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A Randomized, Multicenter Open Label Study Comparing Early Administration of Azathioprine Plus IFX to Steroids Plus Azathioprine for Acute Severe Colitis (ACTIVE)

Primary Purpose

Ulcerative Colitis

Status
Completed
Phase
Phase 4
Locations
France
Study Type
Interventional
Intervention
Azathioprine
Infliximab
Prednisolone
Hydrocortisone
Sponsored by
Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ulcerative Colitis

Eligibility Criteria

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

Inclusion Criteria:

  • Age > 18 years.
  • Diagnosis of UC according to Lennard-Jones criteria (Appendix 1).
  • Endoscopically demonstrated colorectal lesions localized above the anal margin and extending at least up to 15cm proximally (Endoscopic Mayo subscore ≥ 2).
  • Acute flare requiring hospitalization
  • Severe acute flare of UC with a Lichtiger Index score > 10 at Day -3
  • Adequate contraception for male or female subjects of childbearing potential, which will be continued throughout the study and at least 3 months after study termination.

3.2 EXCLUSION CRITERIA

  • Pregnant or breast-feeding woman.
  • Previous treatment with infliximab.
  • Treatment with adalimumab or golimumab within 8 weeks before randomization
  • Treatment with vedolizumab within 4 weeks before randomization
  • Azathioprine or 6-mercaptopurine treatment initiated more than 4 weeks before screening.
  • Ongoing intravenous steroids for more than 96 hours at time of the screening
  • Contraindication for anti-TNF therapy
  • Indication for immediate surgery.
  • History of colorectal dysplasia.
  • Diagnosis of Crohn's disease or indeterminate colitis
  • Positive stool tests for amoebiasis and/or positive bacteriological culture for Salmonella, Shigella, Yersinia and Campylobacter and/or presence of Clostridium difficile B toxin in the stools.
  • Renal failure (creatininemia > upper limit of normal laboratory value).
  • Uncontrolled high blood pressure.
  • HIV, HBV viral infection (except the presence of positive anti-HBs antibodies) with serology not older than 3 months.
  • Uncontrolled bacterial or active viral infection.
  • Past medical history of malignant condition in the last 5 years (including leukaemia, lymphoma and myelodysplasia) except for baso-cellular cutaneous cancers.
  • Past medical history of myocardial infarction or heart failure.
  • Intradermal reaction to Tuberculin (Tubertest® 5 units) > 5mm or positive interferon-gamma release assay (Quantiferon®)
  • Active tuberculosis
  • Untreated latent tuberculosis (see national recommendations. Appendix 2).
  • Abnormal blood count with polynuclear neutrophils < 1,500 G/L or white cells < 3,000, or platelets < 100,000 G/L.
  • Unexplained rise higher than 3 times the normal level for transaminases, alkaline phosphatases and/or higher than twice the normal level for bilirubin.
  • Severe acute or chronic medical or psychiatric condition that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in judgement of the investigator, would make the subject inappropriate for entry in this study.
  • Subjects who, in the opinion of the investigator, will be uncooperative or unable to comply with study procedures.
  • Participation in another clinical trial.

Sites / Locations

  • Chu Besancon
  • CHU de CLERMONT FERRAND- Hopital Estain
  • APHP- Hopital BEAUJON
  • Hopital Louis Mourrier
  • Henri Mondor Hospital
  • Chu Kremlin Bicetre
  • CHRU Lille
  • Chu Montpellier
  • CHU de NICE- Hopital Archet 2
  • Hopital Saint Louis
  • Hopital St Antoine
  • Hopital Saint Joseph
  • CHU RENNES - Hopital Pontchaillou
  • Chu Rouen
  • Chu Saint Etienne
  • CHU NANCY - Hopital Brabois

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Combination therapy arm

Azathioprine arm

Arm Description

Infliximab 5 mg/kg plus Azathioprine 2-2.5 mg/kg/day. Azathioprine will be introduced at day 5-7 and continued until week 52. Azathioprine dose regimen will be between 2 and 2.5 mg/kg/d, as close as possible to 2.5 mg/kg/d, or to 1.5 mg/kg/d for 6-mercaptopurine, in one daily intake.

