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

Sponsor

Fen Li (Other)

Overall Status

Unknown status

CT.gov ID

NCT02878161

Collaborator

(none)

240

Enrollment

Arms

Duration (Months)

Study Details

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.

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

Study Type:

Interventional

Anticipated 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 :

Jan 1, 2016

Anticipated Primary Completion Date :

Dec 1, 2019

Anticipated Study Completion Date :

Dec 1, 2019

Arms and Interventions

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 Names: MTX Biological: infliximab infliximab :intravenous injection 200mg,every times,0,2,6,14week ,4 times) Other Names: 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 Names: 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 Names: 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 Names: 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 Names: MTX Biological: etanercept Etanercept :hypodermic injection,25mg/twice a week Other Names: 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 Names: 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 Names: 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 Names: 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 Names: MTX Biological: adalimumab Adalimumab:hypodermic injection,40mg/twice a week Other Names: 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 Names: 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 Names: 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 Names: prednisone,methylprednisolone,etc.

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 Names:

MTX

Biological: infliximab

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

Other Names:

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 Names:

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 Names:

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 Names:

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 Names:

MTX

Biological: etanercept

Etanercept :hypodermic injection,25mg/twice a week

Other Names:

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 Names:

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 Names:

non steroidal anti inflammatory drugs

Drug: Glucocorticoids (permitted,not necessary)

Other Names:

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 Names:

MTX

Biological: adalimumab

Adalimumab:hypodermic injection,40mg/twice a week

Other Names:

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 Names:

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 Names:

non steroidal anti inflammatory drugs

Drug: Glucocorticoids (permitted,not necessary)

Other Names:

prednisone,methylprednisolone,etc.

Outcome Measures

Primary Outcome Measures

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

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.
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts 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