E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028417 |
E.1.2 | Term | Myasthenia gravis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to evaluate the efficacy of IGIV-C in subjects with generalized myasthenia gravis (MG) on standard of care treatment at study entry in terms of improvement in MG symptoms as measured by the mean change in Quantitative Myasthenia Gravis (QMG) score from Baseline (Week 0) to Week 24 as compared to placebo. |
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E.2.2 | Secondary objectives of the trial |
1) Percentage of subjects who experience a clinical improvement assessed by QMG score from Baseline (Week 0) to Week 24 where clinical improvement is defined as at least a 3-point decrease in QMG score
2) Percentage of subjects who experience a clinical improvement assessed by the MG Composite from Baseline (Week 0) to Week 24 where clinical improvement is defined as at least a 3-point decrease in the MG Composite
3) Percentage of subjects who experience a clinical improvement assessed by MG –Activities of Daily Living (MG-ADL) from Baseline (Week 0) to Week 24 where clinical improvement is defined as at least a 2-point decrease in MG-ADL |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female, ages 18 to 85 years
2. Anti-AChR antibody positive
3. Confirmed diagnosis of generalized MG. Historically, subjects may have previously had the Myasthenia Gravis Foundation of America (MGFA) Class II, III, IV, or V.
4. MGFA classification of Class II, III, or IVa inclusive at Screening.
5. QMG score ≥10 at Screening. Note: Subjects who only have a history of ocular MG may not enroll.
6. Receiving standard of care MG treatment at a stable dose consisting of any one of the following for the time intervals delineated below (time intervals apply to medications and maintenance of stable dose level):
-Cholinesterase inhibitor (pyridostigmine or equivalent) for at least 2 weeks prior to Screening and no immunosuppressants
- Cholinesterase inhibitor (pyridostigmine or equivalent) for at least 2 weeks priorto Screening and/or only one of the following:
* Prednisone (up to 60 mg/day or equivalent) for at least two months prior to Screening, or
* Azathioprine for at least 6 months prior to Screening, or
* Mycophenolate mofetil for at least 6 months prior to Screening, or
*Methotrexate for at least 6 months prior to Screening, or
* Cyclosporine or tacrolimus for at least 3 months prior to Screening
- Cholinesterase inhibitor (pyridostigmine or equivalent) for at least 2 weeks prior to Screening and/or prednisone (up to 60 mg/day or equivalent) for at least one month prior to Screening and only one of the following:
* Azathioprine for at least 6 months prior to Screening, or
* Mycophenolate mofetil for at least 6 months prior to Screening, or
*Methotrexate for at least 6 months prior to Screening, or
* Cyclosporine or tacrolimus for at least 3 months prior to Screening
7. Subjects must be willing and able to provide written informed consent
8. Subjects must be willing to comply with all aspects of the clinical trial protocol. |
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E.4 | Principal exclusion criteria |
1. Have received cyclophosphamide or any other immunosuppressive agent apart from the ones allowed per inclusion criteria within the past 6 months
2. Any change in MG treatment regimen between Screening (Week -3, Visit 0) and Baseline (Week 0, Visit 1)
3. Greater than two (>2) point change in QMG score, increased or decreased, between Screening (Week -3, Visit 0) and Baseline (Week 0, Visit 1)
4. Any episode of myasthenic crisis in the one month prior to Screening
5. Evidence of malignancy within the past 5 years (nonmelanoma skin cancer, carcinoma in situ of cervix is allowed) or thymoma potentially requiring surgical intervention during the course of the trial (intent to perform thymectomy)
6. Thymectomy within the preceding six months
7. Rituximab, belimumab, eculizumab or any monoclonal antibody used for immunomodulation within the past 12 months
8. Have received immune globulin (Ig) treatment given by IV, subcutaneous, or intramuscular route within the last 3 months
9. Current known hyperviscosity or hypercoagulable state
10. Currently receiving anti-coagulation therapy (vitamin K antagonists, nonvitamin K antagonist oral anticoagulants [e.g., dabigatran etexilate, rivaroxaban, edoxaban, and apixaban], parenteral anticoagulants [e.g., fondaparinux]). Note that oral anti-platelet agents are allowed (e.g., aspirin, clopidogrel, ticlodipine)
11. Plasma exchange (PLEX) performed within the last 3 months
12. History of non-response to IVIg when used in maintenance therapy of the subject’s MG, as judged by the Investigator
13. Any comorbid condition that in the opinion of the Investigator would put the subject at undue safety risk or compromise the ability of the subject to participate in the trial or the scientific integrity of the study
14. Inadequate venous access to support repeated intravenous infusions
15. History of anaphylactic reactions or severe reactions to any blood-derived product
16. History of intolerance to any component of the IP
17. Documented diagnosis of thrombotic complications to polyclonal IVIg therapy in the past
18. History of recent (within the last year) myocardial infarction or stroke
19. Uncontrolled congestive heart failure; embolism; or historically documented (within the last year) electrocardiogram (ECG) changes indicative of myocardial ischemia or atrial fibrillation
20. History of chronic alcoholism or illicit drug abuse (addiction) in the 12 months preceding the Screening/Week -3 (Visit 0)
21. Active psychiatric illness that interferes with compliance or communication with health care personnel
22. Females of child-bearing potential who are pregnant or have a positive serum pregnancy test (beta-human chorionic gonadotropin [β-HCG]-based assay)
23. Females who are breastfeeding
24. Females of child-bearing potential who are unwilling to practice a highly effective method of contraception (oral, injectable or implanted hormonal methods of contraception, placement of an intrauterine device or intrauterine system, condom or occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilization, or true abstinence*) throughout the study.
* True abstinence: When this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods], declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception.)
25. Currently receiving, or having received within 1 month prior to the Screening/Week -3 (Visit 0), any investigational medicinal product or device. In the case of an investigational medicinal product trial, at least five half-lives (if known) must have elapsed prior to Screening.
26. Known Immunoglobulin A (IgA) deficiency and anti-IgA serum antibodies
27. Renal impairment (i.e., serum creatinine exceeds more than 1.5 times the upper limit of normal [ULN] for the expected normal range for the testing laboratory)
28. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels exceeding more than 2.5 times the ULN for the expected normal range for the testing laboratory.
29. Hemoglobin levels <9 g/dL
30. Any medical condition which makes the clinical trial participation unadvisable or which is likely to interfere with the evaluation of the study treatment and/or the satisfactory conduct of the clinical trial according to the Investigator’s judgment. Any factor that in the opinion of the Investigator would compromise the ability of the subject to complete the trial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is improvement in MG symptoms as measured by the mean change in QMG score from Baseline (Week 0) to Week 24 as compared to placebo. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throuhout the study from Baseline (Week 0) to Week 24. |
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E.5.2 | Secondary end point(s) |
1) Percentage of subjects who experience a clinical improvement assessed by QMG score from Baseline (Week 0) to Week 24 where clinical improvement is defined as at least a 3-point decrease in QMG score
2) Percentage of subjects who experience a clinical improvement assessed by the MG Composite from Baseline (Week 0) to Week 24 where clinical improvement is defined as at least a 3-point decrease in the MG Composite
3) Percentage of subjects who experience a clinical improvement assessed by MG-ADL from Baseline (Week 0) to Week 24 where clinical improvement is defined as at least a 2-point decrease in MG-ADL |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Throughout the study, from Baseline (Week 0) to Week 24
2) Throughout the study, from Baseline (Week 0) to Week 24
3) Throughout the study, from Baseline (Week 0) to Week 24 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
Czech Republic |
Estonia |
France |
Germany |
Hungary |
Lithuania |
Poland |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 12 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 12 |