Intravenous steroids will be continue until day 2. Then, steroid therapy will be orally administered at a dose of 40-60 mg/day ou 1 mg/kg/day prednisolone (or equivalent) and progressively reduced by 10mg step every week to 20mg per day, and then reduced by 5mg step every week until stopped. Hydrocortisone intake to prevent steroid weaning will be authorized until supradrenal function normalization. In patients with clinical response at day 7, Azathioprine will be introduced at day 5-7 and continued until week 52. Azathioprine dose regimen will be between 2 and 2.5 mg/kg/d, as close as possible of 2.5 mg/kg/d, or of 1.5 mg/kg/d for 6-mercaptopurine, in one daily intake.

Outcomes

Primary Outcome Measures

Percentage of patients with treatment failure at week 52.
Failure is defined as: absence of steroid-free remission (Total Mayo Disease Activity Index (DAI) score ≤ 2 with no individual subscore > 1) absence of mucosal healing (Endoscopic Mayo DAI subscore ≤ 1) or severe adverse event leading to treatment interruption between day 0 and week 52 or colectomy between day 0 and week 52 or fatality between day 0 and week 52 or infliximab withdrawal for failure and /or intolerance in the combination therapy group or any biological agent introduction in the azathioprine group

Secondary Outcome Measures

Percentage of patients in clinical response at day 7
Percentage of patients in clinical response at day 7 (Lichtiger Index score<10 with a decrease of at least 3 points compared with the baseline score) and at week 14 and week 52 (a decrease from baseline in the Mayo score ≥30% and ≥3 points, accompanied by either a rectal bleeding subscore of 0 or 1 or a decrease from baseline in the rectal bleeding subscore ≥1) - Percentage of patients in clinical remission at day 7, week 14 and week 52

Full Information

First Posted
April 21, 2015
Last Updated
May 30, 2023
Sponsor
Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives
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1. Study Identification

Unique Protocol Identification Number
NCT02425852
Brief Title
A Randomized, Multicenter Open Label Study Comparing Early Administration of Azathioprine Plus IFX to Steroids Plus Azathioprine for Acute Severe Colitis
Acronym
ACTIVE
Official Title
A Randomized, Multicenter Open Label Study Comparing Early Administration of Azathioprine Plus Infliximab to Corticosteroids Plus Azathioprine for Acute Severe Colitis
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
December 2016 (Actual)
Primary Completion Date
June 2022 (Actual)
Study Completion Date
January 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
PHASE : IV TYPE OF STUDY : With direct benefit. DESCRIPTIVE : Multicentre, randomized, open label study. INCLUSION CRITERIA : Acute severe ulcerative colitis. OBJECTIVES : To compare the efficacy and safety of early administration of the combination therapy with infliximab and azathioprine with steroids and azathioprine in patients with acute severe ulcerative colitis treated with intravenous steroids. STUDY TREATMENTS : All patients : Intravenous steroids (0.8 mg/kg/day of methylprednisolone or equivalent) for 5 days. Combination therapy arm: Infliximab 5 mg/kg plus Azathioprine 2-2.5 mg/kg/day. Azathioprine arm: Steroids tapering for 3 months and Azathioprine 2-2.5 mg/kg/day.
Detailed Description
NUMBER OF PATIENTS : 73 patients in each group i.e. a total of 146patients. RECRUITMENT PERIOD : 36 months STUDY DURATION : 12 months PRIMARY END POINT : Treatment failure is defined by: Absence of steroid-free remission at W52 according to the total Mayo Disease Activity Index score OR Absence of mucosal healing (Mayo endoscopic subscore 0-1) OR Adverse event leading to treatment interruption OR Colectomy OR Death OR Infliximab withdrawal in the combination therapy group OR Infliximab introduction in the azathioprine group SECONDARY END POINT: - Clinical response and remission at D7, W14 and W52 (according to Lichtiger score and total Mayo Disease Activity Index score) Endoscopic and histological response Mucosal healing (partial endoscopic Mayo subscore 0) Colectomy rate Adverse events rate Fecal calprotectin Health-economic outcome

