Generalized Myasthenia Gravis
Conditions
Brief summary
The purpose of the study is to evaluate the safety and efficacy of RA101495 in patients with generalized Myasthenia Gravis (gMG). Subjects will be randomized in a 1:1:1 ratio to receive daily SC doses of 0.1 mg/kg RA101495, 0.3 mg/kg RA101495, or matching placebo for 12 weeks.
Interventions
Daily subcutaneous (SC) injection
DRUGPlacebo
Daily subcutaneous (SC) injection
Sponsors
Ra Pharmaceuticals
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
* Diagnosis of gMG \[Myasthenia Gravis Foundation of America (MGFA) Class II-IVa\] at Screening * Positive serology for acetylcholine receptor (AChR) autoantibodies * QMG score ≥ 12 at Screening and Randomization * No change in corticosteroid dose for at least 30 days prior to Randomization or anticipated to occur during the 12-week Treatment Period * No change in immunosuppressive therapy, including dose, for at least 30 days prior to Randomization or anticipated to occur during the 12-week Treatment Period
Exclusion criteria
* Thymectomy within 6 months prior to Randomization or scheduled to occur during the 12 week Treatment Period * History of meningococcal disease * Current or recent systemic infection within 2 weeks prior to Randomization or infection requiring intravenous (IV) antibiotics within 4 weeks prior to Randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Main Portion: Change From Baseline to Week 12 in Quantitative Myasthenia Gravis (QMG) Score | From Baseline to Week 12 | The QMG is a standardized and validated quantitative strength scoring system that was developed specifically for myasthenia gravis (MG). The scale consists of 13 individual assessments, each scored on a 0-3 point scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total score is the sum of the individual scores with a range of 0-39. Higher scores are representative of more severe impairment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Main Portion: Change From Baseline to Week 12 in the Myasthenia Gravis - Quality of Life 15r (MG-QOL15r) Survey | From Baseline to Week 12 | The MG-QOL15r is a 15-item survey that was designed to assess quality of life in participants with MG. The survey consisted of 15 questions and the corresponding responses were each scored on a 0-2 point scale (0=Not much at all, 1=Somewhat, 2=Very Much). The total score is the sum of the 15 individual item scores with a range of 0-30. Higher scores indicate more severe impact of the disease on aspects of the participant's life. |
| Main Portion: Change From Baseline to Week 12 in the MG Composite Scale Total Score | From Baseline to Week 12 | The MG Composite is a 10-item scale that has been used to measure the clinical status of participants with MG, in order to evaluate treatment response. It consists of 10 items which included ptosis (score range=0 to 3), double vision on lateral gaze left/right/both (score range=0 to 4), eye closure (score range=0 to 2), talking (score range=0 to 6), chewing (score range=0 to 6), swallowing (score range=0 to 6), breathing (score range=0 to 9), neck flexion or extension (score range=0 to 4), shoulder abduction (score range=0 to 5) and hip flexion (score range= 0 to 5). The total score is the sum of the 10 individual scores with a range of 0-50. Higher scores in the MG Composite indicate more severe impairment due to the disease. |
| Main Portion: Percentage of Participants With >= 3-point Reduction in QMG Total Score at Week 12 | Week 12 | The QMG is a standardized and validated quantitative strength scoring system that was developed specifically for MG. The scale consists of 13 individual assessments, each scored on a 0-3 point scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total score is the sum of the individual scores with a range of 0-39. Higher scores are representative of more severe impairment. |
| Main Portion: Percentage of Participants Who Required Rescue Therapy Over the 12-week Treatment Period | Up to Week 12 | Percentage of participants who used at least 1 dose of rescue medication were reported. |
