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An Efficacy and Safety Study of Tocilizumab (RoActemra/Actemra) in Participants With Giant Cell Arteritis (GCA)

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01791153
First Posted: February 13, 2013
Last Update Posted: May 18, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Hoffmann-La Roche
  Purpose
This multicenter, randomized, double-blind, placebo-controlled, parallel-group study will evaluate the efficacy and safety of tocilizumab in participants with GCA. The study will consist of 2 parts: a 52-week double-blind treatment period (Part 1) followed by a 104-week open label long-term follow-up period (Part 2). In Part 1 of the study eligible participants will be randomized to receive either tocilizumab every week (qw) or every 2 weeks (q2w) or placebo for 52 weeks, with tapering oral daily doses of prednisone. After Week 52, participants in remission will stop study treatment and enter long-term follow-up, whereas participants with disease activity or flares will receive open-label tocilizumab or other treatment at the discretion of the investigator for a maximum period of 104 weeks.

Condition Intervention Phase
Giant Cell Arteritis Drug: Tocilizumab Drug: Prednisone Drug: Tocilizumab Placebo Drug: Prednisone Placebo Drug: Corticosteroids Drug: Methotrexate Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III, Multicenter, Randomized, Double-Blind Placebo-Controlled Study to Assess the Efficacy and Safety of Tocilizumab in Subjects With Giant Cell Arteritis

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 Weeks Prednisone Taper Versus Placebo + 26 Weeks Prednisone Taper) [ Time Frame: Week 52 ]
    Remission was defined as the absence of flare and normalization of the C-reactive protein (CRP) (less than [<] 1 milligram per deciliter [mg/dL]). Sustained remission was defined as the absence of flare following induction of remission within 12 weeks of randomization and maintained up to Week 52. Flare was determined by the investigator and was defined as the recurrence of signs or symptoms of GCA and/or erythrocyte sedimentation rate (ESR) greater than or equal to (>/=) 30 millimeters per hour (mm/hr) attributable to GCA. A single CRP elevation (>/=1 mg/dL) was not considered as a sign of flare, unless the CRP remained elevated (>/=1 mg/dL) at the next study visit.


Secondary Outcome Measures:
  • Percentage of Participants in Sustained Remission at Week 52 (Tocilizumab + 26 Weeks Prednisone Taper Versus Placebo + 52 Weeks Prednisone Taper) [ Time Frame: Week 52 ]
    Remission was defined as the absence of flare and normalization of the CRP (<1 mg/dL). Sustained remission was defined as the absence of flare following induction of remission within 12 weeks of randomization and maintained up to Week 52. Flare was determined by the investigator and was defined as the recurrence of signs or symptoms of GCA and/or ESR >/=30 mm/hr attributable to GCA. A single CRP elevation (>/=1 mg/dL) was not considered as a sign of flare, unless the CRP remained elevated (>/=1 mg/dL) at the next study visit.

  • Time to First GCA Disease Flare [ Time Frame: Up to 52 weeks ]
    Flare was determined by the investigator and was defined as the recurrence of signs or symptoms of GCA and/or ESR >/=30 mm/hr attributable to GCA. Participants who withdrew from the study prior to Week 52 were censored from the time of withdrawal.

  • Total Cumulative Prednisone Dose [ Time Frame: Up to 52 weeks ]
    The median total cumulative prednisone dose over the 52 weeks for each treatment group and the corresponding 95% confidence intervals are presented.

  • Change From Baseline in Short Form (SF)-36 Questionnaire Score at Week 52 [ Time Frame: Baseline, Week 52 ]
    The SF-36 is a standardized questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical Component Score (PCS) and Mental Component Score (MCS). The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). A positive change from baseline indicates improvement. No imputation was used for missing data. Data was set to missing for participants who received escape therapy.

  • Change From Baseline in Patient Global Assessment (PGA) of Disease Activity Assessed Using Visual Analogue Scale (VAS) at Week 52 [ Time Frame: Baseline, Week 52 ]
    Participants assessed their current disease activity on a 0-100 millimeter (mm) VAS, where 0 mm = no disease activity and 100 mm = maximum disease activity. A negative change from baseline indicates improvement.

  • Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) at Steady State of Tocilizumab [ Time Frame: Baseline and Week 16 (Predose [Hour 0], 24, 48, 72, 96, and 120 or 144 hours postdose); Weeks 1, 2, 17, and 18 (Predose [Hour 0]) ]
    AUCtau is the model-predicted area under the tocilizumab serum concentration versus time curve from time zero to the end of dosing interval. AUCtau is measured in microgram*day per milliliter (mcg*day/mL).

  • Maximum Serum Concentration at Steady State (Cmax,ss) of Tocilizumab [ Time Frame: Baseline and Week 16 (Predose [Hour 0], 24, 48, 72, 96, and 120 or 144 hours postdose); Weeks 1, 2, 17, and 18 (Predose [Hour 0]) ]
    Cmax,ss is maximum model-predicted serum steady state concentration of tocilizumab measured in micrograms per milliliter (mcg/mL).

