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

Primary Purpose

Acute Pancreatitis

Status
Recruiting
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Infusion of 5 mg/kg Infliximab
Infusion of 10 mg/kg Infliximab
0.9% Sodium Chloride (Placebo)
Sponsored by
Professor Robert Sutton
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Pancreatitis

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Royal Liverpool University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

Infusion of 5 mg/kg Infliximab

Infusion of 10 mg/kg Infliximab

0.9% Sodium Chloride (Placebo)

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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

Full Information

First Posted
July 4, 2018
Last Updated
March 1, 2022
Sponsor
Professor Robert Sutton
Collaborators
University of Liverpool, Bangor University, Liverpool University Hospitals NHS Foundation Trust, Medical Research Council, National Institute for Health Research, United Kingdom, Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT03684278
Brief Title
Randomised Treatment of Acute Pancreatitis With Infliximab: Double-blind Multi-centre Trial (RAPID-I)
Acronym
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

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Recruiting
Study Start Date
May 1, 2019 (Actual)
Primary Completion Date
October 31, 2023 (Anticipated)
Study Completion Date
April 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Professor Robert Sutton
Collaborators
University of Liverpool, Bangor University, Liverpool University Hospitals NHS Foundation Trust, Medical Research Council, National Institute for Health Research, United Kingdom, Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Pancreatitis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
290 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Infusion of 5 mg/kg Infliximab
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Infusion of 10 mg/kg Infliximab
Arm Type
Active Comparator
Arm Description
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.
Arm Title
0.9% Sodium Chloride (Placebo)
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Infusion of 5 mg/kg Infliximab
Other Intervention Name(s)
Remicade
Intervention Description
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).
Intervention Type
Drug
Intervention Name(s)
Infusion of 10 mg/kg Infliximab
Other Intervention Name(s)
Remicade
Intervention Description
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).
Intervention Type
Other
Intervention Name(s)
0.9% Sodium Chloride (Placebo)
Intervention Description
250 ml (500 ml if patient weighs over 100 kg) of 0.9% Sodium Chloride
Primary Outcome Measure Information:
Title
Difference in mean serum CRP measured on days 2, 4, 7, 14 and 28
Description
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.
Time Frame
Days 2, 4, 7, 14 and 28
Secondary Outcome Measure Information:
Title
Pain scores
Description
Patient will complete a Numerical Rating Scale.The scale is from 0-10 (0= no pain and 10 = worst pain possible)
Time Frame
First 28 Days
Title
Opiate requirements
Description
Recording of daily morphine equivalents by research team
Time Frame
First 28 days
Title
Nutritional deficit
Description
Number of days nil by mouth +/- specified nutritional support
Time Frame
First 28 days
Title
Decline in serum albumen
Description
Albumen measured via blood samples
Time Frame
First 28 days
Title
Decline in haematocrit
Description
Haematocrit measured via blood sample
Time Frame
First 28 days
Title
Rise in neutrophils
Description
Neutrophils measured in blood samples
Time Frame
First 28 days
Title
Systemic inflammatory response syndrome
Description
Duration from admission in days
Time Frame
First 28 days
Title
Sequential organ failure assessment (SOFA) score
Description
Summed respiratory (0-4), cardiovascular (0-4) and renal (0-4) SOFA scores on each of the first 28 days after hospital admission
Time Frame
First 28 days
Title
Local pancreatic injury
Description
Contrast-enhanced CT scan assessed by a central panel
Time Frame
Day 14 only
Title
Revised Atlanta Classification (RAC)
Description
RAC severity classification (mild, moderate or severe)
Time Frame
90 days after admission
Title
Infective complications
Description
Infective complications reported
Time Frame
First 90 days
Title
Length of hospital stay
Description
Length of time patient remains within hospital as an inpatient
Time Frame
Up to 90 days
Title
Mortality
Description
Patient death
Time Frame
Within the first 90 days
Title
Patient reported outcome
Description
EuroQol EQ-5D-5L
Time Frame
Day 4, Day 14, Day 28 and Day 90
Title
Potential safety signals
Description
Adverse events relating to infliximab including infusion reactions and delayed serum sickness reactions
Time Frame
Up to 90 days
Title
Anti-infliximab antibody concentration
Description
Blood sample analysis to determine the concentration of anti-infliximab antibodies
Time Frame
Day 28
Title
Incremental cost per quality adjusted life years (QALY) gained by trial treatment
Description
QALYs using data from the EQ-5D-5L questionnaire
Time Frame
Days 4, 14 , 28 and 90

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
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 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Matt Smyth, BSc
Phone
TBC
Email
rapid.one@liverpool.ac.uk
First Name & Middle Initial & Last Name or Official Title & Degree
Catherine E Spowart, BSc
Phone
(0) 151 794 9776
Ext
(+44)
Email
catherine.spowart@liverpool.ac.uk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robert Sutton, DPhil, FRCS
Organizational Affiliation
University of Liverpool
Official's Role
Principal Investigator
Facility Information:
Facility Name
Royal Liverpool University Hospital
City
Liverpool
State/Province
Merseyside
ZIP/Postal Code
L7 8XP
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Robert Sutton, DPhil, FRCS
Email
r.sutton@liverpool.ac.uk
First Name & Middle Initial & Last Name & Degree
Sree Subramanian, MD, FRCP
Email
sreedhar.subramanian@addenbrookes.nhs.uk

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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