| Main Portion: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From Baseline to Week 12 | An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A serious adverse event (SAE) is any untoward medical occurrence that at any dose resulted in death, life-threatening, significant or persistent disability/incapacity, congenital anomaly/birth defect, important medical event, initial inpatient hospitalization or prolongation of hospitalization. |
| Main Portion: Change From Baseline to Week 12 in the Myasthenia Gravis - Activities of Daily Living (MG-ADL) Scale | From Baseline to Week 12 | The MG-ADL is a brief 8-item survey designed to evaluate MG symptom severity. The scale consists of 8 items each scored on a 0-3 point scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total score is the sum of the 8 individual scores with range of 0-24. Higher scores are associated with more severe symptoms of MG. |
| Main Portion: Change From Baseline in C5 Levels at Week 12 (Pre-dose) | Baseline and Week 12 (Pre-dose) | Blood samples were collected from participants to assess Complement Component 5C levels. |
| Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | 1, 3 and 6 hours postdose on Day 1; Pre-dose on Week 1, 2, 4, 8 and 12 | RA102758 and RA103488 are the metabolites of RA101495. |
| Main Portion: Maximum Plasma Concentration (Cmax) on Day 1 | Pre-dose, 1, 3 and 6 hours postdose on Day 1 | Cmax is defined as the maximum observed plasma concentration. |
| Main Portion: Time Corresponding to Cmax (Tmax) on Day 1 | Pre-dose, 1, 3 and 6 hours postdose on Day 1 | Tmax is defined as the time to observe maximum plasma concentration. |
| Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | Pre-dose, 1, 3 and 6 hours postdose on Day 1; Pre-dose on Week 1, 2, 4, 8 and 12 | RA102758 and RA103488 are the metabolites of RA101495. |
| Main Portion: Change From Baseline in Sheep Red Blood Cell (sRBC) Lysis Assay at Week 12 (Pre-dose) | Baseline and Week 12 (Pre-dose) | A BioTek ELx800 automated microplate reader is used to measure the optical density at 415 nanometer (nm) of human plasma samples to calculate the percent lysis of sheep erythrocytes that has occurred as a result of total complement activity. The measure of complement activity is determined by the degree of hemolysis of the erythrocytes. |
Countries
Canada, United States
Participant flow
Recruitment details
The study started to enroll participants in October 2017 and concluded in November 2020.
Pre-assignment details
The Participant flow refers to the Intent-to-treat Set for the main portion and Safety Set for the extension portion.
Participants by arm
| Arm | Count |
|---|---|
| RA101495 0.1 mg/kg Participants received RA101495 0.1 mg/kg as a subcutaneous injection once daily for 12 weeks in the main portion. Participants who completed main portion and were eligible to enter in the extension period, continued receiving RA101495 0.1 mg/kg up to 48 weeks (until protocol amendment v3.0) in the extension portion. | 15 |
| RA101495 0.3 mg/kg Participants received RA101495 0.3 mg/kg as a subcutaneous injection once daily for 12 weeks in the main portion. At the end of the treatment period in the main portion, participants received the same dose of study drug in the extension portion until RA101495 is approved and available in the territory, or the sponsor terminates development of RA101495 for generalized myasthenia gravis (gMG). In countries where RA101495 is not approved or marketed, but in which sponsored clinical studies had been conducted, participants received RA101495 through a compassionate use pathway in the extension portion (up to 122 weeks). | 15 |
| Placebo Participants received placebo matched to RA101495 as a subcutaneous injection once daily for 12 weeks in the main portion. At the end of the treatment period in the main portion, participants were randomized to receive either RA101495 0.1 mg/kg (up to 48 weeks) or RA101495 0.3 mg/kg (up to 122 weeks) in the extension portion, as a subcutaneous injection once daily. | 15 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| EP:After Switch to 0.3 mg/kg(Week48-122) | Death | 0 | 2 | 0 | 1 |
