Acute Pancreatitis
Conditions
Brief summary
This study evaluates the effectiveness and safety of infliximab in the treatment of acute pancreatitis in adults. A third of participants will receive one single dose of infliximab via infusion, another third will receive a higher dose of infliximab via infusion and the final third of participants will receive a placebo infusion.
Detailed description
Acute pancreatitis (AP) is an inflammatory disorder of the pancreas causing excruciating pain, gastrointestinal dysfunction and pronounced systemic inflammatory responses with circulatory and respiratory disturbances that can lead to organ failure and death. Tumour necrosis factor alpha (TNFα) has a major role in the pathogenesis and severity of acute pancreatitis. TNFα levels rise early and remain elevated for days in human AP, proportional to severity, presenting a suitable drug target to inhibit the amplified immune responses that further damage the pancreas and drive widespread organ dysfunction. Infliximab is a chimeric monoclonal antibody biologic drug that blocks the actions of tumor necrosis factor alpha (TNF-α) and is normally used to treat autoimmune diseases. Infliximab has been selected as it is given via intravenous infusion, which will ensure rapid bioavailability to treat AP. This is different from most other biologics, which are given subcutaneously. This trial will determine the efficacy of early initiation of anti-TNF treatment in AP, setting new standards for trials in AP. Using a randomised, double-blind, placebo-controlled adaptive design, with two doses of a single intravenous infusion of infliximab at 5 mg/kg or 10 mg/kg, the trial will determine size of any effect and safety of this treatment.
Interventions
DRUGInfusion of 5 mg/kg Infliximab
Infliximab is a prescription drug with marketing authorisation for the treatment of rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis. In the RAPID-I trial infliximab will be used outside the manufacturer's indication for the treatment of AP, and it is classed as an investigational medicinal product (IMP).
DRUGInfusion of 10 mg/kg Infliximab
Infliximab is a prescription drug with marketing authorisation for the treatment of rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis. In the RAPID-I trial infliximab will be used outside the manufacturer's indication for the treatment of AP, and it is classed as an investigational medicinal product (IMP).
250 ml (500 ml if patient weighs over 100 kg) of 0.9% Sodium Chloride
Sponsors
Bangor University
Liverpool University Hospitals NHS Foundation Trust
Medical Research Council
National Institute for Health Research, United Kingdom
Merck Sharp & Dohme LLC
University of Liverpool
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Once the delegated research team member performs randomisation and the staff member responsible for preparation of trial medication is provided with the allocation to either Arm A, B or C, that latter staff member will prepare the infusion, which will be covered by an opaque sleeve and labelled for blinding.
Intervention model description
RAPID-I is a randomised, placebo-controlled, double-blind, multi-centre, three-arm, phase IIb efficacy trial of infliximab in patients with AP. Patients will be randomised (1:1:1 allocation ratio) to receive an intravenous infusion of either 5 mg/kg or 10 mg/kg infliximab or placebo, initiated within 36 hours of admission to hospital with acute pancreatitis. Treatment allocation will only be revealed to those responsible for trial treatment preparation (Pharmacy or an independent research team not administering the trial medication) to ensure the research team administering the treatment remains blinded.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Adult patients attending Accident and Emergency (A&E) at or admitted to recruiting hospitals via a GP with a new diagnosis of AP established by two of the following three criteria: (1) typical continuous upper abdominal pain; (2) amylase and/or lipase three or more times the upper limit of normal; (3) characteristic findings on abdominal imaging (if undertaken urgently by CT or MRI) * Patients in whom trial treatment can be started within 36 hours of admission to hospital with a new diagnosis of acute pancreatitis allowing 120 min for preparation of trial medication * Patients from whom appropriate consent is obtained (from the patient or their legal representative).
Exclusion criteria
* Age \<18 or \>85 * Patients with a bodyweight over 200 kg * Known previous AP within the last 30 days or chronic pancreatitis * Multiple sclerosis, systemic vasculitis, Guillain-Barré syndrome or other demyelinating disorder * Known epilepsy * Moderate to severe heart failure and/or coronary disease (NYHA III/IV) * Severe respiratory conditions including cystic fibrosis, severe asthma and severe chronic obstructive pulmonary disease (COPD) * On home oxygen or home mechanical ventilation * Jaundice and/or known advanced liver disease * Known cancer for which chemotherapy and/or radiotherapy ongoing/completed in last 6 months * Known haematological malignancy * Known cancer with palliative care * Known established infection prior to or suspected infection, including COVID-19, at the time of AP onset * Known history of tuberculosis, or household contact with those with tuberculosis or opportunistic infection * Known history of infective hepatitis * Rare diseases or inborn errors of metabolism that significantly increase the risk of infections, including severe combined immunodeficiency (SCID) and homozygous sickle cell disease * Known live vaccine or infectious agent within one month of admission * Known immunosuppressive or biologic therapy within one month of admission * Known hypersensitivity to infliximab or to inactive components of REMICADE® or to any murine proteins * Known pregnancy or lactation at admission * Females of childbearing potential who do not agree to use adequate contraception up to 6 months after infliximab infusion * Known participation in investigational medicinal product study within last three months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in mean serum CRP measured on days 2, 4 and 14 | Days 2, 4 (+/- 1 day), and 14 (+/- 2 days) | Difference in mean serum CRP measured on (summated as AUC) in the active arms (5 mg/kg or 10 mg/kg) versus the placebo arm. CRP assays will be undertaken on blood samples centrally to ensure standardised measurement, and when central measurements of CRP at specific time points are not available for any patient, CRP measures from that patient's specific recruiting centre will be sought. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Opiate requirements | First 14 days | Recording of daily morphine equivalents by research team |
| Nutritional deficit | First 14 days | Number of days without solid food for first 14 days |
| Decline in serum albumen | First 14 days | Albumen measured via blood samples |
| Rise in neutrophils | First 14 days | Neutrophils measured in blood samples |
| Sequential organ failure assessment (SOFA) score | First 14 days | Summed respiratory (0-4), cardiovascular (0-4) and renal (0-4) SOFA scores on each of the first 28 days after hospital admission |
| Local pancreatic injury | Day 14 +/- 7 days | Contrast-enhanced CT scan assessed by a central panel |
| Revised Atlanta Classification (RAC) | 90 days after admission | RAC severity classification (mild, moderate or severe) |
| Pain scores | First 14 Days | Patient will complete a Numerical Rating Scale.The scale is from 0-10 (0= no pain and 10 = worst pain possible) |
| Length of hospital stay | Up to 90 days | Length of time patient remains within hospital as an inpatient |
| Mortality | Within the first 90 days | Patient death |
| Patient reported outcome | Day 4, Day 14 and Day 90 | EuroQol EQ-5D-5L |
| Potential safety signals | Up to 90 days | Adverse events relating to infliximab including infusion reactions and delayed serum sickness reactions |
| Anti-infliximab antibody concentration | Day 14 | Blood sample analysis to determine the concentration of anti-infliximab antibodies |
| Incremental cost per quality adjusted life years (QALY) gained by trial treatment | Days 4, 14 and 90 | QALYs using data from the EQ-5D-5L questionnaire |
| Infliximab concentration | Day 14 | Infliximab measured in blood samples |
| Infective complications | First 90 days | Infective complications reported |
Countries
United Kingdom
Contacts
Primary ContactMatt Smyth, BSc
Backup ContactCatherine E Spowart, BSc
Outcome results
None listed