<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/NCT03817619</url>
  </required_header>
  <id_info>
    <org_study_id>UMCN-AKF 17.01</org_study_id>
    <nct_id>NCT03817619</nct_id>
  </id_info>
  <brief_title>Bioequivalence Study of Crushed Elbasvir/Grazoprevir Compared to the Whole Tablet</brief_title>
  <acronym>CRUSADE-2</acronym>
  <official_title>Bioequivalence Study of CRUshed ElbaSvir/GrAzoprevir compareD to the wholE Tablet (CRUSADE-2)/Hep-NED005</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Radboud University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Radboud University Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Elbasvir/grazoprevir (Zepatier®) is a once-daily tablet for the treatment of chronic&#xD;
      hepatitis C virus (HCV) GT1a, 1b or 4 infection containing the NS5A inhibitor elbasvir (ELB)&#xD;
      50 mg and the NS3/4A protease inhibitor grazoprevir (GZR) 100 mg.&#xD;
&#xD;
      For patients with swallowing difficulties, administration of whole tablets can be&#xD;
      problematic. In addition, HCV patients that are hospitalized (at intensive care units) due to&#xD;
      severe illness (co-infections/ liver failure) might not be able to swallow medication.&#xD;
      Therefore it is useful to know whether it is possible to administer ELB/GZR through a&#xD;
      different route, like a feeding tube.&#xD;
&#xD;
      In daily practice, information about the safety and efficacy of crushed tablets is lacking&#xD;
      which might result in noncompliance, interruption or discontinuation of expensive HCV&#xD;
      therapy. However, it is not recommended to interrupt treatment because there is no evidence&#xD;
      about the efficacy of the therapy after discontinuation (and restarting).&#xD;
&#xD;
      Currently, patients and healthcare professionals are crushing tablets without information&#xD;
      about efficacy and safety. Depending on the biopharmaceutical characteristics of a drug&#xD;
      formulation, crushing tablets can lead to altered pharmacokinetics of drugs.&#xD;
&#xD;
      It is important to know whether pharmacokinetic parameters are influenced by crushing of&#xD;
      tablets; both a decrease and an increase in exposure may occur. A decrease of the plasma&#xD;
      concentrations of ELB and/or GZR potentially reduces the therapeutic effect of the drugs.&#xD;
      Higher doses or switching to other HCV-drugs might be needed. In contrast, in case a higher&#xD;
      Cmax and/or AUC occurs there might be an increased risk of toxicity.&#xD;
&#xD;
      As a result, crushing the drug is a contra-indication based on the available data. Therefore&#xD;
      this study will be conducted to investigate whether a crushed ELB/GZR tablet is bioequivalent&#xD;
      to ELB/GZR as a whole tablet.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 28, 2019</start_date>
  <completion_date type="Actual">July 30, 2019</completion_date>
  <primary_completion_date type="Actual">July 30, 2019</primary_completion_date>
  <phase>Phase 1</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>
    <intervention_model_description>Open-label, 2-period, randomised, cross-over, single-centre, phase I, single-dose trial in 14 healthy adult subjects.&#xD;
Intrasubject comparison of PK parameters after different administrations of Zepatier</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Bioequivalence AUC0-72h</measure>
    <time_frame>72 hours</time_frame>
    <description>Determination of elbasvir/grazoprevir AUC0-72h by noncompartmental analysis. Descriptive statistics for the plasma concentrations of elbasvir/grazoprevir at each sampling time. Descriptive statistics for each PK parameter per treatment (geometric mean + CV%).&#xD;
Geometric Mean Ratios and 90% confidence intervals of pharmacokinetic parameters of treatment T (Test) vs. treatment R (Reference). AUC0-72h geometric mean ratios for elbasvir and grazoprevir with a 90% Cl falling entirely within the range of 0.7 to 1.43 are considered bioequivalent.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Bioequivalence (Cmax)</measure>
    <time_frame>18 days</time_frame>
    <description>Determination of grazoprevir Cmax by noncompartmental analysis. Geometric Mean Ratios and 90% confidence intervals of pharmacokinetic parameters of T (Test) vs. R (Reference).&#xD;
Cmax geometric mean ratios for elbasvir and grazoprevir with a 90% Cl falling entirely within the range of 0.7 to 1.43 are considered bioequivalent.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability])</measure>
    <time_frame>18 days</time_frame>
    <description>Adverse events after intake of elbasvir/grazoprevir tablets in healthy adult volunteers.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">11</enrollment>
  <condition>Hepatitis C</condition>
  <condition>Deglutition Disorders</condition>
  <arm_group>
    <arm_group_label>Treatment R (reference)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Single-dose ELB/GZR as a whole tablet in a fasted state.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment T (test)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single-dose crushed ELB/GZR in a fasted state.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Zepatier whole tablet</intervention_name>
    <description>Single-dose ELB/GZR as a whole tablet in a fasted state.</description>