  • Minimum Serum Concentration at Steady State (Cmin,ss) of Tocilizumab [ Time Frame: Baseline and Week 16 (Predose [Hour 0], 24, 48, 72, 96, and 120 or 144 hours postdose); Weeks 1, 2, 17, and 18 (Predose [Hour 0]) ]
    Cmin,ss is minimum model-predicted serum steady state concentration of tocilizumab measured in mcg/mL.

  • Minimum Observed Serum Concentration (Ctrough) of Tocilizumab [ Time Frame: Predose (Hour 0) at Baseline and Week 52 ]
    Ctrough is minimum observed serum concentration of tocilizumab measured in mcg/mL.

  • Serum Interleukin-6 (IL-6) Level [ Time Frame: Baseline and Week 52 ]
  • Serum Soluble IL-6 Receptor (sIL-6R) Level [ Time Frame: Baseline and Week 52 ]
  • Erythrocyte Sedimentation Rate (ESR) [ Time Frame: Baseline and Week 52 ]
    ESR is a laboratory test that provides a non-specific measure of inflammation. The test assesses the rate at which red blood cells fall in a test tube. Normal range is 0-30 mm/hr. A higher rate is consistent with inflammation.

  • C-Reactive Protein (CRP) Level [ Time Frame: Baseline and Week 52 ]
    The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement.

  • Percentage of Participants With Anti-Tocilizumab Antibodies [ Time Frame: Baseline up to Week 52 ]
    All samples were tested by screening assay, and those samples that were positive were further analyzed by a confirmation assay to confirm specificity. Percentage of participants who has a positive confirmation assay result any time after the initial drug administration with a negative confirmation assay result at baseline was reported.


Enrollment: 251
Actual Study Start Date: July 22, 2013
Estimated Study Completion Date: April 30, 2018
Primary Completion Date: April 11, 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1: Tocilizumab qw + 26 weeks prednisone taper
Participants will receive tocilizumab at a dose of 162 milligrams (mg) as subcutaneous (SC) injection qw up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants will receive prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52.
Drug: Tocilizumab
Tocilizumab will be administered at a dose of 162 mg as SC injection qw or q2w for 52 weeks in Part 1 of the study and at a dose 162 mg as SC injection qw for 104 week at the discretion of the investigator in Part 2 of the study.
Other Name: RoActemra, Actemra, RO4877533
Drug: Prednisone
Prednisone will be administered at tapering oral doses as tablets daily for 26 or 52 weeks according to the protocol-defined schedule in Part 1 of the study. Prednisone will also be administered as escape therapy to treat disease flares in an open-label manner during Part 1 at a dose and duration selected by the investigator.
Drug: Prednisone Placebo
Prednisone placebo will be administered as tablets orally daily according to the protocol-defined schedule (from Week 26 to Week 52) in Part 1 of the study.
Experimental: Part 1: Tocilizumab q2w + 26 weeks prednisone taper
Participants will receive tocilizumab at a dose of 162 mg as SC injection q2w (and tocilizumab placebo q2w starting from Week 2) up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants will receive prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52.
Drug: Tocilizumab
Tocilizumab will be administered at a dose of 162 mg as SC injection qw or q2w for 52 weeks in Part 1 of the study and at a dose 162 mg as SC injection qw for 104 week at the discretion of the investigator in Part 2 of the study.
Other Name: RoActemra, Actemra, RO4877533
Drug: Prednisone
Prednisone will be administered at tapering oral doses as tablets daily for 26 or 52 weeks according to the protocol-defined schedule in Part 1 of the study. Prednisone will also be administered as escape therapy to treat disease flares in an open-label manner during Part 1 at a dose and duration selected by the investigator.
Drug: Tocilizumab Placebo
Tocilizumab placebo will be administered as SC injection qw or q2w for 52 weeks in Part 1 of the study.
Drug: Prednisone Placebo
Prednisone placebo will be administered as tablets orally daily according to the protocol-defined schedule (from Week 26 to Week 52) in Part 1 of the study.
Placebo Comparator: Part 1: Placebo + 26 weeks prednisone taper
Participants will receive tocilizumab placebo as SC injection qw up to 52 weeks along with prednisone and/or prednisone placebo according to the protocol-defined schedule. Participants will receive prednisone tapering oral daily doses during the first 26 weeks and prednisone placebo from Week 26 up to Week 52.
Drug: Prednisone
Prednisone will be administered at tapering oral doses as tablets daily for 26 or 52 weeks according to the protocol-defined schedule in Part 1 of the study. Prednisone will also be administered as escape therapy to treat disease flares in an open-label manner during Part 1 at a dose and duration selected by the investigator.
Drug: Tocilizumab Placebo
Tocilizumab placebo will be administered as SC injection qw or q2w for 52 weeks in Part 1 of the study.
Drug: Prednisone Placebo
Prednisone placebo will be administered as tablets orally daily according to the protocol-defined schedule (from Week 26 to Week 52) in Part 1 of the study.
Placebo Comparator: Part 1: Placebo + 52 weeks prednisone taper
Participants will receive tocilizumab placebo as SC injection qw up to 52 weeks along with prednisone and/or prednisone placebo according to a protocol-defined schedule. Participants will receive prednisone tapering oral daily doses for 52 weeks.
Drug: Prednisone
Prednisone will be administered at tapering oral doses as tablets daily for 26 or 52 weeks according to the protocol-defined schedule in Part 1 of the study. Prednisone will also be administered as escape therapy to treat disease flares in an open-label manner during Part 1 at a dose and duration selected by the investigator.
Drug: Tocilizumab Placebo
Tocilizumab placebo will be administered as SC injection qw or q2w for 52 weeks in Part 1 of the study.
Drug: Prednisone Placebo
Prednisone placebo will be administered as tablets orally daily according to the protocol-defined schedule (from Week 26 to Week 52) in Part 1 of the study.
Experimental: Part 2: Open-Label Tocilizumab qw
Participants without sustained remission at Week 52 will receive open-label tocilizumab at a dose of 162 mg as SC injection qw and/or corticosteroids and/or methotrexate at the discretion of the investigator for a maximum of 104 weeks.
Drug: Tocilizumab
Tocilizumab will be administered at a dose of 162 mg as SC injection qw or q2w for 52 weeks in Part 1 of the study and at a dose 162 mg as SC injection qw for 104 week at the discretion of the investigator in Part 2 of the study.
Other Name: RoActemra, Actemra, RO4877533
Drug: Corticosteroids
Participants without sustained remission at Week 52 will receive corticosteroids at a dose and schedule at the discretion of the investigator for a maximum of 104 weeks.
Drug: Methotrexate
Participants without sustained remission at Week 52 will receive methotrexate at a dose and schedule at the discretion of the investigator for a maximum of 104 weeks.

