A phase II randomised placebo controlled double blind trial of Interleukin 1 blockade in Acute Severe Colitis
Ulcerative colitis (UC) is an inflammatory condition of the large bowel associated with diarrhoea, pain and bleeding that affects 120,000 people in the UK. Patients at the most severe extreme, who are hospitalised with acute severe UC (ASUC), have largely been excluded from clinical trials. Therefore limited research into new treatments for this patient group has taken place. Consequently, the initial management of ASUC has remained unchanged since 1955 and involves giving steroids through a drip. Around half of these patients do not improve after 3-5 days and need 'rescue therapy' with strong drugs to suppress the immune system. For those receiving rescue therapy, there is a 50% chance of needing major surgery to remove the large bowel. This surgery results in the need for an external drain for the faecal material through the skin (stoma), as well as long-term physical and psychological complications.
A randomised, placebo-controlled trial of anakinra in patients with ASUC offers an opportunity to understand whether this drug can benefit patients by impacting upon outcomes in a clinically meaningful manner. Although no formal health economic analysis is planned given the scale and limitations of the trial, the low cost of the trial intervention and the high cost of the outcomes we are trying to prevent (rescue therapy, prolonged admission, surgery) mean that there is also a strong possibility for potential health economic benefits to arise from a successful trial outcome.
IASO is a trial to evaluate whether anakinra is an effective treatment for patients with ASUC. The trial will test whether anakinra can reduce the need for medical or surgical rescue therapy and improve outcomes including colectomy in patients with ASUC when given alongside corticosteroids. The primary aim is to compare the clinical effects of anakinra with placebo when given in addition to current standard care. The secondary aims include assessing the effects of the intervention on disease biology and bowel inflammation, as well as drug safety, and effects on longer term health and patient-reported quality of life. The trial also aims to generate scientific data to permit analysis of plasma and tissue markers of response (both to anakinra and to steroids), in particular showing the effects of IL-1 blockade on the mucosal immune system. The trial will seek to validate a transcriptional predictor of outcomes in UC that we have previously reported.
IASO will be a multi-centre study based in UK NHS acute hospitals. The primary objective of this trial is to compare the clinical effects of anakinra with placebo when given in addition to current standard care in patients with acute severe colitis. We plan to include approximately 20 centres in the trial. All sites will recruit, treat and follow up participants equally, but a subset of sites will also recruit participants into the optional endoscopic sub-study involving one additional flexible sigmoidoscopy with biopsy collection. We plan to include approximately 214 participants in the trial with 40 participants also included in the optional endoscopic sub-study.
Main inclusion criteria
To be included in the trial the participant must:
- Be aged 16–80 years inclusive
- Have given written informed consent to participate
- Be hospitalised with clinically confirmed or suspected diagnosis of acute severe ulcerative colitis and a MTWSI score ≥11
- Have a requirement for treatment with IV corticosteroids in the judgement of the treating clinician, with the possibility to receive a first dose of trial drug within 36 hours of commencement of IV corticosteroids
Main exclusion criteria
The presence of any of the following will preclude participant inclusion:
- Pregnant or breast-feeding women
- Oral corticosteroid dosing for the treatment of UC and for a duration of 8 weeks or more immediately prior to commencement of IV corticosteroid dosing
- History of severe hepatic impairment (e.g. Child-Pugh = Grade C)
- Moderate or Severe renal impairment (estimated glomerular filtration rate [eGFR] <60ml/min/1.73m2)
- Neutropenia (neutrophil count <1.5x109/l)
- Previous treatment with anakinra for any indication
- Documented hypersensitivity to the active substance or to any of the excipients or to E. coli derived proteins; latex allergy
- Evidence (from blood cultures etc) or clinical suspicion of systemic infection*
- Current or previous cytomegalovirus (CMV) infection requiring treatment with anti-viral agents
- Current treatment with anti-TNF-α/ciclosporin therapy or anti-TNF-α/ciclosporin discontinuation within previous 16 weeks
- A history of pulmonary TB infection
- Any absolute contraindication to IV corticosteroid
- History of malignancy (with the exception of non-melanoma skin cancer) or colonic dysplasia
- Rectal therapy in previous 14 days prior to admission (sub-study exclusion only)
- Receipt of another IMP as part of a CTIMP within the previous 16 weeks
*Concurrent prescription of antibiotics to cover for the possibility of GI infection whilst awaiting stool culture and/or PCR-based detection results, or the possibility of bacterial translocation relating to severe colitis, is not an exclusion criterion where the physician suspects ulcerative colitis is the most likely diagnosis.
Funders and sponsors
Professor Arthur Kaser
Clinical Trials Coordinator: Kerstin Wolf
Telephone: 01223 257204 | Email: firstname.lastname@example.org