Conditions: Graves Ophthalmopathy
Keywords: GSK2136525 Pharmacodynamics Safety Otelixizumab Thyroid eye disease Graves' ophthalmopathy Repeat dose Intravenous infusion Tolerability EUGOGO
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: no

Brief summary:
The purpose of this study is to investigate the safety and tolerability of otelixizumab in patients with Graves' ophthalmopathy (thyroid eye disease). There is currently no alternative therapy available for this condition other than treatment with steroids, or radiotherapy and surgery. The study also includes a comparison of the current steroid treatment, methylprednisolone, with the proposed new otelixizumab treatment.

Detailed description:
This is a study of otelixizumab, a monoclonal antibody (MAb) directed against the human lymphocyte antigen CD3 (a protein found on a certain type of white blood cell). This will be an open-label, comparator-controlled, two part study to evaluate the safety and tolerability of otelixizumab in patients with Graves' ophthalmopathy (GO). It will also look to see if otelixizumab affects GO and how it works compared to methylprednisolone (the standard treatment for active GO).

In Part A, between one and four groups of 5 patients will receive doses of otelixizumab administered over 8 days. The first dose level will provide a low cumulative dose, this low dose level has been safely administered in previous studies. Safety and clinical response data will be reviewed after 8 weeks, if no clinical response is seen and there are no safety concerns, the dose of otelixizumab will be increased and a new group of subjects will enter Part A. In subsequent groups cumulative medium low, medium high, and high doses of otelixizumab may be investigated. However if a clinical response is seen at the lowest dose the study will move directly to Part B.

In Part B, patients will receive either otelixizumab at the dose set from Part A, over 8 days (5 patients) or methylprednisolone weekly for 12 weeks (5 patients). All dosing will be by intravenous infusion. All participants will undergo long term safety evaluation for 48 months.

Key assessments include vital signs, 12-lead ECG, liver function tests, thyroid function, viral monitoring, monitoring of cortisol and ACTH levels, laboratory safety tests and adverse event (side effect) data. Assessment of GO severity will be evaluated using recommended assessments including clinical activity assessments and quality of life questionnaires. Measurements of exploratory biomarkers (proteins found naturally in the blood) are also included in this study.

Arms:
arm 1: Up to 4 cohorts of 5 patients receive dose rising treatments of otelixizumab arm 2: Parallel dosing group in Part B receive otelixizumab over 8 days at a dose decided upon results from Part A arm 3: Parallel dosing group in Part B of weekly doses of methylprednisolone for 12 weeks

Interventions: intervention 1: Otelixizumab - low dose intervention 2: Otelixizumab - medium low dose intervention 3: Otelixizumab - medium high dose intervention 4: Otelixizumab - high dose intervention 5: Otelixizumab intervention 6: Methylprednisolone
Intervention descriptions: intervention 1: 8 day dose rising intravenous infusions of a low dose of otelixizumab intervention 2: 8 day dose rising intravenous infusions of a medium low dose of otelixizumab intervention 3: 8 day dose rising intravenous infusions of a medium high dose of otelixizumab intervention 4: 8 day dose rising intravenous infusions of a high dose of otelixizumab intervention 5: 8 day dose rising intravenous infusions of otelixizumab administered at a dose decided upon results from Part A. intervention 6: Weekly intravenous infusions of methylprednisolone administered as 500 mg per week for 6 weeks and then 250 mg per week for 6 weeks

Protocol document: