A randomized, double blind, balanced, two treatment, two period, two sequence, single dose, crossover pharmacokinetic and pharmacodynamic bioequivalence study of Soluble Insulin Injection R 40 IU/mL of Unichem Laboratories Ltd., India with Huminsulin R 40 IU/mL of Eli Lilly and company (India) Pvt. Ltd in healthy human adult male subjects using Euglycemic clamp technique under fasting conditions.
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 56
- 试验地点
- 1
- 主要终点
- Primary Pharmacodynamic parameters: GIR-AUC0-t & GIRmax
研究概览
简要总结
| Sponsor: |
Unichem Laboratories Limited,
Unichem Bhavan
Prabhat Estate, Off S.V.Road, Jogeshwari (West), Mumbai – 400 102
|Investigational product
Test Product :Soluble Insulin Injection R 40 IU/mL of Unichem Laboratories Ltd., India.
|Reference Product: Huminsulin R 40 IU/mL of Eli Lilly and company (India) Pvt. Ltd.
|Title of protocol
A randomized, double blind, balanced, two treatment, two period, two sequence, single dose, crossover pharmacokinetic and pharmacodynamic bioequivalence study of Soluble Insulin Injection R 40 IU/mL of Unichem Laboratories Ltd., India with Huminsulin R 40 IU/mL of Eli Lilly and company (India) Pvt. Ltd in healthy human adult male subjects using Euglycemic clamp technique under fasting conditions.
|Study center(S)
Clinical Study Center
Ecron Acunova Limited (Formerly known as Manipal Acunova Limited), V floor, MCODS Building, KMC Hospital, Attavar,
Mangalore- 575 001, India.
Clinical Laboratory Facility
Clinical Testing Laboratory,
Ecron Acunova Limited (Formerly known as Manipal Acunova Limited),
IV Floor, Sri Shirdi Sai Baba Cancer Hospital and Research Centre,
Manipal - 576 104, India
Tel.: +91-820-6621122, Fax: +91-820-2571999
And/or
KMC Laboratory Services,
KMC Hospital, Dr. B.R. Ambedkar Circle,
Mangalore – 575 001, India, Tel.: +91-824-2444590 [Ext: Lab-5055]
And/or
Clinical Laboratory facility,
Kasturba Hospital, Manipal - 576 104, India, Tel.: +91-820-2922201.
Bio analysis
Ecron Acunova Limited (formerly known as Manipal Acunova Limited),
Mobius Towers, SJR I-Park, EPIP Zone, Whitefield,
Bangalore - 560 066, India
Tel.: +91-80-66915749 Fax: +91-80-66915719,
Mobile: +91-8904783936.
Pharmacokinetic and Statistical analysis
Ecron Acunova Limited (Formerly known as Manipal Acunova Limited),
Mobius Towers, SJR I-Park, EPIP Zone, Whitefield, Bangalore - 560 066, India. Tel.: +91-80-6691 5726, Fax: +91-80-6691 5719,
Mobile: +91-9494982021.
|Objectives
The primary objective of this study is to compare and evaluate the pharmacokinetics and Pharmacodynamics of single dose of Soluble Insulin Injection R 40 IU/mL of Unichem Laboratories Ltd., India and Huminsulin R 40 IU/mL of Eli Lilly and Company (India) Pvt. Ltd. in healthy human adult male subjects using Euglycemic clamp technique under fasting conditions.
The secondary objective of this study is to monitor the safety and tolerability of a single dose of Insulin Injection R 40 IU/mL when administered in healthy human adult male subjects using Euglycemic clamp technique under fasting conditions.
|Study population
A total of 56 normal, healthy, adult male, human, subjects aged between 18 to 45 years will be subjects will be included in the study.
|Main criteria of inclusion
a) Normal healthy human adult male volunteers between 18-45 years (both ages inclusive) of age, who have given written informed consent and are willing to participate in the study.
b) Volunteer having Body Mass Index of 18.50 to 24.90 Kg/m2 (both inclusive).
c) Volunteer with no evidence of underlying disease during the pre-study screening, medical history, physical examination and laboratory investigations performed within 21 days prior to commencement of the study and during at the time of check-in of each period.
d) Volunteer whose pre-study screening laboratory tests are either normal or within acceptable limits or are considered by the Investigator to be of no clinical significance with respect to his/her participation in the study.
e) Volunteer with negative test for alcohol, drugs of abuse, hepatitis B & C and who is negative or non-reactive for antibodies to HIV 1 and 2 and RPR.
f) Volunteer having a 12 lead ECG recording within normal limits.
g) Volunteer with normal chest X-ray taken within 6 months prior to the day of dosing of period 1.
h) Volunteer with normal renal function.
i) Volunteer will be available for the entire study period and is capable of understanding and communicating with the investigators and clinical study facility staff.
