Randomised treatment of Acute Pancreatitis with Infliximab: Double-blind, placebo-controlled, multi-centre trial

ISRCTN	ISRCTN16935761
DOI	https://doi.org/10.1186/ISRCTN16935761
ClinicalTrials.gov (NCT)	NCT03684278
Clinical Trials Information System (CTIS)	2017-003840-19
Protocol serial number	38354
Sponsor	University of Liverpool
Funder	NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: 15/20/01

Submission date: 04/06/2018
Registration date: 08/06/2018
Last edited: 01/07/2026

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Digestive System

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Acute pancreatitis is a serious condition in which the pancreas becomes inflamed and is damaged. It causes intense abdominal pain and may lead to multiple organ failure. Those suffering from the disease may need help with breathing, heart and kidney function. One in twenty patients with acute pancreatitis dies, which is more likely to happen to those who develop organ failure. Treatment can be prolonged, often with extended stays in hospital of many weeks. To date many drugs have been tested to treat acute pancreatitis, but none cure the illness or accelerate recovery. This study tests a drug called infliximab, which is made from natural protein and is currently used to treat bowel and joint disease. Infliximab works by blocking an important process in the progression of the disease. This process leads to inflammation in both the pancreas and other parts of the body. The study also looks to see if there are any links between genes and the development of acute pancreatitis, and to see if there are any links between the genes and the way infliximab works. This may help target the right treatment to the right patients and help gain understanding of how infliximab works. If infliximab is beneficial in the treatment of acute pancreatitis, major improvements will be possible in the health of a large number of NHS patients, patient suffering and hospital waiting times will be reduced, and significant savings will be made to NHS costs.

Who can participate?
Adult patients attending A&E with acute pancreatitis

What does the study involve?
Participants are randomly allocated to receive a single, 2-hour infusion of either 5 mg/kg infliximab, 10 mg/kg infliximab, or placebo (dummy drug). Infliximab is given within half a day of a patient arriving in hospital, much earlier than with other drugs tested in acute pancreatitis. Whilst the patient is in hospital, information is recorded and blood samples are taken. Patients are followed up until Day 90 (Day 1 beginning from when the patient receives the trial infusion).

What are the possible benefits and risks of participating?
Acute pancreatitis is a common and serious disease that needs emergency admission to hospital, but there are no medicines to cure the illness or speed up recovery. By taking part in this study, participants may find their symptoms of acute pancreatitis get better. Infliximab helps in bowel and joint disease and early research shows that infliximab may help patients with acute pancreatitis. The results of this study may help others with acute pancreatitis and will be valuable in developing new medicines to treat acute pancreatitis. Millions of patients in the world have been treated with infliximab for various diseases. Infliximab is a safe medicine and usually very well tolerated. Side effects from infliximab are uncommon. Most side effects occur with repeated doses of infliximab, unlike in this study which tests a single dose of infliximab. The two side effects that could occur with a single dose of infliximab, although unlikely, are allergic reactions (also known as infusion reactions) and infections. This study also requires exposures to ionising radiation. Depending on their clinical indications, participants will receive a chest x-ray at screening and a dual phase CT scan for the diagnosis and/or monitoring of pancreatitis. Depending upon the clinical indications, the number of CT scans as standard of care can vary but is likely to be less than three, although more may be performed if indicated. Participants will only receive one additional examination although it is noted that this examination may be performed as part of the standard of care.

Where is the study run from?
1. Royal Liverpool and Broadgreen University Hospitals NHS Trust (UK)
2. Glasgow Royal Infirmary (UK)
3. University Hospitals Birmingham NHS Foundation Trust (UK)
4. Leeds Teaching Hospital NHS Trust (UK)

When is the study starting and how long is it expected to run for?
June 2019 to March 2027

Who is funding the study?
National Institute for Health Research (NIHR) (UK)

Who is the main contact?
Rapid.One@liverpool.ac.uk

Contact information

Mr Matthew Smyth
Scientific

Clinical Trials Research Centre
University of Liverpool
2nd Floor Institute of Child Health
Alder Hey Children's NHS
Foundation Trust
Liverpool
L12 2AP
United Kingdom

