The primary objective of this study is to evaluate the efficacy of optimized thiopurine therapy. Secondary objectives are a cost-utility and budget impact analysis of optimized thiopurine therapy and the identification of biomarkers in mucosal…
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Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main endpoint of this study is clinical and endoscopic remission at week
52.
Secondary outcome
* Occurrence of (serious) adverse events ((S)AE)
* Leukocyte counts
* Liver function tests
* 6-TGN levels & 6-MMP levels
* Occurrence of treatment failure
* Occurrence of flares and upscaling treatment / escape medication
* Treatment costs
* Quality of life
* Biomarkers, cell types and microbiome in colon biopsies
* Fecal Volatile Organic Compounds (VOC's)
* Fecal microbiome sequencing
* RAC genotypes in blood samples
Background summary
Thiopurines are commonly used as maintenance treatment for UC. It is estimated
that approximately 25% of UC patients in the Netherlands receive treatment with
thiopurines. However, no prospective well-designed studies are available on
this topic. Trials that have been conducted are small in size and results are
conflicting. Hence, clinical practice is dominated by support from low quality
evidence. Moreover, outcome measures used in different trials vary considerably
and the tools used to assess clinical disease activity are numerous and
diverse. Consequently, clinical decisions on maintenance treatment may be
overly heterogeneous and tend to upscaling treatment regimens prematurely.
These inconsistent results are, at least in part, due to intolerance or drug
toxicity causing (early) withdrawal of thiopurines and as a result inefficacy.
Development of adverse events (but also inefficacy) during thiopurine therapy
can largely be explained by its complex metabolism. In recent years, it has
become standard care to optimize thiopurine therapy based on thiopurine
metabolite measurements in case of therapeutic failure. In published
prospective thiopurine trials, this Therapeutic Drug Montioring (TDM) based
strategy has not been applied, despite present solid evidence supporting this
beneficial strategy. The enduring uncertainty on the efficacy of thiopurine
therapy in UC paves the way for a prospective trial, in which thiopurine
therapy is given in its most optimal way by standard TDM.
Study objective
The primary objective of this study is to evaluate the efficacy of optimized
thiopurine therapy. Secondary objectives are a cost-utility and budget impact
analysis of optimized thiopurine therapy and the identification of biomarkers
in mucosal biopsies, feces and blood as potential predictors of thiopurine
response.
Study design
Double-blind, randomised, placebo-controlled trial.
Intervention
Patients will receive treatment with oral prednisone 40 mg/day for 2 weeks,
followed by fixed tapering over 6 weeks or with oral budesonide 9 mg/day during
8 weeks. 5-ASA treatment will be continued during the trial in all patients.
Half of the patients will be randomized to concomitant placebo treatment and
the other half will receive mercaptopurine (6-MP) 1-1.5 mg/kg/day.
Study burden and risks
The main goal of this study is to evaluate te efficacy of optimized treatment
with thiopurines for UC patients. Patients that would receive thiopurines in
frame of their standard care are potential candidates for this study. We
hypothesize that by applying TDM, we achieve better treatment results and
reduce side effects in the mercaptopurine group. When compared to standard
care, the risk of thiopurine treatment is therefore expected to be lower in
this trial.
In the placebo group patients are possibly at higher risk of developing a flare
when compared to the mercaptopurine group. In case of symptoms suggesting a
flare, patients will undergo all standard procedures to confirm this and to
exclude other causes. If a flare is confirmed, the patient will be unblinded
from the study and escape medication is started at the discretion of the
treating phycisian.
Colonoscopy and sigmoïdoscopy are safe procedures, but complications such as
bleeding and perforation may occur (0,2 %, 0,1 %). Patients will be subjected
to two sigmoidoscopies for this study in order to assess the mucosal condition
before and after treatment. This is according to standard care. The endoscopies
are necessary for this study since assessment of the mucosal condition is the
best way to assess treatment effect. If otherwise, this study would be
conducted sub optimally and the results would be futile.
Meibergdreef 9
Amsterdam Zuidoost 1105AZ
NL
Meibergdreef 9
Amsterdam Zuidoost 1105AZ
NL
Listed location countries
Age
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 focal high grade dysplasia or 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. Leukopenia (Neutrophil count < 1,8x10^9/L)
18. Thrombocytopenia (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
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
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-005260-41-NL |
| ClinicalTrials.gov | NCT02910245 |
| CCMO | NL55253.018.15 |