A Phase I, Randomized, Double-blind, Placebo- and Positive-controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics/Pharmacodynamics (PK/PD) of Multiple Oral Doses of H008 (Carenoprazan Hydrochloride Tablets) in Healthy Volunteers
Overview
- Phase
- Phase 1
- Intervention
- H008
- Conditions
- Erosive Esophagitis
- Sponsor
- Jiangsu Carephar Pharmaceutical Co., Ltd.
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- The number and incidence of AEs in HVs of multiple oral dose of H008 (Safety and Tolerability)
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This will be a Phase I, randomized, double-blind, positive- and placebo-controlled study to evaluate the safety, tolerability, and PK/PD of multiple oral doses of H008 in healthy adult subjects.
Two dose levels of H008 at 20 mg and 40 mg will be studied in two sequential cohorts. Each cohort will be enrolled with 12 subjects (8 on H008, 2 on placebo and 2 on positive control drug). Subjects are only allowed to participate in one of the two cohorts. Both the investigational product and placebo will be given in a double blinded manner, while the positive control drug will be given in an open-label manner.Dose escalation to the next cohort will be permitted only when safety data until follow-up and PK data until 48 hours post-last dose, from all subjects in previous cohorts are reviewed, and the investigational product is deemed well tolerated.
The study will consist of a screening period, a baseline period, a 7-day repeated-dose period and a safety follow-up period.
Detailed Description
Screening Period After signing the informed consent, all subjects will undergo a screening assessment within 4 weeks prior to the start of study treatment (Days -28 to -3). Baseline Period Eligible subjects at screening will come to the clinic 2 days prior to the first dosing and begin their 11-day confinement period (Day -2 to Day 9). On Day -2, subjects will undergo baseline examinations. On Day -1, subjects will be monitored for their intragastric pH using a pH probe inserted into the stomach. The intragastric pH will be measured continuously for 48 h (Day -1 to Day 2), and data within the first 24 h will be used as baseline for PD evaluation. Subject's eligibility will be confirmed prior to first dosing (morning of Day 1). Repeated-dose Period On each day during the treatment period, subjects will receive the investigational product (H008, 20 mg or 40 mg), matching placebos or positive control drug (Lansoprazole, 30 mg) according to the randomization schedule after a minimum 10-hour overnight fasting. No water is allowed within 1 hour before the drug administration. Subjects will be instructed to take the drugs with approximately 240 mL (8 oz) room temperature water, and swallow the tablets or capsules whole without chewing. On Days 1 to 7, no food or water is allowed within at least 2 hours post-dose, except the water ingested during dosing. Subjects should avoid lying down for 2 hours post-dose, except when ECG or vital sign measurements are performed. Standard lunch and dinner will be provided at approximately 4 and 10 hours post-dose on Days 1 and 7. On Days 2 to 6, standard breakfast, lunch and dinner will be provided at approximately 2, 5 and, 10 hours post-dose. Serial PK blood samples will be collected for all subjects from pre-dose (Day 1) to 48 h after the last dose (Day 9). Detailed PK sampling plan is presented in Table 1.3-1. Another 24-h intragastric pH measurement will be performed from pre-dose on Day 7 until 24 h after the Day 7 dosing. All subjects will be closely monitored for safety during their stay in the clinic. Subjects will be discharged 48 hours after their last dosing (Day 9) if no clinically significant adverse events occur. Follow-up Period A follow-up safety assessment will be performed on Day 16 ± 1 at clinic. Unscheduled follow-ups should be performed for any clinically significant AE until it returns to normal or baseline or steady state.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Adult, male and female volunteers, 18 to 55 years of age, inclusive, at the time of dosing.
- •Ability to understand and willingness to sign a written informed consent form (the consent form must be signed by the subject prior to any study-specific procedures).
- •Willingness and ability to comply with study procedures and follow-up examination.
- •Body mass index (BMI) ≥18 to ≤30 kg/m2 and total body weight ≥50.0 kg for males and ≥45.0 kg for females at screening.
- •If female and of childbearing potential (premenopausal and not surgically sterile), the subject:Must have a negative serum pregnancy test at screening. The serum pregnancy test must be obtained prior to the first administration of H-008 (≤72 hours prior to dosing) in all women.
- •Must agree to use an acceptable method of effective contraception for the duration of the study and for 3 months after receiving the last dose of study treatment.
- •If male, the subject agrees to:
- •Use an acceptable method of effective contraception (a dual method of contraception: condom with spermicide in conjunction with use of an intrauterine device (IUD), condom with spermicide in conjunction with use of a diaphragm, condom with birth control patch or vaginal ring, or condom with oral, injectable, or implanted contraceptive) for the duration of the study and for 3 months after receiving study treatment.
