Generalized Myasthenia Gravis
Conditions
Brief summary
A randomized, double-blind, placebo controlled, multicenter Phase 3 trial to evaluate the efficacy, safety, tolerability, quality of life and impact on normal daily activities of ARGX-113 in patients with gMG.
Interventions
BIOLOGICALARGX-113
Intravenous administration of ARGX-113
BIOLOGICALPlacebo
Intravenous administration of placebo
Sponsors
argenx
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 No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with the ability to understand the requirements of the trial, provide written informed consent, and comply with the trial protocol procedures. 2. Male or female patients aged ≥ 18 years. 3. Diagnosis of MG with generalized muscle weakness meeting the clinical criteria for diagnosis of MG as defined by the Myasthenia Gravis Foundation of America (MGFA) class II, III, IVa and IVb. Other, more specific inclusion criteria are defined in the protocol
Exclusion criteria
1. Pregnant and lactating women, and those intending to become pregnant during the trial or within 90 days after the last dosing. 2. Male patients who are sexually active and do not intend to use effective methods of contraception during the trial or within 90 days after the last dosing or male patients who plan to donate sperm during the trial or within 90 days after the last dosing. 3. MGFA Class I and V patients. 4. Patients with worsening muscle weakness secondary to concurrent infections or medications. 5. Patients with known seropositivity or who test positive for an active viral infection at Screening with: * Hepatitis B Virus (HBV) (except patients who are seropositive because of HBV vaccination) * Hepatitis C Virus (HCV) * Human Immunodeficiency Virus (HIV) Other, more specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of MG-ADL Responders During Cycle 1 (C1); Analyzed in the AChR-Ab Seropositive Population | Baseline up to Day 63 (end of TC1) | The MG-ADL is an 8-item patient-reported scale to assess MG symptoms and their effects on daily activities. The scale comprises 2 items on daily life activities and 6 items on symptoms. The MG-ADL total score range is 0-24, with higher scores indicative of greater disease severity. A patient was considered an MG-ADL responder during C1 if there was a reduction of ≥2 points on the MG-ADL total score (compared to baseline of C1 \[C1B\]) for ≥4 consecutive weeks with the first reduction occurring no later than 1 week after the last infusion of IMP in C1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Quantitative Myasthenia Gravis (QMG) Responders During C1; Analyzed in the AChR-Ab Seropositive Population | Baseline up to Day 63 (end of TC1) | The QMG scale quantifies disease severity based on impairments of body functions and structures as defined by the International Classification of Disability and Health. The QMG scale consists of 13 items that measure endurance or fatigability, and accounts for fluctuations in disease state. The QMG total score range is 0-39, with higher scores indicative of greater disease severity. A patient was considered a QMG responder during C1 if there was a reduction of ≥3-points on the QMG total score (compared to C1B) for ≥4 consecutive weeks with the first reduction occurring no later than 1 week after the last infusion of IMP in C1. |
| Percentage of MG-ADL Responders During C1; Analyzed in the Overall Population | Baseline up to Day 63 (end of TC1) | The percentage of MG-ADL responders during C1 in the overall population is reported for this secondary end point; percentage of MG-ADL responders during C1 in the AChR-Ab seropositive population is reported previously as a primary end point. |
| Percentage of Time That Patients Had a Clinically Meaningful Improvement (CMI) in MG-ADL Total Score up to and Including Day 126; Analyzed in the AChR-Ab Seropositive Population | Baseline up to Day 126 | An MG-ADL CMI was defined as a reduction of ≥2 points on the total MG-ADL score compared to study entry baseline (SEB). |
| Time From Week 4 to Qualify for Retreatment; Analyzed in the AChR-Ab Seropositive Population | Week 4 up to Day 182 (end of study [EoS]) | Time to qualify for retreatment was defined as time from the Week 4 assessment until the first visit with a \<2-point reduction compared to SEB in the MG-ADL total score and MG-ADL total score ≥5 points with \>50% of the total score attributable to nonocular symptoms. |
| Percentage of Early MG-ADL Responders During C1; Analyzed in the AChR-Ab Seropositive Population | Baseline up to Day 63 (end of TC1) | A patient was considered an early MG-ADL responder during C1 if there was a reduction of ≥2 points on the MG-ADL total score (compared to C1B) for ≥4 consecutive weeks with the first reduction occurring no later than Week 2 (ie, after 1 or maximum 2 infusions of IMP in C1). |
Countries
Belgium, Canada, Czechia, Denmark, France, Georgia, Germany, Hungary, Italy, Japan, Netherlands, Poland, Russia, Serbia, United Kingdom, United States
Participant flow
Recruitment details
Study was conducted in generalized myasthenia gravis (gMG) patients at 56 sites worldwide. Patients were randomized 1:1 within each stratum (Japanese/non-Japanese, acetylcholine receptor-antibody \[AChR-Ab\] status and standard of care \[SoC; ie, concomitant gMG treatment\]) to receive ARGX-113 intravenous (IV) 10 milligrams/kilogram (mg/kg) or placebo, in addition to SoC. Patients completing the study were eligible to roll over into a follow-up study ARGX-113-1705.
