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

Sponsor

Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives (Other)

Overall Status

Recruiting

CT.gov ID

NCT02425852

Collaborator

(none)

146

Enrollment

Locations

Arms

Anticipated Duration (Months)

9.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Ulcerative Colitis	Drug: Azathioprine Drug: Infliximab Drug: Prednisolone Drug: Hydrocortisone	Phase 4

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

146 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 1, 2016

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Combination therapy arm 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.	Drug: Azathioprine Azathioprine alone versus Azathioprine and IFX Drug: Infliximab
Active Comparator: Azathioprine arm 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.	Drug: Azathioprine Azathioprine alone versus Azathioprine and IFX Drug: Prednisolone Drug: Hydrocortisone

Arm

Intervention/Treatment

Active Comparator: Combination therapy arm

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.

Drug: Azathioprine

Azathioprine alone versus Azathioprine and IFX

Drug: Infliximab

Active Comparator: Azathioprine arm

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.

Drug: Azathioprine

Azathioprine alone versus Azathioprine and IFX

Drug: Prednisolone

Drug: Hydrocortisone

Outcome Measures

Primary Outcome Measures

Percentage of patients with treatment failure at week 52. [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 [7 days]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Chu Besancon	Besancon	France	25030
2	CHU de CLERMONT FERRAND- Hopital Estain	Clermont-Ferrand	France	67000
3	APHP- Hopital BEAUJON	Clichy	France	92110
4	Hopital Louis Mourrier	Colombes	France	92700
5	Henri Mondor Hospital	Creteil	France	94010
6	Chu Kremlin Bicetre	Le Kremlin-Bicêtre	France
7	CHRU Lille	Lille	France
8	Chu Montpellier	Montpellier	France	34295
9	CHU de NICE- Hopital Archet 2	Nice	France	06200
10	Hopital Saint Louis	Paris	France	75010
11	Hopital St Antoine	Paris	France	75012
12	Hopital Saint Joseph	Paris	France	75014
13	CHU RENNES - Hopital Pontchaillou	Rennes	France
14	Chu Rouen	Rouen	France	76031
15	Chu Saint Etienne	St Etienne	France	42270
16	CHU NANCY - Hopital Brabois	Vandoeuvre Les Nancy	France	54500

Sponsors and Collaborators

Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives

Investigators

Principal Investigator: Aurélien Amiot, MD, Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives
Principal Investigator: Laurent Peyrin-Biroulet, MD, PhD, Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives