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Predictability Studies on the Efficacy of TNF-α Inhibitors in Chinese RA From "Real World"

Primary Purpose

Rheumatoid Arthritis

Status
Unknown status
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
methotrexate(necessary)
infliximab
etanercept
adalimumab
leflunomide (permitted, not necessary)
NSAIDs (permitted,not necessary)
Glucocorticoids (permitted,not necessary)
Sponsored by
Fen Li
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Rheumatoid Arthritis focused on measuring rheumatoid arthritis, tumor necrosis factor α inhibitor, predictive, iTRAQ, signal pathway

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • signed the consents voluntarily
  • age between 18-75 years old

  • patients were meet the American College of Rheumatology(ACR)

    • European League Against Rheumatism(EULAR) 2009 diagnostic criteria (total scores beyond 6)
  • for severe RA patients DAS28-CRP≥5.1
  • The participants receiving Infliximab plus Methotrexate will be invited to enroll the study.
  • The participants receiving Etanercept plus Methotrexate will be invited to enroll the study.
  • The participants receiving Adalimumab plus Methotrexate will be invited to enroll the study.

Exclusion Criteria:

  • The patient have the disease history or the disease of cardiovascular, respiratory system, liver, gastrointestinal tract, endocrine, hematology, neurology or psychiatric disturbance, and investigator believe that there are some risks for patients with these disease history or disease when use study drugs, or these disease history or disease will disturb the interpret of data
  • Patients with cancer in situ or exist the possibility of cancer malignancies
  • Basically or completely loss of mobility, lack self-care ability, such as rely on a wheelchair or bed-ridden .
  • Experimental examination display any of the following:

Aspartate aminotransferase or alanine aminotransferase>1.5 times of the upper limit of the normal value Total bilirubin>1.5 times of the upper limit of the normal value Total white blood cells <2500 cells/L absolute neutrophil count <1200 cells/L lymphocyte count <750 cells/L platelet<100000/L

  • Patients with symptomatic herpes simplex
  • Latent tuberculosis signal (PPD+++ OR T-SPOT>5 )
  • Positive result of the hepatitis B virus (HBV):

HBsAg + Or HBeAg + Or HBeAg + Or HBcAb + Or HBV DNA +

  • hepatitis C virus(HCV)+ or HCV RNA +
  • HIV infection or HIV+
  • 1 months before join the group, from a clinical point of view,patients have a serious infection caused by the virus, bacteria, fungi, or parasites
  • Pregnancy 、 location 、prepare for conceive in one years or there is risk to impregnate their partners
  • Patients received any biological therapies for 6 months, or participated any other clinical trials of new drugs
  • A history of drug allergy
  • A history of heavy drink
  • vaccinate the live vaccine recently

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm Type

    Experimental

    Experimental

    Experimental

    Arm Label

    A group

    B group

    C group

    Arm Description

    Infliximab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.

    Etanercept plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.

    Adalimumab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.

    Outcomes

    Primary Outcome Measures

    EULAR (European League Against Rheumatism) response will be assessed among patients of 3 groups
    EULAR (European League Against Rheumatism) response is based on changes of DAS28-CRP. The following good, moderate and no response are defined based on changes of DAS28-CRP from baseline to weeks 14: >1.2 units are good response; 0.6-1.2 units are moderate response; ≤0.6 units are no response. The DAS28-CRP will be calculated at every visit within the clinical database. The components of the DAS28-CRP score assessment are: Tender/Painful Joint Count (28); Swollen Joint Count (28), hsCRP, and the Subject General Health VAS assessment. This efficacy measurement will be made at baseline and weeks 14.

    Secondary Outcome Measures

    The changes of TNF level with different EULAR response will be assessed among patients of 3 groups.
    The TNF level assessment is a direct measurement using ELISA by testing patients' serum. This measurement will be made at baseline and weeks 14. The classification of EULAR response and the calculation of DAS28-CRP are based on above of Primary Outcome Measure.
    The changes of Interest proteins with different EULAR response will be assessed among patients of 3 group.
    Interest proteins will be screened by iTRAQ (isobaric tags for relative and absolute quantitation). This measurement will be made at baseline and weeks 14 by comparing part of patients with good response or no response. Interest proteins being screened will be verified by Western Blot among all patients of 3 groups. The classification of EULAR response and the calculation of DAS28-CRP are based on above of Primary Outcome Measure.
    The SNP (Single nucleotide polymorphism) of gene about TNF with different EULAR response will be assessed among patients of 3 groups.
    SNP of TNF gene will be tested by PCR-RFLP (Polymerase Chain Reaction -Restriction Fragment Length Polymorphism). This measurement will be made at weeks 14 among all 3 groups' patients. The classification of EULAR response and the calculation of DAS28-CRP are based on above of Primary Outcome Measure.
    The SNP of gene about interest proteins with different EULAR response will be assessed among patients of 3 groups.
    SNP of gene about interest proteins will tested by PCR-HRM(Polymerase Chain Reaction-high resolution melting). This measurement will be made at weeks 14 among all 3 groups' patients. Interest proteins are screened and verified on above of Secondary Outcome Measure. The classification of EULAR response and the calculation of DAS28-CRP are based on above of Primary Outcome Measure.