    <arm_group_label>Treatment R (reference)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Zepatier crushed tablet</intervention_name>
    <description>Single-dose crushed ELB/GZR in a fasted state.</description>
    <arm_group_label>Treatment T (test)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subject is at least 18 and not older than 55 years at screening.&#xD;
&#xD;
          -  Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day for at&#xD;
             least 3 months prior to Day 1.&#xD;
&#xD;
          -  Subject weighs at least 40 kg.&#xD;
&#xD;
          -  Subject has a Quetelet Index (Body Mass Index) of 18 to 30 kg/m2, extremes included.&#xD;
&#xD;
          -  Subject is able and willing to sign the Informed Consent Form prior to screening&#xD;
             evaluations.&#xD;
&#xD;
          -  Subject is in good age-appropriate health condition as established by medical history,&#xD;
             physical examination, and electrocardiography, results of biochemistry, hematology and&#xD;
             urinalysis testing within 4 weeks prior to Day 1. Results of biochemistry, hematology&#xD;
             and urinalysis testing should be within the laboratory's reference ranges. If&#xD;
             laboratory results are not within the reference ranges, the subject is included on&#xD;
             condition that the Investigator judges that the deviations are not clinically&#xD;
             relevant. This should be clearly recorded.&#xD;
&#xD;
          -  Subject has a normal blood pressure and pulse rate, according to the Investigator's&#xD;
             judgment.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Creatinine clearance below 60 mL/min.&#xD;
&#xD;
          -  Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.&#xD;
&#xD;
          -  Positive hepatitis B or C test&#xD;
&#xD;
          -  Pregnant female (as confirmed by an hCG test performed less than 4 weeks before day 1)&#xD;
             or breast-feeding female. Female subjects of childbearing potential without adequate&#xD;
             contra-ception, e.g. hysterectomy, bilateral tubal ligation, (non-hormonal)&#xD;
             intrauterine device, total abstinence, double barrier methods, or two years&#xD;
             post-menopausal. They must agree to take precautions in order to prevent a pregnancy&#xD;
             throughout the entire conduct of the study.&#xD;
&#xD;
          -  Therapy with any drug (for two weeks preceding Day 1), except for acetaminophen (max 2&#xD;
             gram/day).&#xD;
&#xD;
          -  Relevant history or presence of pulmonary disorders (especially COPD), cardiovascular&#xD;
             disorders, neurological disorders (especially seizures and migraine), psychiatric&#xD;
             disorders, gastro-intestinal disorders, renal and hepatic disorders (clinically&#xD;
             relevant increased ALAT/ASAT or hyperbilirubinemia), hormonal disorders (especially&#xD;
             diabetes mellitus), coagulation disorders.&#xD;
&#xD;
          -  Relevant history or current condition that might interfere with drug absorption,&#xD;
             distribution, metabolism or excretion.&#xD;
&#xD;
          -  History of or current abuse of drugs, alcohol or solvents (positive drugs of abuse&#xD;
             test).&#xD;
&#xD;
          -  Inability to understand the nature and extent of the study and the procedures&#xD;
             required.&#xD;
&#xD;
          -  Participation in a drug study within 60 days prior to Day 1.&#xD;
&#xD;
          -  Donation of blood within 60 days prior to Day 1.&#xD;
&#xD;
          -  Febrile illness within 3 days before Day 1.&#xD;
&#xD;
          -  Co-worker of Radboud university medical center.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>RTCCS Radboudumc</name>
      <address>
        <city>Nijmegen</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <link>
    <url>https://pubmed.ncbi.nlm.nih.gov/32544221/</url>
    <description>paper</description>
  </link>
  <reference>
    <citation>Pijnenburg DWM, van Seyen M, Abbink EJ, Colbers A, Drenth JPH, Burger DM. Pharmacokinetic similarity demonstrated after crushing of the elbasvir/grazoprevir fixed-dose combination tablet for HCV infection. J Antimicrob Chemother. 2020 Sep 1;75(9):2661-2665. doi: 10.1093/jac/dkaa230.</citation>
    <PMID>32544221</PMID>
  </reference>
  <verification_date>August 2019</verification_date>
  <study_first_submitted>January 21, 2019</study_first_submitted>
  <study_first_submitted_qc>January 23, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 25, 2019</study_first_posted>
  <last_update_submitted>October 16, 2020</last_update_submitted>
  <last_update_submitted_qc>October 16, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 19, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis C</mesh_term>
    <mesh_term>Deglutition Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Elbasvir-grazoprevir drug combination</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/NCT03817619
org study id: UMCN-AKF 17.01
nct id: NCT03817619
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Elbasvir/grazoprevir (Zepatier®) is a once-daily tablet for the treatment of chronic
      hepatitis C virus (HCV) GT1a, 1b or 4 infection containing the NS5A inhibitor elbasvir (ELB)
      50 mg and the NS3/4A protease inhibitor grazoprevir (GZR) 100 mg.

