A Randomized, Double-Blind, Placebo-Controlled, Dose Escalation Study of TRX-100 Evaluating the Safety, Pharmacokinetics, and Food Effect of Single Ascending Doses of TRX-100 in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Incidence of TEAEs
研究概览
简要总结
This is a Phase 1b, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, pharmacokinetics, and food effect of single oral doses of TRX-100 tablets and capsules in healthy adult volunteers. Up to 32 participants will be enrolled in four cohorts and randomized within each cohort to receive TRX-100 or matching placebo.
详细描述
This is a Phase 1b, randomized, double-blind, placebo-controlled, dose-escalation study of single oral doses of TRX-100 tablets and capsules in healthy male and female volunteers 18 to 65 years of age. The study evaluates safety, tolerability, the pharmacokinetics of TRX-100 and its active metabolite TRX-101, and the effect of food on pharmacokinetics.
Up to 32 participants will be enrolled in four cohorts of 8 participants each. Within each cohort, participants will be randomized 6:2 to receive TRX-100 or matching placebo. Cohort A will receive 240 mg TRX-100 tablets or matching placebo under fed conditions. Cohort B will receive 480 mg TRX-100 tablets or matching placebo under fasted conditions. Cohort C will receive 480 mg TRX-100 tablets or matching placebo under fed conditions. Cohort D will receive 480 mg TRX-100 capsules or matching placebo under fed conditions.
Cohorts A and B may be dosed in parallel. Cohort C will begin only after the Safety Review Committee has reviewed available blinded safety data and initial pharmacokinetic data from Cohort A and confirmed that exposure levels are acceptable. Cohort D will begin after completion of Cohort C.
Participants will be confined at the clinical facility from Day -1 through Day 4 and will return for outpatient safety and pharmacokinetic assessments through the end-of-study visit on Day 28 (±2 days). The food effect at 480 mg will be evaluated primarily by comparing Cohort B under fasted conditions with Cohort C under fed conditions; data from Cohort D under fed conditions will also be used.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects.
- •Adult males and females, 18 to 65 years of age (inclusive) at screening.
- •Body mass index (BMI) ≥ 18.5 and ≤ 32.0 kg/m2, with a body weight (to 1 decimal place) ≥ 50.0 kg at screening.
- •Medically healthy without clinically significant abnormalities (in the opinion of the Investigator) at the screening visit, including:
- •Physical examination without any clinically significant findings in the opinion of the investigator.
- •Systolic blood pressure in the range of 90 mm Hg to 149 mm Hg; diastolic blood pressure in the range of 50 mm Hg to 90 mm Hg after 5 minutes in a supine or semi-supine position.
- •Heart rate (HR) in the range of 40 to 100 bpm after 5 minutes in a supine position
- •Body temperature (tympanic or oral) in the range 35.5°C to 37.5°C (inclusive).
- •No clinically significant findings in serum chemistry, hematology, coagulation, and urinalysis tests as judged by the Investigator, including the following specific findings:
- •i. Haemoglobin, platelet count, WBC count, lymphocyte count, and neutrophil count within normal ranges (as per local laboratory standard ranges) or out-of-range values deemed not clinically significant (NCS) by the Investigator.
- •ii. AST, ALT and total bilirubin < 1.5 x ULN (note: for participants with Gilbert's syndrome, ULN for total bilirubin is considered to be 2.9 mg/dL).
- •iii. Triplicate 12-lead ECG (taken after the volunteer has been supine for at least 5 minutes) with a QTcF ≤ 450 msec for males and ≤ 470 msec for females and no clinically significant abnormalities.
- •iv. Hemoglobin A1C (HbA1c) level within the local laboratory standard reference range
- •Be willing to refrain from smoking (including tobacco, nicotine replacement therapy, e-cigarettes) from 7 days prior to dose administration on Day 1 to Day 12 (inclusive).
- •Be willing to abstain from alcohol consumption at least 48 hours prior to dosing on Day -1 and throughout the study.
- •Female volunteers must:
- •Be of nonchildbearing potential, i.e., surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy) at least 6 weeks before screening or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause and a follicle-stimulating hormone (FSH) level >40 IU/L at the screening visit), or
- •If of childbearing potential, must:
- •i. Have a negative pregnancy test at the screening visit and on admission to the clinic on Day-
- •ii. Agree not to attempt to become pregnant or donate ova from signing the consent form until at least 30 days after the last dose of the study drug.
- •iii. Agree to use adequate contraception (defined as use of a condom by the male partner combined with use of a highly effective method of contraception) from one month prior to screening until at least 30 days after the last dose of study drug, if not exclusively in a same-sex relationship or abstinent as a committed lifestyle.
- •Male volunteers must:
- •Agree not to donate sperm from signing the consent form until at least 90 days after the last dose of study drug.
- •If engaging in sexual intercourse with a female partner who could become pregnant, agree to use adequate contraception (defined as use of a condom combined with use of a highly effective method of contraception) from signing the consent form until at least 30 days after the last dose of study drug.
- •Have suitable venous access for blood sampling.
- •Be willing and able to comply with all study assessments and adhere to the protocol.