    Full Information

    First Posted
    July 12, 2016
    Last Updated
    August 21, 2016
    Sponsor
    Fen Li
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02878161
    Brief Title
    Predictability Studies on the Efficacy of TNF-α Inhibitors in Chinese RA From "Real World"
    Official Title
    Screening Protein Predictive of Response to Tumor Necrosis Factor-α Inhibitors Treatment in Chinese Rheumatoid Arthritis From "Real World" and Investigating Its Mechanism Through Signal Pathway
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    July 2016
    Overall Recruitment Status
    Unknown status
    Study Start Date
    January 2016 (undefined)
    Primary Completion Date
    December 2019 (Anticipated)
    Study Completion Date
    December 2019 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor-Investigator
    Name of the Sponsor
    Fen Li

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    Rheumatoid arthritis (RA) is a chronic and disabling disease. tumor necrosis factor-a(TNF-a) inhibitors have demonstrated an outstanding performance in relieving joint inflammation and retarding bone erosion involved in RA. However, there is still about one-thirds of RA patients had a poor response to TNF α inhibitors. The Investigators hope to discover prediction protein with a domestic genetic background and finally establish prediction system with Chinese characteristics.
    Detailed Description
    Rheumatoid arthritis (RA) is a chronic and disabling disease. TNF-α inhibitors have demonstrated an outstanding performance in relieving joint inflammation and retarding bone erosion involved in RA. However, there is still about one-thirds of RA patients had a poor response to TNF α inhibitors. Currently the personalized biological treatment is the research hotspot. Recent studies focuses on exploring biomarkers predictive of drug response. The research methods such as genomics, transcriptomics, proteomics, metabolomics and immunocytology, have been applied,but they are not successfully integrated. The related studies in China are still at an initial stage, which necessitates an in-depth study in this area. The investigators' preliminary study showed that TNF-α-308 gene polymorphisms existed in Chinese RA patients and phosphoinositide 3-kinase/Akt signal pathway was activated in proliferated synovial fibroblasts stimulated by TNF-α. Therefore, for the first attempt in China, the investigators intend to screen for differential proteins by using isobaric tags for relative and absolute quantitation(iTRAQ) technique in RA patients receiving anti-TNF-α therapy, and then verify the predictive effects of selected differential proteins from the upstream gene polymorphism to the downstream protein expression. The investigators will also explore the mechanisms of differential proteins involved in TNF-α related signal pathway by using in vitro gene transfer, siRNA interference, and RA animal models. Through this study investigator hope to discover some prediction proteins with a domestic genetic background and finally establish a prediction system with Chinese characteristics.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Rheumatoid Arthritis
    Keywords
    rheumatoid arthritis, tumor necrosis factor α inhibitor, predictive, iTRAQ, signal pathway

