<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/NCT03268317</url>
  </required_header>
  <id_info>
    <org_study_id>NAEIPWCHCTBDAAD</org_study_id>
    <nct_id>NCT03268317</nct_id>
  </id_info>
  <brief_title>Neuropsychiatric Adverse Effects in Patients With Chronic Hepatitis C Treated by Direct Acting Antiviral Drugs</brief_title>
  <official_title>Neuropsychiatric Adverse Effects in Patients With Chronic Hepatitis C Treated by Direct Acting Antiviral Drugs</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assiut University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assiut University</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Neuropsychiatric adverse effects of direct acting antiviral drugs, especially Sofosbuvir and&#xD;
      Daclatasvir combination therapy (with or without ribavirin) in patients with chronic&#xD;
      hepatitis C , genotype four (the predominant genotype in Egypt).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Treatment of hepatitis C virus, a virus infecting over one hundred seventy million worldwide,&#xD;
      has evolved over the last two decades and moved from interferon-alpha monotherapy to&#xD;
      pegylated interferon-alpha in combination with ribavirin therapy. Despite enhanced sustained&#xD;
      virological response rates, psychiatric illness remains a barrier to widespread hepatitis C&#xD;
      virus treatment uptake due to the neuropsychiatric risks associated with interferon-alpha.The&#xD;
      next generation of hepatitis C virus therapeutic agents is direct acting antivirals that&#xD;
      still require the use of interferon-ribavirin combination therapy.&#xD;
&#xD;
      Poorly managed psychiatric illness can lead not only to treatment discontinuation,but also&#xD;
      poor adherence to treatment and serious psychiatric sequels, such as suicide.&#xD;
&#xD;
      Data on neuropsychiatric adverse effects of direct acting antivirals is limited and&#xD;
      predominantly derived from landmark clinical trials for boceprevir and telaprevir.These first&#xD;
      generation direct acting antivirals are currently not in use due to their multiple side&#xD;
      effects ,the need for concomitant interferon-alpha ,and there wide drug-drug interactions.&#xD;
      Recently the treatment of hepatitis C virus has undergone a paradigm shift with the&#xD;
      introduction of the second generation of direct acting antivirals. This interferon-free&#xD;
      modality has brought about exceptional cure rates with sustained virological response&#xD;
      exceeding ninety hundred percent, with better tolerability, minimized side effects and short&#xD;
      duration of treatment . Of the current hepatitis C virus treatment regimens, the combinations&#xD;
      of Sofosbuvir plus daclatasvir have shown a high efficacy rate in achieving sustained&#xD;
      virological response in genotype one patients.&#xD;
&#xD;
      To the investigators' knowledge, the development of neuropsychiatric side effects with the&#xD;
      use of these second generation direct acting antivirals in absence of interferon therapy, as&#xD;
      well as the impact of the expected high sustained virological response to therapy on the&#xD;
      psychiatric condition of patients with chronic hepatitis C (in absence of cirrhosis) have not&#xD;
      been studied. Therefore, the purpose of this work is to evaluate the neuropsychiatric adverse&#xD;
      effects of direct acting antivirals,especially Sofosbuvir and Daclatasvir combination therapy&#xD;
      (with or without ribavirin) in patients with chronic hepatitis C, genotype four (the&#xD;
      predominant genotype in Egypt).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">January 2018</start_date>
  <completion_date type="Anticipated">January 2020</completion_date>
  <primary_completion_date type="Anticipated">January 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Hamilton anxiety scale (HAM-A) in patients with chronic hepatitis C treated by DAAs</measure>
    <time_frame>12 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Hamilton depression scale (HAM-D) in patients with chronic hepatitis C treated by DAAs</measure>
    <time_frame>12 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>EEG in patients with chronic hepatitis C treated by DAAs</measure>
