| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Immune thrombocytopenic purpura |
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| E.1.1.1 | Medical condition in easily understood language |
| Immune thrombocytopenic purpura |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10074667 |
| E.1.2 | Term | Immune thrombocytopenic purpura |
| E.1.2 | System Organ Class | 100000004851 |
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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 |
Part A:
To assess the safety and tolerability of a single ascending dose of intravenous administration of M254 in healthy volunteers.
Part B:
To assess the safety and tolerability of a single intravenous administration of M254 in immune thrombocytopenic purpura (ITP) patients compared to 1000 mg/kg intravenous immunoglobulin (IVIg).
Part C:
To assess the safety of a single intravenous administration of M254 compared to 1000 mg/kg of IVIg.
To characterize the PD of single intravenous administration of M254 compared to 1000 mg/kg IVIg.
Part D:
To assess the safety and tolerability of repeated intravenous administration of M254 in ITP patients. |
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| E.2.2 | Secondary objectives of the trial |
Part A:
To characterize the pharmacokinetics (PK) of a single intravenous administration of M254 at different doses in healthy volunteers.
Part B:
To characterize the PK of a single intravenous administration of M254 at different doses in ITP patients.
Part C:
To characterize the PK of a single intravenous administration of M254 at different doses.
Part D:
To characterize the PK of repeated intravenous doses of M254 in ITP patients.
To assess PD of repeated intravenous doses of M254 in ITP patients.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant must be ≥ 18 and ≤ 55 years of age inclusive, at the time of signing the informed consent form (ICF).
2. Good health as indicated by medical history (without hemolysis or thrombosis that may impact current study), physical examination, vital signs (with systolic blood pressure below 140 mmHg), clinical laboratory tests, and 12-lead electrocardiogram, and all abnormal findings are assessed as not clinically significant by the Investigator.
3. Body weight must be between 50 and 110 kg, inclusive, and body mass index (BMI) between 18.5 and 30 kg/m2, inclusive, at screening.
4. Healthy male and females are eligible.
a.Male participants:
• If male, surgically or biologically sterile. If not sterile, agreement to use an acceptable form of birth control with sexual partner or abstain from sexual relations for 100 days following the last treatment.
b. Female participants:
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
◦ Not a woman of childbearing potential (WOCBP) (Surgically sterilized via hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or of non-childbearing potential (i.e., postmenopausal for at least 1 year).
OR
◦ A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 90 days after the last dose of study intervention.
• Of child-bearing potential, with a fertile male sexual partner, willing to use 2 adequate methods of contraception from 30 days prior to dosing until 90 days after the last dose of study treatment. Adequate contraception is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom. Also, total abstinence, in accordance with the lifestyle of the subject, is acceptable.
5. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
6. Ability to speak, read, and understand primary medical care language(s) at the site.
7. If female, a negative serum pregnancy test at screening and a negative urine or serum pregnancy test at check-in to the clinic for the baseline visit, and not nursing or planning a pregnancy through 90 days following the last dose of study medication.
Patients:
1. Participant must be 18 to 64 years of age, inclusive, at the time of signing the ICF.
2. Diagnosed with ITP (with or without splenectomy) according to the Hematology Guidelines for at least 3 months prior to screening.
3. Platelet count ≥ 15 × 10^9/L and < 50 × 10^9/L within 96 hours prior to start of study drug infusion on Day 1
4. Body weight must be within a range that allows for the planned M254 infusion time to be completed in < 4 hours.
5. Maintenance immunosuppressive therapy, steroid therapy, cyclosporine A, mycophenolate mofetil, azathioprine, thrombopoietin receptor agonists, or danazol are allowed, but the dosages of all these medications must be stable for at least 4 weeks prior to Visit 1 (Day 1).
6. No history of clotting disorder other than ITP including no myocardial infarction within the last 6 months. No arrhythmia known to increase the risk of thrombotic events (eg, atrial fibrillation).
For inclusion criteria patients nr. 07 - 10 please see protocol; no more possibility here.
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| E.4 | Principal exclusion criteria |
Healthy volunteers:
1. Previously received M254.
2. History of any drug allergy, hypersensitivity, or intolerance to any drug product that in the opinion of the Investigator would place the subject at particular risk and compromise the safety of the subject in the
study.
3. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, psychiatric disease, or any other condition, that in the opinion of the Investigator would jeopardize the safety of the subject or the validity of the study results.
4. History of splenectomy, asthma (with the exception of childhood asthma that has resolved), chronic obstructive pulmonary disease, or recurrent or current gastrointestinal or respiratory infections.
