Phase 1 Study of Safety, Tolerability and Pharmacokinetics of SPR994
Condition: Healthy Volunteers
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 2 parts: a single ascending dose (SAD) part, followed by a multiple
      ascending dose (MAD) part. In SAD, all subjects will receive 1 dose of SPR994 (100, 300, 600
      or 900 mg) or placebo, except for subjects enrolled in food effect cohorts in which subjects
      will receive one dose following a 10 hour fast and a second dose in the fed state following a
      minimum 5 days washout period. There is a single, optional, open-label control cohort that
      may enroll, in which all 8 subjects will receive Orapenem® (tebipenem pivoxil fine granules).
      In MAD, subjects will receive multiple doses of SPR994 (300 or 600 mg) or placebo for 14
      consecutive days at either BID or TID dosing. In both parts, cohorts will be exposed to
      increasing doses of SPR994 with various extended release formulations.
    

Detailed description: 
      This study is a randomized, double-blind, placebo-controlled, combined single and multiple
      ascending dose (SAD and MAD) trial. Up to one hundred fifty two (152) subjects aged 18-55,
      who fulfill the inclusion/exclusion criteria, may be enrolled in this study. Up to a total of
      17 SAD and 2 MAD cohorts of eight subjects each will be examined. Subjects in each cohort
      will be randomized 3:1 to receive SPR994 at doses ranging from 100 mg to 900 mg or placebo in
      various immediate and timed release formulations. One SAD control cohort, Cohort 12, may be
      enrolled in which eight subjects will receive a single dose of Orapenem® at 300 mg in a fed
      and fasted state. Dosing is complete in SAD Cohorts 1-3, 6 and 7. Subjects in Cohorts 1-3
      received a single dose of SPR994 and subjects in food effect Cohorts 6 and 7 each received 2
      doses. Subjects enrolled in SAD Cohorts 8 and beyond will receive a single dose of SPR994 or
      placebo in a fasted state and a second dose following a standardized meal to investigate food
      effect on the pharmacokinetics of SPR994 and TBPM. SAD Cohorts 8 through 10 may run in a
      staggered or concurrent manner before enrollment of further cohorts. Blinded pharmacokinetic
      data will be reviewed at the conclusion of Cohort 10 (300 mg fasted & fed). Should the PK be
      optimized in one of the various time released formulations, the Sponsor may decide to proceed
      to enrollment of the 600 mg Cohorts using the optimal formulation; other timed release
      formulations may also be explored at 300 mg dose in a staggered or concurrent manner until an
      optimal formulation(s) is identified. When an optimal formulation(s) is identified, the 600
      mg Cohorts may run in a staggered or concurrent manner. SAD Cohorts 16 (100 mg fasted) and 17
      (900 mg fasted) may run prior to or in a staggered or concurrent manner with MAD Cohorts 4
      (300 mg) and 5 (600 mg). During the MAD part of the study, subjects will receive 27 doses of
      SPR994 or placebo over a period of 14 days. Based on the observed PK of SPR994 in prior
      cohorts, the total number of doses may be increased to 40 doses of SPR994 or placebo
      administered TID over 14 days; only one dose will be administered on Day 14 to allow for PK
      sample collection In both SAD and MAD parts of the study, the Cohorts will be exposed to
      increasing doses of SPR994. Each part (SAD and MAD) of the study will consist of 3 periods: a
      screening period, a treatment period, and a follow-up period. The safety and tolerability of
      SPR994 will be assessed based on the types and frequency of adverse events (AEs) reported;
      concomitant medication usage; and changes from baseline in physical examination, weight,
      vital signs, ECG, and standard clinical laboratory tests. A Safety Management Group (SMG)
      will review the data of cohorts prior to escalating to the next dose level.
    

Intervention name(s): SPR994; Placebo Oral Tablet; Orapenem®
Intervention type(s): Drug; Drug; Drug
Intervention description(s): SAD: Double-blind dosing will occur in all SAD Cohorts except for Cohort 12. In each cohort, six subjects will receive one of five different timed release formulations of SPR994 and 2 subjects will receive placebo. Subjects in SAD Cohorts 2, 3, 6, 16 and 17 will receive a single dose following a 10-h fast. Subjects in SAD Cohorts 1, 8-15 will receive one dose of SPR994 or placebo following a 10-h fast on Day 1 and a second dose following consumption of a standardized meal on Day 7. The dose escalation steps may be altered following review of the safety data of each cohort.
MAD: Double-blind dosing will occur in all MAD Cohorts. Subjects will receive multiple doses of an optimal timed release formulation of SPR994 in MAD Cohort 4 (300 mg) and Cohort 5 (600 mg) or placebo for 14 consecutive days at either BID or TID dosing beginning on Day 1.; Mannitol 200SD SAD: Two subjects in each cohort will receive matching placebo. MAD: Two participants in each cohort will receive matching placebo.; Tebipenem pivoxil granules
Other intervention name(s): SPR994 Oral Tablet; Placebo; Orapenem® fine granules
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized, double-blind, placebo-controlled, combined single and multiple ascending dose (SAD and MAD) trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: safety; tolerability; pharmacokinetics; SPR994