An open-label, balanced, randomized, single-dose, three-treatment, four-sequence, four-period, reference replicate crossover bioequivalence study of two Test drug products [Test1 and Test2] of Barnidipine Hydrochloride Modified-Release Capsules 20 mg of Centaur Pharmaceuticals Pvt. Ltd. India with Cyress 20, 20 mg capsules met gereguleerde afgifte (Barnidipine hydrochloride) [Reference] of BModesto Minervaweg 2 8239 DL Lelystad Netherlands, in healthy, adult, male, human subjects under fasting conditions.
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 16
- 试验地点
- 1
研究概览
简要总结
Title of the study An open-label, balanced, randomized, single-dose, three-treatment, four-sequence, four-period, reference replicate crossover bioequivalence study of two Test drug products i.e. Test1 and Test2 of Barnidipine Hydrochloride Modified-Release Capsules 20 mg of Centaur Pharmaceuticals Pvt. Ltd. India with Cyress 20, 20 mg capsules met gereguleerde afgifte (Barnidipine hydrochloride) i.e. Reference of BModesto Minervaweg 2 8239 DL Lelystad Netherlands, in healthy, adult, male, human Subjects under fasting conditions.
Protocol number: LBS-015-25/1, Version 01
Regulatory submission: EMA
Indication and usage: Mild to moderate essential hypertension.
Study design:
Open-label,
Balanced,
Randomized,
Single-dose,
Three-treatment,
Four-sequence,
Four-period,
Reference replicate crossover
Under fasting conditions
Primary objective
To investigate bioequivalence between two individual Test drug products [Test1 and Test2] of Barnidipine Hydrochloride Modified-Release Capsules 20 mg of Centaur Pharmaceuticals Pvt. Ltd. India and Reference drug product of Cyress 20, 20 mg capsules met gereguleerde afgifte (Barnidipine hydrochloride) of BModesto Minervaweg 2 8239 DL Lelystad Netherlands, in healthy, adult, male, human Subjects following single dose administration of 1 capsule of Test1 or Test2 or Reference drug product under fasting conditions with a washout period of at least 14 days between two consecutive periods, by means of rate and extent of absorption.
Secondary objective
To monitor the safety of the participating Subjects in this bioequivalence study determined by means of hematology, clinical biochemistry, vital signs and physical examination, 12-lead ECG and AE/SAE monitoring.
Number of Subjects LifeSan Clinical Research, Division of Centaur Pharmaceuticals Pvt. Ltd.
Basement – A and B wing, Ground floor – A wing, 5th floor – B wing and 6th floor – A and B wing, Centaur House, Near Hotel Grand Hyatt, Santacruz [East], Mumbai 400055, India.
Drug Product
Test drug product (T1): Barnidipine Hydrochloride Modified-Release Capsules 20 mg of Centaur Pharmaceuticals Pvt. Ltd. India
Test drug product (T2): Barnidipine Hydrochloride Modified-Release Capsules 20 mg of Centaur Pharmaceuticals Pvt. Ltd. India
Reference drug product (R): Cyress 20, 20 mg capsules met gereguleerde afgifte (Barnidipine hydrochloride) of BModesto Minervaweg 2 8239 DL Lelystad Netherlands
One capsule of ‘Test1’ or ‘Test2’ or ‘Reference’ drug product will be administered orally with 240 ± 2 mL of water at ambient temperature in each period as per randomization sequence generated by the biostatistician of LCR, if following all conditions are met:
At least 10.000 hrs. fasting prior to scheduled dosing time
Water restriction enforced 1.000 hr. prior to scheduled dosing time
Normal vital parameters demonstrated in pre-dose vital signs examination conducted within 1.000 hr. prior to scheduled dosing time.
Pre-dose sample is collected within 1.000 hr. prior to scheduled dosing time
Suitability is defined by the qualified medical staff
Washout period: At least 14 days between 2 consecutive drug product administrations
Duration of the study: At least 48 days
Hosing of Subjects: In each period of study, Subjects will be housed in clinical facility until 48.000 hrs. after IMP administration.
Discharge: In each period of study, Subjects will be discharged at 48.000 hrs. after IMP administration.
Ambulatory visits: In each period of study, Subjects will return to clinical facility at 72.000 and 96.000 hrs. after IMP administration.
Admission in the period I of the study: Subjects will be asked to report to the clinical facility of LifeSan Clinical Research [LCR] at early morning on the admission day and will be admitted in ward at least 13.000 hrs. before IMP administration.
