The Bioequivalence Study of Two Different Formulations of Olmesartan Medoxomil After a Single Oral Dose Administration Under Fasting Conditions.
Condition: Bioequivalence
Study type: Interventional
Phase: Phase 1

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      A subject who withdraws or is withdrawn during the pretrial evaluations but before receiving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).
    

Intervention name(s): Olmesartan Medoxomil 40 mg; Olmetec®
Intervention type(s): Drug; Drug
Intervention description(s): Olmesartan Medoxomil is manufactured by Pharmtechnology LLC, Republic of Belarus. Each film-coated tablet contains 40 mg of olmesartan medoxomil.; Olmetec® is manufactured by Daiichi Sankyo Europe GmbH, Germany. Each film-coated tablet contains 40 mg of olmesartan medoxomil.
Other intervention name(s): the test product; the reference product
Intervention MeSH terms: Olmesartan; Olmesartan Medoxomil
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Other
Keywords: Olmesartan Medoxomil; Bioequivalence; Olmetec