Evaluation of Satralizumab Efficacy and Safety in Moderate-to-Severe Thyroid Eye Disease: A Phase III Randomized, Double-Masked, Placebo-Controlled Study

Trial ID: 2023-503669-50-00
Protocol: GP44729
Sponsor: F. Hoffmann-La Roche AG

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Diseases & Conditions

Graves' disease

Objectives

The primary objective of this study is to evaluate the **efficacy** of subcutaneous satralizumab compared with placebo at Week 24, specifically focusing on the proptosis response in participants with moderate-to-severe thyroid eye disease. Proptosis, or the forward displacement of the eye, is a significant clinical feature of thyroid eye disease, and its reduction is crucial for improving patient outcomes and quality of life.

Secondary objectives include: - Evaluating the efficacy of subcutaneous satralizumab compared with placebo at Week 24 based on overall response. - Assessing the efficacy based on reduction in the clinical activity score. - Assessing the efficacy based on change in proptosis from baseline to Week 24. - Evaluating the efficacy based on health-related quality of life using the Graves’ Ophthalmopathy Quality of Life Questionnaire. - Assessing the efficacy based on reduction/improvement in diplopia. - Assessing the efficacy based on improvement in orbital pain. - Evaluating the safety and tolerability of satralizumab. - Characterizing the satralizumab pharmacokinetic profile.

Participants

The clinical trial involves a total of **87 participants** diagnosed with **Moderate-to-Severe Thyroid Eye Disease** (TED). The study population includes both male and female subjects, aged 18 years and older, with no vulnerable populations selected. Participants were chosen based on specific inclusion criteria, which required a clinical diagnosis of either active or chronic inactive TED. Active TED patients must exhibit a clinical activity score (CAS) of 3 or higher, while chronic inactive TED patients must have a CAS of less than 3 for at least six months prior to screening. All participants are required to be euthyroid or have mild hypo or hyperthyroidism with the background disease under control. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants have a stable health status concerning their thyroid condition, with no recent progression in symptoms for chronic inactive TED patients.

Plans and Procedures

The clinical trial is designed as a **randomized**, double-masked, placebo-controlled, multicenter study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab in participants with moderate-to-severe **thyroid eye disease**. The trial aims to assess the efficacy of subcutaneous satralizumab compared with placebo at Week 24, focusing on proptosis response. The study is expected to commence recruitment on December 13, 2023, and conclude by November 17, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, clinical diagnosis, and disease activity. The trial will include follow-up visits at specified intervals to monitor the primary and secondary endpoints, including proptosis reduction, clinical activity score changes, and quality of life improvements. The end-of-study visit will occur at Week 24, where final assessments will be conducted to evaluate the trial's outcomes.

The expected length of participant involvement is approximately 24 weeks, with conditions for early termination including significant adverse events or non-compliance with the study protocol. Participants will be monitored for adverse events, changes in vital signs, and laboratory test results throughout the trial. The study will also measure serum concentrations of satralizumab and estimate pharmacokinetic parameters using population pharmacokinetic modeling.

Treatment

The clinical trial involves the evaluation of **Satralizumab**, a humanized anti-IL-6 receptor monoclonal antibody, identified by the scientific product code **PRD9016776**. This experimental medication is administered subcutaneously and is specifically relabeled for clinical trial use. Satralizumab is being tested for its efficacy in treating moderate-to-severe **Thyroid Eye Disease**. The pharmaceutical form, dosage, and specific administration schedule are not detailed in the provided data.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-masked, placebo-controlled study. The placebo is designed to match the experimental treatment in appearance and administration route to ensure blinding of participants and investigators. The frequency and dosage of the placebo administration are aligned with those of the experimental treatment to maintain consistency in the trial protocol.

Several auxiliary treatments are included in the study, identified by their respective scientific product codes: **SUB20313**, **SUB05647MIG**, **SUB06250MIG**, **SUB12570MIG**, **SUB03360MIG**, and **H02AB**. These auxiliary treatments are characterized by their chemical or protein origins, with specific roles in the trial not explicitly detailed in the data. The administration routes, dosages, and schedules for these auxiliary treatments are not specified, and their use is likely supportive or adjunctive to the primary experimental and placebo treatments.

Participant compliance with the treatment regimen is monitored throughout the study, although specific methods for compliance monitoring are not described in the provided information. The trial's main objective is to assess the efficacy of Satralizumab compared to placebo at Week 24, focusing on the proptosis response in participants.

