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

Acute Pancreatitis Clinical Trial

— RAPID-I  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03684278
• Other study ID #: UoL001326
• Secondary ID: 2017-003840-1915
• Status: Recruiting
• Phase: Phase 2
• Start date: May 1, 2019
• Est. completion date: April 30, 2024

Study information

• Verified date: March 2022
• Source: University of Liverpool
• Contact: Matt Smyth, BSc
• Phone: TBC
• Email: rapid.one[@]liverpool.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 290
• Est. completion date: April 30, 2024
• Est. primary completion date: October 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Pancreatitis
• Pancreatitis

Intervention

Drug:
• Infusion 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).
• Infusion 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).

Other:
• 0.9% Sodium Chloride (Placebo)
250 ml (500 ml if patient weighs over 100 kg) of 0.9% Sodium Chloride

Locations

Country	Name	City	State
United Kingdom	Royal Liverpool University Hospital	Liverpool	Merseyside

Sponsors (8)

Lead Sponsor	Collaborator
Professor Robert Sutton	Bangor University, Liverpool Clinical Trials Centre, Liverpool University Hospitals NHS Foundation Trust, Medical Research Council, Merck Sharp & Dohme Corp., National Institute for Health Research, United Kingdom, University of Liverpool

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Opiate requirements	Recording of daily morphine equivalents by research team	First 28 days
Secondary	Nutritional deficit	Number of days nil by mouth +/- specified nutritional support	First 28 days
Secondary	Decline in serum albumen	Albumen measured via blood samples	First 28 days
Secondary	Decline in haematocrit	Haematocrit measured via blood sample	First 28 days
Secondary	Rise in neutrophils	Neutrophils measured in blood samples	First 28 days
Secondary	Systemic inflammatory response syndrome	Duration from admission in days	First 28 days
Secondary	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
Secondary	Local pancreatic injury	Contrast-enhanced CT scan assessed by a central panel	Day 14 only
Secondary	Revised Atlanta Classification (RAC)	RAC severity classification (mild, moderate or severe)	90 days after admission
Secondary	Infective complications	Infective complications reported	First 90 days
Secondary	Length of hospital stay	Length of time patient remains within hospital as an inpatient	Up to 90 days
Secondary	Mortality	Patient death	Within the first 90 days
Secondary	Patient reported outcome	EuroQol EQ-5D-5L	Day 4, Day 14, Day 28 and Day 90
Secondary	Potential safety signals	Adverse events relating to infliximab including infusion reactions and delayed serum sickness reactions	Up to 90 days
Secondary	Anti-infliximab antibody concentration	Blood sample analysis to determine the concentration of anti-infliximab antibodies	Day 28
Secondary	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