Low-dose azathioprine and allopurinol versus azathioprine monotherapy in patients with ulcerative colitis (AAUC): An investigator-initiated, open, multicenter, parallel-arm, randomised controlled trial

Marianne Kiszka-Kanowitz; Klaus Theede; Sandra Bohn Thomsen; Jacob Tveiten Bjerrum; Jørn Brynskov; Ida Benedikte Gottschalck; Elena Akimenko; Karen Lisa Hilsted; Anders Neumann; Signe Wildt; Lone Larsen; Jens Kristian Munk; Per Holger Ibsen; Huma Gul Rehana Janjua; Lise Lotte Gluud; Anette Mertz-Nielsen

doi:10.1016/j.eclinm.2022.101332

Low-dose azathioprine and allopurinol versus azathioprine monotherapy in patients with ulcerative colitis (AAUC): An investigator-initiated, open, multicenter, parallel-arm, randomised controlled trial

EClinicalMedicine. 2022 Mar 5:45:101332. doi: 10.1016/j.eclinm.2022.101332. eCollection 2022 Mar.

Authors

Marianne Kiszka-Kanowitz¹, Klaus Theede¹, Sandra Bohn Thomsen¹, Jacob Tveiten Bjerrum², Jørn Brynskov², Ida Benedikte Gottschalck², Elena Akimenko², Karen Lisa Hilsted¹, Anders Neumann³, Signe Wildt⁴, Lone Larsen⁵, Jens Kristian Munk¹, Per Holger Ibsen¹, Huma Gul Rehana Janjua¹, Lise Lotte Gluud¹, Anette Mertz-Nielsen¹

Affiliations

¹ Gastro Unit, Copenhagen University Hospital Hvidovre, Kettegårds Alle 30, Hvidovre 2600 , Denmark.
² Herlev University Hospital, Herlev, Denmark.
³ Viborg University Hospital, Viborg, Denmark.
⁴ Køge University Hospital, Køge, Denmark.
⁵ Aalborg University Hospital, Aalborg, Denmark.

Abstract

Background: Retrospective studies suggest that for patients with ulcerative colitis (UC) combination therapy with low-dose azathioprine and allopurinol (L-AZA/ALLO) may result in higher remission rates than monotherapy with azathioprine (AZA). We prospectively investigated the effects of these drugs for remission in patients with moderate-to-severe UC.

Methods: Open-label, unblinded, randomised, controlled, investigator-initiated, multicentre study conducted at eight hospital sites in Denmark. Adult patients with established UC, who were steroid dependent/refractory, thiopurine naïve, had a normal thiopurine methyltransferase, and achieved remission with steroids or infliximab were eligible for inclusion. Patients were randomly assigned by the investigators (1:1) to 52 weeks of treatment with once daily oral AZA (median dose 50 mg) combined with ALLO 100 mg versus AZA monotherapy (median dose 200 mg), using a computer-generated randomisation list with blocks of six. The trial was open without masking. All randomised patients who received at least one dose of study drug were included in primary and safety analyses (intention to treat population). The primary outcome was steroid and infliximab free remission after 52 weeks, defined as a Mayo Score of ≤1 and no rectal bleeding. The trial is completed and is registered in ClinicalTrials.gov (ClinicalTrials.gov NCT03101800).

Findings: Between January 9, 2017 and February 10, 2021, 47 patients were randomised to l-AZA/ALLO and 42 to AZA and received at least one dose of the study drug. After 52 weeks, 20 of 47 (43%) patients in the l-AZA/ALLO group and nine of 42 (21%) patients in the AZA group achieved remission (odds ratio 2·54 [95% CI 1·00 to 6.78, p < 0·048]). Fourteen patients (30%) in the l-AZA/ALLO group and 16 (38%) in the AZA group were withdrawn from the study due to adverse events.

Interpretation: This study suggests that after one year l-AZA/ALLO therapy may be associated with a beneficial effect on steroid- and infliximab-free clinical remission in patients with moderate-to-severe UC and should be considered as first line therapy.

Funding: Funding for AAUC was provided by The Capital Region of Denmark (Regionernes Medicinpulje (6062/16)).

Keywords: Allopurinol; Azathioprine; Randomised trial; Reatment; Ulcerative colitis.

Associated data

ClinicalTrials.gov/NCT03101800