Pharmacokinetic Interactions of Quadruple Therapy With Anaprazole/Amoxicilin/Clarithromycin/Bismuth

A Single-center, Randomized, Open-label, Crossover Study to Evaluate the Pharmacokinetic Drug-drug Interaction of the Quadruple Therapy With Anaprazole/Amoxicilin/Clarithromycin/Bismuth in Healthy Chinese Male Subjects

A single-center, randomized, open-label, crossover study to evaluate the pharmacokinetic drug-drug interaction and safety of the quadruple therapy with Anaprazole 20mg/Amoxicilin 1000mg/Clarithromycin 500mg/Bismuth Potassium Citrate 0.6g in healthy Chinese male subjects.

Study Overview

• Status: Unknown
• Conditions: Healthy Male Volunteers
• Intervention / Treatment: Drug: Anaprazole Sodium; Drug: Amoxicillin; Drug: Clarithromycin; Drug: Bismuth

Detailed Description

The study composed of 2 cohorts, using a 4*4 or 2*2 crossover design in cohort 1 and 2, respectively. 4 rotating treatment sequences in cohort 1, each treatment sequence comprised 4 treatment periods, separated by a washout period of 9 days; 2 rotating treatment sequences in cohort 2, each treatment sequence comprised 2 treatment periods, separated by a washout period of 9 days

• Study Type: Interventional
• Enrollment (Anticipated): 32
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• 1.The subject is capable of understanding and complying with protocol requirements, and signed and dated a written informed consent form voluntarily
• 2.The subject is a Chinese adult male, aged 18 to 35 years, inclusive.
• 3.The subject is a H. pylori-negative via UBT.
• 4.The subject weighed at least 50.0 kg and had a body mass index (BMI) between 19.0 kg/m^2 and 26.0 kg/m^2, inclusive.
• 5.Has clinical laboratory evaluations, vital signs and ECG testing within the reference range, and medical history and physicial examination results are normal. Participants with evaluations outside the reference range that are deemed not clinically significant by the investigator may be included at investigator discretion
• 6.The subject with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 3 months after last dose.
• 7.The subjects have a good lifestyle and can keep good communication with the investigators and comply with the requirements of clinical trial

Exclusion Criteria:

• 1.Has clinical significant drug allergy or allergic disease history(Such as asthma, urticaria, eczema dermatitis, etc), or has hypersensitivity or allergy to investigatory drugs or related supplements；
• 2.Has clinical significant ECG abnormal history or family history of long QT syndrome(Grandparents, parents and siblings)

• 3.Any disease or medical history that may significantly affect the absorption, distribution, metabolism, and excretion of drugs, or any condition that may pose a hazard to the subject. Such as:

