Thyroid Eye Disease
Conditions
Keywords
Thyroid Eye Disease, Thyroid-Associated Ophthalmopathy, Dysthyroid Ophthalmopathy, Graves Eye Disease, Graves Orbitopathy, Myopathic Ophthalmopathy, Congestive Ophthalmopathy, Edematous Ophthalmopathy, Infiltrative Ophthalmopathy, Thyroid-Associated Orbitopathy, Graves Disease
Brief summary
The investigational drug, veligrotug (VRDN-001), is a monoclonal antibody that inhibits the activity of a cell surface receptor called insulin-like growth factor-1 receptor (IGF-1R). Inhibition of IGF-1R may help to reduce the inflammation and associated tissue swelling that occurs in participants with thyroid eye disease (TED). The primary objective of this clinical trial is to establish the safety, tolerability, and efficacy of veligrotug, and the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of veligrotug in active TED participants who received 10 milligrams (mg)/kilogram (kg).
Interventions
DRUGVeligrotug
5 IV Infusions of veligrotug 10 mg/kg
DRUGPlacebo
5 IV Infusions of veligrotug matched placebo
Sponsors
Viridian Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria for Active TED Participants (THRIVE): * Must have moderate to severe active TED with documented evidence of ocular symptoms or signs that began within 15 months prior to screening * Must have Clinical Activity Score (CAS) of ≥ 3 on the 7-item scale for the study eye * Must agree to use highly effective contraception as specified in the protocol * Female TED participants must have a negative serum pregnancy test at screening Key
Exclusion criteria
for Active TED Participants (THRIVE): * Must not have received prior treatment with another anti-IGF-1R therapy or any investigational agent for TED * Must not have used systemic corticosteroids or selenium within 2 weeks prior to Day 1 * Must not have received rituximab, tocilizumab or other immunosuppressive agents or any other therapy for TED within 8 weeks prior to Day 1 * Must not have received an investigational agent for any condition within 8 weeks prior to Day 1 * Must not have a pre-existing ophthalmic condition in the study eye that in the opinion of the Investigator would confound interpretation of the study results * Must not have had previous orbital irradiation or surgery for TED in the study eye * Must not have a history of inflammatory bowel disease * Must not have a history of or screening audiometry assessment of clinically significant (as determined by investigator) ear pathology, relevant ear surgery, or hearing loss * Female TED participants must not be pregnant or lactating Note: Prior thyroidectomy, radioactive iodine (RAI) treatment, or orbital decompression surgery limited to bone only are NOT exclusions.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proptosis Responder Rate (PRR) in the Study Eye As Measured by Exophthalmometer | Baseline to Week 15 | Proptosis responder in the study eye was defined as a reduction of proptosis of ≥2 millimeters (mm) from baseline in the study eye (without a corresponding increase of ≥2 mm in the fellow eye) as measured by exophthalmometer. Missing data were imputed with the Multiple Imputation method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Proptosis in the Study Eye As Measured by Exophthalmometer | Baseline, Week 15 | Proptosis was defined as distance between the lateral orbital rim and the most anterior position of the cornea in mm, measured using an exophthalmometer. Missing data were imputed with the Multiple Imputation method. |
| PRR in the Most Proptotic Eye As Measured by Magnetic Resonance Imaging (MRI)/Computed Tomography (CT) | Week 15 | Proptosis responder in the most proptotic eye by MRI/CT was defined as a reduction of proptosis of ≥2 mm from baseline in the most proptotic eye by MRI/CT (without a corresponding increase of ≥2 mm in the other eye) as measured by MRI/CT. Missing data were imputed using the Exophthalmometer Imputation method, as applicable. |
| Change From Baseline in Proptosis in the Most Proptotic Eye As Measured by MRI/CT | Baseline, Week 15 | Measurement of proptosis conducted by the central imaging reading center using MRI/CT of the orbits acquired without contrast. Measurements were conducted by 2 independent readers with adjudication if the difference between the 2 primary readers in proptosis measurement exceeded 5% (calculated as the difference divided by the larger measurement). The average of 2 (or 3 if adjudicated) measurements were used for analyses. Missing data were imputed using the Exophthalmometer Imputation method, as applicable. |