| EP:After Switch to 0.3 mg/kg(Week48-122) | Subject withdrew consent | 0 | 1 | 0 | 0 |
| EP:After Switch to 0.3 mg/kg(Week48-122) | Withdrawal by Subject | 0 | 1 | 0 | 0 |
| EP:Before Switch to 0.3 mg/kg(Week13-48) | Subject withdrew consent | 1 | 0 | 0 | 0 |
| Main Portion (12 Weeks) | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Main Portion (12 Weeks) | Subject withdrew consent | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | RA101495 0.1 mg/kg | RA101495 0.3 mg/kg | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 4 Participants | 2 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 11 Participants | 13 Participants | 38 Participants |
| Age, Continuous | 45.5 years STANDARD_DEVIATION 15.6 | 54.5 years STANDARD_DEVIATION 14.9 | 48.4 years STANDARD_DEVIATION 15.7 | 49.5 years STANDARD_DEVIATION 15.5 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 13 Participants | 11 Participants | 12 Participants | 36 Participants |
| Sex: Female, Male Female | 8 Participants | 5 Participants | 11 Participants | 24 Participants |
| Sex: Female, Male Male | 7 Participants | 10 Participants | 4 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 14 | 0 / 15 | 1 / 22 | 0 / 21 | 2 / 21 |
| other Total, other adverse events | 15 / 15 | 12 / 14 | 14 / 15 | 22 / 22 | 17 / 21 | 21 / 21 |
| serious Total, serious adverse events | 0 / 15 | 5 / 14 | 3 / 15 | 5 / 22 | 4 / 21 | 11 / 21 |
Outcome results
Primary
Main Portion: Change From Baseline to Week 12 in Quantitative Myasthenia Gravis (QMG) Score
The QMG is a standardized and validated quantitative strength scoring system that was developed specifically for myasthenia gravis (MG). The scale consists of 13 individual assessments, each scored on a 0-3 point scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total score is the sum of the individual scores with a range of 0-39. Higher scores are representative of more severe impairment.
Time frame: From Baseline to Week 12
Population: The modified ITT (mITT) population included all participants in the ITT population who had received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RA101495 0.1 mg/kg (mITT) | Main Portion: Change From Baseline to Week 12 in Quantitative Myasthenia Gravis (QMG) Score | -5.5 score on a scale | Standard Error 1.2 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Change From Baseline to Week 12 in Quantitative Myasthenia Gravis (QMG) Score | -6.0 score on a scale | Standard Error 1.2 |
| Placebo (mITT) | Main Portion: Change From Baseline to Week 12 in Quantitative Myasthenia Gravis (QMG) Score | -3.2 score on a scale | Standard Error 1.2 |
p-value: =0.094180% CI: [-4.5, -0.1]ANCOVA
p-value: =0.053880% CI: [-5.1, -0.6]ANCOVA
Secondary
Main Portion: Change From Baseline in C5 Levels at Week 12 (Pre-dose)
Blood samples were collected from participants to assess Complement Component 5C levels.
Time frame: Baseline and Week 12 (Pre-dose)
Population: The PD population included all participants in mITT Population who had at least 1 evaluable PD assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RA101495 0.1 mg/kg (mITT) | Main Portion: Change From Baseline in C5 Levels at Week 12 (Pre-dose) | 57.349 micrograms/milliliter (ug/mL) | Standard Error 7.057 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Change From Baseline in C5 Levels at Week 12 (Pre-dose) | 54.302 micrograms/milliliter (ug/mL) | Standard Error 6.804 |
| Placebo (mITT) | Main Portion: Change From Baseline in C5 Levels at Week 12 (Pre-dose) | -2.774 micrograms/milliliter (ug/mL) | Standard Error 6.237 |
p-value: <0.000180% CI: [47.839, 72.408]ANCOVA
p-value: <0.000180% CI: [44.955, 69.197]ANCOVA
Secondary
Main Portion: Change From Baseline in Sheep Red Blood Cell (sRBC) Lysis Assay at Week 12 (Pre-dose)
A BioTek ELx800 automated microplate reader is used to measure the optical density at 415 nanometer (nm) of human plasma samples to calculate the percent lysis of sheep erythrocytes that has occurred as a result of total complement activity. The measure of complement activity is determined by the degree of hemolysis of the erythrocytes.
