Microbiota Analysis to Predict Outcomes of Rheumatoid Arthritis Patients Treated With JAK-inhibitor

NCT04530305 | Unknown

• 1 other identifier: RECHMPL19_0224-UF7806
• Study Type: observational
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

Personalized medicine in which each patient would receive the ideal personalized treatment and regimen, holds great promise to improve patient's care. However, previous studies failed to establish validated predictors of response to disease-modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). JAK inhibitors is a new class of DMARDs with great efficacy that might be even superior to anti-TNF drugs. As there are chemicals, their production cost is much cheaper than biological therapies and they will probably be central in patient's care in the coming years. Three are currently available: upadacitinib (UPA) tofacitinib and baricitinib. Our study will focus on UPA. Clinical outcomes mainly depend on i) factors influencing drug metabolism \& concentrations and ii) adequacy between drug target and the inflammation pathways involved in the patient's disease. Humans carry in their gut trillions of germs, which are now known to be key players in health and disease. Those germs possess many enzymes and strongly modulate human enzymes expression. Gut-microbiota can, indeed, directly metabolize oral drugs and control the expression of the cytochrome P450 3A4 (CYP3A4), the main enzyme metabolizing TOFA. We showed, in a preliminary mouse experiment, that modifying gut-microbiota composition changes JAKi effects on signaling pathways. We thus believe that models including gut-microbiota composition together with markers of immune activation will predict clinical outcomes in RA patients treated with UPA. Main and secondary objectives: To build predictive models for clinical outcomes (efficacy and safety) of RA patients treated with UPA based on microbiota analysis and markers f immune activation. Methodolgy: This multicentric longitudinal prospective study will include 60 patients with RA and inadequate response to methotrexate. The clinical outcomes studied will be EULAR non-response at 3 months as defined by the European league against rheumatism EULAR (primary outcome), achievement of low-disease activity at 6 months or incident adverse events (secondary outcomes). Gut microbiota will be assessed at baseline and M3 from thawed fecal samples. DNA will be purified using QIAamp DNA stool mini kit (Qiagen) and qualify using Qubit and TapeStation 4200 (Agilent). Library will be prepared by amplification of V1-V2 and V3-V4 regions from the bacterial 16S rRNA genes and will be qualified by q-PCR and amplicons will be sequenced by MiSeq (Illumina). Initial bioinformatic analysis and taxonomies will be carried out using the QIIME2 software. Immune activation will be assessed through JAK-STAT pathway activation by JAK STAT signaling pathway RT² profiler PCR Array (Qiagen) which profiles expression of 84 genes related to Jak and Stat-mediated signaling. UPA concentrations will be assessed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) at baseline and 3 months. Statistical classifiers (Neural network algorithm, Linear and Quadratic Discriminant Analysis, Support Vector Machine, Random forests, Shrinkage Methods, or Nearest Neighbors) incorporating microbiome, JAK STAT signaling pathway gene expression and clinical data, will be used to determine profiles associated with UPA clinical response and safety. Patients who will prematurely stop UPA (before 3 months) for adverse events or loss of follow-up will be considered as non-responders.

Conditions

Rheumatoid Arthritis

Outcome Measures

Primary Outcomes (1)

• EULAR response

  Response will be defined following European league against rheumatism EULAR definition that is a decrease \>0.6 points of Disease-Activity-Score 28-joints (DAS28-CRP) and a DAS28-CRP≤5.1 at 3 months . Patients who will prematurely stop UPA (before 3 months) for adverse events, RA flair or loss of follow-up will be considered as non-responders.

  3 months

Secondary Outcomes (7)

• EULAR good response

  3 and 6 months

• Achievement of low-disease activity:

  6 months

• Adverse events

  during the 6 month follow-up

• Baseline gut-microbiota

  baseline, 3 and 6 months

• UPA concentrations

  0, 3 and 6 months

Interventions

Upadacitinib <15 MG [Rinvoq] DRUG

Patients with RA for who the introduction of upadacitinib has been decided will be proposed the study. If they accept, they will be followed for 6 months with 3 visits (baseline, 3 and 6 months) which is the usual standard care. In addition to routine markers, stool and blood will be collected at baseline and 3 months specifically for the study.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with RA fulfilling American College of Rheumatology (ACR)/ European league against rheumatism (EULAR) 2010 criteria with inadequate response to MTX for who a treatment with UPA will be prescribed in standard care to control disease activity

You may qualify if:

• Patients with RA fulfilling American College of Rheumatology (ACR)/ European league against rheumatism (EULAR) 2010 criteria
• Patients with inadequate response to MTX
• Patients receiving MTX as adjuvant therapy or will receive UPA as monotherapy

You may not qualify if:

• Patients with contraindication to upadacitinib
• Patients previously treated with biological DMARDs or JAK inhibitors
• Patients treated with ≥ 10 mg/day of glucocorticoids
• Use of IV glucocorticoids in the previous month
• Previous use of biological DMARDs (TNF inhibitors, rituximab, abatacept, tocilizumab) or JAK inhibitors
• Absence of informed consent
• Pregnancy planned for the duration of the study, Women pregnant or breastfeeding women
• Major protected by law or patient under guardianship

Sponsors & Collaborators

• University Hospital, Montpellier: lead

Study Sites (1)

CHU de Montpellier

Montpellier, 34295, France

RECRUITING

Biospecimen

Retention: SAMPLES WITHOUT DNA

PAXgene tubes for blood RNA analysis stools for feces analysis plasma for upadacitinib concentration assessement

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

upadacitinib

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Claire DAIEN, Prof

  Montpellier Hospital and University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Claire I DAIEN, Prof

CONTACT

467338710; c-daien@chu-montpellier.fr

Alban POUVREAU

CONTACT

4 67 33 24 82; a-boissin@chu-montpellier.fr

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 24, 2020
• First Posted: August 28, 2020
• Study Start: January 7, 2021
• Primary Completion: April 1, 2024
• Study Completion: October 1, 2024
• Last Updated: September 14, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)