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Rheumatoid ArthritisPhase 4NCT02878161

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

A Phase 4 study testing methotrexate(necessary), infliximab and etanercept in people with Rheumatoid Arthritis, run by Fen Li.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Rheumatoid Arthritis
What is being tested?
methotrexate(necessary), infliximab and etanercept
Could I receive a placebo?
No, everyone receives an active treatment
How many people
240 participants
Where
No sites listed yet
Study dates
Jan 2016to Dec 2019
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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
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  • 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

About this study

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

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.

Read the 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.

Being tested
methotrexate(necessary), infliximab, etanercept, adalimumab, leflunomide (permitted, not necessary)
Keywords
rheumatoid arthritis, tumor necrosis factor α inhibitor, predictive, iTRAQ, signal pathway
Medical subject headings
Arthritis, Rheumatoid

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • methotrexate(necessary)Drug

    Also called MTX

    Methotrexate will be received orally with dosage of 10mg/ week for every patient and MTX dose must be stable for at least 4 weeks.

  • infliximabBiological

    Also called IFX

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

  • etanerceptBiological

    Also called ETN

    Etanercept :hypodermic injection,25mg/twice a week

  • adalimumabBiological

    Also called ADA

    Adalimumab:hypodermic injection,40mg/twice a week

  • leflunomide (permitted, not necessary)Drug

    Also called LEF

    LEF will be permitted if patient had received for 1 month before enrollment and will not be changed for 14 weeks.

  • NSAIDs (permitted,not necessary)Drug

    Also called non steroidal anti inflammatory drugs

    NSAIDs will be allowed if patient had received for 1 month before enrollment and will not be changed for 14 weeks.

  • Glucocorticoids (permitted,not necessary)Drug

    Also called prednisone,methylprednisolone,etc.

    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.

Study groups in NCT02878161
Study groupRoleWhat they receive
A groupExperimentalInfliximab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
Receives: Drug: methotrexate(necessary); Biological: infliximab; Drug: leflunomide (permitted, not necessary); Drug: NSAIDs (permitted,not necessary); Drug: Glucocorticoids (permitted,not necessary)
B groupExperimentalEtanercept plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
Receives: Drug: methotrexate(necessary); Biological: etanercept; Drug: leflunomide (permitted, not necessary); Drug: NSAIDs (permitted,not necessary); Drug: Glucocorticoids (permitted,not necessary)
C groupExperimentalAdalimumab plus Methotrexate , Leflunomide and NSAIDs and Glucocorticoids are permitted but not necessary included.
Receives: Drug: methotrexate(necessary); Biological: adalimumab; Drug: leflunomide (permitted, not necessary); Drug: NSAIDs (permitted,not necessary); Drug: Glucocorticoids (permitted,not necessary)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Baseline, Weeks 14

Secondary outcomes (4)

  1. 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.

    Measured: Baseline, Weeks 14

  2. 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.

    Measured: Baseline, Weeks 14

  3. 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.

    Measured: Weeks 14

  4. 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.

    Measured: Weeks 14

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Aug 2016 (estimated)
  2. Study startJan 2016
  3. Primary completionDec 2019 (estimated)
  4. Study completionDec 2019 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Basic science
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
240 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02878161
Sponsor's protocol ID
XYEYY-GZ81571599-20160118-1
Status last verified
Jul 2016
First submitted
12 Jul 2016
Last updated
25 Aug 2016
Results posted
No
Data monitoring committee
No
Individual data sharing
No

Publications

  • van Vollenhoven RF. Switching between anti-tumour necrosis factors: trying to get a handle on a complex issue. Ann Rheum Dis. 2007 Jul;66(7):849-51. doi: 10.1136/ard.2007.069872.

    PubMed 17576784

  • Radstake TR, Svenson M, Eijsbouts AM, van den Hoogen FH, Enevold C, van Riel PL, Bendtzen K. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis. 2009 Nov;68(11):1739-45. doi: 10.1136/ard.2008.092833. Epub 2008 Nov 19.

    PubMed 19019895

  • Miossec P, Verweij CL, Klareskog L, Pitzalis C, Barton A, Lekkerkerker F, Reiter S, Laslop A, Breedveld F, Abadie E, Flamion B, Dere W, Mpofu S, Goel N, Ethgen D, Mitlak B, Ormarsdottir S, Rao R, Tsouderos Y, Reginster JY; Group for Respect of Ethics and Excellence in Science (GREES). Biomarkers and personalised medicine in rheumatoid arthritis: a proposal for interactions between academia, industry and regulatory bodies. Ann Rheum Dis. 2011 Oct;70(10):1713-8. doi: 10.1136/ard.2011.154252. Epub 2011 Jul 22.

    PubMed 21784723

  • Zeng Z, Duan Z, Zhang T, Wang S, Li G, Gao J, Ye D, Xu S, Xu J, Zhang L, Pan F. Association between tumor necrosis factor-alpha (TNF-alpha) promoter -308 G/A and response to TNF-alpha blockers in rheumatoid arthritis: a meta-analysis. Mod Rheumatol. 2013 May;23(3):489-95. doi: 10.1007/s10165-012-0699-5. Epub 2012 Jul 4.

    PubMed 22760475

  • Kang CP, Lee KW, Yoo DH, Kang C, Bae SC. The influence of a polymorphism at position -857 of the tumour necrosis factor alpha gene on clinical response to etanercept therapy in rheumatoid arthritis. Rheumatology (Oxford). 2005 Apr;44(4):547-52. doi: 10.1093/rheumatology/keh550. Epub 2005 Feb 3.