Phone	+44 (0)151 794 9774
Email	Rapid.One@liverpool.ac.uk

Study information

Primary study design	Interventional
Study design	Randomised; Interventional; Design type: Treatment, Drug
Secondary study design	Randomised controlled trial
Scientific title	Phase IIb, randomised, double-blind, placebo-controlled, multi-centre trial of infliximab with transcriptomic biomarker and mechanism evaluation in patients with acute pancreatitis
Study acronym	RAPID-I
Study objectives	Acute pancreatitis is a serious condition in which the pancreas becomes inflamed and is damaged. It causes intense abdominal pain and may lead to multiple organ failure. Those suffering from the disease may need help with breathing, heart and kidney function. One out of twenty patients with acute pancreatitis dies, which is more likely to happen to those who develop organ failure. Treatment can be prolonged, often with extended stays in hospital of many weeks. To date many drugs have been tested to treat acute pancreatitis, but none cure the illness or accelerate recovery. In this trial we are testing a drug called infliximab, which is made from natural protein and is currently used to treat bowel and joint disease. Infliximab works by blocking an important process in the progression of the disease. This process leads to inflammation in both the pancreas and other parts of the body. In the trial, infliximab is given once within half a day of a patient arriving in hospital, much earlier than with other drugs tested in acute pancreatitis. Whilst the patient is in hospital, information will be recorded and blood samples will be taken. Patients will be followed up for 90 days after trial treatment. The study will also look to see if there are any links between genes and the development of acute pancreatitis, and to see if there are any links between the genes and the way infliximab works. This may help target the right treatment to the right patients and help gain understanding of how infliximab works. If infliximab is beneficial in the treatment of acute pancreatitis, major improvements will be possible in the health of a large number of NHS patients, patient suffering and hospital waiting times will be reduced and significant savings will be made to NHS costs.
Ethics approval(s)	Approved 04/07/2018, South Central - Oxford C Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 02071048271; oxfordc.rec@hra.nhs.uk), ref: 18/SC/0262
Health condition(s) or problem(s) studied	Acute pancreatitis
Intervention	Current interventions: Participants will be randomised using an online web randomisation system, by a delegated member of the research team to receive a single, 2-hour infusion of either: Arm A: 5 mg/kg infliximab Arm B: 10 mg/kg infliximab (Following the recommendation of the Independent Data and Safety Monitoring Committee, the 10 mg/kg infliximab arm was stopped on 19/05/2026 owing to a lack of efficacy) Arm C: placebo (0.9% sodium chloride) Participants will be randomised to treatment allocations in a ratio of 1:1:1, stratified by individual research sites. Patients will only receive a single, 2-hour infusion of their treatment allocation. Infliximab is given within half a day of a patient arriving in hospital, much earlier than with other drugs tested in acute pancreatitis. Whilst the patient is in hospital, information will be recorded and blood samples will be taken. Patients will be followed up until Day 90 (Day 1 beginning from when the patient receives the trial infusion). Previous interventions: Participants will be randomised using an online web randomisation system, by a delegated member of the research team to receive a single, 2-hour infusion of either: Arm A: 5 mg/kg infliximab Arm B: 10 mg/kg infliximab Arm C: placebo (0.9% sodium chloride) Participants will be randomised to treatment allocations in a ratio of 1:1:1, stratified by individual research sites. Patients will only receive a single, 2-hour infusion of their treatment allocation. Infliximab is given within half a day of a patient arriving in hospital, much earlier than with other drugs tested in acute pancreatitis. Whilst the patient is in hospital, information will be recorded and blood samples will be taken. Patients will be followed up until Day 90 (Day 1 beginning from when the patient receives the trial infusion).
Intervention type	Drug
Phase	Phase II
Drug / device / biological / vaccine name(s)	Infliximab