Pre-assignment details
Total study duration was up to 28 weeks, including a 2-week screening period, an initial 8-week treatment cycle (TC) and intertreatment cycle (ITC) of variable length depending on the patient. Patients had to be on a stable dose of SoC and not have received immunoglobulins by IV, subcutaneous or intramuscular route, or plasma exchange, \< 1 month prior to screening. The study included both AChR-Ab seropositive and seronegative patients; AChR-Ab detection in serum was performed during screening.
Participants by arm
| Arm | Count |
|---|---|
| ARGX-113 Patients received ARGX-113 IV 10 mg/kg administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle. | 84 |
| Placebo Patients received matching placebo administered as a 1-hour infusion every 7 days for 4 infusions (Days 1, 8, 15, and 22) in each cycle. | 83 |
| Total | 167 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Rescue Therapy Needed | 0 | 1 |
| Overall Study | Sponsor Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 4 |
Baseline characteristics
| Characteristic | ARGX-113 | Placebo | Total |
|---|---|---|---|
| AChR-Ab status Negative | 19 Participants | 19 Participants | 38 Participants |
| AChR-Ab status Positive | 65 Participants | 64 Participants | 129 Participants |
| Age, Continuous | 45.9 years STANDARD_DEVIATION 14.41 | 48.2 years STANDARD_DEVIATION 14.97 | 47.0 years STANDARD_DEVIATION 14.69 |
| Age, Customized 18 - <65 years | 73 Participants | 69 Participants | 142 Participants |
| Age, Customized >= 65 years | 11 Participants | 14 Participants | 25 Participants |
| Concomitant gMG treatment No NSIDs | 33 Participants | 32 Participants | 65 Participants |
| Concomitant gMG treatment Nonsteroidal Immunosuppressive Drugs (NSIDs) | 51 Participants | 51 Participants | 102 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 7 Participants | 2 Participants | 9 Participants |
| Race/Ethnicity, Customized Japanese | 8 Participants | 7 Participants | 15 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 69 Participants | 73 Participants | 142 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 7 Participants | 16 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 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 | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 69 Participants | 72 Participants | 141 Participants |
| Sex: Female, Male Female | 63 Participants | 55 Participants | 118 Participants |
| Sex: Female, Male Male | 21 Participants | 28 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 84 | 0 / 83 |
| other Total, other adverse events | 49 / 84 | 48 / 83 |
| serious Total, serious adverse events | 4 / 84 | 7 / 83 |
Outcome results
Primary
Percentage of MG-ADL Responders During Cycle 1 (C1); Analyzed in the AChR-Ab Seropositive Population
The MG-ADL is an 8-item patient-reported scale to assess MG symptoms and their effects on daily activities. The scale comprises 2 items on daily life activities and 6 items on symptoms. The MG-ADL total score range is 0-24, with higher scores indicative of greater disease severity. A patient was considered an MG-ADL responder during C1 if there was a reduction of ≥2 points on the MG-ADL total score (compared to baseline of C1 \[C1B\]) for ≥4 consecutive weeks with the first reduction occurring no later than 1 week after the last infusion of IMP in C1.
