A Double-blind, Randomized, Two-period, Two-treatment, Two-sequence, Crossover, Balanced, Single Subcutaneous Dose Pharmacodynamic Comparative Equivalence Study of Enoxaparin Sodium Pre-filled Syringes BP (Injection) 40 mg/0.4 ml (4,000 IU/0.4 mL) of Venus Remedies Limited, India and 'Clexane®' (Enoxaparin Sodium Injection Solution in a Pre-filled Syringe) 4,000 IU (40 mg)/0.4 ml of Sanofi, Germany in Healthy Adult Human Subjects Under Fasting Conditions
Overview
- Phase
- Phase 1
- Intervention
- Enoxaparin Sodium (Venus Remedies Limited)
- Conditions
- Healthy
- Sponsor
- Venus Remedies Limited
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- Amax for Anti-Xa and Anti-IIa
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
This is a single-dose, randomized, double-blind, two-period, two-treatment, two-sequence, crossover, balanced, pharmacodynamic (PD) study with 7 days wash-out period. The objective of this study is to assess the bioequivalence between the Enoxaparin (Venus Remedies Limited, India) and its innovator product (Clexane®, Sanofi, Germany).
Detailed Description
Enoxaparin is a widely used low-molecular-weight heparin (LMWH) obtained by alkaline β-eliminative cleavage of heparin benzyl ester derived from the porcine intestinal mucosa. Currently, several biosimilars/generics of LMWHs with differing potencies are being developed and marketed in various parts of the world. They differ in their PK and PD properties, which could be possibly due to the depolymerization processes or the manufacturing methods that result in its structural variability. Therefore, it is important that the potency of each biosimilar LMWH be compared with its innovator's molecule. The PK properties and bioavailability of LMWHs are routinely determined by pharmacodynamic (PD) surrogates such as Anti-Xa activity, Anti-IIa activity, tissue factor pathway inhibitor (TFPI) and activated partial thromboplastin time (aPTT). This study was designed as a double-blind, randomized, two-period, two-treatment, two-sequence, crossover, balanced, single-dose pharmacodynamic study in healthy, adult, human subjects under fasting conditions to compare and evaluate the pharmacodynamic profile of test product \[Enoxaparin Sodium prefilled syringe BP; 40 mg/0.4 mL (Venus Remedies Limited, India)\] with that of reference product \['Clexane®' Enoxaparin Sodium prefilled syringe; 40 mg/0.4 mL (Sanofi, Germany)\]. The study was conducted with 24 subjects in accordance with protocol. After overnight fasting of at least 08 hours, a single dose of either test product or reference product was administered to the subjects slowly by subcutaneous route (shaved abdominal wall) alternated in both period between left or right anterolaterally in a supine posture under the supervision of trained study personnel. The subjects received the test product (A) and reference product (B) in the study as per the randomization schedule. Participants were randomly selected for one of the two sequences: either AB or BA. The washout period between administration of study drugs in each period was 7 days. Blood samples to assess PD parameters were collected in both study periods at the following time points: pre-dose (0.0 hour) and at 0.5, 1.0, 1.5, 2.0, 2.333, 2.667, 3.0, 3.333, 3.667, 4.0, 4.5, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, and 24.0 hours after dosing. The Anti-Xa and Anti-IIa activity was measured by the chromogenic method using commercial reagent kits - STA®-liquid Anti-Xa, Diagnostica Stago and Actichrome® Heparin (Anti-IIa) kit, Biomedica Diagnostics, respectively. TFPI was assessed using Enzyme-Linked Immunosorbent Assay (ELISA) kit (Quantikine® Human TFPI ELISA kit) and aPTT was determined using clotting assay reagent kit - STA-C.K. Prest® 5-Diagnostica Stago. Statistical analysis was performed on the pharmacodynamic data to assess bioequivalence between the test product to the reference product. The average bioequivalence of the products was concluded if two-sided 90% CI for the test to the reference ratio of the population means was within 80% and 125% interval for each of the Ln-transformed data, Amax and AUECt for Anti-Xa and Anti-IIa (primary objective).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Volunteers must fulfill all of the following inclusion criteria to be eligible for participation in the study, unless otherwise specified.
- •Age: 18 to 45 years old, both inclusive.
- •Gender: Male and/or non-pregnant, non-lactating female.
- •A. Female of childbearing potential must have a negative serum beta human chorionic gonadotropin (β-HCG) pregnancy test performed within 28 days prior to first dosing day. They must be using an acceptable form of contraception.
- •B. For female of childbearing potential, acceptable forms of contraception include the following:
- •i. Non hormonal intrauterine device in place for at least 3 months prior to the start of the study and remaining in place during the study period, or
- •ii. Barrier methods containing or used in conjunction with a spermicidal agent, or
- •iii. Surgical sterilization or
- •iv. Practicing sexual abstinence throughout the course of the study.
- •C. Female will not be considered of childbearing potential if one of the following is reported and documented on the medical history:
Exclusion Criteria
- •Volunteers must not be enrolled in the study if they meet any one of the following criteria:
- •History of hypersensitivity or idiosyncratic reaction to Enoxaparin Sodium, pork, heparin or its derivatives, other low molecular weight heparins or other related drugs, or any of its formulation ingredients.
- •Have significant diseases or clinically significant abnormal findings during screening \[medical history, physical examination (clinical examination), laboratory evaluations, ECG, chest X-ray recording, obstetrics and gynecological history and examination (for female volunteers)\].
