Condition category
Digestive System
Date applied
04/06/2018
Date assigned
08/06/2018
Last edited
14/08/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

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 2021

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

Who is the main contact?
Mr Sean Gaines
Sean.gaines@liverpool.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Mr Sean Gaines

ORCID ID

Contact details

Clinical Trials Research Centre
University of Liverpool
1st Floor Institute of Child Health
Alder Hey Children's NHS
Foundation Trust
Liverpool
L12 2AP
United Kingdom
+44 (0)151 794 9774
Sean.gaines@liverpool.ac.uk

Additional identifiers

EudraCT number

2017-003840-19

ClinicalTrials.gov number

Protocol/serial number

38354

Study information

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

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

South Central - Oxford C Research Ethics Committee, 04/07/2018, ref: 17/FC/0262
MHRA, 13/08/2018
HRA approval pending

Study design

Randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Specialty: Gastroenterology, Primary sub-specialty: Pancreatico-biliary; UKCRC code/ Disease: Oral and Gastrointestinal/ Disorders of gallbladder, biliary tract and pancreas

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

Phase

Phase II

Drug names

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 trial start date

01/01/2018

Overall trial end date

30/04/2021

Reason abandoned (if study stopped)

Eligibility

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 type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 290; UK Sample Size: 290

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

01/07/2018

Recruitment end date

30/09/2020

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Royal Liverpool and Broadgreen University Hospitals NHS Trust (Lead Site)
Royal Liverpool University Hospital Prescot Street
Liverpool
L7 8XP
United Kingdom

Trial participating centre

Glasgow Royal Infirmary
West Of Scotland Pancreatic Unit Castle Street
Glasgow
G4 0SF
United Kingdom

Trial participating centre

University Hospitals Birmingham NHS Foundation Trust
Trust HQ, PO Box 9551 Queen Elizabeth Medical Centre Edgbaston
Birmingham
B15 2TH
United Kingdom

Trial participating centre

Leeds Teaching Hospital NHS Trust
St James’s University Hospital Beckett Street
Leeds
LS9 7TF
United Kingdom

Sponsor information

Organisation

University of Liverpool

Sponsor details

-
Liverpool
L69 3BX
United Kingdom
+44 (0)151 794 8739
sponsor@liv.ac.uk

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: 15/20/01

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal as soon as possible after trial completion.

IPD sharing statement
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

30/04/2022

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

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