Phase 1 SAD/MAD Study of CVN766 in Healthy Volunteers
Condition: Safety Issues; Tolerance
Study type: Interventional
Phase: Phase 1

Summary: 
      Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability, and Pharmacokinetic Study
      of Escalating Single and Multiple Doses of CVN766 in Healthy Subjects
    

Detailed description: 
      Study Design:

      This is a Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-dose
      ascending study in healthy subjects with concurrent PK sampling from blood plasma, urine, and
      cerebrospinal fluid. The overall study design is outlined below:

      Part 1: Single-Dose Regimen and Fasted-Fed Crossover For the single-dose regimen,
      approximately 40 healthy male or female subjects will be enrolled in 1 of 5 single-dose
      cohorts (designated as S1 through S5, respectively) in an ascending fashion. Each cohort will
      consist of 8 subjects randomized to CVN766 or placebo, whereby 6 subjects will receive a
      single oral dose of CVN766 suspension, and 2 subjects will receive a matching placebo
      suspension under overnight fasted conditions. Subjects will remain fasted for 4 hours
      post-dose. Consumption of water is permitted as desired except for 1 hour before and after
      administration of Study Drug. Sentinel dosing (1 subject to receive CVN766 and 1 subject to
      receive placebo) will be used in each cohort to ensure adequate safety and tolerability
      evaluation prior to administering CVN766 or placebo to the remainder of subjects within the
      cohort. After blinded review by the Safety Review Group (SRG) of 24-hour, post-dose safety
      and tolerability data from the sentinel group, the remaining 6 subjects of each cohort may be
      dosed provided that the adverse event (AE) profile in the first 2 subjects is considered
      acceptable. To accommodate the lumbar puncture in the S3 fasted cohort, after the sentinel
      group, the remaining 6 subjects dosing may be staggered every two days. The planned dose
      levels will be 5, 15, 45, 125, and 250 mg CVN766. The SRG will review all available blinded
      safety, tolerability, clinical laboratory results (minimally including samples collected from
      subjects through 72-hours post-dose), and pharmacokinetic (PK) data after each cohort and
      before subsequent dose escalation. Each following dose level may be higher, lower, or remain
      the same as the preceding cohort, dependent on the recommendation of the SRG.

      Additional cohort(s) may be added if deemed necessary by the SRG to fully characterize the
      safety and tolerability of CVN766. For example, if the maximum tolerated dose (MTD) is not
      reached with cohort S5, additional cohorts with higher dose levels may be considered. Such
      additional cohorts will follow the same schedule of events as for cohorts S1 through S5.
      Additional/Alternative PK timepoints may be implemented if the SRG determines this is
      necessary to fully characterize the PK profile of CVN766.

      To assess the effect of food on CVN766 bioavailability in suspension formulation, single-dose
      administration will be repeated in a single cohort (S3) after ingestion of a standardized
      high-fat, high-calorie meal according to FDA Guidance for Industry (Food-effect
      bioavailability and fed bioequivalence studies, Dec 2002). Once the safety of the S3 cohort
      dose level has been assessed, the S3 cohort subjects will return to the clinic (no sooner
      than 14 days after their prior dose, or at least 4 half-lives, has lapsed based on
      preliminary PK data, whichever is longer). They will receive the same dose as before,
      administered after ingesting a standardized breakfast. Subjects will finish the entire
      content of their breakfast within 25 minutes and will receive an investigational product 30
      minutes (± 5 minutes) after beginning the meal. Sentinel dosing will not be required for
      subjects returning to the clinic for the fed regimen. If the CVN766 PK parameters in the
      fasted S3 cohort reveal poor absorption with inconclusive results, the fed cohort will be
      deferred until a higher dose level.

      Subjects for all cohorts will be admitted to the study unit 1 day prior to dosing and remain
      in the unit for safety and PK assessments. On Day 1, subjects will undergo safety monitoring
      and PK sampling from blood plasma through 72 hours post-dose and, for cohort S3 (fasted)
      only, from CSF via lumbar puncture at 3 hours post-dose. The total confinement period will be
      4 nights, unless extended at the discretion of the Investigator, e.g., for monitoring and/or
      management of AEs. Follow-up assessments will occur on approximately Days 8 and 14 and +21
      and +28 for cohort S3.

