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

Phase 4

• Conditions: Rheumatoid Arthritis
• Interventions: Drug: methotrexate(necessary); Biological: etanercept; Biological: infliximab; Biological: adalimumab; Drug: leflunomide (permitted, not necessary); Drug: NSAIDs (permitted,not necessary); Drug: Glucocorticoids (permitted,not necessary)

• Registration Number: NCT02878161
• Lead Sponsor: Fen Li

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.

Study Timeline

• Study Start: 2016-01
• Status Verified: 2016-07
• Study First Submitted: 2016-07-12
• Study First Submitted QC: 2016-08-21
• Last Update Submitted: 2016-08-21
• Study First Posted: 2016-08-25
• Last Update Posted: 2016-08-25
• Primary Completion: 2019-12
• Study Completion: 2019-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 240

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
B group	etanercept	Etanercept plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
B group	leflunomide (permitted, not necessary)	Etanercept plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
A group	methotrexate(necessary)	Infliximab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
A group	infliximab	Infliximab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
A group	leflunomide (permitted, not necessary)	Infliximab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
A group	NSAIDs (permitted,not necessary)	Infliximab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
A group	Glucocorticoids (permitted,not necessary)	Infliximab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
B group	methotrexate(necessary)	Etanercept plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
B group	Glucocorticoids (permitted,not necessary)	Etanercept plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
B group	NSAIDs (permitted,not necessary)	Etanercept plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
C group	methotrexate(necessary)	Adalimumab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
C group	adalimumab	Adalimumab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
C group	leflunomide (permitted, not necessary)	Adalimumab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
C group	NSAIDs (permitted,not necessary)	Adalimumab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
C group	Glucocorticoids (permitted,not necessary)	Adalimumab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.

Primary Outcome Measures

Name	Time	Method
EULAR (European League Against Rheumatism) response will be assessed among patients of 3 groups	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

Name	Time	Method
The changes of Interest proteins with different EULAR response will be assessed among patients of 3 group.	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.
The SNP (Single nucleotide polymorphism) of gene about TNF with different EULAR response will be assessed among patients of 3 groups.	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.
The SNP of gene about interest proteins with different EULAR response will be assessed among patients of 3 groups.	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.
The changes of TNF level with different EULAR response will be assessed among patients of 3 groups.	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.