Time frame: Baseline up to Day 63 (end of TC1)
Population: Analysis was performed in the AChR-Ab seropositive population using the modified intention-to-treat (mITT) analysis set which included all randomized patients with a value for the MG-ADL total score at baseline and at least 1 postbaseline timepoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ARGX-113 | Percentage of MG-ADL Responders During Cycle 1 (C1); Analyzed in the AChR-Ab Seropositive Population | 67.7 percentage of patients |
| Placebo | Percentage of MG-ADL Responders During Cycle 1 (C1); Analyzed in the AChR-Ab Seropositive Population | 29.7 percentage of patients |
Comparison: Analysis with a 2-sided exact test (using logistic regression) at the 2-sided 5% significance level in the AChR-Ab seropositive population, stratified by Japanese versus (vs) non-Japanese and NSID vs no NSID as concomitant gMG treatment, with cycle baseline MG-ADL total score as covariate.~The treatment effect was presented as the odds ratio. An odds ratio of more than 1 represents a higher response rate for ARGX-113 compared to placebo.p-value: <0.000195% CI: [2.213, 11.528]Regression, Logistic
Secondary
Percentage of Early MG-ADL Responders During C1; Analyzed in the AChR-Ab Seropositive Population
A patient was considered an early MG-ADL responder during C1 if there was a reduction of ≥2 points on the MG-ADL total score (compared to C1B) for ≥4 consecutive weeks with the first reduction occurring no later than Week 2 (ie, after 1 or maximum 2 infusions of IMP in C1).
Time frame: Baseline up to Day 63 (end of TC1)
Population: Analysis was performed in the AChR-Ab seropositive population using the mITT analysis set which included all randomized patients with a value for the MG-ADL total score at baseline and at least 1 postbaseline timepoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ARGX-113 | Percentage of Early MG-ADL Responders During C1; Analyzed in the AChR-Ab Seropositive Population | 56.9 percentage of patients |
| Placebo | Percentage of Early MG-ADL Responders During C1; Analyzed in the AChR-Ab Seropositive Population | 25.0 percentage of patients |
Secondary
Percentage of MG-ADL Responders During C1; Analyzed in the Overall Population
The percentage of MG-ADL responders during C1 in the overall population is reported for this secondary end point; percentage of MG-ADL responders during C1 in the AChR-Ab seropositive population is reported previously as a primary end point.
Time frame: Baseline up to Day 63 (end of TC1)
Population: Analysis was performed in the overall population (including both AChR-Ab seropositive and seronegative patients) using the mITT analysis set which included all randomized patients with a value for the MG-ADL total score at baseline and at least 1 postbaseline timepoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ARGX-113 | Percentage of MG-ADL Responders During C1; Analyzed in the Overall Population | 67.9 percentage of patients |
| Placebo | Percentage of MG-ADL Responders During C1; Analyzed in the Overall Population | 37.3 percentage of patients |
Comparison: Analysis with a 2-sided exact test (using logistic regression) at the 2-sided 5% significance level in the overall population, stratified by AChR-Ab status (seropositive vs seronegative), Japanese vs non-Japanese and NSID vs no NSID as concomitant gMG treatment, with cycle baseline MG-ADL total score as covariate.~The treatment effect was presented as the odds ratio. An odds ratio of more than 1 represents a higher response rate for ARGX-113 compared to placebo.p-value: <0.000195% CI: [1.854, 7.578]Regression, Logistic
Secondary
Percentage of Quantitative Myasthenia Gravis (QMG) Responders During C1; Analyzed in the AChR-Ab Seropositive Population
The QMG scale quantifies disease severity based on impairments of body functions and structures as defined by the International Classification of Disability and Health. The QMG scale consists of 13 items that measure endurance or fatigability, and accounts for fluctuations in disease state. The QMG total score range is 0-39, with higher scores indicative of greater disease severity. A patient was considered a QMG responder during C1 if there was a reduction of ≥3-points on the QMG total score (compared to C1B) for ≥4 consecutive weeks with the first reduction occurring no later than 1 week after the last infusion of IMP in C1.
