<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01704898</url>
  </required_header>
  <id_info>
    <org_study_id>bdbeq-efv600/icuvita-020</org_study_id>
    <nct_id>NCT01704898</nct_id>
  </id_info>
  <brief_title>Efavirenz Comparative Bioavailability</brief_title>
  <acronym>efv600</acronym>
  <official_title>Comparative Bioavailability Study of Two Efavirenz 600 mg Formulations in Healthy Volunteers.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Center for Clinical Pharmacology Research Bdbeq S.A.</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of the Republic, Uruguay</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Center for Clinical Pharmacology Research Bdbeq S.A.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective of this study is to determine the average bioequivalence of a generic&#xD;
      efavirenz 600 mg tablet (test formulation)compared with Stocrin(R) 600 mg tablets (Reference&#xD;
      formulation).The study is designed as an open label, randomized, crossover, 2-treatments,&#xD;
      2-period, 2-sequence, single dose pharmacokinetic study conducted in healthy volunteers.&#xD;
      Subjects will be randomized to receive generic efavirenz 600 (Test formulation) or Stocrin(R)&#xD;
      600 tablets (Reference formulation)on study day 1 (period 1). Subjects will undergo a 24 hour&#xD;
      intensive pharmacokinetic evaluation after ingesting a single dose of either the Test or&#xD;
      Reference formulation. Subjects will provide additional pharmacokinetic samples 36, 48, 72,&#xD;
      120 and 192 hours postdose, respectively. Subjects will complete a wash out period from day 8&#xD;
      to day 28 during wich no study drug will be ingested. On day 29 subjects will ingest either&#xD;
      the Test or the Reference formulation (opposite to the formulation received on period 1). All&#xD;
      subjects undergo another 24 hour intensive pharmacokinetic evaluation and pharmacokinetics&#xD;
      samples on days 36, 48, 72, 120, 192 pos dose, respectively. Adverse events and and&#xD;
      concomitant medication will be documented throughout the study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The primary objective of this study is to determine the average bioequivalence of generic&#xD;
      efavirenz 600 mg tablet (test formulation)compared with Stocrin(R) 600 mg tablets (Reference&#xD;
      formulation).The study is designed as an open label, randomized, crossover, 2-treatments,&#xD;
      2-period, 2-sequence, single dose pharmacokinetic study conducted in healthy volunteers.&#xD;
&#xD;
      Subjects will be randomized to receive generic efavirenz 600 (Test formulation) or Stocrin(R)&#xD;
      600 tablets (Reference formulation)on study day 1 (period 1), then they will undergo a 24&#xD;
      hour intensive pharmacokinetic evaluation after ingesting a single dose of either the Test or&#xD;
      Reference formulation. Additional pharmacokinetic samples 36, 48, 72, 120 and 192 hours&#xD;
      postdose will be drawn.&#xD;
&#xD;
      Subjects will complete a wash out period form day 8 to day 28 during which no study drug will&#xD;
      be ingested. On day 29 (period 2) they will ingest either the Test or the Reference&#xD;
      formulation (opposite to the formulation received on period 1). All subjects undergo another&#xD;
      24 hour intensive pharmacokinetic evaluation and pharmacokinetics samples on days 36, 48, 72,&#xD;
      120, 192 pos-dose, respectively, will be drawn. Adverse events and concomitant medication&#xD;
      will be documented throughout the study.&#xD;
&#xD;
      The sample size is 28 and is based on a 15% dropout rate (due to lost to follow-up, treatment&#xD;
      discontinuation, etc.) Since the investigators are expecting four subjects not to complete&#xD;
      the study,24 evaluable subjects are finally expected. If the discontinuation rate is greater&#xD;
      than 15%, the investigators will continue to enroll until they get 24 evaluable subjects.&#xD;
&#xD;
      The primary endpoint is to determine average bioequivalence for Test and Reference&#xD;
      formulation of efavirenz according to the FDA guidance on bioequivalence testing. The ratio&#xD;
      of the Test to Reference formulation mean for efavirenz AUC0-192, AUC0-inf and Cmax and the&#xD;
      90% confidence interval around each mean ratio will be determined. Average bioequivalence&#xD;
      will be met if 90% confidence interval around de AUC and Cmax mean ratios for efavirenz falls&#xD;
      within the FDA's predefined limits of 0.80 to 1.25.&#xD;
&#xD;
      Safety will be evaluated by administering a questionnaire to the subjects during the study .&#xD;
      This questionnaire will list the most frequent adverse effects already described for the&#xD;
      innovator (Stocrin(R)). Safety will also be evaluated from vital signs recordings, lab tests&#xD;
      out of the limits fixed in the study protocol and Psychiatric Evaluations during screening,&#xD;