    <time_frame>12 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Visual evoked potential in patients with chronic hepatitis C treated by DAAs</measure>
    <time_frame>12 months</time_frame>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Hepatitis C</condition>
  <arm_group>
    <arm_group_label>Patients with chronic hepatitis C treated by DAAs</arm_group_label>
    <description>All subjects will be given the same treatment regimen which includes Sofosbuvir 400 mg orally/24 hours (pre-breakfast) and Daclatasvir 60 mg orally/24 hours after lunch with or without ribavirin for a total period of 12 weeks.</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Patients will be recruited from the Viral Hepatitis Clinic of Tropical Medicine Department,&#xD;
        at Al-Rajhi Liver University Hospital Assiut, Egypt where these medications (DAAs) are&#xD;
        available free for all insurance uncovered patients.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with chronic hepatitis C only will be included.&#xD;
&#xD;
          -  Patients who are eligible for treatment by DAAs only.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Cirrhotic patients will be excluded based on USS, APRI score index and FIB4 index.&#xD;
&#xD;
          -  Hepatitis B infected patients will also be excluded.&#xD;
&#xD;
          -  Patients with current or previous history of neuropsychiatric disorders will be&#xD;
             excluded.&#xD;
&#xD;
          -  Failure to obtain consent.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Esam Darwish</last_name>
    <phone>01224785281</phone>
    <email>darwishe@aun.edu.eg</email>
  </overall_contact>
  <reference>
    <citation>Wasley A, Alter MJ. Epidemiology of hepatitis C: geographic differences and temporal trends. Semin Liver Dis. 2000;20(1):1-16. doi: 10.1055/s-2000-9506.</citation>
    <PMID>10895428</PMID>
  </reference>
  <reference>
    <citation>Dieperink E, Ho SB, Tetrick L, Thuras P, Dua K, Willenbring ML. Suicidal ideation during interferon-alpha2b and ribavirin treatment of patients with chronic hepatitis C. Gen Hosp Psychiatry. 2004 May-Jun;26(3):237-40. doi: 10.1016/j.genhosppsych.2004.01.003.</citation>
    <PMID>15121353</PMID>
  </reference>
  <reference>
    <citation>Ademmer K, Beutel M, Bretzel R, Jaeger C, Reimer C. Suicidal ideation with IFN-alpha and ribavirin in a patient with hepatitis C. Psychosomatics. 2001 Jul-Aug;42(4):365-7. doi: 10.1176/appi.psy.42.4.365. No abstract available. Erratum In: Psychosomatics 2002 Jan-Feb;43(1):88. Clemens J [corrected to Jaeger C].</citation>
    <PMID>11496031</PMID>
  </reference>
  <reference>
    <citation>Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, George J, Rizzetto M, Shouval D, Sola R, Terg RA, Yoshida EM, Adda N, Bengtsson L, Sankoh AJ, Kieffer TL, George S, Kauffman RS, Zeuzem S; ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011 Jun 23;364(25):2405-16. doi: 10.1056/NEJMoa1012912.</citation>
    <PMID>21696307</PMID>
  </reference>
  <reference>
    <citation>Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011 Mar 31;364(13):1195-206. doi: 10.1056/NEJMoa1010494.</citation>
    <PMID>21449783</PMID>
  </reference>
  <reference>
    <citation>Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, Fried MW, Adler M, Reesink HW, Martin M, Sankoh AJ, Adda N, Kauffman RS, George S, Wright CI, Poordad F; ILLUMINATE Study Team. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011 Sep 15;365(11):1014-24. doi: 10.1056/NEJMoa1014463. Erratum In: N Engl J Med. 2011 Oct 20;365(16):1551.</citation>
    <PMID>21916639</PMID>
  </reference>
  <reference>
    <citation>Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N, Burroughs M, Brass CA, Albrecht JK, Esteban R; HCV RESPOND-2 Investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011 Mar 31;364(13):1207-17. doi: 10.1056/NEJMoa1009482.</citation>
    <PMID>21449784</PMID>
  </reference>
  <reference>
    <citation>Gutierrez JA, Lawitz EJ, Poordad F. Interferon-free, direct-acting antiviral therapy for chronic hepatitis C. J Viral Hepat. 2015 Nov;22(11):861-70. doi: 10.1111/jvh.12422. Epub 2015 Jun 17.</citation>
    <PMID>26083155</PMID>
  </reference>