5. Any illness within 5 days, or clinically significant airway infections within 30 days, prior to first study drug dosing.
6. On fluid restriction.
7. Any prescription medication(s) within 14 days of dose administration (or 5 half-lives, whichever is longer) or any non-prescribed systemic or topical medication (including any herbal product) within 7 days prior to dose administration.
8. Plans to participate in another clinical trial while enrolled in this study and/or received an investigational drug and/or device within 60 days prior to dose administration.
9. Positive urine drug screen at screening.
10. Positivity for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) at screening.
11. History or current diagnosis of substance dependence (except nicotine and caffeine) or alcohol abuse over the past 2 years, according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR).
12. Smokes or has smoked more than 5 cigarettes per day in the last 90 days and is unable to stop smoking during in-patient observation period in clinic.
13. Unwilling to abstain from alcohol for at least 24 hours prior to dosing with study medication until the time of discharge from the study unit and at least 24 hours prior to each ambulatory visit.
14. Donation or significant loss of whole blood (480 mL or more) within 30 days or plasma within 14 days prior to admission.
15. Vaccination within 1 month before dosing, or plans to receive vaccination within 3 months after the last dose.
16. Veins unsuitable for cannulation or multiple venipunctures on either arm.
17. Patients with any prior history of arterial or venous thrombosis, AND ≥ 2 of the following risk factors: hormone replacement therapy, systemic contraception (containing estrogen), smoking, diabetes, hypercholesterolemia, medication for hypertension, cancer, hereditary thrombophilic disorders (eg, Factor V Leiden, antithrombin III deficiency, antiphospholipid syndrome, etc), hyperviscosity (cryoglobulines and chylomicronemia)
18. Patients with selective IgA deficiency with known anti-IgA antibodies.
Patients:
1. Patients with any prior history of arterial or venous thrombosis, AND ≥ 2 of the following risk factors: hormone replacement therapy, systemic contraception (containing estrogen), smoking, diabetes, hypercholesterolemia, medication for hypertension, cancer, hereditary thrombophilic disorders (eg, Factor V Leiden, antithrombin III deficiency, antiphospholipid syndrome, etc), hyperviscosity (cryoglobulines and chylomicronemia)
2. Any clinically relevant abnormality, other than ITP, which in the opinion of the Investigator makes the patient unsuitable for participation in the study.
3. Female patients who are nursing or pregnant at screening or pre-dose on Day 1.
4. History of alcohol/drug abuse or dependence within 12 months of the study.
5. Rituximab within 3 months of screening
6. Patient has consumed aspirin, aspirin-containing compounds, salicylates, anticoagulants, quinine or non-steroidal anti-inflammatories (NSAIDs) for > 3 consecutive days within 2 weeks of the study start and until the end of the study.
7. Consumption of any herbal or dietary supplements, excluding vitamin or mineral supplements, within 1 week of the study start.
8. If known from prior medical history, non-response to IVIg. Nonresponse to IVIg is defined as increase of platelet count did not rise above 50 × 10^9/L within 14 days of treatment.
9. History of platelet agglutination that prevents reliable measurement of platelet counts.
10. Any laboratory or clinical evidence for HIV infection.
For exclusion criteria patients nr. 11 - 21 please see protocol; no more possibility here.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A:
Incidence and severity of adverse events (AEs) following administration of M254 at single dose levels.
Clinically significant changes in clinical safety labs, vital signs, and electrocardiograms (ECGs) with M254 administration.
Part B:
Incidence and severity of AEs following administration of M254 at single dose levels and 1000 mg/kg IVIg.
Clinically significant changes in clinical safety labs, vital signs, and ECGs following M254 administration and 1000 mg/kg IVIg.
Part C:
Incidence and severity of AEs of M254 and 1000 mg/kg IVIg.
Clinically significant changes in clinical safety labs, vital signs, and ECGs following M254 administration and 1000 mg/kg IVIg.
Platelet response after M254 administration compared to IVIg.
Part D:
Incidence and severity of AEs with repeated administration of M254.
Clinically significant changes in clinical safety labs, vital signs, and ECGs with M254 administration.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Part A:
Measurements of PK parameters of M254 following the administration of a single intravenous dose.
Part B:
Measurements of PK parameters of M254 following the administration of a single intravenous dose.
Part C:
Measurements of PK parameters of M254 following the administration of a single intravenous dose.
Part D:
Measurements of PK parameters of M254 following the administration of a repeated intravenous doses.
Platelet response after repeated M254 administration. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Study is double blind for Part A (Netherlands only), but it is open for the remainder of the trial. |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Spain |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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