to 4 strains of influenza present in the Autumn 22 vaccine (continuous OD 450nm read out) measured using ELISA [For those who receive flu vaccination only] at baseline and 3 weeks post SARS-CoV-2 vaccination 5. Disease activity questions (raised temperature, enlarged or new lymph nodes) measured using a non-validated questionnaire answered by participants electronically at baseline, 3 and 12 weeks post-SARS-CoV-2 vaccination or a participant attending their 3-week clinic visit – if the adherence questions have not been completed they will be asked to complete the questions at that visit 6. Full Blood Count (Haemoglobin, platelet levels and lymphocyte levels) measured using standard medical laboratory methods at baseline, 3 and 12 weeks post SARS-CoV-2 vaccination 7. Blood Film (presence of new prolymphocytes, smear cells or lymphocytosis) measured using standard medical laboratory methods at baseline, 3 and 12 weeks post SARS-CoV-2 vaccination 8. Lactate dehydrogenase levels measured using standard medical laboratory methods at baseline, 3 and 12 weeks post SARS-CoV-2 vaccination 9. Health-related quality of life (HRQoL) measured using the EORTC-QLQ-CLL17 scales (symptom burden, physical condition/fatigue, and worries/fears on health and functioning) at baseline, 3 and 12 weeks post-SARS-CoV-2 vaccination 10. Self-reported adherence measured using a non-validated questionnaire answered by participants electronically at 3 weeks post-SARS CoV-2 vaccination – or a participant attending their 3-week clinic visit – if the adherence questions have not been completed they will be asked to complete the questions at that visit |
| Overall study start date | 01/08/2022 |
| Completion date | 31/01/2024 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 120 |
| Total final enrolment | 99 |
| Key inclusion criteria | 1. Aged 18 years and over 2. Confirmed diagnosis of chronic lymphocytic leukaemia 3. Taking oral NICE-approved BTKi therapy (Acalabrutinib or Ibrutinib) for at least 12 months since the date of initiation of therapy 4. Has achieved complete remission (CR; including CR with incomplete marrow recovery), partial remission (PR; including nodular PR or PR with lymphocytosis) or stable disease by the International Workshop on CLL (iwCLL) response criteria 5. Considered able to temporarily pause (suspend) BTKi therapy for three weeks without the risk of a substantial increase in disease activity 6. Anticipated to take BTKi over the next 4 months (i.e. not in the STATIC trial arm where therapy is stopped) 7. Willing to accept either study arm allocation 8. Able to give informed consent 9. Eligible for a planned vaccination for COVID-19 |
| Key exclusion criteria | 1. Insufficient time for applying the intervention prior to the planned COVID-19 vaccination. 2. Diagnosed with alternative conditions requiring treatment with BTKi 3. Treated with anti-CD20 antibody therapy in the last 18 months or planning to start it 4. Concurrent immune suppressive treatments in the last 3 months specifically: methotrexate, ciclosporin, BCL-2 inhibitors, azathioprine, mycophenolate, prednisolone, biologic agents 5. Any contraindication to COVID-19 vaccination 6. Richter’s transformation requiring active therapy 7. Radiotherapy or cancer chemotherapy in the last 6 months 8. Active solid organ cancer (people with skin cancer or those cured of solid organ cancer are eligible) 9. Receiving or has received in the past 6 months immunoglobulin replacement therapy 10. Receiving or has received in the past 6 months monoclonal antibody against COVID-19 spike protein |
| Date of first enrolment | 23/09/2022 |
| Date of final enrolment | 30/06/2023 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Mindelsohn Way
Edgbaston
Birmingham
B15 2GW
United Kingdom
Denmark Hill
London
SE5 9RS
United Kingdom
Stoke-on-trent
ST4 6QG
United Kingdom
Hucknall Road
Nottingham
NG5 1PB
United Kingdom
Oxford
OX3 7LE
United Kingdom
Lyndon
West Bromwich
B71 4HJ
United Kingdom
Pensnett Road
Dudley
DY1 2HQ
United Kingdom
Clifford Bridge Road
Coventry
CV2 2DX
United Kingdom
Bodelwyddan
Rhyl
LL18 5UJ
United Kingdom
Derriford Road
Crownhill
Plymouth
PL6 8DH
United Kingdom
Lodge Road
Caerleon
Newport
NP18 3XQ
United Kingdom
Sponsor information
University/education
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
| Phone | +44 (0)1214143344 |
|---|---|
| researchgovernance@contacts.bham.ac.uk | |
| Website | https://www.birmingham.ac.uk/index.aspx |
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- NIHR Efficacy and Mechanism Evaluation Programme, EME
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/03/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | The sponsor will retain ownership of all data arising from the study. Publication and dissemination of study results and associated study publications (e.g. the study protocol, statistical analysis plan (SAP) and secondary analyses) will be in accordance with the OCTRU Standard Operating Procedure and irrespective of study findings. The study protocol will be published in an open-access peer-reviewed journal in accordance with the Standard Protocol Items: Recommendations for Interventional Trials statement (SPIRIT, www.spirit-statement.org/). The study results will be published in an open-access journal, in accordance with the NIHR’s policy on open-access research. The study will be reported following the Consolidated Standards of Reporting Trials guideline (CONSORT) including any applicable extensions to this. The Template for Intervention Description and Replication (TIDieR) statement will be used for reporting the intervention. |
| IPD sharing plan | The sponsor will retain ownership of all data arising from the study. Participant level dataset and statistical code will be made available upon reasonable request to OCTRU and the CI, once the IMPROVE study findings have been published in full. Some specific data items may not be shared in order to maintain participant anonymity. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | 28/09/2023 | 29/09/2023 | Yes | No | |
| Results article | 01/04/2025 | 03/04/2025 | Yes | No |
Editorial Notes
03/04/2025: Publication reference added.
17/01/2024: The total final enrolment was added.
29/09/2023: Publication reference added.
28/04/2023: Aneurin Bevan University Local Health Board was added as a trial participating centre.
17/04/2023: University Hospitals Plymouth NHS Trust was added as a trial participating centre.
27/03/2023: The recruitment end date has been changed from 31/03/2023 to 30/06/2023.
27/01/2023: Glan Clwyd Hospital was added as a trial participating centre. Ethics approval details added.
12/10/2022: The Dudley Group NHS Foundation Trust and University Hospitals Coventry & Warwickshire NHS Trust have been added as trial participating centres.
20/09/2022 Trial's existence confirmed by NIHR.