Primary outcome measure(s)	Mean serum C-reactive protein in either active arm (5 mg/kg or 10 mg/kg) versus the placebo arm measured using standard methods (summated as area under the curve) at Days 2, 4 (+/- 1 day) and 14 (+/- 2 days) Previous primary outcome as of 01/07/2026: The primary efficacy outcome measure will be the difference in mean serum C-reactive protein measured on Days 2, 4, 7, 14 and 28 (summated as area under the curve) in either active arm (5 mg/kg or 10 mg/kg) versus the placebo arm; Timepoint(s): End of the study
Key secondary outcome measure(s)	Current key secondary outcomes as of 01/07/2026: 1. Cumulative pain score measured using a numerical rating scale (between 0-10) for the first 28 days 2. Opiate requirements measured using the recording of daily morphine equivalents for the first 28 days 3. Nutritional deficit measured using the recording of the number of days without solid food for the first 28 days 4. Decline in serum albumin (negative AUC) measured using blood samples for the first 28 days 5. Rise in neutrophils (AUC) measured using blood samples for the first 28 days 6. Organ function, disease progression, and mortality risk measured using the cumulative Sequential Organ Failure Assessment (SOFA) score for the first 28 days 7. Local pancreatic injury measured using contrast-enhanced computerised tomography scan (CECT day 14 +/- 7 days) 8. Infection measured using selected data collection up until day 90 9. Length of stay measured using selected data collection up until day 90 10. Mortality measured using selected data collection up until day 90 11. Patient reported outcome measured using the EQ-5D-5L on Days 4 (+/- 1 day), 14 (+/- 2 days) and 90 (+/- 7 days). Previous key secondary outcomes: 1. Cumulative Pain Scores: patients will complete a numerical rating scale (between 0-10) for the first 28 days 2. Opiate requirements: recording of daily morphine equivalents for the first 28 days 3. Nutritional deficit: number of days nil by mouth +/- nutritional support for the first 28 days 4. Decline in serum albumin, measured via blood samples for the first 28 days 5. Decline in haematocrit, measured via blood samples for the first 28 days 6. Rise in neutrophils, measured via blood samples for the first 28 days 7. Presence and duration of systemic inflammatory response syndrome, present (duration of response) or absent, for the first 28 days 8. Cumulative serial organ failure assessment (SOFA score) for the first 28 days 9. Local pancreatic injury, measured using a contrast-enhanced CT scan, assessed by a centralised panel on Day 14 10. Pancreatic sufficiency, measured by: 10.1. Faecal elastase on Day 28 and Day 90 10.2. HbA1c on Day 90 11. Severity classification, measured using the Revision of the Atlanta Classification (RAC), as and when classified 12. Infective complications, any complications reported, for the first 90 days 13. Length of hospital stay, length of time patients remain within the hospital as an inpatient, up to Day 90 14. Mortality within the first 90 days 15. Patient-reported outcome: patients will complete EuroQol EQ-5D-5L, including the EQ-VAS (visual analogue scale) questionnaire on Days 4, 14, 28 and 90 16. Potential safety signals, adverse events relating to infliximab, including infusion reactions and delayed serum sickness reactions, up to 90 days 17. Further safety signal, reports of significant increase in the incidence of infective complications associated with the use of infliximab over placebo, up to 90 days 18. Antibodies to infliximab assessed using blood sample analysis on Day 28 19. Absolute and/or relative expression of selected transcripts: blood samples collected for exploratory safety analyses using selected transcripts on Days 2, 4, 7, 14 and 28 20. Cytokine and leucocyte subsets profiles, assessed using blood sample analysis on Days 2, 4, 7, 14 and 28 21. Discriminant function (trial treatment versus placebo) of efficacy measures across domains: clinical, laboratory, critical care, local injury, infection, length of stay and patient reported outcome domains: selected data collected for the trial will be used for this outcome up until day 90 22. Incremental cost per quality adjusted life years (QALY) gained by trial treatment, measured using data from the EQ-5D-5L questionnaire on Days 4, 14 , 28 and 90 23. Time to recruitment of target sample size (290 patients, anticipated to be 24 months). Please note as adaptive design is used target sample size may reduce.
Completion date	07/03/2027