- •Any disease or condition like diabetes, psychosis or others, which might compromise the haemopoeitic, gastrointestinal, renal, hepatic, cardiovascular, respiratory, central nervous system or any other body system.
- •History or presence of bronchial asthma.
- •Use of any hormone replacement therapy within 3 months prior to the first dose of study medication.
- •A depot injection or implant of any drug within 3 months prior to the first dose of study medication.
- •Use of CYP enzyme inhibitors or inducers within 30 days prior to the first dose of study medication (see http://medicine.iupui.edu/clinpharm/ddis/main-table).
- •History or evidence of drug dependence.
- •History of difficulty with donating blood or difficulty in accessibility of veins.
Arms & Interventions
Cohort 1 - AB treatment sequence
Period 1 - Test Product (A): Enoxaparin Sodium pre-filled syringe BP 40 mg/0.4 ml of Venus Remedies Limited, India. Period 2 - Reference Product (B): 'Clexane®' (Enoxaparin Sodium pre-filled syringe; 40 mg/0.4 ml) of Sanofi, Germany.
Intervention: Enoxaparin Sodium (Venus Remedies Limited)
Cohort 1 - AB treatment sequence
Period 1 - Test Product (A): Enoxaparin Sodium pre-filled syringe BP 40 mg/0.4 ml of Venus Remedies Limited, India. Period 2 - Reference Product (B): 'Clexane®' (Enoxaparin Sodium pre-filled syringe; 40 mg/0.4 ml) of Sanofi, Germany.
Intervention: Enoxaparin Sodium (Sanofi)
Cohort 2 - BA treatment sequence
Period 1 - Reference Product (B): 'Clexane®' (Enoxaparin Sodium pre-filled syringe; 40 mg/0.4 ml) of Sanofi, Germany. Period 2 - Test Product (A): Enoxaparin Sodium pre-filled syringe BP 40 mg/0.4 ml of Venus Remedies Limited, India.
Intervention: Enoxaparin Sodium (Venus Remedies Limited)
Cohort 2 - BA treatment sequence
Period 1 - Reference Product (B): 'Clexane®' (Enoxaparin Sodium pre-filled syringe; 40 mg/0.4 ml) of Sanofi, Germany. Period 2 - Test Product (A): Enoxaparin Sodium pre-filled syringe BP 40 mg/0.4 ml of Venus Remedies Limited, India.
Intervention: Enoxaparin Sodium (Sanofi)
Outcomes
Primary Outcomes
Amax for Anti-Xa and Anti-IIa
Time Frame: pre-dose (0.0 hour) and at 0.5, 1.0, 1.5, 2.0, 2.333, 2.667, 3.0, 3.333, 3.667, 4.0, 4.5, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, and 24.0 hours after drug administration
Maximum measured Anti-Xa and Anti-IIa plasma activity over the time span specified
AUECt for Anti-Xa and Anti-IIa
Time Frame: pre-dose (0.0 hour) and at 0.5, 1.0, 1.5, 2.0, 2.333, 2.667, 3.0, 3.333, 3.667, 4.0, 4.5, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, and 24.0 hours after drug administration
The area under the plasma activity/concentration-time curve from the time 0 to the last measurable concentration, as calculated by the linear trapezoidal method, for Anti-Xa and Anti-IIa
Secondary Outcomes
- t1/2 for Anti-Xa and Anti-IIa(pre-dose (0.0 hour) and at 0.5, 1.0, 1.5, 2.0, 2.333, 2.667, 3.0, 3.333, 3.667, 4.0, 4.5, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, and 24.0 hours after drug administration)
- Amax for ratio of Anti-Xa/Anti-IIa activity, TFPI (Baseline corrected and baseline uncorrected) and aPTT (Baseline corrected and baseline uncorrected).(pre-dose (0.0 hour) and at 0.5, 1.0, 1.5, 2.0, 2.333, 2.667, 3.0, 3.333, 3.667, 4.0, 4.5, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, and 24.0 hours after drug administration)
- AUECt for ratio of Anti-Xa/Anti-IIa activity, TFPI (Baseline corrected and baseline uncorrected) and aPTT (Baseline corrected and baseline uncorrected)(pre-dose (0.0 hour) and at 0.5, 1.0, 1.5, 2.0, 2.333, 2.667, 3.0, 3.333, 3.667, 4.0, 4.5, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, and 24.0 hours after drug administration)
- AUECi for Anti-Xa and Anti-IIa(pre-dose (0.0 hour) and at 0.5, 1.0, 1.5, 2.0, 2.333, 2.667, 3.0, 3.333, 3.667, 4.0, 4.5, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, and 24.0 hours after drug administration)
- Tmax for Anti-Xa and Anti-IIa(pre-dose (0.0 hour) and at 0.5, 1.0, 1.5, 2.0, 2.333, 2.667, 3.0, 3.333, 3.667, 4.0, 4.5, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, and 24.0 hours after drug administration)
- Kel for Anti-Xa and Anti-IIa(pre-dose (0.0 hour) and at 0.5, 1.0, 1.5, 2.0, 2.333, 2.667, 3.0, 3.333, 3.667, 4.0, 4.5, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, and 24.0 hours after drug administration)
- AUECi for ratio of Anti-Xa/Anti-IIa activity and TFPI (Baseline corrected and baseline uncorrected)(pre-dose (0.0 hour) and at 0.5, 1.0, 1.5, 2.0, 2.333, 2.667, 3.0, 3.333, 3.667, 4.0, 4.5, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, and 24.0 hours after drug administration)