Time frame: Baseline and Week 12 (Pre-dose)
Population: The pharmacodynamic (PD) population included all participants in mITT Population who had at least 1 evaluable PD assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RA101495 0.1 mg/kg (mITT) | Main Portion: Change From Baseline in Sheep Red Blood Cell (sRBC) Lysis Assay at Week 12 (Pre-dose) | -81.822 percent lysis of sheep erythrocytes | Standard Error 2.469 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Change From Baseline in Sheep Red Blood Cell (sRBC) Lysis Assay at Week 12 (Pre-dose) | -94.914 percent lysis of sheep erythrocytes | Standard Error 2.908 |
| Placebo (mITT) | Main Portion: Change From Baseline in Sheep Red Blood Cell (sRBC) Lysis Assay at Week 12 (Pre-dose) | 0.775 percent lysis of sheep erythrocytes | Standard Error 2.571 |
p-value: <0.000180% CI: [-87.249, -77.946]ANCOVA
p-value: <0.000180% CI: [-100.794, -90.585]ANCOVA
Secondary
Main Portion: Change From Baseline to Week 12 in the MG Composite Scale Total Score
The MG Composite is a 10-item scale that has been used to measure the clinical status of participants with MG, in order to evaluate treatment response. It consists of 10 items which included ptosis (score range=0 to 3), double vision on lateral gaze left/right/both (score range=0 to 4), eye closure (score range=0 to 2), talking (score range=0 to 6), chewing (score range=0 to 6), swallowing (score range=0 to 6), breathing (score range=0 to 9), neck flexion or extension (score range=0 to 4), shoulder abduction (score range=0 to 5) and hip flexion (score range= 0 to 5). The total score is the sum of the 10 individual scores with a range of 0-50. Higher scores in the MG Composite indicate more severe impairment due to the disease.
Time frame: From Baseline to Week 12
Population: The mITT population included all participants in the ITT population who had received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RA101495 0.1 mg/kg (mITT) | Main Portion: Change From Baseline to Week 12 in the MG Composite Scale Total Score | -5.3 score on a scale | Standard Error 1.5 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Change From Baseline to Week 12 in the MG Composite Scale Total Score | -7.4 score on a scale | Standard Error 1.6 |
| Placebo (mITT) | Main Portion: Change From Baseline to Week 12 in the MG Composite Scale Total Score | -3.3 score on a scale | Standard Error 1.6 |
p-value: =0.186680% CI: [-4.9, 0.9]ANCOVA
p-value: =0.039180% CI: [-7, -1.1]ANCOVA
Secondary
Main Portion: Change From Baseline to Week 12 in the Myasthenia Gravis - Activities of Daily Living (MG-ADL) Scale
The MG-ADL is a brief 8-item survey designed to evaluate MG symptom severity. The scale consists of 8 items each scored on a 0-3 point scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total score is the sum of the 8 individual scores with range of 0-24. Higher scores are associated with more severe symptoms of MG.
Time frame: From Baseline to Week 12
Population: The mITT population included all participants in the ITT population who had received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RA101495 0.1 mg/kg (mITT) | Main Portion: Change From Baseline to Week 12 in the Myasthenia Gravis - Activities of Daily Living (MG-ADL) Scale | -3.3 score on a scale | Standard Error 0.9 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Change From Baseline to Week 12 in the Myasthenia Gravis - Activities of Daily Living (MG-ADL) Scale | -3.4 score on a scale | Standard Error 0.9 |
| Placebo (mITT) | Main Portion: Change From Baseline to Week 12 in the Myasthenia Gravis - Activities of Daily Living (MG-ADL) Scale | -1.1 score on a scale | Standard Error 0.9 |
p-value: =0.039280% CI: [-4, -0.6]ANCOVA
p-value: =0.04780% CI: [-3.9, -0.5]ANCOVA
Secondary
Main Portion: Change From Baseline to Week 12 in the Myasthenia Gravis - Quality of Life 15r (MG-QOL15r) Survey
The MG-QOL15r is a 15-item survey that was designed to assess quality of life in participants with MG. The survey consisted of 15 questions and the corresponding responses were each scored on a 0-2 point scale (0=Not much at all, 1=Somewhat, 2=Very Much). The total score is the sum of the 15 individual item scores with a range of 0-30. Higher scores indicate more severe impact of the disease on aspects of the participant's life.
