Safety, Pharmacokinetics and Pharmacodynamics Study With 2B3-201 in Healthy Subjects and Multiple Sclerosis(MS) Patients

Study Overview
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Brief Summary
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In this first in human study the aim is to assess the safety, pharmacokinetics and pharmacodynamics of 2B3-201 in a randomized, first in human, double-blind, placebo- and active comparator- controlled 3-way crossover study in 18 healthy male subjects (part 1). Furthermore, the findings obtained from part 1 will be extended and confirmed in a subsequent parallel open label study in 18 healthy male and 12 MS patients and an open label study with methylprednisolone as comparator in 12 female volunteers (part 2).

Official Title
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Randomized, Double-blind, Placebo- and Active Comparator- Controlled Crossover Study in Healthy Male Subjects and an Open Label Study in Healthy Subjects and MS Patients to Assess the Safety, Pharmacokinetics and Pharmacodynamics of 2B3-201

Conditions
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Healthy Volunteers, Multiple Sclerosis

Intervention / Treatment
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* Drug: 2B3-201
* Drug: Placebo
* Drug: Methylprednisolone hemisuccinate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy subjects Healthy male or female subjects, 18 to 45 years of age, inclusive. Healthy status is defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, hematology, blood chemistry, and urinalysis. Body mass index (BMI) between 18 and 30 kg/m2, inclusive, and with a minimum weight of 50 kg. Able to participate and willing to give written informed consent and to comply with the study restrictions. Relapsing MS patients Age: 18 to 65 years, both men and women. Patients with relapsing multiple sclerosis (RMS), defined as below, with an acute exacerbation, who in the opinion of the treating physician should undergo a 3 - 5 day course of high dose methylprednisolone; Patients with Relapsing Remitting Multiple Sclerosis (RRMS). Patients with Secondary Progressive Multiple Sclerosis (SPMS) and Patients with clinically isolated syndromes (CIS) who show dissemination of lesions in time (DIT) and space (DIS) on MRI scans according to the 2010 McDonald criteria. Able to participate and willing to comply with the study restrictions. Understands and signs the written informed consent prior to any of the testing under this protocol, including screening tests and evaluations that are not considered part of the subject's routine care. Exclusion Criteria: Healthy volunteers: Any subject who is pregnant or breastfeeding. A urine pregnancy test should be performed in female subjects of childbearing potential (defined as < 2 years after last menstruation and not surgically sterile) prior to the start of the study treatment. For female subjects of childbearing potential (defined as < 2 years after last menstruation and not surgically sterile) and male subjects who are not surgically sterile or with female partners of childbearing potential: absence of effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal gel) will be a contraindication. Not willing to use double-barrier contraception, for the duration of the study and for 3 months after the last dose. Positive test for drugs of abuse at screening or pre-dose. History of alcohol consumption exceeding 2 standard drinks per day on average (1 standard drink = 10 grams of alcohol) within 3 months of screening. Alcohol consumption will be prohibited during study confinement and at least 48 hours before screening, before dosing, and before each scheduled visit. History or symptoms of any significant disease including (but not limited to), neurological, psychiatric, endocrine, cardiovascular, respiratory, gastrointestinal, hepatic, or renal disorder. Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening. Systolic blood pressure (SBP) greater than 140 mm Hg or less than 90 mm Hg, and diastolic blood pressure (DBP) greater than 90 mm Hg or less than 50 mm Hg. Use of any medications (prescription or over-the-counter [OTC]), vitamin, mineral, herbal, and dietary supplements within 21 days of study drug administration. Exceptions are paracetamol (up to 4 g/day). Use of CYP3A4-inhibiting drugs, including quinine containing drinks (bitter lemon and tonic water) is prohibited within 21 days of study drug administration Subject has used grapefruit, grapefruit juice, grapefruit-containing products, Seville oranges, or pomelo-containing products, within 14 days prior to day -1. Clinically significant abnormalities, as judged by the investigator, in laboratory test results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis). In the case of uncertain or questionable results, tests performed during screening may be repeated before randomization to confirm eligibility or judged to be clinically irrelevant for healthy subjects. Participation in an investigational drug or device study within 3 months prior to screening. Donation of blood over 500 mL within three months prior to screening. Concomitant disease or condition that could interfere with, or for which the treatment of might interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the subject in this study. Smoker of more than 10 cigarettes per day prior to screening or who use tobacco products equivalent to more than 10 cigarettes per day. Clinically significant abnormal ECG, as judged by the Investigator. Current infection or inflammation study within 1 month prior to screening Recent vaccinations study within 3 months prior to screening. Positive Mantoux test of 5 mm or more. Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, or multiple drug allergies (non-active hay fever is acceptable). Unwillingness or inability to comply with the study protocol for any other reason. RMS patients: Previous acute exacerbations, and/or corticosteroid treatment or ACTH < 1 month before present exacerbation, Hypersensitivity to methylprednisolone. Prior use of immunosuppressive treatments / disease-modifying drugs (DMDs) other than interferon-beta, glatiramer acetate, fingolimod, dimethylfumarate or teriflunomide within 12 months of the index episode. Shorter periods may be allowed at the discretion of the PI and after approval from the sponsor. Subjects may continue their current therapy with interferons, glatiramer acetate, fingolimod, or teriflunomide throughout the course of the study. Non-steroidal anti-inflammatory agents, including salicylic acid, should be avoided during the administration of the steroid therapy. If absolutely necessary they are permitted for subjects to treat interferon side effects, when the patient is not responding to acetaminophen/paracetamol. Current or recent (within 30 days of first study treatment) treatment with any other investigational drug or participation in any other investigational study Evidence of psychiatric illness History of any significant cardiac, gastrointestinal, hepatic, pulmonary, renal or active immunosuppressive disease. Immune deficiency or any other medical conditions that would preclude corticosteroid therapy. Any patient who is pregnant or breastfeeding. A urine pregnancy test should be performed in female subjects of childbearing potential (defined as < 2 years after last menstruation and not surgically sterile) prior to the start of the study treatment. For female subjects of childbearing potential (defined as < 2 years after last menstruation and not surgically sterile) and male subjects who are not surgically sterile or with female partners of childbearing potential: absence of effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal gel) will be a contraindication. Physical examination results or laboratory findings that may interfere with the planned treatment, affect patient compliance or place the patient at a high risk of treatment-related complications. Known hypersensitivity to any of the cyclodextrin or any excipients in 2B3-201 (e.g. PEG, Cholesterol, HSPC or GSH).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2B3-201 150mg<br>2B3-201 150mg, once, IV infusion in 1000ml 5% dextrose/ Methylprednisolone hemisuccinate 1000mg, once, IV infusion in 1000ml 5% dextrose/ Placebo, once, IV infusion 1000ml 5% dextrose | Drug: 2B3-201<br> <br> * Other names: 2B3-201: glutathione PEGylated-liposomal methylprednisolone;Drug: Placebo<br> <br> * Other names: 5% Dextrose;Drug: Methylprednisolone hemisuccinate<br> <br> * Other names: Solu-Medrol;|
| Experimental: 2B3-201 300mg<br>2B3-201 300mg, once, IV infusion in 1500ml 5% dextrose/ Methylprednisolone hemisuccinate 300mg, once, IV infusion in 1500ml 5% dextrose/ Placebo, once, IV infusion 1500ml 5% dextrose | Drug: 2B3-201<br> <br> * Other names: 2B3-201: glutathione PEGylated-liposomal methylprednisolone;Drug: Placebo<br> <br> * Other names: 5% Dextrose;Drug: Methylprednisolone hemisuccinate<br> <br> * Other names: Solu-Medrol;|
