BN201 SAD MAD Study in Healthy Subjects
Condition: Optic Neuritis; Optic; Neuritis, With Demyelination
MeSH terms: Neuritis; Optic Neuritis; Demyelinating Diseases
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to investigate the safety, tolerability, pharmacokinetics, and
      pharmacodynamics of single and multiple doses of BN201 in healthy subjects.

      This is a phase I, randomised, double-blind, placebo-controlled study to assess the safety,
      tolerability, pharmacokinetics and pharmacodynamics of BN201 in healthy subjects following
      single ascending doses and two cohorts of multiple doses. The study will be conducted in two
      parts (Part A and Part B). Part A (up to 8 single ascending doses (SD)) will be conducted in
      32 subjects (4 interlocking cohorts of 8 subjects). Part B (up to 2 multiple ascending doses
      (MD)) will be conducted in 16 subjects (2 cohorts of 8 subjects). Subjects in Part A will
      undergo a screening period (Day -28 to Day -2), two in-patient treatment periods compromising
      3 overnight stays (from Day -1 to Day 3) with a wash out period of at least 14 days between
      dose administrations and a follow up visit 12 to 16 days following administration of IMP.
      Subjects in Part B will undergo a screening period (Day -28 to Day -2), an in-patient
      treatment period compromising 7 overnight stays (from Day -1 to Day 7) and a follow up visit
      12 to 16 days following final administration of Investigational Medicinal Product (IMP).
    

Detailed description: 
      Screening (Days -28 to -2) Screening assessments will be performed within 28 days of the
      first dose to ensure the eligibility of participants. Assessments will include medical
      history, demographics, concomitant medication check, physical examination, body weight,
      height, BMI, HIV, Hepatitis B and Hepatitis C screen, drugs of abuse and alcohol screen,
      routine laboratory assessments (biochemistry, haematology and urinalysis), 12-lead ECG, EEG
      monitoring, brain MRI scan, vital signs (supine systolic and diastolic blood pressure, pulse)
      and body temperature. Female participants will also be screened for pregnancy and hormone
      status. A C-SSRS questionnaire will also be performed at screening for Part B only.

      Treatment Period

      Part A:

      Up to four cohorts ((SD1), (SD2), (SD3), (SD4)) of eight subjects will be randomly assigned
      to receive either two single intravenous doses of BN201, two single intravenous doses of
      placebo or one single intravenous dose of BN201 and placebo (per treatment period) over two
      treatment periods (Period 1 and Period 2). Within each cohort, 6 subjects will receive BN201
      and 2 subjects will receive placebo. Two "dose leader" subjects will be dosed on the same
      day, at least 48 h before the remaining subjects in the cohort. Of these two subjects, one
      will be dosed with BN201 and the other with placebo. The Chief Investigator (or delegate)
      must confirm it is safe to continue with the dosing of the remainder of the cohort following
      review of appropriate safety data. The remaining 6 subjects of the cohort (five randomised to
      active and one to placebo) will then be dosed.

      Subjects will be admitted to the clinical unit in the morning of Day -1 and will remain in
      the unit until the 48 h post dose scheduled assessments and procedures have been performed
      (Day 3). On Day -1 of each Treatment Period subjects' eligibility will be re-assessed and
      blood and urine samples will be collected for laboratory safety tests (including drugs of
      abuse and alcohol screen, biochemistry, haematology, urinalysis and serum pregnancy test). A
      12-lead ECG, vital signs (supine systolic and diastolic blood pressure, pulse), body
      temperature, adverse event and concomitant medication checks will be performed. The
      intravenous dose of BN201 or placebo will be based on body weight measured on Day -1. An
      evening snack will be consumed at least 10 hours (h) before (each) dose administration.

      After an overnight fast of at least 10 h, dose administration will occur on the morning of
      Day 1 between 08:00 and 11:00 whilst subjects are in a semi supine position. The subjects
      will remain in this position until 2 h post-infusion, however other positions are temporarily
      allowed for scheduled assessment requirements. Fasting will continue until 4 h after start of
      infusion; a standardised meal will then be administered.

      Subjects will be discharged from the clinical unit on Day 3 (48 h post-dose) providing there
      are no ongoing safety concerns. There will be a wash out period of at least 14 days between
      dose administrations prior to subjects returning for their treatment 2 scheduled assessments
      and procedures.

      The following assessments will be made during treatment Period 1 and Period 2:

        -  Safety assessments: Adverse event (AEs) and concomitant medication check, physical
           examination, laboratory safety assessments (drugs of abuse and alcohol screen,
           biochemistry, haematology, urinalysis and serum pregnancy test), 12-lead ECG, telemetry,
           Holter monitoring, EEG monitoring, vital signs (supine systolic and diastolic blood
           pressure, pulse) and body temperature, infusion site reaction assessment.

        -  Pharmacokinetics (PK) assessments: Blood sample collection for measurement of BN201 in
           plasma.

        -  Pharmacodynamics (PD) assessments: Blood sample collection for measurement of
           phosphorylation of N-myc downstream-regulated gene 1 (NDGR1) in peripheral blood
           mononuclear cells (PBMCs).

        -  Pharmacogenomic assessments: Blood sample will be collected for potential genotyping of
           deoxyribonucleic acid (DNA) sequence variants to explore potential relationships with
           PK/PD and or tolerability.

