A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of LWP779 in Healthy Participants
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- Longwood Pharmaceuticals (Hangzhou) Co., Ltd.
- Enrollment
- 76
- Locations
- 1
- Primary Endpoint
- Number and proportion of participants with a treatment-emergent adverse event (TEAE)
Overview
Brief Summary
This study is a randomized, double-blind, placebo-controlled clinical trial featuring both single ascending dose (SAD), food effect and multiple ascending dose (MAD) phases intended to evaluate the safety, tolerability, PK, PD, and active metabolites of LWP779 after oral administration in healthy participants.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •1\. Capable of understanding the written informed consent document; willingly provides valid, signed written informed consent;
- •2\. Males and females aged 18 to 65 years old (inclusive) at the time of signing the ICF.
- •3.No history of past or current diseases or abnormalities involving the cardiac, hepatic, renal, gastrointestinal, nervous, respiratory, or ocular systems, as well as psychiatric or metabolic abnormalities, that are clinically significant as judged by the investigator.
- •4.Participants must be confirmed healthy through medical history, VS, physical examination, clinical laboratory tests , and a 12-lead ECG;
- •5\. Body mass index (BMI) of 18.0 to 32.0 kg/m2 inclusive and body weight not less than 50 kg at the time of screening and Day -
- •6\. Participants must agree to take the investigator-approved effective contraceptive measures during the trial as required by the investigator.
- •7.Normal renal function (defined as eGFR ≥ 80 mL/min/1.73 m2) at screening and Day -
- •8\. Ability to swallow and retain oral medication.
- •9.No suicidal ideation, as demonstrated by a score of "0" on the Columbia Suicide Severity Rating Scale (C-SSRS) at screening or Day -1.
Exclusion Criteria
- •1.Known hypersensitivity to LWP779 or any of its constituents.
- •2.Known or suspected tumor.
- •3.History of unexplained syncope, symptomatic hypotension or hypoglycemia.
- •4.Presence of orthostatic hypotension at screening or Day -
- •5.Participants with any ocular diseases (e.g., glaucoma, fundus macular degeneration, corneal lesions, retinopathy, etc.).
- •6.Family history of long QTc syndrome; mean QTcF interval \>450 msec for males and \>470 msec for females or presence of any other mean ECG abnormality at screening or Day -1 deemed clinically significant by the PI/medical delegate.
- •7.Resting pulse rate \<45 bpm or \>100 bpm at screening, or Day -
- •8.Systolic blood pressure \< 90 or \>160 mm Hg and/or diastolic blood pressure \< 50 or \> 95 mm Hg at screening or Day -
- •9.History of unstable ischemic heart disease, recent (within 6 months of screening) myocardial infarction, or presence of clinically significant cardiac arrhythmia.
- •10.Ongoing liver disease or unexplained liver function test (LFT) elevations, defined as ALT, AST, gamma glutamyl transferase (GGT), alkaline phosphatase (ALP) or total/direct bilirubin \> 1.5x ULN at screening or Day -
Arms & Interventions
Single Ascending Dose - 600 mg
Intervention: LWP779 (Drug)
Single Ascending Dose - 600 mg
Intervention: Placebo of LWP779 (Drug)
Single Ascending Dose - 150 mg
Intervention: LWP779 (Drug)
Single Ascending Dose - 150 mg
Intervention: Placebo of LWP779 (Drug)
Single Ascending Dose - 300 mg
Intervention: LWP779 (Drug)
Single Ascending Dose - 300 mg
Intervention: Placebo of LWP779 (Drug)
Single Ascending Dose - 900 mg
Intervention: LWP779 (Drug)
Single Ascending Dose - 900 mg
Intervention: Placebo of LWP779 (Drug)
Single Ascending Dose - 1200 mg
Intervention: LWP779 (Drug)
Single Ascending Dose - 1200 mg
Intervention: Placebo of LWP779 (Drug)
Outcomes
Primary Outcomes
Number and proportion of participants with a treatment-emergent adverse event (TEAE)
Time Frame: From baseline to Day 7 (±1) for SAD, baseline to Day16 (±2) for FE, baseline to Day 14 (± 2) for MAD
12-lead electrocardiogram (ECG) (QT Interval)
Time Frame: From baseline to Day 7 (±1) for SAD, baseline to Day16 (±2) for FE, baseline to Day 14 (± 2) for MAD
Number of participants with abnormal vital signs
Time Frame: From baseline to Day 7 (±1) for SAD, baseline to Day16 (±2) for FE, baseline to Day 14 (± 2) for MAD
Number of participants with abnormal physical examination findings
Time Frame: From baseline to Day 7 (±1) for SAD, baseline to Day16 (±2) for FE, baseline to Day 14 (± 2) for MAD
Columbia Suicide Severity Rating Scale (C-SSRS)
Time Frame: From baseline to Day 7 (±1) for SAD, baseline to Day16 (±2) for FE, baseline to Day 14 (± 2) for MAD
The Columbia Suicide Severity Rating Scale (C-SSRS) is used to assess suicidal ideation and suicidal behavior. Within the module "Answer for Actual Suicidal Attempts Only", the scoring range is 0 to 5. A score of 0 indicates no physical damage or very minor physical damage (e.g. surface scratches), and a score of 5 indicates death.
