A Randomized, Double-blind, Placebo-Controlled Phase II Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of ARGX-113 in Patients With Myasthenia Gravis Who Have Generalized Muscle Weakness
Overview
- Phase
- Phase 2
- Intervention
- ARGX-113
- Conditions
- Myasthenia Gravis
- Sponsor
- argenx
- Enrollment
- 24
- Locations
- 19
- Primary Endpoint
- Mean Change From Baseline in Vital Signs: Weight
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This is a randomized, double-blind, placebo-controlled, multicenter Phase II study to evaluate the safety, efficacy, and pharmacokinetics of ARGX-113 for the treatment of autoimmune Myasthenia Gravis (MG) with generalized muscle weakness.
Detailed Description
Myasthenia Gravis (MG) is an autoimmune disorder characterized in most cases by T cell and antibody responses to neuromuscular junction proteins such as skeletal muscle nicotinic acetylcholine receptor (AChR). Antibodies against epitopes of the AChR of the neuromuscular junction cause failure of neuromuscular transmission, resulting in the characteristic fatigue and weakness associated with this severe disorder. The study will evaluate an innovative candidate in MG.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Have the ability to understand the requirements of the study, provide written informed consent (including consent for the use and disclosure of research-related health information), and comply with the study protocol procedures (including required study visits).
- •Male or female patients aged ≥18 years.
- •Diagnosis of autoimmune MG with generalized muscle weakness meeting the clinical criteria for diagnosis of MG as defined by the Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II, III, or IVa, and likely not in need of a respirator for the duration of the study as judged by the Investigator.
- •The confirmation of the diagnosis should be documented and supported by:
- •Positive serologic test for anti-AChR antibodies before Screening and
- •at least 1 of the following 3 tests: (i) History of abnormal neuromuscular transmission test demonstrated by single-fiber electromyography or repetitive nerve stimulation or (ii) History of positive edrophonium chloride test, or (iii) Patient has demonstrated improvement in MG signs on oral cholinesterase inhibitors as assessed by the treating physician.
- •A total score of ≥ 5 on the MG ADL at Screening and Baseline with more than 50% of this score attributed to non ocular items.
- •Patients are required to be on a stable dose of their MG treatment prior to randomization. For patients receiving AZA, other NSIDs, steroids, and/or cholinesterase inhibitors as concomitant medications the following conditions will apply:
- •AZA: treatment initiated at least 12 months ago and no dose changes in the last 6 months before screening.
- •Other NSIDs (e.g., methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil, and cyclophosphamide) treatment initiated at least 6 months ago and no dose changes in the last 3 months before Screening.
Exclusion Criteria
- •Females who are pregnant or lactating.
- •MGFA Class I, IVb, and V.
- •Have an active infection, a recent serious infection (i.e., requiring injectable antimicrobial therapy or hospitalization) within the 8 weeks prior to Screening; or history of or known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or Mycobacterium tuberculosis. Patients must have negative test results for HBV surface antigen, HBV core antibody, HCV antibody, HIV 1 and 2 antibodies, and a negative QuantiFERON®-TB Gold test at Screening. Patients with an indeterminate QuantiFERON®-TB Gold test result will be allowed one retest; if not negative on retesting, the patient will be excluded.
- •At Screening, have clinically significant laboratory abnormalities or as below:
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \> 2 x upper limit of normal (ULN).
- •Total serum bilirubin of \> 1.5 x ULN (except for Grade 1 hyperbilirubinemia solely due to a medical diagnosis of Gilbert's syndrome).
- •Serum creatinine \> 1.5 mg/dL and creatinine clearance \< 50 ml/min (using the Chronic Kidney Disease Epidemiology \[CKD-EPI\]-Creatinine formula).
- •Clinically Significant proteinuria (i.e., \> 3 x ULN).
- •Hemoglobin ≤ 9 g/L.
- •Thyroid stimulating hormone or thyroglobulin outside of the central laboratory normal range.
Arms & Interventions
ARGX-113
During the Treatment period, eligible patients will be randomized at a 1:1 ratio to receive ARGX-113
Intervention: ARGX-113
Placebo
During the Treatment period, eligible patients will be randomized at a 1:1 ratio to receive placebo
Intervention: Placebo
Outcomes
Primary Outcomes
Mean Change From Baseline in Vital Signs: Weight
Time Frame: Baseline and Days 8,15, 22, 29, 36, 43, 50, 64 and 78
The patients' weight as measured pre-dose on dosing days 1,8,15 and 22 and also during the follow up period. The mean change from baseline at each time point is presented. Baseline is defined as the last non-missing value before first dose of study medication.