  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   50 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of GCA classified according to age >/=50 years; history of ESR >/=50 mm/hr or history of CRP >/=2.45 mg/dL; and at least one of the following: unequivocal cranial symptoms of GCA or symptoms of polymyalgia rheumatica [PMR]; and at least one of the following: temporal artery biopsy revealing features of GCA or evidence of large-vessel vasculitis by angiography or cross-sectional imaging
  • New onset (diagnosis within 6 weeks of baseline) or refractory (diagnosis greater than [>] 6 weeks before baseline and previous treatment with >/= 40 milligrams per day prednisone [or equivalent] for at least 2 consecutive weeks at any time) GCA
  • Active disease (presence of clinical signs and symptoms [cranial or PMR] and ESR >/=30 mm/hour or CRP >/=1 mg/dL) within 6 weeks of baseline visit

Exclusion Criteria:

  • Major surgery within 8 weeks prior to screening or planned within 12 months after randomization
  • Transplanted organs (except corneas with transplant performed >3 months prior to screening)
  • Major ischemic event, unrelated to GCA, within 12 weeks of screening
  • Prior treatment with any of the following: investigational agent within 12 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening; cell-depleting therapies including investigational agent; intravenous (IV) gamma globulin or plasmapheresis within 6 months of baseline; alkylating agents or with total lymphoid irradiation; tocilizumab; hydroxychloroquine, cyclosporine A, azathioprine, or mycophenolate mofetil within 4 weeks of baseline; etanercept within 2 weeks of baseline; infliximab, certolizumab, golimumab, abatacept, or adalimumab within 8 weeks of baseline; anakinra within 1 week of baseline; tofacitinib; cyclophosphamide within 6 months of baseline; >100 milligrams of daily IV methylprednisolone within 6 weeks of baseline
  • Participants requiring systemic glucocorticoids for conditions other than GCA, which, in the opinion of the investigator, would interfere with adherence to the fixed glucocorticoid taper regimen and/or to assessment of efficacy in response to the test article
  • History of severe allergic reactions to monoclonal antibodies or to prednisone
  • Evidence of serious uncontrolled concomitant disease (for example, cardiovascular, respiratory, renal, endocrine, psychiatric, corneal ulcers/injuries, or gastrointestinal [GI] disease)
  • Current liver disease, as determined by the investigator
  • History of diverticulitis, inflammatory bowel disease, or other symptomatic GI tract condition that might predispose to bowel perforation
  • Known active or history of recurrent bacterial, viral fungal, mycobacterial, or other infection
  • Primary or secondary immunodeficiency
  • Evidence of malignancies diagnosed within previous 5 years (except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that have been excised and cured)
  • Inadequate hematologic, renal or liver function
  • Positive for hepatitis B or hepatitis C infection
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01791153


  Show 109 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01791153     History of Changes
Other Study ID Numbers: WA28119
2011-006022-25 ( EudraCT Number )
First Submitted: February 12, 2013
First Posted: February 13, 2013
Results First Submitted: April 10, 2017
Results First Posted: May 18, 2017
Last Update Posted: May 18, 2017
Last Verified: April 2017

Additional relevant MeSH terms:
Arteritis
Giant Cell Arteritis
Polymyalgia Rheumatica
Vasculitis
Vascular Diseases
Cardiovascular Diseases
Vasculitis, Central Nervous System
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Skin Diseases, Vascular
Skin Diseases
Autoimmune Diseases
Immune System Diseases
Muscular Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Methotrexate
Prednisone
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents


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