Graves' Ophthalmopathy
Conditions
Keywords
IMVT-1401, Graves' Orbitopathy, Thyroid Eye Disease
Brief summary
The purpose of this study was to evaluate safety, tolerability, and pharmacodynamic parameters of RVT-1401 in graves' ophthalmopathy (GO) patients.
Interventions
DRUGRVT-1401
RVT-1401 is a fully human anti-neonatal Fc receptor (FcRn) monoclonal antibody.
Sponsors
Immunovant Sciences GmbH
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open label study
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 GO with a Clinical Activity Score (CAS) ≥ 4 for the most severely affected eye at Screening (on the 7-item scale) and Baseline (on the 10-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 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 \[IV\] or oral) with a cumulative dose equivalent to ≥ 1 g of methylprednisolone for the treatment of GO within 3 weeks prior to Screening. 2. Use of rituximab, tocilizumab, or any monoclonal antibody for immunomodulation within the past 9 months prior to Baseline. 3. Total IgG level \< 6g/L at Screening. 4. Absolute neutrophil count \<1500 cells/mm3 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 |
|---|---|---|
| Mean Change From Baseline in Levels of Anti-thyroid-stimulating Hormone Receptor (Anti-TSHR) Antibodies at Week 7 | Baseline; Week 7 | The serum levels of anti-TSHR antibodies were determined. Change from Baseline was calculated as the Week 7 value minus the Baseline value. A negative change from Baseline represents clinical improvement. |
| Number of Participants With Any Treatment-emergent Adverse Event (TEAE), Serious AE (SAE), Treatment-related Adverse Event (AE), and Death During the 6-week Treatment Period | from Baseline up to Week 6 | AEs were defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAEs were defined as AEs that either started on or after the date of the first dose of study drug and on or before the date of the last dose of study drug + 42 days, or had no recorded start date and the stop date was in between the date of the first dose and the last dose of study drug + 42 days. SAEs were defined as any untoward medical occurrence that, at any dose: resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event that may have jeopardized the participant or may have required medical or surgical intervention to prevent one of the other outcomes listed in the definition. |
| Number of Participants With Clinically Significant Findings Related to Vital Signs | up to Week 18 | Clinical significance was determined by the investigator. |
| Number of Participants With a Change From Normal Physical Examination Findings at Baseline to Abnormal Physical Examination Findings at the End of the Study | up to Week 18 | Abnormality was determined by the investigator. |
| Number of Participants With Clinically Significant Findings Related to Electrocardiograms (ECGs) | up to Week 18 | Clinical significance was determined by the investigator. |
| Percent Change From Baseline in Total Immunoglobulin G (IgG), IgG1, IgG2, IgG3, and IgG4 Levels | Baseline; Week 7; Week 6 and 7 combined | The serum levels of total IgG and IgG subclasses (1-4) were determined. Percent change from Baseline was calculated as the mean value at the specified time frame (Week 7, Week 6 and 7 combined) minus the Baseline value, divided by the Baseline value x 100. A negative percent change from Baseline represents clinical improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Proptosis in the Study Eye and Non-study Eye at Week 7 | Baseline; Week 7 | The study eye was defined as the most severely affected eye at the Baseline visit. In the event that both eyes were affected the same, the right eye was deemed as the study eye. Participants who did not achieve a proptosis response were censored at the date of their last proptosis measurement that occurred in both eyes. Change from Baseline was calculated as the Week 7 value minus the Baseline value. A negative change from Baseline represents clinical improvement. |
| Number of Participants With an Overall Proptosis Response | Up to Week 18 | Proptosis responders were defined as participants with a ≥2 mm reduction in study eye without deterioration (≥2 mm increase) in the fellow eye. Participants who did not achieve a proptosis response were censored at the date of their last proptosis measurement that occurred in both eyes. |
| Area Under the Concentration-time Curve From Time 0 to 168 Hours (AUC0-168h) of RVT-1401 | Pre-dose; Day 1, Day 3, Day 5, Day 8, Day 15, Day 22, Day 29, Day 36, Day 38, Day 40, Week 7, Week 8 | Pharmacokinetic (PK) parameters were not estimated because the sparse PK sampling schedule did not allow for accurate estimates of these parameters. |
| Maximum Concentration (Cmax) of RVT-1401 | Pre-dose; Day 1, Day 3, Day 5, Day 8, Day 15, Day 22, Day 29, Day 36, Day 38, Day 40, Week 7, Week 8 | PK parameters were not estimated because the sparse PK sampling schedule did not allow for accurate estimates of these parameters. |
| Serum Concentration at the End of the Dosing Interval (Ctrough) of RVT-1401 | Week 2, Week 3, Week 4, Week 5, Week 6 Day 36, and Week 7 | — |
| Number of Participants With Anti-RVT-1401 Antibody and Confirmed Anti-RVT-1401 Antibody at Week 7 | Week 7 | The serum levels of anti-RVT-1401 antibodies were determined. In the initial analysis the samples with responses equal to or above the plate-specific cut-point were identified as potentially positive while those below the cut-point were considered negative. These potentially positive samples were reanalyzed in confirmatory assay. Samples with percent inhibition greater than or equal to the confirmatory cut-point were considered confirmed positive and those below were considered negative. |
Countries
Canada
Participant flow
Pre-assignment details
A total of 8 participants were screened for the study. Only 7 participants were randomized; 1 participant failed to meet the screening criteria.
