Identifying markers of successful dose reduction in the maintenance phase of tofacitinib treatment of ulcerative colitis
| ISRCTN | ISRCTN18820528 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN18820528 |
| IRAS number | 276727 |
| Secondary identifying numbers | IRAS 276727, CPMS 49789 |
- Submission date
- 09/08/2021
- Registration date
- 07/09/2021
- Last edited
- 20/11/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Digestive System
Plain English summary of protocol
Background and study aims
Tofacitinib is an orally administered drug that has been shown to be effective in patients with moderate to severe ulcerative colitis (UC), an incurable, chronic inflammatory condition of the large bowel. The tofacitinib clinical trials demonstrate that the 10mg twice daily maintenance dose is superior to the 5mg twice daily dose in those with prior treatment failure for UC. Accordingly, many practitioners favour continuing the 10mg twice daily dose in higher-risk patients with prior treatment-resistant disease, rather than dropping to the 5mg twice daily maintenance dose at week 8 (or week 16 in those slower to respond).
This dosing decision needs to be balanced against the potential risk of continuing at the higher dose; there is a higher risk of side effects such as infection and blood clots with the 10mg twice daily dose.
Given that most patients who are receiving tofacitinib are treatment resistant, there is an urgent need to identify ways to predict which patients are more likely to flare should their dose reduce. Such biomarkers would enable us to risk stratify our patients at the point of consideration of dose reduction, to enable assessment of the risk and benefit of dose reduction versus continuation at the higher dose.
This study aims to explore clinical and laboratory-based markers (from blood and colon tissue), which in turn may to help make key treatment decisions for tofacitinib-treated patients. We hypothesise that patients who relapse following dose reduction will have changes in cytokine expression of their pro-inflammatory T cells in peripheral blood mononuclear cells (PBMCs), increased STAT activation in PBMCs, and possibly signature genes in their colonic tissue.
Who can participate?
Adults aged 18 years or above with a history of ulcerative colitis, as defined by standard clinical criteria and who are having their tofacitinib dose reduced from 10mg BD to 5mg BD in view of an adequate response, as decided by their treating clinical team, and are undergoing routine endoscopy.
What does the study involve?
Participants will go ahead with participants flexible sigmoidoscopy (camera test) as planned. The endoscopist will take a series of 12 extra biopsies for this study in addition to 2-4 standard biopsies. The biopsy samples will be used for two purposes; 1, to make another assessment of how active participants' colitis is and 2, to carry out scientific analysis to identify genes that may act as predictors of relapse. This analysis aims to study RNA (a photocopy of the DNA), which acts as a messenger and can give important clues about the processes that occur within the bowel during disease relapse.
Immediately following the procedure, in addition to standard baseline blood tests we will also take an additional vial of blood for this study (approximately 5 teaspoons). This will be to allow us to perform analyses looking for inflammatory messengers and markers that may predict relapse.
Should participants undergo another flexible sigmoidoscopy if participants were to relapse, and after 44 weeks of dose reduction as is standard, the study biopsies and blood tests will be repeated in addition to standard tests. Otherwise, participants will be managed by the participants treating team in the standard way. Participants' participation in the study will end if the relapse means that participants need to stop tofacitinib and commence a different drug, or if the relapse means that participants require surgery to remove the large bowel. Participating in this study will not affect how participants are treated. We will monitor participants' progress and collect participants' data that will come from participants' standard investigations and management.
What are the possible benefits and risks of participating?
Although there are no direct benefits to the patient by taking part, the results and analyses from this study may help other patients who have ulcerative colitis and are being treated with tofacitinib.
Where is the study run from?
Guy's and St Thomas' NHS Foundation Trust (UK)
When is the study starting and how long is it expected to run for?
August 2019 to October 2023
Who is funding the study?
Pfizer (UK)
Who is the main contact?
Dr Sailish Honap, shonap@nhs.net
Contact information
Public
Department of Gastroenterology
St Thomas' Hospital
Westminster Bridge Road
Lambeth
London
SE1 7EH
United Kingdom
 ORCID ID |
0000-0001-6657-2763 |
|---|---|
| Phone | +44 (0)207 1882499 |
| shonap@nhs.net |
Scientific
Department of Gastroenterology
St Thomas' Hospital
Westminster Bridge Road
Lambeth
London
SE1 7EH
United Kingdom
| ORCID ID |
0000-0003-0972-8148 |
|---|---|
| Phone | +44 (0)2071882499 |
| peter.irving@gstt.nhs.uk |
Scientific
Department of Immunobiology
Floor 2, Borough Wing
Guy’s Hospital
St Thomas’ Street
London
SE1 9RT
United Kingdom
| ORCID ID |
0000-0002-5620-1982 |
|---|---|
| Phone | +44 (0)2071889614 |
| susan.john@kcl.ac.uk |
Study information
| Study design | Prospective multi-centre observational study |
|---|---|
| Primary study design | Observational |
| Secondary study design | Cohort study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | 40268 BRITE_PIS_03_08_21v2.0.docx |
| Scientific title | Biomarkers of Relapse In ulcerative colitis patients after Tofacitinib dose rEduction (BRITE) |
| Study acronym | BRITE |
| Study objectives | We hypothesise that patients who relapse following maintenance dose reduction of tofacitinib will have increased markers of pro-inflammatory effector T cells in peripheral blood and inflamed mucosal tissue. The principal questions we aim to address are as follows; 1. Is there increased activation of STAT proteins in peripheral blood in patients who relapse? 2. Are there changes in cytokine expression in peripheral T cells that predict relapse? 3. Can we identify signature gene(s) that serve as a biomarker to predict relapse? |
