The Bioequivalence Study of Two Different Formulations of Olmesartan Medoxomil After a Single Oral Dose Administration Under Fasting Conditions.

Study Overview
=================
Brief Summary
-----------------
This single dose study is designed in accordance with EMA (the European Medicines Agency) regulatory guidelines, with the aim of characterizing the bioavailability of olmesartan in the two formulations in healthy subjects. As this is a bioequivalence trial where each subject will receive each study treatment in a crossover fashion, a control group is not included. Within the clinical portion of the study each subject will receive a single oral dose of the test and the reference formulation in compliance with the generated randomization code. The primary study endpoints are the pharmacokinetic (PK) parameters Cmax and AUC0-t of olmesartan.

Detailed Description
-----------------
This is a single center, randomized, 2-treatment, 2-period, 2-sequence, crossover, single dose study design, in which 32 healthy adult subjects will receive one of the study treatments during each study period. The objective of this study is to determine the bioequivalence of two different formulations of olmesartan after a single oral dose administration under fasting conditions. The intra-subject variation following a single dose of olmesartan appears to be around 25% for Cmax and around 18% for AUC0-t. Statistically, given that the expected Test to Reference ratio of geometric least-squares means (LSmeans) should fall within 95 and 105%, it is estimated that the lowest number of subjects to meet the 80 to 125% bioequivalence range with a statistical a priori power of at least 80% is about 28. Therefore, the inclusion of 32 subjects should be sufficient to account for the possibility of drop-outs, variations around the estimated intra-subject coefficient of variation (CV) and to conclude in favor of the hypothesis of bioequivalence with sufficient statistical power. Subject eligibility for this study will be determined at the screening visit and eligible subjects will be admitted to the clinical research unit at least 10 hours prior to drug administration for each study period. A subject who withdraws or is withdrawn during the pretrial evaluations but before receiving the first dose (the test or the reference product) in Period 1 will not be considered as a drop-out and will not be included in the final database. Standbys should be recruited and available to replace any subject who withdraws prior to the first drug administration. On-study drop-outs will not be replaced. Altasciences will generate the randomization code with a computer program according to the study design, the number of subjects and the sequence of treatment administration. The random allocation of each sequence of treatment administration to each subject will be done in such a way that the study is balanced. Once generated, the randomization code will be final and will not be modified. Eligible subjects will be randomized to one of two treatment sequences. There will be two sequences in the study: AB and BA, where A = the test product, B = the reference product (see detailed description of A and B items in Section Arms and Interventions). For each study period, subjects will receive a single 40 mg oral dose of olmesartan medoxomil (the test or the reference formulation). Study participants will be aware they will receive different formulations of the same drug, without being informed which product (Test or Reference) is being administered.The date and time of each dose will be recorded. For each subject, all scheduled postdose activities and assessments will be performed relative to the time of study drug administration. Fasting will continue for at least 4 hours following drug administration, after which a standardized lunch will be served. A supper and a light snack will be served at appropriate times thereafter, but not before 9 hours after dosing. Water will be provided as needed until 1 hour predose. Water will be allowed beginning 1 hour after the administration of the drug. A total of 21 blood samples will be collected (one tube of 3 mL each) in each study period for pharmacokinetic (PK) assessments.The first blood sample will be collected prior to drug administration while the others will be collected up to 48 hours after drug administration. Given that the parent compound, olmesartan medoxomil, is rapidly and completely converted to the pharmacologically active metabolite, olmesartan, and that no intact olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma, olmesartan medoxomil cannot be reliably measured. Therefore, the analyte to be measured in the present study will be olmesartan. Olmesartan plasma concentrations will be measured according to a validated bioanalytical method. Subjects are to be discharged from the clinic after the 24-hour postdose PK sample collection, and following medical approval. However, they may be advised to stay at the clinical site for safety reasons, if judged necessary by the physician in charge. Subjects will return to the clinic for blood collections at 36 and 48 hours postdose. The expected terminal elimination half-life observed after a single oral 40 mg dose of olmesartan medoxomil tablets under fasting conditions is 9.4 hours. To avoid any carry-over effect, a wash-out of 7 calendar days is planned between drug administrations. The decision of which subjects will be included in the PK analysis is to be documented by the pharmacokineticist (or delegate) and approved by the sponsor before the start of the sampleanalysis by the bioanalytical facility. Subjects who are expected to provide evaluable PK data for both the Test and Reference products (based on viable PK samples) will be included in the PK analysis. Concentration data of the remaining subjects will be presented separately. Subjects who do not complete the sampling schedule of one or more study periods may be included in the PK and statistical analysis and bioequivalence determination for only the PK parameters that are judged not to be affected by the missing sample(s). Statistical analysis of Tmax will be based on a non-parametric approach. Statistical analysis of all other PK parameters will be based on an Analysis of Variance (ANOVA) model. Two-sided 90% confidence interval of the ratio of geometric LSmeans obtained from the ln-transformed PK parameters will be calculated. Statistical inference of olmesartan will be based on a bioequivalence approach using the following standards: the ratio of geometric LSmeans with corresponding 90% confidence interval calculated from the exponential of the difference between the Test and the Reference for the ln-transformed parameters Cmax and AUC0-t should all be within the 80.00 to 125.00% bioequivalence range. The safety population will include all subjects who received at least one formulation (Test or Reference). Safety assessments will include vital signs, clinical laboratory tests and AE monitoring. Additional safety measurements may be performed at the discretion of the investigator for reasons related to subject safety.The physician in charge will be present at the clinical site for at least the first 4 hours following each drug administration and will remain available at all times throughout the study. Total study duration: up to 32 days (including screening).

Official Title
-----------------
Single Dose Crossover Comparative Bioavailability Study of Olmesartan Medoxomil 40 mg Film-coated Tablets in Healthy Adult Subjects Under Fasting Conditions.

Conditions
-----------------
Bioequivalence

Intervention / Treatment
-----------------
* Drug: Olmesartan Medoxomil 40 mg
* Drug: Olmetec®


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 1. Provision of signed and dated informed consent form (ICF) 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. Healthy male or female adult volunteer 4. A female volunteer meeting one of the following criteria: Physiological postmenopausal status, defined as the following: absence of menses for at least one year prior to the first study drug administration (without an alternative medical condition); and Follicle stimulating hormone (FSH) levels ≥ 40 mIU/mL at screening; or 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 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. 5. Volunteer aged at least 18 years but not older than 55 years 6. Volunteer with a body mass index (BMI) within 18.5 kg/m2 to 30.0 kg/m2, inclusively 7. 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 8. 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 9. 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 lactating at screening Females who are pregnant according to the pregnancy test at screening Seated pulse rate less than 50 Beats per Minute (bpm) or more than 100 bpm at the screening visit or prior to the first study drug administration Seated blood pressure below 110/60 mmHg at the screening visit or prior to the first study drug administration History of significant hypersensitivity to olmesartan 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 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 or Hepatitis C Virus tests Volunteers who have already been included in a previous group for this clinical study Volunteers who took olmesartan 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
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Sequence AB<br>16 subjects assigned to the sequence AB will receive a single 40 mg dose of the test product Olmesartan Medoxomil (1 x 40 mg film-coated tablet), marked as A in the sequence, in Period 1 and a single 40 mg dose of the reference product Olmetec® (1 x 40 mg film-coated tablet), marked as B in the sequence, in period 2. These treatments will be administered orally with approximately 240 mL of water at ambient temperature, in the morning, following a minimum of 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken. | Drug: Olmesartan Medoxomil 40 mg<br>* Olmesartan Medoxomil is manufactured by Pharmtechnology LLC, Republic of Belarus. Each film-coated tablet contains 40 mg of olmesartan medoxomil.<br>* Other names: the test product;Drug: Olmetec®<br>* Olmetec® is manufactured by Daiichi Sankyo Europe GmbH, Germany. Each film-coated tablet contains 40 mg of olmesartan medoxomil.<br>* Other names: the reference product;|
| Other: Sequence BA<br>16 subjects assigned to the sequence BA will receive a single 40 mg dose of the reference product Olmetec® (1 x 40 mg film-coated tablet), marked as B in the sequence, in Period 1 and a single 40 mg dose of the test product Olmesartan Medoxomil (1 x 40 mg film-coated tablet), marked as A in the sequence, in period 2. These treatments will be administered orally with approximately 240 mL of water at ambient temperature, in the morning, following a minimum of 10-hour overnight fast. The tablet must be swallowed whole and must not be chewed or broken. | Drug: Olmesartan Medoxomil 40 mg<br>* Olmesartan Medoxomil is manufactured by Pharmtechnology LLC, Republic of Belarus. Each film-coated tablet contains 40 mg of olmesartan medoxomil.<br>* Other names: the test product;Drug: Olmetec®<br>* Olmetec® is manufactured by Daiichi Sankyo Europe GmbH, Germany. Each film-coated tablet contains 40 mg of olmesartan medoxomil.<br>* Other names: the reference product;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of olmesartan in plasma after administration of the test and the reference products | Maximum observed concentration in plasma | Time points 0.00 (prior to each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration | 
| AUC0-t of olmesartan in plasma after administration of the test and the reference products | Cumulative area under the concentration time curve calculated from 0 to time of last observed quantifiable concentration (TLQC) using the linear trapezoidal method | Time points 0.00 (prior to each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tmax of olmesartan in plasma after administration of 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 each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration | 
| TLQC of olmesartan in plasma after administration of the test and the reference products | Time of last observed quantifiable concentration | Time points 0.00 (prior to each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration | 
| AUC0-INF of olmesartan in plasma after administration of the test and the reference products | Area under the concentration time curve extrapolated to infinity, calculated as AUC0-t + ĈLQC (the predicted concentration at time TLQC) / λZ (apparent elimination rate constant) | Time points 0.00 (prior to each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration | 
| Residual area of olmesartan in plasma after administration of the test and the reference products | Extrapolated area (i.e. percentage of AUC0-INF due to extrapolation from TLQC to infinity) | Time points 0.00 (prior to each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration | 
| Time point where the log-linear elimination phase begins (TLIN) of olmesartan in plasma after administration of the test and the reference products | Time point where the log-linear elimination phase begins | Time points 0.00 (prior to each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration | 
| λZ of olmesartan in plasma after administration of 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 each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration | 
| Terminal elimination half-life (Thalf) of olmesartan in plasma after administration of the test and the reference products | Terminal elimination half-life, calculated as ln(2)/λZ | Time points 0.00 (prior to each drug administration) and 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 hours after each drug administration | 
| Number of treatment-emergent adverse events for the test and the reference products | The safety population will include all subjects who received at least one dose of the test or the reference product. Any significant changes will be recorded as treatment-emergent adverse events only if they are judged clinically significant by the qualified investigator or delegate. | Up to 10 days (after the first drug administration until the completion of clinical part of the study) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Olmesartan Medoxomil, Bioequivalence, Olmetec