j) Volunteer should be non-smokers and without a history of alcohol.
k) Subjects with normal results of 2 hours Oral Glucose Tolerance Test (OGTT)
|Dosage and duration of treatment
Each subject will receive a single dose of test and reference products (0.3 IU/kg of body weight) by subcutaneous injection over two periods of the study.
|Screening procedures
Demographic data, Medical history, General physical examination, Family history of Diabetes Mellitus, 12-lead ECG, chest X-ray (PA view), Hematology, Clinical bio- chemistry, Serology, Urine analysis, Tests for alcohol (in breath), Drugs of abuse, Oral Glucose Tolerance Test (OGTT), HbA1c, PT, APTT & Thyroid function test (TSH, T3 & T4).
|Methodology
All subjects will be explained about the study procedures and written informed consent will be obtained from each subject before performing any study related procedure. The subjects will be fully informed of their
responsibilities and of all the procedures involved in the trial, the possible risks and disadvantages of being dosed with Unichem soluble Insulin Injection R 40 IU/mL to Huminsulin R 40 IU/mL, Eli Lilly and company (India) Pvt. Ltd. and heir rights while participating in the trial.
They will have the opportunity to ask questions. If the subjects wish to participate in the trial, they will have to read, sign and date an informed consent form prior to the performance of any study related procedure.
The subjects will be selected on the basis of inclusion and exclusion criteria.
All the subjects will be admitted in the clinical research unit in the evening prior to the dosing day and fasted for at least 10 hours before dose administration of investigational product.
The trial drugs dose (test or reference product) will be a single dose of 0.3 IU/kg of body weight. The trial products will be administered to the subject while in supine posture by subcutaneous injection in the Para-umbilical skin fold in accordance with the randomization schedule.
Activities, including the glucose Clamp Procedure:
On the day of dosing for each subject, on one hand the subject will be cannulated to collect the blood samples for PK and PD analysis. On the other hand the subjects will be cannulated for intravenous infusion of 20% dextrose solution.
After overnight fasting of 10.00 hours, pre-dose blood samples of 0.3 mL will be collected at -00.50, -00.33 and -00.17 hrs prior to dosing for the determination of base line blood glucose (mg/dl) in each period. Mean blood glucose level (mg/dl) will be calculated from these three pre-dose blood (-00.50, -00.33 and -00.17 hrs) glucose values (mg/dl) for each subject and the mean value minus 5 will be considered as the clamp value for the subject (target clamp range will be ± 3 mg/dl of clamp value) in each period.
If the difference between the lowest pre-dose blood glucose value and the highest pre- dose blood glucose value is more than 5 mg/dl, then the decision regarding the aberrant pre-dose blood glucose value will be decided by the investigator. When the range is found to be beyond 5 mg/dl, a new sample will be collected and estimated for glucose value and clamp value will be calculated by excluding the aberrant pre-dose blood glucose value.
If Initial mean fasting pre-dose blood glucose value (-00.50, -00.33 and -00.17 hrs) is less than 70 mg/dL or Greater than 99 mg/dL then the subject should be withdrawn from the Study.
If difference of initial fasting pre-dose blood glucose value (-00.50, -00.33 and -00.17 hrs) exceed the limit of 10 mg/dL then the subject should be withdrawn from the Study.
It should be ensured that 20% Dextrose Solution and Insulin Syringe for all the study subjects will be used from same Batch or Lot. The same will also be recorded in the CRF.
Drug Administration:
Prior to dosing, the injection site will be verified and ensured that the site is normal by the Investigator. The injection site will be marked with a waterproof pen prior to dosing followed by single dose of (0.3 IU/kg of body weight in period 1) Test product or Reference product will be on the marked injection site in supine posture by subcutaneous injection in the right or left side of paraumblical skin fold.
Each subject will randomly receive a single dose (0.3 IU/kg of body weight in period 1) of test or reference product by subcutaneous injection in each study period as per randomization schedule.
Blood Sampling:
Pharmacokinetic Samples
A total of 28 blood samples will be collected from each subject in pre-specified vacuum tubes containing K3 EDTA in each study period. The pre-dose samples (1×6.0 mL) will be collected at -00.50, -00.33 -00.17 and 00.00 hours before dosing in each study period (00.00 hour PK sample will be taken 05 min before the administration of Investigational Product). The post-dose samples (1×6.0 mL) will be collected at 00.50, 00.75, 01.00, 01.25, 01.50, 01.75, 02.00, 02.25, 02.50, 02.75, 03.00, 03.25, 03.50,
03.75, 04.00, 04.25, 04.50, 05.00, 05.50, 06.00, 07.00, 08.00, 10.00 and 12.00 hours after dosing in each study period.