  <reference>
    <citation>Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, Lawitz E, Lok AS, Hinestrosa F, Thuluvath PJ, Schwartz H, Nelson DR, Everson GT, Eley T, Wind-Rotolo M, Huang SP, Gao M, Hernandez D, McPhee F, Sherman D, Hindes R, Symonds W, Pasquinelli C, Grasela DM; AI444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014 Jan 16;370(3):211-21. doi: 10.1056/NEJMoa1306218. Erratum In: N Engl J Med. 2014 Apr 10;370(15):1469.</citation>
    <PMID>24428467</PMID>
  </reference>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>August 25, 2017</study_first_submitted>
  <study_first_submitted_qc>August 29, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 31, 2017</study_first_posted>
  <last_update_submitted>August 29, 2017</last_update_submitted>
  <last_update_submitted_qc>August 29, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 31, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Assiut University</investigator_affiliation>
    <investigator_full_name>Mariana Tharwat</investigator_full_name>
    <investigator_title>Principle investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis A</mesh_term>
    <mesh_term>Hepatitis C</mesh_term>
    <mesh_term>Hepatitis C, Chronic</mesh_term>
    <mesh_term>Hepatitis</mesh_term>
  </condition_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/NCT03268317
org study id: NAEIPWCHCTBDAAD
nct id: NCT03268317
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Neuropsychiatric adverse effects of direct acting antiviral drugs, especially Sofosbuvir and
      Daclatasvir combination therapy (with or without ribavirin) in patients with chronic
      hepatitis C , genotype four (the predominant genotype in Egypt).
Treatment of hepatitis C virus, a virus infecting over one hundred seventy million worldwide,
      has evolved over the last two decades and moved from interferon-alpha monotherapy to
      pegylated interferon-alpha in combination with ribavirin therapy. Despite enhanced sustained
      virological response rates, psychiatric illness remains a barrier to widespread hepatitis C
      virus treatment uptake due to the neuropsychiatric risks associated with interferon-alpha.The
      next generation of hepatitis C virus therapeutic agents is direct acting antivirals that
      still require the use of interferon-ribavirin combination therapy.

      Poorly managed psychiatric illness can lead not only to treatment discontinuation,but also
      poor adherence to treatment and serious psychiatric sequels, such as suicide.

      Data on neuropsychiatric adverse effects of direct acting antivirals is limited and
      predominantly derived from landmark clinical trials for boceprevir and telaprevir.These first
      generation direct acting antivirals are currently not in use due to their multiple side
      effects ,the need for concomitant interferon-alpha ,and there wide drug-drug interactions.
      Recently the treatment of hepatitis C virus has undergone a paradigm shift with the
      introduction of the second generation of direct acting antivirals. This interferon-free
      modality has brought about exceptional cure rates with sustained virological response
      exceeding ninety hundred percent, with better tolerability, minimized side effects and short
      duration of treatment . Of the current hepatitis C virus treatment regimens, the combinations
      of Sofosbuvir plus daclatasvir have shown a high efficacy rate in achieving sustained
      virological response in genotype one patients.

      To the investigators' knowledge, the development of neuropsychiatric side effects with the
      use of these second generation direct acting antivirals in absence of interferon therapy, as
      well as the impact of the expected high sustained virological response to therapy on the
      psychiatric condition of patients with chronic hepatitis C (in absence of cirrhosis) have not
      been studied. Therefore, the purpose of this work is to evaluate the neuropsychiatric adverse
      effects of direct acting antivirals,especially Sofosbuvir and Daclatasvir combination therapy
      (with or without ribavirin) in patients with chronic hepatitis C, genotype four (the
      predominant genotype in Egypt).
