A Study of RVT-1401 in Myasthenia Gravis (MG) Patients
- Conditions
- Myasthenia Gravis
- Interventions
- Drug: RVT-1401Drug: Placebo
- Registration Number
- NCT03863080
- Lead Sponsor
- Immunovant Sciences GmbH
- Brief Summary
The purpose of the current study is to assess safety/tolerability and key pharmacodynamic (PD) effects that are considered to be associated with clinical benefit (reduction of total IgG and anti-AChR-IgG) in Myasthenia Gravis patients following treatment with RVT-1401 (also known as IMVT-1401) compared to placebo.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 17
- Male or female ≥ 18 years of age.
- Myasthenia Gravis Foundation of America (MGFA) Class II-IVa and likely not in need of a respirator for the duration of the study as judged by the Investigator.
- QMG score ≥12 at Screening and Baseline.
Other, more specific inclusion criteria are defined in the protocol.
- Use of rituximab, belimumab, eculizumab or any monoclonal antibody for immunomodulation within 6 months prior to first dosing.
- Immunoglobulins given by SC, IV (IVIG), or intramuscular route, or plasmapheresis/plasma exchange (PE) within 4 weeks before Screening.
- Thymectomy performed < 12 months prior to screening.
- Total IgG level <6 g/L (at screening).
- Absolute neutrophil count <1500 cells/mm3(at screening).
Other, more specific exclusion criteria are defined in the protocol
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Regimen A RVT-1401 RVT-1401 680 mg weekly for 6 weeks + optional open-label extension (RVT-1401, 340 mg every 2 weeks for 6 weeks) Regimen B RVT-1401 RVT-1401 340 mg weekly for 6 weeks + optional open-label extension (RVT-1401, 340 mg every 2 weeks for 6 weeks) Placebo RVT-1401 Placebo for 6 weeks + optional open-label extension (RVT-1401, 340 mg every 2 weeks for 6 weeks) Placebo Placebo Placebo for 6 weeks + optional open-label extension (RVT-1401, 340 mg every 2 weeks for 6 weeks)
- Primary Outcome Measures
Name Time Method Open-label Extension Period: Number of Participants With Clinically Significant Changes in Vital Signs Up to Week 18 Vital signs including SBP, DBP, pulse rate and temperature were measured after resting for at least 5 minutes in a semi-supine position.
Double-blind Treatment Period: Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters Up to Week 7 Clinical laboratory parameters included clinical chemistry, hematology and urinalysis.
Double-Blind Treatment Period: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Up to Week 18 An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. 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.
Double-Blind Treatment Period: Number of Participants With Clinically Significant Changes in Vital Signs Up to Week 7 Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate and temperature were measured after resting for at least 5 minutes in a semi-supine position.
Double-blind Treatment Period: Percent Change From Baseline in Levels of Total Immunoglobulin G (IgG) Baseline (Day 1) and Up to Week 7 Serum samples were collected for the analysis of total immunoglobulin G. Percent change from Baseline was calculated as the mean value at the specified time frame (Week 7) minus the Baseline value, divided by the Baseline value x 100.
Open-Label Extension Period: Number of Participants Reporting AEs and SAEs Up to Week 18 An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TEAEs are defined as those AEs that started or worsened in severity after the initiation of study drug administration. 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.
Double-Blind Treatment Period: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Up to Week 7 Twelve-lead ECG was performed after 5 minutes of rest in the supine position.
Double-blind Treatment Period: Percent Change From Baseline in IgG Subclasses 1, 2, 3 and 4 Baseline (Day 1) and Up to Week 7 Serum samples were collected for the analysis of IgG 1, 2, 3 and 4 levels. Percent change from Baseline was calculated as the mean value at the specified time frame (Week 7) minus the Baseline value, divided by the Baseline value x 100.
Open-label Extension Period: Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters Up to Week 18 Clinical laboratory parameters included clinical chemistry, hematology and urinalysis.
Open-label Extension Period: Number of Participants With Clinically Significant Changes in ECG Up to Week 18 Twelve-lead ECG was performed after 5 minutes of rest in the supine position.
Double-Blind Treatment Period: Percent Change From Baseline in Anti-acetylcholine Receptor Immunoglobulin G (Anti-AChR-IgG) at Week 7 Baseline (Day 1) and Week 7 Serum samples were collected for the analysis of Anti-AChR-IgG. Percent change from Baseline was calculated as the mean value at the specified time frame (Week 7) minus the Baseline value, divided by the Baseline value x 100.
