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

Rheumatoid Arthritis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01638715
• Other study ID #: BIOBIO Study
• Secondary ID: 2012-000139-21
• Status: Completed
• Phase: Phase 4
• Start date: May 2012
• Est. completion date: August 1, 2018

Study information

• Verified date: October 2018
• Source: Medical University of Vienna
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 115
• Est. completion date: August 1, 2018
• Est. primary completion date: August 1, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

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.
• 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.
• 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.
• 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©).

Locations

Country	Name	City	State
Austria	AKH Wien	Vienna
Austria	Gesundheitszentrum Mariahilf	Vienna
Austria	Hanusch Krankenhaus	Vienna
Austria	Krankenhaus Hietzing	Vienna
Austria	Wilhelminenspital	Vienna
Austria	Ordination Wels (Private Medical Office)	Wels
Czechia	Institute of Rheumatology	Praha 2
Russian Federation	V. A. Nasonova Research Institute of Rheumatology	Moscow
Switzerland	Kantonsspital St.Gallen, Klinik für Rheumatologie	St.Gallen

Sponsors (1)

Lead Sponsor	Collaborator
Medical University of Vienna

Countries where clinical trial is conducted

Austria,  Czechia,  Russian Federation,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Absolute Change in the Simplified Disease Activity Index (SDAI)		24 Weeks
Secondary	Relative Change in the SDAI in percent		24 Weeks
Secondary	Absolute and relative change in the Clinical Disease Activity Index (CDAI) in percent		24 Weeks
Secondary	Absolute and relative change in the Disease Activity Score 28 (DAS28) in percent		24 weeks
Secondary	Achieving an SDAI or CDAI response (50%, 70%, 85%)		24 Weeks
Secondary	Achieving a EULAR response (European League Against Rheumatism)		24 Weeks
Secondary	Achieving an ACR response (20%, 50%, 70%) (American College of Rheumatology)		24 Weeks
Secondary	Change in quality of life (EuroQoL-5D, SF-36)		24 weeks
Secondary	Change in fatigue (Fatigue Score on the Visual Analog Scale)		24 Weeks
Secondary	Proportion achieving a low disease activity state (SDAI =11)		24 Weeks
Secondary	Proportion achieving a remission state (SDAI =3.3)		24 Weeks
Secondary	Radiographic progression - (Van der Heijde/Sharp Score)		6 months and 12 months
Secondary	Change in physical function (HAQ)		24 Weeks
Secondary	Change in sleep (Sleep Score on the Visual Analog Scale)		24 Weeks