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A Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of ARGX-113 in Patients With Myasthenia Gravis Who Have Generalized Muscle Weakness

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ClinicalTrials.gov Identifier: NCT02965573
Recruitment Status : Completed
First Posted : November 17, 2016
Last Update Posted : October 23, 2018
Sponsor:
Collaborator:
Quintiles, Inc.
Information provided by (Responsible Party):
argenx BVBA

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.

Condition or disease Intervention/treatment Phase
Myasthenia Gravis Biological: ARGX-113 Drug: Placebo Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : December 30, 2016
Actual Primary Completion Date : October 20, 2017
Actual Study Completion Date : October 20, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: ARGX-113
During the Treatment period, eligible patients will be randomized at a 1:1 ratio to receive ARGX-113
Biological: ARGX-113
Placebo Comparator: Placebo
During the Treatment period, eligible patients will be randomized at a 1:1 ratio to receive placebo
Drug: Placebo



Primary Outcome Measures :
  1. Change in the incidence and severity of adverse events (AEs) and serious AEs (SAEs) from baseline. [ Time Frame: Day 1 to Day 78±1 ]
    The AEs and SAES that the subjects have had will be recorded in the electronic case report forms during the subject's participation in the study. The incidence and the severity of these reported AEs and SAEs will be compared with the baseline data.

  2. Change in vital signs, ECG, and laboratory assessments from baseline. [ Time Frame: Day 1 to Day 78±1 ]
    The vital signs of subjects as well as laboratory assessments of the subjects will be analyzed.


Secondary Outcome Measures :
  1. Score change in Myasthenia Gravis Activities from baseline [ Time Frame: Day 1 to Day 78±1 ]
    Patient-reported scale to assess MG symptoms and their effects on daily activities. It evaluates the capacity to perform different activities of daily living.

  2. Score change in Quantitative Myasthenia Gravis Score from baseline [ Time Frame: Day 1 to Day 78±1 ]
    The score quantifies disease severity based on impairments of body functions and structures as defined by the International Classification of Disability and Health.

  3. Score change in Myasthenia Gravis Composite Score from baseline [ Time Frame: Day 1 to Day 78±1 ]
    The score combined physician examination and patient reported outcomes.

  4. Score change in quality of life for Myasthenia Gravis from baseline [ Time Frame: Day 1 to Day 78±1 ]
    The Quality of Life scale for Myasthenia Gravis is a quality of life scale or survey of patient's responses and addresses MG-specific psychological well-being and social functioning.

  5. Maximum reduction occurred in Myasthenia Gravis Activities of Daily Living Scale from baseline [ Time Frame: Day 1 to Day 78±1 ]
    Patient-reported scale to assess MG symptoms and their effects on daily activities.

  6. Maximum reduction occurred in Quantitative Myasthenia Gravis Score from baseline [ Time Frame: Day 1 to Day 78±1 ]
    It quantifies disease severity based on impairments of body functions and structures as defined by the International Classification of Disability and Health.

  7. Maximum reduction occurred in Myasthenia Gravis Composite Score from baseline [ Time Frame: Day 1 to Day 78±1 ]
    Items combining physician examination and patient reported outcomes.

  8. Maximum reduction occurred in 15-item quality of life scale for Myasthenia Gravis revised version from baseline [ Time Frame: Day 1 to Day 78±1 ]
    The Quality of Life scale for Myasthenia Gravis is a quality of life scale or survey of patient's responses and addresses MG-specific psychological well-being and social functioning.

  9. Maximum Observed Concentration (Cmax) [ Time Frame: Day 1 to Day 78±1 ]
    Cmax curves

  10. Time of Maximum Concentration (tmax) [ Time Frame: Day 1 to Day 78±1 ]
    Tmax curves

  11. Concentration prior to dosing (Ctrough) [ Time Frame: Day 1 to Day 78±1 ]
    Ctrough curves

  12. Half-life, (t1/2,λz) [ Time Frame: Day 1 to Day 78±1 ]
    t1/2 curves

  13. Accumulation ratio (Rac) [ Time Frame: Day 1 to Day 78±1 ]
    Rac curves



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  • 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]1, before the MGQoL15r, MG ADL, QMG, and MGC assessments.

    • 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.
    • 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.
    • 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:

  • 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.
    • International normalized ratio (INR) or activated partial thromboplastin time (aPTT) > 1.2 x ULN.
    • Total immunoglobulin G level < 6 g/L.
  • Body Mass Index (BMI) at Screening ≥ 35 kg/m2.
  • 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.
  • Use of any biological therapy or investigational drug within 3 months or 5 half-lives of the drug (whichever is longer) before Screening.
  • Immunoglobulins given by IV (IVIg), or intramuscular route, or plasmapheresis/plasma exchange (PE) within 4 weeks before Screening.
  • 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).
  • Have received vaccinations within 4 weeks before Screening or have any vaccinations planned during the study.
  • 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.
  • 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.
  • 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.
  • 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.
  • Thymectomy when performed < 3 months prior to Screening.
  • History or presence of alcoholism or drug/chemical/substance abuse within 2 years before Screening per Investigator's opinion.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02965573


Locations
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United States, California
US
Los Angeles, California, United States
US
Orange, California, United States
United States, Florida
US
US, Florida, United States
United States, Indiana
US
US, Indiana, United States
United States, North Carolina
US
US, North Carolina, United States
United States, Ohio
US
US, Ohio, United States
Belgium
BEL
Gent, Belgium
BEL
LEU, Belgium
Canada, Ontario
CAN
CAN, Ontario, Canada
Canada, Quebec
CAN
CAN, Quebec, Canada
Italy
IT
IT, Bergamo, Italy
IT
IT, Milano, Italy
IT
IT, Roma, Italy
Netherlands
NL
NL, Netherlands
Poland
PO
PO, Malopolska, Poland
PO
PO, Pomorskie, Poland
Spain
ESP
ESP, Barcelona, Spain
ESP
ESP, Madrid, Spain
Sweden
SW
Southwest, Sweden
Sponsors and Collaborators
argenx BVBA
Quintiles, Inc.
Investigators
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Study Director: Antonio Guglietta, MD argenx BVBA

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Responsible Party: argenx BVBA
ClinicalTrials.gov Identifier: NCT02965573     History of Changes
Other Study ID Numbers: ARGX-113-1602
2016-002938-73 ( EudraCT Number )
First Posted: November 17, 2016    Key Record Dates
Last Update Posted: October 23, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Layout table for MeSH terms
Muscle Weakness
Paresis
Myasthenia Gravis
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Pathologic Processes
Signs and Symptoms
Autoimmune Diseases of the Nervous System
Neuromuscular Junction Diseases
Neuromuscular Diseases
Autoimmune Diseases
Immune System Diseases