Time frame: From Baseline to Week 12
Population: The mITT population included all participants in the ITT population who had received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RA101495 0.1 mg/kg (mITT) | Main Portion: Change From Baseline to Week 12 in the Myasthenia Gravis - Quality of Life 15r (MG-QOL15r) Survey | -7.4 score on a scale | Standard Error 1.7 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Change From Baseline to Week 12 in the Myasthenia Gravis - Quality of Life 15r (MG-QOL15r) Survey | -5.9 score on a scale | Standard Error 1.7 |
| Placebo (mITT) | Main Portion: Change From Baseline to Week 12 in the Myasthenia Gravis - Quality of Life 15r (MG-QOL15r) Survey | -2.1 score on a scale | Standard Error 1.7 |
p-value: =0.01780% CI: [-8.4, -2.1]ANCOVA
p-value: =0.062480% CI: [-6.9, -0.6]ANCOVA
Secondary
Main Portion: Maximum Plasma Concentration (Cmax) on Day 1
Cmax is defined as the maximum observed plasma concentration.
Time frame: Pre-dose, 1, 3 and 6 hours postdose on Day 1
Population: The PK Population included all participants in mITT population who had at least 1 evaluable PK assessment. 1 Participant (who was randomized to Placebo) mistakenly received Zilucoplan on Day 1 following a dispensing error (which was documented as a minor PD). Due to data confidentiality reasons, the results have not been reported for the placebo arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RA101495 0.1 mg/kg (mITT) | Main Portion: Maximum Plasma Concentration (Cmax) on Day 1 | 1945.467 ng/mL | Standard Deviation 407.273 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Maximum Plasma Concentration (Cmax) on Day 1 | 4858.643 ng/mL | Standard Deviation 1004.457 |
Secondary
Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio
RA102758 and RA103488 are the metabolites of RA101495.
Time frame: Pre-dose, 1, 3 and 6 hours postdose on Day 1; Pre-dose on Week 1, 2, 4, 8 and 12
Population: The PK Population included all participants in mITT population who had at least 1 evaluable PK assessment. Here Number Analyzed signifies number of participants who were evaluable at specified time points. 1 Participant (who was randomized to Placebo) mistakenly received Zilucoplan on Day 1 following a dispensing error (which was documented as a minor PD). Due to data confidentiality reasons, the results have not been reported for the placebo arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Day 1: Pre-dose | NA ratio | — |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Day 1: 1 hour postdose | 0.000 ratio | Standard Deviation 0 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Day 1: 3 hours postdose | 0.000 ratio | Standard Deviation 0 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Day 1: 6 hours postdose | 0.000 ratio | Standard Deviation 0 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Week 1: Pre-dose | 0.121 ratio | Standard Deviation 0.033 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Week 2: Pre-dose | 0.182 ratio | Standard Deviation 0.038 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Week 4: Pre-dose | 0.197 ratio | Standard Deviation 0.072 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Week 8: Pre-dose | 0.195 ratio | Standard Deviation 0.057 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Week 12: Pre-dose | 0.184 ratio | Standard Deviation 0.065 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Day 1: Pre-dose | NA ratio | — |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Day 1: 1 hour postdose | 0.000 ratio | Standard Deviation 0 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Day 1: 3 hours postdose | 0.000 ratio | Standard Deviation 0 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Day 1: 6 hours postdose | 0.000 ratio | Standard Deviation 0 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Week 1: Pre-dose | 0.079 ratio | Standard Deviation 0.037 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Week 2: Pre-dose | 0.104 ratio | Standard Deviation 0.044 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Week 4: Pre-dose | 0.106 ratio | Standard Deviation 0.046 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Week 8: Pre-dose | 0.118 ratio | Standard Deviation 0.044 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Week 12: Pre-dose | 0.116 ratio | Standard Deviation 0.035 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Week 1: Pre-dose | 0.099 ratio | Standard