Efficacy of Tocilizumab in Association to Steroids in Giant Cell Arteritis With Cerebro-vascular Involvement (TOGIAC)
Primary Purpose
Giant Cell Arteritis, Neurovascular Disorder
Status
Recruiting
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Tocilizumab
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Giant Cell Arteritis focused on measuring Giant Cell Arteritis, ischemic complication/ ischemic event, Cerebro-vascular involvement, Steroids, Tocilizumab, Horton's Giant Cell Arteritis, Vascular Diseases, Neurovascular Diseases, Cerebrovascular Disorders
Eligibility Criteria
Inclusion Criteria:
- Age > 60 years
- Diagnosis of
- GCA (according to ACR criteria or positive temporal artery biopsy) (de novo and/or relapse) And neurovascular involvement:
- Either Ischemic stroke (including TIA) in the vertebro-basilar or carotid territory (symptomatic arterial involvement)
- Either PET uptake of vertebral and/or carotid arteries (extra or intra cranial) and/or angioCT or angioMRI showing arterial involvement consistent with vasculitis (asymptomatic arterial involvement)
- Inclusion should be done
- within 4 weeks after the stroke concerning the "symptomatic" patients
- within 4 weeks after the diagnosis of GCA (or relapse) concerning the patients with asymptomatic neurovascular involvement.
- Within 14 days after starting the corticosteroids
- Signed Informed Consent Form
- Affiliation to social security
Exclusion Criteria:
Exclusion Criteria :
- Other proven cause of stroke: atrial fibrillation, significant atheromatous stenosis of carotid or vertebro-basilar arteries
Contraindication to and precaution in use of tocilizumab:
- Treatment with any investigational agent within 12 weeks (or 5 half-lives of the investigational drug, whichever was longer) of screening
- Previous treatment with cell-depleting therapies, including investigational agents,including but not limited to Campath (alemtuzumab), anti-CD4, anti-CD5, anti-CD3, anti-CD19, and anti-CD20
- Treatment with IV gamma globulin or plasmapheresis within 24 weeks of baseline
- Previous treatment with alkylating agents, such as chlorambucil, or with total lymphoid irradiation
- Previous treatment with TCZ
- Immunization with a live/attenuated vaccine within 4 weeks prior to baseline or simultaneously with tocilizumab treatment
- Treatment with hydroxychloroquine, cyclosporine A, azathioprine, or mycophenolate mofetil (MMF) within 4 weeks of baseline
- Treatment with etanercept within 2 weeks; infliximab, certolizumab, golimumab,abatacept, or adalimumab within 8 weeks; or anakinra within 1 week of baseline
- Previous treatment with tofacitinib
- Treatment with cyclophosphamide within 24 weeks of baseline
- History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies or to prednisone
- Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), psychiatric, osteoporosis/osteomalacia, glaucoma, corneal ulcers/injuries, or gastrointestinal disease
- Current liver disease, as determined by the investigator
- History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower GI disease such as Crohn's disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose a patient to perforations
- Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to tuberculosis [TB] and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of the nail beds)
- Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks of screening
- Active TB requiring treatment within the previous 3 years
- Patients treated for TB with no recurrence within 3 years and patients treated for latent TB within 3 years were eligible.
- Primary or secondary immunodeficiency (history of or currently active)
- Evidence of malignant disease or malignancies diagnosed within the previous 5 years (except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that had been excised and cured)
- History of alcohol, drug, or chemical abuse within 1 year prior to screening
- Body weight >150 kg
- Serum creatinine >1.4 mg/dL (124 µmol/L) in female patients and 1.6 mg/dL (141 µmol/L) in male patients
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)× 3 Upper limit of normal (ULN)>
- Platelet count < 100 109/L (100,000/mm3)
- Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L)
- White blood cells <3.0 x109/L (3000/mm3)
- Absolute neutrophil count < 2.0 x 109/L (2000/mm3)
- Absolute lymphocyte count < 0.5 X 109/L (500/mm3)
- Positive hepatitis B surface antigen or hepatitis C antibody
- Contraindication to aspirin, clopidogrel, steroids use, rifampicin and/or isoniazid
- Major surgery within 8 weeks prior to screening or planned major surgery within 12 months after randomization, except arterial thrombectomy if necessary for ischemic stroke
- Transplanted organs (except corneal transplant performed more than 3 months prior to screening)
- Inability to provide informed consent
- Participation in another interventional research
Sites / Locations
- Saint Antoine Hospital, Neurology Unit, Assistance Publique-Hôpitaux de ParisRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
tocilizumab 162mg/0.9mL administered subcutaneously (SC) weekly during 24 weeks
placebo administered subcutaneously (SC) weekly during 24 weeks
Arm Description
Tocilizumab 162mg/0.9mL administered subcutaneously (SC) weekly during 24 weeks
Placebo administered subcutaneously (SC) weekly during 24 weeks
Outcomes
Primary Outcome Measures
Percentage of patients in complete remission of GCA with absence of ischemic stroke recurrence at 24 weeks under tocilizumab.
