Mercaptopurine Therapy in Ulcerative Colitis

Phase 3

• Conditions: Colitis, Ulcerative
• Interventions: Drug: Mercaptopurine (Purinethol); Drug: Placebo; Drug: Mesalamine; Drug: Prednisone

• Registration Number: NCT02910245
• Lead Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Brief Summary

This project is a double-blind, randomized, placebo-controlled, multicenter trial in the Netherlands. The aim of this study is to investigate the therapeutic efficacy of optimized 6-mercaptopurine (6-MP) in ulcerative colitis patients. Therapeutic drug monitoring (TDM) will be performed in order to optimize treatment outcomes and objective endoscopic endpoints will be used.

Detailed Description

Subjects will receive treatment with oral prednisone 40 mg/day for 2 weeks, followed by fixed tapering over 6 weeks. Half of the subjects will be randomized to concomitant 6-MP 1-1.5 mg/kg/day and half will receive concomitant placebo treatment. During the entire course of the trial all subjects will receive maintenance treatment with 5-ASA in an oral dose of at least 2 gram per day. Subjects will be subjected to one colonoscopy at baseline and one sigmoidoscopy in week 52 in order to assess endoscopic disease activity.

Data will be collected using electronic case report forms (eCRF) with Castor EDC. Quality and data validation procedures will be applied to ensure the validity and accuracy of the clinical database. Monitoring of the study will be done according to the GCP guidelines and following a monitoring plan. The financier of the study, ZonMw Goed Gebruik Geneesmiddelen, has the right to perform an audit if seen necessary.

Study Timeline

• Study First Submitted: 2016-09-09
• Study First Submitted QC: 2016-09-19
• Study First Posted: 2016-09-22
• Study Start: 2016-11
• Status Verified: 2020-01
• Last Update Submitted: 2020-01-06
• Last Update Posted: 2020-01-07
• Primary Completion: 2022-04-30
• Study Completion: 2022-04-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 136

Inclusion Criteria

1. Confirmed diagnosis of UC by endoscopy and histopathology
2. Patients between 18 and 80 years of age
3. Active disease, despite oral treatment with at least 2g/day 5-ASA
4. Treatment with oral corticosteroids is required

Exclusion Criteria

1. Prior treatment with thiopurines
2. Prior treatment with biologics (e.g. anti-TNF agents and vedolizumab)
3. Current pregnancy (a pregnancy test will be performed if necessary according to the treating physician)
4. Chronic Obstructive Pulmonary Disease (COPD)
5. Acute coronary heart disease
6. (Bacterial) gastroenteritis has to be treated first
7. Coagulation disorders
8. Active malignancy
9. History of colonic dysplasia/cancer
10. Extensive colonic resection, i.e. subtotal colectomy with <15 cm colon in situ
11. Concomitant therapy with drugs interfering with MP metabolism, like allopurinol, ribavirin or anti-epileptics.
12. Known systemic fungal infections or parasitic infections have to be treated first
13. Known duodenal or ventricular ulcus
14. Substance abuse, such as alcohol (> 80 gram/day - one standard glass contains 10 gram of alcohol), I.V. drugs and inhaled drugs. If the subject has a history of substance abuse, to be considered for inclusion into the protocol, the subject must have abstained from using the abused substance for at least 2 years. Subjects receiving methadone within the past 2 years are also excluded
15. Positive tuberculosis screen (when a screening is performed at the discretion of the treating physician)
16. Active hepatitis B virus or hepatitis C virus infection defined as a positive anti-HCV, HBsAg and/or anti-HBcore screening.
17. Leucopenia (Neutrophil count < 1,8x10^9/L)
18. Thrombopenia (Platelets < 90x10^9/L)
19. Elevated liver enzymes (>2x ULN)
20. Abnormal renal function (eGFR< 30 mL/min)
21. Other conditions which in the opinion of the investigator may interfere with the subject's ability to comply with the study procedure