排除标准
- •History or presence of significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic or neurological disease, including any acute illness or major surgery within the past 3 months determined by the PI to be clinically significant.
- •History of surgery or hospitalisation within 30 days prior to screening, or surgery planned during the study.
- •Acute infections within 4 weeks prior to screening or current infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medications.
- •Presence or history of any abnormality or illness, including gastrointestinal surgery, liver, kidney, or other conditions, which in the opinion of the PI may affect absorption, distribution, metabolism or elimination of the study drug.
- •Any history of malignant disease in the last 5 years (excludes surgically resected skin squamous cell or basal cell carcinoma).
- •Presence of clinically relevant immunosuppression from, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia.
- •Use of or plans to use systemic immunosuppressive (e.g., corticosteroids by any route, methotrexate, azathioprine, cyclosporine) or immunomodulating medications (e.g., interferon) during the study and within 5 half-lives of individual agent or within 28 days (whichever is longer) prior to dosing.
- •Use of or plans to use agents (e.g., grapefruit and grapefruit products) that have clinically significant interaction with CYP3A4 or the use of any medications that could have a significantly impact on organ function (e.g., barbiturates, omeprazole, cimetidine) during the study and within 5 half-lives of individual agent or within 7 days (whichever is longer) prior to dosing.
- •History of risk factors for torsade de pointes (including a family history of long QT syndrome or sudden cardiac death) or clinically significant arrythmia.
- •Positive test results for active human immunodeficiency virus (HIV-1 or HIV-2), hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies at the screening visit.
- •Estimated creatinine clearance < 60 mL/min using the Cockcroft-Gault formula at the screening visit.
- •Creatine kinase >2 x ULN at Day -
- •History of any drug or alcohol abuse in the past 2 years defined as >21 units of alcohol per week for males and >14 units of alcohol per week for females. Where 1 unit = 360 mL of beer, 150 mL wine, or 30 mL of spirits.
- •Positive drugs of abuse or alcohol breath test results at the screening visit or on Day -
- •Use of any prescription medications or any over-the-counter medication (including herbal products, nutritional, calcium-enriched dietary supplements, antacids, laxatives, minerals and hormone supplements) within 14 days or at least 5 half-lives of the medication (whichever is longer) prior to the first study drug administration and during the study, with the exception of oral, injectable and implanted contraceptives, occasional use of paracetamol (doses of 500 mg up to every 6 hours or 2 g per day maximum for no more than 3 consecutive days) or ibuprofen (doses of 400 mg up to every 6 hours or 1.2 g per day maximum for no more than 3 consecutive days), topical ointments, vitamins, dietary supplements and medications used to manage AEs.
- •Demonstrated clinically significant (required intervention, e.g., emergency room visit, epinephrine administration) allergic reactions (e.g., food, drug, or atopic reactions, asthmatic episodes) which, in the opinion of the Investigator, would interfere with the volunteer's ability to participate in the trial.
- •Known hypersensitivity to any of the study drug ingredients.
- •Use of any inactivated vaccinations within 14 days, or any live vaccinations within 30 days prior to the first study drug administration and during the study. Note: Participants vaccinated for COVID-19 or influenza within at least 2 weeks prior to dosing or earlier will be considered eligible for enrolment as long as they do not present with post-vaccination clinical symptoms, have a negative rapid antigen test (in the case of COVID-19), and are deemed otherwise healthy.
- •Females who are breastfeeding or planning to breast feed at any time during the study.
- •Donation of blood or plasma within 30 days prior to first study drug administration, or loss of whole blood of more than 500 mL within 30 days prior to first study drug administration, or receipt of a blood transfusion within 1 year of first study drug administration.
- •Receiving an investigational drug in another clinical trial within 30 days or 5 half-lives of the investigational agent (whichever is longer) prior to the first study drug administration.
- •Any other condition or prior therapy that in the opinion of the Investigator would make the volunteer unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.
- •Any history of long-COVID infection (defined by continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation).
- •Any history of severe influenza, defined as a confirmed diagnosis of influenza resulting in hospitalization, or symptoms severe enough to disrupt daily activities for more than 7 consecutive days.
研究组 & 干预措施
Cohort A: 240 mg tablets, fed
Up to 8 healthy volunteers will be randomized 6:2 to receive a single oral dose of TRX-100 240 mg tablets or matching tablet placebo, respectively, under fed conditions.
干预措施: Placebo (Drug)
Cohort B: 480 mg tablets, fasted
Up to 8 healthy volunteers will be randomized 6:2 to receive a single oral dose of TRX-100 480 mg tablets or matching tablet placebo, respectively, under fasted conditions.
干预措施: Placebo (Drug)
Cohort C: 480 mg tablets, fed
Up to 8 healthy volunteers will be randomized 6:2 to receive a single oral dose of TRX-100 480 mg tablets or matching tablet placebo, respectively, under fed conditions. Dosing will begin only after Safety Review Committee review of available blinded safety data and initial pharmacokinetic data from Cohort A.