| Experimental: 2B3-201 450mg<br>2B3-201 450mg, once, IV infusion in 2500ml 5% dextrose/ Methylprednisolone hemisuccinate 1000mg, once, IV infusion in 2500ml 5% dextrose/ Placebo, once, IV infusion 2500ml 5% dextrose | Drug: 2B3-201<br> <br> * Other names: 2B3-201: glutathione PEGylated-liposomal methylprednisolone;Drug: Placebo<br> <br> * Other names: 5% Dextrose;Drug: Methylprednisolone hemisuccinate<br> <br> * Other names: Solu-Medrol;|
| Experimental: 450mg 2B3-201<br>2B3-201 450mg, once, IV infusion in 2500ml 5% dextrose | Drug: 2B3-201<br> <br> * Other names: 2B3-201: glutathione PEGylated-liposomal methylprednisolone;|
| Experimental: 300mg 2B3-201<br>2B3-201 300mg, once, IV infusion in 1500ml 5% dextrose | Drug: 2B3-201<br> <br> * Other names: 2B3-201: glutathione PEGylated-liposomal methylprednisolone;|
| Experimental: 2B3-201 450mg male volunteers<br>2B3-201 450mg, once, IV infusion in 1500ml 5% dextrose | Drug: 2B3-201<br> <br> * Other names: 2B3-201: glutathione PEGylated-liposomal methylprednisolone;|
| Experimental: 2B3-201 300mg or 450mg female volunteers<br>2B3-201 300mg or 450mg, once, IV infusion in 1500 or 2500ml 5% dextrose/ Methylprednisolone hemisuccinate 1000mg, once, IV infusion in 1500 or 2500ml 5% dextrose | Drug: 2B3-201<br> <br> * Other names: 2B3-201: glutathione PEGylated-liposomal methylprednisolone;Drug: Methylprednisolone hemisuccinate<br> <br> * Other names: Solu-Medrol;|
| Experimental: Relapsing MS patients; 2B3-201 450 mg<br>2B3-201 450mg, once, IV infusion in 2500ml 5% dextrose | Drug: 2B3-201<br> <br> * Other names: 2B3-201: glutathione PEGylated-liposomal methylprednisolone;|
| Experimental: Relapsing MS patients; 2B3-201 dose tbd<br>2B3-201 (dose to be determined), once, IV infusion in 5% dextrose | Drug: 2B3-201<br> <br> * Other names: 2B3-201: glutathione PEGylated-liposomal methylprednisolone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with adverse events as a measure of safety and tolerability of 2B3-201 | Safety and tolerability of 2B3-201, in comparison to free methylprednisolone hemisuccinate and placebo and the safety and tolerability of 2B3-201amongst the different study populations: healthy male and female subjects and MS patients, additionally the safety and tolerability of 2B3-201 with hydroxypropyl β-cyclodextrin added to the infusion bag will be assessed in healthy male subjects | 3 weeks | 
| Pharmacokinetics in plasma of intravenously administered 2B3-201 in terms of Cmax, Volume of distribution, half-life (T1/2), area under the plasma concentration-time curve (AUC), Clearance (CL) | Pharmacokinetics of 2B3-201, in comparison to free methylprednisolone hemisuccinate and placebo and the pharmacokinetics of 2B3-201amongst the different study populations: healthy male and female subjects and MS patients. Additionally the pharmacokinetics of 2B3-201 with hydroxypropyl β-cyclodextrin added to the infusion bag will be assessed in healthy male subjects | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure changes in central nervous system (CNS) functioning after intravenous administration of 2B3-201 by using the Neurocart test battery | Neurocart test battery (Pharmaco-EEG, Maze learning, Visual verbal Learning test, Stroop test, Adaptive tracking, VAS Bond & Lader and VAS Bowdle, Eye movements, LSEQ sleep questionnaire) as a measure of pharmacodynamic effects of 2B3-201 on CNS functioning in comparison to free methylprednisolone hemisuccinate and placebo; | 3 weeks | 
| Changes in levels of Hypothalamic-pituitary-adrenal (HPA) axis hormones as a measure of pharmacodynamic effects of 2B3-201 in comparison to free methylprednisolone hemisuccinate and placebo; |  | 3 weeks | 
| Changes in levels of fasting blood glucose as a measure of pharmacodynamic effects of 2B3-201 in comparison to free methylprednisolone hemisuccinate and placebo; |  | 3 weeks | 
| Changes in levels of osteocalcin concentrations as a measure of pharmacodynamic effects of 2B3-201 in comparison to free methylprednisolone hemisuccinate and placebo; |  | 3 weeks | 
| Changes in levels of lymphocyte count as a measure of pharmacodynamic effects of 2B3-201 in comparison to free methylprednisolone hemisuccinate and placebo; |  | 3 weeks | 
| Changes in levels of complement factors during infusion as a measure of pharmacodynamic effects of 2B3-201 in comparison to free methylprednisolone hemisuccinate and placebo; |  | 3 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy volunteers, first in human, 2B3-201, methylprednisolone, CNS-targeting, liposomal, crossover, placebo controlled, active controlled, multiple sclerosis, multiple sclerosis relapse