| Change From Baseline in CAS in the Study Eye | Baseline, Week 15 | The CAS was based on 7 components: spontaneous retrobulbar pain, pain on attempted eye movements (upward, side to-side, and downward gazes), conjunctival redness, redness of the eyelids, chemosis, swelling of the caruncle or plica and swelling of the eyelids. Each component was scored as present or absent (scored as 1 or 0, respectively), and the CAS was given as the sum of the scores (range, 0 to 7, with higher scores indicating greater level of inflammation). Missing data were imputed with the Multiple Imputation method. |
| Overall Responder Rate (ORR) Comprising of PRR and Clinical Activity Responder Rate in the Study Eye | Baseline to Week 15 | ORR in the study eye was comprised of PRR in the study eye (reduction of proptosis of ≥ 2 mm from baseline \[without a corresponding increase of ≥ 2 mm in the fellow eye\]) and clinical activity responder in the study eye (reduction in clinical activity score \[CAS\] ≥ 2 points from baseline \[without a corresponding increase of ≥ 2 points in the fellow eye\]). CAS ranged from 0 to 7, with higher scores indicating greater level of inflammation. Proptosis (distance between the lateral orbital rim and the most anterior position of the cornea in mm) was measured using an exophthalmometer. Missing data were imputed with Multiple Imputation method. |
| Clinical Activity Responder Rate in the Study Eye | Week 15 | Clinical activity responder rate in the study eye was defined as a reduction in CAS ≥2 points from baseline in the study eye (without a corresponding increase of ≥2 points in the fellow eye). Missing data were imputed with the Multiple Imputation method. |
| Diplopia Responder Rate | Week 15 | Diplopia responder was defined as reduction in Gorman subjective diplopia score of ≥1 from baseline for participants with baseline Gorman subjective diplopia score \>0. Gorman subjective diplopia score (range, 0 to 3) includes 4 categories: no diplopia (absent, scored as 0), diplopia in the primary position of gaze when the participant is tired or awakening (intermittent, scored as 1), diplopia at extremes of gaze (inconstant, scored as 2), and continuous diplopia in the primary or reading position (constant, scored as 3). Missing data were imputed with the Multiple Imputation method. |
| Diplopia Resolution Rate | Week 15 | Diplopia resolution was defined as reduction in Gorman subjective diplopia score to 0 from baseline for participants with baseline Gorman subjective diplopia score \>0. Gorman subjective diplopia score (range, 0 to 3) includes 4 categories: no diplopia (absent, scored as 0), diplopia in the primary position of gaze when the participant is tired or awakening (intermittent, scored as 1), diplopia at extremes of gaze (inconstant, scored as 2), and continuous diplopia in the primary or reading position (constant, scored as 3). Missing data were imputed with the Multiple Imputation method. |
| Percentage of Participants With a CAS of 0 or 1 in the Study Eye | Week 15 | The CAS was based on 7 components: spontaneous retrobulbar pain, pain on attempted eye movements (upward, side to-side, and downward gazes), conjunctival redness, redness of the eyelids, chemosis, swelling of the caruncle or plica and swelling of the eyelids. Each component was scored as present or absent (scored as 1 or 0, respectively), and the CAS was given as the sum of the scores (range, 0 to 7, with higher scores indicating greater level of inflammation). Missing data were imputed with the Multiple Imputation method. |
Countries
Australia, France, Germany, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
As prespecified, data were collected and reported for the participants. Therefore, the 'Ns' reported below = number of participants analyzed regardless of which eye was evaluated. The primary and secondary efficacy analyses and safety analysis were measured in the pre-specified study eye per individual participant.
Pre-assignment details
Ocular assessments were performed in both eyes at baseline. Study eye was the most proptotic eye by exophthalmometer at baseline. If both eyes were equally proptotic, then the eye with the worse visual acuity (VA) was designated as the study eye. If proptosis and VA were equal in both eyes, then the right eye was designated as the study eye.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 48.9 years STANDARD_DEVIATION 12.42 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 29 Participants |
| Race/Ethnicity, Customized Race Asian | 9 Participants |
| Race/Ethnicity, Customized Race Black or African American | 3 Participants |
| Race/Ethnicity, Customized Race Missing | 11 Participants |
| Race/Ethnicity, Customized Race Not Reported | 1 Participants |
| Race/Ethnicity, Customized Race Other | 15 Participants |
| Race/Ethnicity, Customized Race White | 70 Participants |
| Sex: Female, Male Female | 31 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 38 |
| other Total, other adverse events | 63 / 75 | 19 / 38 |
| serious Total, serious adverse events | 7 / 75 | 0 / 38 |
Outcome results
None listed