Phase II Study of Subcutaneous Tocilizumab and Intravenous Pulse Steroid Versus Steroid Monotherapy in Acute Anterior Ischemic Optic Neuropathy with Giant Cell Arteritis

The primary objective of this study is to evaluate whether induction therapy with four subcutaneous injections of **tocilizumab** over one month, in conjunction with a conventional steroid regimen, can improve ocular outcomes in patients with acute anterior ischemic optic neuropathy (AION) associated with Giant Cell Arteritis (GCA). This is clinically relevant as AION related to GCA can lead to significant visual impairment, and improving ocular outcomes could enhance the quality of life for affected patients.

Secondary objectives include:

• Determining if the same induction therapy can stabilize visual outcomes in AION related to GCA.
• Assessing visual stabilization at week 8 post-treatment, defined as the absence of visual improvement or deterioration.
• Evaluating the efficacy of the 1-month tocilizumab treatment on other manifestations of GCA.
• Monitoring the occurrence of an increase of two lines or more in visual acuity on the ETDRS chart at weeks 4 and 13.
• Measuring changes in Mean Deviation (MD) on an automated Visual Field (SITA Standard Humphrey 24-2) at weeks 4, 8, and 13.
• Examining changes in angio-OCT between baseline and week 4, focusing on the superficial and deep vascular plexus to detect decreased ischemia in peripapillary and macular areas.
• Assessing the recurrence rate at week 13.
• Evaluating the safety of the treatment.
• Identifying immunological biomarkers predictive of the response to tocilizumab.

The clinical trial involves participants diagnosed with **Giant Cell Arteritis** (GCA) and experiencing Acute Anterior Ischemic Optic Neuropathy (AION) characterized by sudden and painless loss of vision, with pallid swelling of the optic disc, of no more than one-week duration. The study population includes both male and female subjects aged 50 years or older. Participants are required to have social insurance. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. The selection criteria focus on individuals with a confirmed diagnosis of GCA and AION, ensuring that the study population is specifically targeted to those affected by these conditions. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is a **randomized**, non-comparative, phase II study designed to evaluate the efficacy of **tocilizumab** in combination with intravenous pulse steroids versus intravenous pulse steroids alone for the treatment of **acute anterior ischemic optic neuropathy** associated with **giant cell arteritis**. The trial employs a Simon two-stage optimal design and is not a low-intervention study. Participants will be randomly assigned to receive either subcutaneous tocilizumab at a dose of 162 mg weekly for four weeks or the standard intravenous pulse steroid regimen. The primary objective is to assess ocular improvement at week 8, defined as an increase of at least two lines of visual acuity on the ETDRS chart.

The trial is expected to last until December 2025, with recruitment having commenced in September 2020. Participants will be involved in the study for a maximum of 13 weeks. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age (50 years or older), diagnosis of giant cell arteritis, and acute anterior ischemic optic neuropathy characterized by sudden vision loss. Follow-up visits are scheduled at weeks 4, 8, and 13 to monitor visual acuity, visual field changes, and other clinical and biological parameters. The end-of-study visit will occur at week 13, where final assessments will be conducted.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The study will also evaluate secondary endpoints, including stabilization of vision, changes in visual field mean deviation, and improvements in other manifestations of giant cell arteritis. Safety will be assessed through the monitoring of adverse events and immunological biomarkers of response to tocilizumab. The trial aims to provide insights into the potential benefits of combining tocilizumab with conventional steroid therapy in improving ocular outcomes in this patient population.

The clinical trial involves the administration of **tocilizumab**, marketed as RoActemra, which is provided as a 162 mg **solution for injection** in a pre-filled syringe. This experimental medication is administered via **subcutaneous injection**. The dosing schedule consists of four injections over a one-month period, with each injection given every seven days. The maximum daily dose is 162 mg, and the total dose over the treatment period is 648 mg. Participant compliance with the dosing schedule is monitored throughout the trial.

In addition to the experimental treatment, the study includes the use of **methylprednisolone hemisuccinate**, marketed as SOLUMEDROL. This comparator treatment is provided as a powder and solvent for solution injectable, with a dosage of 1 g. It is administered via **intravenous injection**. The maximum daily dose is 15 mg/kg, with a total dose of 45 mg/kg over a treatment period of three days. This treatment serves as a standard-of-care therapy in the trial.

Another non-experimental treatment used in the study is **prednisone**, marketed as PREDNISONE VIATRIS. This medication is provided in a 20 mg tablet form and is administered orally. The maximum daily dose is 1 mg/kg, with a total dose of 1 mg/kg over a treatment period of three days. This treatment is used in conjunction with the comparator therapy to assess its efficacy in the trial.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is defined as ocular improvement at week 8 (W8), characterized by an increase of at least two lines of visual acuity on the ETDRS chart. Secondary endpoints include stabilization of vision at W8, occurrence of visual improvement at weeks 4 (W4) and 13 (W13), and changes in Mean Deviation (MD) measured on an automatized Visual Field (SITA Standard Humphrey 24-2) at W4, W8, and W13. Additionally, changes in angio-OCT between baseline and W4 will be evaluated to assess the decrease of ischemia in peripapillary and macular areas.

Further secondary endpoints involve the proportion of patients with improvement of other manifestations of Giant Cell Arteritis (GCA) and biological improvement, indicated by CRP and ESR levels, at W4, W8, and W13. The influence of a 1-month treatment with **tocilizumab** on the recurrence of acute anterior ischemic optic neuropathy (AION) and GCA at W13 will also be assessed, along with the time to first recurrence of GCA. Safety will be evaluated through the monitoring of adverse events and serious adverse events. Immunological biomarkers of response to **tocilizumab** will be assessed at baseline (W0), W4, and W13.