Clinical trial NCT03588156: Single-dose PK Study of Benapenem In Healthy Subjects
Official title: Single-dose Tolerability Study of Benapenem for Injection in Phase I Clinical Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Subject
Keywords: Healthy Subject
PK Study
Tolerability
Safety Evaluation
Lead sponsor: Sihuan Pharmaceutical Holdings Group Ltd.
Sponsor class: INDUSTRY
First posted: 2018-07-17
Enrollment: 98
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 11 dose groups within 62.5 mg \~ 4000 mg for single-dose tolerability study to carried out from low-dose group to high-dose group
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of subjects with clinically significant findings in vital signs
timeFrame: Change from Baseline at Day1, Day2, Day4 after dosing
measure: Number of subjects with clinically significant findings in laboratory parameters
timeFrame: Change from Baseline at Day1, Day2, Day4 after dosing
measure: Number of subjects with clinically significant 12-lead ECGs
timeFrame: Change from Baseline at Day1, Day2, Day4 after dosing
Secondary outcomes:
measure: AUC(0-24) of Benapenem
timeFrame: 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
measure: Maximum observed plasma concentration (Cmax) of Benepenem
timeFrame: 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
measure: Time to maximum observed plasma concentration (tmax) of Benapenem
timeFrame: 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
Other outcomes:
Locations:
Study officials:
affiliation: Peking University First Hospital
name: Yan Zhu, Doctor
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.