Comparative Efficacy and Safety of Sirolimus Versus Methylprednisolone in Patients with Active Thyroid Eye Disease

The primary objective of this study is to evaluate whether **Sirolimus** is more effective and associated with fewer side effects compared to conventional treatment with corticosteroids in patients with active **thyroid eye disease**. This is clinically relevant as it aims to identify a potentially safer and more effective treatment option for managing this condition, which can significantly impact patients' quality of life.

Secondary objectives include determining whether treatment with Sirolimus results in fewer metabolic complications than the established treatment with intravenous corticosteroids. This aspect is crucial for understanding the broader safety profile of Sirolimus in comparison to corticosteroids, which are known for their metabolic side effects.

The clinical trial involves participants diagnosed with **thyroid eye disease** (TED), specifically those with active TED associated with Graves' disease. The study population includes both male and female subjects aged between 18 and 80 years. Participants are required to be in generally good health, with their thyroid condition under control, either euthyroid or with mild hypo- or hyperthyroidism. The trial does not include a vulnerable population. Participants must have experienced the onset of active TED symptoms within six months prior to the baseline. Lifestyle considerations include the requirement for women of childbearing potential to use reliable contraception throughout the trial, and male participants must use barrier contraceptive methods if sexually active with a female partner of childbearing potential. All participants must be vaccinated according to national guidelines. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy and safety of **sirolimus** compared to conventional treatment with corticosteroids in patients with active **thyroid eye disease**. This is a randomized, double-blind, controlled trial with an estimated duration from June 2024 to May 2028. Participants will be randomly assigned to receive either sirolimus as an oral solution or methylprednisolone as an intravenous infusion. The trial will include several key phases, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as a clinical diagnosis of Graves' disease associated with active thyroid eye disease and a Clinical Activity Score (CAS) of ≥4 for the most severely affected eye.

Following the screening, eligible participants will undergo a baseline visit where initial assessments and measurements will be conducted. The primary endpoint of the study is a ≥2 point reduction in CAS from baseline at week 12. Secondary endpoints include a ≥2 mm reduction in proptosis and vertical lid aperture, a ≥1 class improvement in eye motility assessed by the Gorman score, and a ≥6 points improvement in the GO-QOL score, all evaluated at week 12. Participants will attend regular follow-up visits to monitor progress and assess any adverse effects, with the final visit marking the end of the study period.

The expected length of participant involvement is up to 12 months, with conditions for early termination including significant adverse events or withdrawal of consent. Participants must adhere to the study protocol, including the use of reliable contraception for women of childbearing potential and barrier methods for male participants with partners of childbearing potential. The trial aims to provide valuable insights into the comparative effectiveness of sirolimus and corticosteroids, potentially influencing future treatment strategies for thyroid eye disease.

The clinical trial involves the administration of **Solu-Medrol S.A.B. (Sine Alcohol Benzylicus)**, a pharmaceutical product containing the active substance **methylprednisolone**. This medication is provided in the form of a powder and solvent for the preparation of an injection solution, specifically designed for intravenous infusion. The maximum daily dose of methylprednisolone is 500 mg, with a total maximum dose of 8000 mg over a treatment period of up to 12 weeks. The product is manufactured by Pfizer S.A. and is authorized for use in Belgium. The administration of this medication will be closely monitored to ensure participant compliance and to assess any potential side effects.

In comparison, the trial also includes the administration of **Rapamune**, an oral solution containing the active substance **sirolimus**. This medication is provided as a 1 mg/mL oral solution, with a maximum daily dose of 0.5 mg and a total maximum dose of 45 mg over a 12-week treatment period. Rapamune is manufactured by Pfizer Europe MA EEIG and is authorized for use in Norway. The oral administration route will be utilized, and participant adherence to the dosing schedule will be monitored throughout the study. The objective of the trial is to evaluate the efficacy and safety profile of sirolimus compared to conventional corticosteroid treatment in patients with active thyroid eye disease.

The efficacy of the clinical trial comparing **Sirolimus** against corticosteroids in the treatment of patients with active thyroid eye disease will be assessed using both primary and secondary endpoints. The primary endpoint is defined as a reduction of at least 2 points in the Clinical Activity Score (CAS) from baseline at week 12. This score is a validated measure used to evaluate the activity of thyroid eye disease.

Secondary endpoints include a reduction of at least 2 mm from baseline in proptosis in one eye at week 12, a reduction of at least 2 mm from baseline in vertical lid aperture in one eye at week 12, and an improvement of at least 1 class in eye motility from baseline as assessed by the Gorman score at week 12. The Gorman score categorizes eye motility as follows: 1 = no diplopia, 2 = intermittent diplopia, 3 = inconstant (gaze-evoked) diplopia, and 4 = constant diplopia in primary or reading position. Additionally, an improvement of at least 6 points in the Graves' Ophthalmopathy Quality of Life (GO-QOL) score will be evaluated.

These efficacy parameters will be measured and collected at baseline and at week 12 of the trial. The analysis will focus on the changes from baseline to week 12, providing insights into the comparative effectiveness of Sirolimus versus corticosteroids in managing active thyroid eye disease.