Randomised Treatment of Acute Pancreatitis With Infliximab: Double-blind Multi-centre Trial (RAPID-I)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase IIb, Randomised, Double-blind, Placebo-controlled, Multi-centre Trial of Infliximab With Transcriptomic Biomarker and Mechanism Evaluation in Patients With Acute Pancreatitis.

Conditions
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Acute Pancreatitis

Intervention / Treatment
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* Drug: Infusion of 5 mg/kg Infliximab
* Drug: Infusion of 10 mg/kg Infliximab
* Other: 0.9% Sodium Chloride (Placebo)


Participation Criteria
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Eligibility Criteria
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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 the onset of abdominal pain 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 Onset of abdominal pain over 24 h before admission Previous AP 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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 the onset of abdominal pain. Treatment allocation will only be revealed to those responsible for trial treatment preparation (Pharmacy or an independent research time not administering the trial medication) to ensure the research team administering the treatment remains blinded.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Infusion of 5 mg/kg Infliximab<br>Infliximab (Remicade) to be administered as a one time intravenous infusion in 250 ml (500 ml if patient weighs over 100 kg) 0.9% sodium chloride solution over a period of 2 hours. Dosage calculated at 5 mg of Infliximab, per kg of patient body weight. | Drug: Infusion of 5 mg/kg Infliximab<br>* 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).<br>* Other names: Remicade;|
| Active Comparator: Infusion of 10 mg/kg Infliximab<br>Infliximab (Remicade) to be administered as a one time intravenous infusion in 250 ml (500 ml if patient weighs over 100 kg) 0.9% sodium chloride solution over a period of 2 hours. Dosage calculated at 10 mg of Infliximab, per kg of patient body weight. | Drug: Infusion of 10 mg/kg Infliximab<br>* 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).<br>* Other names: Remicade;|
| Placebo Comparator: 0.9% Sodium Chloride (Placebo)<br>250 ml (500 ml if patient weighs over 100 kg) 0.9% Sodium Chloride to be administered as a one time intravenous infusion over a period of 2 hours. | Other: 0.9% Sodium Chloride (Placebo)<br>* 250 ml (500 ml if patient weighs over 100 kg) of 0.9% Sodium Chloride<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in mean serum CRP measured on days 2, 4, 7, 14 and 28 | 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. | Days 2, 4, 7, 14 and 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain scores | Patient will complete a Numerical Rating Scale.The scale is from 0-10 (0= no pain and 10 = worst pain possible) | First 28 Days | 
| Opiate requirements | Recording of daily morphine equivalents by research team | First 28 days | 
| Nutritional deficit | Number of days nil by mouth +/- specified nutritional support | First 28 days | 
| Decline in serum albumen | Albumen measured via blood samples | First 28 days | 
| Decline in haematocrit | Haematocrit measured via blood sample | First 28 days | 
| Rise in neutrophils | Neutrophils measured in blood samples | First 28 days | 
| Systemic inflammatory response syndrome | Duration from admission in days | First 28 days | 
| Sequential organ failure assessment (SOFA) score | Summed respiratory (0-4), cardiovascular (0-4) and renal (0-4) SOFA scores on each of the first 28 days after hospital admission | First 28 days | 
| Local pancreatic injury | Contrast-enhanced CT scan assessed by a central panel | Day 14 only | 
| Revised Atlanta Classification (RAC) | RAC severity classification (mild, moderate or severe) | 90 days after admission | 
| Infective complications | Infective complications reported | First 90 days | 
| Length of hospital stay | Length of time patient remains within hospital as an inpatient | Up to 90 days | 
| Mortality | Patient death | Within the first 90 days | 
| Patient reported outcome | EuroQol EQ-5D-5L | Day 4, Day 14, Day 28 and Day 90 | 
| Potential safety signals | Adverse events relating to infliximab including infusion reactions and delayed serum sickness reactions | Up to 90 days | 
| Anti-infliximab antibody concentration | Blood sample analysis to determine the concentration of anti-infliximab antibodies | Day 28 | 
| Incremental cost per quality adjusted life years (QALY) gained by trial treatment | QALYs using data from the EQ-5D-5L questionnaire | Days 4, 14 , 28 and 90 |