Efficacy of AlbenDazole to inDuce mUcosal healing in Patients with Crohn's disease on anti-TNF monotherapy: ADD UP

Rationale: Crohn’s disease (CD) is a chronic inflammatory bowel disorder (IBD) with a major impact on quality of life. Mucosal healing is an important treatment outcome to prevent long term complications of the disease. Regulatory M2 type macrophages play a key role in wound healing and were shown to be induced by anti-TNF treatment in vitro and in vivo. Moreover, thiopurines promote anti-TNF induced mucosal healing and enhance the generation of anti-TNF induced M2 macrophages, which might be a key underlying mechanism of action. The use of thiopurines however, is accompanied by evident downsides. In up to 25% thiopurines need to be discontinued due to intolerance or side effects. We aimed to find an alternative and initiated a drug screen in collaboration with the target Discovery Institute at the University of Oxford.

A library of 1600 FDA approved compounds was screened for the capacity to potentiate anti-TNF medicated induction of M2 macrophages in vitro using a human mixed lymphocyte reaction. During this screen, several benzimidazoles, including albendazole and mebendazole, were identified. Our preclinical work at the Tytgat Institute at the AMC confirmed that albendazole potentiates the efficacy of anti-TNFα therapy both in vitro and in an IBD mouse model. Albendazole is an antihelminthic agent with a well described safety profile. Potentially it could be a novel therapeutic agent for anti-TNF-α combination therapy in patients with Crohn’s disease.

Objective: To evaluate the safety and efficacy of 12 weeks albendazole treatment added to anti-TNF monotherapy in adult patients with Crohn’s disease with incomplete mucosal healing.

Study design: Multicentre randomised double-blind, placebo-controlled trial with 2 parallel groups (albendazole and placebo)
Study population: Adult Crohn’s disease patients with incomplete mucosal healing (SES-CD > 6 or ≥4 for isolated ileal disease) on anti-TNF monotherapy (either infliximab or adalimumab) for ≥4 months. Only patients with therapeutic drug levels and no measurable anti-drug antibodies are eligible. Concomittant use of an immunomodulator (methotrexate, azathioprine, 6-mercaptopurine, 6-thioguanine) within three months before enrollment is an exclusion criterion. Patients who previously failed on combination therapy (anti-TNF + immunomodulator) – defined as discontinuation on this combination therapy due to refractory disease activity – are also not eligible for enrollment. A detailed overview of in- and exclusion criteria can be found at et section 4.1 and 4.1 (page 15 & 16).

Intervention: 110 subjects are randomly assigned to receive either albendazole or placebo (1:1) in combination with continued anti-TNF treatment at unchanged dose. Patients will receive oral albendazole treatment for 12 weeks in a weight adjusted dosage or placebo.

Main study endpoints: Proportion of patients with absence of ulcers on centrally read endoscopies after 12 weeks of albendazole and anti-TNF combination treatment compared to placebo
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: It seems plausible that patients have benefit from the addition of albendazole to anti-TNF monotherapy. According to the extensive experience with albendazole (in similar dosage and duration) for other indications, the drug is known with a positive safety profile. In order to remain vigilant concerning possible side effects, several safety measures are in place. Firstly, an interim analysis will be performed after 15 patients in each arm have finished the intervention phase (week 12). Stopping rules, with emphasis primarily on patient safety and secondarily on efficacy, are in place which will guide the choice whether or not to continue. The interim analysis will be evaluated by a DSMB. Secondly, repeated blood samples are taken to monitor complete blood count and liver enzymes. Predefined criteria are in place concerning dose adjustments following liver enzyme elevation.

Peripheral blood is sampled 5 times on top of standard clinical care with a negligible risk and low burden. Subjects will be subjected to one additional (end of study) ileocolonoscopy on top of standard clinical care. This ileocolonoscopy is performed in order to assess endoscopic disease activity and evaluate the intervention’s efficacy. Patients have established increased risk of persistent intestinal inflammation as determined by a repeated elevated faecal calprotectin. As part of standard clinical care patients will receive a screening colonoscopy to objectify refractory mucosal inflammation. During endoscopy biopsies are taken to determine histological disease activity. The procedure itself in combination with biopsy procurement include a minimal risk of complications, mainly bleeding or perforation (<1:10.000)[1]. In case a complication occurs, endoscopic treatment (clip placement to achieve hemostasis) is effective in most cases. Rarely, hospital admission with/without surgical intervention, antibiotic therapy and/or blood transfusion is required. Patients need to fill in 3 quality of life questionnaires and 1 ‘Patient Reported Outcome’ questionnaire at three different timepoints. Moreover, 1 cost questionnaire required for the economic evaluation will be administered at week 12 and week 36.

Albendazole could be a novel therapeutic agent for anti-TNF alpha combination therapy in patients with Crohn's disease

The study design will comprise three phases (figure 1):

1) Screening phase (up to 14 days) to determine patients’ eligibility for the study

2) Intervention phase (12 weeks)

3) Follow up phase (24 weeks)

110 subjects are randomly assigned to receive either albendazole or placebo (1:1) in combination with continued anti-TNF treatment at unchanged dose. Patients will receive oral albendazole treatment for 12 weeks in a weight adjusted dosage or placebo