AX-8 Drug Safety, Tolerability and Plasma Levels in Healthy Subjects
Condition: Healthy
Study type: Interventional
Phase: Phase 1

Summary: 
      The main purpose of the study is to see how safe the study drug AX-8 is and how well it is
      tolerated when administered at different dose levels in healthy participants.

      The study will also investigate pharmacokinetics (PK), i.e how the study drug is taken up,
      metabolized (broken down) and eliminated.
    

Detailed description: 
      The primary objective of the study is to investigate the safety and tolerability of ascending
      AX-8 oral doses, i.e. orally disintegrating tablets (ODTs), administrated twice for one day
      (Day 1) in healthy participants.

      The secondary objectives are to investigate the pharmacokinetic (PK) profile and the
      subjective sensory attributes (e.g. basic tastes, palatability, cooling) of ascending AX-8
      oral doses (ODTs), administered twice for one day in healthy participants.

      The study consists of two parts.

      Part 1

      The first part of the study (Part 1) is an ascending dose, open-label, single center study in
      healthy participants. Part 1 will consist of a Screening Period (Days -28 to -1) to assess
      eligibility to participate in the study, 4 Treatment Periods (Day 1 to Day 2; one overnight
      stay for each treatment period) with a minimum washout period of 48 hours between doses
      (however a longer period will be required for dose escalation / safety review decisions, as
      required) and a Follow-Up Visit 7 to 14 days post last dose.

      During each treatment period, participants will be admitted to the study center on the
      morning of Day 1 and discharged from the study center on the morning of Day 2 (i.e. after the
      pre-discharge procedures have been performed). Participants will attend a Follow-Up Visit (or
      Early Withdrawal Visit as applicable) to complete the study.

      The end of the study will be the date of the last study visit for the last participant in the
      study (LPLV).

      It is planned to include 10 eligible participants into Part 1 of the study to receive AX-8
      ODTs administered orally which will be dissolved on the tongue (oromucosal route of
      administration). Participants will receive doses of AX-8 ODTs up to 80 mg/day, administered
      split over 2 dosing time points (i.e. 0 hour and + 8 hours), as follows:

        -  Treatment Period 1: 2 x 5 mg tablets, 10 mg total;

        -  Treatment Period 2: 2 x 10 mg tablets, 20 mg total;

        -  Treatment Period 3: 2 x 20 mg tablets, 40 mg total;

        -  Treatment Period 4: 2 x 40 mg tablets, 80 mg total.

      Dosing in each sequential treatment period will be staggered; after the first 2 participants
      (i.e. sentinel group) are dosed there will be at least a 24-hour observation period from the
      morning dose (0 hour) before the remaining 8 participants are dosed. The remaining
      participants will be dosed if the sentinel group shows no clinically significant safety or
      tolerability concerns (including available safety electrocardiograms [ECGs], vital signs
      measurements, physical examinations and review of any adverse events [AEs]) at the discretion
      of the PI. Any clinically significant findings from the sentinel group in the opinion of the
      PI will be discussed with the Sponsor prior to dosing of the remaining 8 participants.

      Dose escalation will be based on safety and tolerability data from each treatment period. In
      addition, available PK data from Treatment Period 1 (5 mg; twice daily) and Treatment Period
      2 (10 mg; twice daily) will be used to support dose escalation decisions for Treatment Period
      3 (20 mg; twice daily) and Treatment Period 4 (40 mg; twice daily).

      Escalation to the next higher dose level (i.e. next sequential treatment period) will not
      take place until the site's PI and the Sponsor have determined that adequate safety and
      tolerability data from the previous treatment period has been demonstrated to permit
      proceeding to the next sequential treatment period (i.e. higher dose level). The minimum data
      package required for dose escalation decisions will include safety and tolerability data
      through Day 2 in a minimum of 6 participants (including available safety ECGs, vital signs
      measurements, physical examinations, clinical laboratory tests and review of any adverse
      events). Safety reports will be produced summarizing the safety data of the participants. The
      justification for selection of the dose will be prepared by the investigator for the proposed
      dose escalation and documented in the dose escalation meeting minutes.

      Additional participants may be enrolled if it is deemed appropriate by the site's PI and the
      Sponsor to repeat a dose level or to study an intermediate dose level (lower than those
      planned). Repetition of a dose level will not be permitted for dose levels that met any of
      the stopping rules.

      Part 2

      The first part of the study (Part 1) has been completed, i.e. 10 participants were recruited
      and received AX-8 (10 mg to 80 mg/day) over 4 treatment periods (in a dose escalation
      regimen) and have attended their follow-up visits. The interim analysis of the study data
      from Part 1 has concluded that tablet dissolution time was too long, affecting systemic
      exposure to AX-8, probably due to the instructions for administration. Consequently, it was
      decided to re-evaluate the 5 mg and 40 mg AX-8 tablets with other administration
      instructions.

      It is planned that 10 participants will be enrolled into Part 2 of the study to receive a
      total dose of 45 mg split into two doses on Day 1 (Dose 1 (5 mg): +0 h, Dose 2 (40 mg): + 8
      h).

      Part 2 will consist of a Screening Period (Days -28 to -1) to assess eligibility to
      participate in the study, 1 Treatment Period (Day 1 to Day 2; one overnight stay) and a
      Follow-Up Visit 7 to 14 days post last dose. There will be no dose escalation decisions nor
      dose staggering of participants as the doses to be administered in Part 2 are lower than the
      highest dose level administered in Part 1.

      For Part 1 and Part 2; blood samples will be taken pre and post each dose to measure plasma
      concentrations of AX-8, despropyl AX-8 (metabolite C, MetC) and potentially other AX-8
      metabolites and compounds. Subjective assessments to characterise the sensory attributes of
      the AX-8 ODTs (e.g. feeling factors and taste) will be performed pre and post each dose.
      Safety assessments will be performed throughout the study and will include monitoring adverse
      events (AEs), physical examinations, vital signs, 12-lead ECGs, and clinical laboratory
      tests.

      The duration of the study will be approximately 65 days for subjects enrolled in Part 1 and
      approximately 44 days for subjects enrolled in Part 2; however, the actual duration will
      depend on the length of the screening period and the washout periods (as appropriate).
    

Intervention name(s): AX-8 Part 1; AX-8 Part 2
Intervention type(s): Drug; Drug
Intervention description(s): 5, 10, 20, and 40 mg AX-8 orally disintegrating tablets (ODTs), up to 80 mg/day split over 2 time points, 8 hours apart (i.e. Dose 1: 0 hour and Dose 2: + 8 hours). AX-8 ODTs will be administered orally and will be dissolved on the back of the tongue while the subject is in a sitting position. The subjects will be instructed not to suck, chew or swallow the tablet, i.e. to allow it to dissolve on the back of the tongue without any further intervention.; 5 and 40 mg AX-8 orally disintegrating tablets (ODTs), 45 mg/day split over 2 time points, 8 hours apart (i.e. Dose 1: 0 hour and Dose 2: + 8 hours). AX-8 ODTs will be administered orally and will be dissolved in the mouth while the subject is in a sitting position. The subjects will be instructed to actively move the tablet around in their mouth (i.e. active oral manipulation of the tablet) until it is fully dissolved.
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: A first group of 10 participants will be enrolled in the Part 1 of the study (arm 1).
Based on the results of Part 1, a second group of 10 participants will be enrolled in Part 2 of the study (arm 2).
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: open-label; phase 1; safety; tolerability; pharmacokinetics; healthy volunteers; AX-8