ORBIT: A Study of the Efficacy and Safety of Secukinumab 300 mg in Patients With Thyroid Eye Disease (TED)

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04737330

Collaborator

(none)

Enrollment

Locations

Arms

38.2

Anticipated Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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. 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 is to demonstrate the efficacy and safety of secukinumab 300 mg s.c. in adults with active, moderate to severe TED.

Condition or Disease	Intervention/Treatment	Phase
Thyroid Eye Disease Graves Orbitopathy	Drug: Secukinumab Drug: Placebo	Phase 3

Detailed Description

This study will have 2 different analysis strategies and corresponding primary, secondary and exploratory objective and endpoint definitions.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

70 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

This is a two-year multi-center Phase 3 study in patients with active, moderate to severe TED, with a randomized, parallel-group, double-blind, placebo-controlled treatment period and a follow-up/retreatment period. This study consists of the following 3 periods: Screening period (Week -6 to Baseline); Double-blind treatment period (Baseline to Week 16); and Follow-up/open-label retreatment period (Week 16 up to Week 108)This is a two-year multi-center Phase 3 study in patients with active, moderate to severe TED, with a randomized, parallel-group, double-blind, placebo-controlled treatment period and a follow-up/retreatment period. This study consists of the following 3 periods: Screening period (Week -6 to Baseline); Double-blind treatment period (Baseline to Week 16); and Follow-up/open-label retreatment period (Week 16 up to Week 108)

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Nov 29, 2021

Anticipated Primary Completion Date :

Apr 27, 2023

Anticipated Study Completion Date :

Feb 5, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Investigational Arm Investigational Arm - Secukinumab 300 mg s.c. at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12	Drug: Secukinumab Secukinumab 300 mg s.c. at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12 Other Names: AIN457
Placebo Comparator: Control Arm - placebo Control arm - placebo s.c. at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12	Drug: Placebo Placebo s.c. at Baseline, Weeks 1, Week 2, Week 3, Week 4, Week 8, Week 12

Arm

Intervention/Treatment

Active Comparator: Investigational Arm

Investigational Arm - Secukinumab 300 mg s.c. at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12

Drug: Secukinumab

Secukinumab 300 mg s.c. at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12

Other Names:

AIN457

Placebo Comparator: Control Arm - placebo

Control arm - placebo s.c. at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12

Drug: Placebo

Placebo s.c. at Baseline, Weeks 1, Week 2, Week 3, Week 4, Week 8, Week 12

Outcome Measures

Primary Outcome Measures

Plan A - Proportion of participants achieving overall response [16 weeks]
Overall Response is defined as a ≥ 2-point reduction in clinical activity score (CAS) AND ≥ 2 mm reduction in proptosis from Baseline in study eye, provided there is no corresponding deterioration in CAS or proptosis (≥ 2 point or 2 mm increase, respectively) in the fellow eye
Plan B - Proportion of patients achieving response in reduction of proptosis [16 weeks]
Reduction of proptosis is defined as reduction of ≥ 2 mm from Baseline in the study eye without deterioration (≥ 2 mm increase) of proptosis in the fellow eye.

Secondary Outcome Measures

Plan A - Proportion of patients achieving response in reduction of clinical activity score (CAS) [16 weeks]
Reduction of CAS at Week 16 defined as reduction of ≥ 2 points from Baseline in the study eye without deterioration (≥ 2 point increase) of CAS in the fellow eye.
Plan A - Proportion of patients achieving response in reduction of proptosis [16 weeks]
Reduction of proptosis is defined as reduction of ≥ 2 mm from Baseline in the study eye without deterioration (≥ 2 mm increase) of proptosis in the fellow eye.
Plan A - Proportion of patients achieving response in diplopia [16 weeks]
Proportion of participants with Baseline diplopia > 0 and a reduction of ≥ 1 grade with no corresponding deterioration (≥ 1 grade worsening) in the fellow eye at Week 16.
Plan A - Mean change from Baseline to Week 16 in CAS in the study eye [16 weeks]
Average change in clinical activity score (CAS)
Plan A - Mean change from Baseline to Week 16 in proptosis in the study eye [16 weeks]
Average change in proptosis in study eye. Proptosis is protrusion of the eyeball. Exophthalmos means the same, and this term is usually used when describing proptosis due to Grave's disease
Plan A - Proportion of patients with improvement in EUGOGO disease severity [16 weeks]
TED disease severity will be assessed at the frequency indicated in the study schedule based on the signs and symptoms in accordance with the European Group of Graves' Orbitopathy (EUGOGO) guideline (Bartalena et al 2016)
Plan A - Mean change from Baseline to Week 16 in GO-QoL score [16 weeks]
Average change in the Graves' ophthalmopathy quality of life questionnaire (GO-QOL) score. The GO-QoL contains 8 questions on visual functioning and 8 questions on appearance; answers on each subscale are transformed to scores ranging from 0 (worst) to 100 (best).
Plan A - Number of participants with Adverse Events [Through study completion, up to two years]
Adverse Events (AEs) are any untoward sign or symptom that occurs during Plan A study treatment period
Plan B - Proportion of patients achieving response in reduction of CAS [16 weeks]
Reduction of CAS is defined as reduction of ≥ 2 points from Baseline in the study eye without deterioration (≥ 2 point increase) of CAS in the fellow eye
Plan B - Proportion of patients achieving overall response [16 weeks]
Proportion of participants with ≥ 2 point reduction in CAS AND ≥ 2 mm reduction in proptosis from Baseline in the study eye, provided there is no corresponding deterioration in CAS or proptosis (≥ 2 point or 2 mm increase, respectively) in the fellow eye.
Plan B - Proportion of patients achieving response in diplopia [16 weeks]
Proportion of participants with Baseline diplopia > 0 and a reduction of ≥ 1 grade with no corresponding deterioration (≥ 1 grade worsening) in the fellow eye at Week 16
Plan B - Mean change from Baseline to Week 16 in CAS in the study eye. [16 weeks]
Average change in clinical activity score (CAS)
Plan B - Mean change from Baseline to Week 16 in proptosis in the study eye. [16 weeks]
Average change in proptosis in study eye. Proptosis is protrusion of the eyeball. Exophthalmos means the same, and this term is usually used when describing proptosis due to Grave's disease
Plan B - Mean change from Baseline to Week 16 in GO-QoL score [16 weeks]
Average change in the Graves' ophthalmopathy quality of life questionnaire (GO-QOL) score. The GO-QoL contains 8 questions on visual functioning and 8 questions on appearance; answers on each subscale are transformed to scores ranging from 0 (worst) to 100 (best).
Plan B - Number of participants with Adverse Events [Through study completion, up to two years]
Adverse Events (AEs) are any untoward sign or symptom that occurs during Plan B study treatment period

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient must be able to understand and communicate with the investigator and comply with the requirements of the study and must give a written, signed and dated informed consent before any study assessment is 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 show a similar degree of proptosis, other inflammatory signs and symptoms (CAS) should be 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 should 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).

Exclusion Criteria:

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-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. Respective washout periods detailed in the study protocol have to be adhered to.
History of hypersensitivity to any of the study drug constituents. Other protocol specified exclusion criteria apply.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Novartis Investigative Site	Essen	Germany	45147
2	Novartis Investigative Site	Frankfurt	Germany	60318
3	Novartis Investigative Site	Frankfurt	Germany	60590
4	Novartis Investigative Site	Freiburg	Germany	79106
5	Novartis Investigative Site	Gottingen	Germany	37075
6	Novartis Investigative Site	Leipzig	Germany	04103
7	Novartis Investigative Site	Mainz	Germany	55131