Phase 2b Randomized Double-Mask Placebo-Controlled Trial of Linsitinib in Active Moderate to Severe Thyroid Eye Disease

The primary objective of this study is to evaluate the effect of **linsitinib** versus placebo on the proptosis responder rate at Week 24 in subjects with active, moderate to severe **Thyroid Eye Disease** (TED). Proptosis, or the forward displacement of the eye, is a significant clinical manifestation of TED, and its reduction is crucial for improving patient outcomes and quality of life.

Secondary objectives include:

• Evaluating the effect of linsitinib versus placebo on the mean change from baseline to Week 24 in proptosis measurement in the primary study eye.
• Assessing the effect on the overall responder rate using the Clinical Activity Scale (CAS) and proptosis in the contralateral non-study eye at Week 24.
• Determining the effect on the percentage of subjects with a CAS value of 0 or 1 at Week 24 in the primary study eye.
• Evaluating the effect on the mean change from baseline to Week 24 in the Graves’ Ophthalmopathy Quality of Life (GO-QoL) questionnaire overall score.

The clinical trial involves participants diagnosed with **Thyroid Eye Disease (TED)**, specifically those with a clinical diagnosis of Graves’ Disease and/or autoimmune Hashimoto’s thyroiditis associated with active moderate to severe TED. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults. Participants are required to be euthyroid or have mild hypo- or hyperthyroidism at the time of screening. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. The selection criteria emphasize individuals with TED that is not sight-threatening but significantly impacts daily life, with a diagnosis made within 12 months prior to the screening visit. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, double-blind, placebo-controlled study designed to evaluate the safety, pharmacokinetics, and efficacy of **linsitinib** in subjects with active, moderate to severe **Thyroid Eye Disease (TED)**. The trial is structured to assess the primary endpoint of proptosis responder rate at Week 24, with secondary endpoints including changes in proptosis measurement, Clinical Activity Scale (CAS) scores, and quality of life assessments. The study will involve the administration of linsitinib in a film-coated tablet form, with a maximum daily dose of 300 mg, over a treatment period of up to 24 weeks.

Participants will be involved in the trial for an estimated duration of 24 weeks, with the trial expected to conclude by November 2025. The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as a clinical diagnosis of Graves’ Disease or autoimmune Hashimoto’s thyroiditis associated with TED, followed by baseline assessments. Subsequent visits will occur at regular intervals to monitor safety, efficacy, and pharmacokinetics, culminating in an end-of-study visit at Week 24. Conditions that may lead to early termination from the study include significant adverse events or non-compliance with the study protocol.

Inclusion criteria require participants to be euthyroid or have mild thyroid dysfunction, with TED diagnosed within 12 months prior to screening. The study aims to provide comprehensive data on the therapeutic potential of linsitinib in managing TED, with a focus on improving proptosis and overall quality of life for affected individuals. The trial's design ensures rigorous assessment through its double-blind methodology, minimizing bias and enhancing the reliability of the results.

The clinical trial involves the administration of **Linsitinib**, an investigational medication, to evaluate its safety, pharmacokinetics, and efficacy in subjects with active, moderate to severe **Thyroid Eye Disease**. Linsitinib is provided in the form of a film-coated tablet, with each tablet containing the active substance Linsitinib. The medication is administered orally, with a maximum daily dose of 300 mg. The total maximum dose over the treatment period is 50,400 mg, with the treatment duration extending up to 24 weeks. The pharmaceutical formulation is developed by Vasaragen, Inc., and is classified as a chemical substance.

In addition to Linsitinib, the study includes a placebo control group. The placebo tablets are designed to match the physical characteristics of the active Linsitinib tablets. These placebo tablets are formulated as a direct powder blend, comprising microcrystalline cellulose, lactose monohydrate, and magnesium stearate, and are compressed into tablet form. The placebo is administered orally, following the same dosing schedule as the active treatment, to ensure blinding and maintain the integrity of the study design.

Efficacy in this clinical trial will be assessed primarily through the **proptosis responder rate** at Week 24. This endpoint evaluates the effect of linsitinib compared to placebo in subjects with active, moderate to severe Thyroid Eye Disease (TED). Secondary efficacy endpoints include the change from baseline to Week 24 in proptosis measurement in the primary study eye, the overall responder rate in Clinical Activity Scale (CAS) or proptosis in the contralateral non-study eye at Week 24, the percentage of subjects with a CAS value of 0 or 1 at Week 24 in the primary study eye, and the mean change from baseline to Week 24 in the Graves’ Ophthalmopathy Quality of Life (GO-QoL) questionnaire overall score.

Measurements will be collected at specified timepoints, with the primary endpoint assessed at Week 24. The proptosis responder rate and changes in proptosis measurement will be determined using validated scales and clinical assessments. The CAS and GO-QoL questionnaire will be utilized to evaluate clinical activity and quality of life, respectively. Data collection and analysis will adhere to rigorous standards to ensure the reliability and validity of the efficacy assessments.