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

NCT02048358 | Terminated Phase 1

• 2 other identifiers: 2B3-201-CR-0012013-004077-28
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 2

Brief Summary

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).

Conditions

Healthy Volunteers; Multiple Sclerosis

Keywords

Healthy volunteers; first in human; 2B3-201; methylprednisolone; CNS-targeting; liposomal; crossover; placebo controlled; active controlled; multiple sclerosis; multiple sclerosis relapse

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• Measure changes in central nervous system (CNS) functioning after intravenous administration of 2B3-201 by using the Neurocart test battery

  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

Other Outcomes (2)

• Optimization of the infusion schedule for 2B3-201 with or without the addition of an anti-histaminic drug to minimize the likelihood of non-allergic infusion reactions.

  3 weeks

• Changes in neurological examination, Expanded Disability Systems Score (EDSS) and Multiple Sclerosis functional composite (MSFC) after a single dose of 2B3-201 in RMS patients having an acute disease exacerbation, as a measure of clinical efficacy

  6 weeks

Study Arms (9)

2B3-201 150mg

EXPERIMENTAL

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; Drug: Placebo; Drug: Methylprednisolone hemisuccinate

2B3-201 300mg

EXPERIMENTAL

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; Drug: Placebo; Drug: Methylprednisolone hemisuccinate

2B3-201 450mg

EXPERIMENTAL

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; Drug: Placebo; Drug: Methylprednisolone hemisuccinate

450mg 2B3-201

EXPERIMENTAL

2B3-201 450mg, once, IV infusion in 2500ml 5% dextrose

Drug: 2B3-201

300mg 2B3-201

EXPERIMENTAL

2B3-201 300mg, once, IV infusion in 1500ml 5% dextrose

Drug: 2B3-201

2B3-201 450mg male volunteers

EXPERIMENTAL

2B3-201 450mg, once, IV infusion in 1500ml 5% dextrose

Drug: 2B3-201

2B3-201 300mg or 450mg female volunteers

EXPERIMENTAL

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; Drug: Methylprednisolone hemisuccinate

Relapsing MS patients; 2B3-201 450 mg

EXPERIMENTAL

2B3-201 450mg, once, IV infusion in 2500ml 5% dextrose

Drug: 2B3-201

Relapsing MS patients; 2B3-201 dose tbd

EXPERIMENTAL

2B3-201 (dose to be determined), once, IV infusion in 5% dextrose

Drug: 2B3-201

Interventions

2B3-201 DRUG

Also known as: 2B3-201: glutathione PEGylated-liposomal methylprednisolone

2B3-201 150mg; 2B3-201 300mg; 2B3-201 300mg or 450mg female volunteers; 2B3-201 450mg; 2B3-201 450mg male volunteers; 300mg 2B3-201; 450mg 2B3-201; Relapsing MS patients; 2B3-201 450 mg; Relapsing MS patients; 2B3-201 dose tbd

Placebo DRUG

Also known as: 5% Dextrose

2B3-201 150mg; 2B3-201 300mg; 2B3-201 450mg

Methylprednisolone hemisuccinate DRUG

Also known as: Solu-Medrol

2B3-201 150mg; 2B3-201 300mg; 2B3-201 300mg or 450mg female volunteers; 2B3-201 450mg

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• BBB-Therapeutics B.V.: lead

Study Sites (2)

VUmc, PET and neurology clinical research unit

Amsterdam, North Holland, 1081 HV, Netherlands

Location

Centre for Human Drug Research (CHDR)

Leiden, 2333 CH, Netherlands

Location

Related Publications (1)

• Gaillard PJ, Appeldoorn CC, Rip J, Dorland R, van der Pol SM, Kooij G, de Vries HE, Reijerkerk A. Enhanced brain delivery of liposomal methylprednisolone improved therapeutic efficacy in a model of neuroinflammation. J Control Release. 2012 Dec 28;164(3):364-9. doi: 10.1016/j.jconrel.2012.06.022. Epub 2012 Jun 23.

  PMID: 22732475 BACKGROUND

MeSH Terms

Conditions

Multiple Sclerosis

Interventions

Glucose; Methylprednisolone Hemisuccinate

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Hexoses; Monosaccharides; Sugars; Carbohydrates; Methylprednisolone; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Geert-Jan Groeneveld, MD, PhD

  Center for Human Drug Research

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 17, 2014
• First Posted: January 29, 2014
• Study Start: November 1, 2013
• Primary Completion: January 1, 2015
• Study Completion: February 1, 2015
• Last Updated: February 6, 2015

Record last verified: 2015-02

Locations

NL (2)