Percentage of participants with complete remission of GCA, defined as an absence of clinical signs of GCA, a CRP levels less than 10 mg/l and an absence of new ischemic stroke signs at MRI realized at 24 weeks after the tocilizumab initiation
Secondary Outcome Measures
Compare within tocilizumab and placebo groups the percentage of clinical and MRI ischemic stroke recurrence at 24 weeks
the efficacy of weekly tocilizumab on the prevention of stroke recurrence will be measured by the percentage of stroke recurrence compared to control group in patients with GCA during 52 weeks at week 4, 12, 24 and 52
The relapse-free survival
Number of patients who had relapsed as defined as major if clinical symptoms are present, or as minor in the case of isolated acute pase reactants increase
Compare within tocilizumab and placebo groups the time to remission in patients with GCA during 52 weeks.
the time to remission will be assessed in comparison with the control group in patients with GCA during 52 weeks at week 4, 12, 24 and 52 Number of days between treatment induction and signs of remission.
Compare within tocilizumab and placebo groups the improvement of neurovascular radiological involvement during 52 weeks
Proportion of patient with neurovascular radiological involvement defined as angio-CT improvement of vasculitis lesions and /or improvement or disappearance of PET FDG uptake.
Compare within tocilizumab and placebo groups the steroid sparing effect at 24 weeks
Cumulative steroid dose at 24 weeks
Mortality at week 4, 12, 24 and 52
Percentages of deaths at week 4, 12, 24 and 52.
Evolution of degree of disability or dependence at week 4, 12, 24 and 52
Percentages of patients with rankin score 0-1
Percentage of Participants with Adverse Events/ serious adverse events
Percentage of participants with adverse events, treatment-related adverse events or serious adverse event as assessed by CTCAE v4.0, at week 4, 12, 24 and 52
Full Information
NCT ID
NCT04888221
First Posted
March 25, 2021
Last Updated
July 3, 2023
Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Roche Chugai, Roche Pharma AG
1. Study Identification
Unique Protocol Identification Number
NCT04888221
Brief Title
Efficacy of Tocilizumab in Association to Steroids in Giant Cell Arteritis With Cerebro-vascular Involvement
Acronym
TOGIAC
Official Title
Efficacy of Tocilizumab in Association to Steroids in Giant Cell Arteritis With Cerebro-vascular Involvement (ToGiAC)
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 24, 2021 (Actual)
Primary Completion Date
March 2024 (Anticipated)
Study Completion Date
March 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Roche Chugai, Roche Pharma AG
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
A French multicenter randomised and placebo-controlled study recruiting patients who present neurovascular involvement related to GCA (> 60 years) with symptomatic (stroke) or asymptomatic forms. The aim of this study is to assess the efficacy of tocilizumab to induce complete remission of GCA with cerebrovascular involvement (clinical and biological) and absence of clinical and MRI ischemic stroke recurrence at 24 weeks.
Detailed Description
Giant cell arteritis (GCA) in the elderly is considered a medical emergency in case of ischemic complication, urgent treatment is needed and high doses of intravenous steroids are used. To date, usual treatments added to steroids have not been shown to be effective in reducing the risk of ischemic event recurrence in GCA.
Recently, the efficacy of tocilizumab has been demonstrated as a steroid-sparing agent and a long-term complete remission agent. The aim of this study is to address the potential benefits of tocilizumab as induction therapy in combination with high dose steroids to improve the neurovascular involvement in GCA.