After obtaining the informed consent, all volunteers will undergo urine alcohol test, urine screen for presence of drugs of abuse, 12-lead ECG in supine position followed by vital signs and systemic medical examination. Further, they will be assessed from inclusion-exclusion criteria and will be admitted in the ward, once they are declared as eligible for the study.
Admission in the study in period II/ III/ IV: In the period II, III and IV, admission procedures will be identical with the exception of any informed consent. Protocol compliance will be judged as part of admission procedure.
Overnight pre-dose fasting: All Subjects will undergo an overnight fasting for at least 10.000 hrs. prior to scheduled dosing time.
Pre-dose procedures:
Cannulation: On the day of IMP administration, a cannula will be inserted in the prominent vein Subject’s forearm or dorsal aspect of arm before IMP administration.
Pre-dose vital signs examination will be conducted within 1.000 hr. prior to scheduled dosing time.
Pre-dose sample will be collected within 1.000 hr. prior to scheduled dosing time.
Water restriction will be enforced 1.000 hr. prior to scheduled dosing time.
Dosing: One capsule of Test1 or Test2 or Reference IMP will be administered at scheduled time as per the randomization schedule with 240 ± 2 mL of water at ambient temperature after suitability of the Subject is decided by the qualified medical staff. The dosing activity will be performed under sodium vapor lamp.
Pharmacokinetic blood sampling: The concentration of barnidipine will be determined in plasma separated from venous blood samples collected in K3EDTA vacutainers during period I, II, III and IV at following 26 time points: At 0.000 hr. [pre-dose, collected within 1.000 hr. of dosing] and at 1.000, 2.000, 3.000, 4.000, 4.333, 4.667, 5.000, 5.333, 5.667, 6.000, 6.333, 6.667, 7.000, 7.500, 8.000, 9.000, 10.000, 12.000, 18.000, 24.000, 30.000, 36.000, 48.000, 72.000 and 96.000 hrs. after IMP administration. The collection of blood samples will be performed under sodium vapor lamp.
Total blood loss: Four [4] mL blood will be collected at each sampling time point. Total blood loss will not exceed 462.0 ± 10 mL. This blood loss includes blood loss for general screening, PSSA and discarded blood.
Restrictions:
All the Subjects will be restricted to sitting posture on bed for first 1.000 hr. post-dose followed by lie-on-bed postural restriction until at least 8.000 hrs. post-dose. During this period, all study procedures will be conducted bedside.
Water restriction will begin 1.000 hr. prior to IMP administration and continue until 1.000 hr. post-dose, except for 240 ± 2 mL of water administered with the IMP.
In case of natural urge during restriction period, the Subjects will be allowed to visit toilet but must be accompanied by clinical custodian staff.
The other restrictions are described in the section 13.4 of the protocol.
Vital signs examination: During their confinement period and at ambulatory visits, vital signs examination & well-being assessment will be performed at the following times:
At the time of admission [Pulse, BP, RR and temperature]
Pre-dose [Pulse, BP and temperature] within 1.000 hr. prior to scheduled dosing time
At 2.000, 5.000, 9.000, 14.000, 22.000, 30.000 and 37.000 hrs. after IMP administration [Pulse, BP and temperature]
At the time of discharge at 48.000 hrs. [Pulse, BP, RR and temperature]
At the time of ambulatory visits at 72.000 and 96.000 hrs. [Pulse, BP and temperature]
Vital signs and medical examination could be conducted any time in case of medical necessity
Meals: During their confinement period, Subjects will be given standardized meals at the following times in each period:
Dinner at least 12.000 hrs. prior to scheduled dosing time
Lunch at 4.000 and 28.000 hrs. after IMP administration
Snacks at 8.000 and 32.000 hrs. after IMP administration
Dinner at 12.000 and 36.000 hrs. after IMP administration
Breakfast at 24.000 hrs. after IMP administration
12-lead ECG examination: 12-lead ECG examination will be conducted at the following times in each period:
At the time of admission after volunteer/ Subject is found eligible through urine alcohol test and urine screen for presence of drugs of abuse
At the time of discharge
At the time of PSSA
As per investigator’s discretion any time during the study
Special procedure: Since barnidipine is light-sensitive, the study procedures of drug product receipt, dispensing, dosing, sample collection, matrix separation, segregation and bioanalysis will be conducted under sodium vapor lamp.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 盲法
- None
入排标准
- 年龄范围
- 18.00 Year(s) 至 45.00 Year(s)（—）
- 性别
- All
入选标准
- •1.Healthy, Indian, male, human volunteers aged from 18 to 45 years (both inclusive).
