<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/NCT03236506</url>
  </required_header>
  <id_info>
    <org_study_id>2016GA03</org_study_id>
    <secondary_id>2017-001039-38</secondary_id>
    <nct_id>NCT03236506</nct_id>
  </id_info>
  <brief_title>A Direct obserVed therApy vs fortNightly CollEction Study for HCV Treatment - ADVANCE HCV Study</brief_title>
  <acronym>ADVANCE</acronym>
  <official_title>A Direct obserVed therApy vs fortNightly CollEction Study for HCV Treatment - ADVANCE HCV Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Dundee</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Dundee</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Hepatitis C is a blood borne virus that can seriously damage the liver. An estimated 50,000&#xD;
      Scots have been infected with Hepatitis C virus (HCV). The main driver for spread of HCV&#xD;
      infection is intravenous drug use. As HCV is highly infectious by the blood borne route&#xD;
      through needle sharing, it can infect the person who injects drugs (PWID) early in their&#xD;
      habit.&#xD;
&#xD;
      Around two thirds of people who are infected are unaware of it, and often show no symptoms&#xD;
      over a long period of time. While there is presently no vaccination for Hepatitis C, improved&#xD;
      treatments with shorter duration are now available. This raises the possibility of using&#xD;
      therapy as prevention, turning the epidemic off at source, by targeting active PWID who are&#xD;
      the main source of new infections. Modelling work illustrates the startling possibility and&#xD;
      impact of treating drug users to reduce the prevalence of HCV.&#xD;
&#xD;
      The focus of this trial will be to ascertain whether oral treatment regimens are effective in&#xD;
      the treatment as prevention scenario in an active PWID population where illicit drug taking&#xD;
      and poor adherence may reduce treatment efficacy. The investigators will trial 3 different&#xD;
      methods of delivering treatment and will trial an unlicensed combined treatment against HCV&#xD;
      genotype 3 infection of shortened duration since current regimens for this genotype are&#xD;
      limited.&#xD;
&#xD;
      The investigators will recruit 135 participants and randomise them to one of three arms:&#xD;
      daily, directly observed therapy; fortnightly dispensing of drugs; fortnightly dispensing of&#xD;
      drugs with a psychological adherence intervention. Randomisation will be stratified according&#xD;
      to HCV genotype. Participants will be treated for 12 or 8 weeks depending on genotype and&#xD;
      followed up 12 weeks post treatment for the measurement of sustained viral response (SVR).&#xD;
      The primary outcome measure will be SVR at 12 weeks post treatment (SVR12), as this measure&#xD;
      of cure is the determinant of sufficient compliance and efficacy within the 3 treatment arms.&#xD;
      Analysis will be by modified intention to treat of all participants who receive one dose of&#xD;
      therapy, to show non-inferiority fortnightly dispensing is easier to deliver than daily&#xD;
      dispensing.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hepatitis C is a blood borne virus that can seriously damage the liver. An estimated 50,000&#xD;
      Scots have been infected with Hepatitis C virus (HCV). The main driver for spread of HCV&#xD;
      infection is intravenous drug use. As HCV is highly infectious by the blood borne route&#xD;
      through needle sharing, it can infect the PWID early in their habit. With the advent of more&#xD;
      effective therapies of shortening duration, it raises the possibility of using therapy as&#xD;
      prevention, turning the epidemic off at source, by targeting active infected drug users who&#xD;
      are the main source of new infections.&#xD;
&#xD;
      The modelling work of Martin et al, raises the startling possibility of the profound impact&#xD;
      of treating small numbers of drug users on the prevalence of HCV, the work shows that&#xD;
      treating as few as 10-20 per 1000 drug users per year can reduce HCV prevalence by 50-90%&#xD;
      over 10 years. This has generated in the HCV field, the concept of treatment as prevention.&#xD;
      The scale of the benefit is exponentially related to prevalence of HCV in the population, the&#xD;
      lower the prevalence the bigger the impact. The model has some limitations, it groups all&#xD;
      drug users together and assumes a similar risk of infection for those on methadone and those&#xD;
      actively injecting and assumes a high rate of turn over from methadone back to active&#xD;
      injecting and further assumes treatment is only possible during the opiate substitution&#xD;
      phase.&#xD;
&#xD;
      Oral anti-HCV regimens that are interferon free and have virtually no side-effects are now&#xD;
      the standard of care in conventional treatment populations. The medication should be taken&#xD;
      daily to optimise therapeutic success, and if adherence is poor in the actively injecting&#xD;
      population it is possible that the effectiveness of the new oral drugs will be reduced. It is&#xD;
      key to know if all oral directly acting antivirals (DAA) regimens are robust and maintain SVR&#xD;
      rates in this population. The real world SVR rate combined with drug cost, re-infection rate&#xD;
      and emergence of viral resistance will determine if this treatment as prevention model is&#xD;
      cost-effective with DAAs. Directly observed therapy (DOT) is the ultimate adherence aid, but&#xD;
      it is more costly and draconian so that it may discourage participants, especially this&#xD;
      group, from taking up therapy. Therefore the investigators need to demonstrate that treatment&#xD;
