Bioequivalence Study of Two Formulations of Telmisartan 80 mg Tablets in Healthy Adult Volunteers Under Fasting State

Study Overview
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Brief Summary
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This single center, randomized, single dose, full replicate, crossover comparative laboratory-blinded study will be conducted in healthy male and female volunteers in order to determine the bioequivalence of two different formulations of telmisartan 80 mg tablets after oral administration under fasting conditions.

Detailed Description
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The study is characterized by single center, randomized, single dose, laboratory-blinded, 4-period, 2-sequence, full replicate crossover design.The objective is to determine the bioequivalence of two different formulations of telmisartan after a single oral dose administration under fasting conditions. The test product is Telmisartan 80 mg tablets manufactured by Pharmtechnology LLC, Belarus. The reference product is Micardis 80 mg tablets manufactured by Boehringer Ingelheim Ellas AE, Greece. The primary study endpoints are the pharmacokinetic parameters Cmax and AUC0-T of telmisartan. Eligible 26 healthy adult subjects will be randomized to the one of two predetermined sequences: ABAB or BABA where A = the test product, B = the reference product. Clinical part of the study will include 4 periods; in each of them a single 80 mg dose of telmisartan will be administered orally with approximately 240 mL of water, in the morning, following a 10-hour overnight fast. Wash-out period between treatment administrations will last at least 14 calendar days. Subjects will be confined to the clinical site from at least 10 hours prior to each drug administration until 24 hours following each drug administration. Subjects will return to the clinical site for the remaining blood samples. In each study period, 21 blood samples will be collected for pharmacokinetic assessments. The first blood sample will be collected prior to drug administration while the others will be collected up to 72 hours after drug administration (0.17, 0.33, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 9.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00 postdose) . Total study duration: up to 74 days (including screening). Telmisartan plasma concentrations will be measured by a validated bioanalytical method. Statistical analysis of pharmacokinetic parameters will be based on an ANOVA model. Two-sided 90% confidence interval of the ratio of geometric LSmeans will be obtained from the ln-transformed pharmacokinetic parameters. Statistical inference of telmisartan will be based on a bioequivalence approach using the following standards: average bioequivalence (the ratio of geometric LSmeans with corresponding 90% confidence interval calculated from the exponential of the difference between the test and the reference product for the ln-transformed parameters Cmax and AUC0-T should all be within the 80.00 to 125.00% bioequivalence range); scaled-average-bioequivalence (in the event that the Cmax reference-to-reference within-subject CV is greater than 30%, that its test-to-reference geometric LSmeans ratio is within the bioequivalence range of 80.00 125.00% and the average bioequivalence criteria are not met, a scaling approach to the bioequivalence assessment will be used).

Official Title
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Single Dose, Full Replicate, Crossover Comparative Bioavailability Study of Telmisartan 80 mg Tablets in Healthy Male and Female Volunteers / Fasting State

Conditions
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Bioequivalence

Intervention / Treatment
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* Drug: Telmisartan
* Drug: Micardis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form (ICF) Stated willingness to comply with all study procedures and availability for the duration of the study Healthy male or female adult volunteer A female volunteer meeting one of the following criteria: (1) Physiological postmenopausal status, defined as the following: absence of menses for at least one year prior to the first study drug administration (not due to amenorrhea secondary to lactation); and Follicle stimulating hormone (FSH) levels ≥ 40 mIU/mL at screening; OR (2) Surgical postmenopausal status, defined as the following: bilateral oophorectomy; and absence of menses for at least 90 days prior to the first study drug administration; and FSH levels ≥ 40 mIU/mL at screening; OR (3) Hysterectomy with FSH levels ≥ 40 mIU/mL at screening If the postmenopausal volunteer has an FSH of < 40 mIU/mL, but meets the above criteria in either (1), (2) or (3) and all the other inclusion criteria, the volunteer may be included in the study if the estradiol serum level measured at screening is equal to or below 150 pmol/L. In the case of hysterectomy, if FSH and estradiol do not meet the criteria, inclusion of the volunteer will be based on medical judgment. Volunteer aged at least 18 years but not older than 55 years Volunteer with a body mass index (BMI) within 18.5 kg/m2 to 30.0 kg/m2, inclusively Light-, non- or ex-smoker. A light smoker is defined as someone using 10.0 nicotine units or less per day for at least 90 days prior to the first study drug administration. An ex smoker is defined as someone who completely stopped using nicotine products for at least 180 days prior to the first study drug administration Clinical laboratory values within the laboratory's stated normal range; if not within this range, they must be without clinical significance, as determined by an investigator Have no clinically significant diseases captured in the medical history or evidence of clinically significant findings on the physical examination (including vital signs) and/or ECG, as determined by an investigator Exclusion Criteria: Females who are pregnant according to the pregnancy test at screening Seated blood pressure below 105/60 mmHg at the screening visit or prior to the first study drug administration History of significant hypersensitivity to telmisartan or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs Presence of significant gastrointestinal, liver or kidney disease, or any other condition known to interfere with drug absorption, distribution, metabolism or excretion, or known to potentiate or predispose to undesired effects History of significant gastrointestinal, liver or kidney disease, or surgery that may affect drug bioavailability, including but not limited to cholecystectomy History of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic or dermatologic disease Presence of clinically significant ECG abnormalities at the screening visit, as defined by medical judgment History of rare hereditary problems of fructose, galactose and/or lactose intolerance, lactase deficiency or glucose-galactose malabsorption Maintenance therapy with any drug or significant history of drug dependency or alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic) Any clinically significant illness in the 28 days prior to the first study drug administration Use of any prescription drugs (with the exception of hormone replacement therapy) in the 28 days prior to the first study drug administration, that in the opinion of an investigator would put into question the status of the volunteer as healthy Any history of tuberculosis Positive test result for alcohol and/or drugs of abuse at screening or prior to the first drug administration Positive screening results to HIV Ag/Ab Combo, Hepatitis B surface Antigen (HBsAG (B) (hepatitis B)) or Hepatitis C Virus (HCV (C)) tests Volunteers who have already been included in a previous group for this clinical study Volunteers who took telmisartan in the 28 days prior to the first study drug administration Volunteers who took an Investigational Product (IP) in the 28 days prior to the first study drug administration Volunteers who donated 50 mL or more of blood in the 28 days prior to the first study drug administration Donation of 500 mL or more of blood (Canadian Blood Services, Hema-Quebec, clinical studies, etc.) in the 56 days prior to the first study drug administration

