Bioequivalence Study of Two Formulations of Tablets Ramipril/Hydrochlorothiazide 10 mg/25 mg in Healthy Volunteers Under Fasting Conditions
Condition: Bioequivalence
Study type: Interventional
Phase: Phase 1

Summary: 
      This is an open-labeled, with blinding bioanalytical stage, randomized, two period, two
      sequences, single-center, crossover, comparative study, where each participant will be
      randomly assigned to the reference (Tritace® Plus, 10 mg/25 mg tablets) or the test
      (Ramipril/Hydrochlorothiazide, 10 mg/25 mg tablets) formulation in each period of study
      (sequences Test-Reference (TR) or Reference-Test (RT)), in order to evaluate if both
      formulations are bioequivalent.
    

Detailed description: 
      This is an open-labeled, with blinding bioanalytical stage, randomized, two period,
      crossover, a single-center, comparative, single-dose study, in which 50 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 combination ramipril/hydrochlorothiazide after a single oral dose administration under
      fasting conditions.

      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 12 hours prior to drug
      administration for each study period.

      Hospitalization in the first period of the study will last no more than 36 hours, after
      which, in the absence of indications for an extension of hospitalization, each subject will
      be released home; after that, the first period of the study will be completed.

      The procedures of the second study period will be identical to the first period.

      After completing all the procedures of the second study period, each subject will undergo a
      final examination, after which, in case of the absence of adverse events and indications for
      prolonging hospitalization, the study for the subjects will be considered completed.

      The total duration of the study for the subject will be no more than 46 days.

      Eligible subjects will be randomized to one of two treatment sequences. There will be two
      sequences in the study: TR and RT, where T = the test product, R = the reference product.

      For each study period, subjects will receive a single 10 mg/25 mg oral dose of
      ramipril/hydrochlorothiazide (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. 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. Breakfast will be
      organized 4 hours after taking the drug, lunch after 8 hours, dinner after 12 hours.

      Water will be provided as needed until 1 hour predose. Water will be allowed beginning 2
      hours after the administration of the drug.

      A total of 24 blood samples will be collected (one tube of 6 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 72 hours after drug administration.

      The concentration of ramipril, ramiprilat and hydrochlorothiazide will be determined using
      high performance liquid chromatography with mass spectrometric detection according to a
      method developed and validated in the analytical laboratory.

      Statistical analysis of all PK parameters will be based on an 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 ramipril, ramiprilat and hydrochlorothiazide 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 AUC0-72 should
      all be within the 80.00 to 125.00% bioequivalence range.
    

Intervention name(s): Ramipril/Hydrochlorothiazide tablet 10 mg/25 mg; Tritace® Plus tablet 10 mg/25 mg
Intervention type(s): Drug; Drug
Intervention description(s): Ramipril/Hydrochlorothiazide is manufactured by Pharmtechnology LLC, Republic of Belarus. Each tablet contains 10 mg of ramipril and 25 mg of hydrochlorothiazide.; Tritace® Plus is manufactured by Sanofi S.p.A., Italy (holder of the registration certificate: Sanofi-Aventis Deutschland GmbH, Germany). Each tablet contains 10 mg of ramipril and 25 mg of hydrochlorothiazide.
Other intervention name(s): The test product; The reference product
Intervention MeSH terms: Hydrochlorothiazide; Ramipril
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Other
Keywords: Ramipril; Hydrochlorothiazide; Bioequivalence; Tritace® Plus