      For patients with swallowing difficulties, administration of whole tablets can be
      problematic. In addition, HCV patients that are hospitalized (at intensive care units) due to
      severe illness (co-infections/ liver failure) might not be able to swallow medication.
      Therefore it is useful to know whether it is possible to administer ELB/GZR through a
      different route, like a feeding tube.

      In daily practice, information about the safety and efficacy of crushed tablets is lacking
      which might result in noncompliance, interruption or discontinuation of expensive HCV
      therapy. However, it is not recommended to interrupt treatment because there is no evidence
      about the efficacy of the therapy after discontinuation (and restarting).

      Currently, patients and healthcare professionals are crushing tablets without information
      about efficacy and safety. Depending on the biopharmaceutical characteristics of a drug
      formulation, crushing tablets can lead to altered pharmacokinetics of drugs.

      It is important to know whether pharmacokinetic parameters are influenced by crushing of
      tablets; both a decrease and an increase in exposure may occur. A decrease of the plasma
      concentrations of ELB and/or GZR potentially reduces the therapeutic effect of the drugs.
      Higher doses or switching to other HCV-drugs might be needed. In contrast, in case a higher
      Cmax and/or AUC occurs there might be an increased risk of toxicity.

      As a result, crushing the drug is a contra-indication based on the available data. Therefore
      this study will be conducted to investigate whether a crushed ELB/GZR tablet is bioequivalent
      to ELB/GZR as a whole tablet.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Open-label, 2-period, randomised, cross-over, single-centre, phase I, single-dose trial in 14 healthy adult subjects.
Intrasubject comparison of PK parameters after different administrations of Zepatier
primary purpose: Treatment
masking: None (Open Label)
measure: Bioequivalence AUC0-72h
time frame: 72 hours
description: Determination of elbasvir/grazoprevir AUC0-72h by noncompartmental analysis. Descriptive statistics for the plasma concentrations of elbasvir/grazoprevir at each sampling time. Descriptive statistics for each PK parameter per treatment (geometric mean + CV%).
Geometric Mean Ratios and 90% confidence intervals of pharmacokinetic parameters of treatment T (Test) vs. treatment R (Reference). AUC0-72h geometric mean ratios for elbasvir and grazoprevir with a 90% Cl falling entirely within the range of 0.7 to 1.43 are considered bioequivalent.
measure: Bioequivalence (Cmax)
time frame: 18 days
description: Determination of grazoprevir Cmax by noncompartmental analysis. Geometric Mean Ratios and 90% confidence intervals of pharmacokinetic parameters of T (Test) vs. R (Reference).
Cmax geometric mean ratios for elbasvir and grazoprevir with a 90% Cl falling entirely within the range of 0.7 to 1.43 are considered bioequivalent.
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability])
time frame: 18 days
description: Adverse events after intake of elbasvir/grazoprevir tablets in healthy adult volunteers.
arm group label: Treatment R (reference)
arm group type: Active Comparator
description: Single-dose ELB/GZR as a whole tablet in a fasted state.
arm group label: Treatment T (test)
arm group type: Experimental
description: Single-dose crushed ELB/GZR in a fasted state.
intervention type: Drug
intervention name: Zepatier whole tablet
description: Single-dose ELB/GZR as a whole tablet in a fasted state.
arm group label: Treatment R (reference)
intervention type: Drug
intervention name: Zepatier crushed tablet
description: Single-dose crushed ELB/GZR in a fasted state.
arm group label: Treatment T (test)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Netherlands
url: https://pubmed.ncbi.nlm.nih.gov/32544221/
description: paper
citation: Pijnenburg DWM, van Seyen M, Abbink EJ, Colbers A, Drenth JPH, Burger DM. Pharmacokinetic similarity demonstrated after crushing of the elbasvir/grazoprevir fixed-dose combination tablet for HCV infection. J Antimicrob Chemother. 2020 Sep 1;75(9):2661-2665. doi: 10.1093/jac/dkaa230.
PMID: 32544221
responsible party type: Sponsor
mesh term: Hepatitis C
mesh term: Deglutition Disorders
mesh term: Elbasvir-grazoprevir drug combination