Clinical trial NCT02965573: A Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of ARGX-113 in Patients With Myasthenia Gravis Who Have Generalized Muscle Weakness
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myasthenia Gravis
Lead sponsor: argenx
Sponsor class: INDUSTRY
Collaborators: name: Quintiles, Inc.
First posted: 2016-11-17
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. 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).
2. Male or female patients aged ≥18 years.
3. 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.
4. 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.
5. 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.
   * Steroids treatment initiated at least 3 months prior to and no dose changes in the last month before Screening.
   * Cholinesterase inhibitors: to be on a stable dose for \>2 weeks before Screening.

   Note: cholinesterase inhibitors must be held for at least 12 hours consistent with the revised manual for the QMG test as recommended by the Myasthenia Gravis Foundation of America Inc (MGFA), before the MGQoL15r, MG-ADL, QMG, and MGC assessments.
6. Females of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Visit 1 prior to administration of IMP. Female of childbearing potential are defined as all female participants unless they are postmenopausal (defined by continuous amenorrhea) for at least 2 years with a Follicle stimulating hormone (FSH) \> 40 IU/L or are surgically sterile (i.e., who had a hysterectomy, bilateral oophorectomy, or have current documented tubal ligation or any other permanent female sterilization procedure). Determination of FSH levels can be used to confirm postmenopausal status in amenorrheic patients not on hormonal replacement therapy if the test result is within the postmenopausal range per the central laboratory.
7. Female participants of childbearing potential must agree to use a highly effective method of contraception (i.e., pregnancy rate of less than 1% per year) during the study and for 90 days after the discontinuation of the IMP. Adequate contraceptive methods include combined hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine devices (IUDs), intrauterine hormone-releasing system (IUS), true sexual abstinence (when this is in line with the preferred and usual lifestyle of the participant), bilateral tubal occlusion, or a female participant who is not of childbearing potential. Female participants and female partners of male study participants using a hormonal contraceptive must also use a barrier method (i.e., condom or occlusive cap \[diaphragm or cervical/vault caps\]) and should have been stable on their hormonal contraceptive treatment for at least 4 weeks before Screening.
8. Sterilized male patients who have had vasectomy with documented aspermia post procedure can be included. In addition, male patients must be advised not to donate sperm during this period from signing of Informed Consent Form (ICF), throughout the duration of the study, and for 90 days after the last administration of IMP. Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use effective method of double barrier contraception (e.g., condom with spermicidal cream or jelly, 1 hormonal plus 1 barrier method or 2 simultaneous barrier methods). Male patients practicing true sexual abstinence (when this is in line with the preferred and usual lifestyle of the participant) can be included.

Exclusion Criteria:

1. Females who are pregnant or lactating.
2. MGFA Class I, IVb, and V.
3. 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.
4. 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.
   * International normalized ratio (INR) or activated partial thromboplastin time (aPTT) \> 1.2 x ULN.
   * Total immunoglobulin G level \< 6 g/L.
5. Body Mass Index (BMI) at Screening ≥ 35 kg/m2.
6. Use of rituximab, belimumab, eculizumab or any monoclonal antibody for immunomodulation within 6 months prior to first dosing. Patients with prior exposure to rituximab must have CD19 counts within the normal range per the central laboratory at Screening.
7. Use of any biological therapy or investigational drug within 3 months or 5 half-lives of the drug (whichever is longer) before Screening.
8. Immunoglobulins given by IV (IVIg), or intramuscular route, or plasmapheresis/plasma exchange (PE) within 4 weeks before Screening.
9. Have known autoimmune disease other than MG that would interfere with the course and conduct of the study (such as uncontrolled thyroid disease or severe RA).
10. Have received vaccinations within 4 weeks before Screening or have any vaccinations planned during the study.
11. Have a history of malignancy, including malignant thymoma, or myeloproliferative or lymphoproliferative disorders at any time, unless deemed cured by adequate treatment with no evidence of recurrence for ≥5 years before Screening. Patients with completely excised nonmelanoma skin cancers (such as basal cell carcinoma or squamous cell carcinoma) or cervical carcinoma in situ would be permitted at any time.
12. Have a history of cerebrovascular accident or myocardial infarction within the last 12 months before Screening, or current severe/unstable angina, arrhythmia, symptomatic congestive heart failure New York Heart Association (NYHA) class III or IV, or uncontrolled hypertension.
13. Have clinical evidence of significant unstable or uncontrolled acute or chronic diseases (i.e., cardiovascular, pulmonary, hematologic, gastrointestinal, endocrinologic, hepatic, renal, neurologic, malignancy, or infectious diseases) which, in the opinion of the Investigator, could confound the results of the study or put the patient at undue risk.
14. Major past surgery (e.g., heart valve replacement, hip replacement) that, in the opinion of the Investigator, poses a risk to patient's safety or interferes with the study evaluation, procedures or completion.
15. Thymectomy when performed \< 3 months prior to Screening.
16. History or presence of alcoholism or drug/chemical/substance abuse within 2 years before Screening per Investigator's opinion.