Pharmacodynamic Samples
A total of 147 (1×0.3 mL) blood samples will be collected in Lithium Heparin tubes in each study period. After overnight fasting of 10 hours pre-dose samples (1×0.3mL) will be collected at -00.50, -00.33 -00.17 for blood glucose estimation to calculate the target glucose clamp range. The post-dose samples will be collected in in Lithium Heparin tubes for blood glucose estimation, every 5 minutes from the time of dosing till 12 hours post dose or till termination of clamp procedure, by using a blood glucose analyzer [Glucose Analyzer (YSI 2900)] for each subject in each study period.
|Safety Parameters
Vital Signs:
Vital signs (blood pressure, pulse rate, respiratory rate, heart rate and oral temperature) will be measured before and after check-in, prior to dosing on dosing day and at 02.00, 04.00, 06.00, 08.00, 10.00, 12.00 and 24.00 hours post-dose in each study period. The vital signs measurement will be performed at the time of post-study safety sample collection, if safety sample is not taken at the time of last blood draw of the study. Subject will be connecting to the patient monitor prior to dosing and continued till the termination of the clamp procedure.
All these measurements (except check-in day and pre-dose vital signs examinations) will be completed within  01.00 hour of the scheduled time so as not to interfere with scheduled blood sampling times. The actual time of measurement will be recorded in the CRF.
ECG Monitoring;
12-Lead ECG monitoring will be done prior to dosing on dosing day, after termination of clamp procedure of each study period and during post study safety analysis.
Well-being:
Subjects will be asked about their well-being before and after check-in, prior to dosing on dosing day and approximately at 02.00, 04.00, 06.00, 08.00, 10.00, 12.00 and 24.00 hours post-dose in each study period. In addition, at all times, subjects may report side effects spontaneously to the monitoring staff. The same will also be recorded in the CRF. The enquiry of wellbeing will be done at the time of post-study safety sample collection, if safety sample is not taken at the time of last blood draw of the study.
Local tolerability Assessment:
Assessment of injection site will be performed for each subject at 02.00, 04.00, 06.00, 08.00, 10.00 and 12.00 hours post-dose in each study period.
This assessment will be completed within 15 minutes of the scheduled time so as not to interfere with scheduled blood sampling times. The actual time of assessment will be recorded in the CRF.
Post glucose clamp measurements:
After 12.00 hours post dose glucose clamp will be terminated for each subject in each period and fresh juice will be provided to the subjects and if, required blood glucose level will be measured in Glucose Analyzer (YSI 2900) as per Investigator’s discretion. Then subjects will be provided with a study meal. After the consumption of meal Blood glucose level will be measured using Accu-Chek Glucometer for safety reasons.
|Pharmacokinetic Parameters:
Primary pharmacokinetic parameters: AUC0-t & Cmax
Secondary pharmacokinetic parameters: AUC0-4, AUC0-6, AUC0-12, AUC4-12, AUC6-12, AUC0-inf, Tmax, t1/2 & Kel
|Pharmacodynamic Parameters:
Primary Pharmacodynamic parameters: GIR-AUC0-t & GIRmax
Secondary Pharmacodynamic parameters: Time to onset of action & TGIRmax
|Pharmacokinetics/ Pharmacodynamic
Pharmacokinetic Parameter
Based on the 90% confidence intervals for the difference of means of ln-transformed Cmax and AUC0-t conclusions will be drawn whether the test product is bioequivalent to the reference product under fasting conditions. The acceptance range for bioequivalence is 80.00-125.00% for the 90% confidence intervals for the difference of means of ln-transformed Cmax and AUC0-t with respect to Insulin.
Pharmacodynamic Parameter
Based on the 95% confidence intervals for the difference of means of ln-transformed GIR-AUC0-t & GIRmax conclusions will be drawn whether the test product is bioequivalent to the reference product under fasting conditions. The acceptance range for bioequivalence is 80.00-125.00% for the 95% confidence intervals for the difference of means of ln-transformed GIR-AUC0-t & GIRmax with respect to Glucose Infusion Rate (GIR).
研究设计
- 研究类型
- Interventional
- 分配方式
- Computer generated randomization
- 盲法
- Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded
入排标准
- 年龄范围
- 18.00 Year(s) 至 45.00 Year(s)（—）
- 性别
- Male
入选标准
- •Normal healthy human adult male volunteers between 18-45 years (both ages inclusive) of age, who have given written informed consent and are willing to participate in the study.
- •Volunteer having Body Mass Index of 18.50 to 24.90 Kg/m2 (both inclusive).
- •Volunteer with no evidence of underlying disease during the pre-study screening, medical history, physical examination and laboratory investigations performed within 21 days prior to commencement of the study and during at the time of check-in of each period.