Mean Change From Baseline in Vital Signs: Blood Pressure
Time Frame: Baseline and Days 8,15, 22, 29, 36, 43, 50, 64 and 78
The patients' diastolic and systolic blood pressure were measured pre-dose on dosing days 1,8,15 and 22 and also during the follow up period. The mean change from baseline at each time point is presented. Baseline is defined as the last non-missing value before first dose of study medication.
Mean Change From Baseline in Vital Signs: Heart Rate
Time Frame: Baseline and Days 8,15, 22, 29, 36, 43, 50, 64 and 78
The patients' heart rate was measured pre-dose on dosing days 1,8,15 and 22 and also during the follow up period. The mean change from baseline at each time point is presented. Baseline is defined as the last non-missing value before first dose of study medication.
Mean Change From Baseline in Vital Signs: Temperature
Time Frame: Baseline and Days 8,15, 22, 29, 36, 43, 50, 64 and 78
The patients' temperature was measured pre-dose on dosing days 1,8,15 and 22 and also during the follow up period. The mean change from baseline at each time point is presented. Baseline is defined as the last non-missing value before first dose of study medication.
Number of Patients With Abnormal Clinical Laboratory Findings Reported as TEAEs
Time Frame: Day 1 to Day 78
Sampling for clinical laboratory tests including hematology, clinical chemistry, and urinalysiswas performed pre-dose on dosing Days 1, 8, 15 and 22 and throughout the follow up period. Patients fasted for at least 8 hours prior to this sampling. Abnormal laboratory values, or test results were not reported as TEAEs unless they were associated with clinical signs and symptoms that were considered clinically relevant, required therapy or led to treatment discontinuation. Patients reporting TEAEs in any of the laboratory parameters during the study are presented.
Number of Patients With Treatment Emergent Adverse Events (TEAES) and Treatment Emergent Serious Adverse Events (SAEs)
Time Frame: Day 1 to Day 78
TEAEs were defined as AEs that first occurred or worsened in severity after the first administration of the treatment. A treatment emergent SAE was any untoward medical occurrence that resulted in death; was life-threatening; required inpatient hospitalization or prolongation of existing hospitalization;resulted in persistent or significant disability or incapacity; was a congenital abnormality or birth defect; or other medically significant events. All TEAEs observed were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 with descriptions of severity for each AE based on the following general guideline: Grade 1= mild; Grade 2 = moderate; Grade 3 = severe or medically significant but not immediately life-threatening; Grade 4 = life-threatening consequences; Grade 5 = death related to AE.
Number of Patients With Abnormal Clinically Relevant Findings in Electrocardiogram (ECG) Parameters
Time Frame: Day 1 to Day 78
ECG parameters of heart rate, PR, QT, and QRS interval were read locally and performed pre-dose on dosing days 1,8,15 and 22 and on the last follow up visit on Day 78. Any patients recording abnormal clinically relevant findings during the study are presented.
Secondary Outcomes
- Maximum Reduction From Baseline in MGC Score(Day 1 to Day 78)
- PK Parameters - Median Time of Occurrence of Cmax (Tmax) of ARGX-113(Days 1, 8 15 and 22.)
- PK Parameters - Apparent Terminal Half-life (t1/2 Lambda z) of ARGX-113(Day 22)
- Maximum Reduction From Baseline in MGQoL15r Score(Day 1 to Day 78)
- Mean Change From Baseline in MGC Score(Baseline and Days 8,15, 22, 29, 36, 43, 50, 64 and 78)
- Mean Change From Baseline in MGQoL15r Score(Baseline and Days 8,15, 22, 29, 36, 43, 50, 64 and 78)
- Mean Percent Change From Baseline in Immunoglobulins (IgGs)(Baseline, Days 22 and 78)
- Mean Change From Baseline in Myasthenia Gravis-Activities of Daily Living (MG-ADL) Score(Baseline and Days 8,15, 22, 29, 36, 43, 50, 64 and 78)
- Mean Change From Baseline in QMG Score(Baseline and Days 8,15, 22, 29, 36, 43, 50, 64 and 78)
- Maximum Reduction From Baseline in MG-ADL Score(Day 1 to Day 78)
- Pharmacokinetic (PK) Parameters - Plasma Concentrations of ARGX-113(Days 1, 8, 15 and 22)
- PK Parameters - Accumulation Ratio (Rac) of ARGX-113(Days 1 and 22.)
- Maximum Reduction From Baseline in QMG Score(Day 1 to Day 78)
- Mean Percent Change From Baseline in Anti-Acetylcholine Receptor (AChR) Antibodies(Baseline, Days 22 and 78)
- Number of Patients With an Anti-drug Antibodies (ADA) Response(Baseline up to Day 78)