Myasthenia Gravis
Conditions
Brief summary
This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of Immune Globulin (Human), 10% Caprylate/Chromatography Purified (IGIV-C) as a corticosteroid (CS)-sparing agent in subjects with CS-dependent Myasthenia Gravis (MG).
Detailed description
This study consists of 2 phases: IGIV-C Run-in Phase and Corticosteroid Tapering/IGIV-C Maintenance Phase. In the Run-in Phase, subjects will receive a total of 3 doses of IGIV-C (1 loading dose of 2 g/kg and 2 maintenance doses of 1 g/kg) while maintaining a stable dose of corticosteroids. In the CS Tapering/IGIV-C Maintenance Phase, subjects will continue 1 g/kg IGIV-C and begin a prescribed CS tapering regimen where the CS dose is decreased every 3 weeks. Approximately 60 subjects are planned to be enrolled in the study across multiple centers in North America and Europe. The total duration of study participation for each subject is up to 45 weeks.
Interventions
DRUGIGIV-C
Run-Phase: 1 loading dose of 2 g/kg IGIV-C and 2 maintenance doses of 1 g/kg IGIV-C Corticosteroid Tapering/IGIV-C Maintenance Phase: 1 g/kg IGIV-C every 3 weeks for up to 36 weeks
DRUGPlacebo
Sponsors
Grifols Therapeutics LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Anti-acetylcholine receptor antibody positive * Confirmed diagnosis of generalized MG historically meeting the clinical criteria for diagnosis of MG defined by the Myasthenia Gravis Foundation of America (MGFA) classification of Class II, III, IV, or V historically * At Screening, subjects may have symptoms controlled by CS or were MGFA Class II-IVa inclusive (Class IVb and Class V excluded). Subjects who only have a history of ocular MG may not enroll. * On systemic CS for a minimum period of at least 3 months and on a stable CS dose of \>=15 mg/day and \<=60 mg/day (prednisone equivalent) for the month prior to Screening. * Had a tapering CS dose that the study investigator considered to be appropriate. * At least 1 previous completed attempt to taper CS in order to minimize CS dose (lowest feasible dose based on observed MG signs and symptoms)
Exclusion criteria
* Any dose change in concomitant immunosuppressant therapy, other than CS, in the prior 6 months * Any change in CS dose or acetylcholinesterase inhibitor (e.g., pyridostigmine) dose in the 1 month prior to Screening * A 3-point change in Quantitative Myasthenia Gravis score, increased or decreased, between the Screening/Week -3 (Visit 0) and Baseline (Week 0 \[Visit 1\]) * Any episode of myasthenic crisis (MC) in the 1 month prior to Screening, or (at any time in the past) MC or hospitalization for MG exacerbation associated with a previous CS taper attempt * Evidence of malignancy within the past 5 years (non-melanoma skin cancer, carcinoma in situ of cervix is allowed) or thymoma potentially requiring surgical intervention during the course of the trial (intent to perform thymectomy) * Thymectomy within the preceding 6 months prior to Screening * Rituximab, belimumab, eculizumab or any monoclonal antibody used for immunomodulation within the past 12 months prior to Screening * Have received immune globulin treatment given by IV, subcutaneous, or intramuscular route within the last 3 months prior to Screening * Received plasma exchange performed within the last 3 months prior to Screening * History of anaphylactic reactions or severe reactions to any blood-derived product * History of recent (within the last year) myocardial infarction or stroke * Uncontrolled congestive heart failure; embolism; or historically documented (within the last year) electrocardiogram changes indicative of myocardial ischemia or atrial fibrillation * Current known hyperviscosity or hypercoagulable state * Currently receiving anti-coagulation therapy. Oral anti-platelet agents are allowed (e.g., aspirin, clopidogrel, ticlopidine) * Females of child-bearing potential who are pregnant, have a positive serum pregnancy test, breastfeeding, or are unwilling to practice a highly effective method of contraception throughout the study. * Renal impairment * Aspartate aminotransferase or alanine aminotransferase levels exceeding more than 2.5 times the upper limit of normal for the expected normal range for the testing laboratory. * Hemoglobin (Hb) levels \<9 g/dL
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Subjects Achieving a 50% or Greater Reduction in CS Dose (Prednisone or Equivalent) From Baseline to Week 39 | Baseline/Week 0 (Visit 1) and Week 39 (Visit 14). | The average daily CS dose was derived for each subject at each scheduled visit based on the prescribed dose and the time interval taking into account any prescribed dose changes between routinely scheduled visits. Subjects who discontinued the study early with adverse outcomes related to MG were considered as not achieving a 50% or greater reduction. The missing dose reduction at Week 39 was imputed using the worst observation carried forward (WOCF) method. For subjects who did not have CS dose prescribed at Week 39 due to other reasons, the last observation carried forward (LOCF) method was used to impute the prescribed CS dose at Week 39. Baseline was defined as the last non-missing measurement taken prior to first dose of study medication. The percent of subjects achieving ≥50% reduction in CS dose from baseline to Week 39 is presented for each treatment group overall and for the baseline daily prednisone equivalent dose level stratification categories. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Change in Daily CS Dose (Prednisone or Equivalent) From Baseline to Week 39 | Baseline/Week 0 (Visit 1) and Week 39 (Visit 14). | The average daily CS dose was derived for each subject at each scheduled visit based on the prescribed dose and the time interval taking into account any prescribed dose changes between routinely scheduled visits. For subjects who discontinued the study early with adverse outcomes related to MG, the missing dose reduction at Week 39 was imputed using the WOCF method. For subjects who had missing CS dose reduction at Week 39 due to other reasons, the missing CS dose was imputed using the LOCF method. Baseline was defined as the last non-missing measurement taken prior to first dose of study medication. The least squares (LS) mean percent change from baseline in daily CS dose to Week 39 is presented for each treatment group. |