- Secondary Outcome Measures
Name Time Method Open-label Extension Period: 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, Week 9, Week 12 and Week 14 Blood samples were collected for the analysis of Pharmacokinetic parameter Cmax.
Open-label Extension Period: Ctrough of RVT-1401 Pre-dose Blood samples were planned to be collected at indicated time points to measure the concentration of RVT-1401 pre-dose (Ctrough) as an assessment of the pharmacokinetic RVT-1401.
Double-Blind Treatment Period: 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 Blood samples were collected for the analysis of Pharmacokinetic parameter Cmax.
Double-Blind Treatment Period: Trough Concentrations (Ctrough) of RVT-1401 Pre-dose Blood samples were planned to be collected at indicated time points to measure the concentration of RVT-1401 pre-dose (Ctrough) as an assessment of the pharmacokinetic RVT-1401.
Double-Blind Treatment Period: Percentage of Participants With an Improvement/ Response on the QMG Score From Baseline Baseline (Day 1) to Week 7 The response is defined as improvement from Baseline on the QMG score by =\> 3 points. The QMG score is a physician-reported outcome measure was used to assess MG disease severity and pattern of deficits based on quantitative testing of affected muscle groups. The scale comprised of 13 test items that were graded on a scale of 0 (no myasthenic findings) to 3 (maximal myasthenic deficits). The total sum across all 13 items represents the QMG score. QMG total scores range from 0 to 39 for a given visit, with higher scores indicating more severe disease. Baseline was defined as the last non-missing value prior to the date (time) of first dose of study drug. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Double-Blind Treatment Period: Change From Baseline in the Myasthenia Gravis Composite Score (MGC) Score Baseline (Day 1) and at Week 2, Week 3, Week 4, Week 5, Week 6 (Day 36), Week 7 The MGC was developed by selecting the best performing items from 3 commonly used Myasthenia Gravis specific scales (QMG, Myasthenia Gravis manual muscle test, and MG-ADL) and is comprised of 10 functional domains: 3 ocular, 3 bulbar, 1 respiratory, 1 neck, and 2 limb items. The total score ranges from 0 (no myasthenic findings) to 50 (maximal myasthenic deficits). The scale measures symptoms and signs of MG in these domains incorporating both physician and participant-reported test items. Higher scores correlate with clinical worsening of the disease. Baseline was defined as the last non-missing value prior to the date (time) of first dose of study drug. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Double-Blind Treatment Period: 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 Blood samples were collected for the analysis of Pharmacokinetic parameter AUC (0-168h).
Double-Blind Treatment Period: Change From Baseline in the Myasthenia Gravis Quality of Life 15 Revised Score (MG-QOL 15r) Score Baseline (Day 1) and at Week 4 and Week 7 The MG-QOL15r is a participant-reported questionnaire designed to assess how a participant's Myasthenia Gravis affects different aspects related to their quality of life. The scale includes 15 items that are graded on a scale of 0 to2; the total across is the sum of all 15 items and represents the MG-QOL15r score. The range of the MG-QOL15r score is 0 - 30. Higher scores indicate worse outcomes. Baseline was defined as the last non-missing value prior to the date (time) of first dose of study drug. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Double-Blind Treatment Period: Number of Participants Reporting Confirmed Positive Anti-RVT-1401 Antibodies Up to Week 7 The serum levels of anti-RVT-1401 antibodies were determined. All samples that were potentially positive were analyzed with the confirmation assay where presence of anti-RVT-1401 was confirmed; the therapeutic antibody was used to compete with the analytical responses of anti-drug antibody (ADA) to assess specificity of screened positive samples.
Open-Label Extension Period: Number of Participants Reporting Confirmed Positive Anti-RVT-1401 Antibodies Up to Week 18 The serum levels of anti-RVT-1401 antibodies were determined. All samples that were potentially positive were analyzed with the confirmation assay where presence of anti-RVT-1401 was confirmed; the therapeutic antibody was used to compete with the analytical responses of ADA to assess specificity of screened positive samples.
Open-label Extension Period: 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, Week 9, Week 12 and Week 14 Pharmacokinetic parameters were not estimated because the sparse PK sampling schedule did not allow for accurate estimates of these parameters.