    PubMed 15695296

  • Miceli-Richard C, Comets E, Verstuyft C, Tamouza R, Loiseau P, Ravaud P, Kupper H, Becquemont L, Charron D, Mariette X. A single tumour necrosis factor haplotype influences the response to adalimumab in rheumatoid arthritis. Ann Rheum Dis. 2008 Apr;67(4):478-84. doi: 10.1136/ard.2007.074104. Epub 2007 Aug 2.

    PubMed 17673491

  • Nishimoto T, Seta N, Anan R, Yamamoto T, Kaneko Y, Takeuchi T, Kuwana M. A single nucleotide polymorphism of TRAF1 predicts the clinical response to anti-TNF treatment in Japanese patients with rheumatoid arthritis. Clin Exp Rheumatol. 2014 Mar-Apr;32(2):211-7. Epub 2013 Dec 9.

    PubMed 24321457

  • Potter C, Hyrich KL, Tracey A, Lunt M, Plant D, Symmons DP, Thomson W, Worthington J, Emery P, Morgan AW, Wilson AG, Isaacs J, Barton A; BRAGGSS. Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis. Ann Rheum Dis. 2009 Jan;68(1):69-74. doi: 10.1136/ard.2007.084715. Epub 2008 Mar 28.

    PubMed 18375541

  • Padyukov L, Lampa J, Heimburger M, Ernestam S, Cederholm T, Lundkvist I, Andersson P, Hermansson Y, Harju A, Klareskog L, Bratt J. Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis. Ann Rheum Dis. 2003 Jun;62(6):526-9. doi: 10.1136/ard.62.6.526.

    PubMed 12759288

  • Davila-Fajardo CL, Marquez A, Pascual-Salcedo D, Moreno Ramos MJ, Garcia-Portales R, Magro C, Alegre-Sancho JJ, Balsa A, Cabeza-Barrera J, Raya E, Martin J. Confirmation of -174G/C interleukin-6 gene promoter polymorphism as a genetic marker predicting antitumor necrosis factor treatment outcome. Pharmacogenet Genomics. 2014 Jan;24(1):1-5. doi: 10.1097/FPC.0000000000000013.

    PubMed 24253594

  • Coulthard LR, Taylor JC, Eyre S; Biologics in Rheumatoid Arthritis Genetics and Genomics; Robinson JI, Wilson AG, Isaacs JD, Hyrich K, Emery P, Barton A, Barrett JH, Morgan AW, McDermott MF. Genetic variants within the MAP kinase signalling network and anti-TNF treatment response in rheumatoid arthritis patients. Ann Rheum Dis. 2011 Jan;70(1):98-103. doi: 10.1136/ard.2010.133249. Epub 2010 Aug 30.

    PubMed 20805296

  • Potter C, Cordell HJ, Barton A, Daly AK, Hyrich KL, Mann DA, Morgan AW, Wilson AG; Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS); Isaacs JD. Association between anti-tumour necrosis factor treatment response and genetic variants within the TLR and NFkappaB signalling pathways. Ann Rheum Dis. 2010 Jul;69(7):1315-20. doi: 10.1136/ard.2009.117309. Epub 2010 May 6.

    PubMed 20448286

  • Tan RJ, Gibbons LJ, Potter C, Hyrich KL, Morgan AW, Wilson AG, Isaacs JD; BRAGGSS; Barton A. Investigation of rheumatoid arthritis susceptibility genes identifies association of AFF3 and CD226 variants with response to anti-tumour necrosis factor treatment. Ann Rheum Dis. 2010 Jun;69(6):1029-35. doi: 10.1136/ard.2009.118406. Epub 2010 May 5.

    PubMed 20444755

  • Cui J, Saevarsdottir S, Thomson B, Padyukov L, van der Helm-van Mil AH, Nititham J, Hughes LB, de Vries N, Raychaudhuri S, Alfredsson L, Askling J, Wedren S, Ding B, Guiducci C, Wolbink GJ, Crusius JB, van der Horst-Bruinsma IE, Herenius M, Weinblatt ME, Shadick NA, Worthington J, Batliwalla F, Kern M, Morgan AW, Wilson AG, Isaacs JD, Hyrich K, Seldin MF, Moreland LW, Behrens TW, Allaart CF, Criswell LA, Huizinga TW, Tak PP, Bridges SL Jr, Toes RE, Barton A, Klareskog L, Gregersen PK, Karlson EW, Plenge RM. Rheumatoid arthritis risk allele PTPRC is also associated with response to anti-tumor necrosis factor alpha therapy. Arthritis Rheum. 2010 Jul;62(7):1849-61. doi: 10.1002/art.27457.

    PubMed 20309874

  • Krintel SB, Essioux L, Wool A, Johansen JS, Schreiber E, Zekharya T, Akiva P, Ostergaard M, Hetland ML. CD6 and syntaxin binding protein 6 variants and response to tumor necrosis factor alpha inhibitors in Danish patients with rheumatoid arthritis. PLoS One. 2012;7(6):e38539. doi: 10.1371/journal.pone.0038539. Epub 2012 Jun 7.

    PubMed 22685579

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing methotrexate(necessary), infliximab and etanercept in people with Rheumatoid Arthritis, run by Fen Li.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 25 Aug 2016. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

EULAR (European League Against Rheumatism) response will be assessed among patients of 3 groups (time frame: Baseline, Weeks 14). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02878161, which also lists 43 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Aug 2016.

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