Bio-equivalence Study Between SAPHRIS and Asenapine
Condition: Schizophrenia; Bipolar Disorder
MeSH terms: Schizophrenia; Bipolar Disorder
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a Multiple-dose, steady state, three-way reference-replicated crossover study.

      The purpose of this Study is to determine the bio-equivalence between SAPHRIS and Asenapine
      10mg sublingual tablets.
    

Detailed description: 
      Molecule Name Asenapine Country of submission US

      PRODUCT DETAILS

      Test formulation

      Drug name: Asenapine Sublingual Tablet EQ 10mg base Manufactured by: Sun Pharmaceutical
      Industries, Ltd.

      Reference formulation

      Drug name: SAPHRIS® (Asenapine) sublingual tablets Manufactured by: Schering Corporation, a
      Subsidiary of Merck & Co., Inc.

      STUDY DESIGN

      Title An open-label, randomized, two treatment, multi-site, multiple dose, steady state,
      three-way, reference-replicated crossover, pharmacokinetic study to determine the in-vivo
      bioequivalence between Asenapine 10 mg sublingual tablet and SAPHRIS® (asenapine) 10 mg
      sublingual tablet

      Study Design Multiple-dose, steady state, three-way reference-replicated crossover study

      Type of Study Pharmacokinetic (PK)

      Number of subjects 57 randomized to complete 42 subjects

      Dosing Test or Reference drug (EQ 10mg) base sublingual tablets are to be taken twice daily,
      once in the morning and once in the evening, for a period of 7 days before crossing-over to
      receive the next drug assigned for a period of 7 days, followed by a period of 7 days where
      the third drug assigned will be received.. There will be a total of three 7-day treatment
      periods during which each subject will receive the test product in one period and the
      reference product in two other periods.

      To ensure optimal absorption, subjects will be instructed to place the tablet under the
      tongue and allow it to dissolve completely. The tablet will dissolve in saliva. Tablets will
      not be crushed, chewed, or swallowed

      Housing Subjects will be housed in the clinic or hospital for a multiple days in each period
      during treatment and the collection of pharmacokinetic samples. Housing will be provided for:

        -  Day 1 and Day 8 or 15 (12-hour confinement)

        -  Days 6-7

        -  Days 13-14

        -  Days 20-21

      Investigators may choose to house subjects during the interim days between specified
      in-patient clinic visits, either in the clinic or at an appropriate off-site facility such as
      a hotel or motel. Housing offers may be made to each subject population according to the
      respective Investigator's judgment as to what is best for his/her patients. Such interim
      housing is not to be considered as study visits, but will be offered at the discretion of the
      Investigator to all subjects in his/her clinic, at his/her discretion, and simply to improve
      subject compliance and attempt to reduce variability.

      Subjects will be confined for at least 12 hours after initial dosing of either SAPHRIS®
      (Asenapine) or Asenapine sublingual tablets. Subjects will be required to remain supine for 6
      hours following the initial dose. Subjects may get up briefly in order to relieve themselves.

      Washout period There will be no washout period

      Sampling time points Blood samples will be collected over a dosing interval on day 7,
      following preliminary sampling on days 5 and 6 to confirm steady-state conditions. The
      sampling time points are as follows:

        -  Day 5 (1 sample)

        -  Day 6 (1 sample)

        -  Day 7 (15 samples) 0.0(pre-dose), 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0,
           6.0, 8.0, 10.0, 12.0

      Dietary Plan Subjects will fast for at least 8 hours prior to and 4 hours after the
      administration of the morning dose of the test or reference treatment on day 7 of each period
      (i.e., the days on which blood samples are to be collected to assess the concentration-time
      curve). All meals on day 7 will be standardized during the study. Water may be allowed,
      except for 1 hour before and 1 hour after drug administration, when no liquid will be
      permitted.

      Special requirements

        -  Subjects will remain in the supine position for the first 6 hours after the first dose,
           even if they were previously on a stable dose of asenapine maleate.

