A Randomized, Multi-Center Biomarker Trial to Predict Therapeutic Responses of Patients With Rheumatoid Arthritis to a Specific Biologic Mode of Action

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2015 by Medical University of Vienna
Sponsor:
Information provided by (Responsible Party):
Daniel Aletaha, Medical University of Vienna
ClinicalTrials.gov Identifier:
NCT01638715
First received: July 3, 2012
Last updated: October 14, 2015
Last verified: October 2015
  Purpose
The purpose of this study is to find biological response patterns of patients with rheumatoid arthritis to drugs with different biologic modes of action. This study should help to predict therapeutic responses and to find the right therapy for the right patient.

Condition Intervention Phase
Rheumatoid Arthritis
Drug: Remicade
Drug: Orencia
Drug: Ro-Actemra
Drug: Mabthera
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized, Multi-Center Biomarker Trial to Predict Therapeutic Responses of Patients With Rheumatoid Arthritis to a Specific Biologic Mode of Action

Resource links provided by NLM:


Further study details as provided by Medical University of Vienna:

Primary Outcome Measures:
  • Absolute Change in the Simplified Disease Activity Index (SDAI) [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Relative Change in the SDAI in percent [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]
  • Absolute and relative change in the Clinical Disease Activity Index (CDAI) in percent [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]
  • Absolute and relative change in the Disease Activity Score 28 (DAS28) in percent [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • Achieving an SDAI or CDAI response (50%, 70%, 85%) [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]
  • Achieving a EULAR response (European League Against Rheumatism) [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]
  • Achieving an ACR response (20%, 50%, 70%) (American College of Rheumatology) [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]
  • Change in quality of life (EuroQoL-5D, SF-36) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • Change in fatigue (Fatigue Score on the Visual Analog Scale) [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]
  • Proportion achieving a low disease activity state (SDAI ≤11) [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]
  • Proportion achieving a remission state (SDAI ≤3.3) [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]
  • Radiographic progression - (Van der Heijde/Sharp Score) [ Time Frame: 6 months and 12 months ] [ Designated as safety issue: No ]
  • Change in physical function (HAQ) [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]
  • Change in sleep (Sleep Score on the Visual Analog Scale) [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 200
Study Start Date: May 2012
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Infliximab
Infliximab (Remicade®) will be administered i.v.at a dose of 3 mg/kg at 0 and 2 weeks, and 5 mg/kg at weeks 6, 14, and 22, 30, 38, and 46.
Drug: Remicade
- Infliximab (Remicade®) will be administered i.v. at a dose of 3 mg/kg at 0 and 2 weeks, and 5 mg/kg at weeks 6, 14, and 22, 30, 38, and 46.
Experimental: Abatacept
Abatacept (Orencia®) will be given i.v. at weeks 0, 2, 4, and then every 4 weeks until week 48 at a weight adjusted dose: <60 kg Body weight (BW): 500 mg; >60-100 kg BW: 750 mg; alternatively, based on preference and shared decision between patient and physician, patients randomized to the abatacept arm may receive s.c.application at a dose of 125mg weekly.
Drug: Orencia
- Abatacept (Orencia®) will be given i.v. at weeks 0, 2, 4, and then every 4 weeks until week 48 at a weight adjusted dose: <60 kg Body weight (BW): 500 mg; >60-100 kg BW: 750 mg; alternatively, based on preference and shared decision between patient and physician, patients randomized to the abatacept arm may receive s.c. application at a dose of 125mg weekly.
Experimental: Tocilizumab
Tocilizumab (Ro-Actemra®) will be administered every 4 weeks at a dose of 8 mg/kg BW (maximum dose of 800 mg); The employed dosage will be calculated using manufacturer guidelines; alternatively, based on preference and shared decision between patient and physician, patients randomized to the tocilizumab arm may receive s.c. application at a dose of 162mg every week.
Drug: Ro-Actemra
- Tocilizumab (Ro-Actemra®) will be administered every 4 weeks at a dose of 8 mg/kg BW (maximum dose of 800 mg); The employed dosage will be calculated using manufacturer guidelines; alternatively, based on preference and shared decision between patient and physician, patients randomized to the tocilizumab arm may receive s.c. application at a dose of 162mg every week.
Experimental: Rituximab
Rituximab (Mabthera®) will be given as 1000mg at weeks 0 and 2, and then repeated at weeks 24 and 26. Patients will receive 100 mg methylprednisolon i.v. before each infusion, as well as 1000mg paracetamol, as well as 50mg diphenhydramine hydrochloride (Dibondrin©).
Drug: Mabthera

