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A Study of the Effects of RoActemra/Actemra (Tocilizumab) on Neutrophils in Patients With Active Rheumatoid Arthritis Who Have an Inadequate Response to Biologic and/or Non-biologic DMARDs.

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01195272
First received: September 2, 2010
Last updated: November 11, 2014
Last verified: November 2014

September 2, 2010
November 11, 2014
August 2010
March 2012   (final data collection date for primary outcome measure)
  • Mean Percentage of Cells Staining Positive for Annexin V Binding in Apoptosis [ Time Frame: Visits 2, 3, 5, and 8 (Baseline and Weeks 4, 12 and 24) ] [ Designated as safety issue: No ]
    Aging neutrophils translocate phosphatidylserine from the inner leaflet of the plasma membrane to the outer leaflet during the early stages of apoptosis. This translocation can be measured due to the affinity of fluorescein isothiocyanate (FITC)-labeled annexin V to bind exposed phosphatidylserine. Cells that stain positive to Annexin V binding are apoptotic. At 4 hours (hrs) and 20 hrs stimulated and control samples were analyzed for levels of apoptosis.
  • Mean Percentage of Cells Staining Positive for Annexin V Binding With Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) [ Time Frame: Visits 2, 3, 5, and 8 (Baseline and Weeks 4, 12 and 24) ] [ Designated as safety issue: No ]
    Aging neutrophils translocate phosphatidylserine from the inner leaflet of the plasma membrane to the outer leaflet during the early stages of apoptosis. This translocation can be measured due to the affinity of FITC-labeled annexin V to bind exposed phosphatidylserine. Cells that stain positive to Annexin V binding are apoptotic. At 4 hrs and 20 hrs stimulated and control samples were analyzed for levels of apoptosis. GM-CSF is an agent that delays apoptosis. Percentage of cells that stained positive for Annexin V binding in the presence or absence of GM-CSF (GM-CSF delayed or constitutive) were determined by flow cytometry.
  • Mean Fluorescence Intensity of CD11b on Neutrophil Surface [ Time Frame: Visits 2, 3, and 5 (Baseline and Weeks 4 and 12) ] [ Designated as safety issue: No ]
    Neutrophils were incubated with labeled antibodies against CD11b. Flow cytometry was used to determine the mean fluorescence intensity. Greater fluorescence correlates with greater adhesion, migration, and ingestion of complement-opsonized particles.
  • Mean Fluorescence Intensity of CD18 on Neutrophil Surface [ Time Frame: Visits 2, 3, and 5 (Baseline and Weeks 4 and 12) ] [ Designated as safety issue: No ]
    Neutrophils were incubated with labeled antibodies against CD18. Flow cytometry was used to determine the mean fluorescence intensity. Greater fluorescence correlates with greater adhesion, migration, and ingestion of complement-opsonized particles.
  • Mean Fluorescence Intensity of CD62L (L Selectin) on Neutrophil Surface [ Time Frame: Visits 2, 3 and 5 (Baseline and Weeks 4 and 12) ] [ Designated as safety issue: No ]
    Neutrophils were incubated with labeled antibody against CD62L (L selectin). Flow cytometry was used to determine the mean fluorescence intensity. Greater fluorescence correlates with greater adhesion of neutrophils to vessel walls.
  • Mean Fluorescence Intensity of CD63 on Neutrophil Surface [ Time Frame: Visits 2, 3, and 5 (Baseline and Weeks 4 and 12) ] [ Designated as safety issue: No ]
    Neutrophils were incubated with labeled antibody against CD63b. Flow cytometry was used to determine the mean fluorescence intensity. Greater fluorescence correlates with greater azurophilic degranulation, an indicator of greater microbe killing.
  • Mean Fluorescence Intensity of Interleukin-6 Receptor (Il-6R) on Neutrophil Surface [ Time Frame: Visits 2, 3, and 5 (Baseline and Weeks 4 and 12) ] [ Designated as safety issue: No ]
    Neutrophils were incubated with labeled antibody against IL-6R. Flow cytometry was used to determine the mean fluorescence intensity. Greater fluorescence correlates with greater density of membrane bound IL-6 receptor.
  • Mean Fluorescence Intensity of Membrane Bound Tumor Necrosis Factor Alpha (mTNFα) on Neutrophil Surface [ Time Frame: Visits 2, 3, and 5 (Baseline and Weeks 4 and 12) ] [ Designated as safety issue: No ]
    Neutrophils were incubated with labeled antibody against mTNF. Flow cytometry was used to determine the mean fluorescence intensity. Greater fluorescence correlates to a greater density of membrane bound TNF.
  • Mean Chemiluminescence (Area Under the Concentration-time Curve [AUC]) of Neutrophil Reactive Species Production Using Formyl-Methionyl-Leucyl-Phenylalanine (fMLP) Stimulation [ Time Frame: Visit 2, 3, 5, and 8 (Baseline and predose at Weeks 4, 12 and 24) ] [ Designated as safety issue: No ]
    Using luminol as a substrate for reactive oxidants, a chemical reaction is produced resulting in photon emission (chemiluminescence). fMLP stimulation is mediated through the fMLP receptor on the cell surface. The fMLP response is only observed in primed neutrophils and response is a measure of in vivo priming. Measurements of reactive oxygen species are calculated as total chemiluminescence or the AUC.
  • Mean Chemiluminescence (AUC) of Neutrophil Reactive Species Production Using Phorbol 12-Myristate 13-Acetate (PMA) Stimulation [ Time Frame: Visit 2, 3, 5, and 8 (Baseline and predose at Weeks 4, 12 and 24) ] [ Designated as safety issue: No ]
    Using luminol as a substrate for reactive oxidants, a chemical reaction is produced resulting in photon emission (chemiluminescence). PMA is a receptor-independent stimulator of the respiratory burst and the PMA response measures the total capacity of neutrophils to generate reactive oxidants. Measurements of reactive oxygen species are calculated as total chemiluminescence or the AUC.
  • Percentage of Neutrophils Positive for Propidium Iodide (PI)-Labeled Staphylococcus Aureus (S. Aureus) Uptake [ Time Frame: Visit 2, 3, 5, and 8 (Baseline and Weeks 4, 12 and 24) ] [ Designated as safety issue: No ]
    S. aureus were heat killed then labeled with PI and opsonized with AB serum (SAPI). S. aureus was then incubated with the neutrophils for 30 minutes at 37 degrees Celsius. The neutrophils were washed, then the percentage of cells positive for the labeled S. aureus (that is, phagocytosed) was calculated via flow cytometry. A higher percentage represented more active phagocytosis.
  • Percentage of Neutrophils Positive for Dihydrorhodamine-123 (DHR) Oxidation [ Time Frame: Visit 2, 3, 5, and 8 (Baseline and Weeks 4, 12 and 24) ] [ Designated as safety issue: No ]
    Phagocytosis can be measured by incubating neutrophils with PI-labeled heat killed S. aureus following incubation for 30 minutes. Neutrophils are co-incubated with DHR, which becomes oxidized by the products of the respiratory burst generated during phagocytosis. Fluorescence can then be measured by flow cytometry.
Effects on neutrophil function and survival: Neutrophil morphology by light microscopy, function by ex vivo surface molecule expression using flow cytometry, survival by ex vivo evaluation of apoptosis utilizing a combination of techniques [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01195272 on ClinicalTrials.gov Archive Site
  • Disease Activity Score Based on 28-Joint Count (DAS28) [ Time Frame: Screening, Baseline, and Weeks 4, 8, 12, 16, 20, 24, 36, 48, and 52 ] [ Designated as safety issue: No ]
    The DAS28 is a combined index for measuring disease activity in rheumatoid arthritis. The index includes swollen and tender joint counts, acute phase response (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]), and general health status. The DAS28, which uses a 28 joint count, is derived from the original DAS, which includes a 44 swollen joint count. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.
  • Percentage of Participants With Acceptable and Not Acceptable Benefit-Risk Assessments [ Time Frame: Weeks 12, 24, and 36 ] [ Designated as safety issue: No ]
    Benefit:Risk was defined at the participant level. It was considered acceptable if the DAS28 improvement represented at least a moderate European League Against Rheumatism (EULAR) response. The risks were based on the known adverse event (AE) profile of tocilizumab rather than on the actual AEs experienced by each participant
Safety and benefit-risk assessments, according to Summary of Product Characteristics (SPC) and improvements in disease activity score (DAS28) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
A Study of the Effects of RoActemra/Actemra (Tocilizumab) on Neutrophils in Patients With Active Rheumatoid Arthritis Who Have an Inadequate Response to Biologic and/or Non-biologic DMARDs.
A 52 Week, Single Center, Open-label Study to Evaluate Neutrophil Function and Survival Effects of Tocilizumab (TCZ) in Patients With Active Rheumatoid Arthritis (RA) on Background Non-biologic DMARDs Who Have an Inadequate Response to Current Non-biologic DMARD and/or Anti-TNF Therapy