Participants by arm
| Arm | Count |
|---|---|
| RVT-1401 Participants received a RVT-1401 680 milligram (mg) subcutaneous (SC) injection weekly for 2 weeks, followed by a 340 mg SC injection weekly for 4 weeks. | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Participant Moved | 1 |
| Overall Study | Unable to Come to Site Due to COVID 19 | 1 |
Baseline characteristics
| Characteristic | RVT-1401 |
|---|---|
| Age, Continuous | 56.7 Years STANDARD_DEVIATION 14.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 3 Participants |
| Total Immunoglobulin G (IgG), IgG1, IgG2, IgG3, and IgG4 Levels IgG | 11.29 grams per liter (g/L) STANDARD_DEVIATION 1.71 |
| Total Immunoglobulin G (IgG), IgG1, IgG2, IgG3, and IgG4 Levels IgG1 | 5.11 grams per liter (g/L) STANDARD_DEVIATION 1.11 |
| Total Immunoglobulin G (IgG), IgG1, IgG2, IgG3, and IgG4 Levels IgG2 | 3.74 grams per liter (g/L) STANDARD_DEVIATION 0.96 |
| Total Immunoglobulin G (IgG), IgG1, IgG2, IgG3, and IgG4 Levels IgG3 | 0.61 grams per liter (g/L) STANDARD_DEVIATION 0.35 |
| Total Immunoglobulin G (IgG), IgG1, IgG2, IgG3, and IgG4 Levels IgG4 | 0.49 grams per liter (g/L) STANDARD_DEVIATION 0.34 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 7 |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 0 / 7 |
Outcome results
Primary
Mean Change From Baseline in Levels of Anti-thyroid-stimulating Hormone Receptor (Anti-TSHR) Antibodies at Week 7
The serum levels of anti-TSHR antibodies were determined. Change from Baseline was calculated as the Week 7 value minus the Baseline value. A negative change from Baseline represents clinical improvement.
Time frame: Baseline; Week 7
Population: PD Population. Only participants with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RVT-1401 | Mean Change From Baseline in Levels of Anti-thyroid-stimulating Hormone Receptor (Anti-TSHR) Antibodies at Week 7 | Baseline | 19.72 international units/milliliter (IU/mL) | Standard Deviation 15.073 |
| RVT-1401 | Mean Change From Baseline in Levels of Anti-thyroid-stimulating Hormone Receptor (Anti-TSHR) Antibodies at Week 7 | Week 7 | -10.59 international units/milliliter (IU/mL) | Standard Deviation 9.827 |
Primary
Number of Participants With a Change From Normal Physical Examination Findings at Baseline to Abnormal Physical Examination Findings at the End of the Study
Abnormality was determined by the investigator.
Time frame: up to Week 18
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RVT-1401 | Number of Participants With a Change From Normal Physical Examination Findings at Baseline to Abnormal Physical Examination Findings at the End of the Study | 0 Participants |
Primary
Number of Participants With Any Treatment-emergent Adverse Event (TEAE), Serious AE (SAE), Treatment-related Adverse Event (AE), and Death During the 6-week Treatment Period
AEs were defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAEs were defined as AEs that either started on or after the date of the first dose of study drug and on or before the date of the last dose of study drug + 42 days, or had no recorded start date and the stop date was in between the date of the first dose and the last dose of study drug + 42 days. SAEs were defined as any untoward medical occurrence that, at any dose: resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event that may have jeopardized the participant or may have required medical or surgical intervention to prevent one of the other outcomes listed in the definition.