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ulcerative Colitis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
65 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Combination therapy arm
Arm Type
Active Comparator
Arm Description
Infliximab 5 mg/kg plus Azathioprine 2-2.5 mg/kg/day. Azathioprine will be introduced at day 5-7 and continued until week 52. Azathioprine dose regimen will be between 2 and 2.5 mg/kg/d, as close as possible to 2.5 mg/kg/d, or to 1.5 mg/kg/d for 6-mercaptopurine, in one daily intake.
Arm Title
Azathioprine arm
Arm Type
Active Comparator
Arm Description
Intravenous steroids will be continue until day 2. Then, steroid therapy will be orally administered at a dose of 40-60 mg/day ou 1 mg/kg/day prednisolone (or equivalent) and progressively reduced by 10mg step every week to 20mg per day, and then reduced by 5mg step every week until stopped. Hydrocortisone intake to prevent steroid weaning will be authorized until supradrenal function normalization. In patients with clinical response at day 7, Azathioprine will be introduced at day 5-7 and continued until week 52. Azathioprine dose regimen will be between 2 and 2.5 mg/kg/d, as close as possible of 2.5 mg/kg/d, or of 1.5 mg/kg/d for 6-mercaptopurine, in one daily intake.
Intervention Type
Drug
Intervention Name(s)
Azathioprine
Intervention Description
Azathioprine alone versus Azathioprine and IFX
Intervention Type
Drug
Intervention Name(s)
Infliximab
Intervention Type
Drug
Intervention Name(s)
Prednisolone
Intervention Type
Drug
Intervention Name(s)
Hydrocortisone
Primary Outcome Measure Information:
Title
Percentage of patients with treatment failure at week 52.
Description
Failure is defined as: absence of steroid-free remission (Total Mayo Disease Activity Index (DAI) score ≤ 2 with no individual subscore > 1) absence of mucosal healing (Endoscopic Mayo DAI subscore ≤ 1) or severe adverse event leading to treatment interruption between day 0 and week 52 or colectomy between day 0 and week 52 or fatality between day 0 and week 52 or infliximab withdrawal for failure and /or intolerance in the combination therapy group or any biological agent introduction in the azathioprine group
Time Frame
Week 52
Secondary Outcome Measure Information:
Title
Percentage of patients in clinical response at day 7
Description
Percentage of patients in clinical response at day 7 (Lichtiger Index score<10 with a decrease of at least 3 points compared with the baseline score) and at week 14 and week 52 (a decrease from baseline in the Mayo score ≥30% and ≥3 points, accompanied by either a rectal bleeding subscore of 0 or 1 or a decrease from baseline in the rectal bleeding subscore ≥1) - Percentage of patients in clinical remission at day 7, week 14 and week 52
Time Frame
7 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age > 18 years. Diagnosis of UC according to Lennard-Jones criteria (Appendix 1). Endoscopically demonstrated colorectal lesions localized above the anal margin and extending at least up to 15cm proximally (Endoscopic Mayo subscore ≥ 2). Acute flare requiring hospitalization Severe acute flare of UC with a Lichtiger Index score > 10 at Day -3 Adequate contraception for male or female subjects of childbearing potential, which will be continued throughout the study and at least 3 months after study termination. 