Efficacy

The efficacy of satralizumab in the treatment of moderate-to-severe **Thyroid Eye Disease (TED)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of participants with active disease achieving a reduction of at least 2mm in proptosis from baseline at Week 24 in the study eye, without any deterioration in the fellow eye. Secondary endpoints include various measures such as the proportion of participants achieving an overall response at Week 24, defined by a reduction in Clinical Activity Score (CAS) and proptosis, and changes in proptosis and CAS from baseline to Week 24. Additional secondary endpoints involve improvements in the Visual Functioning and Appearance sub-scale scores of the Grave's orbitopathy-Quality of Life (GO-QoL) questionnaire, reduction in diplopia, and absence of motility-induced and spontaneous pain at Week 24.

These efficacy parameters will be measured and collected at specified timepoints, primarily at baseline (Day 1) and Week 24. The assessments will utilize validated scales and questionnaires, such as the CAS and GO-QoL, to ensure accurate and reliable data collection. The analysis will focus on comparing the outcomes between the satralizumab and placebo groups, with particular attention to the changes from baseline and the achievement of predefined response criteria. The study is designed to provide comprehensive insights into the efficacy of satralizumab in managing TED symptoms and improving patient quality of life.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age >=18 years at the time of signing Informed Consent Form
FOR ACTIVE TED PATIENTS: Clinical diagnosis of active thyroid eye disease (TED) with clinical activity score (CAS) >= 3 (on the 7 item scale) at screening and baseline (Day 1) in the study eye  FOR CHRONIC INACTIVE TED PATIENTS: Clinical diagnosis of stable, chronic (inactive) TED, as determined by participant medical records indicating CAS < 3 (on a 7-item scale) in both eyes for at least 6 months prior to screening, or all of the following: o No progression in proptosis for at least 6 months prior to screening o If participant has a history of diplopia due to TED, no progression in diplopia for at least 6 months prior to screening o No new inflammatory TED symptoms for at least 6 months prior to screening.
FOR ACTIVE TED PATIENTS: Diagnosis of active moderate-to-severe TED; usually associated with proptosis (exophthalmos) >= 3 mm above normal for race and gender in the study eye. Additionally, participants must have one or more of the following: lid retraction >=2 mm, moderate or severe soft tissue involvement, and/or inconstant or constant diplopia.  FOR CHRONIC INACTIVE TED PATIENTS: History and presence at screening and baseline of chronic TED as estimated by treating physician with proptosis (exophthalmos) >= 3 mm above normal for race and gender in the study eye. Additionally, participants must have one or more of the following: lid retraction >=2 mm, moderate or severe soft tissue involvement, and/or inconstant or constant diplopia.
FOR ACTIVE TED PATIENTS: Onset of active TED symptoms in the study eye (as determined by participant medical records) <= 12 months prior to baseline (Day 1)  FOR CHRONIC INACTIVE TED PATIENTS: Initial TED diagnosis >12 months but < 10 years prior to screening
Euthyroid with the background disease under control, or have mild hypo or hyperthyroidism
FOR CHRONIC INACTIVE TED PATIENTS: CAS <3 (on a 7-item scale) in both eyes at screening and baseline (Day 1) visits

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Exclusion Criteria

Decrease in CAS or proptosis of >= 2 points or >= 2 mm, respectively, in the study eye between Screening and Baseline visit (Day 1)
Requiring immediate surgical ophthalmological intervention or planning corrective surgery or irradiation during the course of the study, in the judgment of the investigator
Identified pre-existing ophthalmic disease that, in the judgment of the investigator, would preclude study participation or complicate interpretation of study results, including corneal decompensation unresponsive to medical management and including ophthalmic diseases that will likely require prohibited therapy during the study
FOR ACTIVE TED: Any prior CS use (IV or oral) with a cumulative dose equivalent to >= 1 g of methylprednisolone or equivalent for the treatment of any condition within 3 months prior to screening. FOR CHRONIC INACTIVE TED: Use of any CSs (periocular, IV, oral, IVT injections or implants) for any indication within 3 weeks prior to screening.
Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes an individual's safe participation in and completion of the study
Pregnant or breastfeeding, or intention of becoming pregnant during the study or within 3 months after the final dose of satralizumab