Time frame: from Baseline up to Week 6
Population: Safety Population: all participants who received at least one dose of study treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RVT-1401 | Number of Participants With Any Treatment-emergent Adverse Event (TEAE), Serious AE (SAE), Treatment-related Adverse Event (AE), and Death During the 6-week Treatment Period | TEAEs | 7 Participants |
| RVT-1401 | Number of Participants With Any Treatment-emergent Adverse Event (TEAE), Serious AE (SAE), Treatment-related Adverse Event (AE), and Death During the 6-week Treatment Period | SAEs | 0 Participants |
| RVT-1401 | Number of Participants With Any Treatment-emergent Adverse Event (TEAE), Serious AE (SAE), Treatment-related Adverse Event (AE), and Death During the 6-week Treatment Period | Treatment-related AEs | 6 Participants |
| RVT-1401 | Number of Participants With Any Treatment-emergent Adverse Event (TEAE), Serious AE (SAE), Treatment-related Adverse Event (AE), and Death During the 6-week Treatment Period | Deaths | 0 Participants |
Primary
Number of Participants With Clinically Significant Findings Related to Electrocardiograms (ECGs)
Clinical significance was determined by the investigator.
Time frame: up to Week 18
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RVT-1401 | Number of Participants With Clinically Significant Findings Related to Electrocardiograms (ECGs) | 0 Participants |
Primary
Number of Participants With Clinically Significant Findings Related to Vital Signs
Clinical significance was determined by the investigator.
Time frame: up to Week 18
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RVT-1401 | Number of Participants With Clinically Significant Findings Related to Vital Signs | 0 Participants |
Primary
Percent Change From Baseline in Total Immunoglobulin G (IgG), IgG1, IgG2, IgG3, and IgG4 Levels
The serum levels of total IgG and IgG subclasses (1-4) were determined. Percent change from Baseline was calculated as the mean value at the specified time frame (Week 7, Week 6 and 7 combined) minus the Baseline value, divided by the Baseline value x 100. A negative percent change from Baseline represents clinical improvement.
Time frame: Baseline; Week 7; Week 6 and 7 combined
Population: Pharmacodynamic (PD) Population: all participants who had a Baseline PD measurement and at least 1 post-Baseline PD measurement and received at least 1 dose of study drug. Only participants with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RVT-1401 | Percent Change From Baseline in Total Immunoglobulin G (IgG), IgG1, IgG2, IgG3, and IgG4 Levels | Total IgG (Week 6 and 7 combined) | -65.00 Percent change | Standard Deviation 10.78 |
| RVT-1401 | Percent Change From Baseline in Total Immunoglobulin G (IgG), IgG1, IgG2, IgG3, and IgG4 Levels | Total IgG (Week 7) | -64.83 Percent change | Standard Deviation 17.65 |
| RVT-1401 | Percent Change From Baseline in Total Immunoglobulin G (IgG), IgG1, IgG2, IgG3, and IgG4 Levels | IgG1 (Week 7) | -67.16 Percent change | Standard Deviation 18.89 |
| RVT-1401 | Percent Change From Baseline in Total Immunoglobulin G (IgG), IgG1, IgG2, IgG3, and IgG4 Levels | IgG2 (Week 7) | -56.91 Percent change | Standard Deviation 24.66 |
| RVT-1401 | Percent Change From Baseline in Total Immunoglobulin G (IgG), IgG1, IgG2, IgG3, and IgG4 Levels | IgG3 (Week 7) | -70.05 Percent change | Standard Deviation 21.71 |
| RVT-1401 | Percent Change From Baseline in Total Immunoglobulin G (IgG), IgG1, IgG2, IgG3, and IgG4 Levels | IgG4 (Week 7) | -61.28 Percent change | Standard Deviation 16.25 |
Secondary
Area Under the Concentration-time Curve From Time 0 to 168 Hours (AUC0-168h) of RVT-1401
Pharmacokinetic (PK) parameters were not estimated because the sparse PK sampling schedule did not allow for accurate estimates of these parameters.
Time frame: Pre-dose; Day 1, Day 3, Day 5, Day 8, Day 15, Day 22, Day 29, Day 36, Day 38, Day 40, Week 7, Week 8
Population: PK Population: all participants who received at least one dose of study drug and had at least 1 post-dose PK sample assayed for RVT-1401. Only 2 non-Ctrough time point samples were collected after the first dose (on Day 3 and Day 5) and last dose (on Day 38 and Day 40). As a result, having 2 sparse time point samples did not allow to accurately estimate AUC0-168h parameter.
Secondary
Maximum Concentration (Cmax) of RVT-1401
PK parameters were not estimated because the sparse PK sampling schedule did not allow for accurate estimates of these parameters.
Time frame: Pre-dose; Day 1, Day 3, Day 5, Day 8, Day 15, Day 22, Day 29, Day 36, Day 38, Day 40, Week 7, Week 8
Population: PK Population. PK parameters were not estimated because the sparse PK sampling schedule did not allow for accurate estimates of these parameters. Only 2 non-Ctrough time point samples were collected after the first dose (on Day 3 and Day 5) and last dose (on Day 38 and Day 40). As a result, having 2 sparse time point samples did not allow to accurately estimate Cmax parameter.