| Median Time to First Episode of MG Worsening | From Baseline/Week 0 (Visit 1) to Week 39 (Visit 14). | The time to the first episode of MG worsening was defined as the time between baseline and the first instance of QMG total score increase by ≥4 points relative to Baseline/Week 0. The QMG total score is the sum of all 13 items and ranges from 0 to 39. Higher values represent greater severity of illness. If one or more items were missing at a given assessment, the total score was set to missing. The median time to MG worsening was calculated based on Kaplan-Meier methodology. Baseline was defined as the last non-missing measurement taken prior to the first dose of study medication. |
Countries
Belgium, Canada, Czechia, Estonia, France, Germany, Hungary, Lithuania, Poland, United States
Participant flow
Recruitment details
Sixty subjects with a confirmed diagnosis of generalized myasthenia gravis (MG) historically meeting the clinical criteria for MG diagnosis Class II, III, IV or V of the Myasthenia Gravis Foundation of America were randomized. The study was conducted in 8 countries from November 2015 to February 2019.
Pre-assignment details
Subjects had symptoms at screening controlled by corticosteroids (CS), had been dependent on systemic CS for at least the preceding 3 months and had received a stable dose of CS for at least 1 month immediately prior to the screening visit.
Participants by arm
| Arm | Count |
|---|---|
| IGIV-C IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive IGIV-C were given a loading dose of 2 g/kg by IV infusion at Baseline/Week 0 (Visit 1) and 2 maintenance doses of 1 g/kg at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase.
CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses (1 g/kg) every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of IGIV-C was given. The last CS dose reduction was at Week 36 (Visit 13).
Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments. | 30 |
| Placebo IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive placebo were given 3 doses of placebo matching IGIV-C by IV infusion at Baseline/Week 0 (Visit 1) and at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase.
CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses of placebo matching IGIV-C every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of placebo was given. The last CS dose reduction was at Week 36 (Visit 13).
Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments. | 30 |
| Total Title | 60 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 4 |
| Overall Study | MG worsening | 4 | 1 |
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Total Title | Placebo | IGIV-C |
|---|---|---|---|
| Age, Continuous | 48.1 years STANDARD_DEVIATION 15.67 | 48.5 years STANDARD_DEVIATION 14.51 | 47.6 years STANDARD_DEVIATION 16.99 |
| Baseline Daily Prednisone Equivalent Dose Level Stratification Categories 15 mg to 40 mg/day | 57 Participants | 28 Participants | 29 Participants |
| Baseline Daily Prednisone Equivalent Dose Level Stratification Categories 41 to 60 mg/day | 3 Participants | 2 Participants | 1 Participants |
| Baseline QMG Total Score | 11.6 units on a scale STANDARD_DEVIATION 6.69 | 11.2 units on a scale STANDARD_DEVIATION 6.48 | 12.1 units on a scale STANDARD_DEVIATION 6.98 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 58 Participants | 28 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 54 Participants | 27 Participants | 27 Participants |
| Sex: Female, Male Female | 34 Participants | 18 Participants | 16 Participants |
| Sex: Female, Male Male | 26 Participants | 12 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 30 | 2 / 30 |
| other Total, other adverse events | 21 / 30 | 24 / 30 |
| serious Total, serious adverse events | 4 / 30 | 6 / 30 |
Outcome results
Primary
Percent of Subjects Achieving a 50% or Greater Reduction in CS Dose (Prednisone or Equivalent) From Baseline to Week 39
The average daily CS dose was derived for each subject at each scheduled visit based on the prescribed dose and the time interval taking into account any prescribed dose changes between routinely scheduled visits. Subjects who discontinued the study early with adverse outcomes related to MG were considered as not achieving a 50% or greater reduction. The missing dose reduction at Week 39 was imputed using the worst observation carried forward (WOCF) method. For subjects who did not have CS dose prescribed at Week 39 due to other reasons, the last observation carried forward (LOCF) method was used to impute the prescribed CS dose at Week 39. Baseline was defined as the last non-missing measurement taken prior to first dose of study medication. The percent of subjects achieving ≥50% reduction in CS dose from baseline to Week 39 is presented for each treatment group overall and for the baseline daily prednisone equivalent dose level stratification categories.
