Clinical trial NCT03578588: Benapenem PK Phase Ib Multiple-dose Study
Official title: Single-dose Pharmacokinetic, Multiple-dose Tolerability and Pharmacokinetic Studies of Benapenem for Injection in Phase I Clinical Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Health, Subjective
Keywords: single dose
multiple dose
Pharmacokinetic
Tolerability
Healthy Subject
Benapenem
Lead sponsor: Sihuan Pharmaceutical Holdings Group Ltd.
Sponsor class: INDUSTRY
First posted: 2018-07-06
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: A single-center, randomized, open-label, three-period and three-crossover trial design is adopted in the single-dose pharmacokinetic study; A single-center, randomized, open- label, and dose escalation trial design is used in the multiple-dose tolerability and pharmacokinetic studies
Primary purpose: TREATMENT

Brief summary: A single-center, randomized, open-label, three-period and three-crossover trial design is adopted in the single-dose pharmacokinetic study. 12adult volunteers, are assigned to 3 groups, B1（250mg), B2 (500mg), and B3 (1000mg). Each group of subjects receive single-dose test drug at different dosages in each period.

The tolerability and pharmacokinetic studies are performed simultaneously. Two doses, 250 mg and 500 mg, are proposed for multiple-dose tolerability and pharmacokinetic studies. The subjects are divided into two groups, C1 and C2, 12 subjects in each group, half males and half females. 250 mg group is performed first. Each subject receives only one dose, intravenous drip, once daily, for 7 consecutive days

Detailed description: A single-center, randomized, open-label, three-period and three-crossover trial design is adopted in the single-dose pharmacokinetic study. Twelve healthy adult volunteers, half male and female, are enrolled and randomly assigned to three groups, B1, B2, and B3. The subjects in three groups receive three doses, 250 mg, 500 mg and 1000 mg. Each group of subjects receive single-dose test drug at different dosages in each period.

A single-center, randomized, open- label, and dose escalation trial design is used in the multiple-dose tolerability and pharmacokinetic studies. The tolerability and pharmacokinetic studies are performed simultaneously. Two doses, 250 mg and 500 mg, are proposed for multiple-dose tolerability and pharmacokinetic studies. The subjects are divided into two groups, C1 and C2, 12 subjects in each group, half males and half females. 250 mg group is performed first. After completion of observation and confirming that the drug can be safely tolerated, study on 500 mg group is then performed. Each subject receives only one dose, intravenous drip, once daily, for 7 consecutive days

Eligibility criteria: Inclusion Criteria:

* Male or female healthy subjects, aged 18 \~ 45;
* Body weight ≥ 50 kg and body mass index 19.0 \~ 24.0 kg/m2;
* 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
* Normal or mild abnormalities without clinical significance in the standard 12-lead ECG;
* Signing informed consent form

Exclusion Criteria:

* Regular smoking, alcohol abuse, and drug abuse;
* Use of drugs with known damage to an organ within three months;
* History of specific allergies, or history of drug allergy, especially those allergic to lactams and excipients of test drug;
* Febrile illnesses within three days before the screening;
* Patients with mental illness or psychotic disorder in the past;
* 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.
* Taking any medication, including traditional Chinese medicine;
* 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;
* Having participated in other investigational drug trial in the preceding three months;
* Blood donation for 360 ml or more within three months before the screening;
* Heart rate\<50 bpm or \>100 bpm;
* Systolic blood pressure \< 90 mmHg or ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg or \< 60 mmHg;
* 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;
* Women who are planning to become pregnant within 6 months, or male subjects who are planning to make his spouse pregnant within 6 months;
* HBsAg, HCV antibody, HIV antibody, and Treponema Pallidum antibody positive;
* Urine drug-of-abuse testing positive;
* Any other factor that makes the subject not suitable for the trial as indicated by the investigator.

Primary outcomes:
measure: AUC(0-24) of Benapenem
timeFrame: Pre dose and 0.25,0.5,0.75,1,1.5, 2, 2.5, 3, 4, 6,8,12, 24,36,48 hours after Dosing
measure: Maximum observed plasma concentration (Cmax) of Benapenem
timeFrame: Pre dose and 0.25,0.5,0.75,1,1.5, 2, 2.5, 3, 4, 6,8,12, 24,36,48 hours after Dosing
measure: Time to maximum observed plasma concentration (tmax) of Benapenem
timeFrame: Pre dose and 0.25,0.5,0.75,1,1.5, 2, 2.5, 3, 4, 6,8,12, 24,36,48 hours after Dosing
measure: Time to elimination half-life (t1/2) of Benapenem
timeFrame: Pre dose and 0.25,0.5,0.75,1,1.5, 2, 2.5, 3, 4, 6,8,12, 24,36,48 hours after Dosing
Secondary outcomes:
measure: Number of subjects with clinically significant findings in vital signs
timeFrame: Screening and Day1, Day 2, Day4 after dosing
measure: Number of subjects with clinically significant findings in laboratory parameters
timeFrame: Screening and Day1, Day 2, Day4 after dosing
measure: Number of subjects with adverse events and serious adverse events
timeFrame: Screening and Day1, Day 2, Day4 after dosing
measure: Number of subjects with clinically significant 12-lead ECGs
timeFrame: Screening and Day1, Day 2, Day4 after dosing
Other outcomes:
Locations:
Study officials:
affiliation: Peking University First Hospital
name: Yuan Lv, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.