    7. Study Design

    Primary Purpose
    Basic Science
    Study Phase
    Phase 4
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Non-Randomized
    Enrollment
    240 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    A group
    Arm Type
    Experimental
    Arm Description
    Infliximab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
    Arm Title
    B group
    Arm Type
    Experimental
    Arm Description
    Etanercept plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
    Arm Title
    C group
    Arm Type
    Experimental
    Arm Description
    Adalimumab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
    Intervention Type
    Drug
    Intervention Name(s)
    methotrexate(necessary)
    Other Intervention Name(s)
    MTX
    Intervention Description
    Methotrexate will be received orally with dosage of 10mg/ week for every patient and MTX dose must be stable for at least 4 weeks.
    Intervention Type
    Biological
    Intervention Name(s)
    infliximab
    Other Intervention Name(s)
    IFX
    Intervention Description
    infliximab :intravenous injection 200mg,every times,0,2,6,14week ,4 times)
    Intervention Type
    Biological
    Intervention Name(s)
    etanercept
    Other Intervention Name(s)
    ETN
    Intervention Description
    Etanercept :hypodermic injection,25mg/twice a week
    Intervention Type
    Biological
    Intervention Name(s)
    adalimumab
    Other Intervention Name(s)
    ADA
    Intervention Description
    Adalimumab:hypodermic injection,40mg/twice a week
    Intervention Type
    Drug
    Intervention Name(s)
    leflunomide (permitted, not necessary)
    Other Intervention Name(s)
    LEF
    Intervention Description
    LEF will be permitted if patient had received for 1 month before enrollment and will not be changed for 14 weeks.
    Intervention Type
    Drug
    Intervention Name(s)
    NSAIDs (permitted,not necessary)
    Other Intervention Name(s)
    non steroidal anti inflammatory drugs
    Intervention Description
    NSAIDs will be allowed if patient had received for 1 month before enrollment and will not be changed for 14 weeks.
    Intervention Type
    Drug
    Intervention Name(s)
    Glucocorticoids (permitted,not necessary)
    Other Intervention Name(s)
    prednisone,methylprednisolone,etc.
    Intervention Description
    Glucocorticoids (prednisone less than 10mg/day, or equal dosage of other similar drugs) will be permitted if the patient had received for 1 month before enrollment and the dosage will not be changed during the period.
    Primary Outcome Measure Information:
    Title
    EULAR (European League Against Rheumatism) response will be assessed among patients of 3 groups
    Description
    EULAR (European League Against Rheumatism) response is based on changes of DAS28-CRP. The following good, moderate and no response are defined based on changes of DAS28-CRP from baseline to weeks 14: >1.2 units are good response; 0.6-1.2 units are moderate response; ≤0.6 units are no response. The DAS28-CRP will be calculated at every visit within the clinical database. The components of the DAS28-CRP score assessment are: Tender/Painful Joint Count (28); Swollen Joint Count (28), hsCRP, and the Subject General Health VAS assessment. This efficacy measurement will be made at baseline and weeks 14.
    Time Frame
    Baseline, Weeks 14
    Secondary Outcome Measure Information:
    Title
    The changes of TNF level with different EULAR response will be assessed among patients of 3 groups.
    Description
    The TNF level assessment is a direct measurement using ELISA by testing patients' serum. This measurement will be made at baseline and weeks 14. The classification of EULAR response and the calculation of DAS28-CRP are based on above of Primary Outcome Measure.
    Time Frame
    Baseline, Weeks 14
    Title
    The changes of Interest proteins with different EULAR response will be assessed among patients of 3 group.
    Description
    Interest proteins will be screened by iTRAQ (isobaric tags for relative and absolute quantitation). This measurement will be made at baseline and weeks 14 by comparing part of patients with good response or no response. Interest proteins being screened will be verified by Western Blot among all patients of 3 groups. The classification of EULAR response and the calculation of DAS28-CRP are based on above of Primary Outcome Measure.
    Time Frame
    Baseline, Weeks 14
    Title
    The SNP (Single nucleotide polymorphism) of gene about TNF with different EULAR response will be assessed among patients of 3 groups.
    Description
    SNP of TNF gene will be tested by PCR-RFLP (Polymerase Chain Reaction -Restriction Fragment Length Polymorphism). This measurement will be made at weeks 14 among all 3 groups' patients. The classification of EULAR response and the calculation of DAS28-CRP are based on above of Primary Outcome Measure.
    Time Frame
    Weeks 14
    Title
    The SNP of gene about interest proteins with different EULAR response will be assessed among patients of 3 groups.
    Description
    SNP of gene about interest proteins will tested by PCR-HRM(Polymerase Chain Reaction-high resolution melting). This measurement will be made at weeks 14 among all 3 groups' patients. Interest proteins are screened and verified on above of Secondary Outcome Measure. The classification of EULAR response and the calculation of DAS28-CRP are based on above of Primary Outcome Measure.
    Time Frame
    Weeks 14

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    75 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: signed the consents voluntarily age between 18-75 years old patients were meet the American College of Rheumatology(ACR) European League Against Rheumatism(EULAR) 2009 diagnostic criteria (total scores beyond 6) for severe RA patients DAS28-CRP≥5.1 The participants receiving Infliximab plus Methotrexate will be invited to enroll the study. The participants receiving Etanercept plus Methotrexate will be invited to enroll the study. The participants receiving Adalimumab plus Methotrexate will be invited to enroll the study. Exclusion Criteria: The patient have the disease history or the disease of cardiovascular, respiratory system, liver, gastrointestinal tract, endocrine, hematology, neurology or psychiatric disturbance, and investigator believe that there are some risks for patients with these disease history or disease when use study drugs, or these disease history or disease will disturb the interpret of data Patients with cancer in situ or exist the possibility of cancer malignancies Basically or completely loss of mobility, lack self-care ability, such as rely on a wheelchair or bed-ridden . Experimental examination display any of the following: Aspartate aminotransferase or alanine aminotransferase>1.5 times of the upper limit of the normal value Total bilirubin>1.5 times of the upper limit of the normal value Total white blood cells <2500 cells/L absolute neutrophil count <1200 cells/L lymphocyte count <750 cells/L platelet<100000/L Patients with symptomatic herpes simplex Latent tuberculosis signal (PPD+++ OR T-SPOT>5 ) Positive result of the hepatitis B virus (HBV): HBsAg + Or HBeAg + Or HBeAg + Or HBcAb + Or HBV DNA + hepatitis C virus(HCV)+ or HCV RNA + HIV infection or HIV+ 1 months before join the group, from a clinical point of view,patients have a serious infection caused by the virus, bacteria, fungi, or parasites Pregnancy 、 location 、prepare for conceive in one years or there is risk to impregnate their partners Patients received any biological therapies for 6 months, or participated any other clinical trials of new drugs A history of drug allergy A history of heavy drink vaccinate the live vaccine recently
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Fen Li, doctor
    Organizational Affiliation
    Central South University
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No
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