Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03555058 |
| Other study ID # |
4945-18-SMC |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
July 3, 2018 |
| Est. completion date |
December 26, 2023 |
Study information
| Verified date |
February 2024 |
| Source |
Sheba Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
A prospective randomized three-arms controlled trial of Crohn's Disease (CD) patients in
remission of <24 months duration. Patients will undergo screening by Magnetic Resonance
Enterography (MRE) and patency capsule, and (if agreeing by separate consent) a baseline
colonoscopy. Patients in whom patency of small bowel is proven will undergo video-capsule
using the dedicated Inflammatory-Bowel Disease (IBD)-capsule (PillCam Crohn's). Patients with
Lewis score>350 for worst small bowel segment will be classified as high-risk and will be
randomized for continued standard treatment or proactive treatment. Proactive treatment will
consist of escalating/switching biologic treatment according to the pre-defined therapeutic
drug monitoring (TDM)-based treatment-intensification protocol, or will consist of initiating
biologic therapy in high-risk patients not receiving biologics at the time of enrollment.
Both high-risk patients arms - the continued standard treatment and the proactive arm - will
be followed up by clinic visits with physical examination, inflammatory and immune markers'
assessment and microbiome analysis every 3 months and by serial video-capsule endoscopy (VCE)
studies+ intestinal UltraSound (US) every six months. Patients who are classified as low-risk
patients, as per Lewis score<350 at baseline, will continue standard treatment and be
similarly followed. All enrolled patients will undergo MRE at the end of the trial. All
patients will undergo in addition blood and stool sampling for inflammatory markers,
immune-phenotyping and microbiome analysis. All patients will undergo MRE at the end of the
trial.
Description:
1. Entry procedures: Patients will undergo clinical examination and history taking and then
will undergo patency capsule. If patency is proven, patients will undergo a third
generation pan-enteric capsule endoscopy (PillCam Crohn), ileocolonoscopy with biopsies
(by separate consent), MRE, Intestinal US, biomarkers, immune & microbiome analysis, and
health related quality of life assessment and patient reported outcome (PRO) standard
questionnaires. (see Appendix 1 for complete protocol of baseline pan-enteric capsule
endoscopy and ileocolonoscopy evaluation, Appendix 2 for complete protocol of MRE
examination, Appendix 3 for blood and stool sample collection protocols, Appendix 4 for
Intestinal US protocol, appendix 5 for microbiomic analysis protocol, appendix 6 for
health related quality of life/cost assessments, appendix 7 for Immune analysis).
2. Follow-up procedures: Capsule endoscopy, nutritional and intestinal US studies will be
performed every 6 months for the total study duration of 2 years. For patients with only
small bowel disease these will be without preparation. Additionally, periodic (every 3
months) assessment will be performed for inflammatory, microbiome, imaging attributes,
quality of life and immunophenotyping, as outlined below in description of tasks for
work packages.
3. Risk stratification and outcomes: Based on VCE results and according to the predictive
algorithm defined by the first project's results, patients will be classified as high
risk if having Lewis score (LS) ≥350 for the small bowel tertile with the highest score,
or as having low risk (LS<350 highest tertile score) for future relapse of disease.
Low risk patients will continue the monitoring scheme and their treatment regimen unaltered.
Patients with LS ≥350 will be randomized to either continue follow-up with unaltered therapy
or to proactive therapy optimization with TDM assessment. Therapy will be optimized based on
the optimization protocol described below, with the aim to prevent flares and complications.
Follow up to determine the occurrence of clinical flares and complications as well as the
status of inflammatory process will be performed for all patients q3months. Study will be
terminated and a patient will be withdrawn upon disease flare or complication or if a change
of CD medications was instituted (except for treating verified infectious complication such
as C. difficile infection) and such a patient will be considered a non-responder. A patient
will also be withdrawn if in the opinion of the Principle Investigator (PI), a new adverse
event or medical condition is present that endangers the patient's wellbeing if the study
protocol is adhered to. To maintain temporally-restricted blinding, VCE results will be
disclosed up to three months following the performance of VCE.
* In a sub-group of consenting patients, stool samples for microbiome analysis (see below)
will be collected daily for a designated period of time. In a sub-group of consenting
patients, additional on-line data collection methods will be employed (see below).
Risk-based intervention: Patients meeting the VCE-based high-risk criteria and who were
randomized to proactive treatment arm will receive therapy intensification within 30 days.
Re-assessment of response to the intensified therapy will be performed by repeated VCE and
bio-markers after 6 months. The intensification protocol will be as appears below. Briefly,
patients receiving immunomodulators,5-Aminosalicylates (5ASA) or no treatment at the time
they are found to have high risk of imminent flare or complication will receive induction
with a biologic of the anti-Tumor necrosis Factor (TNF)- Infliximab (IFX), Adalimumab (ADA)-
or anti-integrin (VDZ) classes as per standard induction protocols for these agents. The
choice of the biologic will be guided by the treating physician's discretion as per the
individual patient-related considerations. In patients already on a biologic, intervention
will be guided by protocolized TDM results for patients on anti-TNFs, whereas patients
receiving vedolizumab will first receive an interval-halving intervention. Protocolized
anti-TNF TDM-based intervention will comprise of increasing the dose of anti-TNF, or
switching anti-TNF, or switching out-of-class according to the drug/anti-drug antibodies
thresholds and algorithms set by previous works by our group in this field, using the same
assay that will be employed in the present trial. Re-adjustment of therapy according to these
principles will be performed if 6-month VCE re-assessment does not show a reduction of
patient risk score to the range of a low risk VCE-based score. Patients who received an
intervention and in whom follow-up 6 months VCE does not show a reduction of 225 points on
the Lewis score or highest segment Lewis score of <350, will receive the next protocolized
drug optimization.
Intervention protocol in proactive arm based on current treatment and TDM finding:
ADL with drug level<8mcg/ml/AAA<4mcg/ml-eq ADL dose-doubling ADL with drug level
<8mcg/ml/AAA>4mcg/ml-eq Switch anti TNF or add IMM ADL with drug level >8mcg/ml Switch out of
class IFX with drug level <6mcg/ml/ATI<9mcg/ml-eq IFX dose-doubling IFX with drug level
<6mcg/ml/ATI>9mcg/ml-eq Switch anti TNF or add IMM IFX with drug level >6mcg/ml Switch out of
class VDZ e/8 week VDZ interval halving VDZ e4W/CD3CD45RO target occupied >85% Switch out of
class VDZ e4W/ CD3CD45RO target occupied<85% VDZ double-dosing 600/4w UST 90mg/SC e12w or
e/8W Shorten interval e/4w No treatment, 5-ASA or AZA/6MP >> Start biologic ADL - adalimumab,
IFX- infliximab, VDZ - vedolizumab UST - Ustekinumab AAA- antibodies to adalimumab, ATI
antibodies to infliximab, IMM - immunomodulator