Time frame: Baseline/Week 0 (Visit 1) and Week 39 (Visit 14).
Population: The mITT population included all randomized subjects who received at least 1 dose of study medication. Subjects were classified according to randomized treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IGIV-C | Percent of Subjects Achieving a 50% or Greater Reduction in CS Dose (Prednisone or Equivalent) From Baseline to Week 39 | All subjects | 60.0 percentage of subjects |
| IGIV-C | Percent of Subjects Achieving a 50% or Greater Reduction in CS Dose (Prednisone or Equivalent) From Baseline to Week 39 | 15 mg to 40 mg/day | 58.6 percentage of subjects |
| IGIV-C | Percent of Subjects Achieving a 50% or Greater Reduction in CS Dose (Prednisone or Equivalent) From Baseline to Week 39 | 41 mg to 60 mg/day | 100.0 percentage of subjects |
| Placebo | Percent of Subjects Achieving a 50% or Greater Reduction in CS Dose (Prednisone or Equivalent) From Baseline to Week 39 | All subjects | 63.3 percentage of subjects |
| Placebo | Percent of Subjects Achieving a 50% or Greater Reduction in CS Dose (Prednisone or Equivalent) From Baseline to Week 39 | 15 mg to 40 mg/day | 60.7 percentage of subjects |
| Placebo | Percent of Subjects Achieving a 50% or Greater Reduction in CS Dose (Prednisone or Equivalent) From Baseline to Week 39 | 41 mg to 60 mg/day | 100.0 percentage of subjects |
Comparison: An unstratified analysis using Fisher's exact test was used for treatment comparison without adjustment for stratified baseline prednisone equivalent dose level due to the small cell size. The odds ratio and confidence intervals are calculated overall (i.e. all mITT subjects).p-value: =195% CI: [0.27, 2.787]Fisher Exact
Secondary
Mean Percent Change in Daily CS Dose (Prednisone or Equivalent) From Baseline to Week 39
The average daily CS dose was derived for each subject at each scheduled visit based on the prescribed dose and the time interval taking into account any prescribed dose changes between routinely scheduled visits. For subjects who discontinued the study early with adverse outcomes related to MG, the missing dose reduction at Week 39 was imputed using the WOCF method. For subjects who had missing CS dose reduction at Week 39 due to other reasons, the missing CS dose was imputed using the LOCF method. Baseline was defined as the last non-missing measurement taken prior to first dose of study medication. The least squares (LS) mean percent change from baseline in daily CS dose to Week 39 is presented for each treatment group.
Time frame: Baseline/Week 0 (Visit 1) and Week 39 (Visit 14).
Population: The mITT population included all randomized subjects who received at least 1 dose of study medication. Subjects were classified according to randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| IGIV-C | Mean Percent Change in Daily CS Dose (Prednisone or Equivalent) From Baseline to Week 39 | -52.57 percent change | Standard Error 8.835 |
| Placebo | Mean Percent Change in Daily CS Dose (Prednisone or Equivalent) From Baseline to Week 39 | -54.15 percent change | Standard Error 8.835 |
Comparison: Treatment comparison of percent change in daily CS dose from baseline to Week 39. The Analysis of Covariance model included the percent change from baseline in daily CS dose as the dependent variable, treatment as a fixed effect and baseline daily CS dose as covariate.p-value: =0.995% CI: [-23.52, 26.68]ANCOVA
Secondary
Median Time to First Episode of MG Worsening
The time to the first episode of MG worsening was defined as the time between baseline and the first instance of QMG total score increase by ≥4 points relative to Baseline/Week 0. The QMG total score is the sum of all 13 items and ranges from 0 to 39. Higher values represent greater severity of illness. If one or more items were missing at a given assessment, the total score was set to missing. The median time to MG worsening was calculated based on Kaplan-Meier methodology. Baseline was defined as the last non-missing measurement taken prior to the first dose of study medication.
Time frame: From Baseline/Week 0 (Visit 1) to Week 39 (Visit 14).
Population: The mITT population included all randomized subjects who received at least 1 dose of study medication. Subjects were classified according to randomized treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IGIV-C | Median Time to First Episode of MG Worsening | NA weeks |
| Placebo | Median Time to First Episode of MG Worsening | NA weeks |