- Rituximab (Mabthera®) will be given as 1000mg at weeks 0 and 2, and then repeated at weeks 24 and 26.

Patients will receive 100 mg methylprednisolon i.v. before each infusion, as well as 1000mg paracetamol, as well as 50mg diphenhydramine hydrochloride (Dibondrin©).


Detailed Description:
The investigators propose a randomised, multi-centre strategic biomarker trial of rheumatoid arthritis (RA) patients with failure to methotrexate or leflunomide to one of the four current biological modes of action: targeting TNF (infliximab); co-stimulation (abatacept); IL-6R (tocilizumab); and B cells (rituximab); all agents are licensed for RA and have evidence for efficacy in this indication. Predictors of response to therapy after 24 weeks will be analysed, and include baseline and follow up assessments of clinical, functional, structural, laboratory tests (routine, autoantibodies, cytokines, gene expression, and susceptibility genes). In a second phase, patients not achieving LDA/REM will be randomised to one of the remaining MoA. Two hundred patients, who are started on a new biological therapy will be enrolled over an estimated period of 5 years; 50 patients per group will be included, and studied for a period of 12 months.
  Eligibility

Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Men and women, ≥18 and ≤75 years of age, capable of understanding and signing an informed consent.
  2. Classifiable RA according to the 2010 ACR/EULAR criteria (American College of Rheumatology/European League Against Rheumatism classification criteria) or 1987 ARA criteria (Criteria of American Rheumatology Association) (present or past) (2;3)
  3. Duration of RA ≤3 years
  4. Ongoing conventional DMARD therapy (Disease Modifying Antirheumatic Drugs) with methotrexate (at least 20mg/week, or lower if not tolerated in higher doses) or leflunomide (≥100mg/week), for ≥6 months or ≥3 months with documented worsening of disease activity.
  5. Clinical Disease Activity Index (CDAI)≥15 corresponding to moderate to severe disease activity.

Exclusion Criteria:

  1. Be incapacitated, largely or wholly bedridden, or confined to a wheelchair, or have little or no ability for self care.
  2. Weigh more than 100 kg
  3. Use glucocorticoids >10 mg/day prednisone or equivalent
  4. Have previously received other treatments for their rheumatic disease:

    1. intra-muscular or intra-articular injection of steroids in the previous month.
    2. monoclonal antibodies or antibody fragments, licenced or investigational
    3. any investigational drug within 3 months prior to screening or within 5 half-lives of the investigational agent, whichever is longer.
    4. Azathioprine or other cytostatic drugs.
  5. Have a history of receiving human/murine recombinant products or a known allergy to murine products.
  6. Have documentation of seropositivity for human immunodeficiency virus (HIV), or a positive test for hepatitis B surface antigen or hepatitis C ¬antibodies.
  7. Have hypergammaglobulinemia
  8. Have a history of alcohol or substance abuse within the preceding 6 months.
  9. Have or have had a known history of

