EValuating the efficacy Of upadacitinib and combination upadacitinib pLus risankizumab for the treatment of fistulising perianal Crohn's Disease – an open-label Phase IV a randomisEd controlled trial
| ISRCTN | ISRCTN71771495 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN71771495 |
| Integrated Research Application System (IRAS) | 1012946 |
| Sponsor's protocol code number | 176584 |
| Sponsor | Imperial College London |
| Funder | AbbVie |
- Submission date
- 28/07/2026
- Registration date
- 25/09/2026
- Last edited
- 25/09/2026
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Digestive System
Plain English summary of protocol
Background and study aims
A perianal fistula is an abnormal tunnel that forms between the back passage and the skin around the bottom. Fistulas can happen for different reasons. When this happens in people with Crohn’s disease (CD), it is called fistulising perianal Crohn's disease (fpCD). fpCD can cause pain around the bottom, leakage and difficulty controlling bowel movements. It is usually treated with medicine to calm down the inflammation and surgery.
It is unclear which treatments work best for people with fpCD. A recent priority-setting partnership brought patients, clinicians, and researchers together to set the top 10 research priorities for fpCD. The highest priority was finding the best treatment strategy for fpCD. This study aims to address this.
Recent research suggests that a newer treatment, licensed for CD, called upadacitinib (Upa), might be helpful in treating fpCD. We aim to research how helpful this drug is in treating fpCD in a clinical trial.
Another drug (Risa) may also be helpful in treating fpCD. Risa works on a different part of the immune system to Upa. We aim to see if combining risa with upa will help more people with fpCD than taking upa alone.
Who can participate?
Patients aged 18 years and over with active fpCD
What does the study involve?
Everyone will be given the Upa medicine. Half of people taking part in this study will also receive Risa on top of Upa. This study will look at how well the study drugs can heal fistulas and whether the fistula has stopped draining and whether the inflammation has settled on an MRI scan. We will also look at other areas that are important to people living with fpCD, such as improvement in controlling their bowel movements, depression, and quality of life. Participants will be followed up for a year after entering the study. With consent, we will also ask for sample donations from people taking part, including blood, stool, tissue and swabs.
What are the possible benefits and risks of participating?
Upadacitinib is a licensed medication in the UK that is given to people with a number of different health conditions, including Crohn’s disease. Eligibility will be assessed prior to informed consent, including an assessment of any previous reactions and treatments with JAK inhibitors.
In some cases, side effects may occur. The most common reported side effect is an infection in the nose and throat. Most cases are mild and can be dealt with using over-the-counter medication. Other less common side effects include fever, flu, headaches, acne, shingles, an increase in a type of fat in your blood, tiredness and weight gain.
Risankizumab is a licensed medication in the UK that is given to people with a number of different health conditions, including Crohn’s disease.
The most common reported side effects include the common cold, infections of the nose and throat, pain and redness where the needle went in, tiredness, itching and fungal skin infections. Where risankizumab is occurring at home, the site nurse will check in each time the participant has administered the dose. The participant will be fully trained on how to do the dose, as well as advised on good hygiene when administering the dose at home.
Participant safety will be monitored closely throughout, and a DMEC oversight committee will review presented safety data at frequent periods throughout the trial.
The type of MRI scan uses a dye called contrast to get more detailed images. A contrast dye is a chemical that is injected into the body through a vein in the arm or groin. Sometimes people can have a reaction to this. This happens in fewer than 1 in 100 people (6 in 1000). This will be explained at the informed consent stage and a check will be made by the site team at eligibility to ensure the participant can have an MRI scan safely.
The risks of a blood test are small but in some cases can include pain, a bruise at the point where the blood is taken, redness and swelling of the vein, infection, and sometimes fainting. This will be explained at each procedure and the participant will be monitored in clinic at each blood draw.
Pregnancy will be assessed at screening. Patients on JAK-inhibitor medication are advised not to become pregnant because of the potential for harm to the unborn baby. Pregnancy tests will be taken throughout the 52 weeks (if applicable). Likewise, these women must use an effective contraceptive during the course of this study.
Where is the study run from?
Imperial College London (UK)
When is the study starting and how long is it expected to run for?
September 2026 to December 2029
Who is funding the study?
AbbVie (USA)
Who is the main contact?