  • Inflammatory bowel disease, gastric ulcer, duodenal ulcer, gastrointestinal / rectal bleeding, persistent nausea, or other clinically significant gastrointestinal abnormalities;
  • Has suffered from gastrointestinal diseases or complications that may affect the absorption of drugs (ie: malabsorption, gastroesophageal reflux, peptic ulcer, erosive esophagitis, frequent heartburn) within 6 months before screening or had history of gastrointestinal surgery (for example: gastrectomy, gastrointestinal anastomosis, intestinal resection, gastric bypass, gastric segmentation or gastric banding, cholecystectomy, except for appendicitis surgery and proctectomy);
  • Evidence of liver disease or clinically impaired liver function at the time of screening (eg AST, ALT or total bilirubin> 1.5 times ULN);
  • A history or evidence of nephropathy or renal insufficiency at the time of screening, showing clinically significant abnormality of creatinine or abnormal urine composition (such as proteinuria, creatinine> 176.8 umol / L, etc.)
  • Has difficulty swallowing oral preparations.
• 4.Thyroid stimulating hormone (TSH)> ULN; or serum free triiodothyronine (FT3)> ULN; or serum free thyroxine (FT4)> ULN at the time of screening;
• 5. Frequent smokers and alcoholics within 3 months before screening (smoke more than 5 cigarettes / day, drink more than 21 units of alcohol per week, 1 unit = 360 mL beer or 45 mL liquor or 150 mL wine), or can't stop using any tobacco products, and alcohol intake during the study period ; or those who have a positive alcohol breath test before enrollment;
• 6. Has received any investigational compound (including post-marketing investigational drugs) or participated in clinical trials of any drugs /devices within 3 months before screening;
• 7. A history of drug abuse within 12 months before screening or a positive urine test result at screening;
• 8. Has used any prescription drugs, non-prescription drugs (including chemical drugs, vitamin drugs, Chinese herbal medicines, etc.) within 4 weeks before administration of investigational drugs;
• 9. Has taken foods that affect CYP3A4 (such as grapefruit or beverages containing grapefruit) within 2 weeks before administration of investigational drugs;
• 10. Human immunodeficiency virus antibody, hepatitis B surface antigen, hepatitis C antibody, and Treponema pallidum specific antibody test results were positive at screening;
• 11. Has difficulty in venous blood collection or halo acupuncture;
• 12.Blood donation / blood loss ≥200 mL within 1 month, or ≥400 mL within 3 months before screening; or has blood donation plan during the period of medication of investigational drugs and within 3 months after drug withdrawal;
• 13. Has special dietary requirements and cannot follow the unified dietary arrangements;
• 14. Any conditions in which considered by investigator not be appropriate to participate in this trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Anaprazole Sodium enteric-coated tablet; Administered orally twice daily (e.g., 8am,8pm) for 5 consecutive days in 1 of 4 treatment periods of cohort 1 ( only once on the morning of D5 of treatment periods), one tablet each time.	Drug: Anaprazole Sodium; Anaprazole Sodium isthePPI inhibitor
EXPERIMENTAL: Amoxicillin capsules; "Administered orally twice daily (e.g., 8am,8pm) for 5 consecutive days in 1 of 4 treatment periods of cohort 1 ( only once on the morning of D5 of treatment periods), 2 capsules each time.	Drug: Amoxicillin; antibiotic
EXPERIMENTAL: Clarithromycin tablet; "Administered orally twice daily (e.g., 8am,8pm) for 5 consecutive days in 1 of 4 treatment periods of cohort 1 ( only once on the morning of D5 of treatment periods), 2 tablets each time.	Drug: Clarithromycin; antibiotic
EXPERIMENTAL: Anaprazole + Amoxicillin +Clarithromycin; "Cohort 1: Administered orally twice daily (e.g., 8am,8pm) for 5 consecutive days in 1 of 4 treatment periods ( only once on the morning of D5 of treatment periods). Cohort 2: Administered orally on an empty stomach once on the morning of D1 of treatment periods	Drug: Anaprazole Sodium; Anaprazole Sodium isthePPI inhibitor; Drug: Amoxicillin; antibiotic; Drug: Clarithromycin; antibiotic
EXPERIMENTAL: Anaprazole + Amoxicillin +Clarithromycin+Bismuth; Administered orally on an empty stomach once on the morning of D1 of treatment periods in cohort 2	Drug: Anaprazole Sodium; Anaprazole Sodium isthePPI inhibitor; Drug: Amoxicillin; antibiotic; Drug: Clarithromycin; antibiotic; Drug: Bismuth; Bismuth is to protect the gastric mucosa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort 1: Css,max of anaprazole (parent drug, KBP-3571) and its enantiomer（KBP-3570）and its major metabolites (KBP-1123 and KBP-1144), Unchanged amoxicillin, Unchanged clarithromycin and its metabolite (14-hydroxyclarithromycin)	Css,max is the peak plasma concentration at steady state	Hour 0.5 pre-dose and 0.5，1，1.5，2，2.5，3，3.5，4，4.5，5，6，7，8，10，12，24 hours post-dose of Day 5，Day 19，Day 33，Day 47
Cohort 1: AUC of anaprazole (parent drug, KBP-3571) and its enantiomer（KBP-3570）and its major metabolites (KBP-1123 and KBP-1144), Unchanged amoxicillin, Unchanged clarithromycin and its metabolite (14-hydroxyclarithromycin)	AUC is area under the plasma concentration-time curve	Hour 0.5 pre-dose and 0.5，1，1.5，2，2.5，3，3.5，4，4.5，5，6，7，8，10，12，24 hours post-dose of Day 5，Day 19，Day 33，Day 47
Cohort 2: Cmax of anaprazole (parent drug, KBP-3571) and its enantiomer（KBP-3570）and its major metabolites (KBP-1123 and KBP-1144), Unchanged amoxicillin, Unchanged clarithromycin and its metabolite (14-hydroxyclarithromycin)	Cmax is the peak plasma concentration	Hour 0.5 pre-dose and 0.5，1，1.5，2，2.5，3，3.5，4，4.5，5，6，7，8，10，12，24 hours post-dose of Day 1，Day 11
Cohort 2: AUC of anaprazole (parent drug, KBP-3571) and its enantiomer（KBP-3570）and its major metabolites (KBP-1123 and KBP-1144), Unchanged amoxicillin, Unchanged clarithromycin and its metabolite (14-hydroxyclarithromycin)	AUC is area under the plasma concentration-time curve	Hour 0.5 pre-dose and 0.5，1，1.5，2，2.5，3，3.5，4，4.5，5，6，7，8，10，12，24 hours post-dose of Day 1，Day 11

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of subjects with adverse events and serious adverse events as assessed by CTCAE v5.0	All adverse events will be monitored in each subject	From signing informed consent to study completion. 56 days minimum, 68 days maximum(Cohort 1); 30 days minimum, 32 days maximum(Cohort 2)

Collaborators and Investigators

• Sponsor: Sihuan Pharmaceutical Holdings Group Ltd.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): July 1, 2020
• Primary Completion (ANTICIPATED): September 30, 2020
• Study Completion (ANTICIPATED): October 15, 2020

Study Registration Dates

• First Submitted: May 15, 2020
• First Submitted That Met QC Criteria: June 21, 2020
• First Posted (ACTUAL): June 23, 2020

Study Record Updates

• Last Update Posted (ACTUAL): June 23, 2020
• Last Update Submitted That Met QC Criteria: June 21, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Antacids; Amoxicillin; Clarithromycin; Bismuth
• Other Study ID Numbers: 3571-DDI-1006

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No