    1. serious infections (such as, but not limited to hepatitis, pneumonia, or pyelonephritis) in the previous 3 months.
    2. opportunistic infections (eg, herpes zoster, cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis, or mycobacteria other than TB) within 12 months prior to screening.
    3. a chronic or recurrent infectious disease (eg, chronic renal infection, chronic chest infection, COPD, sinusitis, recurrent urinary tract infection, open, draining or infected skin wound or ulcer etc.).
  10. Have undergone any joint replacement surgery.
  11. Be men and women of childbearing potential without use of adequate birth control measures (e.g., abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, implantable or injectable contraceptives or surgical sterilization), and willingness to continue this precaution for the duration of the study until 6 months after receiving the last medication.
  12. Be considered ineligible according to the tuberculosis (TB) eligibility assessment and screening, or show a positive test for latent Tbc using Quantiferon assay, unless treatment with INH has been installed for at least 2 weeks prior to starting trial drug.
  13. Show evidence of malignancy, or lymphoproliferative disease, or any history of malignancy within the previous 5 years, with the exception of basal cell or squamous cell carcinoma of the skin that has been fully excised with no evidence of recurrence.
  14. Have current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, or cerebral disease.
  15. Be unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack of easy access.
  16. Have presence of a transplanted solid organ (with the exception of a corneal transplant > 3 months prior to screening).
  17. Have a concomitant diagnosis or history of congestive heart failure (New York Heart Association - NYHA - class III or IV) or diverticulitis.
  18. Have a known history of a demyelinating disease, such as multiple sclerosis.
  19. Be women who are pregnant, nursing, or planning pregnancy within 6 months after the last infusion
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01638715

Contacts
Contact: Daniel Aletaha, MD 0043 1 40400 ext 4349 daniel.aletaha@meduniwien.ac.at

Locations
Austria
Barmherzige Brüder, Krankenhaus Graz-Eggenburg Not yet recruiting
Graz, Austria, 8020
Contact: Raimund Lunzer, MD    0043 316 5989 ext 6646    Raimund.Lunzer@bbgraz.at   
Principal Investigator: Raimund Lunzer, MD         
Gesundheitszentrum Mariahilf Recruiting
Vienna, Austria, 1060
Contact: Johann Hitzelhammer, MD    00431 601 22 40601    johann.hitzelhammer@wgkk.at   
Principal Investigator: Johann Hitzelhammer, MD         
AKH Wien Recruiting
Vienna, Austria, 1090
Contact: Daniel Aletaha, MD    0043 1 40400 4349    daniel.aletaha@meduniwien.ac.at   
Principal Investigator: Daniel Aletaha, MD         
Krankenhaus Hietzing Recruiting
Vienna, Austria, 1130
Contact: Jutta Stieger, MD    00431 80110 3180    jutta.stieger@wienkav.at   
Principal Investigator: Jutta Stieger, MD         
Hanusch Krankenhaus Completed
Vienna, Austria, 1140
Wilhelminenspital Completed
Vienna, Austria, 1160
Ordination Wels (Private Medical Office) Recruiting
Wels, Austria, 4600
Contact: Rudolf Puchner, MD    0043 7242 ext 706 25    rudolf.puchner@cc-net.at   
Principal Investigator: Rudolf Puchner, MD         
Russian Federation
V. A. Nasonova Research Institute of Rheumatology Recruiting
Moscow, Russian Federation, 115522
Contact: Dmitry Karateev, MD    07 499 61 ext 431 73    dekar@inbox.ru   
Principal Investigator: Dmitry Karateev, MD         
Sponsors and Collaborators
Medical University of Vienna
Investigators
Study Director: Daniel Aletaha, MD Medical University of Vienna
  More Information

Responsible Party: Daniel Aletaha, Principal Investigator, Medical University of Vienna
ClinicalTrials.gov Identifier: NCT01638715     History of Changes
Other Study ID Numbers: BIOBIO Study  2012-000139-21 
Study First Received: July 3, 2012
Last Updated: October 14, 2015
Health Authority: Austria: Agency for Health and Food Safety

Keywords provided by Medical University of Vienna:
Rheumatoid Arthritis
Biologic therapies
Biomarker
Mode of Action

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Rituximab
Abatacept
Infliximab
Diphenhydramine
Promethazine
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Immunosuppressive Agents
Anesthetics, Local
Anesthetics
Central Nervous System Depressants
Sensory System Agents
Peripheral Nervous System Agents
Antiemetics
Autonomic Agents
Gastrointestinal Agents
Histamine H1 Antagonists
Histamine Antagonists
Histamine Agents
Neurotransmitter Agents

ClinicalTrials.gov processed this record on July 27, 2016