Amalia Ndoutoumou, rgit.ctimp.team@imperial.ac.uk
Contact information
Scientific, Public
The Media Works, 191 Wood Lane
London
W12 7FP
United Kingdom
| Phone | +44 (0)20 7594 3191 ext 00 |
|---|---|
| rgit.ctimp.team@imperial.ac.uk |
Scientific, Public
68 Wood Lane, 1st Floor
London
W12 7RH
United Kingdom
| jessica.smith1@imperial.ac.uk |
Principal investigator
Commonwealth Building, Hammersmith Hospital, Du Cane Road
London
W12 0HS
United Kingdom
| nicholas.powell@imperial.ac.uk |
Scientific
IBD Clinical Research Fellow and PhD candidate (Powell Lab)
Department of Metabolism, Digestion & Reproduction, Imperial College London
10th Floor, Commonwealth Building
Hammersmith Hospital Campus
Du Cane Road
London
W12 0NN
United Kingdom
| eathar.shakweh10@imperial.ac.uk |
Study information
| Primary study design | Interventional |
|---|---|
| Allocation | Randomized controlled trial |
| Masking | Open (masking not used) |
| Control | Active |
| Assignment | Parallel |
| Purpose | Treatment, Safety |
| Scientific title | EValuating the efficacy Of upadacitinib and combination upadacitinib pLus risankizumab for the treatment of fistulising perianal Crohn's Disease – an open-label Phase IV a randomisEd controlled trial |
| Study acronym | U-EVOLVE |
| Study objectives | Primary objective: The primary objective is to compare the efficacy of upadacitinib monotherapy with upadacitinib plus risankizumab combination therapy for the induction of clinical and radiological perianal fistula response in fistulising perianal Crohn’s disease (fpCD). Secondary objective: To characterise the molecular landscape of fpCD and treatment response through multiomic profiling in a translational sub-study. |
| Ethics approval(s) |
Not yet submitted |
| Health condition(s) or problem(s) studied | Fistulising perianal Crohn's disease (fpCD) |
| Intervention | Participants will be randomised in a 1:1 ratio using the Sealed Envelope randomisation system to one of two parallel treatment arms: Arm 1: Upadacitinib monotherapy Participants will receive upadacitinib orally at a dose of 45 mg once daily from baseline to Week 12, followed by 30 mg once daily from Week 12 to Week 48. Arm 2: Upadacitinib and risankizumab combination therapy Participants will receive upadacitinib orally at a dose of 45 mg once daily from baseline to Week 12, followed by 30 mg once daily from Week 12 to Week 48. Participants will also receive risankizumab 600 mg by intravenous infusion at Weeks 0, 4 and 8, followed by risankizumab 360 mg by subcutaneous injection every 8 weeks from Week 12 to Week 44. |
| Intervention type | Drug |
| Phase | Phase IV |
| Drug / device / biological / vaccine name(s) | Updacitinib, risankizumab |
| Primary outcome measure(s) |
The proportion of participants achieving combined clinical and radiological fistula response, where clinical fistula response is defined as a reduction of 50% or more in the number of fistula tracts that were draining at baseline assessed by clinical examination, and radiological fistula response is defined as a reduction of 4 points or more from baseline in the Magnetic Resonance Novel Index for Fistula Imaging in Crohn’s Disease (MAGNIFI-CD) score, assessed by blinded central review of pelvic magnetic resonance imaging (MRI) performed for fistula assessment, at Week 24. |
| Key secondary outcome measure(s) |
1. The proportion of participants achieving complete closure of all treated external fistula openings without development of a new fistula, abscess or significant fluid collection at Week 24, defined as clinical closure of all treated external fistula openings, with no development of a new fistula or abscess and no fluid collection measuring more than 1 cm in at least two of three dimensions on pelvic MRI performed for fistula assessment, assessed by blinded central review at Week 24. |
| Completion date | 31/12/2029 |
Eligibility
| Participant type(s) | |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 63 Years |
| Sex | All |
| Target sample size at registration | 160 |
| Key inclusion criteria | 1. Adults aged 18-63 years 2. Diagnosis of Crohn's disease (CD) with a minimum duration of at least 3 months 3. At least one active draining perianal fistula as a complication of CD, confirmed by magnetic resonance imaging (MRI) 4. Able to provide written informed consent |
