Graves' Ophthalmopathy (GO)
Conditions
Keywords
IMVT-1401, Graves' Orbitopathy, Thyroid Eye Disease
Brief summary
The purpose of the current study is to assess the efficacy and safety/tolerability of three dose regimens of RVT-1401 in the treatment of active, moderate to severe GO participants. In addition, the study is designed to characterize the effect of RVT-1401 exposure on reduction in anti-TSHR IgG
Interventions
DRUGRVT-1401 (Administered via subcutaneous injection)
RVT-1401 is a fully human anti-neonatal Fc receptor (FcRn) monoclonal antibody.
OTHERPlacebo (Administered via subcutaneous injection)
Placebo
Sponsors
Immunovant Sciences GmbH
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
1. Male or female ≥18 years of age. 2. Clinical diagnosis of Graves' disease with hyperthyroidism associated with active, moderate to severe Graves' Ophthalmopathy (GO) with a Clinical Activity Score (CAS) ≥4 for the most severely affected eye at Screening and Baseline (on the 7-item scale). 3. Onset of active GO within 9 months of screening. 4. Moderate-to-severe active GO (not sight-threatening but has an appreciable impact on daily life), usually associated with one or more of the following: lid retraction ≥2 millimeters (mm), moderate or severe soft tissue involvement, proptosis ≥3 mm above normal for race and gender, and/or inconstant or constant diplopia. 5. Other, more specific inclusion criteria are defined in the protocol
Exclusion criteria
1. Use of any steroid (intravenous, oral, steroid eye drops) for the treatment of GO or other conditions within 3 weeks prior to Screening. Steroids cannot be initiated during the trial. Exceptions include topical and inhaled steroids which are allowed. 2. Use of rituximab, tocilizumab, or any monoclonal antibody for immunomodulation within the past 9 months prior to Baseline. 3. Total IgG level \<6 grams per liter (g/L) at Screening. 4. Absolute neutrophil count \<1500 cells per meter squared (cells/mm\^3) at Screening. 5. Participants with 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 at Screening. 6. Previous orbital irradiation or surgery for GO. 7. Other, more specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Proptosis Response at Week 13 | Baseline; Week 13 | Proptosis was assessed using an exophthalmometer. A proptosis response was defined as having at least a 2 millimeter (mm) reduction in study eye proptosis without a deterioration (at least a 2 mm increase) in the fellow eye at the same visit. The study eye was defined as the most severely affected eye at the baseline visit. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) | From Baseline up to Week 20 | AEs - any untoward medical occurrences in a participant, temporally associated with use of a medicinal product, whether or not considered related to the product. Clinically significant changes determined by the Investigator such as vital signs, ECGs, and clinical laboratory values were also reported as AEs. TEAE is defined as an AE that starts on or after the first dose of the study drug and before 30 days after the last dose of the study drug. SAEs were defined as any untoward medical occurrences that: resulted in death; were life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in disability/incapacity; were congenital anomaly/birth defects; were important medical events that may have jeopardized the participant or may have required medical or surgical intervention; invasive or malignant cancers; and development of drug dependency or drug abuse. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Least Square Mean Percent Change From Baseline in Binding Anti-thyroid-stimulating Hormone Receptor (TSHR) Antibody Levels to Week 13 | Baseline and Week 13 | Binding Anti-TSHR antibody serum levels are directly associated with GO clinical features. Baseline was the last available assessment prior to the time of the first dose unless it was specified otherwise and was identified as Day 1. A negative change from baseline in binding anti-TSHR antibody levels indicated therapeutic benefit. |
| Least Square Mean Percent Change From Baseline in Total IgG Levels | Baseline and Week 13 | Blood samples we collected to determine total IgG levels. Baseline was the last available assessment prior to the time of the first dose unless it was specified otherwise and was identified as Day 1. A negative change from baseline in the IgG levels indicated therapeutic benefit. |
| Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | Baseline and Week 13 | Blood samples were collected to determine IgG 1,2,3 and 4 levels. Baseline was the last available assessment prior to the time of the first dose unless it was specified otherwise and was identified as Day 1. A negative change from baseline in the IgG levels indicated therapeutic benefit. |
Countries
Canada, Germany, Italy, Spain, United States
Participant flow
Pre-assignment details
A total of 96 participants were screened, of which 65 participants were enrolled and randomized into the study. The total duration of the study was up to 20 weeks.
