Predictive Factors of Clinical Response to Ustekinumab in Active Crohn's Disease (SAFARI)

Identification of Biological Predictive Factors of Clinical Response to Ustekinumab in Patients With Anti-Tumor Necrosis Factor (TNF) Antagonists Refractory Crohn's Disease: Interest of Dosage of C Reactive Protein (CRP), Calprotectin, Ustekinumab Through Levels and Antibodies

Ustekinumab is a fully human Immune Globulin Gk (IgGk) monoclonal antibody against the common p40 subunit of interleukin-12 and interleukin-23, which are implicated in the pathogenesis of inflammatory bowel disease. Its efficiency to induce and maintain clinical response in patients with anti TNF resistant Crohn's disease has been proved in several clinical trials, and the profile of safety of this treatment was good, but the investigators have few data about biological characteristics of patients treated by Ustekinumab, particularly about ustekinumab through levels and rate of patients developing anti ustekinumab antibodies during the induction and maintenance stages, and no predictive factors of clinical response have been identified yet.

The aim of this study will be to assess the evolution of biological markers of inflammation and ustekinumab trough levels and antibodies, in responders and non responders patients treated by ustekinumab, in order to identify predictive factors of clinical response.

The investigators will perform a prospective observational study, including the patients followed in the University hospital center of Lyon and treated by ustekinumab for a moderate to severe Crohn's disease (with a HBI score≥4 ). All the patients included will have been previously treated by at least one anti TNF and/or Vedolizumab, with specified criteria for a primary non response, a secondary loss of response or unacceptable side effects.

Then, clinical and biological data will be collected for each patient at the inclusion, and then at weeks 4, 8, 16, 24: HBI score, sides effects, extra intestinal manifestations, steroids withdraw, CRP, calprotectin, ustekinumab trough levels and ustekinumab antibodies.

The investigators will compare responding and non responding patients at week 16 (end of the induction period) according to these data.

The hypothesis the investigators state is that an early and significant decrease of the inflammation markers in blood and stools associated with a high ustekinumab through level in blood is associated with a clinical response at week 16 in the patients treated by ustekinumab

Study Overview

• Status: Completed
• Conditions: Crohn Disease
• Intervention / Treatment: Biological: Evaluation of biological predictive factors of clinical response to ustekinumab

• Study Type: Observational
• Enrollment (Actual): 18

Contacts and Locations

Study Locations

• France
  • Pierre-Bénite, France, 69495
    • Centre Hospitalier Lyon Sud

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 18 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

This study is conducted in adults with moderate to severe active Crohn's disease who are resistant to TNF and Vedolizumab.

Description

Inclusion Criteria:

• Age > 18 years old
• Man or non pregnant woman
• Diagnostic attested of Crohn's disease
• Active Crohn's disease, with HBI score ≥ 4
• Previous treatment by at least one anti TNF and / or vedolizumab,, with primary non response, secondary loss of response or unacceptable side effects
• Formal indication of treatment by ustekinumab
• Patient informed and not opposed to his participation at the study

Exclusion Criteria:

• Pregnancy
• Evolutive cancer
• Evolutive and uncontrolled infection
• Psychiatric pathology that could interfere with the follow-up
• Refusal of the patient