Number of participants with abnormal laboratory tests results
Time Frame: From baseline to Day 7 (±1) for SAD, baseline to Day16 (±2) for FE, baseline to Day 14 (± 2) for MAD
Number of participants with abnormal ophthalmoscopic-examination findings
Time Frame: From baseline to Day 7 (±1) for SAD, baseline to Day16 (±2) for FE, baseline to Day 14 (± 2) for MAD
Secondary Outcomes
- C-QTc in the dose escalation part of SAD（in the dose groups of ≥300 mg）(Wthin 30 minutes before administration and to 24 hours after administration.)
- Maximum concentration (Cmax) of LWP779 and its active metabolites in plasma(Within 30 minutes before administration to 48 hours after single administration)
- Time to reach Cmax (Tmax) of LWP779 and its active metabolites in plasma(Within 30 minutes before administration to 48 hours after single administration)
- Total area under the concentration time curve (AUC) of LWP779 and its active metabolites in plasma(Within 30 minutes before administration to 48 hours after single administration)
- Apparent terminal half-life (t1/2) of LWP779 and its active metabolites in plasma(Within 30 minutes before administration to 48 hours after single administration)
- Terminal elimination rate constant (λz) of LWP779 and its active metabolites in plasma(Within 30 minutes before administration to 48 hours after single administration)
- Apparent clearance (CL/F) of LWP779 and its active metabolites in plasma(Within 30 minutes before administration to 48 hours after single administration)
- Apparent volume of distribution divided by bioavailability (Vd/F) of LWP779 and its active metabolites in plasma(Within 30 minutes before administration to 48 hours after single administration)
- Lag time (tlag) of LWP779 and its active metabolites in plasma(Within 30 minutes before administration to 48 hours after single administration)
- Steady-state minimum concentration (Cmin,ss) of LWP779 and its active metabolites in plasma(Wthin 30 minutes before administration to 24 hours after multiple administration on Day 1 and Day 7, and 30 min pre-dose on Day 5 and Day 6.)
- Steady-state maximum concentration (Cmax,ss) of LWP779 and its active metabolites in plasma(Wthin 30 minutes before administration to 24 hours after multiple administration on Day 1 and Day 7, and 30 min pre-dose on Day 5 and Day 6.)
- Steady-state average concentration (Cavg,ss) of LWP779 and its active metabolites in plasma(Wthin 30 minutes before administration to 24 hours after multiple administration on Day 1 and Day 7, and 30 min pre-dose on Day 5 and Day 6.)
- Area under the concentration-time curve from time zero to tau (AUC0-τ) of LWP779 and its active metabolites in plasma(Wthin 30 minutes before administration to 24 hours after multiple administration on Day 1 and Day 7, and 30 min pre-dose on Day 5 and Day 6.)
- Time to reach Cmax (Tmax) of LWP779 and its active metabolites in plasma(Wthin 30 minutes before administration to 24 hours after multiple administration on Day 1 and Day 7, and 30 min pre-dose on Day 5 and Day 6.)
- Terminal elimination rate constant (λz) of LWP779 and its active metabolites in plasma(Wthin 30 minutes before administration to 24 hours after multiple administration on Day 1 and Day 7, and 30 min pre-dose on Day 5 and Day 6.)
- Apparent terminal half-life (t1/2) of LWP779 and its active metabolites in plasma(Wthin 30 minutes before administration to 24 hours after multiple administration on Day 1 and Day 7, and 30 min pre-dose on Day 5 and Day 6.)
- Accumulation index (AUC0-τ (D7) / AUC0-τ (D1)) of LWP779 and its active metabolites in plasma(Wthin 30 minutes before administration to 24 hours after multiple administration on Day 1 and Day 7, and 30 min pre-dose on Day 5 and Day 6.)
- Cmax (D7) / Cmax (D1)) of LWP779 and its active metabolites in plasma(Wthin 30 minutes before administration to 24 hours after multiple administration on Day 1 and Day 7, and 30 min pre-dose on Day 5 and Day 6.)