Time frame: Baseline up to Day 63 (end of TC1)
Population: Analysis was performed in the AChR-Ab seropositive population using the mITT analysis set which included all randomized patients with a value for the MG-ADL total score at baseline and at least 1 postbaseline timepoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ARGX-113 | Percentage of Quantitative Myasthenia Gravis (QMG) Responders During C1; Analyzed in the AChR-Ab Seropositive Population | 63.1 percentage of patients |
| Placebo | Percentage of Quantitative Myasthenia Gravis (QMG) Responders During C1; Analyzed in the AChR-Ab Seropositive Population | 14.1 percentage of patients |
Comparison: Analysis with a 2-sided exact test (using logistic regression) at the 2-sided 5% significance level in the AChR-Ab seropositive population, stratified by Japanese vs non-Japanese and NSID vs no NSID as concomitant gMG treatment, with cycle baseline QMG total score as covariate.~The treatment effect was presented as the odds ratio. An odds ratio of more than 1 represents a higher response rate for ARGX-113 compared to placebo.p-value: <0.000195% CI: [4.179, 31.2]Regression, Logistic
Secondary
Percentage of Time That Patients Had a Clinically Meaningful Improvement (CMI) in MG-ADL Total Score up to and Including Day 126; Analyzed in the AChR-Ab Seropositive Population
An MG-ADL CMI was defined as a reduction of ≥2 points on the total MG-ADL score compared to study entry baseline (SEB).
Time frame: Baseline up to Day 126
Population: Analysis was performed in the AChR-Ab seropositive population using the mITT analysis set which included all randomized patients with a value for the MG-ADL total score at baseline and at least 1 postbaseline timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ARGX-113 | Percentage of Time That Patients Had a Clinically Meaningful Improvement (CMI) in MG-ADL Total Score up to and Including Day 126; Analyzed in the AChR-Ab Seropositive Population | 48.714 percentage of time | Standard Error 6.163 |
| Placebo | Percentage of Time That Patients Had a Clinically Meaningful Improvement (CMI) in MG-ADL Total Score up to and Including Day 126; Analyzed in the AChR-Ab Seropositive Population | 26.649 percentage of time | Standard Error 6.316 |
Comparison: Analysis of covariance (ANCOVA) in the AChR-Ab seropositive population with treatment, baseline MG-ADL total score, Japanese vs non-Japanese, and NSID vs no NSID as concomitant gMG treatment as the covariates.p-value: 0.000195% CI: [10.949, 33.181]ANCOVA
Secondary
Time From Week 4 to Qualify for Retreatment; Analyzed in the AChR-Ab Seropositive Population
Time to qualify for retreatment was defined as time from the Week 4 assessment until the first visit with a \<2-point reduction compared to SEB in the MG-ADL total score and MG-ADL total score ≥5 points with \>50% of the total score attributable to nonocular symptoms.
Time frame: Week 4 up to Day 182 (end of study [EoS])
Population: Analysis was performed in the AChR-Ab seropositive population using the mITT analysis set which included all randomized patients with a value for the MG-ADL total score at baseline and at least 1 postbaseline timepoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ARGX-113 | Time From Week 4 to Qualify for Retreatment; Analyzed in the AChR-Ab Seropositive Population | 35.0 days |
| Placebo | Time From Week 4 to Qualify for Retreatment; Analyzed in the AChR-Ab Seropositive Population | 8.0 days |
Comparison: Analysis was performed in the AChR-Ab seropositive population and the p-value was calculated using the log-rank test, stratified by Japanese vs non-Japanese and NSID vs no NSID as concomitant gMG treatment.p-value: 0.2604Log Rank