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group Ustekinumab; Patients presenting an active crohn's disease (HBI score ≥ 4) with an indication of treatment by ustekinumab because of failure or unacceptable side effects of previous treatments, and who have already been treated by at least one anti TNF The patients must be 18 years old or older.	Biological: Evaluation of biological predictive factors of clinical response to ustekinumab; The clinical response is defined as a decrease in the Crohn's Disease Activity Index (CDAI) score ≥ 100 points or a decrease in the HBI score ≥ 3 points.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of serum ustekinumab trough concentrations (expressed in microg/mL) at week 8.	Dosage of ustekinumab through level and ustekinumab antibodies: one 4ml blood sample	Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of serum ustekinumab trough concentrations (expressed in microg/mL) at week 4.	Dosage of ustekinumab through level and ustekinumab antibodies: one 4ml blood sample	Week 4
Measurement of serum ustekinumab trough concentrations (expressed in microg/mL) at week 16.	Dosage of ustekinumab through level and ustekinumab antibodies: one 4ml blood sample	Week 16
Measurement of serum ustekinumab trough concentrations (expressed in microg/mL) at week 24.	Dosage of ustekinumab through level and ustekinumab antibodies: one 4ml blood sample	Week 24
Dosage in blood at week 4	-Inflammation markers are evaluated : Dosage of CRP and leucocytes in blood: two 4ml blood sample	Week 4
Dosage in blood at week 8	-Inflammation markers are evaluated : Dosage of CRP and leucocytes in blood: two 4ml blood sample	Week 8
Dosage in blood at week 16	-Inflammation markers are evaluated : Dosage of CRP and leucocytes in blood: two 4ml blood sample	Week 16
Dosage in blood at week 24	-Inflammation markers are evaluated : Dosage of CRP and leucocytes in blood: two 4ml blood sample	Week 24
Dosage of calprotectin in stools at week 4	-Inflammation markers are evaluated : Dosage of calprotectin in stools: one about 50 mg stools sample	Week 4
Dosage of calprotectin in stools at week 8	-Inflammation markers are evaluated : Dosage of calprotectin in stools: one about 50 mg stools sample	Week 8
Dosage of calprotectin in stools at week 16	-Inflammation markers are evaluated : Dosage of calprotectin in stools: one about 50 mg stools sample	Week 16
Dosage of calprotectin in stools at week 24	-Inflammation markers are evaluated : Dosage of calprotectin in stools: one about 50 mg stools sample	Week 24
Physical evaluation at week 4	Clinical evaluation is realized by a medical visit with physical examination	Week 4
Physical evaluation at week 8	Clinical evaluation is realized by a medical visit with physical examination	Week 8
Physical evaluation at week 16	Clinical evaluation is realized by a medical visit with physical examination	Week 16
Physical evaluation at week 24	Clinical evaluation is realized by a medical visit with physical examination	Week 24
Clinical evaluation at week 4	Clinical evaluation is realized by a medical visit with evaluation of: the efficiency of the treatment: evaluation of well being, abdominal pain, stools numbers per day, presence or not of peri anal lesion, arthralgia, fever; the tolerance/potential side effects of the treatment: infections, headache, skin rash, nausea, allergic reaction, or any clinical manifestation that could be imputed to the treatment	Week 4
Clinical evaluation at week 8	Clinical evaluation is realized by a medical visit with evaluation of: the efficiency of the treatment: evaluation of well being, abdominal pain, stools numbers per day, presence or not of peri anal lesion, arthralgia, fever; the tolerance/potential side effects of the treatment: infections, headache, skin rash, nausea, allergic reaction, or any clinical manifestation that could be imputed to the treatment	Week 8
Clinical evaluation at week 16	Clinical evaluation is realized by a medical visit with evaluation of: the efficiency of the treatment: evaluation of well being, abdominal pain, stools numbers per day, presence or not of peri anal lesion, arthralgia, fever; the tolerance/potential side effects of the treatment: infections, headache, skin rash, nausea, allergic reaction, or any clinical manifestation that could be imputed to the treatment	Week 16
Clinical evaluation at week 24	Clinical evaluation is realized by a medical visit with evaluation of: the efficiency of the treatment: evaluation of well being, abdominal pain, stools numbers per day, presence or not of peri anal lesion, arthralgia, fever; the tolerance/potential side effects of the treatment: infections, headache, skin rash, nausea, allergic reaction, or any clinical manifestation that could be imputed to the treatment	Week 24

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2018
• Primary Completion (Actual): August 29, 2018
• Study Completion (Actual): September 23, 2019

Study Registration Dates

• First Submitted: October 30, 2017
• First Submitted That Met QC Criteria: November 21, 2017
• First Posted (Actual): November 24, 2017

Study Record Updates

• Last Update Posted (Actual): August 24, 2022
• Last Update Submitted That Met QC Criteria: August 23, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: anti-TNF; Crohn Disease; cohort; Ustekinumab; CRP; Vedolizumab; calprotectin
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Dermatologic Agents; Ustekinumab
• Other Study ID Numbers: 69HCL17_0218

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No