      in the wash out period and 15 days after the last administration of the study medication.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>April 2013</start_date>
  <completion_date type="Actual">August 2013</completion_date>
  <primary_completion_date type="Actual">June 2013</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Area Under the Curve for efavirenz (AUC0-192)</measure>
    <time_frame>0 to 192 h</time_frame>
    <description>The area under the concentration-time curve (AUC0-192) for efavirenz in a time frame of 8 days.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Concentration for efavirenz (Cmax)</measure>
    <time_frame>0 to 192 h</time_frame>
    <description>The maximum concentration taken form the curve concentration vs. time for efavirenz.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Curve 0 to infinity for efavirenz (AUC0-inf)</measure>
    <time_frame>0 to infinity</time_frame>
    <description>Area under the concentration-time curve from time 0 to infinity for efavirenz.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to the Cmax for efavirenz (tmax)</measure>
    <time_frame>0 to 192 h</time_frame>
    <description>It is the time elapsed from 0 time to the Cmax time for efavirenz</description>
  </secondary_outcome>
  <other_outcome>
    <measure>First order elimination rate constant for efavirenz (Ke)</measure>
    <time_frame>0 to 192 h</time_frame>
    <description>It is the firs order efavirenz elimination rate constant, calculated from the final elimination phase of the curve concentration vs. time.</description>
  </other_outcome>
  <other_outcome>
    <measure>Elimination Half Life (T1/2e)</measure>
    <time_frame>0-92 h</time_frame>
    <description>This outcome measures the rate of drug elimination form the body.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>Efavirenz 600 Test-Stocrin 600 Reference</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Efavirenz 600 mg will be randomly assigned.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Stocrin 600 Reference-Efavirenz 600 Test</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Stocrin 600 mg will be randomly assigned.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Efavirenz 600 Test-Stocrin 600 Reference</intervention_name>
    <arm_group_label>Efavirenz 600 Test-Stocrin 600 Reference</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Stocrin 600 Reference-Efavirenz 600 Test</intervention_name>
    <arm_group_label>Stocrin 600 Reference-Efavirenz 600 Test</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male,&#xD;
&#xD;
          -  Caucasians&#xD;
&#xD;
          -  Age &gt;=18 and &lt;=50,&#xD;
&#xD;
          -  BMI&gt;18 and BMI&lt;30 kg/m2&#xD;
&#xD;
          -  HIV-1 negative, B Hepatitis negative, C Hepatitis negative.&#xD;
&#xD;
          -  Able to give consent,&#xD;
&#xD;
          -  Non/light-smoking,&#xD;
&#xD;
          -  Lab screening and EKG within the limits stipulated in the protocol.&#xD;
&#xD;
          -  Healthy as determine by medical examination.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects with any current or past history of psychiatric disorder.&#xD;
&#xD;
          -  Subjects receiving any prescription or over-the-counter product.&#xD;
&#xD;
          -  Subjects using any form of recreational drug.&#xD;
&#xD;
          -  Subjects who has eaten grapefruit or drunk grapefruit juice during the last 15 days&#xD;
             before administration of study drug.&#xD;
&#xD;
          -  Subjects who had had xanthine containing beverages (mate, coffee, tea, chocolate,&#xD;
             etc.) during 48 ours previous to study drug administration.&#xD;
&#xD;
          -  Subjects with history of hepatic disease, renal disease, GI diseases, chronic&#xD;
             infectious disease, heart disease, lung disease, neurologic disease, endocrine&#xD;
             disease, etc.&#xD;
&#xD;
          -  Subjects suffering any acute disease at screening or check-in.&#xD;
&#xD;
          -  Alanine S. Transaminase(AST)/Alanine L. Transaminase(ALT) &gt; 3 times upper limit of&#xD;
             normal (ULN).&#xD;
&#xD;
          -  Bilirubin &gt; 2.5 times ULN.&#xD;
&#xD;
          -  Amylase &gt; 2 times ULN.&#xD;
&#xD;
          -  Absolute Neutrophil Count &lt;1000/mL.&#xD;
&#xD;
          -  Hgb &lt; 9.0 g/dl.&#xD;
&#xD;
          -  Platelets &gt; 50.000 cell/mm3,&#xD;
&#xD;
          -  Serum Creatinine &gt; 2.5 mg/dl&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Francisco E. Estevez, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Center for Clinical Pharmacology Research Bdbeq S.A.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Center for Cllinical Pharmacology Research-Bdbeq S.A.</name>
      <address>
        <city>Montevideo</city>
        <zip>11600</zip>
        <country>Uruguay</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Uruguay</country>
  </location_countries>
  <reference>
