Rhizomelic Chondrodysplasia Punctata Clinical Trial
Official title:
A Phase 1, Randomized, Double-blind, Placebo-controlled, Combined Single and Multiple Ascending Dose Study of PPI-1011 in Subjects to Assess Safety, Tolerability, and Pharmacokinetics
PPI-1011 is being developed as a docosahexaenoic acid (DHA) containing plasmalogen precursor with good long-term stability, specifically for the treatment of rhizomelic chondrodysplasia punctata (RCDP), which is an ultra rare type of peroxisomal biogenesis disorder (PBD). The goal of treatment with PPI-1011 is to increase the levels of plasmalogens within circulation and tissues, with the hope that this will normalize plasmalogen levels in the body and result in clinical improvement to patients. The present study is a first-in-human (FIH), phase 1, randomized, double-blind, placebo-controlled, dose-escalation study to assess the safety, tolerability and pharmacokinetics (PK) of single and multiple ascending doses of PPI-1011 administered orally to healthy subjects. The study consists of 5 planned single-dose cohorts (n = 8 per cohort, total randomized 6 active: 2 placebo) with sentinel design. Following a review of the safety and PK data by the safety review committee and submission to Health Canada the study will be expanded to include 2 planned multiple-dose cohorts (n = 8 per cohort, total randomized 6 active: 2 placebo).
This is a randomized, double-blind, placebo-controlled, first-in-human (FIH) study of PPI-1011 in healthy male and non-pregnant, non-lactating female volunteers. The study will consist of two parts: single ascending dose (SAD) and multiple ascending dose (MAD). The study will evaluate the safety, tolerability and PK in 5 planned SAD cohorts with sentinel design (n=8 per cohort, total randomized 6 active: 2 placebo) and 2 planned MAD cohorts (n=8 per cohort, total randomized 6 active: 2 placebo). Based on accumulating data, additional single-dose and/or a multiple-dose cohort(s) (n=8 per cohort) may be added to better assess the safety, tolerability, or PK profile of PPI-1011 to meet study objectives and try to determine the maximum tolerated dose. A sentinel dose in 2 participants (1:1 PPI-1011: placebo) will be performed in each single-dose cohort to evaluate the safety and tolerability at planned doses. Additional cohort(s) will be dosed in case a different dose(s) is required based upon the emerging safety and PK data from the main cohort(s) to provide better assessment for the safety, tolerability, or PK of PPI-1011. A sentinel design may not be applicable when a cohort with the same or a higher drug exposure has already been evaluated. Single Ascending Dose (SAD): The 5 planned single-dose levels are: Cohort A 10 mg/kg PPI-1011 or Placebo Cohort B 25 mg/kg PPI-1011 or Placebo Cohort C 50 mg/kg PPI-1011 or Placebo Cohort D 75 mg/kg PPI-1011 or Placebo Cohort E 100 mg/kg PPI-1011 or Placebo Dose levels may be changed and/or additional cohorts may be added based on emerging safety and PK data. Subjects enrolled in the single-dose treatment cohorts will receive a single dose of the study drug (PPI-1011 or placebo) orally on Day 1. A period of at least 24 hours will be required between administering study drug to the first 2 subjects (1 active, 1 placebo) and the 6 remaining subjects (5 active, 1 placebo) in the cohort. If no major safety concerns are observed following 24 hours of observation, dosing of the remaining 6 participants in that cohort may proceed. The dose-escalation may proceed after the Safety Review Committee review of the blinded safety data up to at least Day 3 from all participants in the preceding single-dose cohort. The dose escalation decision will be based on safety evaluation for an acceptable safety profile as determined by the SRC. Cohorts A, B, C, D, and E will be dosed in a non-fasting state. Multiple Ascending Dose (MAD): The 2 planned multiple-dose levels are: Cohort AA: Study Drug Dose*: TBD mg/kg PPI-1011 or Placebo Dosing Regimen*: 1 x TBD mg/kg every 24 hours Duration (Days): 14 Total Dose (mg/kg): TBD Cohort BB: Study Drug Dose*: TBD mg/kg PPI-1011 or Placebo Dosing Regimen*: 1 x TBD mg/kg every 24 hours Duration (Days): 14 Total Dose (mg/kg): TBD Cohorts AA and BB will be dosed in a non-fasting state. *MAD dosing levels will be decided after review of the safety and PK data from the SAD cohorts. The SRC will propose doses, which will be submitted to Health Canada, together with the safety and PK data from the SAD. Dose levels may be further adjusted based on emerging safety and PK data from MAD cohorts. Subjects enrolled in the multiple-dose treatment cohorts will receive oral doses of the study drug (PPI-1011 or placebo) once daily at 24-hour intervals. Thus, the total number of doses subjects will receive in a MAD cohort will be up to 14 doses. The doses for these cohorts will be selected after review of the blinded safety and PK data by the SRC and submitted to Health Canada. The dose in the MAD will not exceed the doses tested in the SAD. Treatment Phases: Single-Dose Cohorts (In-Clinic): Participants will check in on Day -1. On Day 1, participants will receive a single dose of PPI-1011 or placebo. Participants will remain confined in the clinic from Day -1 until Day 2 (at least 36 hours after dosing). Participant can stay longer in the clinic if deemed necessary upon the Investigator's discretion. Single-Dose Cohorts (Outpatient Visits): After completing the in-house confinement period, participants will return to the clinic for an outpatient visit on Day 3, Day 4, Day 5 and Day 6. Multiple-Dose Cohorts (In-Clinic): Participants will check in on Day -1. Participants will receive oral doses of PPI-1011 or placebo from Day 1 to Day 14. Participants will remain confined in the clinic from Day -1 through Day 15 (at least 36 hours after the last dose). Participant can stay longer in the clinic if deemed necessary upon the Investigator's discretion. Multiple-Dose Cohorts (Outpatient Visits): After completing the confinement period, participants will return to the clinic for an outpatient visit on Day 16, Day 17, Day 18 and Day 19. Study Numbers: Fifty-six (56) healthy volunteers are planned to be enrolled in this study. Forty (40) subjects will be enrolled in the SAD portion of the study and 16 subjects will be enrolled in the MAD portion (n=8 per cohort). For SAD cohorts, each cohort will enroll a minimum of 3 subjects of each sex, with at least 2 males and 2 females randomized to the active treatment. The same may be implemented for MAD cohorts based on emerging safety and PK data. Additional subjects (in single [n=8] or multiple dose [n=8] cohorts) may be added to better assess the safety, tolerability, or PK of PPI-1011 to meet study objectives. ;
| Status | Clinical Trial | Phase | |
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| Recruiting |
NCT04031287 -
RCDP Natural History Study
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