- •Weight not less than 50 Kg. and body mass index should be within 20.00–29.95 kg/m2 [weight in kg / (height in m)2].
- •Voluntarily willing and capable to give written and signed informed consent prior to participation in the study.
- •Availability for the entire study period and willingness to adhere to the protocol and study requirements.
- •Willing to undergo pre- and post-study physical examinations and clinical laboratory investigations.
- •Having no current or past significant disease as well as clinically significant observations from medical history or physical examination or vital signs examination during screening.
- •Having normal values or clinically acceptable values of investigations of clinical laboratory examination during screening [exception: SGOT/ SGPT/ S.
- •Alkaline phosphatase and S.
- •total bilirubin, which should be normal].
- •12-lead ECG in supine position done as part of screening and admission procedure is within normal limits or showing clinically insignificant artifacts as per qualified medical staff.
- •Normal chest X-ray findings or findings that have no clinical correlation.
- •Determined as eligible through 2-D transthoracic echocardiography conducted within 10 days prior to admission in period I of the study
- •Having not consumed alcohol at least 24.000 hrs.
- •prior to admission in the study justified by negative urine-alcohol test and who agree not to consume any amount of alcohol throughout the conduct of the study.
- •Negative urine test for drug of abuse (amphetamine, barbiturate, tetrahydrocannabinoids, morphine, cocaine, benzodiazepine).
- •Not consumption of xanthine-containing derivatives [coffee, tea, cola drinks, chocolate] and grapefruit or orange or citrus fruits/ juice/ products for at least 48.000 hrs.
- •prior to admission in the study.
- •Non-smokers [Definition – Those who do not have history of smoking or having quit smoking for more than 3 years].
排除标准
- •H/O allergy or sensitivity to barnidipine or to any dihydropyridine or history of any drug hypersensitivity or intolerance, which, in the opinion of the investigator, will compromise the safety of the Subject in the study.
- •H/O of rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.
- •History of unstable angina pectoris and acute myocardial infarction.
- •H/O use of strong inhibitors of CYP3A [e.g. antiproteases, ketoconazole, itraconazole, erythromycin and clarithromycin etc.] or inducers of CYP3A [e.g. rifampicin, carbamazepine etc.] at least within 14 days of admission in the study.
- •Clinically significant findings from 2-D transthoracic echocardiography interpreted by the cardiologist.
- •History or presence of hepatic dysfunction established by elevated serum transaminases (SGOT/ SGPT) or alkaline phosphatase [at least 1.5 times of upper normal range].
- •History or presence of renal function impairment established by serum creatinine 1.5 times or more of upper reference range.
- •History or presence of any other clinically relevant systemic disease such as renal, hepatic, pulmonary, endocrine, ophthalmic or metabolic disorder (e.g. diabetes mellitus), malignancy or immunodeficiency disorder.
- •Irregular mealtimes, skipping meals, periods of fasting or dietary changes within last 3 months prior to enrollment in the study.
- •Participation in another clinical study or a blood donation program or having had blood loss of more than 450 mL during the last 90 days.
- •Seropositive for VDRL, HIV or hepatitis B or C infection.
- •Any clinically significant abnormality (to be determined by the investigator) following review of screening laboratory data, X-ray interpretation, 12-lead ECG and full physical examination
- •Vital sign abnormalities [systolic blood pressure less than 100 or greater than 140 mmHg or diastolic blood pressure less than 60 or greater than 90 mmHg or pulse rate less than 50 bpm or greater than 100 bpm, or oral/axillary temperature less than 95.8ºF or greater than 99.0ºF at the pre-admission physical examination.
- •Having suffered any illness within a week of starting the study or who have been hospitalized within the 3 months preceding the start of the study.
- •Any other clinical condition, which might affect the absorption, distribution, biotransformation or excretion of the study drug.
- •Having taken OTC or prescribed medications, including any enzyme-modifying drugs or any systemic medication within the last 07 days prior to the study.
- •Having a history of alcohol or substance abuse within the last 5 years.
- •Habit of chewing or inhaling nicotine-containing products.
- •Abnormal INR combined with clinical manifestation.
研究者
Dr Mukund Zarapkar
LifeSan Clinical Research, division of Centaur Pharmaceuticals Pvt. Ltd.