The Influence of 5–Aminosalicylates on Thiopurine Metabolite Levels

Ulcerative Colitis Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00167882
• Other study ID #: 2005/28
• Status: Completed
• Phase: Phase 4
• First received: September 9, 2005
• Last updated: September 8, 2006
• Start date: July 2005
• Est. completion date: August 2006

Study information

• Verified date: August 2006
• Source: VU University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the influence of different 5-aminosalicylate concentrations on the metabolism of azathioprine or 6-mercaptopurine in patients with inflammatory bowel disease.

Description:

Background:

The concomitant use of 5-aminosalicylates (5ASA) next to azathioprine (AZA) or 6-mercaptopurine (6MP) in the treatment of inflammatory bowel disease (IBD) may lead to an increased effectiveness of therapy as higher levels of the active metabolite of AZA/6MP (6-thioguaninenucleotides (6TGNs) are measured.

Objectives:

To determine the influence of 5-ASA compounds and its metabolites on the metabolites of AZA/6MP (6TGNs + 6-methylmercaptopurine (6MMP).

Methods:

Patients with quiescent disease under AZA/6MP therapy are eligible. Patients will receive three succeeding regimes (5ASA 2 gram/5ASA 4 gram/ no 5ASA) of 4 weeks next to the standard AZA/6MP therapy. At the start and at the end of every regime 5ASA and its major metabolite (N-acetyl-5ASA) will be determined in serum next to the measurement of 6TGNs and 6MMP in erythrocytes. The safety will monitored by standard laboratory parameters every four weeks.

Population:

Patients with IBD in remission and unchanged AZA/6MP dosages for at least 4 weeks.

Medication:

5ASA (Pentasa ® granules; Ferring) will be administered orally in dosages of 2 or 4 grams daily for a period of 4 weeks.

Endpoints:

The rise or decrease in 6TGNs and 6MMP during the different 5ASA regimes. The evaluation of the safety of co-administrating 5ASA next to AZA/6MP.

Risks:

Side effects of 5ASA use are limited and well known. Some case reports have described the potential risk of developing a myelodepression when AZA/6MP and 5ASA are given together due to the rise in 6TGNs. However, in daily practice both drugs are administered together frequently. The risks of the frequent blood draws are minimal and usually self-limiting (haematoma).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: August 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Adult patients, aged between 18 – 70 years

• Informed consent

• Diagnosis of CD or UC for at least 6 months (histological and endoscopically confirmed)

• Steady state AZA of 6-MP use (an unchanged thiopurine regime for at least 4 weeks)

• Normal liver and kidney function (ALAT / AP / creatinin < 2 x upper normal limit)

• Quiescent disease (HBI score = 4 for CD or modified TLWI score = 4 for UC)

Exclusion Criteria:

• Bone marrow suppression (platelets / leucocytes < 1 x lower normal level)

• Presence of active infection (fever and CRP > 1 x upper normal limit)

• Anemia (hemoglobin < 6 mmol)

• Known duodenal Crohn’s disease interfering significantly with resorptive area

• Small bowel surgery interfering significantly with resorptive area

• Known intolerance to 5-ASA compounds

• Current use of 5-ASA compounds

• Use of 5-ASA compounds within the last 30 days

• Concomitant use of allopurinol, ACE-inhibitors or furosemide

• Pregnancy, expected pregnancy or lactation within 6 months

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Single Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colitis, Ulcerative
• Crohn Disease
• Crohn's Disease
• Inflammatory Bowel Disease
• Inflammatory Bowel Diseases
• Intestinal Diseases
• Ulcerative Colitis

Intervention

Drug:
• 5-aminosalicylate (Pentasa, Ferring)

Locations

Country	Name	City	State
Netherlands	Maasland Hospital	Sittard

Sponsors (1)

Lead Sponsor	Collaborator
VU University Medical Center

Country where clinical trial is conducted

Netherlands, 

References & Publications (3)

Al Hadithy AF, de Boer NK, Derijks LJ, Escher JC, Mulder CJ, Brouwers JR. Thiopurines in inflammatory bowel disease: pharmacogenetics, therapeutic drug monitoring and clinical recommendations. Dig Liver Dis. 2005 Apr;37(4):282-97. Review. — View Citation

de Boer NK, de Graaf P, Wilhelm AJ, Mulder CJ, van Bodegraven AA. On the limitation of 6-tioguaninenucleotide monitoring during tioguanine treatment. Aliment Pharmacol Ther. 2005 Sep 1;22(5):447-51. — View Citation

Derijks LJ, Gilissen LP, Engels LG, Bos LP, Bus PJ, Lohman JJ, Curvers WL, Van Deventer SJ, Hommes DW, Hooymans PM. Pharmacokinetics of 6-mercaptopurine in patients with inflammatory bowel disease: implications for therapy. Ther Drug Monit. 2004 Jun;26(3):311-8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To determine the influence of 5-ASA compounds and its metabolites on the 6-TGN level during steady state AZA or 6-MP dosages
Secondary	To determine the influence of 5-ASA compounds and its metabolites on the 6-MMP level during steady state AZA or 6-MP dose
Secondary	To determine the influence of 5-ASA compounds and its metabolites on the 6-TGMP, 6-TGDP and 6-TGTP levels during steady state AZA or 6-MP dosages
Secondary	To evaluate the safety of co-administrating 5-ASA and AZA or 6-MP in IBD patients