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

Healthy Volunteers Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02048358
• Other study ID #: 2B3-201-CR-001
• Secondary ID: 2013-004077-28
• Status: Terminated
• Phase: Phase 1
• First received: January 17, 2014
• Last updated: February 5, 2015
• Start date: November 2013
• Est. completion date: February 2015

Study information

• Verified date: February 2015
• Source: BBB-Therapeutics B.V.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 47
• Est. completion date: February 2015
• Est. primary completion date: January 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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).

Study Design

Endpoint Classification: Safety Study

Related Conditions & MeSH terms

• Healthy Volunteers
• Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• 2B3-201

• Placebo

• Methylprednisolone hemisuccinate

Locations

Country	Name	City	State
Netherlands	VUmc, PET and neurology clinical research unit	Amsterdam	Noord-Holland
Netherlands	Centre for Human Drug Research (CHDR)	Leiden

Sponsors (1)

Lead Sponsor	Collaborator
BBB-Therapeutics B.V.

Country where clinical trial is conducted

Netherlands, 

References & 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	Yes
Other	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	No
Primary	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 ß-cyclodextrin added to the infusion bag will be assessed in healthy male subjects	3 weeks	Yes
Primary	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 ß-cyclodextrin added to the infusion bag will be assessed in healthy male subjects	3 weeks	No
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	No
Secondary	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	Yes