      A follow-up visit (including a brain MRI scan) will be conducted 12 to 16 days following each
      administration of IMP. If all follow-up assessments are satisfactory to the Investigator
      following Treatment Period 2 the subject will be discharged from the study. If any AEs are
      ongoing, or any assessments not satisfactory subjects may be recalled to the unit for
      follow-up assessments until the Investigator is satisfied the subject may be discharged from
      the study. Subjects will be advised to return or contact the unit at any time if they may be
      experiencing any adverse effects.

      Enrolment of the subsequent cohort will only proceed, if blinded PK and safety data from the
      previous cohort has been reviewed by the Sponsor and Chief Investigator and is found to be
      satisfactory.

      Part B:

      Two cohorts (MD1, MD2) of eight subjects will be randomly assigned to receive either multiple
      intravenous doses of BN201 or multiple intravenous doses of placebo once daily for five
      consecutive days (Day 1 to Day 5). Within each cohort, 6 subjects will receive BN201 and 2
      subjects will receive placebo. Two "dose leader" subjects will be dosed on the same day, at
      least 48 h before the remaining subjects in the cohort. Of these two subjects, one will be
      dosed with BN201 and the other with placebo. The Chief Investigator (or delegate) must
      confirm it is safe to continue with the dosing of the remainder of the cohort following
      review of appropriate safety data. The remaining 6 subjects of the cohort (five randomised to
      active and one to placebo) will then be dosed. The dose levels to be administered will be
      based on the safety, tolerability and PK results of Part A. Cohort MD1 can only be started if
      a higher dose level in the SAD part was well tolerated and that simulated PK modelling for
      multiple dose administration based on PK data from single doses do not suggest that the Cmax
      threshold of 13.3 μg/mL will be exceeded. Enrolment of MD2 will only proceed if blinded PK
      and safety data from subjects in MD1 has been reviewed by the Sponsor and Chief Investigator
      and is found to be satisfactory. A lower dose may be chosen if deemed appropriate following
      review of PK and safety data from Part A.

      Subjects will be admitted to the clinical unit in the morning of Day -1 and will remain in
      the unit until the scheduled assessments and procedures have been performed on Day 7, 48 h
      post-last dose. On Day -1 subjects' eligibility will be re-assessed and blood and urine
      samples will be collected for laboratory safety tests (including drugs of abuse and alcohol
      screen, biochemistry, haematology, urinalysis and serum pregnancy test). A 12-lead ECG, vital
      signs (supine systolic and diastolic blood pressure, pulse), body temperature, quantitative
      sensory testing (QST) and visual analogue scale (VAS) and adverse event and concomitant
      medication checks will be performed. The intravenous dose of BN201 or placebo will be based
      on body weight measured on Day -1. An evening snack will be consumed at least 10 h before
      (each) dose administration.

      After an overnight fast of at least 10 h, dose administration will occur on the mornings of
      Day 1 to Day 5 between 08:00 and 11:00 whilst subjects are in a semi supine position. The
      subjects will remain in this position until 2 h post-infusion, however other positions are
      temporarily allowed for scheduled assessment requirements. Fasting will continue until 4 h
      after start of infusion; a standardised meal will then be administered.

      Subjects will be discharged from the clinical unit on Day 7 providing there are no ongoing
      safety concerns. The following assessments will be made during Day -1 to Day 7:

        -  Safety assessments: Adverse event (AEs) and concomitant medication check, physical
           examination, laboratory safety assessments (drugs of abuse and alcohol screen,
           biochemistry, haematology and urinalysis and serum pregnancy test), 12-lead ECG,
           telemetry, Holter monitoring, EEG monitoring*, vital signs (supine systolic and
           diastolic blood pressure, pulse) and body temperature, infusion site reaction
           assessment, C-SSRS questionnaire, QST and VAS.

        -  PK assessments: Blood sample collection for measurement of BN201 in plasma.

        -  PD assessments: Blood sample collection for measurement of phosphorylation of N-myc
           downstream-regulated gene 1 (NDGR1) in peripheral blood mononuclear cells (PBMCs).

        -  Pharmacogenomic assessments: Blood sample will be collected for potential genotyping of
           deoxyribonucleic acid (DNA) sequence variants to explore potential relationships with
           PK/PD and or tolerability.

             -  EEG monitoring only performed for Part B Cohort 2 if indicated from results from
                Part B Cohort 1

      A follow-up visit (including a brain MRI scan) will be conducted 12 to 16 days following the
      subjects' final administration of IMP. If all follow up assessments are satisfactory to the
      Investigator, the subject will be discharged from the study. If any AEs are ongoing, or any
      assessments not satisfactory subjects may be recalled to the unit for follow-up assessments
      until the Investigator is satisfied the subject may be discharged from the study. Subjects
      will be advised to return or contact the unit at any time if they may be experiencing any
      adverse effects.
    

Intervention name(s): Comparison of BN201 treatment with Placebo
Intervention type(s): Drug
Intervention description(s): Single Dose or Multiple Dose of BN201 IV administration
Other intervention name(s): BN201
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Acute Optic Neuritis (AON); Demyelination; Optic Neuritis