Single Dose Crossover Comparative Bioavailability Study of Two Formulations of Fluconazole 200 mg in Healthy Adult Subjects 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 comparative bioavailability of
      fluconazole 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 fluconazole.
    

Detailed description: 
      This is a single center, randomized, 2-treatment, 2-period, 2-sequence, crossover, single
      dose study design, in which 26 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 fluconazole after a single oral dose administration under fasting conditions. The
      secondary objective of this study is to determine the safety and tolerability of the Test
      product compared to the Reference formulation in healthy subjects.

      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      A subject who withdraws or is withdrawn during the pretrial evaluations but before receiving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 IP 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.

      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.

      Subjects will fast overnight (no food or drink except water), for a minimum of 10 hours prior
      to dosing. 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.

      A total of 22 blood samples will be collected (one tube of 4 mL each) in each study period
      for PK assessments. The first blood sample will be collected prior to drug administration
      while the others will be collected up to 120 hours after drug administration.

      The analyte to be measured in the present study will be fluconazole. Fluconazole 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 48, 72, 96, and 120 hours postdose.

      The expected terminal elimination half-life of fluconazole is 34 hours. To avoid any
      carry-over effect, a wash-out of 21 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 sample
      analysis 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).

      The parameter Tmax will be analyzed using a non-parametric approach. Test of fixed period,
      sequence and treatment effects will be based on the Wilcoxon's rank sum test (Mann-Whitney
      U-test). When appropriate (e.g. small or sparse sample), the exact version of the test will
      also be presented. All primary endpoints will be statistically analyzed using an ANOVA model.
      The fixed factors included in this model will be the subject effect (nested within sequence),
      the treatment received, the period at which it was given, as well as the sequence in which
      each treatment is received.

      The treatment, sequence and period effects will the evaluated at the 5% significance level.
      Explanations for significant effects will be provided for log transformed PK parameters.

      The 90% confidence interval for the exponential of the difference in LSmeans between the Test
      and Reference product will be calculated for the ln-transformed parameters (Test to Reference
      ratio of geometric LSmeans).

      Statistical inference of fluconazole will be based on a bioequivalence approach using the
      following standards:

        1. The ratio of geometric LSmeans with corresponding 90% confidence interval calculated
           from the exponential of the difference between the Test and Reference for the
           lntransformed parameters Cmax and AUC0-T should all be within the 80.00 to 125.00%
           bioequivalence range.

        2. In case if AUC0-T is less than 80% of AUC0-∞ in more than 20% of the observations,
           truncated AUC0-72 will be used for bioequivalence assessment instead of AUC0-T. The
           ratio of geometric LSmeans with corresponding 90% confidence interval calculated from
           the exponential of the difference between the Test and Reference for the ln-transformed
           parameters Cmax and AUC0-72 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 physical examination, clinical laboratory test
      and AE monitoring. Additional safety measurements may be performed at the discretion of the
      investigator for reasons related to subject safety.

      Total study duration: up to 55 days (including screening).
    

Intervention name(s): Fluconazole; Diflucan®
Intervention type(s): Drug; Drug
Intervention description(s): Fluconazole is manufactured by Pharmtechnology LLC, Republic of Belarus. Each tablet contains 200 mg of fluconazole.; Diflucan® is manufactured by Fareva Amboise, France (MAH: PFIZER PHARMA PFE GmbH, Germany). Each hard capsule contains 200 mg of fluconazole.
Other intervention name(s): Test Product; Reference Product
Intervention MeSH terms: Fluconazole
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Other
Keywords: fluconazole; Diflucan®; bioequivalence