    <citation>Kaul S, Ji P, Lu M, Nguyen KL, Shangguan T, Grasela D. Bioavailability in healthy adults of efavirenz capsule contents mixed with a small amount of food. Am J Health Syst Pharm. 2010 Feb 1;67(3):217-22. doi: 10.2146/ajhp090327.</citation>
    <PMID>20101064</PMID>
  </reference>
  <reference>
    <citation>Mathias AA, Hinkle J, Menning M, Hui J, Kaul S, Kearney BP; Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate Single-Tablet Regimen Development Team. Bioequivalence of efavirenz/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen. J Acquir Immune Defic Syndr. 2007 Oct 1;46(2):167-73. doi: 10.1097/QAI.0b013e3181427835.</citation>
    <PMID>17667331</PMID>
  </reference>
  <reference>
    <citation>Frampton JE, Croom KF. Efavirenz/emtricitabine/tenofovir disoproxil fumarate: triple combination tablet. Drugs. 2006;66(11):1501-12; discussion 1513-4. doi: 10.2165/00003495-200666110-00012.</citation>
    <PMID>16906786</PMID>
  </reference>
  <reference>
    <citation>Marier JF, Morin I, Al-Numani D, Stiles M, Morelli G, Tippabhotla SK, Vijan T, Singla AK, Garg M, Di Marco M, Monif T. Comparative bioavailability of a generic capsule formulation of the reverse transcriptase inhibitor efavirenz and the innovator product. Int J Clin Pharmacol Ther. 2006 Apr;44(4):180-4. doi: 10.5414/cpp44180.</citation>
    <PMID>16625987</PMID>
  </reference>
  <verification_date>August 2013</verification_date>
  <study_first_submitted>October 9, 2012</study_first_submitted>
  <study_first_submitted_qc>October 11, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 12, 2012</study_first_posted>
  <last_update_submitted>August 12, 2013</last_update_submitted>
  <last_update_submitted_qc>August 12, 2013</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 14, 2013</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Center for Clinical Pharmacology Research Bdbeq S.A.</investigator_affiliation>
    <investigator_full_name>Francisco E. Estevez-Carrizo, M.D.</investigator_full_name>
    <investigator_title>Chief Medical Officer</investigator_title>
  </responsible_party>
  <keyword>efavirenz</keyword>
  <keyword>bioequivalence</keyword>
  <keyword>fasting</keyword>
  <keyword>healthy volunteers</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Efavirenz</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01704898
org study id: bdbeq-efv600/icuvita-020
nct id: NCT01704898
lead sponsor: 
collaborator: 
has dmc: No
The primary objective of this study is to determine the average bioequivalence of a generic
      efavirenz 600 mg tablet (test formulation)compared with Stocrin(R) 600 mg tablets (Reference
      formulation).The study is designed as an open label, randomized, crossover, 2-treatments,
      2-period, 2-sequence, single dose pharmacokinetic study conducted in healthy volunteers.
      Subjects will be randomized to receive generic efavirenz 600 (Test formulation) or Stocrin(R)
      600 tablets (Reference formulation)on study day 1 (period 1). Subjects will undergo a 24 hour
      intensive pharmacokinetic evaluation after ingesting a single dose of either the Test or
      Reference formulation. Subjects will provide additional pharmacokinetic samples 36, 48, 72,
      120 and 192 hours postdose, respectively. Subjects will complete a wash out period from day 8
      to day 28 during wich no study drug will be ingested. On day 29 subjects will ingest either
      the Test or the Reference formulation (opposite to the formulation received on period 1). All
      subjects undergo another 24 hour intensive pharmacokinetic evaluation and pharmacokinetics
      samples on days 36, 48, 72, 120, 192 pos dose, respectively. Adverse events and and
      concomitant medication will be documented throughout the study.
The primary objective of this study is to determine the average bioequivalence of generic
      efavirenz 600 mg tablet (test formulation)compared with Stocrin(R) 600 mg tablets (Reference
      formulation).The study is designed as an open label, randomized, crossover, 2-treatments,
      2-period, 2-sequence, single dose pharmacokinetic study conducted in healthy volunteers.

      Subjects will be randomized to receive generic efavirenz 600 (Test formulation) or Stocrin(R)
      600 tablets (Reference formulation)on study day 1 (period 1), then they will undergo a 24
      hour intensive pharmacokinetic evaluation after ingesting a single dose of either the Test or
      Reference formulation. Additional pharmacokinetic samples 36, 48, 72, 120 and 192 hours
      postdose will be drawn.

      Subjects will complete a wash out period form day 8 to day 28 during which no study drug will
      be ingested. On day 29 (period 2) they will ingest either the Test or the Reference
      formulation (opposite to the formulation received on period 1). All subjects undergo another
      24 hour intensive pharmacokinetic evaluation and pharmacokinetics samples on days 36, 48, 72,
      120, 192 pos-dose, respectively, will be drawn. Adverse events and concomitant medication
      will be documented throughout the study.