| Key exclusion criteria | 1. Patients with any absolute or relative contraindication to upadacitinib 2. Patients with any absolute or relative contraindication to risankizumab 3. Currently taking part in another Clinical Trial of an Investigational Medicinal Product (CTIMP) 4. Patients unwilling or unable to provide informed consent 5. Patients with contraindications to MRI scans Pregnancy/breastfeeding exclusions: 6. Female patients who are currently/planning to become pregnant, breastfeeding, or currently/planning to donate eggs during the study period 7. Female patients who are able to become pregnant and are not willing and unable to use a highly reliable form of contraception during treatment and for 4 weeks following the final dose of upadacitinib. Acceptable forms of contraception include the following: 7.1. Established use of oral, injected or implanted hormonal methods of contraception. 7.2. Placement of an intrauterine device or intrauterine system 7.3. Male sterilisation if the vasectomised partner is the sole partner for the participant 7.4. Bilateral tubal occlusion 7.5. True abstinence (defined as refraining from any sexual relationship in which the participant may become pregnant), when this is in line with the preferred and usual lifestyle of the participant. Note periodic abstinence and withdrawal are not acceptable methods of contraception. IBD exclusions: 8. Participants previously exposed to, or treated with, upadacitinib for any indication 9. Participants previously exposed to, or treated with, risankizumab for any indication 10. Patients who have had inadequate response or loss of response to JAK inhibitors 11. Patients who have had inadequate or loss of response to p19 inhibitors 12. History of, or concurrent rectovaginal, anovaginal, or entero-vesical fistulae 13. Ulcerative colitis (UC), indeterminate colitis, ischemic colitis, fulminant colitis, or toxic mega-colon 14. Total proctocolectomy, total colectomy or likely requirement for luminal disease surgery during the study 15. Current stoma or reversal of stoma within the past 3 months Infection exclusions: 16. Any active, chronic or recurrent infection that, based on the Investigator's clinical assessment, makes the patient an unsuitable candidate for the study, including: 16.1. Tuberculosis (TB) (active TB, untreated latent TB) 16.2. Active HBV, HCV or HIV infection 16.3. Clinical, radiological or laboratory evidence or suspicion (e.g., positive blood cultures) of systemic bacterial or fungal infection 17. History of one or more prior episodes of disseminated herpes simplex (including eczema herpeticum); history of two or more prior episodes of herpes zoster, or one or more episodes of disseminated herpes zoster 18. In receipt of live vaccines in the 28 days prior to initiating upadacitinib Oncology exclusions: 19. Active malignancy 20. Significant risk factors for malignancy e.g. malignancy within the past 5 years, prior lymphoma, genetic syndromes (e.g., Lynch syndrome, FAP), unless there are no suitable treatment alternatives available 21. Current organ transplant Cardiovascular exclusions: 23. History of confirmed venous thromboembolism (VTE) or pulmonary embolism (PE) in individuals who are not on effective anticoagulation, including: 23.1. Those with a history of deep vein thrombosis (DVT) or PE who no longer require anticoagulation 23.2. Those with a history of DVT or PE requiring anticoagulation, who discontinued anticoagulation therapy due to intolerance or side effects 24. Cardiovascular disease including symptomatic ischemic heart disease, cerebrovascular disease, peripheral vascular disease and history of uncontrolled hypercholesterolaemia or lipidaemia, unless there are no suitable treatment alternatives available Metabolic exclusions: 25. Use of strong CYP3A4 inhibitor medications (azoles, clarithromycin) and co-administration of food and drink containing grapefruit 26. Use of strong CYP3A4 inducer medications (including rifampicin and phenytoin) 27. History of clinically significant (per Investigator’s judgement) illicit drug or alcohol abuse within the last 6 months 28. Screening laboratory values that meet the following criteria at the most recent testing prior to the first dose of study drug: 28.1. Neutropenia (baseline ANC <1 x 10⁹ cells/l) 28.2. Absolute Lymphocyte Count <0.75 x 10⁹ cells/l 28.3. Hb <80 g/l 28.4. Moderate or Severe renal impairment (estimated glomerular filtration rate [eGFR] <30 ml/min/1.73 m²) 28.5. Severe hepatic impairment (Child-Pugh C) |
| Date of first enrolment | 14/09/2026 |
| Date of final enrolment | 15/08/2028 |
Locations
Countries of recruitment
- United Kingdom
- England
Study participating centre
-
-
England
Results and Publications
| Individual participant data (IPD) Intention to share | No |
|---|
Editorial Notes
28/07/2026: Study's existence confirmed by the HRA.