      Part 2: Multiple-Dose Regimen For the multiple-dose regimen, approximately 24 healthy male
      and female subjects age 18 to 50 years old will be enrolled in 1 of the 3 multiple-dose
      cohorts (designated as M1 through M3, respectively) in an ascending fashion. The dose levels
      planned to be studied in the multiple-dose regimen are 45, 125, and 250 mg CVN766 for
      multiple-dose cohorts M1 through M3, respectively. Each multiple-dose cohort will consist of
      8 subjects randomized to CVN766 or placebo, whereby 6 subjects will receive a daily oral dose
      of CVN766, and 2 subjects will receive a matching placebo for 7 days. Dosing will be
      administered in the fasting state; this can be changed by the SRG if exposure is found to be
      higher in the fed state. The planned dosing duration for the multiple-dose cohorts is 7 days.
      However, the duration may be increased to ≤14 days at the discretion of the SRG if
      preliminary PK data suggests steady-state will not be achieved within 6 days of daily dosing.
      For each dose on intensive PK sampling days (first and last days of dosing, e.g., Days 1 and
      7), subjects will remain fasted for 4 hours post-dose. On other dosing days (Days 2-6),
      subjects will remain fasted for 1-hour post-dose. Consumption of water is permitted as
      desired except for 1 hour before and after administration of Study Drug. Unlike the
      single-dose regimen, sentinel dosing within cohorts is not required in the multiple-dose
      regimen.

      Initiation of the multiple-dose regimen will only occur after a full blinded review of all
      safety, tolerability, and clinical laboratory results for the fasting drug administration to
      single-dose Cohort S3 (minimally including samples collected through Day 4) and available PK
      data. For each multiple-dose cohort after the first, the actual choice of dose level may be
      modified by the SRG after the available blinded safety, tolerability, clinical laboratory
      results, and PK data in the preceding multiple-dose and corresponding single-dose cohorts
      (i.e., multiple-dose Cohort M2 will not initiate until the data review for multiple-dose
      Cohort M1 and single-dose cohort S4 is complete). Each subsequent dose level may be higher,
      lower, or remain the same as the preceding.

      Additional multiple-dose cohort(s) may be added if deemed necessary by the SRG to fully
      characterize the safety and tolerability of CVN766. Such additional cohorts will follow the
      same schedule of events as for prior multiple-dose cohorts. Additional/Alternative PK
      timepoints may be implemented if the SRG determines this is necessary to fully characterize
      the PK profile of CVN766.

      Subjects for all multiple-dose cohorts will be admitted to the study unit 1 day prior to
      dosing and remain in the unit for the duration of the dosing period and for at least 48 hours
      after the last dose for safety and PK assessments before discharge. On treatment Days 1 and
      7, subjects will undergo safety monitoring and PK sampling from blood plasma through 48 hours
      post-dose and, in cohort M1 only, from urine through 24 hours post-dose. In cohorts M1 and
      M2, on treatment Day 7 (or last day of dosing, if extended beyond Day 7), subjects will
      additionally undergo PK sampling from CSF via lumbar puncture at 3 hours post-dose. If needed
      to resolve questions arising from prior cohorts' data, subjects in cohort M3 also may, at SRG
      discretion, undergo PK sampling from CSF via lumbar puncture, the choice of day (e.g., Day 1
      or Day 7) and sampling time to be decided by SRG. Subjects in MAD cohorts may be asked to
      return to the clinic for an additional PK sample 3 days after the last dose (e.g., Day 10)
      depending on emerging PK data, i.e., t½). The total confinement period will be 9 nights
      unless extended for additional dosing days or management of AEs. Follow-up assessments will
      occur approximately 7 and 14 days after the final dose.
    

Intervention name(s): CVN766
Intervention type(s): Drug
Intervention description(s): highly selective orexin-1 receptor (Ox1R) antagonist
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: For the single-dose regimen, approximately 40 healthy male or female subjects will be enrolled in 1 of 5 single-dose cohorts (designated as S1 through S5, respectively) in an ascending fashion. Each cohort will consist of 8 subjects randomized to CVN766 or placebo, whereby 6 subjects will receive a single oral dose of CVN766 suspension, and 2 subjects will receive a matching placebo suspension under overnight fasted conditions.
For the multiple-dose regimen, approximately 24 healthy male and female subjects age 18 to 50 years old will be enrolled in 1 of the 3 multiple-dose cohorts (designated as M1 through M3, respectively) in an ascending fashion. The dose levels planned to be studied in the multiple-dose regimen are 45, 125, and 250 mg CVN766 for multiple-dose cohorts M1 through M3, respectively.
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: PK; Efficacy