      The sample size is 28 and is based on a 15% dropout rate (due to lost to follow-up, treatment
      discontinuation, etc.) Since the investigators are expecting four subjects not to complete
      the study,24 evaluable subjects are finally expected. If the discontinuation rate is greater
      than 15%, the investigators will continue to enroll until they get 24 evaluable subjects.

      The primary endpoint is to determine average bioequivalence for Test and Reference
      formulation of efavirenz according to the FDA guidance on bioequivalence testing. The ratio
      of the Test to Reference formulation mean for efavirenz AUC0-192, AUC0-inf and Cmax and the
      90% confidence interval around each mean ratio will be determined. Average bioequivalence
      will be met if 90% confidence interval around de AUC and Cmax mean ratios for efavirenz falls
      within the FDA's predefined limits of 0.80 to 1.25.

      Safety will be evaluated by administering a questionnaire to the subjects during the study .
      This questionnaire will list the most frequent adverse effects already described for the
      innovator (Stocrin(R)). Safety will also be evaluated from vital signs recordings, lab tests
      out of the limits fixed in the study protocol and Psychiatric Evaluations during screening,
      in the wash out period and 15 days after the last administration of the study medication.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Single (Investigator)
measure: Area Under the Curve for efavirenz (AUC0-192)
time frame: 0 to 192 h
description: The area under the concentration-time curve (AUC0-192) for efavirenz in a time frame of 8 days.
measure: Maximum Concentration for efavirenz (Cmax)
time frame: 0 to 192 h
description: The maximum concentration taken form the curve concentration vs. time for efavirenz.
measure: Area Under the Curve 0 to infinity for efavirenz (AUC0-inf)
time frame: 0 to infinity
description: Area under the concentration-time curve from time 0 to infinity for efavirenz.
measure: Time to the Cmax for efavirenz (tmax)
time frame: 0 to 192 h
description: It is the time elapsed from 0 time to the Cmax time for efavirenz
measure: First order elimination rate constant for efavirenz (Ke)
time frame: 0 to 192 h
description: It is the firs order efavirenz elimination rate constant, calculated from the final elimination phase of the curve concentration vs. time.
measure: Elimination Half Life (T1/2e)
time frame: 0-92 h
description: This outcome measures the rate of drug elimination form the body.
arm group label: Efavirenz 600 Test-Stocrin 600 Reference
arm group type: Other
description: Efavirenz 600 mg will be randomly assigned.
arm group label: Stocrin 600 Reference-Efavirenz 600 Test
arm group type: Other
description: Stocrin 600 mg will be randomly assigned.
intervention type: Drug
intervention name: Efavirenz 600 Test-Stocrin 600 Reference
arm group label: Efavirenz 600 Test-Stocrin 600 Reference
intervention type: Drug
intervention name: Stocrin 600 Reference-Efavirenz 600 Test
arm group label: Stocrin 600 Reference-Efavirenz 600 Test
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Francisco E. Estevez, M.D.
role: Principal Investigator
affiliation: Center for Clinical Pharmacology Research Bdbeq S.A.
facility: 
country: Uruguay
citation: Kaul S, Ji P, Lu M, Nguyen KL, Shangguan T, Grasela D. Bioavailability in healthy adults of efavirenz capsule contents mixed with a small amount of food. Am J Health Syst Pharm. 2010 Feb 1;67(3):217-22. doi: 10.2146/ajhp090327.
PMID: 20101064
citation: Mathias AA, Hinkle J, Menning M, Hui J, Kaul S, Kearney BP; Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate Single-Tablet Regimen Development Team. Bioequivalence of efavirenz/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen. J Acquir Immune Defic Syndr. 2007 Oct 1;46(2):167-73. doi: 10.1097/QAI.0b013e3181427835.
PMID: 17667331
citation: Frampton JE, Croom KF. Efavirenz/emtricitabine/tenofovir disoproxil fumarate: triple combination tablet. Drugs. 2006;66(11):1501-12; discussion 1513-4. doi: 10.2165/00003495-200666110-00012.
PMID: 16906786
citation: Marier JF, Morin I, Al-Numani D, Stiles M, Morelli G, Tippabhotla SK, Vijan T, Singla AK, Garg M, Di Marco M, Monif T. Comparative bioavailability of a generic capsule formulation of the reverse transcriptase inhibitor efavirenz and the innovator product. Int J Clin Pharmacol Ther. 2006 Apr;44(4):180-4. doi: 10.5414/cpp44180.
PMID: 16625987
responsible party type: Principal Investigator
investigator affiliation: Center for Clinical Pharmacology Research Bdbeq S.A.
investigator full name: Francisco E. Estevez-Carrizo, M.D.
investigator title: Chief Medical Officer
mesh term: Efavirenz