Ascending Dose Study of CT1812 in Healthy Volunteers
Condition: Cognitive Impairment
MeSH terms: Cognitive Dysfunction
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a double-blind, placebo controlled, ascending dose, multi-cohort trial. The study
      will be conducted in two phases: a single ascending dose (SAD) phase "Part A", followed by a
      multiple ascending dose (MAD) phase "Part B". In Part A, subjects will receive one dose of
      study drug. In Part B, subjects within a cohort will receive the same dose daily for 14 days.
      In both parts, sequential cohorts will be exposed to increasing doses of CT1812 in order to
      identify the maximum tolerated dose (MTD).
    

Detailed description: 
      Part A - Single Ascending Dose in up to 54 Subjects

      Screening procedures will occur on Days -21 to -3. Subjects will be admitted to the clinical
      research unit for up to 5 days. Administration of a single dose of study drug will occur on
      Day 1. Following completion of all safety assessments and blood draws for PK analyses,
      subjects will be discharged on Day 3 or Day 4, depending on cohort.

      Double-blind dosing will occur in cohorts 1 through 6. In these cohorts, 6 subjects will
      receive CT1812 and 2 will receive placebo. Doses will be escalated per protocol.

      In cohort 1 only, 2 subjects (1 placebo/1 active CT1812) will be dosed 24 hours prior to the
      remaining subjects in the cohort. The remaining 6 subjects will be dosed if no safety
      concerns are identified in the first 2 subjects (the last 6 subjects will be admitted to the
      research unit one day later than the initial 2 subjects). In cohorts 2 through 7, all
      subjects will be enrolled and dosed together.

      Following completion of each cohort, bioanalytical analyses for CT1812 PK will be performed
      and plasma Cmax concentrations will be reviewed. Enrollment of additional cohorts and dose
      escalations will not occur until safety assessments and PK analyses have been completed in
      the prior cohort.

      The dose escalation plan may be adjusted in response to pharmacokinetic analyses,
      particularly if the relationship between dose and Cmax becomes non-proportional. If an MTD or
      a maximum allowable exposure is established at less than 650 mg (~8.45 mg/kg), fewer cohorts
      may be required, reducing the number of study subjects. Should an MTD not be identified (i.e.
      all doses are well tolerated and review of PK analyses reveal no clinical concerns),
      additional cohorts at higher doses may be enrolled. The maximum dose administered will not
      exceed 1350 mg (~18 mg/kg).

      At the completion of dose escalation, one additional cohort of 6 subjects will be
      administered open-label CT1812 at the highest well-tolerated dose or potential therapeutic
      dose, 30 minutes following a standardized meal to test for food effects.

      All subjects will be admitted to the clinical research unit on Day 0. Dosing will take place
      on the morning of Day 1. Blood draws for assessment of PK parameters will occur pre-dose and
      at 15, 30, 45, 60, and 90 minutes post dose as well as at 2, 3, 4, 8, 12, 24, 36 and 48 hours
      post dose. Subjects in cohorts 5 and 6 will have an additional sample drawn 72 hours after
      dosing. Subjects will be released on Day 3 or 4 following completion of all blood draws and
      safety assessments.

      Part B - Multiple Ascending Dose in up to 60 Subjects

      Following identification of the MTD in Part A and analysis of the pharmacokinetic data from
      Part A, the multiple ascending dose Part B will commence in 4 cohorts.

      Screening procedures will occur on Days -21 to -3. Subjects will be admitted to the clinical
      research unit for 17 days. Once daily administration of study drug will be initiated at 25%
      of the MTD established in Part A. Dosing will occur on Days 1 - 14. Following completion of
      all safety assessments and blood draws for PK analyses, subjects will be discharged on Day
      16.

      In cohorts 3 and 4 only, subjects will undergo lumbar puncture and CSF sampling for CT1812
      concentration analysis (single-point) at the steady state Tmax (time after dosing TBD).

      In addition to cohorts 1-4, two cohorts of subjects aged 65 to 75 may be enrolled and dosed
      following identification of the multiple-dose MTD.
    

Intervention name(s): CT1812; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Doses will be escalated in the following sequence: 10mg, 30mg, 90mg, 180mg, 360mg, 650mg.; Matching placebo administered.
Other intervention name(s): Study drug
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Alzheimer's Disease; Mild Cognitive Impairment