Participants by arm
| Arm | Count |
|---|---|
| RVT-1401 680 mg/Week Participants received a RVT-1401 680 milligram (mg) subcutaneous (SC) injection weekly for 12 weeks. | 18 |
| RVT-1401 340 mg/Week Participants received a RVT-1401 340 mg SC injection weekly for 12 weeks. | 19 |
| RVT-1401 255 mg/Week Participants received a RVT-1401 255 mg SC injection weekly for 12 weeks. | 10 |
| Placebo Participants received a matching placebo SC injection weekly for 12 weeks. | 18 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Overall Study | Non-compliance with study drug | 0 | 0 | 1 | 0 |
| Overall Study | Pregnancy | 1 | 0 | 0 | 0 |
| Overall Study | Study terminated by sponsor | 6 | 4 | 2 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | RVT-1401 255 mg/Week | RVT-1401 340 mg/Week | RVT-1401 680 mg/Week |
|---|---|---|---|---|---|
| Age, Continuous | 47.8 Years STANDARD_DEVIATION 10.64 | 46.1 Years STANDARD_DEVIATION 12.47 | 44.3 Years STANDARD_DEVIATION 12.61 | 52.4 Years STANDARD_DEVIATION 8.08 | 46.6 Years STANDARD_DEVIATION 9.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 62 Participants | 18 Participants | 10 Participants | 17 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Mean Clinical Activity Score (CAS) | 5.0 Units on a scale STANDARD_DEVIATION 0.94 | 5.2 Units on a scale STANDARD_DEVIATION 1.04 | 4.9 Units on a scale STANDARD_DEVIATION 0.99 | 5.1 Units on a scale STANDARD_DEVIATION 0.94 | 4.8 Units on a scale STANDARD_DEVIATION 0.86 |
| Mean Proptosis | 22.72 Millimeters (mm) STANDARD_DEVIATION 3.19 | 22.7 Millimeters (mm) STANDARD_DEVIATION 2.7 | 22.3 Millimeters (mm) STANDARD_DEVIATION 2.95 | 23.0 Millimeters (mm) STANDARD_DEVIATION 3.97 | 22.7 Millimeters (mm) STANDARD_DEVIATION 3.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 63 Participants | 18 Participants | 10 Participants | 18 Participants | 17 Participants |
| Sex: Female, Male Female | 50 Participants | 14 Participants | 8 Participants | 13 Participants | 15 Participants |
| Sex: Female, Male Male | 15 Participants | 4 Participants | 2 Participants | 6 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 19 | 0 / 10 | 0 / 18 |
| other Total, other adverse events | 16 / 18 | 16 / 19 | 8 / 10 | 16 / 18 |
| serious Total, serious adverse events | 0 / 18 | 0 / 19 | 1 / 10 | 0 / 18 |
Outcome results
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs)
AEs - any untoward medical occurrences in a participant, temporally associated with use of a medicinal product, whether or not considered related to the product. Clinically significant changes determined by the Investigator such as vital signs, ECGs, and clinical laboratory values were also reported as AEs. TEAE is defined as an AE that starts on or after the first dose of the study drug and before 30 days after the last dose of the study drug. SAEs were defined as any untoward medical occurrences that: resulted in death; were life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in disability/incapacity; were congenital anomaly/birth defects; were important medical events that may have jeopardized the participant or may have required medical or surgical intervention; invasive or malignant cancers; and development of drug dependency or drug abuse.