Eligibility

Participant type(s)	Patient
Age group	Mixed
Lower age limit	18 Years
Upper age limit	85 Years
Sex	All
Target sample size at registration	290
Key inclusion criteria	Current participant inclusion criteria as of 01/07/2026: 1. Adult patients attending A&E at or admitted to recruiting hospitals via a General Practitioner with a new diagnosis of AP established by two of: 1.1. Typical continuous upper abdominal pain 1.2. Amylase and/or lipase three or more times the upper limit of normal 1.3. Characteristic findings on abdominal imaging (if undertaken urgently by CT or magnetic resonance imaging, MRI);↲ and 2) Patients in whom trial treatment can be started as soon as possible and within 36 hours of admission, allowing 120 min within the 36-hour period for preparation of trial medication; and 3) Patients from whom appropriate consent is obtained (consent to be given by the patient or their legal representative). Previous participant inclusion criteria as of 14/08/2018: 1. Adult patients attending A&E at or admitted to recruiting hospitals via a general practitioner with a new diagnosis of AP established by two of: 1.1. Typical continuous upper abdominal pain 1.2. Amylase and/or lipase three or more times the upper limit of normal; 1.3. Characteristic findings on abdominal imaging (if undertaken urgently by CT or magnetic resonance imaging, MRI); 2. Patients in whom trial treatment can be started within 12 hours of recorded admission and allowing 120 min for pharmacy to prepare trial medication 3. Patients from whom appropriate consent is obtained (consent to be given by the patient or their legal representative). Previous participant inclusion criteria: 1. Adult patients attending A&E at recruiting centres from whom appropriate consent is obtained (consent to be given by the patient or their legal representative) 2. Patients in whom trial treatment can be started within 12 hours of admission (allowing 120 min for Pharmacy to prepare trial medication) 3. A new diagnosis of AP (all severity levels) as established by two of: 3.1. Typical continuous upper abdominal pain 3.2. Amylase and/or lipase three or more times the upper limit of normal 3.3. Characteristic findings on abdominal imaging (if undertaken urgently) NB Please note all severity levels of AP are to be included in the trial
Key exclusion criteria	Current exclusion criteria as of 01/07/2026: 1. Age <18 or >85 2. Patients with a body weight of over 200 kilograms 3. Known previous AP diagnosed within the last 30 days or known chronic pancreatitis 4. Known multiple sclerosis, systemic vasculitis, Guillain-Barré syndrome or other demyelinating disorder 5. Known epilepsy 6. Moderate to severe heart failure and/or coronary heart disease (New York Heart Association (NYHA) Functional Class III/IV) 7. Known severe respiratory conditions, including cystic fibrosis, severe asthma and severe chronic obstructive pulmonary disease (COPD), on home oxygen or home mechanical ventilation 8. Jaundice (serum bilirubin >50 µmol/L), and/or known advanced liver disease, on waiting list for liver transplantation or considered unsuitable for transplantation 9. Known cancer for which chemotherapy and/or radiotherapy is ongoing or was completed within less than 6 months from admission 10. Known haematological malignancy 11. Known cancer that is end-stage with ongoing palliative care or for which palliative care is appropriate 12. Known established infection prior to or suspected infection, including COVID-19§, at the time of AP onset 13. Known history of (including that identified on chest x-ray) or household contact with individuals who have tuberculosis or opportunistic infection 14. Known history of infective hepatitis (unless recovered from previous hepatitis A) 15. Known rare diseases or inborn errors of metabolism that significantly increase the risk of infections, including severe combined immunodeficiency (SCID) and homozygous sickle cell disease 16. Known immunosuppressive or biologic therapy within one month of admission 17. Known live vaccines or therapeutic infectious agents within one month of admission 18. Known hypersensitivity to infliximab or to inactive components of infliximab or to any murine proteins 19. Known pregnancy or lactation at the time of admission 20. Women of childbearing potential who do not agree to use adequate contraception (includes prior surgical sterilisation; birth control pill, patch or injection; intrauterine device; male or female condom (but not both); female cap with spermicide or total sexual abstinence; but not periodic abstinence, withdrawal or spermicides only), up to 6 months after trial infusion treatment 21. Known to be currently participating in a trial testing any investigational medicinal product or participation in a clinical study involving a medicinal product in the last three months Previous key exclusion criteria: 1. Age < 18 or > 85 2. Body weight > 200 kg 3. Onset of abdominal pain more than 24 hours before admission to the hospital 4. Known previous acute pancreatitis or chronic pancreatitis 5. Known multiple sclerosis, systemic vasculitis, Guillain-Barré syndrome or other demyelinating disorder 6. Known epilepsy 7. Moderate to severe heart failure and/or coronary heart disease (New York Heart Association (NYHA) Functional Class III/IV) 8. On home oxygen or home mechanical ventilation 9. Known advanced liver disease, on waiting list for liver transplantation or considered unsuitable for transplantation 10. Known cancer for which chemotherapy and/or radiotherapy is ongoing or was completed within less than 6 months from admission 11. Known haematological malignancy 12. Known cancer that is end-stage with ongoing palliative care or for which palliative care is appropriate 13. Known established infection prior to the onset of acute pancreatitis 14. Known history of (including that identified on chest x-ray) or household contact with individuals who have tuberculosis or opportunistic infection 15. Known history of infective hepatitis 16. Known immunosuppressive or biologic therapy within one month of admission 17. Known live vaccines or therapeutic infectious agents within one month of admission 18. Known hypersensitivity to infliximab or to inactive components of REMICADE® or to any murine proteins 19. Known pregnancy or lactation at the time of admission 20. Women of childbearing potential who do not agree to use adequate contraception up to Day 90 21. Known to be currently participating in a trial testing any investigational medicinal product or participation in a clinical study involving a medicinal product in the last three months
Date of first enrolment	05/06/2019
Date of final enrolment	30/11/2026