Primary outcomes:
measure: Number of Patients With Treatment Emergent Adverse Events (TEAES) and Treatment Emergent Serious Adverse Events (SAEs)
timeFrame: Day 1 to Day 78
measure: Mean Change From Baseline in Vital Signs: Blood Pressure
timeFrame: Baseline and Days 8,15, 22, 29, 36, 43, 50, 64 and 78
measure: Mean Change From Baseline in Vital Signs: Heart Rate
timeFrame: Baseline and Days 8,15, 22, 29, 36, 43, 50, 64 and 78
measure: Mean Change From Baseline in Vital Signs: Temperature
timeFrame: Baseline and Days 8,15, 22, 29, 36, 43, 50, 64 and 78
measure: Mean Change From Baseline in Vital Signs: Weight
timeFrame: Baseline and Days 8,15, 22, 29, 36, 43, 50, 64 and 78
measure: Number of Patients With Abnormal Clinically Relevant Findings in Electrocardiogram (ECG) Parameters
timeFrame: Day 1 to Day 78
measure: Number of Patients With Abnormal Clinical Laboratory Findings Reported as TEAEs
timeFrame: Day 1 to Day 78
Secondary outcomes:
measure: Mean Change From Baseline in Myasthenia Gravis-Activities of Daily Living (MG-ADL) Score
timeFrame: Baseline and Days 8,15, 22, 29, 36, 43, 50, 64 and 78
measure: Mean Change From Baseline in QMG Score
timeFrame: Baseline and Days 8,15, 22, 29, 36, 43, 50, 64 and 78
measure: Mean Change From Baseline in MGC Score
timeFrame: Baseline and Days 8,15, 22, 29, 36, 43, 50, 64 and 78
measure: Mean Change From Baseline in MGQoL15r Score
timeFrame: Baseline and Days 8,15, 22, 29, 36, 43, 50, 64 and 78
measure: Maximum Reduction From Baseline in MG-ADL Score
timeFrame: Day 1 to Day 78
measure: Maximum Reduction From Baseline in QMG Score
timeFrame: Day 1 to Day 78
measure: Maximum Reduction From Baseline in MGC Score
timeFrame: Day 1 to Day 78
measure: Maximum Reduction From Baseline in MGQoL15r Score
timeFrame: Day 1 to Day 78
measure: Pharmacokinetic (PK) Parameters - Plasma Concentrations of ARGX-113
timeFrame: Days 1, 8, 15 and 22
measure: PK Parameters - Median Time of Occurrence of Cmax (Tmax) of ARGX-113
timeFrame: Days 1, 8 15 and 22.
measure: PK Parameters - Apparent Terminal Half-life (t1/2 Lambda z) of ARGX-113
timeFrame: Day 22
measure: PK Parameters - Accumulation Ratio (Rac) of ARGX-113
timeFrame: Days 1 and 22.
measure: Mean Percent Change From Baseline in Immunoglobulins (IgGs)
timeFrame: Baseline, Days 22 and 78
measure: Mean Percent Change From Baseline in Anti-Acetylcholine Receptor (AChR) Antibodies
timeFrame: Baseline, Days 22 and 78
measure: Number of Patients With an Anti-drug Antibodies (ADA) Response
timeFrame: Baseline up to Day 78
Other outcomes:
Locations:
city: Irvine
country: United States
facility: Investigator Site 19
state: California
city: Los Angeles
country: United States
facility: Investigator Site 17
state: California
city: Tampa
country: United States
facility: Investigator Site 15
state: Florida
city: Indianapolis
country: United States
facility: Investigator Site 16
state: Indiana
city: Chapel Hill
country: United States
facility: Investigator Site 14
state: North Carolina
city: Dublin
country: United States
facility: Investigator Site 18
state: Ohio
city: Gent
country: Belgium
facility: Investigator Site 2
city: Leuven
country: Belgium
facility: Investigator Site 1
city: Montréal
country: Canada
facility: Investigator Site 4
city: Toronto
country: Canada
facility: Investigator Site 3
city: Bergamo
country: Italy
facility: Investigator Site 7
city: Milano
country: Italy
facility: Investigator Site 6
city: Roma
country: Italy
facility: Investigator Site 5
city: Leiden
country: Netherlands
facility: Investigator Site 8
city: Gdańsk
country: Poland
facility: Investigator Site 10
city: Kraków
country: Poland
facility: Investigator Site 9
city: Barcelona
country: Spain
facility: Investigator Site 12
city: Madrid
country: Spain
facility: Investigator Site 11
city: Solna
country: Sweden
facility: Investigator Site 13
Study officials:
affiliation: argenx
name: Antonio Guglietta, MD
role: STUDY_DIRECTOR
References: