Bioequivalence Study of Two Formulations of Propafenone 300 mg Film-coated Tablets in Healthy Adult Volunteers After a Single Oral Dose Administration Under Fasting Conditions
Condition: Bioequivalence
Study type: Interventional
Phase: Phase 1

Summary: 
      This bioequivalence study will be conducted in healthy male and female volunteers in order to
      determine the bioequivalence of two different formulations of propafenone after a single oral
      dose administration under fasting conditions.
    

Detailed description: 
      This is a single center, randomized, single dose, laboratory-blinded, 2-treatment, 4-period,
      2-sequence, full replicate crossover design, in which 32 healthy adult subjects will receive
      one of the study treatments during each study period.

      The intra-subject variation following a single dose of propafenone appears to be around 36%
      for maximum observed concentration (Cmax) in plasma and around 34% for cumulative area under
      the concentration time curve calculated from 0 to time of last observed quantifiable
      concentration using the linear trapezoidal method (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 in a full
      replicate design study. Therefore, the inclusion of 32 subjects in a full replicate design
      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. Food and fluid intake other than water will be
      controlled for each confinement period and for all subjects. Water will be provided as needed
      until 1 hour predose. Water will be allowed beginning 1 hour after the administration of the
      drug.

      A subject who withdraws or is withdrawn during the pretrial evaluations but before receiving
      the investigational product 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.

      For each study period, subjects will receive a single 300 mg oral dose of propafenone, under
      fasting conditions and undergo a 36-hour sample collection. 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. A total of 21 blood samples will be
      collected in each study period for pharmacokinetic (PK) assessments. The time of PK blood
      sample collection will be calculated relative to the time of treatment administration. The
      actual time of all PK blood draws will be recorded and reported for all subjects.

      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 collection at 36 hours postdose. The drug administrations
      in each period will be separated by at least 7 calendar days.

      The duration of the clinical portion of this study (excluding the screening period) is
      expected to be approximately 24 days. The actual overall study duration may vary.

      Blood samples for PK determination will be processed, split, stored, and shipped according to
      the sample processing instructions supplied by the bioanalytical facility. Propafenone plasma
      concentrations will be measured according to a validated bioanalytical method.

      Samples from all subjects who received at least one of the investigational products will be
      assayed and propafenone plasma levels will be reported. 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 sample analysis by the bioanalytical
      facility. The evaluation of plasma PK parameters will take into account all actual PK
      sampling times.

      For the average bioequivalence (unscaled) approach, the calculation of the within-subject
      standard deviation (Swr), and the scaled-average-bioequivalence analyses, data from those
      subjects who have at least one evaluable period of Test product and at least one evaluable
      period of Reference product will be included in the PK and statistical analysis. An unequal
      number of subjects per sequence may be used. 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 inference of propafenone will be based on a bioequivalence (BE) 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
           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 BE criteria is
           not met, a scaling approach to the bioequivalence assessment will be used. The 90%
           confidence interval calculated from the exponential of the difference between the Test
           and Reference product for the ln-transformed parameter Cmax should be within the widened
           acceptance criteria using scaled-average-bioequivalence.

      The safety population will include all subjects who received at least one dose of one of the
      investigational products. Safety assessments will include physical examination, vital signs,
      12-lead ECG, clinical laboratory tests, and adverse event (AE) monitoring. Additional safety
      measurements may be performed at the discretion of the investigator for reasons related to
      subject safety. The safety endpoints are the incidence of AEs, laboratory abnormality
      assessments, vital signs and ECG findings. Any significant changes will be recorded as
      adverse events only if they are judged clinically significant by the qualified investigator
      or delegate.
    

Intervention name(s): Propafenone; Rytmonorm
Intervention type(s): Drug; Drug
Intervention description(s): Propafenone is manufactured by Pharmtechnology LLC, Republic of Belarus. Each tablet contains 300 mg of propafenone hydrochloride.; Rytmonorm is manufactured by Famar Lyon, France (MAH: Mylan Healthcare GmbH, Germany). Each tablet contains 300 mg of propafenone hydrochloride.
Other intervention name(s): the test product; the reference product
Intervention MeSH terms: Propafenone
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: There will be two sequences in the study: A-B-A-B and B-A-B-A, where A = the test product, B = the reference product (see detailed description of A and B items below).
Masking: Single (Outcomes Assessor)
Primary purpose: Other
Keywords: propafenone; bioequivalence; Rytmonorm