Deviation 0.044 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Day 1: Pre-dose | NA ratio | — |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Day 1: Pre-dose | NA ratio | — |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Day 1: 1 hour postdose | 0.000 ratio | Standard Deviation 0 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Week 12: Pre-dose | 0.131 ratio | Standard Deviation 0.041 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Day 1: 3 hours postdose | 0.000 ratio | Standard Deviation 0 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Day 1: 1 hour postdose | 0.000 ratio | Standard Deviation 0 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Day 1: 6 hours postdose | 0.013 ratio | Standard Deviation 0.044 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Week 2: Pre-dose | 0.114 ratio | Standard Deviation 0.037 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Week 1: Pre-dose | 0.202 ratio | Standard Deviation 0.038 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Day 1: 3 hours postdose | 0.001 ratio | Standard Deviation 0.001 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Week 2: Pre-dose | 0.307 ratio | Standard Deviation 0.057 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Week 8: Pre-dose | 0.127 ratio | Standard Deviation 0.04 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Week 4: Pre-dose | 0.323 ratio | Standard Deviation 0.072 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Day 1: 6 hours postdose | 0.015 ratio | Standard Deviation 0.045 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Week 8: Pre-dose | 0.301 ratio | Standard Deviation 0.07 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA103488/RA101495- Week 4: Pre-dose | 0.119 ratio | Standard Deviation 0.038 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Metabolites (RA102758 and RA103488) to Parent Ratio | RA102758/RA101495- Week 12: Pre-dose | 0.303 ratio | Standard Deviation 0.061 |
Secondary
Main Portion: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A serious adverse event (SAE) is any untoward medical occurrence that at any dose resulted in death, life-threatening, significant or persistent disability/incapacity, congenital anomaly/birth defect, important medical event, initial inpatient hospitalization or prolongation of hospitalization.
Time frame: From Baseline to Week 12
Population: The safety population included all participants who had received at least 1 dose of study drug (i.e., mITT Population), with participants to be analyzed based on the actual treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RA101495 0.1 mg/kg (mITT) | Main Portion: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 15 Participants |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 12 Participants |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 5 Participants |
| Placebo (mITT) | Main Portion: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 14 Participants |
| Placebo (mITT) | Main Portion: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 3 Participants |
Secondary
Main Portion: Percentage of Participants Who Required Rescue Therapy Over the 12-week Treatment Period
Percentage of participants who used at least 1 dose of rescue medication were reported.
Time frame: Up to Week 12
Population: The mITT population included all participants in the ITT population who had received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RA101495 0.1 mg/kg (mITT) | Main Portion: Percentage of Participants Who Required Rescue Therapy Over the 12-week Treatment Period | 6.7 percentage of participants |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Percentage of Participants Who Required Rescue Therapy Over the 12-week Treatment Period | 0 percentage of participants |
| Placebo (mITT) | Main Portion: Percentage of Participants Who Required Rescue Therapy Over the 12-week Treatment Period | 20.0 percentage of participants |
Secondary
Main Portion: Percentage of Participants With >= 3-point Reduction in QMG Total Score at Week 12
The QMG is a standardized and validated quantitative strength scoring system that was developed specifically for MG. The scale consists of 13 individual assessments, each scored on a 0-3 point scale (i.e., 0=none, 1=mild, 2=moderate, and 3=severe). The total score is the sum of the individual scores with a range of 0-39. Higher scores are representative of more severe impairment.