        -  Subjects will be adequately hydrated. This may be achieved by administering 240 mL of
           water before the overnight fast, 240 mL of water one hour before dosing, and beginning
           no sooner than 1 hour after drug administration, 240 mL of water every 2 hours for 6
           hours post-dosing. Subjects will not eat or drink for 10 minutes after drug
           administration.

        -  Subjects must be adequately informed of possible cardiovascular adverse effects in the
           consent form.

      Safety Parameters

        -  White blood cell (WBC) counts will be monitored and asenapine maleate sublingual tablet
           treatment modified, if necessary, in accordance with the leukopenia, neutropenia and
           agranulocytosis warning in the labeling of the reference listed drug product.

        -  Subjects requiring modification of asenapine maleate sublingual tablet treatment will be
           dropped from the study and provided with prompt medical care.

        -  Blood pressure, heart rate, and body temperature will be monitored during the study and
           immediate medical care provided for any significant abnormalities.

        -  Subject medical histories, physical examination and laboratory reports, and all
           incidents of possible adverse reactions will be reported.

      Analyte(s) to measure Asenapine in plasma

      Pharmacokinetic parameters

      Asenapine AUC0-tau, Cmax, Tmax, Cmin and %Fluctuation will be estimated for each subject and
      period using WinNonlin version 5.2 or higher. The trough samples collected just prior to the
      morning dose on Days 5, 6 and 7 in each period will be evaluated to demonstrate that
      steady-state has been achieved by the final morning dose in each period.

      Statistical Analysis

      The primary pharmacokinetic parameters (Cmax, AUC0-tau,) and Cmin will be natural
      log-transformed (ln) prior to statistical analyses. Any ln-transformed parameter where the
      observed intra-subject CV for the reference product is at least 30% (swr ≥ 0.294) will be
      evaluated using the scaled average bioequivalence (SABE) method. The GLM procedure of SAS
      will be used to conduct the SABE analyses, as well as to estimate the intra-subject CV for
      the reference product. The statistical model for the GLM procedure will contain only a term
      for Sequence*Site. The linearized Scaled Average Bioequivalence statistic and the upper 95%
      Confidence Bound on the statistic will be estimated. The ratio of geometric means (T/R) will
      also be calculated.

      Plasma concentrations at each time point, Tmax, %Fluctuation, and any ln-transformed
      pharmacokinetic parameter where the observed intra-subject CV of the reference product is
      less than 30% (swr < 0.294), will be evaluated using the average (unscaled) bioequivalence
      (ABE) approach will be used. The MIXED procedure of SAS will be used in this case with a
      statistical model that includes terms for Sequence, Site, Sequence*Site, Subject nested
      within Sequence*Site, Period nested within Site, Treatment, and if necessary, Treatment*Site.
      A separate statistical analysis will be done to determine if the Treatment*Site term is
      statistically significant (p<0.05) and needs to be retained in the model. If this term is not
      significant, it will be dropped from the statistical model for the definitive statistical
      evaluation. The ratio of geometric means (T/R) and 90% confidence intervals for the ratio,
      based on least-squares means from the analysis of the log-transformed PK Parameter, will be
      calculated.

      Bioequivalence criteria Bioequivalence will be concluded for those primary parameters
      evaluated by SABE if:

        -  The geometric mean Test-to-Reference ratio falls within the range of 0.800 to 1.250.

        -  The 95% upper confidence bound on the linearized SABE statistic.

      Bioequivalence will be concluded for those primary parameters evaluated by ABE if:

      The 90% confidence interval on the geometric mean Test-to Reference ratio is contained within
      the interval 0.800 to 1.250.

      Fluctuation for the test product will be evaluated for comparability with the fluctuation of
      the reference product.

      Report format eCTD
    

Intervention name(s): SAPHRIS; Asenapine
Intervention type(s): Drug; Drug
Intervention description(s): 10 mg BID sublingual tablet; 10 mg BID sublingual tablet
Intervention MeSH terms: Asenapine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Other