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

August 21, 2016 updated by: Fen Li

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

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Anticipated)

240

Phase

  • Phase 4

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: NON_RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / 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
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.
Biological: etanercept
Etanercept :hypodermic injection,25mg/twice a week
Other Names:
  • ETN
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
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.
Biological: adalimumab
Adalimumab:hypodermic injection,40mg/twice a week
Other Names:
  • ADA

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Baseline, Weeks 14

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Baseline, Weeks 14
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.
Baseline, Weeks 14
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.
Weeks 14
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.
Weeks 14

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fen Li

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2016

Primary Completion (ANTICIPATED)

December 1, 2019

Study Completion (ANTICIPATED)

December 1, 2019

Study Registration Dates

First Submitted

July 12, 2016

First Submitted That Met QC Criteria

August 21, 2016

First Posted (ESTIMATE)

August 25, 2016

Study Record Updates

Last Update Posted (ESTIMATE)

August 25, 2016

Last Update Submitted That Met QC Criteria

August 21, 2016

Last Verified

July 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • XYEYY-GZ81571599-20160118-1

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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