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

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ClinicalTrials.gov Identifier: NCT03684278
Recruitment Status : Recruiting
First Posted : September 25, 2018
Last Update Posted : July 3, 2019
Sponsor:
Collaborators:
Clinical Trials Research Centre
Bangor University
University of Liverpool
Royal Liverpool and Broadgreen University Hospitals NHS Trust
Medical Research Council
National Institute for Health Research, United Kingdom
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Professor Robert Sutton, University of Liverpool

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.

Condition or disease Intervention/treatment Phase
Acute Pancreatitis Drug: Infusion of 5 mg/kg Infliximab Drug: Infusion of 10 mg/kg Infliximab Other: 0.9% Sodium Chloride (Placebo) Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 290 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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 12 hours of admission to the Accident and Emergency Medicine Department. Treatment allocation will only be revealed to Pharmacy to ensure the research team administering the treatment remains blinded.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Once the delegated research team member performs randomisation and the Pharmacist is provided with the allocation to either Arm A, B or C, the Pharmacist will prepare the infusion, which will be covered by an opaque sleeve and labelled for blinding.
Primary Purpose: Treatment
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.
Actual Study Start Date : May 1, 2019
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : April 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Pancreatitis
Drug Information available for: Infliximab

Arm Intervention/treatment
Active Comparator: Infusion of 5 mg/kg Infliximab
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
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 Name: Remicade

Active Comparator: Infusion of 10 mg/kg Infliximab
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
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 Name: Remicade

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




Primary Outcome Measures :
  1. Difference in mean serum CRP measured on days 2, 4, 7, 14 and 28 [ Time Frame: 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 :
  1. Pain scores [ Time Frame: First 28 Days ]
    Patient will complete a Numerical Rating Scale.The scale is from 0-10 (0= no pain and 10 = worst pain possible)

  2. Opiate requirements [ Time Frame: First 28 days ]
    Recording of daily morphine equivalents by research team

  3. Nutritional deficit [ Time Frame: First 28 days ]
    Number of days nil by mouth +/- specified nutritional support

  4. Decline in serum albumen [ Time Frame: First 28 days ]
    Albumen measured via blood samples

  5. Decline in haematocrit [ Time Frame: First 28 days ]
    Haematocrit measured via blood sample

  6. Rise in neutrophils [ Time Frame: First 28 days ]
    Neutrophils measured in blood samples

  7. Systemic inflammatory response syndrome [ Time Frame: First 28 days ]
    Duration from admission in days

  8. Sequential organ failure assessment (SOFA) score [ Time Frame: First 28 days ]
    Summed respiratory (0-4), cardiovascular (0-4) and renal (0-4) SOFA scores on each of the first 28 days after hospital admission

  9. Local pancreatic injury [ Time Frame: Day 14 only ]
    Contrast-enhanced CT scan assessed by a central panel

  10. Revised Atlanta Classification (RAC) [ Time Frame: 90 days after admission ]
    RAC severity classification (mild, moderate or severe)

  11. Infective complications [ Time Frame: First 90 days ]
    Infective complications reported

  12. Length of hospital stay [ Time Frame: Up to 90 days ]
    Length of time patient remains within hospital as an inpatient

  13. Mortality [ Time Frame: Within the first 90 days ]
    Patient death

  14. Patient reported outcome [ Time Frame: Day 4, Day 14, Day 28 and Day 90 ]
    EuroQol EQ-5D-5L

  15. Potential safety signals [ Time Frame: Up to 90 days ]
    Adverse events relating to infliximab including infusion reactions and delayed serum sickness reactions

  16. Anti-infliximab antibody concentration [ Time Frame: Day 28 ]
    Blood sample analysis to determine the concentration of anti-infliximab antibodies

  17. Incremental cost per quality adjusted life years (QALY) gained by trial treatment [ Time Frame: Days 4, 14 , 28 and 90 ]
    QALYs using data from the EQ-5D-5L questionnaire



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 12 hours of recorded admission and allowing 120 min for Pharmacy to prepare 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)
  • 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 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
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03684278


Contacts
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Contact: Sean B Gaines, BSc (0) 151 794 9774 ext (+44) sean.gaines@liverpool.ac.uk
Contact: Catherine E Spowart, BSc (0) 151 794 9776 ext (+44) catherine.spowart@liverpool.ac.uk

Locations
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United Kingdom
Royal Liverpool University Hospital Recruiting
Liverpool, Merseyside, United Kingdom, L7 8XP
Contact: Robert Sutton, DPhil, FRCS       r.sutton@liverpool.ac.uk   
Contact: Sree Subramanian, MD, FRCP       Sreedhar.Subramanian@rlbuht.nhs.uk   
Sponsors and Collaborators
Professor Robert Sutton
Clinical Trials Research Centre
Bangor University
University of Liverpool
Royal Liverpool and Broadgreen University Hospitals NHS Trust
Medical Research Council
National Institute for Health Research, United Kingdom
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Robert Sutton, DPhil, FRCS University of Liverpool

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Responsible Party: Professor Robert Sutton, Professor of Surgery, University of Liverpool
ClinicalTrials.gov Identifier: NCT03684278     History of Changes
Other Study ID Numbers: UoL001326
2017-003840-19 ( EudraCT Number )
15/20/01 ( Other Grant/Funding Number: MRC and NIHR EME )
First Posted: September 25, 2018    Key Record Dates
Last Update Posted: July 3, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Pancreatitis
Pancreatic Diseases
Digestive System Diseases
Infliximab
Dermatologic Agents
Gastrointestinal Agents
Antirheumatic Agents