Locations

Countries of recruitment

United Kingdom
England
Scotland
Wales

Study participating centres

Royal Liverpool and Broadgreen University Hospitals NHS Trust (Lead Site)

Royal Liverpool University Hospital
Prescot Street
Liverpool
L7 8XP
England

Leeds Teaching Hospital NHS Trust

St James’s University Hospital
Beckett Street
Leeds
LS9 7TF
England

John Radcliffe Hospital

Headley Way
Headington
Oxford
OX3 9DU
England

Aberdeen Royal Infirmary

Foresterhill Road
Aberdeen
AB25 2ZN
Scotland

University Hospital Aintree

Fazakerley Hospital
Lower Lane
Liverpool
L9 7AL
England

University College London Hospital

250 Euston Road
London
NW1 2PG
England

Royal Devon and Exeter Hospital

Gladstone Road
Exeter
EX1 2ED
England

University Hospital of Wales

Heath Park
Cardiff
CF14 4XW
England

University Hospital of North Tees

Hardwick Road
Stockton-on-tees
TS19 8PE
England

Results and Publications

Individual participant data (IPD) Intention to share	No

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No

Editorial Notes

01/07/2026: The following changes were made:
1. A public title was added.
2. Date of first enrolment was changed from 30/09/2018 to 05/06/2019.
3. Date of final enrolment was changed from 30/04/2023 to 30/11/2026.
4. Completion date was changed from 30/04/2023 to 07/03/2027.
5. The interventions, primary and key secondary outcomes, key inclusion and exclusion criteria were updated.
6. Wales was added as a country of recruitment, and the study centres were updated.
02/11/2022: The intention to publish date has been changed from 30/04/2022 to 30/10/2022.
02/09/2022: The following changes were made to the trial record:
1. The contact was changed.
2. The overall end date was changed from 30/04/2021 to 30/04/2023.
3. The recruitment end date was changed from 30/09/2020 to 30/04/2023.
4. The plain English summary was updated to reflect these changes.
24/04/2020: Due to current public health guidance, recruitment for this study has been paused.
10/01/2020: ClinicalTrials.gov number added.
19/07/2019: Ethics approval details added.
22/03/2019: The condition was updated from "Specialty: Gastroenterology, Primary sub-specialty: Pancreatico-biliary; UKCRC code/ Disease: Oral and Gastrointestinal/ Disorders of gallbladder, biliary tract and pancreas" to "Acute pancreatitis".
16/08/2018: The following changes were made to the trial record:
1. Ethics approval information has been added.
2. The recruitment start date has been changed from 01/07/2018 to 30/09/2018.
14/08/2018: The following changes were made to the trial record:
1. Ethics approval information has been added.
2. Drug phase information has been added.
3. Pancreatic sufficiency was added as secondary outcome measure 10.
4. The participant inclusion criteria have been updated.
5. Participant exclusion criterion 2 was added.
6. Manchester University NHS Foundation Trust and University College London Hospitals NHS Foundation Trust were removed as trial participating centres.
7. Manchester University NHS Foundation Trust and University College London Hospitals NHS Foundation Trust were removed as study sites from the plain English summary.