- •Volunteer whose pre-study screening laboratory tests are either normal or within acceptable limits or are considered by the Investigator to be of no clinical significance with respect to his/her participation in the study.
- •Volunteer with negative test for alcohol, drugs of abuse, hepatitis B & C and who is negative or non-reactive for antibodies to HIV 1 and 2 and RPR.
- •Volunteer having a 12 lead ECG recording within normal limits.
- •Volunteer with normal chest X-ray taken within 6 months prior to the day of dosing of period
- •Volunteer with normal renal function.
- •Volunteer will be available for the entire study period and is capable of understanding and communicating with the investigators and clinical study facility staff.
- •Volunteer should be non-smokers and without a history of alcohol.
- •Subjects with normal results of 2 hours Oral Glucose Tolerance Test (OGTT).
排除标准
- •Volunteer who has hypersensitivity to Insulin or related class of drugs.
- •Volunteer who has family history of diabetes mellitus.
- •Volunteer with history or presence of significant cardiovascular, respiratory, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological or psychiatric disease.
- •More specifically, volunteer with history or presence of significant: History of Alcohol or drug abuse.
- •History of smoking, even single cigarette, bidis or any other form.
- •Asthma, urticaria or other allergic type reactions after taking any medication.
- •Clinically significant illness within 4 weeks before the start of the study.
- •History of clinically relevant allergy (except for untreated, asymptomatic, seasonal allergies at time of dosing) or any allergic reactions to any drugs.
- •History of vascular collapse.
- •Volunteer who is scheduled for surgery any time during study or within 07 days after study completion.
- •Volunteer with history of difficulty in donating blood Volunteer who, through completion of any other clinical or bioequivalence study or otherwise would have donated in excess of 350 mL of blood in the last 90 days.
- •Volunteer who has taken prescription medication or over-the-counter products (including vitamins and products from natural origin e.g. St. John’s Wort) within 14 days prior to administration of IP in period 1, including topical medication meant for systemic absorption.
- •Volunteer who was hospitalized within 28 days prior to administration of the study medication.
- •Volunteer who has unsuitable veins for repeated venipuncture.
- •Volunteer who has Potassium level < 3.5 mmol/L.
- •Any abnormal laboratory value or physical finding which may interfere with the interpretation of test results or cause a health hazard for the volunteer if he participates in the study.
- •Volunteer having evidence of skin lesions on forearm of signs of vein puncture on the forearm suggestive of recent donation or participation in clinical trial.
- •Volunteer who has: Systolic blood pressure less than 90 mm of Hg or more than 140 mm of Hg Diastolic blood pressure less than 60 mm of Hg or more than 90 mm of Hg. Minor deviations (2-4 mm of Hg) at check-in may be acceptable at the discretion of the Investigator.
- •Use of systemic corticosteroids, monoamine oxidase (MAO) inhibitors, prostaglandin blockers, systemic non-selective beta-blockers, growth hormones Any use of non-steroid anti-inflammatory drugs (NSAIDs) except for low-dose Aspirin is not allowed within 7 days prior to dosing and on the dosing day Use of any insulin product in the past.
结局指标
主要结局
Primary Pharmacodynamic parameters: GIR-AUC0-t & GIRmax
时间窗: PK samples: A total of 28 PK blood samples (each sample of 6 ml)for determination of insulin & C-peptide will be drawn at at -00.50, -00.33 -00.17 hrs pre-dose 00.50, 00.75, 01.00, 01.25, 01.50, 01.75, 02.00, 02.25, 02.50, 02.75, 03.00, 03.25, 03.50, | 03.75, 04.00, 04.25, 04.50, 05.00, 05.50, 06.00, 07.00, 08.00, 10.00 and 12.00 post dose. | PD samples: A total of 147 (1×0.3 mL) blood samples will be collected every 5 minutes from the time of dosing till 12 hours post dose
Primary pharmacokinetic parameters: AUC0-t & Cmax
时间窗: PK samples: A total of 28 PK blood samples (each sample of 6 ml)for determination of insulin & C-peptide will be drawn at at -00.50, -00.33 -00.17 hrs pre-dose 00.50, 00.75, 01.00, 01.25, 01.50, 01.75, 02.00, 02.25, 02.50, 02.75, 03.00, 03.25, 03.50, | 03.75, 04.00, 04.25, 04.50, 05.00, 05.50, 06.00, 07.00, 08.00, 10.00 and 12.00 post dose. | PD samples: A total of 147 (1×0.3 mL) blood samples will be collected every 5 minutes from the time of dosing till 12 hours post dose
次要结局
- Secondary pharmacokinetic parameters: AUC0-4, AUC0-6, AUC0-12, AUC4-12, AUC6-12, AUC0-inf, Tmax, t1/2 & Kel(Secondary Pharmacodynamic parameters: Time to onset of action & TGIRmax)