Clinical trial NCT03362853: A Study Evaluating the Effect of a Single-dose Oral Administration of Nemonoxacin Capsule on QTc Intervals and Heart Rhythms of Healthy Subjects and the Influence of Food Intake on QTc Intervals and Pharmacokinetic Characteristics
Official title: A Randomized, Single-center, Placebo and Positive Control, 4-period and 4-crossover Clinical Study Evaluating the Effect of a Single-dose Oral Administration of Nemonoxacin Malate Capsule on QTc Intervals and Heart Rhythms of Healthy Subjects as Well as the Influence of Food Intake on QTc Intervals and Pharmacokinetic Characteristics
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Lead sponsor: TaiGen Biotechnology Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2017-12-05
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: A randomized, single-center, placebo and positive control, 4-period and 4-crossover clinical study with the following main purposes: (1) To evaluate the effect of a single-dose oral administration of nemonoxacin malate capsule on QTc intervals and heart rhythms of healthy subjects. (2) To evaluate the influence of food intake on QTc intervals and pharmacokinetic characteristics.


Eligibility criteria: Inclusion Criteria:

1. Male or female, aged between 18 and 40 during the screening period.
2. A volunteer's Body Mass Index (BMI) had to be between 19\~24 kg/m2, and a male volunteer's body weight was no less than 50 kg, while female, no less than 45 kg.
3. A subject was judged as a healthy one by investigators according to his/her medical history, physical examination, 12-lead ECG examination, and laboratory test results.
4. A female subject:

   1. was post-menopausal for at least 1 year, or
   2. had been surgically sterilized, or
   3. met the following conditions if she was fertile: (i)her urine pregnancy test results were negative before she started the trial, and (ii)she agreed to use an approved birth control method (e.g. oral contraceptive, spermicide, condom, or intrauterine contraceptive device) throughout the study, and agreed to continue using birth control method within 1 month after the study, and (iii)she may not breastfeed.
5. A male subject had to use a reliable birth control method (using a condom, or his partner executed the foresaid criteria) throughout the study and within 1 month after the study.
6. A subject had never used tobacco or nicotine products within 1 month before receiving the study drug.
7. A subject had never drunk alcohol or drunk more than 12 times within 3 months before receiving the study drug.
8. A subject was willing to completely abstain from foods or beverages containing caffeine or xanthine such as coffee, tea, chocolate, alcohol, grapefruit juice, orange juice, etc within 24 hours before receiving the study drug and during his/her Stage I ward stay.
9. A subject was willing to sign the Informed Consent Form.

Exclusion Criteria:

1. had any personal or family history of sudden cardiac death, myocardial ischemia, myocardial infarction, congestive heart failure, long QT syndrome, hypokalemia, myocarditis, exertional dyspnea, cerebrovascular accident, venous thromboembolism, etc; or
2. needed to use medicine to treat QTc interval prolongation (e.g. Category I or III antiarrhythmic drugs, please refer to Appendix 1) or medicine to treat heart disease; or
3. was found to have abnormal mean values of parameters in 12-lead ECG during the screening: PR \>240 ms, QRS \>110 ms, male QTcF \>430 ms (the automated machine-derived QTcF results in Lead II ECG were used and needed to be confirmed by the investigators), female QTcF \>450 ms (the automated machine-derived QTcF results in Lead II ECG were used and needed to be confirmed by the investigators), bradycardia (heart rate \<50 bpm); or
4. had clinical abnormalities in 12-lead ECG during screening (e.g. atrioventricular block, torsades de pointes (TdP), other types of ventricular tachycardia, ventricular fibrillation and ventricular flutter, clinically significant T wave changes, or any 12-lead ECG abnormalities that may influence QTc intervals); or
5. had systolic blood pressure \>140 mmHg or \<90 mmHg, diastolic blood pressure \>90 mmHg, pulse \<50 bpm or \>100 bpm during the screening; or
6. had a positive result in hepatitis B virus or hepatitis C virus serology test; or
7. had a positive pregnancy test result or was currently in lactation period; or
8. was found to have any laboratory test value that was outside the reference value (normal value±10%) during the screening, and that was deemed to have clinical significance by investigators; or
9. had a history of diabetes or cardiovascular disease, liver disease or kidney disease; or
10. had malabsorption syndrome or any other gastrointestinal disease that may influence drug absorption; or
11. had any history of epileptic seizures, or mental disease that may affect protocol compliance, or had a suicidal risk, or had history of alcohol or prohibited drug abuse; or
12. had any disease known to severely affect the immune system, e.g. history of human immunodeficiency virus (HIV) infection, hematologic or solid organ malignancy, or had a splenectomy, etc; or
13. had a hypersensitive idiosyncrasy or hypersensitivity to any drugs, including quinolones or fluoroquinolones; or
14. had a surgery or trauma history within 6 months before receiving the study drug; or
15. had, as shown from his/her medical history, used any known liver enzyme inducer or liver enzyme inhibitor such as benzedrine, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, phencyclidine, etc within 30 days before receiving the study drug; or
16. had used any other trial drugs within 30 days before receiving the study drug; or
17. had used any prescription drugs or Chinese herbal medicines within 14 days before receiving the study drug; or
18. had used any OTC drugs or nutrition supplements (including the products containing multivalent cation such as calcium, aluminum, magnesium, iron, and zinc, as well as sucralfate, antacids, nutrition supplements, vitamin complex, and dietary metal supplements, etc) within 7 days before receiving the study drug; or
19. had donated ≥400 ml of blood within 3 months before drug administration; or
20. had, as judged by the investigators, any past or current disease or physical condition that may affect the safety or effect evaluation of the study drug; or
21. was identified by the investigators as unsuitable to participate in the study.

Primary outcomes:
measure: ECG analysis - baseline-adjusted mean QTcF
timeFrame: 2 days
Secondary outcomes:
measure: ECG analysis - baseline-adjusted mean QTcB
timeFrame: 2 days
measure: ECG analysis - baseline-adjusted mean QTcP
timeFrame: 2 days
measure: Safety analysis
timeFrame: 33 days
measure: Maximum Plasma Concentration (Cmax)
timeFrame: 2 day
measure: Time at Which Maximum Plasma Concentration was Observed (Tmax)
timeFrame: 2 day
measure: Area Under the Plasma Concentration-Time Curve Calculated to the Last Measured Concentration (AUC(0~t))
timeFrame: 2 day
measure: Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUC(0~∞))
timeFrame: 2 day
measure: Lambda-z (λz)
timeFrame: 2 day
measure: half-life (t1/2)
timeFrame: 2 day
measure: Oral Clearance (CLt/F)
timeFrame: 2 day
Other outcomes:
Locations:
Study officials:
References:
citation: Zhao C, Lv Y, Li X, Hou F, Ma X, Wei M, Kang Z, Cui L, Xia Y, Liu Y, Tian J. Effects of Nemonoxacin on Thorough ECG QT/QTc Interval: A Randomized, Placebo- and Positive-controlled Crossover Study in Healthy Chinese Adults. Clin Ther. 2018 Jun;40(6):983-992. doi: 10.1016/j.clinthera.2018.04.014. Epub 2018 May 24.