Double-blind Treatment Period: Change From Baseline in the Quantitative Myasthenia Gravis Score (QMG) Score Baseline (Day 1) and at Week 2, Week 3, Week 4, Week 5, Week 6 (Day 36) and Week 7 The QMG score is a physician-reported outcome measure was used to assess MG disease severity and pattern of deficits based on quantitative testing of affected muscle groups. The scale comprised of 13 test items that were graded on a scale of 0 (no myasthenic findings) to 3 (maximal myasthenic deficits). The total sum across all 13 items represents the QMG score. QMG total scores range from 0 to 39 for a given visit, with higher scores indicating more severe disease. Baseline was defined as the last non-missing value prior to the date (time) of first dose of study drug. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Double-Blind Treatment Period: Change From Baseline in the Myasthenia Gravis Activities of Daily Living (MG-ADL) Score Baseline (Day 1) and at Week 2, Week 3, Week 4, Week 5, Week 6 (Day 36), Week 7 The MG-ADL is an 8-item, participant-reported outcome measure that assessed Myasthenia Gravis symptoms and their effects on activities of daily living, with each response graded from 0 (normal) to 3 (most severe). The MG-ADL score was calculated by totaling the rating for each of the 8 items. Total MG-ADL scores range from 0 to 24 with higher scores indicating more severe disease. Baseline was defined as the last non-missing value prior to the date (time) of first dose of study drug. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Double-Blind Treatment Period: Percentage of Participants With an Improvement/ Response on the MG-ADL Score Baseline (Day 1) to Week 7 The response was defined as improvement (decrease) from Baseline on the MG-ADL score by =\> 2 points. The MG-ADL is an 8-item, participant-reported outcome measure that assessed Myasthenia Gravis symptoms and their effects on activities of daily living, with each response graded from 0 (normal) to 3 (most severe). The MG-ADL score was calculated by totaling the rating for each of the 8 items. Total MG-ADL scores range from 0 to 24 with higher scores indicating more severe disease. Baseline was defined as the last non-missing value prior to the date (time) of first dose of study drug.
Double-Blind Treatment Period: Percentage of Participants With an Improvement on the MGC Score Baseline (Day 1) to Week 7 The response was defined as improvement (decrease) from Baseline on the MGC score by =\> 3 points. The MGC was developed by selecting the best performing items from 3 commonly used Myasthenia Gravis specific scales (QMG, Myasthenia Gravis manual muscle test, and MG-ADL) and is comprised of 10 functional domains: 3 ocular, 3 bulbar, 1 respiratory, 1 neck, and 2 limb items. The total score ranges from 0 (no myasthenic findings) to 50 (maximal myasthenic deficits). The scale measures symptoms and signs of MG in these domains incorporating both physician and participant-reported test items. Higher scores correlate with clinical worsening of the disease. Baseline was defined as the last non-missing value prior to the date (time) of first dose of study drug.
Trial Locations
- Locations (20)
IMC/Diagnostic and Medical Clinic
🇺🇸Mobile, Alabama, United States
Care Access Research
🇺🇸Pasadena, California, United States
Montreal Neurological Institute and Hospital
🇨🇦Montreal, Quebec, Canada
UC Irvine - MDA ALS and Neuromuscular Center
🇺🇸Orange, California, United States
Allegheny Neurological Associates
🇺🇸Pittsburgh, Pennsylvania, United States
Rare Disease Research
🇺🇸Atlanta, Georgia, United States
Dent Institute
🇺🇸Amherst, New York, United States
University of Buffalo
🇺🇸Buffalo, New York, United States
Hospital for Special Surgery
🇺🇸New York, New York, United States
London Health Sciences Centre
🇨🇦London, Ontario, Canada
University Health Network Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
The Neurology Center of Southern California
🇺🇸Carlsbad, California, United States
University of Alberta Hospitals - Division of Pulmonary Medicine
🇨🇦Edmonton, Alberta, Canada
CSNA
🇺🇸Colorado Springs, Colorado, United States
Ottawa Hospital Research Institute
🇨🇦Ottawa, Ontario, Canada
UTSW James W. Aston Ambulatory Care Center - Neurology Clinic
🇺🇸Dallas, Texas, United States
Phoenix Neurological Associates
🇺🇸Phoenix, Arizona, United States
Neurological Services of Orlando
🇺🇸Orlando, Florida, United States
University of Minnesota - Department of Neurology
🇺🇸Minneapolis, Minnesota, United States
Yale School of Medicine Department of Neurology
🇺🇸New Haven, Connecticut, United States