Single-dose PK Study of Benapenem In Healthy Subjects

Single-dose Tolerability Study of Benapenem for Injection in Phase I Clinical Healthy Subjects

To design 11 dose groups within 62.5 mg ~ 4000 mg for single-dose tolerability study. A single-center, randomized, blinded, placebo-controlled, dose escalation trial design is adopted. 8 subjects each in 62.5 mg, 125 mg, 3000 mg and 4000 mg dose groups, 10 subjects each in other groups, including 2 placebo-controlled subjects. To be carried out from low-dose group to high-dose group. The next dose group can be studied only when the observation of the previous dose group is completed and it is confirmed that the drug is safely tolerated. The test should be stopped in case of serious adverse reactions, or when more subjects experience adverse reactions and have reached termination criteria of the trial, even if the maximum dose has not been reached.

Infusion time is planned to be 30 min in 62.5 mg, 125 mg and 250 mg ; two infusion time, 30 min and 60 min, in 500 mg, 1000 mg and 2000 mg groups. If subjects can tolerate 60-min infusion, the same dose group at infusion time of 30 min is added. The 3000 mg and 4000 mg dose groups only receive 60-min infusion for investigation of tolerability.

Study Overview

• Status: Completed
• Conditions: Healthy Subject
• Intervention / Treatment: Drug: Placebo; Drug: Benapenem

Detailed Description

It is planned to design 11 dose groups within 62.5 mg ~ 4000 mg for single-dose tolerability study. A single-center, randomized, blinded, placebo-controlled, dose escalation trial design is adopted. There are 8 subjects each in 62.5 mg, 125 mg, 3000 mg and 4000 mg dose groups, and 10 subjects each in other groups. Each group consists of half males and half females, including 2 placebo-controlled subjects (1 male and 1 female). The trial is carried out from low-dose group to high-dose group. Each subject only receives one dose of test drug, which is dissolved in 100 mL of 0.9% NS, intravenous drip. During the trial, the adverse events of subjects should be closely followed. The next dose group can be studied only when the observation of the previous dose group is completed and it is confirmed that the drug is safely tolerated. The test should be stopped in case of serious adverse reactions, or when more subjects experience adverse reactions and have reached termination criteria of the trial, even if the maximum dose has not been reached.

In order to investigate possible effect of infusion rate on the tolerability and to ensure the safety of subjects, the infusion time is planned to be 30 min in 62.5 mg, 125 mg and 250 mg low-dose groups; two infusion time, 30 min and 60 min, in 500 mg, 1000 mg and 2000 mg groups. Under the circumstance that subjects can tolerate 60-min infusion, the same dose group at infusion time of 30 min is added to investigate the possible effect of infusion rate on the tolerability. The 3000 mg and 4000 mg dose groups only receive 60-min infusion for investigation of tolerability.

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1) Male or female healthy subjects, aged 18~45;
• 2) Body weight ≥ 50 kg and body mass index 19.0~24.0 kg/m2;
• 3) Prior to the test, physical examination, blood routine, urine routine, liver and kidney functions, and related examinations normal, or mild abnormalities in indicators while without clinical significance as indicated by the investigator;
• 4)Normal or mild abnormalities without clinical significance in the standard 12-lead ECG;
• 5)Signing informed consent form

Exclusion Criteria:

• 1) Regular smoking, alcohol abuse, and drug abuse;
• 2)Use of drugs known damage to an organ within three months;
• 3)History of specific allergies, or history of drug allergy, especially those allergic to lactams and excipients of test drug;
• 4)Febrile illnesses within three days before the screening;
• 5)Patients with mental illness or psychotic disorder in the past;
• 6)Past mental and nervous system diseases (epilepsy, stroke, cerebrovascular disorder, etc.), gastrointestinal disorder (such as stomach ulcers, gastritis, etc.) or disorder of other systems (such as cardiovascular, respiratory, hematological, or endocrine system, etc.) diseases or medical history.
• 7)Habitually taking any medication, including traditional Chinese medicine;
• 8)Having taken any medication that may affect test results within two weeks before the screening, such as antibiotics, NSAIDs, aluminum- or magnesium-containing antacids, diuretics, anticoagulants, central nervous system depressants, and any drug that may affect the drug absorption;
• 9)Having participated in other investigational drug trial in the preceding three months;
• 10)Blood donation for 360 ml or more within three months before the screening;
• 11)Heart rate < 50 bpm or > 100 bpm;
• 12)Systolic blood pressure<90mmHg or ≥ 140mmHg, diastolic blood pressure ≥ 90 mmHg or < 60 mmHg;
• 13)Women who are pregnant or breastfeeding, or who may be pregnant without adopting acceptable contraception, or who have a positive result in serum pregnancy test;
• 14)Women who are planning to become pregnant within 6 months, or male subjects who are planning to make his spouse pregnant within 6 months;
• 15)HBsAg, HCV antibody, HIV antibody, and Treponema pallidum antibody positive;
• 16)Urine drug-of-abuse testing positive;
• 17)Any other factor that makes the subject not suitable for the trial as indicated by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Benapenem; Investigatial Product: Benapenem: 11 group : 62.5mg one dose; 125mg one dose;250mg one dose;500mg one dose 30min infusion;500mg one dose 60min infusion ;1000mg one dose 30min infusion; 1000mg one dose 60min infusion 2000mg one dose 30min infusion;2000mg one dose 60min infusion;3000mg one dose 60min infusion;4000mg one dose 60min infusion	Drug: Benapenem; Dose-escalation For 11 level dose groups A1 ~ A11(each 62.5mg/kg, 125mg/kg, 250mg/kg, 500mg/kg, 1000mg/kg 60min infusion, 1000mg/kg 30min infusion, 2000mg/kg 60 min infusion, 2000mg/kg 30min infusion, 3000mg/kg, 4000mg/kg), 10 subjects (8 for the study drug and 2 for placebo) are randomized to each dose group; Other Names: 5081
PLACEBO_COMPARATOR: Placebo; Placebo control 11 group : 62.5mg one dose;125mg one dose;250mg one dose;500mg one dose 30min infusion;500mg one dose 60min infusion ;1000mg one dose 30min infusion; 1000mg one dose 60min infusion 2000mg one dose 30min infusion;2000mg one dose 60min infusion;3000mg one dose 60min infusion;4000mg one dose 60min infusion	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of subjects with clinically significant findings in vital signs	Vitals signs such as systolic and diastolic blood pressure, heart rate, and pulse rate will be measured in a semi-supine position after 5 minutes of rest.	Change from Baseline at Day1, Day2, Day4 after dosing
Number of subjects with clinically significant findings in laboratory parameters	Hematology and clinical chemistry and Urine Routine abnormalities will be monitored	Change from Baseline at Day1, Day2, Day4 after dosing
Number of subjects with clinically significant 12-lead ECGs	Single 12-lead ECGs will be obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF intervals	Change from Baseline at Day1, Day2, Day4 after dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC(0-24) of Benapenem	AUC(0-24) is the area under the curve from time 0 to 24 hour	In each group: Pre dose and 0.25,0.5,0.75,1,1.5, 2, 2.5, 3, 4, 6,8,12, 24hour after dosing
Maximum observed plasma concentration (Cmax) of Benepenem		In each group: Pre dose and 0.25,0.5,0.75,1,1.5, 2, 2.5, 3, 4, 6,8,12, 24hour after dosing
Time to maximum observed plasma concentration (tmax) of Benapenem		In each group: Pre dose and 0.25,0.5,0.75,1,1.5, 2, 2.5, 3, 4, 6,8,12, 24hour after dosing

Collaborators and Investigators

• Sponsor: Sihuan Pharmaceutical Holdings Group Ltd.
• Investigators: Principal Investigator: Yan Zhu, Doctor, Peking University First Hospital

Publications and helpful links

General Publications

• Zhao CY, Lv Y, Zhu Y, Wei MJ, Liu MY, Ji XW, Kang ZS, Xia YH, Tian JH, Ma Y, Liu Y. A First-in-Human Safety, Tolerability, and Pharmacokinetics Study of Benapenem in Healthy Chinese Volunteers. Antimicrob Agents Chemother. 2019 Feb 26;63(3):e02188-18. doi: 10.1128/AAC.02188-18. Print 2019 Mar.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 11, 2015
• Primary Completion (ACTUAL): September 17, 2015
• Study Completion (ACTUAL): September 17, 2015

Study Registration Dates

• First Submitted: May 16, 2018
• First Submitted That Met QC Criteria: July 3, 2018
• First Posted (ACTUAL): July 17, 2018

Study Record Updates

• Last Update Posted (ACTUAL): July 17, 2018
• Last Update Submitted That Met QC Criteria: July 3, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Tolerability; Healthy Subject; PK Study; Safety Evaluation
• Other Study ID Numbers: 5081-CPK-1001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: no plan to make individual participant data

Drug and device information, study documents

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