Clinical trial NCT03684278: Randomised Treatment of Acute Pancreatitis With Infliximab: Double-blind, Placebo-controlled, Multi-centre 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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Pancreatitis
Lead sponsor: University of Liverpool
Sponsor class: OTHER
Collaborators: name: Bangor University
name: Liverpool University Hospitals NHS Foundation Trust
name: Medical Research Council
name: National Institute for Health Research, United Kingdom
name: Merck Sharp & Dohme LLC
First posted: 2018-09-25
Enrollment: 290
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Difference in mean serum CRP measured on days 2, 4 and 14
timeFrame: Days 2, 4 (+/- 1 day), and 14 (+/- 2 days)
Secondary outcomes:
measure: Pain scores
timeFrame: First 14 Days
measure: Opiate requirements
timeFrame: First 14 days
measure: Nutritional deficit
timeFrame: First 14 days
measure: Decline in serum albumen
timeFrame: First 14 days
measure: Rise in neutrophils
timeFrame: First 14 days
measure: Sequential organ failure assessment (SOFA) score
timeFrame: First 14 days
measure: Local pancreatic injury
timeFrame: Day 14 +/- 7 days
measure: Revised Atlanta Classification (RAC)
timeFrame: 90 days after admission
measure: Infective complications
timeFrame: First 90 days
measure: Length of hospital stay
timeFrame: Up to 90 days
measure: Mortality
timeFrame: Within the first 90 days
measure: Patient reported outcome
timeFrame: Day 4, Day 14 and Day 90
measure: Potential safety signals
timeFrame: Up to 90 days
measure: Anti-infliximab antibody concentration
timeFrame: Day 14
measure: Incremental cost per quality adjusted life years (QALY) gained by trial treatment
timeFrame: Days 4, 14 and 90
measure: Infliximab concentration
timeFrame: Day 14
Other outcomes:
Locations:
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
state: Aberdeenshire
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
state: Cornwall
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
state: Devon
city: London
country: United Kingdom
facility: University College London Hospital
state: Greater London
city: London
country: United Kingdom
facility: St Mary's Hospital
state: Greater London
city: London
country: United Kingdom
facility: Charing Cross Hospital
state: Greater London
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
state: Merseyside
city: Liverpool
country: United Kingdom
facility: Aintree University Hospital
state: Merseyside
city: Whiston
country: United Kingdom
facility: Whiston Hospital
state: Merseyside
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
state: Nottinghamshire
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
state: Oxfordshire
city: Leeds
country: United Kingdom
facility: St James's University Hospital
state: West Yorkshire
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
Study officials:
affiliation: University of Liverpool
name: Robert Sutton, DPhil, FRCS
role: PRINCIPAL_INVESTIGATOR
References: