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.
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Proportion of patients with absence of ulcers on centrally read endoscopies
after 12 weeks of albendazole and anti-TNF combination treatment compared to
placebo
Secondary outcome
1.Proportion of patients with endoscopic response on centrally read endoscopies
defined as a reduction in the Simple Endoscopic Severity index (SES-CD) score
by >= 50% compared to baseline
2.Proportion of patients with endoscopic remission on centrally read
endoscopies defined as a SES-CD score < 3 in general or < 2 in case of L1
(ileal) disease
3.Costs per Quality Adjusted Life year (QALY)
4.Clinical endpoints:
4.1Change in CDAI from baseline to W12
4.1.1Clinical remission: CDAI < 150
4..1.2 Clinical (partial) response: decrease in CDAI >= 70 points [CR-70])
4.2 General and change in quality of life, as measured by the IBDQ, SF-36 and
EQ-5D-5L at baseline, week 12 and 36
4.3 Patient Reported Outcome Measure (PROM): assessment of the general and
change in functional status and well-being measured from the patients*
perspective by the IBD-CONTROL questionnaire [25], at baseline, week 12 and 36
4.4 Occurrence of (serious) adverse events (SAE)
5. Change in Anti-TNF serum concentration and anti-drug-antibodies from
baseline to W12
6. Proportion of patients with hs-CRP < 5mg/L at W12
7. Proportion of patients with fecal calprotectin < 250 µg/g at W12
8. Proportion of patients with fecal calprotectin <100 µg/g at W12
9. Histological changes from baseline to W12 based on centrally read scanned
biopsies using the colonic and ileal global histologic disease activity scoring
system (CGHAS/IGHAS, appendix 14.2) and the Robarts histology index (RHI,
appendix 14.3).
10. Presence of type 2 regulatory wound-healing macrophages (CD14+CD68+CD206+)
by immunohistochemical staining and fluorescence-activated cell sorting on
intestinal biopsies
Background summary
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 ant-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.
Study 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
Double-blind placebo-controlled randomized clinical trial. This trial will
comprise two phases. In phase 1 30 patients will be included. After 15 patients
in each treatment arm have completed the intervention phase (12 weeks
albendazole/placebo treatment) and thereby have reached the primary outcome
assessment, an interim analysis will be conducted. The results of the interim
analysis will be interpreted by a DSMB. The members of the DSMB will draw up
recommendations based on predefined stopping rules and dose reduction rules.
Depending on the recommendations of the DSMB the second phase of the trial will
be initiated in which the remaining 80 patients will be included.
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 matched placebo
Study burden and risks
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 several 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, (Yao, M.D., 2009,
Gastrointest Endosc)). In case a complication occurs, endoscopic treatment
(hemostasis/clipping) is effective in most cases. Rarely, hospital admission
with/without surgical intervention, antibiotic therapy and/or blood transfusion
can be required. Patients need to fill in 3 quality of life questionnaires and
1 *Patient Reported Outcome* questionnaire at three different timepoints.
Moreover, 2 questionnaires concerning the economic evaluation need to filled in
at week 12 and week 36.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
1. Patients >= 18 years and <=65 years
2. Diagnosis of CD, based on endoscopy and histopathologic examination of
mucosal biopsies
3. Written informed consent
4. Active disease as defined by a repeated faecal calprotectine >= 250 µg/g at 2
consecutive occasions (>=2 weeks and <=3 months interval) AND absence of mucosal
healing as defined by and SES-CD > 6 (>= 4 for L1 (ileal) disease) on
consecutive ileocolonoscopy
5. On anti-TNF monotherapy (ADM at a dose of 40mg Subcutaneous (SC) every week
(QW) or every other week (Q2W) and IFX at a dose of approximately 5mg/kg every
eight weeks) for a period of at least 6 months
6. No active combination therapy: anti-TNF + an immunomodulator (IMM). Prior
use of co-therapy where IMM stopped due to stable disease, prior IMM
monotherapy and prior intolerance to IMM*s are eligible
7. Therapeutic serum concentrations of anti-TNF at baseline (for IFX >= 3 µg/ml
and for adalimumab (ADM) >= 5 µg/ml and undetectable levels of anti-drug
antibodies (ADA*s)
Exclusion criteria
1. Patients < 18 years or >65 years old
2. Ulcerative colitis or indeterminate colitis
3. Currently ongoing malignancy
4. Women: current pregnancy wish, pregnancy or lactation. Men: active child wish
5. Use of an immunomodulator (including azathioprine, methotrexate,
6-thioguanine or 6 mercaptopurine)
6. Prior failure on anti-TNF and immunomodulatory combination therapy due to
refractory disease per treating physicians opinion
7. Presence of measurable anti-drug antibodies and absence of therapeutic
anti-TNF drug levels
8. Elevated liver enzymes (ALAT, ASAT, LDH, γ-GT, AF) >1.5 times the upper
limit of normal (ULN)
9. Current use of any CYP3A4 inducing or inhibiting agents
10. Leukopenia (neutrophil count < 1.8x10^9/L) and/or thrombopenia <50 x 10^9/L
11. Other conditions which in the opinion of the investigator may interfere
with the subject*s ability to comply with the study procedure
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-001737-85-NL |
| CCMO | NL63032.018.17 |
| OMON | NL-OMON29213 |