Efficacy of Tocilizumab with Steroids in Giant Cell Arteritis with Cerebrovascular Involvement: A Randomized, Placebo-Controlled Phase III Trial

Trial ID: 2024-511906-21-00
Protocol: APHP191062
Sponsor: Assistance Publique Hopitaux De Paris

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Diseases & Conditions

Giant cell arteritis

Objectives

The primary objective of this study is to assess the **efficacy** of tocilizumab in inducing complete remission of **giant cell arteritis** (GCA) with cerebrovascular involvement. This includes evaluating both clinical and radiological parameters, as well as the absence of clinical and MRI ischemic stroke recurrence at 24 weeks. This objective is clinically relevant as it aims to determine the potential of tocilizumab to effectively manage GCA, a condition that can lead to significant morbidity due to its vascular complications.

Secondary objectives include evaluating:

Relapse-free survival
Time to remission
Serious adverse event-free survival
Neurovascular imaging improvement
Number and percentages of deaths
Number and percentages of patients with a Rankin score of 0-1
Percentage of clinical and MRI ischemic stroke recurrence at 24 weeks
Influence of tocilizumab treatment on cumulative steroid dose at 24 weeks
Safety of tocilizumab assessed by adverse events

These secondary objectives provide a comprehensive evaluation of the treatment's impact on disease progression, patient outcomes, and safety profile, which are crucial for understanding the broader implications of tocilizumab use in this patient population.

Participants

The clinical trial focuses on participants diagnosed with **giant cell arteritis** with cerebrovascular involvement. The study population includes both male and female subjects aged over 60 years. Participants are required to have a diagnosis of giant cell arteritis, confirmed either by American College of Rheumatology criteria or a positive temporal artery biopsy, with neurovascular involvement. This involvement is defined by PET uptake of vertebral and/or carotid arteries or angioCT/MRI showing arterial involvement inconsistent with atherosclerosis. The trial does not include a vulnerable population. Participants must have been diagnosed within four weeks of a stroke for symptomatic cases or within four weeks of a giant cell arteritis diagnosis or relapse for asymptomatic cases. Additionally, inclusion must occur within 21 days of starting corticosteroids. The sponsor has not provided information regarding the total number of participants. All participants are required to sign an informed consent form and have an affiliation to social security. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy** of **tocilizumab** in combination with steroids for patients diagnosed with **giant cell arteritis** with cerebrovascular involvement. This is a phase III, randomized, double-blind, placebo-controlled trial. The trial aims to assess the ability of tocilizumab to induce complete remission of the disease, characterized by the absence of clinical and MRI ischemic stroke recurrence at 24 weeks. The trial is expected to run until August 2025, with recruitment having commenced in September 2021.

Participants will be randomly assigned to receive either tocilizumab or a placebo, administered via subcutaneous injection. The maximum treatment period is 24 weeks, with a maximum daily dose of 162 mg and a total dose not exceeding 3888 mg. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits at weeks 4, 12, 24, and 52 to monitor progress and assess endpoints, and an end-of-study visit to evaluate the overall outcomes and safety of the treatment.

Inclusion criteria require participants to be over 60 years of age, have a confirmed diagnosis of giant cell arteritis with neurovascular involvement, and have signed an informed consent form. Participants must be affiliated with social security and meet specific timing criteria related to the onset of symptoms and initiation of corticosteroid treatment. The primary endpoint is the composite measure of complete remission, while secondary endpoints include relapse-free survival, time to remission, and safety assessments.

Participant involvement is expected to last up to 52 weeks, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with the study protocol. The trial will rigorously monitor safety, with particular attention to adverse events such as nasopharyngitis, headache, hypertension, and serious adverse events like upper respiratory tract infections. The study aims to provide valuable insights into the treatment of giant cell arteritis with cerebrovascular involvement, potentially improving patient outcomes and informing future therapeutic strategies.

Treatment

The clinical trial involves the administration of **Tocilizumab**, an experimental medication, to evaluate its efficacy in inducing complete remission of giant cell arteritis with cerebrovascular involvement. **Tocilizumab** is provided in the form of a **solution for injection** and is administered via **subcutaneous injection**. The maximum daily dose is 162 mg, with a total maximum dose of 3888 mg over the treatment period. The treatment duration is set for a maximum of 24 weeks. The active substance in **Tocilizumab** is a protein of other origin, specifically designed for this trial. The medication is blinded to ensure unbiased results.

The study also includes a **placebo** group to serve as a comparator to the experimental treatment. The **placebo** is designed to mimic the administration of **Tocilizumab** without containing the active substance. The placebo is administered in a similar manner to maintain the integrity of the study's blinding process. The placebo does not have an active pharmaceutical form or substance, ensuring that any observed effects can be attributed to the active treatment.

Efficacy

The efficacy of **tocilizumab** in the treatment of giant cell arteritis (GCA) with cerebrovascular involvement will be assessed through a composite primary endpoint. This endpoint includes the complete remission of GCA, evaluated clinically, biologically, and through PET uptake, as well as the absence of clinical and MRI ischemic stroke recurrence at 24 weeks. Secondary endpoints will further evaluate efficacy by measuring relapse-free survival, time to remission, and serious adverse event-free survival at weeks 4, 12, 24, and 52. Additionally, neurovascular imaging improvement will be assessed through angio-CT and PET FDG uptake at the same timepoints.

Other secondary endpoints include the percentage of clinical and MRI ischemic stroke recurrence at 24 weeks, the influence of tocilizumab on cumulative steroid dose, and the safety profile of tocilizumab, which will be assessed by monitoring adverse events such as nasopharyngitis, headache, hypertension, injection site reactions, and serious adverse events including upper respiratory tract infections, liver damage, neutropenia, and hypercholesterolemia. The efficacy assessments will be conducted using validated clinical and imaging methods to ensure accurate and reliable data collection throughout the trial duration.

Inclusion and Exclusion Criteria

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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: 􀂃 Defined by PET uptake of vertebral and/or carotid arteries (extra or intra cranial) or angioCT/MRI showing arterial involvement inconsistent with atherosclerosis 􀂃 Either Ischemic stroke (including TIA) in the vertebro-basilar or carotid territory (symptomatic arterial involvement) 􀂃 Without Ischemic stroke (including TIA) (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 21 days after starting the corticosteroids
Signed Informed Consent Form
Affiliation to social security

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Exclusion Criteria

Other proven cause of stroke: atrial fibrillation, significant atheromatous stenosis of carotid or vertebro-basilar arteries
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 within 6 months before the baseline
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 within 2 months before the baseline
Previous treatment with tocilizumab (TCZ) within 6 months before the baseline
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 within 2 months before the baseline
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 izoniazid
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