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: In compliance with full replicate design there are two sequences in the study: ABAB and BABA where A = the test product, B = the reference product (see detailed description of items below).
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Sequence ABAB<br>Subjects assigned to sequence ABAB will receive a single 80 mg dose of the test product Telmisartan (1 x 80 mg tablet) marked as A in the sequence in Periods 1 and 3 and a single 80 mg dose of the reference product Micardis (1 x 80 mg tablet) marked as B in the sequence in periods 2 and 4. These treatments will be administered orally with approximately 240 mL of water at ambient temperature, in the morning, following a 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken. | Drug: Telmisartan<br>* Telmisartan is manufactured by Pharmtechnology LLC, Belarus. Each tablet contains 80 mg of telmisartan.<br>* Other names: the test product;Drug: Micardis<br>* Micardis is manufactured by Boehringer Ingelheim Ellas AE, Greece. Each tablet contains 80 mg of telmisartan.<br>* Other names: the reference product;|
| Other: Sequence BABA<br>Subjects assigned to sequence BABA will receive a single 80 mg dose of the reference product Micardis (1 x 80 mg tablet) marked as B in the sequence in periods 1 and 3 and a single 80 mg dose of the test product Telmisartan (1 x 80 mg tablet) marked as A in the sequence in Periods 2 and 4. These treatments will be administered orally with approximately 240 mL of water at ambient temperature, in the morning, following a 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken. | Drug: Telmisartan<br>* Telmisartan is manufactured by Pharmtechnology LLC, Belarus. Each tablet contains 80 mg of telmisartan.<br>* Other names: the test product;Drug: Micardis<br>* Micardis is manufactured by Boehringer Ingelheim Ellas AE, Greece. Each tablet contains 80 mg of telmisartan.<br>* Other names: the reference product;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of telmisartan for the test and the reference products | Maximum concentration in plasma among observed concentrations at pre-specified time points | Time points 0.00 (prior to drug administration) and 0.17, 0.33, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 9.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00 hours after drug administration | 
| AUC0-T of telmisartan for the test and the reference products | Cumulative area under the concentration time curve calculated from 0 to time of last observed quantifiable concentration | Time points 0.00 (prior to drug administration) and 0.17, 0.33, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 9.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00 hours after drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tmax of telmisartan for the test and the reference products | Time of maximum observed concentration; if it occurs at more than one time point, Tmax is defined as the first time point with this value | Time points 0.00 (prior to drug administration) and 0.17, 0.33, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 9.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00 hours after drug administration | 
| TLQC of telmisartan for the test and the reference products | Time of last observed quantifiable concentration | Time points 0.00 (prior to drug administration) and 0.17, 0.33, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 9.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00 hours after drug administration | 
| AUC0-∞ of telmisartan for the test and the reference products | Area under the concentration time curve extrapolated to infinity, calculated as AUC0-T + ĈLQC/λZ, where ĈLQC is the predicted concentration at time TLQC | Time points 0.00 (prior to drug administration) and 0.17, 0.33, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 9.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00 hours after drug administration | 
| Residual area of telmisartan for the test and the reference products | Extrapolated area (i.e. percentage of AUC0-∞ due to extrapolation from TLQC to infinity) | Time points 0.00 (prior to drug administration) and 0.17, 0.33, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 9.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00 hours after drug administration | 
| TLIN of telmisartan for the test and the reference products | Time point where the log-linear elimination phase begins | Time points 0.00 (prior to drug administration) and 0.17, 0.33, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 9.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00 hours after drug administration | 
| λZ of telmisartan for the test and the reference products | Apparent elimination rate constant, estimated by linear regression of the terminal linear portion of the log concentration versus time curve | Time points 0.00 (prior to drug administration) and 0.17, 0.33, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 9.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00 hours after drug administration | 
| Thalf of telmisartan for the test and the reference products | Terminal elimination half-life, calculated as ln(2)/λZ | Time points 0.00 (prior to drug administration) and 0.17, 0.33, 0.50, 0.67, 0.83, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 9.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00 hours after drug administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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telmisartan, bioequivalence, Micardis