Mechanistic Studies of B- and T-Cell Function in RA Patients Treated With TNF Antagonists, Tocilizumab, or Abatacept

NCT02353780 | Terminated Phase 4 Results

• 1 other identifier: STUDY19040127
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

An Agency for Healthcare Research and Quality executive summary indicated that better comparative effectiveness trial designs are needed to determine the relative merits of existing versus new and expensive biologic drug therapies for rheumatoid arthritis (RA). There are now 9 biologic therapies approved for treating RA. Four classes of biologics (TNF antagonists, B-cell inhibitors, T-cell co-stimulator blocker, and Interleukin-6 receptor blocker) are approved for use in RA patients with moderate or severe disease activity. Several critical questions have arisen, such as 1) what therapy should be prescribed after failure of methotrexate and/or other oral disease modifying antirheumatic drugs (DMARDs) to adequately control disease activity; 2) what is the level of efficacy of the various biologic therapies when compared in head-to-head trials; and 3) what are the mechanisms associated with failure of methotrexate and/or other oral DMARD therapy and responsiveness to biologic therapies. The MAZERATI study will provide the foundation for answering these questions and determining the mechanisms associated with these biologic therapies.

Conditions

Rheumatoid Arthritis (RA)

Keywords

Rheumatoid arthritis; TNF inhibitors

Outcome Measures

Primary Outcomes (1)

• Mechanistic Comparisons (Changes in Frequencies of Peripheral Blood Immune Cell Subsets Following Institution of a Subcutaneously Administered TNF Antagonist, Tocilizumab or Abatacept.)

  There will be no primary efficacy endpoints for the study. The primary endpoint of the study will be changes in frequencies of peripheral blood immune cell subsets following institution of a subcutaneously administered TNF antagonist, tocilizumab or abatacept. Flow ctyometry was performed on peripheral blood T cells to determine frequency of Th17/TfH cells based on cell surface markers.

  0 to 3 months

Secondary Outcomes (9)

• Efficacy (CDAI)

  0 to 3 months

• Efficacy (DAS)

  3 month and 6 month

• ACR20, 50, and 70 Response

  3 month and 6 month

• Efficacy (EULAR)

  3 month and 6 month

• Adherence

  3 month and 6 month

Study Arms (3)

Different TNF inhibitor

ACTIVE COMPARATOR

The participant will be prescribed any TNF antagonist in this arm. The treating rheumatologist selects the TNF antagonist and the appropriate options for that therapy.

Drug: TNF Antagonist (enbrel, humire, remicade, cimzia, symponi)

Abatacept

ACTIVE COMPARATOR

The participant will be prescribed abatacept in this arm. The treating rheumatologist selects the appropriate options for that therapy.

Drug: Abatacept

Tocilizumab

ACTIVE COMPARATOR

The participant will be prescribed tocilizumab. The treating rheumatologist selects the appropriate options for that therapy.

Drug: Tocilizumab

Interventions

TNF Antagonist (enbrel, humire, remicade, cimzia, symponi) DRUG

TNF Antagonist; treating rheumatologist selects specifics for the therapy chosen.

Also known as: Enbrel, Humira, Remicade, Cimzia, Symponi

Different TNF inhibitor

Abatacept DRUG

Abatacept; SQ; specifics to be determined by the treating rheumatologist.

Also known as: Orencia

Abatacept

Tocilizumab DRUG

Tocilizumab; SQ; specifics determined by the treating rheumatologist.

Also known as: Actemra

Tocilizumab

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Diagnosis of RA by a physician as defined by the 1987 and/or 2010 ACR criteria.
• years of age or less than or equal to 64 at the time of diagnosis of RA.
• RA Disease Activity CDAI \> 10
• If using oral corticosteroids, must have been on stable dose (≤ 10 mg/day) for at least 2 weeks prior to study drug initiation.
• PPD negative or if PPD positive documentation of therapy with INH for at least 1 month prior to study initiation and negative chest x-ray.
• Must have been treated within the past year with either methotrexate (MTX), leflunomide (LEF), hydrochloroquine (HCQ) and/or sulfasalazine (SSZ) for ≥ 3 months.
• Prior or concurrent use of other oral DMARD therapy, including MTX, leflunomide, SSZ, and HCQ, is permitted. Patients taking oral DMARDs must be on stable doses of DMARDs for at least 4 weeks prior to study drug initiation. Subjects are not required to be taking an oral DMARD.

You may not qualify if:

• Use of cyclophosphamide, penicillamine, cyclosporine A, tacrolimus or gold therapy is not permitted in the 6 months prior to enrollment.
• Patients who are using or have used other biologic agents or tofacitinib concomitantly or prior to this study
• History of active and/or chronic infection such as hepatitis, pneumonia, pyelonephritis,herpetic infections or chronic skin infections and any active opportunistic infection, including but not limited to evidence of active cytomegalovirus, active Pneumocystis carinii, aspergillosis, histoplasmosis or atypical mycobacterium infection.
• Active TB or evidence of latent TB (positive PPD skin test or a history of old or latent TB on chest x-ray) without adequate therapy for TB.
• Pregnant or lactating women.
• Patients with current signs or symptoms of uncontrolled renal, gastrointestinal, endocrine, pulmonary, cardiac, neurologic or cerebral disease.
• Diagnosis of liver disease or elevated hepatic enzymes, as defined by ALT, AST or both \>1.5 x the upper limit of normal (ULN) or total bilirubin \> ULN.
• Any of the following hematologic abnormalities, confirmed by repeat tests:
• White blood count \< 3,000/µL or \> 14,000/µL
• Lymphocyte count \<500/µL
• Platelet count \< 100,000/µL
• Hemoglobin \< 8.0 g/dL
• Neutrophil count \< 2,000 cells/µL
• Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.
• Immunization with a live/attenuated vaccine within 2 months prior to baseline or 3 months of last study visit.

Sponsors & Collaborators

• Dr. Larry W. Moreland: lead
• Genentech, Inc.: collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (1)

University of Pittsburgh

Pittsburgh, Pennsylvania, 15261, United States

Location

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Tumor Necrosis Factor Inhibitors; Etanercept; Infliximab; Certolizumab Pegol; Adalimumab; Abatacept; tocilizumab

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Anti-Inflammatory Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Peptide Fragments; Peptides; Amino Acids, Peptides, and Proteins; Immunoglobulin Constant Regions; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Receptors, Tumor Necrosis Factor; Receptors, Cytokine; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Antibodies, Monoclonal; Antibodies; Polyethylene Glycols; Polymers; Macromolecular Substances; Immunoglobulin Fab Fragments; Antibodies, Monoclonal, Humanized; Immunoconjugates

Limitations and Caveats

Due to the small number of patients enrolled in each group, it was not possible to perform statistical analyses of the primary endpoints. These are fairly broad measures that require large numbers to identify patterns in subset changes.

Results Point of Contact

• Title: Larry Moreland, MD
• Organization: University of Pittsburgh

lwm5@pitt.edu

412-648-4098

Study Officials

• Larry W. Moreland, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Chief, Division of Rheumatology and Clinical Immunology

Study Record Dates

• First Submitted: June 30, 2013
• First Posted: February 3, 2015
• Study Start: March 1, 2015
• Primary Completion: December 30, 2017
• Study Completion: November 30, 2018
• Last Updated: October 1, 2020
• Results First Posted: October 1, 2020

Record last verified: 2020-09

Locations

US (1)