This open-label, single arm study will assess the effect of RoActemra/Actemra (tocilizumab) on neutrophils and monitor safety and benefit-risk of RoActemra/Actemra treatment in patients with active rheumatoid arthritis who have an inadequate response to current biologic or non-biologic disease-modifying antirheumatic drugs (DMARDs). Patients will receive RoActemra/Actemra at a dose of 8 mg/kg intravenously every 4 weeks, either as monotherapy or in combination with their current non-biologic DMARD. Anticipated time on study treatment is 52 weeks.

Not Provided
Interventional
Phase 4
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Rheumatoid Arthritis
Drug: tocilizumab [RoActemra/Actemra]
8 mg/kg iv every 4 weeks, 52 weeks
Experimental: Single Arm
Intervention: Drug: tocilizumab [RoActemra/Actemra]
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
21
March 2012
March 2012   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Adult patients, >/= 18 years of age
  • Moderate to severe active rheumatoid arthritis of >/= 6 months duration
  • DAS28 >/= 3.2 at screening and baseline
  • Inadequate response to biologic or non-biologic DMARDs
  • Biologic DMARDs must be withdrawn (approximately 5 half-lives for the agent) before first dose of study drug
  • If continuing on a non-biologic DMARD, dose should be stable for at least 8 weeks
  • Oral corticosteroids must have been at stable dose for at least 25 out of 28 days prior to baseline

Exclusion Criteria:

  • Major surgery (including joint surgery) within 8 weeks prior to screening or not recovered from prior surgery
  • Rheumatic autoimmune disease other then RA
  • Functional class IV as defined by the American College of Rheumatology (ACR) classification
  • Prior history of or current inflammatory joint disease other than RA
  • Previous treatment with any cell-depleting therapies
  • Intraarticular or parenteral corticosteroids within 4 weeks prior to baseline
  • Active infection or history of recurrent infection
  • Positive for HIV or hepatitis B or C
  • History of or current primary or secondary immunodeficiency
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United Kingdom
 
NCT01195272
ML25243, 2010-018331-18
Not Provided
Hoffmann-La Roche
Hoffmann-La Roche
Not Provided
Study Director: Clinical Trials Hoffmann-La Roche
Hoffmann-La Roche
November 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP