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

Primary Purpose

Thyroid Eye Disease, Graves Orbitopathy

Status
Terminated
Phase
Phase 3
Locations
Germany
Study Type
Interventional
Intervention
Secukinumab
Placebo
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Thyroid Eye Disease focused on measuring TED, Bulging eyes, Exophthalmos

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Investigational Arm

Control Arm - placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

Plan A - Proportion of participants achieving overall response
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
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)
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
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
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
Average change in clinical activity score (CAS)
Plan A - Mean change from Baseline to Week 16 in proptosis in the study eye
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
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
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
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
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
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
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.
Average change in clinical activity score (CAS)
Plan B - Mean change from Baseline to Week 16 in proptosis in the study eye.
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
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
Adverse Events (AEs) are any untoward sign or symptom that occurs during Plan B study treatment period

Full Information

First Posted
November 20, 2020
Last Updated
October 5, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT04737330
Brief Title
A Study of the Efficacy and Safety of Secukinumab 300 mg in Patients With Thyroid Eye Disease (TED)
Acronym
ORBIT
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Terminated
Why Stopped
Analysis of blinded patient data showed a very low probability of the study meeting the primary efficacy endpoints. No safety concerns were identified
Study Start Date
November 29, 2021 (Actual)
Primary Completion Date
May 16, 2023 (Actual)
Study Completion Date
May 16, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. 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 was to demonstrate the efficacy and safety of secukinumab 300 mg s.c. in adults with active, moderate to severe TED.
Detailed Description
This study had 2 different analysis strategies and corresponding primary and secondary objectives and endpoint definitions.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Thyroid Eye Disease, Graves Orbitopathy
Keywords
TED, Bulging eyes, Exophthalmos

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
This was 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 consisted 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
ParticipantInvestigator
Allocation
Randomized
Enrollment
28 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Investigational Arm
Arm Type
Active Comparator
Arm Description
Investigational Arm - Secukinumab 300 mg s.c. at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12
Arm Title
Control Arm - placebo
Arm Type
Placebo Comparator
Arm Description
Control arm - placebo s.c. at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12
Intervention Type
Drug
Intervention Name(s)
Secukinumab
Other Intervention Name(s)
AIN457
Intervention Description
Secukinumab 300 mg s.c. at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo s.c. at Baseline, Weeks 1, Week 2, Week 3, Week 4, Week 8, Week 12
Primary Outcome Measure Information:
Title
Plan A - Proportion of participants achieving overall response
Description
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
Time Frame
16 weeks
Title
Plan B - Proportion of patients achieving response in reduction of proptosis
Description
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.
Time Frame
16 weeks
Secondary Outcome Measure Information:
Title
Plan A - Proportion of patients achieving response in reduction of clinical activity score (CAS)
Description
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.
Time Frame
16 weeks
Title
Plan A - Proportion of patients achieving response in reduction of proptosis
Description
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.
Time Frame
16 weeks
Title
Plan A - Proportion of patients achieving response in diplopia
Description
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.
Time Frame
16 weeks
Title
Plan A - Mean change from Baseline to Week 16 in CAS in the study eye
Description
Average change in clinical activity score (CAS)
Time Frame
16 weeks
Title
Plan A - Mean change from Baseline to Week 16 in proptosis in the study eye
Description
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
Time Frame
16 weeks
Title
Plan A - Proportion of patients with improvement in EUGOGO disease severity
Description
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)
Time Frame
16 weeks
Title
Plan A - Mean change from Baseline to Week 16 in GO-QoL score
Description
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).
Time Frame
16 weeks
Title
Plan A - Number of participants with Adverse Events
Description
Adverse Events (AEs) are any untoward sign or symptom that occurs during Plan A study treatment period
Time Frame
Through study completion, up to two years
Title
Plan B - Proportion of patients achieving response in reduction of CAS
Description
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
Time Frame
16 weeks
Title
Plan B - Proportion of patients achieving overall response
Description
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.
Time Frame
16 weeks
Title
Plan B - Proportion of patients achieving response in diplopia
Description
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
Time Frame
16 weeks
Title
Plan B - Mean change from Baseline to Week 16 in CAS in the study eye.
Description
Average change in clinical activity score (CAS)
Time Frame
16 weeks
Title
Plan B - Mean change from Baseline to Week 16 in proptosis in the study eye.
Description
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
Time Frame
16 weeks
Title
Plan B - Mean change from Baseline to Week 16 in GO-QoL score
Description
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).
Time Frame
16 weeks
Title
Plan B - Number of participants with Adverse Events
Description
Adverse Events (AEs) are any untoward sign or symptom that occurs during Plan B study treatment period
Time Frame
Through study completion, up to two years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Director Novartis Pharmaceuticals
Organizational Affiliation
Sponsor GmbH
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Essen
ZIP/Postal Code
45147
Country
Germany
Facility Name
Novartis Investigative Site
City
Frankfurt
ZIP/Postal Code
60318
Country
Germany
Facility Name
Novartis Investigative Site
City
Freiburg
ZIP/Postal Code
79106
Country
Germany
Facility Name
Novartis Investigative Site
City
Gottingen
ZIP/Postal Code
37075
Country
Germany
Facility Name
Novartis Investigative Site
City
Mainz
ZIP/Postal Code
55131
Country
Germany

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Learn more about this trial

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

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