干预措施: Placebo (Drug)
Cohort D: 480 mg capsules, fed
Up to 8 healthy volunteers will be randomized 6:2 to receive a single oral dose of TRX-100 480 mg capsules or matching capsule placebo, respectively, under fed conditions. Dosing will begin after completion of Cohort C.
干预措施: TRX-100 (Drug)
Cohort D: 480 mg capsules, fed
Up to 8 healthy volunteers will be randomized 6:2 to receive a single oral dose of TRX-100 480 mg capsules or matching capsule placebo, respectively, under fed conditions. Dosing will begin after completion of Cohort C.
干预措施: Placebo (Drug)
Cohort A: 240 mg tablets, fed
Up to 8 healthy volunteers will be randomized 6:2 to receive a single oral dose of TRX-100 240 mg tablets or matching tablet placebo, respectively, under fed conditions.
干预措施: TRX-100 (Drug)
Cohort B: 480 mg tablets, fasted
Up to 8 healthy volunteers will be randomized 6:2 to receive a single oral dose of TRX-100 480 mg tablets or matching tablet placebo, respectively, under fasted conditions.
干预措施: TRX-100 (Drug)
Cohort C: 480 mg tablets, fed
Up to 8 healthy volunteers will be randomized 6:2 to receive a single oral dose of TRX-100 480 mg tablets or matching tablet placebo, respectively, under fed conditions. Dosing will begin only after Safety Review Committee review of available blinded safety data and initial pharmacokinetic data from Cohort A.
干预措施: TRX-100 (Drug)
结局指标
主要结局
Incidence of TEAEs
时间窗: up to Day 28
Number of participants with treatment-emergent adverse events
Incidence of SAEs and AEs leading to discontinuation
时间窗: up to Day 28
Number of participants with serious AEs (SAEs) and AEs leading to discontinuation
Incidence, severity, and relationship of treatment-emergent adverse events
时间窗: From administration of study drug on Day 1 through the end-of-study visit on Day 28 (±2 days).
Number and percentage of participants with treatment-emergent adverse events, summarized by severity and relationship to study drug.
Incidence of serious adverse events and adverse events leading to discontinuation
时间窗: From administration of study drug on Day 1 through the end-of-study visit on Day 28 (±2 days).
Number and percentage of participants with serious adverse events and adverse events leading to discontinuation from the study.
次要结局
- Maximum observed concentration (Cmax)(PK samples will be collected from baseline to Day 4, as wel as Days 6, 8, 12, 16 and 28)
- Time to Cmax (Tmax)(PK samples will be collected from baseline to Day 4, as wel as Days 6, 8, 12, 16 and 28)
- Area under the concentration-time curve from 0 to time of last quantifiable concentration (AUC0-last)(PK samples will be collected from baseline to Day 4, as wel as Days 6, 8, 12, 16 and 28)
- Area under the concentration-time curve from 0 to 24 hours (AUC0-24)(PK samples will be collected from baseline to Day 4, as wel as Days 6, 8, 12, 16 and 28)
- Area under the concentration-time curve from 0 to infinity (AUC0-inf)(PK samples will be collected from baseline to Day 4, as wel as Days 6, 8, 12, 16 and 28)
- Apparent terminal elimination half-life (t1/2)(PK samples will be collected from baseline to Day 4, as wel as Days 6, 8, 12, 16 and 28)
- Total apparent body clearance following oral administration (CL/F)(PK samples will be collected from baseline to Day 4, as wel as Days 6, 8, 12, 16 and 28)
- Apparent volume of distribution following oral administration (Vz/F)(PK samples will be collected from baseline to Day 4, as wel as Days 6, 8, 12, 16 and 28)
- Effect of food on pharmacokinetics of TRX-100 and TRX-101(PK samples will be collected from baseline to Day 4, as wel as Days 6, 8, 12, 16 and 28)
- Effect of food on Tmax of TRX-100 and TRX-10(PK samples will be collected from baseline to Day 4, as wel as Days 6, 8, 12, 16 and 28)
- Maximum observed plasma concentration (Cmax) of TRX-100 and TRX-101(Predose through Day 28 (648 hours post-dose; ±2 days).)
- Time to maximum observed plasma concentration (Tmax) of TRX-100 and TRX-101(Predose through Day 28 (648 hours post-dose; ±2 days).)
- Area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-last)(Predose through Day 28 (648 hours post-dose; ±2 days).)
- Area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24)(Predose through 24 hours post-dose.)
- Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf)(Predose through Day 28 (648 hours post-dose; ±2 days).)
- Apparent terminal elimination half-life (t1/2) of TRX-100 and TRX-101(Predose through Day 28 (648 hours post-dose; ±2 days).)
- Total apparent body clearance following oral administration (CL/F)(Predose through Day 28 (648 hours post-dose; ±2 days).)
- Apparent volume of distribution following oral administration (Vz/F)(Predose through Day 28 (648 hours post-dose; ±2 days).)
- Effect of food on exposure to TRX-100 and TRX-101(Predose through Day 28 (648 hours post-dose; ±2 days).)
- Effect of food on Tmax and other pharmacokinetic parameters of TRX-100 and TRX-101(Predose through Day 28 (648 hours post-dose; ±2 days).)