| Ethics approval(s) | Approved 11/08/2021, Yorkshire & The Humber - Leeds East Research Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, UK; +44 (0)207 104 8018; leedseast.rec@hra.nhs.uk), ref: 21/YH/0148 |
| Health condition(s) or problem(s) studied | Adult patients in the maintenance phase of tofacitinib treatment of ulcerative colitis |
| Intervention | This is a prospective, observational, investigator-initiated study with an overarching objective to identify biochemical and genetic markers of patients more likely to flare after tofacitinib dose reduction. This will eventually allow us to target continued higher dosing of 10mg bd at those patients who are most likely to benefit from it and avoid its use in patients in whom it is potentially unnecessary. Thereby, it would enable using the drug in a safer, more effective, and more economical manner. We will prospectively enrol a cohort of 50 UC patients who have achieved an adequate response to tofacitinib at a dose of 10mg bd and whose dose is being reduced to 5mg bd. Post-induction flexible sigmoidoscopy will be performed as part of routine clinical care and colonic tissue and blood samples will be collected at study entry. Patients' disease course will be followed-up through routine care to the point of flare, or week 44 post-induction. Briefly, to address the study questions above, we will firstly monitor the phosphorylation of STAT proteins in peripheral blood mononuclear cells from patients enrolled in the study, with blood drawn before dose reduction and at the point of flare. Secondly, we will evaluate cytokine expression in peripheral CD4 T cells to see if there are any changes that predict relapse. Finally, we will compare gene expression profiles from colonic tissue of patients who remain symptomless on the lower dose of tofacitinib with those patients who ultimately show clear clinical signs of relapse. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Tofacitinib |
| Primary outcome measure | At week 44 and at relapse (if applicable): 1. Clinical status (simple clinical colitis activity index and partial Mayo score) 2. C-reactive protein and faecal calprotectin 3. Histological markers of disease activity (Nancy histological index) 4. STAT activation in peripheral blood mononuclear cells 5. Cytokine expression in peripheral T cells 6. Gene signatures in colonic biopsies |
| Secondary outcome measures | There are no secondary outcome measures |
| Overall study start date | 23/08/2019 |
| Completion date | 31/10/2023 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 50 |
| Total final enrolment | 50 |
| Key inclusion criteria | 1. Aged 18 years or over, either male or female 2. A history of ulcerative colitis, as defined by standard clinical criteria 3. Patients who are having their tofacitinib dose reduced from 10mg BD to 5mg BD in view of adequate response, as decided by their treating clinical team, and are undergoing routine endoscopy. 4. Sufficient English language skills to understand the patient information sheet and consent form. |
| Key exclusion criteria | 1.Patients undergoing dose reduction for reasons other than adequate response to 10mg bd (ie. active infection or VTE risk). 2. Patients being dose reduced without undergoing endoscopy 3. Patients with insufficient English language skills to understand the patient information sheet and consent form. |
| Date of first enrolment | 10/09/2021 |
| Date of final enrolment | 01/09/2022 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Department of Gastroenterology
1st Floor College House
South Wing
London
SE1 7EH
United Kingdom
Sponsor information
Hospital/treatment centre
R&D Department
16th Floor, Tower Wing
Great Maze Pond
Guy's Hospital
London
SE1 9RT
England
United Kingdom
| Phone | +44 (0)2071889811 |
|---|---|
| R&D@gstt.nhs.uk | |
| Website | https://www.guysandstthomas.nhs.uk/Home.aspx |
"ROR" |
https://ror.org/00j161312 |
University/education
Room 5.31
James Clerk Maxwell Building
57 Waterloo Road
London
SE1 8WA
England
United Kingdom
| Phone | +44 (0)207 8483224 |
|---|---|
| reza.razavi@kcl.ac.uk | |
| Website | https://www.kcl.ac.uk/ |
|
"ROR" |
https://ror.org/0220mzb33 |
Funders
Funder type
Industry
Government organisation / For-profit companies (industry)
- Alternative name(s)
- Pfizer Inc., Pfizer Consumer Healthcare, Davis, Charles Pfizer & Company, Warner-Lambert, King Pharmaceuticals, Wyeth Pharmaceuticals, Seagen
- Location
- United States of America
Results and Publications
| Intention to publish date | 01/09/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Other |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. Data presented and published will be in an aggregated/summarised form and will not be available at participant level. |
| IPD sharing plan | All data generated or analysed during this study will be included in the subsequent results publication. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version 2.0 | 03/08/2021 | 11/08/2021 | No | Yes |
| Protocol file | version 1.0 | 07/06/2021 | 13/08/2021 | No | No |
| HRA research summary | 20/09/2023 | No | No |
Additional files
Editorial Notes
20/11/2024: The intention to publish date was changed from 01/09/2024 to 01/09/2025.
10/10/2023: The contact confirmed the record is up to date.
20/09/2023: A link to the HRA research summary was added.
15/09/2023: The following changes were made to the study record:
1. The study design was changed from 'Prospective single-centre observational study' to 'Prospective multi-centre observational study'.
2. The overall study end date was changed from 01/09/2023 to 31/10/2023.
08/06/2023: The following changes were made to the study record:
1. The recruitment end date was changed from 05/06/2023 to 01/09/2022.
2. The overall study end date was changed from 05/06/2023 to 01/09/2023.
3. The intention to publish date was changed from 05/06/2024 to 01/09/2024.
4. Total final enrolment added.
01/10/2021: The CPMS number was added to the protocol/serial no. field.
11/08/2021: Trial's existence confirmed by Yorkshire & The Humber - Leeds East Research Ethics Committee.
