A Phase I Study of LuoXin Innovate (LXI-15028) in Healthy Chinese Subjects to Evaluate the Pharmacokinetics, Safety and Tolerability.

A Single-center, Randomized, Double-blinded and Placebo-controlled Clinical Study in Healthy Chinese Subjects to Evaluate the Pharmacokinetics, Safety and Tolerability of LXI-15028 After Receiving Escalating Single Oral Doses of LXI-15028 at 50 mg, 100 mg and 200 mg and Multiple Oral Doses of LXI-15028 at 100 mg

"This study is a single-center, randomized, double-blinded and placebo-controlled trial designed not only to assess pharmacokinetics, safety and tolerability of LXI-15028 but also to evaluate the pharmacokinetic characteristics of main metabolite M1 in vivo in 38 healthy adult Chinese subjects after receiving escalating single oral doses of 50 mg, 100 mg and 200 mg and multiple oral doses of 100 mg of LXI-15028.

This study includes 3 dose groups which are 50 mg (Group 1), 100 mg(Group 2) and 200 mg(Group 3) respectively. For 50 mg and 200 mg dose groups, each is planned to enroll 12 healthy subjects (investigational drug :placebo=10:2), half males and half females. Five subjects of each gender will receive LXI-15028, while 1 subject of each gender will receive placebo; 100 mg dose group plans to enroll 14 healthy subjects (investigational drug:placebo=10:4), half males and half females. Five subjects of each gender will receive LXI-15028, while 2 subjects of each gender will receive placebo. Intra-group randomization will be implemented in each dose group; each subject will receive either LXI-15028 or placebo.

This study includes 2 parts of single-dose and multiple-dose administration. The single-dose study will use gradually escalation dosing to evaluate the 3 doses of 50 mg, 100 mg and 200 mg. Within 4 days after each dose is administered, the investigators will assess the safety and tolerability data to decide whether to proceed with the next escalated single dose. Within 4 days of 200 mg single-dose administration, the investigators will assess the safety and tolerability data to decide whether to proceed with 100 mg multiple-dose study. Multiple-dose study will be investigated in 100 mg group only.

The study consists of screening period, treatment period and follow-up in each dose group. The treatment period in 50 mg and 200 mg dose groups include single-dose administration only. While the treatment period in 100 mg dose group includes both single-dose and multiple-dose administration. The subjects in 100 mg dose group will enter multiple-dose period following completing single-dose period.

In escalated single-dose study, the subjects in each dose group will receive single oral dose of 50 mg LXI-15028 tablet or 1 matching placebo tablet at fasted state, or 100 mg LXI-15028 tablet or matching placebo 1 tablet, or 2 100 mg LXI-15028 tablets or 2 matching placebo tablets. Blood samples will be collected before administration (0h), and 15 min (0.25h), 30 min (0.5h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 48h and 72h after administration. In multiple-dose study, the subjects will continuously receive oral 100 mg LXI-15028 tablet or 1 matching placebo tablet once daily (QD) for 10 times. Blood samples of trough concentration will be collected before the 8th to 10th administration (0h) in multiple-dose study. And blood samples will be collected at 15 min (0.25h), 30 min (0.5h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 24h, 48h and 72h after the 10th administration.

The collected blood samples will be processed to obtain plasma. Liquid Chromatographic(LC) /Mass Spectra(MS)/Mass Spectra (MS) method will be used to determine plasma concentrations of LXI-15028 and its major metabolite M1 in order to evaluate the pharmacokinetic characteristics of LXI-15028 and its metabolite M1 after oral administration of LXI-15028 tablet.

The safety will be assessed by physical examination, vital signs, ECG, laboratory examinations and adverse events in subjects receiving LXI-15028 tablet.