- •Abstain from sperm donation for the duration of the study and for 90 days after receiving the last dose of study treatment.
- •Ensure their partner not get pregnant until 3 months following administration of the last dose of study treatment.
Exclusion Criteria
- •A subject is not eligible for the study if any of the following criteria is met:
- •Subjects who have a history of drug allergy or atopic allergic disease (e.g. asthma, urticaria, eczema, dermatitis, etc.) that were clinically significant, or allergic to any known ingredients and excipients of H008 and other PPIs drugs (e.g., Omeprazole, Lansoprazole, Ilaprazole, Esomeprazole, Rabeprazole, etc.).
- •History of alcohol or drug/substance abuse (within 2 years).
- •Positive urine drug screen or alcohol breath test at screening or baseline (Day -2).
- •Subjects who have history of unexplained syncope or fainting or a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia or dehydration.
- •Subjects determined by the Investigator to have any medical condition that could jeopardize their health or prejudice study results (e.g., history of surgery of the gastrointestinal tract, which may interfere with absorption, except for appendectomy and cholecystectomy).
- •Subjects who have used P-gp and/or CYP 450 hepatic microsomal enzyme-inducing or inhibiting drugs (e.g., propafenone, voriconazole, fluconazole, cimetidine) within 30 days of first dosing.
- •Subjects with history or presence of significant cardiovascular, pulmonary, hepatic, gallbladder or biliary tract, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, psychiatric disease, or active sexually transmitted disease.
- •History or clinical evidence of achlorhydria, severe gastrointestinal disease, particularly diarrhea or other conditions affecting gastrointestinal mobility or absorption.
- •Subjects who have difficulty in swallowing oral tablets or capsules.
Arms & Interventions
cohort 1: H008 20mg
H008 20mg tablets, orally, once, daily, for 7 days
Intervention: H008
cohort 1: H008 placebo 20mg
H008 placebo 20mg tablets, orally, once, daily, for 7 days
Intervention: H008 placebo
cohort 1: Lansoprazole 30mg
Lansoprazole 30mg capsule, orally, once, daily, for 7 days
Intervention: Lansoprazole
cohort 2: H008 40mg
H008 40mg tablets, orally, once, daily, for 7 days
Intervention: H008
cohort 2: H008 placebo 40mg
H008 placebo 40mg tablets, orally, once, daily, for 7 days
Intervention: H008 placebo
cohort 2: Lansoprazole 30mg
Lansoprazole 30mg capsule, orally, once, daily, for 7 days
Intervention: Lansoprazole
Outcomes
Primary Outcomes
The number and incidence of AEs in HVs of multiple oral dose of H008 (Safety and Tolerability)
Time Frame: Up to final follow-up (Day16) or early termination.
AEs
The number and incidence of subjects with clinically significant changes of physical examinations (Safety and Tolerability)
Time Frame: Baseline up to Day 16
A baseline physical examination (defined as the pretreatment assessment immediately prior to the start of study drug) will consist of the following body systems: eyes、ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities. All subsequent physical examinations should assess clinically significant changes from the baseline examination.
The number and incidence of subjects with abnormal vital signs of multiple oral dose of H008 (Safety and Tolerability)
Time Frame: Baseline up to Day 16
Subjects with vital signs included body temperature(℃), blood pressure (both systolic and diastolic blood pressure ,mmHg), heart rate（beat per minute,BMP）, and respiratory rate (beat per minute,BMP）.
The number and incidence of subjects with clinical defined abnormal laboratory tests of multiple oral dose of H008 (Safety and Tolerability)
Time Frame: Baseline up to Day 16
hematology，blood chemistry,urinalysis
The number and incidence of subjects with clinical defined abnormal of 12-lead ECG multiple oral dose of H008 (Safety and Tolerability)
Time Frame: Baseline up to Day 16
Full 12-lead ECGs will be recorded using an ECG machine that automatically calculates the heart rate and measures HR、RR、PR, QRS, QT, QTc intervals. The investigator or other qualified physician will interpret each ECG using one of the following categories: within normal limits, abnormal but not clinically significant, or abnormal and clinically significant.
Secondary Outcomes
- To characterize the PK profiles of multiple oral doses of H008 in HVs.(through study completion,an average of 1 year)
- Percentage of Time the pH is Greater than pH 3, pH 4 and pH 5 over a 24 Hour Period(Using a calibrated gastric pH monitor, the measurement of stomach pH will be made continuously over a 24-hour period at Baseline and over a 24-hour period following the administration of study on Days 1 and 7.)
- Percentage of Time the PH is Greater than pH 3, pH 4 and pH 5 from 8 PM to 8 AM(Using a calibrated gastric pH monitor, the measurement of stomach pH will be made continuously over a 12-hour period from 8 PM to 8 AM to assess nocturnal pH)