Time frame: From Baseline up to Week 20
Population: Safety Population: All randomized participants who received at least one dose of either RVT-1401 or placebo.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RVT-1401 680 mg/Week | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) | TEAEs | 16 Participants |
| RVT-1401 680 mg/Week | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| RVT-1401 340 mg/Week | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| RVT-1401 340 mg/Week | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) | TEAEs | 16 Participants |
| RVT-1401 255 mg/Week | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) | TEAEs | 8 Participants |
| RVT-1401 255 mg/Week | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) | TEAEs | 16 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) | SAEs | 0 Participants |
Primary
Percentage of Participants With Proptosis Response at Week 13
Proptosis was assessed using an exophthalmometer. A proptosis response was defined as having at least a 2 millimeter (mm) reduction in study eye proptosis without a deterioration (at least a 2 mm increase) in the fellow eye at the same visit. The study eye was defined as the most severely affected eye at the baseline visit.
Time frame: Baseline; Week 13
Population: Intent-to-Treat (ITT) Population: All randomized participants who received at least one dose of RVT-1401 or placebo and had 1 post-baseline visit. Participants with proptosis assessment at Week 13 were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RVT-1401 680 mg/Week | Percentage of Participants With Proptosis Response at Week 13 | 30.0 Percentage of participants |
| RVT-1401 340 mg/Week | Percentage of Participants With Proptosis Response at Week 13 | 30.8 Percentage of participants |
| RVT-1401 255 mg/Week | Percentage of Participants With Proptosis Response at Week 13 | 0 Percentage of participants |
| Placebo | Percentage of Participants With Proptosis Response at Week 13 | 8.3 Percentage of participants |
p-value: =0.199395% CI: [-11.3, 54.1]Cochran-Mantel-Haenszel
p-value: =0.101695% CI: [-4.8, 53.2]Cochran-Mantel-Haenszel
p-value: =0.296395% CI: [-24, 7.3]Cochran-Mantel-Haenszel
Secondary
Least Square Mean Percent Change From Baseline in Binding Anti-thyroid-stimulating Hormone Receptor (TSHR) Antibody Levels to Week 13
Binding Anti-TSHR antibody serum levels are directly associated with GO clinical features. Baseline was the last available assessment prior to the time of the first dose unless it was specified otherwise and was identified as Day 1. A negative change from baseline in binding anti-TSHR antibody levels indicated therapeutic benefit.
Time frame: Baseline and Week 13
Population: ITT Population. Participants with binding anti-TSHR serum assessments at Week 13 were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| RVT-1401 680 mg/Week | Least Square Mean Percent Change From Baseline in Binding Anti-thyroid-stimulating Hormone Receptor (TSHR) Antibody Levels to Week 13 | -64.605 Percent change |
| RVT-1401 340 mg/Week | Least Square Mean Percent Change From Baseline in Binding Anti-thyroid-stimulating Hormone Receptor (TSHR) Antibody Levels to Week 13 | -69.663 Percent change |
| RVT-1401 255 mg/Week | Least Square Mean Percent Change From Baseline in Binding Anti-thyroid-stimulating Hormone Receptor (TSHR) Antibody Levels to Week 13 | -41.843 Percent change |
| Placebo | Least Square Mean Percent Change From Baseline in Binding Anti-thyroid-stimulating Hormone Receptor (TSHR) Antibody Levels to Week 13 | -4.520 Percent change |
p-value: <0.00195% CI: [-88.857, -31.313]ANCOVA
p-value: <0.00195% CI: [-91.927, -38.358]ANCOVA
p-value: =0.028495% CI: [-70.455, -4.19]ANCOVA
Secondary
Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4
Blood samples were collected to determine IgG 1,2,3 and 4 levels. Baseline was the last available assessment prior to the time of the first dose unless it was specified otherwise and was identified as Day 1. A negative change from baseline in the IgG levels indicated therapeutic benefit.
