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

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ClinicalTrials.gov Identifier: NCT02878161
Recruitment Status : Unknown
Verified July 2016 by Fen Li, Central South University.
Recruitment status was:  Enrolling by invitation
First Posted : August 25, 2016
Last Update Posted : August 25, 2016
Sponsor:
Information provided by (Responsible Party):
Fen Li, Central South University

Study Description
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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.

Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Drug: methotrexate(necessary) Biological: infliximab Biological: etanercept Biological: adalimumab Drug: leflunomide (permitted, not necessary) Drug: NSAIDs (permitted,not necessary) Drug: Glucocorticoids (permitted,not necessary) Phase 4

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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
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 Start Date : January 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: A group
Infliximab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
 Drug: methotrexate(necessary)
Methotrexate will be received orally with dosage of 10mg/ week for every patient and MTX dose must be stable for at least 4 weeks.
Other Name: MTX

Biological: infliximab
infliximab :intravenous injection 200mg,every times,0,2,6,14week ,4 times)
Other Name: IFX

Drug: leflunomide (permitted, not necessary)
LEF will be permitted if patient had received for 1 month before enrollment and will not be changed for 14 weeks.
Other Name: LEF

Drug: NSAIDs (permitted,not necessary)
NSAIDs will be allowed if patient had received for 1 month before enrollment and will not be changed for 14 weeks.
Other Name: non steroidal anti inflammatory drugs

Drug: Glucocorticoids (permitted,not necessary)
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.
Other Name: prednisone,methylprednisolone,etc.
Experimental: B group
Etanercept plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
 Drug: methotrexate(necessary)
Methotrexate will be received orally with dosage of 10mg/ week for every patient and MTX dose must be stable for at least 4 weeks.
Other Name: MTX

Biological: etanercept
Etanercept :hypodermic injection,25mg/twice a week
Other Name: ETN

Drug: leflunomide (permitted, not necessary)
LEF will be permitted if patient had received for 1 month before enrollment and will not be changed for 14 weeks.
Other Name: LEF

Drug: NSAIDs (permitted,not necessary)
NSAIDs will be allowed if patient had received for 1 month before enrollment and will not be changed for 14 weeks.
Other Name: non steroidal anti inflammatory drugs

Drug: Glucocorticoids (permitted,not necessary)
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.
Other Name: prednisone,methylprednisolone,etc.
Experimental: C group
Adalimumab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
 Drug: methotrexate(necessary)
Methotrexate will be received orally with dosage of 10mg/ week for every patient and MTX dose must be stable for at least 4 weeks.
Other Name: MTX

Biological: adalimumab
Adalimumab:hypodermic injection,40mg/twice a week
Other Name: ADA

Drug: leflunomide (permitted, not necessary)
LEF will be permitted if patient had received for 1 month before enrollment and will not be changed for 14 weeks.
Other Name: LEF

Drug: NSAIDs (permitted,not necessary)
NSAIDs will be allowed if patient had received for 1 month before enrollment and will not be changed for 14 weeks.
Other Name: non steroidal anti inflammatory drugs

Drug: Glucocorticoids (permitted,not necessary)
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.
Other Name: prednisone,methylprednisolone,etc.


Outcome Measures
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Primary Outcome Measures :
  1. EULAR (European League Against Rheumatism) response will be assessed among patients of 3 groups [ Time Frame: Baseline, Weeks 14 ]

    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 :
  1. The changes of TNF level with different EULAR response will be assessed among patients of 3 groups. [ Time Frame: Baseline, Weeks 14 ]

    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.


  2. The changes of Interest proteins with different EULAR response will be assessed among patients of 3 group. [ Time Frame: Baseline, Weeks 14 ]

    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.


  3. The SNP (Single nucleotide polymorphism) of gene about TNF with different EULAR response will be assessed among patients of 3 groups. [ Time Frame: Weeks 14 ]

    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.


  4. The SNP of gene about interest proteins with different EULAR response will be assessed among patients of 3 groups. [ Time Frame: Weeks 14 ]

    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.



Eligibility Criteria
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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02878161


Sponsors and Collaborators
Fen Li
Investigators
Layout table for investigator information
Principal Investigator: Fen Li, doctor Central South University
More Information
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Publications:
Cui J, Stahl EA, Saevarsdottir S, Miceli C, Diogo D, Trynka G, Raj T, Mirkov MU, Canhao H, Ikari K, Terao C, Okada Y, Wedrén S, Askling J, Yamanaka H, Momohara S, Taniguchi A, Ohmura K, Matsuda F, Mimori T, Gupta N, Kuchroo M, Morgan AW, Isaacs JD, Wilson AG, Hyrich KL, Herenius M, Doorenspleet ME, Tak PP, Crusius JB, van der Horst-Bruinsma IE, Wolbink GJ, van Riel PL, van de Laar M, Guchelaar HJ, Shadick NA, Allaart CF, Huizinga TW, Toes RE, Kimberly RP, Bridges SL Jr, Criswell LA, Moreland LW, Fonseca JE, de Vries N, Stranger BE, De Jager PL, Raychaudhuri S, Weinblatt ME, Gregersen PK, Mariette X, Barton A, Padyukov L, Coenen MJ, Karlson EW, Plenge RM. Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis. PLoS Genet. 2013 Mar;9(3):e1003394. doi: 10.1371/journal.pgen.1003394. Epub 2013 Mar 28.

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Responsible Party: Fen Li, associate chief physician, Central South University
ClinicalTrials.gov Identifier: NCT02878161    
Other Study ID Numbers: XYEYY-GZ81571599-20160118-1
First Posted: August 25, 2016    Key Record Dates
Last Update Posted: August 25, 2016
Last Verified: July 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Fen Li, Central South University:
rheumatoid arthritis
tumor necrosis factor α inhibitor
predictive
iTRAQ
signal pathway
Additional relevant MeSH terms:
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Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Prednisone
Methylprednisolone
Adalimumab
Etanercept
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Methotrexate
 Infliximab
Glucocorticoids
Leflunomide
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents