A Two-year Multi-center Phase 3 Study to Investigate the Efficacy and Safety of Secukinumab in Adult Patients With Active, Moderate to Severe Thyroid Eye Disease (ORBIT), With a Randomized, Parallel-group, Double-blind, Placebo-controlled, 16-week Treatment Period, and a Follow-up/Retreatment Period
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 28
- 试验地点
- 6
- 主要终点
- Plan A - Percentage of Participants Achieving Overall Response
研究概览
简要总结
Thyroid eye disease (TED) is a rare autoimmune, inflammatory disorder of the orbit and represents the most common extra-thyroidal manifestation of Graves' disease (GD). Several lines of evidence suggest an important role of interleukin-17A (IL-17A) in the pathogenesis of TED; increased levels of IL-17A have been detected in the serum and tears of patients with TED and IL-17A levels correlate with clinical activity of the disease. T-helper 17 cells (Th17 cells) (as well as other cellular sources of IL-17A, e.g., Tc17 cells) have been shown to infiltrate the orbital tissue of affected patients, producing IL-17A. IL-17A stimulates fibroblast activation, leading to retrobulbar tissue expansion and orbital fibrosis, which causes significant functional impairment. Secukinumab is a recombinant high-affinity fully human monoclonal anti-IL-17A antibody currently approved for the treatment of 3 inflammatory/ autoimmune diseases: moderate to severe plaque psoriasis (PsO), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) (ankylosing spondylitis (AS) and non-radiographic axSpA). The purpose of this study was to demonstrate the efficacy and safety of secukinumab 300 mg subcutaneous (s.c.) in adults with active, moderate to severe TED.
详细描述
This study consisted of the following 3 periods:
- Screening period (Week -6 to Baseline):
Participants' eligibility was assessed during the Screening period, which occurred for a maximum of 6 weeks. 2. Treatment period (Baseline to Week 16):
Eligible participants were randomized in a 1:1 ratio to one of the following double-blinded treatment arms:
- Arm 1: Secukinumab 300 mg s.c. at Baseline, Week 1, 2, 3, 4, 8, 12
- Arm 2: Placebo s.c. at Baseline, Week 1, 2, 3, 4, 8, 12
Participants were stratified according to current smoking status (up to 20% smokers per arm) since smoking has a well-known impact on treatment efficacy in TED. 3. Follow-up/open-label retreatment period (Week 16 up to Week 108):
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient had to be able to understand and communicate with the investigator and comply with the requirements of the study and had to give a written, signed and dated informed consent before any study assessment was performed.
- •Male or non-pregnant, non-lactating female patients ≥ 18 years of age.
- •Clinical diagnosis of active, moderate to severe TED (not sight-threatening) in the study eye at Baseline associated with 2 or more of the following:
- •Lid retraction >= 2 mm
- •Moderate or severe soft tissue involvement
- •Exophthalmos >= 3 mm above normal
- •Inconstant or constant diplopia
- •Onset of TED symptoms fewer than 12 months prior to Baseline.
- •CAS >= 4 (on a 7-point scale, with a score of >= 3 indicating active TED) in the more severely affected (study) eye at Screening and Baseline. Note: Proptosis is the primary qualifier for selection of the study eye. In case both eyes showed a similar degree of proptosis, other inflammatory signs and symptoms (CAS) were taken into account by the investigator for the selection of the study eye.
- •Peripheral euthyroidism or mild hypo-/hyperthyroidism defined as free T3 (fT3) and free T4 (fT4) < 30% above/below normal limits at Screening. Every effort was to be made to correct the mild hypo-/hyperthyroidism promptly and to maintain the euthyroid state until the end of this study.
- •Orbital MRI assessment available confirming the diagnosis of TED for patients initially presenting with hypo- or euthyroidism (without treatment for hyperthyroidism) before or at the time of TED diagnosis (to rule out other potential causes of orbital signs and symptoms.
排除标准
- •Improvement in CAS of >= 2 points and/or improvement in proptosis of >= 2 mm in the study eye between Screening and Baseline.
- •Signs of sight-threatening TED defined by optic neuropathy or severe corneal injury.
- •Patients, in the opinion of the investigator, requiring immediate or urgent medical treatment with glucocorticoids for TED.
- •Patients requiring immediate surgical ophthalmological intervention or planning corrective surgery/irradiation during the course of the study.
- •Decreased best corrected visual acuity (BCVA) as defined by a decrease in vision of 2 lines on the Snellen chart, new visual field defect or color defect within the last 6 months.
- •Any other ophthalmic and/or orbital disease or condition that might interfere with the assessment of TED.
- •Previous orbital radiotherapy.
- •Previous ophthalmological/orbital surgery for TED (e.g., orbital decompression).
- •Previous use of biological agents for the treatment of TED.
- •Previous use of systemic, non-biologic, immunomodulatory agents for the treatment of TED (e.g., mycophenolate or cyclosporine).
- •Previous exposure to secukinumab or other biologic drugs directly targeting IL-17A or the IL 17 receptor (e.g., ixekizumab, brodalumab).
- •Previous treatment with rituximab, tocilizumab or teprotumumab.
- •Previous use of systemic corticosteroids for the treatment of TED, except for oral corticosteroids with a cumulative dose equivalent to < 1 g oral prednisone/prednisolone if the corticosteroid was discontinued at least 4 weeks prior to Baseline.
- •Previous treatment with any cell-depleting therapies including but not limited to anti-cluster of differentiation 20 (CD20) or investigational agents (e.g., CAMPATH, anti CD4, anti-CD5, anti-CD3, anti-CD19).
- •Use of other investigational drugs within 5 half-lives of enrollment or within 30 days, whichever is longer.
- •Previous or ongoing use of prohibited treatments (see Appendix 16.1.1-Protocol Section 6.2.2). Respective washout periods detailed in this section needed to be adhered to.
- •History of hypersensitivity to any of the study drug constituents.
- •Other protocol defined Inclusion/Exclusion may apply.
研究组 & 干预措施
Secukinumab 300 mg
Secukinumab 300 mg subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12
干预措施: Secukinumab (Drug)
Placebo
Placebo subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12
干预措施: Placebo (Drug)
结局指标
主要结局
Plan A - Percentage of Participants Achieving Overall Response
时间窗: Baseline, Week 16
The percentage of participants achieving overall response was defined as follows: \>= 2 points reduction in clinical activity score (CAS) AND \>= 2 mm reduction in proptosis from Baseline in the study eye, provided there was no corresponding deterioration in CAS or proptosis (\>= 2 point or 2 mm increase, respectively) in the fellow eye after 16 weeks of treatment. Due to premature study discontinuation, purely descriptive analyses were performed for the primary endpoint.
Plan B - Percentage of Participants Achieving Response in Reduction of Proptosis
时间窗: Baseline, Week 16
The percentage of participants achieving response in reduction of proptosis at Week 16 was defined as follows: reduction of \>= 2 mm from Baseline in the study eye without deterioration (\>= 2 mm increase) of proptosis in the fellow eye. Due to premature study discontinuation, only Plan A was conducted (Plan B was not initiated) for the primary endpoint.
次要结局
- Plan A - Percentage of Participants Achieving Response in Reduction of Clinical Activity Score (CAS)(Baseline, Week 16)
- Plan A - Percentage of Participants Achieving Response in Reduction of Proptosis(Baseline, Week 16)
- Plan A - Percentage of Participants Achieving Response in Diplopia(Baseline, Week 16)
- Plan A - Mean Change From Baseline to Week 16 in Clinical Activity Score (CAS) in the Study Eye(Baseline, Week 2, Week 4, Week 8, Week 12, Week 16)
- Plan A - Mean Change From Baseline to Week 16 in Millimeters (mm) of Proptosis in the Study Eye(Baseline, Week 2, Week 4, Week 8, Week 12, Week 16)
- Plan A - Percentage of Participants With Improvement in EUGOGO Disease Severity(Baseline, Week 2, Week 4, Week 8, Week 12, Week 16)
- Plan A - Graves' Ophthalmopathy Quality of Life Questionnaire (GO-QOL) Score (Score 1: Visual Functioning) Over Time(Baseline, Week 2, Week 4, Week 8, Week 12, Week 16)
- Plan A - Graves' Ophthalmopathy Quality of Life Questionnaire (GO-QOL) Score (Score 2: Psychosocial Functioning) Over Time(Baseline, Week 2, Week 4, Week 8, Week 12, Week 16)
- Plan A - Number of Participants With Adverse Events(From first dose of study treatment until Week 16)
- Plan B - Percentage of Participants Achieving Response in Reduction of Clinical Activity Score (CAS)(Baseline, Week 16)
- Plan B - Percentage of Participants Achieving Overall Response(Baseline, Week 16)
- Plan B - Percentage of Participants Achieving Response in Diplopia(Baseline, Week 16)
- Plan B - Number of Participants With Adverse Events(From first dose of study treatment until Week 16)
- Plan B - Mean Change From Baseline to Week 16 in Clinical Activity Score (CAS) in the Study Eye.(Baseline, Week 16)
- Plan B - Mean Change From Baseline to Week 16 in Proptosis in the Study Eye.(Baseline, Week 16)
- Plan B - Mean Change From Baseline to Week 16 in the Graves' Ophthalmopathy Quality of Life Questionnaire (GO-QOL) Score (Score 1: Visual Functioning)(Baseline, Week 2, Week 4, Week 8, Week 12, Week 16)
- Plan B - Mean Change From Baseline to Week 16 in the Graves' Ophthalmopathy Quality of Life Questionnaire (GO-QOL) Score (Score 2: Psychosocial Functioning)(Baseline, Week 2, Week 4, Week 8, Week 12, Week 16)