3.2 EXCLUSION CRITERIA Pregnant or breast-feeding woman. Previous treatment with infliximab. Treatment with adalimumab or golimumab within 8 weeks before randomization Treatment with vedolizumab within 4 weeks before randomization Azathioprine or 6-mercaptopurine treatment initiated more than 4 weeks before screening. Ongoing intravenous steroids for more than 96 hours at time of the screening Contraindication for anti-TNF therapy Indication for immediate surgery. History of colorectal dysplasia. Diagnosis of Crohn's disease or indeterminate colitis Positive stool tests for amoebiasis and/or positive bacteriological culture for Salmonella, Shigella, Yersinia and Campylobacter and/or presence of Clostridium difficile B toxin in the stools. Renal failure (creatininemia > upper limit of normal laboratory value). Uncontrolled high blood pressure. HIV, HBV viral infection (except the presence of positive anti-HBs antibodies) with serology not older than 3 months. Uncontrolled bacterial or active viral infection. Past medical history of malignant condition in the last 5 years (including leukaemia, lymphoma and myelodysplasia) except for baso-cellular cutaneous cancers. Past medical history of myocardial infarction or heart failure. Intradermal reaction to Tuberculin (Tubertest® 5 units) > 5mm or positive interferon-gamma release assay (Quantiferon®) Active tuberculosis Untreated latent tuberculosis (see national recommendations. Appendix 2). Abnormal blood count with polynuclear neutrophils < 1,500 G/L or white cells < 3,000, or platelets < 100,000 G/L. Unexplained rise higher than 3 times the normal level for transaminases, alkaline phosphatases and/or higher than twice the normal level for bilirubin. Severe acute or chronic medical or psychiatric condition that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in judgement of the investigator, would make the subject inappropriate for entry in this study. Subjects who, in the opinion of the investigator, will be uncooperative or unable to comply with study procedures. Participation in another clinical trial.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Aurélien Amiot, MD
Organizational Affiliation
Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Laurent Peyrin-Biroulet, MD, PhD
Organizational Affiliation
Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives
Official's Role
Principal Investigator
Facility Information:
Facility Name
Chu Besancon
City
Besancon
ZIP/Postal Code
25030
Country
France
Facility Name
CHU de CLERMONT FERRAND- Hopital Estain
City
Clermont-Ferrand
ZIP/Postal Code
67000
Country
France
Facility Name
APHP- Hopital BEAUJON
City
Clichy
ZIP/Postal Code
92110
Country
France
Facility Name
Hopital Louis Mourrier
City
Colombes
ZIP/Postal Code
92700
Country
France
Facility Name
Henri Mondor Hospital
City
Creteil
ZIP/Postal Code
94010
Country
France
Facility Name
Chu Kremlin Bicetre
City
Le Kremlin-Bicêtre
Country
France
Facility Name
CHRU Lille
City
Lille
Country
France
Facility Name
Chu Montpellier
City
Montpellier
ZIP/Postal Code
34295
Country
France
Facility Name
CHU de NICE- Hopital Archet 2
City
Nice
ZIP/Postal Code
06200
Country
France
Facility Name
Hopital Saint Louis
City
Paris
ZIP/Postal Code
75010
Country
France
Facility Name
Hopital St Antoine
City
Paris
ZIP/Postal Code
75012
Country
France
Facility Name
Hopital Saint Joseph
City
Paris
ZIP/Postal Code
75014
Country
France
Facility Name
CHU RENNES - Hopital Pontchaillou
City
Rennes
Country
France
Facility Name
Chu Rouen
City
Rouen
ZIP/Postal Code
76031
Country
France
Facility Name
Chu Saint Etienne
City
St Etienne
ZIP/Postal Code
42270
Country
France
Facility Name
CHU NANCY - Hopital Brabois
City
Vandoeuvre Les Nancy
ZIP/Postal Code
54500
Country
France

12. IPD Sharing Statement

Learn more about this trial

A Randomized, Multicenter Open Label Study Comparing Early Administration of Azathioprine Plus IFX to Steroids Plus Azathioprine for Acute Severe Colitis

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