The study will enroll 66 subjects with GCA (according to ACR criteria or positive temporal artery biopsy) and neurovascular involvement (symptomatic or asymptomatic). It consist of a screening phase (up to 30 days), a baseline/randomization phase and a treatment phase with experimental treatment or placebo (weekly administrated) which could be combined with usual treatments for stroke as antiaggregants and/or anticoagulants (24 weeks). Regular visit will be performed to follow the GCA remission, adverse treatments effects and proceed to radiological and biological evaluations (visit assessment at weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36) until end of study visit at week 52.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Giant Cell Arteritis, Neurovascular Disorder
Keywords
Giant Cell Arteritis, ischemic complication/ ischemic event, Cerebro-vascular involvement, Steroids, Tocilizumab, Horton's Giant Cell Arteritis, Vascular Diseases, Neurovascular Diseases, Cerebrovascular Disorders
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
66 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
tocilizumab 162mg/0.9mL administered subcutaneously (SC) weekly during 24 weeks
Arm Type
Experimental
Arm Description
Tocilizumab 162mg/0.9mL administered subcutaneously (SC) weekly during 24 weeks
Arm Title
placebo administered subcutaneously (SC) weekly during 24 weeks
Arm Type
Placebo Comparator
Arm Description
Placebo administered subcutaneously (SC) weekly during 24 weeks
Intervention Type
Drug
Intervention Name(s)
Tocilizumab
Other Intervention Name(s)
RoActemra, Actemra
Intervention Description
Tocilizumab will be administered subcutaneously at a dose of 162mg/0.9mL weekly (each week, on the same day) from week 0 to week 24.
At the first injection (Baseline D0), a therapeutic education is provided for patients/caregivers who can carry out the injections themselves as part of their usual care.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo administered subcutaneously (SC) weekly during 24 weeks
Primary Outcome Measure Information:
Title
Percentage of patients in complete remission of GCA with absence of ischemic stroke recurrence at 24 weeks under tocilizumab.
Description
Percentage of participants with complete remission of GCA, defined as an absence of clinical signs of GCA, a CRP levels less than 10 mg/l and an absence of new ischemic stroke signs at MRI realized at 24 weeks after the tocilizumab initiation
Time Frame
From date of treatment initiation until 24 weeks.
Secondary Outcome Measure Information:
Title
Compare within tocilizumab and placebo groups the percentage of clinical and MRI ischemic stroke recurrence at 24 weeks
Description
the efficacy of weekly tocilizumab on the prevention of stroke recurrence will be measured by the percentage of stroke recurrence compared to control group in patients with GCA during 52 weeks at week 4, 12, 24 and 52
Time Frame
at week 4, 12, 24 and 52.
Title
The relapse-free survival
Description
Number of patients who had relapsed as defined as major if clinical symptoms are present, or as minor in the case of isolated acute pase reactants increase
Time Frame
up to 52 weeks
Title
Compare within tocilizumab and placebo groups the time to remission in patients with GCA during 52 weeks.
Description
the time to remission will be assessed in comparison with the control group in patients with GCA during 52 weeks at week 4, 12, 24 and 52 Number of days between treatment induction and signs of remission.
Time Frame
at week 4, 12, 24 and 52.
Title
Compare within tocilizumab and placebo groups the improvement of neurovascular radiological involvement during 52 weeks
Description
Proportion of patient with neurovascular radiological involvement defined as angio-CT improvement of vasculitis lesions and /or improvement or disappearance of PET FDG uptake.
Time Frame
at week 4, 12, 24 and 52.
Title
Compare within tocilizumab and placebo groups the steroid sparing effect at 24 weeks
Description
Cumulative steroid dose at 24 weeks
Time Frame
up to 24 weeks
Title
Mortality at week 4, 12, 24 and 52
Description
Percentages of deaths at week 4, 12, 24 and 52.
Time Frame
at week 4, 12, 24 and 52
Title
Evolution of degree of disability or dependence at week 4, 12, 24 and 52
Description
Percentages of patients with rankin score 0-1
Time Frame
at week 4, 12, 24 and 52.
Title
Percentage of Participants with Adverse Events/ serious adverse events
Description
Percentage of participants with adverse events, treatment-related adverse events or serious adverse event as assessed by CTCAE v4.0, at week 4, 12, 24 and 52
Time Frame
at week 4, 12, 24 and 52.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age > 60 years
Diagnosis of
GCA (according to ACR criteria or positive temporal artery biopsy) (de novo and/or relapse) And neurovascular involvement:
Either Ischemic stroke (including TIA) in the vertebro-basilar or carotid territory (symptomatic arterial involvement)
Either PET uptake of vertebral and/or carotid arteries (extra or intra cranial) and/or angioCT or angioMRI showing arterial involvement consistent with vasculitis (asymptomatic arterial involvement)
Inclusion should be done
within 4 weeks after the stroke concerning the "symptomatic" patients
within 4 weeks after the diagnosis of GCA (or relapse) concerning the patients with asymptomatic neurovascular involvement.
