To Evaluate the Safety, Tolerability, PK, and PD of XW003 Injection in Healthy Adult Participants
Condition: Type 2 Diabetes Mellitus; Obesity; Nonalcoholic Steatohepatitis
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 1

Summary: 
      XW003 is an acylated human GLP-1 analogue and is being development for diabetes mellitus,
      obesity and nonalcoholic steatohepatitis (NASH) management. This is a first-in-human (FIH),
      single-centre, double blind, randomised, SAD and MAD study of XW003 conducted in healthy
      adult participants. The study is designed to evaluate the safety, tolerability, PK, and PD of
      XW003 in healthy adult participants.
    

Detailed description: 
      Participants will undergo a Screening period beginning up to 28 days prior to
      randomisation/dose administration. Participants will undergo pre-dose assessments, post-dose
      assessments, and will complete an EOS follow-up visit or early termination (ET) visit.

      Up to 42 participants will be enrolled into one of up to six (6) sequential cohorts (Cohorts
      A1 to A6). Participants in each cohort will be randomised to receive a single subcutaneous
      (SC) dose of either XW003 or matching placebo on Day 1 following an overnight fast. Two
      sentinel participants will receive a single SC dose of XW003 initially. If dosing of these
      sentinel participants proceeds without clinically significant safety signals in the first 48
      hours post-dose, the remaining participants will receive a single dose of XW003 or placebo
      according to the randomisation schedule.

      Participants in Cohorts B1 to B3 (n=10 per cohort) will be randomized to receive a single SC
      dose of either XW003 (n=8) or matching placebo (n=2) once weekly for 6 weeks. Doses will be
      administered following an overnight fast of at least 10 hours.
    

Intervention name(s): Cohort A; Placebo A; Cohort B; Placebo B
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Participants in each cohort (A1 to A6) will be randomised to receive a SC dose of XW003 on Day 1 after overnight fasting by body weight range:
Proposed XW003 Dose Levels (50 kg-75 kg): 0.03mg, 0.1mg, 0.2mg, 0.4mg, 0.8mg and 0.6mg respectively for Cohorts A1 to A6.
Proposed XW003 Dose Levels (76 kg-90 kg): 0.03mg, 0.1mg, 0.25mg, 0.5mg, 1.0 mg and 0.6mg.
These doses are subject to change following SRC review of each cohort - XW003 dose level will not exceed 2.0 mg.; Participants in each cohort (A1 to A6) will be randomised to receive a SC dose of volume-matching placebo on Day 1 after overnight fasting by body weight range:
Proposed Placebo Dose Levels (50 kg-75 kg): 0.03mg, 0.1mg, 0.2mg, 0.4mg, 0.8mg, and 0.6mg respectively for Cohorts A1 to A6.
Proposed Placebo Dose Levels (76 kg-90 kg): 0.03mg, 0.1mg, 0.25mg, 0.5mg, 1.0 mg and 0.6mg.
These doses are subject to change following SRC review of each cohort - dose level will not exceed 2.0 mg.; Participants in cohorts B1 to B3 (n=10 per cohort) will receive multiple SC doses of XW003 (n=8) once weekly for 6 weeks following an overnight fast of at least 10 hours.
Subject to change following SRC review of each cohort.
Following 4 weeks of once weekly dosing, the SRC will review the safety data (and PK data for Cohort B1 only) to determine the treatment for the following cohort and whether dosing can commence in parallel.
At least 3 days prior to Cohort B3 Week 3 (i.e., 3 days prior to the third dose in Cohort B3), the SRC will review the safety and PK data for Cohorts B1 and B2 to determine whether Cohort 3 dosing for Weeks 3 to 6 may commence.; Participants in cohorts B1 to B3 (n=10 per cohort) will receive multiple SC doses of matching placebo (n=2) once weekly for 6 weeks following an overnight fast of at least 10 hours.
Subject to change following SRC review of each cohort.
Following 4 weeks of once weekly dosing, the SRC will review the safety data (and PK data for Cohort B1 only) to determine the treatment for the following cohort and whether dosing can commence in parallel.
At least 3 days prior to Cohort B3 Week 3 (i.e., 3 days prior to the third dose in Cohort B3), the SRC will review the safety and PK data for Cohorts B1 and B2 to determine whether Cohort 3 dosing for Weeks 3 to 6 may commence.
Other intervention name(s): GLP-1 analogue; Placebo; GLP-1 analogue; Placebo
Intervention MeSH terms: Glucagon; Glucagon-Like Peptide 1
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: One of up to six (6) sequential cohorts (Cohorts A1 to A6). Participants in each cohort will be randomised to receive a single subcutaneous (SC) dose of either XW003 or matching placebo on Day 1 following an overnight fast. Two sentinel participants will receive a single SC dose of XW003 initially. If dosing of these sentinel participants proceeds without clinically significant safety signals in the first 48 hours post-dose, the remaining participants will receive a single dose of XW003 or placebo according to the randomisation schedule.
Participants in Cohorts B1 to B3 (n=10 per cohort) will be randomized to receive a single SC dose of either XW003 (n=8) or matching placebo (n=2) once weekly for 6 weeks. Doses will be administered following an overnight fast of at least 10 hours.
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Type 2 Diabetes Mellitus; Obesity; Nonalcoholic Steatohepatitis