Time frame: Week 12
Population: The mITT population included all participants in the ITT population who had received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RA101495 0.1 mg/kg (mITT) | Main Portion: Percentage of Participants With >= 3-point Reduction in QMG Total Score at Week 12 | 66.7 percentage of participants |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Percentage of Participants With >= 3-point Reduction in QMG Total Score at Week 12 | 71.4 percentage of participants |
| Placebo (mITT) | Main Portion: Percentage of Participants With >= 3-point Reduction in QMG Total Score at Week 12 | 53.3 percentage of participants |
Secondary
Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites
RA102758 and RA103488 are the metabolites of RA101495.
Time frame: 1, 3 and 6 hours postdose on Day 1; Pre-dose on Week 1, 2, 4, 8 and 12
Population: The pharmacokinetic (PK) population included all participants in mITT population who had at least 1 evaluable PK assessment. Here Number Analyzed signifies number of participants who were evaluable at specified time points. 1 Participant (who was randomized to Placebo) mistakenly received Zilucoplan on Day 1 following a dispensing error (which was documented as a minor PD). Due to data confidentiality reasons, the results have not been reported for the placebo arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA101495- Week 8: Pre-dose | 5222.067 nanograms/milliliter (ng/mL) | Standard Deviation 688.427 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA101495- Day 1: 3 hours postdose | 1691.267 nanograms/milliliter (ng/mL) | Standard Deviation 469.766 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA101495- Day 1: 6 hours postdose | 1925.357 nanograms/milliliter (ng/mL) | Standard Deviation 330.335 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA101495- Week 1: Pre-dose | 4571.214 nanograms/milliliter (ng/mL) | Standard Deviation 719.566 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA101495- Week 2: Pre-dose | 4914.200 nanograms/milliliter (ng/mL) | Standard Deviation 743.215 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA101495- Week 4: Pre-dose | 5100.286 nanograms/milliliter (ng/mL) | Standard Deviation 859.767 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA101495- Day 1: 1 hour postdose | 652.136 nanograms/milliliter (ng/mL) | Standard Deviation 354.652 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA101495- Week 12: Pre-dose | 5281.333 nanograms/milliliter (ng/mL) | Standard Deviation 1122.372 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758- Day 1: 1 hour postdose | NA nanograms/milliliter (ng/mL) | — |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758- Day 1: 3 hours postdose | NA nanograms/milliliter (ng/mL) | — |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758- Day 1: 6 hours postdose | NA nanograms/milliliter (ng/mL) | — |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758- Week 1: Pre-dose | 252.693 nanograms/milliliter (ng/mL) | Standard Deviation 78.909 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758- Week 2: Pre-dose | 408.847 nanograms/milliliter (ng/mL) | Standard Deviation 94.773 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758- Week 4: Pre-dose | 462.486 nanograms/milliliter (ng/mL) | Standard Deviation 180.098 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758- Week 8: Pre-dose | 474.073 nanograms/milliliter (ng/mL) | Standard Deviation 157.549 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758- Week 12: Pre-dose | 465.665 nanograms/milliliter (ng/mL) | Standard Deviation 195.227 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA103488- Day 1: 1 hour postdose | NA nanograms/milliliter (ng/mL) | — |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA103488- Day 1: 3 hours postdose | NA nanograms/milliliter (ng/mL) | — |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA103488- Day 1: 6 hours postdose | NA nanograms/milliliter (ng/mL) | — |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA103488- Week 1: Pre-dose | 356.186 nanograms/milliliter (ng/mL) | Standard Deviation 162.209 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA103488- Week 2: Pre-dose | 501.847 nanograms/milliliter (ng/mL) | Standard Deviation 218.467 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA103488- Week 4: Pre-dose | 536.266 nanograms/milliliter (ng/mL) | Standard Deviation 275.013 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA103488- Week 8: Pre-dose | 615.740 nanograms/milliliter (ng/mL) | Standard Deviation 229.359 |