Time frame: Baseline and Week 13
Population: ITT Population. Participants with evaluable data were included for the analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RVT-1401 680 mg/Week | Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | IgG1 | -82.040 Percent change |
| RVT-1401 680 mg/Week | Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | IgG2 | -75.346 Percent change |
| RVT-1401 680 mg/Week | Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | IgG3 | -88.260 Percent change |
| RVT-1401 680 mg/Week | Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | IgG4 | -68.559 Percent change |
| RVT-1401 340 mg/Week | Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | IgG3 | -65.211 Percent change |
| RVT-1401 340 mg/Week | Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | IgG2 | -53.678 Percent change |
| RVT-1401 340 mg/Week | Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | IgG4 | -55.391 Percent change |
| RVT-1401 340 mg/Week | Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | IgG1 | -68.141 Percent change |
| RVT-1401 255 mg/Week | Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | IgG3 | -66.182 Percent change |
| RVT-1401 255 mg/Week | Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | IgG4 | -52.916 Percent change |
| RVT-1401 255 mg/Week | Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | IgG1 | -67.784 Percent change |
| RVT-1401 255 mg/Week | Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | IgG2 | -53.879 Percent change |
| Placebo | Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | IgG4 | 0.163 Percent change |
| Placebo | Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | IgG2 | -0.481 Percent change |
| Placebo | Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | IgG3 | 0.503 Percent change |
| Placebo | Least Square Mean Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 | IgG1 | -0.550 Percent change |
Comparison: IgG1p-value: <0.00195% CI: [-93.203, -69.777]ANCOVA
Comparison: IgG1p-value: <0.00195% CI: [-78.562, -56.62]ANCOVA
Comparison: IgG1p-value: <0.00195% CI: [-81.073, -53.394]ANCOVA
Comparison: IgG2p-value: <0.00195% CI: [-86.898, -62.832]ANCOVA
Comparison: IgG2p-value: <0.00195% CI: [-64.799, -41.596]ANCOVA
Comparison: IgG2p-value: <0.00195% CI: [-67.552, -39.245]ANCOVA
Comparison: IgG3p-value: <0.00195% CI: [-103.039, -74.489]ANCOVA
Comparison: IgG3p-value: <0.00195% CI: [-78.742, -52.686]ANCOVA
Comparison: IgG3p-value: <0.00195% CI: [-83.157, -50.214]ANCOVA
Comparison: IgG4p-value: <0.00195% CI: [-80.877, -56.568]ANCOVA
Comparison: IgG4p-value: <0.00195% CI: [-67.182, -43.926]ANCOVA
Comparison: IgG4p-value: <0.00195% CI: [-67.948, -38.21]ANCOVA
Secondary
Least Square Mean Percent Change From Baseline in Total IgG Levels
Blood samples we collected to determine total IgG levels. Baseline was the last available assessment prior to the time of the first dose unless it was specified otherwise and was identified as Day 1. A negative change from baseline in the IgG levels indicated therapeutic benefit.
Time frame: Baseline and Week 13
Population: ITT Population: Participants with evaluable data were included for the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| RVT-1401 680 mg/Week | Least Square Mean Percent Change From Baseline in Total IgG Levels | -79.101 Percent change |
| RVT-1401 340 mg/Week | Least Square Mean Percent Change From Baseline in Total IgG Levels | -65.103 Percent change |
| RVT-1401 255 mg/Week | Least Square Mean Percent Change From Baseline in Total IgG Levels | -57.934 Percent change |
| Placebo | Least Square Mean Percent Change From Baseline in Total IgG Levels | -6.098 Percent change |
Comparison: Week 13p-value: <0.00195% CI: [-82.309, -63.697]ANCOVA
Comparison: Week 13p-value: <0.00195% CI: [-67.821, -50.19]ANCOVA
Comparison: Week 13p-value: <0.00195% CI: [-62.66, -41.012]ANCOVA