Within 14 days after starting the corticosteroids
Signed Informed Consent Form
Affiliation to social security
Exclusion Criteria:
Exclusion Criteria :
Other proven cause of stroke: atrial fibrillation, significant atheromatous stenosis of carotid or vertebro-basilar arteries
Contraindication to and precaution in use of tocilizumab:
Treatment with any investigational agent within 12 weeks (or 5 half-lives of the investigational drug, whichever was longer) of screening
Previous treatment with cell-depleting therapies, including investigational agents,including but not limited to Campath (alemtuzumab), anti-CD4, anti-CD5, anti-CD3, anti-CD19, and anti-CD20
Treatment with IV gamma globulin or plasmapheresis within 24 weeks of baseline
Previous treatment with alkylating agents, such as chlorambucil, or with total lymphoid irradiation
Previous treatment with TCZ
Immunization with a live/attenuated vaccine within 4 weeks prior to baseline or simultaneously with tocilizumab treatment
Treatment with hydroxychloroquine, cyclosporine A, azathioprine, or mycophenolate mofetil (MMF) within 4 weeks of baseline
Treatment with etanercept within 2 weeks; infliximab, certolizumab, golimumab,abatacept, or adalimumab within 8 weeks; or anakinra within 1 week of baseline
Previous treatment with tofacitinib
Treatment with cyclophosphamide within 24 weeks of baseline
History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies or to prednisone
Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), psychiatric, osteoporosis/osteomalacia, glaucoma, corneal ulcers/injuries, or gastrointestinal disease
Current liver disease, as determined by the investigator
History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower GI disease such as Crohn's disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose a patient to perforations
Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to tuberculosis [TB] and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of the nail beds)
Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks of screening
Active TB requiring treatment within the previous 3 years
Patients treated for TB with no recurrence within 3 years and patients treated for latent TB within 3 years were eligible.
Primary or secondary immunodeficiency (history of or currently active)
Evidence of malignant disease or malignancies diagnosed within the previous 5 years (except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that had been excised and cured)
History of alcohol, drug, or chemical abuse within 1 year prior to screening
Body weight >150 kg
Serum creatinine >1.4 mg/dL (124 µmol/L) in female patients and 1.6 mg/dL (141 µmol/L) in male patients
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)× 3 Upper limit of normal (ULN)>
Platelet count < 100 109/L (100,000/mm3)
Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L)
White blood cells <3.0 x109/L (3000/mm3)
Absolute neutrophil count < 2.0 x 109/L (2000/mm3)
Absolute lymphocyte count < 0.5 X 109/L (500/mm3)
Positive hepatitis B surface antigen or hepatitis C antibody
Contraindication to aspirin, clopidogrel, steroids use, rifampicin and/or isoniazid
Major surgery within 8 weeks prior to screening or planned major surgery within 12 months after randomization, except arterial thrombectomy if necessary for ischemic stroke
Transplanted organs (except corneal transplant performed more than 3 months prior to screening)
Inability to provide informed consent
Participation in another interventional research
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sonia ALAMOWITCH, PU-PH
Phone
+ (33)1-49-28-06-51
Email
sonia.alamowitch@aphp.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Arsène MEKINIAN, PU-PH
Phone
+ (33)01-48-95-0765
Email
arsene.mekinian@sat.aphp.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sonia ALAMOWITCH, PU-PH
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Saint Antoine Hospital, Neurology Unit, Assistance Publique-Hôpitaux de Paris
City
Paris
ZIP/Postal Code
75012
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sonia ALAMOWITCH, MD PhD
Phone
+ (33)1-49-28-06-51
Email
sonia.alamowitch@aphp.fr
First Name & Middle Initial & Last Name & Degree
Arsène MEKINIAN, MD PhD
Phone
+ (33)01-48-95-0765
Email
arsene.mekinian@sat.aphp.fr
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Learn more about this trial
Efficacy of Tocilizumab in Association to Steroids in Giant Cell Arteritis With Cerebro-vascular Involvement
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