Secondary
Mean Change From Baseline in Proptosis in the Study Eye and Non-study Eye at Week 7
The study eye was defined as the most severely affected eye at the Baseline visit. In the event that both eyes were affected the same, the right eye was deemed as the study eye. Participants who did not achieve a proptosis response were censored at the date of their last proptosis measurement that occurred in both eyes. Change from Baseline was calculated as the Week 7 value minus the Baseline value. A negative change from Baseline represents clinical improvement.
Time frame: Baseline; Week 7
Population: PD Population. Only participants with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RVT-1401 | Mean Change From Baseline in Proptosis in the Study Eye and Non-study Eye at Week 7 | Baseline, study eye | 23.1 millimeter (mm) | Standard Deviation 3.34 |
| RVT-1401 | Mean Change From Baseline in Proptosis in the Study Eye and Non-study Eye at Week 7 | Change from Baseline to Week 7, study eye | -1.25 millimeter (mm) | Standard Deviation 1.5 |
| RVT-1401 | Mean Change From Baseline in Proptosis in the Study Eye and Non-study Eye at Week 7 | Baseline, non-study eye | 21.9 millimeter (mm) | Standard Deviation 3.63 |
| RVT-1401 | Mean Change From Baseline in Proptosis in the Study Eye and Non-study Eye at Week 7 | Change from Baseline to Week 7, non-study eye | -1.25 millimeter (mm) | Standard Deviation 0.96 |
Secondary
Number of Participants With an Overall Proptosis Response
Proptosis responders were defined as participants with a ≥2 mm reduction in study eye without deterioration (≥2 mm increase) in the fellow eye. Participants who did not achieve a proptosis response were censored at the date of their last proptosis measurement that occurred in both eyes.
Time frame: Up to Week 18
Population: PD Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RVT-1401 | Number of Participants With an Overall Proptosis Response | 3 Participants |
Secondary
Number of Participants With Anti-RVT-1401 Antibody and Confirmed Anti-RVT-1401 Antibody at Week 7
The serum levels of anti-RVT-1401 antibodies were determined. In the initial analysis the samples with responses equal to or above the plate-specific cut-point were identified as potentially positive while those below the cut-point were considered negative. These potentially positive samples were reanalyzed in confirmatory assay. Samples with percent inhibition greater than or equal to the confirmatory cut-point were considered confirmed positive and those below were considered negative.
Time frame: Week 7
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RVT-1401 | Number of Participants With Anti-RVT-1401 Antibody and Confirmed Anti-RVT-1401 Antibody at Week 7 | Initial analysis: negative anti-RVT-1401 antibody | 5 Participants |
| RVT-1401 | Number of Participants With Anti-RVT-1401 Antibody and Confirmed Anti-RVT-1401 Antibody at Week 7 | Initial analysis: potentially positive anti-RVT-1401 antibody | 2 Participants |
| RVT-1401 | Number of Participants With Anti-RVT-1401 Antibody and Confirmed Anti-RVT-1401 Antibody at Week 7 | Confirmed analysis: negative anti-RVT-1401 antibody | 2 Participants |
Secondary
Serum Concentration at the End of the Dosing Interval (Ctrough) of RVT-1401
Time frame: Week 2, Week 3, Week 4, Week 5, Week 6 Day 36, and Week 7
Population: PK Population. Participants with evaluable data were included for the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RVT-1401 | Serum Concentration at the End of the Dosing Interval (Ctrough) of RVT-1401 | Week 2 | 4.018 mg/L | Standard Deviation 5.9584 |
| RVT-1401 | Serum Concentration at the End of the Dosing Interval (Ctrough) of RVT-1401 | Week 3 | 12.075 mg/L | Standard Deviation 14.6431 |
| RVT-1401 | Serum Concentration at the End of the Dosing Interval (Ctrough) of RVT-1401 | Week 4 | 1.284 mg/L | Standard Deviation 2.3063 |
| RVT-1401 | Serum Concentration at the End of the Dosing Interval (Ctrough) of RVT-1401 | Week 5 | 0.167 mg/L | Standard Deviation 0.1682 |
| RVT-1401 | Serum Concentration at the End of the Dosing Interval (Ctrough) of RVT-1401 | Week 6 Day 36 | 0.660 mg/L | Standard Deviation 1.5529 |
| RVT-1401 | Serum Concentration at the End of the Dosing Interval (Ctrough) of RVT-1401 | Week 7 | 0.077 mg/L | Standard Deviation 0.0381 |