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Inclusion Criteria:

• The subjects should voluntarily participate in this trial and sign the informed consent form prior to conducting any trial-related procedures;
• Gender: male or female healthy subjects; Age: 18~45 years old (including 18 and 45 years old);
• The body weight should be equal or greater than 50.0 kg for male and 45.0 kg for female. Body weight index (BMI)= body weight (kg)/[height(m)×height(m)], should be within the range from 19 to 25 (including 19 and 25);
• In the past three years, no history or presence of cardiovascular, hepatic, renal, respiratory, hematological and lymphatic, endocrine, immunological, mental, neurological and gastrointestinal disease; no history of surgery;
• The subjects (including males and females) agree to use medically approved contraceptive methods during the trial period and within 3 months after the end of the trial in order to avoid pregnancy; medically approved contraceptive methods include intrauterine device, physical barrier (male condom, female condom), subcutaneous implant, sustained-release contraceptive, bilateral salpingectomy, bilateral tubal ligation, bilateral vas ligation, etc.;
• The subjects agree not to donate sperms (males) or ova (females) at least 7 days before the first dose, during the study and within 3 months after ending of this study.

Exclusion Criteria:

• The subjects with allergic constitution, for example those with bronchial asthma, allergic to food or pollen, allergic to two or more drugs or those with known history of allergy ; or the subjects with any serious adverse response to Proton Pump Inhibitor or P-CABs previously (e.g., omeprazole, rabeprazole, lansoprazole and TAK-481 ), or known allergy to penicillins or cephalosporins;

• The investigator determines that it may potentially affect absorption, distribution, metabolism or elimination of investigational drug (e.g. organ dysfunction);

• The subjects with a history of drug abuse or drug abuse screening positive;

• The subjects received any drugs (including prescription drugs, Over-The-Counter drugs, herbal medicines, etc.) within 1 month before the screening or are taking drugs, especially CYP3A inhibitor or inducer (see Appendix 1);

• The subjects with clinical significant physical examination abnormalities determined by investigator;

• Heart rate<50 beats/min or >100 beats/min or QTc interval prolonged (male QTcF≥430ms, female QTcF≥450ms) or QRS≥120 msec or other clinically significant ECG abnormalities; 7) The subjects with sitting blood pressure: systolic pressure <90mmHg or ≥ 140mmHg, diastolic pressure ≥90mmHg or <60mmHg, which shows clinical significant abnormalities determined by investigators

• The subjects with any biomarker value of Aspartate aminotransferase (AST),Alanine aminotransferase(ALT), Alkaline phosphatase(ALP),r-Glutamyl Transferase (r-GT), total bilirubin, creatinine above the upper limit of normal or with other clinical significant laboratory examination abnormalities judged by investigators

• The subjects with presence of one of the following infectious diseases;

  1. Virological determination indicates hepatitis B virus surface antigen (HBsAg) positive or anti-hepatitis C virus antibody positive;
  2. Acquired human immunodeficiency virus determination indicates infection; (anti-human immunodeficiency virus antibody positive)
  3. Treponema pallidum infection (anti-treponema pallidum-specific antibody positive).

• Currently smoking or quitting smoking less than 3 months before screening or tobacco screening positive;

• Chronical alcohol user within 5 years prior to screening, or alcohol consumption of more than 14 unit alcohol per week (1 unit alcohol equal to 360 mL beer, or 150 mL grape wine, or 45 mL wine of 40 degree) within 6 months prior to screening;

• Alcohol screening test positive or alcohol intake within 72 h prior to screening;

• Daily drinking a large amount (above 1000 mL) of tea, coffee, cola and/or caffeine-containing beverages within 6 months prior to screening;

• Taking xanthine-containing or caffeine-containing food or beverages (including chocolate, tea, coffee and cola, etc.) from 48 hours prior to screening;

• Taking grapefruit, lime, carambola or any food or beverages made from them within 7 days prior to screening;

• Female subjects with blood pregnancy test positive or during lactation

• Difficulty in blood sampling, or has relevant history, symptoms or signs of blood sampling difficulty;

• Transfusion treatment or blood donation or massive blood loss (exceeding 450 mL) judged by investigators within 3 months prior to screening;

• Participation in any other clinical study within 3 months prior to screening;

• Participation in the planning or execution of this study (e.g., the sponsor or staff in the site);

• Inappropriate to participate in this study for any reason according to the medical judgment of investigators.