Efficacy, Safety, and Tolerability of Subcutaneous Teprotumumab in Moderate-to-Severe Active Thyroid Eye Disease: A Phase 3 Randomized, Double-Masked, Placebo-Controlled Trial

The primary objective of this Phase 3, randomized, double-masked, placebo-controlled, parallel-group, multicenter trial is to evaluate the effect of **teprotumumab** versus placebo on the proptosis responder rate in participants with moderate-to-severe active **Thyroid Eye Disease**. Proptosis responder rate is defined as the percentage of participants achieving a ≥ 2-mm reduction in proptosis from baseline in the study eye without a ≥ 2-mm increase in the fellow eye. This measure is clinically relevant as proptosis is a key symptom of Thyroid Eye Disease, and its reduction can significantly improve patient outcomes and quality of life.

Secondary objectives include evaluating the effect of teprotumumab versus placebo on measures of clinical efficacy and patient-reported outcomes at a specified week. These assessments are crucial for understanding the broader impact of the treatment on patient health and well-being beyond the primary endpoint.

The clinical trial involves a total of **66 participants** diagnosed with **Moderate-to-Severe Active Thyroid Eye Disease**. The study population includes both male and female subjects, aged between 18 and 80 years. Participants were selected based on their clinical diagnosis of Graves' disease associated with active Thyroid Eye Disease (TED), with a Clinical Activity Score (CAS) of 3 or higher for the most severely affected eye. The trial population is not considered vulnerable, and participants must be euthyroid or have mild hypo- or hyperthyroidism, with efforts made to maintain a euthyroid state throughout the trial. Lifestyle considerations such as diet and physical activity are not specified, but participants must not require immediate surgical ophthalmological intervention and should not plan corrective surgery or irradiation during the trial. Women of childbearing potential are required to have negative pregnancy tests at specified intervals. The selection criteria ensure that participants have moderate-to-severe active TED, which is not sight-threatening but significantly impacts daily life.

The clinical trial is a **Phase 3**, randomized, double-masked, placebo-controlled, parallel-group, multicenter study designed to evaluate the efficacy, safety, and tolerability of subcutaneous **teprotumumab** in participants with moderate-to-severe active **thyroid eye disease**. The trial will involve the administration of teprotumumab and a placebo, both delivered as a solution for injection. The primary objective is to assess the proptosis responder rate, defined as the percentage of participants with a ≥ 2-mm reduction from baseline in the study eye without deterioration in the fellow eye. Secondary endpoints include changes in proptosis measurement, Clinical Activity Score (CAS), and diplopia, as well as the overall responder rate and quality of life assessments.

The trial is expected to commence recruitment on December 1, 2024, and conclude by March 31, 2026. Participants will be involved in the study for a duration that aligns with the trial's estimated timeline. The study will begin with a screening visit to confirm eligibility based on inclusion criteria, such as age, diagnosis of Graves' disease with active thyroid eye disease, and euthyroid status. Participants will then be randomized to receive either teprotumumab or placebo. Follow-up visits will be scheduled at regular intervals to monitor safety, efficacy, and adherence to the protocol. The end-of-study visit will occur after the final dose, where comprehensive assessments will be conducted to evaluate the outcomes.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the protocol, or require immediate surgical intervention. The trial is structured to ensure rigorous monitoring and data collection, with the aim of providing robust evidence on the therapeutic potential of teprotumumab in treating moderate-to-severe active thyroid eye disease.

The clinical trial involves the administration of **Teprotumumab**, a **solution for injection**. This experimental medication is provided by Horizon Therapeutics USA Inc. and is identified by the sponsor product code AMG 632. The active substance, teprotumumab, is a protein of other origin, specifically designed for subcutaneous administration. The dosing regimen allows for a maximum daily dose of 999 mg, with the same limit for the total dose amount. The treatment period is capped at 999 days. The trial aims to evaluate the efficacy, safety, and tolerability of subcutaneous teprotumumab in participants with moderate-to-severe active **Thyroid Eye Disease**.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-masked, placebo-controlled trial. The placebo is administered subcutaneously and is designed to match the pharmaceutical form of teprotumumab, although specific details regarding its composition are not provided. The use of a placebo allows for the assessment of teprotumumab's effects by providing a baseline for comparison. Participant compliance with the dosing schedule is monitored throughout the study to ensure the integrity of the trial results.

Efficacy in this clinical trial will be assessed through several primary and secondary endpoints. The primary endpoint is the **proptosis responder rate**, defined as the percentage of participants achieving a ≥ 2-mm reduction in proptosis from baseline in the study eye without a ≥ 2-mm increase in the fellow eye. Secondary endpoints include the mean change from baseline in proptosis measurement at specified weeks, the overall responder rate combining reductions in Clinical Activity Score (CAS) and proptosis, and the percentage of participants achieving a CAS value of 0 or 1. Additional secondary endpoints involve changes in diplopia, with assessments of both diplopia responder rate and complete diplopia responder rate, as well as the mean change in the Graves’ Ophthalmopathy Quality of Life (GO-QoL) questionnaire overall score.

These efficacy parameters will be measured and collected at various timepoints throughout the trial, although specific weeks are not detailed. The assessments will utilize validated scales and questionnaires, such as the CAS and GO-QoL, to ensure reliable and consistent data collection. The analysis will focus on comparing the effects of subcutaneous teprotumumab against placebo in participants with moderate-to-severe active Thyroid Eye Disease, aiming to determine the treatment's impact on proptosis and related symptoms.