| ISRCTN | ISRCTN16935761 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN16935761 |
| EudraCT/CTIS number | 2017-003840-19 |
| ClinicalTrials.gov number | NCT03684278 |
| Secondary identifying numbers | 38354 |
- Submission date
- 04/06/2018
- Registration date
- 08/06/2018
- Last edited
- 02/11/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Digestive System
Plain English Summary
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?
January 2018 to April 2023
Who is funding the study?
National Institute for Health Research (NIHR) (UK)
Who is the main contact?
Rapid.One@liverpool.ac.uk
Contact information
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 |
|---|---|
| Rapid.One@liverpool.ac.uk |
Study information
| Study design | Randomised; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| 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 hypothesis | 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 (Holiday Inn Oxford, Peartree Roundabout, Woodstock Rd, Oxford, OX2 8JD, UK; Tel: +44 (0)207 104 8290, +44 (0)207 104 8041; Email: nrescommittee.southcentral-oxfordc@nhs.net), ref: 18/SC/0262 |
| Condition | Acute pancreatitis |
| Intervention | 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Infliximab |
| Primary outcome measure | 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 |
| Secondary outcome measures | 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 albumen, 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 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 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. |
| Overall study start date | 01/01/2018 |
| Overall study end date | 30/04/2023 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 290; UK Sample Size: 290 |
| Participant inclusion criteria | Current 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 |
| Participant exclusion criteria | 1. Age < 18 or > 85 2. Body weight > 200 kg 3. Onset of abdominal pain more than 24 hours before admission to 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 |
| Recruitment start date | 30/09/2018 |
| Recruitment end date | 30/04/2023 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
Study participating centres
Prescot Street
Liverpool
L7 8XP
United Kingdom
Castle Street
Glasgow
G4 0SF
United Kingdom
Queen Elizabeth Medical Centre
Edgbaston
Birmingham
B15 2TH
United Kingdom
Beckett Street
Leeds
LS9 7TF
United Kingdom
Sponsor information
University/education
-
Liverpool
L69 3BX
England
United Kingdom
| Phone | +44 (0)151 794 8739 |
|---|---|
| sponsor@liv.ac.uk | |
"ROR" |
https://ror.org/04xs57h96 |
Funders
Funder type
Government
No information available
Results and Publications
| Intention to publish date | 30/10/2022 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Planned publication in a high-impact peer reviewed journal as soon as possible after trial completion. |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
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.