observational model: Cohort
time perspective: Prospective
measure: Hamilton anxiety scale (HAM-A) in patients with chronic hepatitis C treated by DAAs
time frame: 12 months
measure: Hamilton depression scale (HAM-D) in patients with chronic hepatitis C treated by DAAs
time frame: 12 months
measure: EEG in patients with chronic hepatitis C treated by DAAs
time frame: 12 months
measure: Visual evoked potential in patients with chronic hepatitis C treated by DAAs
time frame: 12 months
arm group label: Patients with chronic hepatitis C treated by DAAs
description: All subjects will be given the same treatment regimen which includes Sofosbuvir 400 mg orally/24 hours (pre-breakfast) and Daclatasvir 60 mg orally/24 hours after lunch with or without ribavirin for a total period of 12 weeks.
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Esam Darwish
phone: 01224785281
email: darwishe@aun.edu.eg
citation: Wasley A, Alter MJ. Epidemiology of hepatitis C: geographic differences and temporal trends. Semin Liver Dis. 2000;20(1):1-16. doi: 10.1055/s-2000-9506.
PMID: 10895428
citation: Dieperink E, Ho SB, Tetrick L, Thuras P, Dua K, Willenbring ML. Suicidal ideation during interferon-alpha2b and ribavirin treatment of patients with chronic hepatitis C. Gen Hosp Psychiatry. 2004 May-Jun;26(3):237-40. doi: 10.1016/j.genhosppsych.2004.01.003.
PMID: 15121353
citation: Ademmer K, Beutel M, Bretzel R, Jaeger C, Reimer C. Suicidal ideation with IFN-alpha and ribavirin in a patient with hepatitis C. Psychosomatics. 2001 Jul-Aug;42(4):365-7. doi: 10.1176/appi.psy.42.4.365. No abstract available. Erratum In: Psychosomatics 2002 Jan-Feb;43(1):88. Clemens J [corrected to Jaeger C].
PMID: 11496031
citation: Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, George J, Rizzetto M, Shouval D, Sola R, Terg RA, Yoshida EM, Adda N, Bengtsson L, Sankoh AJ, Kieffer TL, George S, Kauffman RS, Zeuzem S; ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011 Jun 23;364(25):2405-16. doi: 10.1056/NEJMoa1012912.
PMID: 21696307
citation: Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011 Mar 31;364(13):1195-206. doi: 10.1056/NEJMoa1010494.
PMID: 21449783
citation: Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, Fried MW, Adler M, Reesink HW, Martin M, Sankoh AJ, Adda N, Kauffman RS, George S, Wright CI, Poordad F; ILLUMINATE Study Team. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011 Sep 15;365(11):1014-24. doi: 10.1056/NEJMoa1014463. Erratum In: N Engl J Med. 2011 Oct 20;365(16):1551.
PMID: 21916639
citation: Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N, Burroughs M, Brass CA, Albrecht JK, Esteban R; HCV RESPOND-2 Investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011 Mar 31;364(13):1207-17. doi: 10.1056/NEJMoa1009482.
PMID: 21449784
citation: Gutierrez JA, Lawitz EJ, Poordad F. Interferon-free, direct-acting antiviral therapy for chronic hepatitis C. J Viral Hepat. 2015 Nov;22(11):861-70. doi: 10.1111/jvh.12422. Epub 2015 Jun 17.
PMID: 26083155
citation: Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, Lawitz E, Lok AS, Hinestrosa F, Thuluvath PJ, Schwartz H, Nelson DR, Everson GT, Eley T, Wind-Rotolo M, Huang SP, Gao M, Hernandez D, McPhee F, Sherman D, Hindes R, Symonds W, Pasquinelli C, Grasela DM; AI444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014 Jan 16;370(3):211-21. doi: 10.1056/NEJMoa1306218. Erratum In: N Engl J Med. 2014 Apr 10;370(15):1469.
PMID: 24428467
responsible party type: Principal Investigator
investigator affiliation: Assiut University
investigator full name: Mariana Tharwat
investigator title: Principle investigator
mesh term: Hepatitis A
mesh term: Hepatitis C
mesh term: Hepatitis C, Chronic
mesh term: Hepatitis