| RA101495 0.1 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA103488- Week 12: Pre-dose | 621.813 nanograms/milliliter (ng/mL) | Standard Deviation 241.354 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA103488- Week 8: Pre-dose | 1234.708 nanograms/milliliter (ng/mL) | Standard Deviation 201.055 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA101495- Day 1: 1 hour postdose | 2272.257 nanograms/milliliter (ng/mL) | Standard Deviation 1246.128 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758- Week 2: Pre-dose | 1473.431 nanograms/milliliter (ng/mL) | Standard Deviation 440.496 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA101495- Day 1: 3 hours postdose | 4176.000 nanograms/milliliter (ng/mL) | Standard Deviation 1211.166 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA103488- Day 1: 6 hours postdose | 85.832 nanograms/milliliter (ng/mL) | Standard Deviation 257.664 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA101495- Day 1: 6 hours postdose | 4636.000 nanograms/milliliter (ng/mL) | Standard Deviation 809.804 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758- Week 4: Pre-dose | 1567.692 nanograms/milliliter (ng/mL) | Standard Deviation 557.745 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA101495- Week 1: Pre-dose | 9223.786 nanograms/milliliter (ng/mL) | Standard Deviation 2365.168 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA103488- Week 4: Pre-dose | 1191.783 nanograms/milliliter (ng/mL) | Standard Deviation 251.853 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA101495- Week 2: Pre-dose | 10222.846 nanograms/milliliter (ng/mL) | Standard Deviation 1662.869 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758- Week 8: Pre-dose | 1432.808 nanograms/milliliter (ng/mL) | Standard Deviation 530.377 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA101495- Week 4: Pre-dose | 10265.917 nanograms/milliliter (ng/mL) | Standard Deviation 1604.004 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA103488- Week 1: Pre-dose | 838.907 nanograms/milliliter (ng/mL) | Standard Deviation 255.419 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA101495- Week 8: Pre-dose | 10075.000 nanograms/milliliter (ng/mL) | Standard Deviation 1872.4 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758- Week 12: Pre-dose | 1459.062 nanograms/milliliter (ng/mL) | Standard Deviation 451.013 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA101495- Week 12: Pre-dose | 10284.846 nanograms/milliliter (ng/mL) | Standard Deviation 1771.586 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA103488- Week 12: Pre-dose | 1307.492 nanograms/milliliter (ng/mL) | Standard Deviation 331.553 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758- Day 1: 1 hour postdose | NA nanograms/milliliter (ng/mL) | — |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA103488- Day 1: 1 hour postdose | NA nanograms/milliliter (ng/mL) | — |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758- Day 1: 3 hours postdose | NA nanograms/milliliter (ng/mL) | — |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA103488- Week 2: Pre-dose | 1135.731 nanograms/milliliter (ng/mL) | Standard Deviation 270.004 |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758- Day 1: 6 hours postdose | NA nanograms/milliliter (ng/mL) | — |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA103488- Day 1: 3 hours postdose | NA nanograms/milliliter (ng/mL) | — |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Plasma Concentration of RA101495 and Its Major Metabolites | RA102758- Week 1: Pre-dose | 849.743 nanograms/milliliter (ng/mL) | Standard Deviation 273.388 |
Secondary
Main Portion: Time Corresponding to Cmax (Tmax) on Day 1
Tmax is defined as the time to observe maximum plasma concentration.
Time frame: Pre-dose, 1, 3 and 6 hours postdose on Day 1
Population: The PK Population included all participants in mITT population who had at least 1 evaluable PK assessment. 1 Participant (who was randomized to Placebo) mistakenly received Zilucoplan on Day 1 following a dispensing error (which was documented as a minor PD). Due to data confidentiality reasons, the results have not been reported for the placebo arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RA101495 0.1 mg/kg (mITT) | Main Portion: Time Corresponding to Cmax (Tmax) on Day 1 | 4.550 hours |
| RA101495 0.3 mg/kg (mITT) | Main Portion: Time Corresponding to Cmax (Tmax) on Day 1 | 4.700 hours |