Endocrine System Diseases, Exophthalmos, Eye Diseases, Graves Ophthalmopathy, Graves Orbitopathy, Hashimoto, IGF1R, Orbital Diseases, Proptosis, Thyroid Associated Ophthalmopathy, Thyroid Diseases, Thyroid Eye Disease
Conditions
Keywords
Thyroid Associated Ophthalmopathies
Brief summary
The overall objective is to study the safety, pharmacokinetics and efficacy of linsitinib (a small molecule IGF-1R inhibitor) administered orally twice daily (BID) vs. placebo, at 24 weeks in the treatment of subjects with active, moderate to severe thyroid eye disease (TED).
Interventions
DRUGLinsitinib
Study medication taken twice daily by mouth
DRUGPlacebo
Placebo taken twice daily by mouth
Sponsors
Sling Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of Graves' Disease and/or autoimmune Hashimoto's thyroiditis associated with active moderate to severe TED with a CAS ≥ 4 (on the 7- item scale) for the most severely affected eye (primary study eye) at Screening and Baseline * Confirmed active TED (not sight-threatening but has an appreciable impact on daily life, with onset (as determined by patient records) within 12 months prior to the Baseline visit and usually associated with one or more of the following: lid retraction ≥ 2 mm, moderate or severe soft tissue involvement, exophthalmos ≥ 3 mm above normal for race and gender, and/or inconstant or constant diplopia. * Subjects must be euthyroid with the participant's baseline disease under control or have mild hypo- or hyperthyroidism (defined as free thyroxine \[FT4\] and free triiodothyronine levels \[FT3\] \< 50% above or below the normal limits) at Screening. * Does not require immediate ophthalmic surgery, radiotherapy to orbits or other ophthalmological intervention at the time of Screening and is not planning for any such treatment during the course of the study.
Exclusion criteria
* Decreased best corrected visual acuity due to optic neuropathy as defined by a decrease in vision of 2 lines on the Snellen chart, new visual field defect, or color defect secondary to optic nerve involvement within the last 6 months. * Corneal decompensation unresponsive to medical management. * Previous orbital irradiation or orbital surgery. * Any glucocorticoid use (intravenous \[IV\] or oral) with a cumulative dose equivalent to \>= 1g of methylprednisolone or equivalent for the treatment of TED within 3 months of Screening. * Prior IGF-1R inhibitor therapy for any condition.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Who Are Proptosis Responders at Week 24 | 24 weeks | Proptosis response is defined as a ≥ 2 mm reduction from Baseline in the primary study eye without deterioration (≥ 2 mm increase) of proptosis in the contralateral non-study eye. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With a CAS Value of 0 or 1 at Week 24 | 24 weeks | A CAS value of 0 or 1 in primary study eye at week 24. In the event of death, the latest CAS observation will be carried forward. Missing values of CAS at week 24 are multiple imputed by using all available prior CAS measures, smoking status and treatment group |
| Percentage of Subjects Who Are Overall Responders at Week 24 | 24 weeks | Overall response is defined as a \>= 2-point reduction from baseline CAS and \>= 2 mm reduction in proptosis in the primary study eye at week 24 without deterioration (\>= 2-point increase) in CAS or deterioration (\>= 2 mm increase) of proptosis in the contralateral non-study eye. In the event of death, the latest CAS/proptosis observations will be carried forward. Missing values of CAS and proptosis measurement in the primary study eye and contralateral non-study eye at week 24 are multiple imputed by using all available prior CAS/proptosis measures, smoking status and treatment group. |
| Change From Baseline in the Graves' Ophthalmopathy Quality of Life (GO-QoL) Questionnaire Overall Score to Week 24. | 24 weeks | Change from baseline to week 24 in Graves' Ophthalmology Quality of Life (GO-QoL) overall score or to last assessed value in case of death. Missing values of GO-QoL overall score up to week 24 are multiple imputed by using all available prior GO-QoL overall score measures, smoking status and treatment group. Overall scale was measured from 0 minimum to 100 maximum (0 is worse health state and 100 is best health state) |
Countries
Canada, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants were recruited at investigative clinic sites and through central recruitment.
Pre-assignment details
A total of 138 participants were screened (all participants who signed informed consent); 90 subjects were randomized after review of inclusion exclusion criteria and 48 were considered screen failures
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 51.3 Years STANDARD_DEVIATION 12.71 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 74 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 30 | 0 / 29 |
| other Total, other adverse events | 9 / 31 | 14 / 30 | 18 / 29 |
| serious Total, serious adverse events | 1 / 31 | 0 / 30 | 2 / 29 |
Outcome results
None listed