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Mercaptopurine (Purinethol)	Mercaptopurine (Purinethol)	Mercaptopurine (Purinethol),1-1.5 mg/kg/day oral, 52 weeks \& Prednisone, 40 mg/day oral, 2 weeks, followed by fixed tapering over 6 weeks OR budesonide (cortiment) 9 mg/day during 8 weeks \& Mesalamine, 2 g/day oral, 52 weeks.
Placebo	Placebo	Placebo, 1-1.5 mg/kg/day, 52 weeks \& Prednisone, 40 mg/day oral, 2 weeks, followed by fixed tapering over 6 weeks OR budesonide (cortiment) 9 mg/day during 8 weeks \& Mesalamine, 2 g/day oral, 52 weeks.
Mercaptopurine (Purinethol)	Mesalamine	Mercaptopurine (Purinethol),1-1.5 mg/kg/day oral, 52 weeks \& Prednisone, 40 mg/day oral, 2 weeks, followed by fixed tapering over 6 weeks OR budesonide (cortiment) 9 mg/day during 8 weeks \& Mesalamine, 2 g/day oral, 52 weeks.
Mercaptopurine (Purinethol)	Prednisone	Mercaptopurine (Purinethol),1-1.5 mg/kg/day oral, 52 weeks \& Prednisone, 40 mg/day oral, 2 weeks, followed by fixed tapering over 6 weeks OR budesonide (cortiment) 9 mg/day during 8 weeks \& Mesalamine, 2 g/day oral, 52 weeks.
Placebo	Prednisone	Placebo, 1-1.5 mg/kg/day, 52 weeks \& Prednisone, 40 mg/day oral, 2 weeks, followed by fixed tapering over 6 weeks OR budesonide (cortiment) 9 mg/day during 8 weeks \& Mesalamine, 2 g/day oral, 52 weeks.
Placebo	Mesalamine	Placebo, 1-1.5 mg/kg/day, 52 weeks \& Prednisone, 40 mg/day oral, 2 weeks, followed by fixed tapering over 6 weeks OR budesonide (cortiment) 9 mg/day during 8 weeks \& Mesalamine, 2 g/day oral, 52 weeks.

Primary Outcome Measures

Name	Time	Method
Clinical and endoscopic remission	After 52 weeks of treatment	Defined as a SCCAI-score ≤ 4, a UCEIS-score ≤ 3 and a total Mayo score ≤ 2, with no individual subscore \>1.

Secondary Outcome Measures

Name	Time	Method
6-MMP levels	Every 6-12 weeks during 52 weeks of treatment
Occurrence of treatment failure	Continue during 52 weeks of treatment
Occurrence of upscaling treatment	Continue during 52 weeks of treatment	Occurrence of upscaling treatment to biologicals (anti-TNF agents or vedolizumab)
Occurrence of subjective thiopurine intolerance	Every 6-12 weeks during 52 weeks of treatment
(Serious) Adverse Events	Continue during 52 weeks of treatment	Occurrence of (serious) adverse events ((S)AE)
Treatment costs	Every 3 months during 52 weeks of treatment	Budget-impact analysis and cost-utility analysis
Leukocyte counts	Every 6 weeks during 52 weeks of treatment
6-TGN levels	Every 6-12 weeks during 52 weeks of treatment
Liver function tests	Every 6-12 weeks during 52 weeks of treatment

Trial Locations

Locations (12)

Meander MC; 🇳🇱 Amersfoort, Netherlands

Amstelland Hospital; 🇳🇱 Amsterdam, Netherlands

OLVG Oost; 🇳🇱 Amsterdam, Netherlands

Flevoziekenhuis; 🇳🇱 Almere, Netherlands

Tergooi Hospital; 🇳🇱 Hilversum, Netherlands

Noordwest Ziekenhuisgroep; 🇳🇱 Alkmaar, Netherlands

Amsterdam UMC, location VUMC; 🇳🇱 Amsterdam, Netherlands

St. Antonius Hospital; 🇳🇱 Nieuwegein, Netherlands

MC Haaglanden; 🇳🇱 Den Haag, Netherlands

Amsterdam UMC, location AMC; 🇳🇱 Amsterdam, Netherlands

Westfriesgasthuis; 🇳🇱 Hoorn, Netherlands

Sint Franciscus Gasthuis; 🇳🇱 Rotterdam, Netherlands