      uptake and adherence is sufficient to maintain the SVR rate at a level which makes treatment&#xD;
      as prevention cost effective. Three means of delivery will be compared: daily DOT vs&#xD;
      fortnightly pick up of therapy vs. fortnightly pick-up of therapy with a psychological&#xD;
      intervention for adherence. The DOT method of treatment has not been explored in this&#xD;
      difficult to find and engage population previously. Contingency management in the form of&#xD;
      protein drinks for successful completion of each fortnight of treatment will be provided in&#xD;
      all three arms of the trial. A comparison of the three pathways mentioned above will show&#xD;
      which pathway shows best acceptability to participants and greatest compliance&#xD;
&#xD;
      The advent of DAAs with their reduced side effect profiles, shorter treatment duration and&#xD;
      high SVR rates have the potential to reduce the burden of treatment providing high levels of&#xD;
      adherence can be maintained. However, the use of DAAs alone are unlikely to be sufficient to&#xD;
      achieve the required levels of adherence. In addition, the use of DAAs will not address the&#xD;
      psychosocial factors known to influence adherence. This trial will therefore investigate the&#xD;
      effectiveness of a nurse-led educational intervention for adherence to DAAs in a PWID&#xD;
      population.&#xD;
&#xD;
      Whilst the combination of Grazoprevir and Elbasvir is licensed for treatment of HCV genotype&#xD;
      1, treatment of HCV genotype 3 is more problematic. The C-SWIFT trial has recently shown that&#xD;
      the combination of Grazoprevir, Elbasvir and Sofosbuvir is an effective and safe 8 week&#xD;
      treatment for HCV genotype 3, resulting in high SVR rates. Whilst all 3 drugs are licensed&#xD;
      for treatment of HCV, the combination is not yet licensed. This combination will be used to&#xD;
      treat HCV genotype 3 infections in this trial.&#xD;
&#xD;
      Hepatitis C virus is prone to develop resistance to DAAs since it has a high replication rate&#xD;
      and therefore forms large numbers of genetically-distinct viral variants. The investigators&#xD;
      will investigate whether participants who do not achieve SVR are infected with a drug&#xD;
      resistant strain of HCV by sequencing the NS3 and NS5A regions of viral nonstructural (NS)&#xD;
      protein present within their blood. The proteins of these genes are targeted by the DAA&#xD;
      medications and if their structure is altered the DAA may no longer be effective.&#xD;
&#xD;
      The trial will also explore whether the taking of illicit drugs affects the efficacy of&#xD;
      treatment. While the main effect is likely to be via adherence, it is also possible that some&#xD;
      of the illicit drugs may interact with the DAAs. A log of illicit drugs used by the&#xD;
      participants will be kept and used to identify any candidate interactions for further&#xD;
      investigation.&#xD;
&#xD;
      This is a randomised, un-blinded trial which will be conducted in the needle exchange&#xD;
      services and pharmacies across Tayside, designed to evaluate the efficacy and feasibility of&#xD;
      DAA therapy, in HCV positive, genotype 1 and 3, active PWIDs, administered via three&#xD;
      different routes:&#xD;
&#xD;
        1. DOT,&#xD;
&#xD;
        2. Fortnightly pick-up&#xD;
&#xD;
        3. Fortnightly pick-up with psychological intervention.&#xD;
&#xD;
      Participants included in the trial will have a reactive Dry Blood Spot (DBS) test to confirm&#xD;
      HCV infection, polymerase chain reaction (PCR) test to confirm active infection and will&#xD;
      currently be using illicit drugs, as confirmed by the participant. Drug screening (by urine&#xD;
      sample) will not be tested at that time.&#xD;
&#xD;
      Participants will be stratified by the genotype of their HCV infection; genotype 1 vs&#xD;
      genotype 3 and randomised to one of three groups; DOT, fortnightly pick-up, or fortnightly&#xD;
      pick-up with psychological adherence intervention.&#xD;
&#xD;
      All PWID are encouraged to have a DBS test annually as part of clinical practice in Tayside.&#xD;
      Upon receipt of a reactive DBS test, potential participants will be briefed about the trial&#xD;
      by the specialist nurse or other trained member of staff and given a participant information&#xD;
      sheet (PIS) informing them of what is involved. Willing individuals will provide written&#xD;
      informed consent and will then have safety bloods drawn to determine eligibility to proceed.&#xD;
&#xD;
      Participants in all three arms of the trial will attend a baseline visit, a randomisation&#xD;
      visit either one (genotype 3) or two (genotype 1) visits during treatment, an end of&#xD;
      treatment visit and an SVR visit.&#xD;
&#xD;
      All participants will be given incentives to continue with their treatment in the trial.&#xD;
      These will consist of protein drinks and will be given at each study visit.&#xD;
&#xD;
      Psychological intervention Participants randomised to fortnightly pick-up with psychological&#xD;
      intervention will have an interview with the study nurse, prior to beginning their treatment,&#xD;
      which will cover the educational intervention designed to aid their compliance with the drug&#xD;
      regimen. The intervention will be based on the Information-Motivation-Behavioural (IMB)&#xD;
      Skills Model of Adherence12 which was originally developed to explain adherence behaviour in&#xD;
      HIV. Recent research suggests this model may have applicability in understanding the&#xD;
      facilitator and barriers to adherence in HCV patients. The model suggests that provision of&#xD;
      medication information, enhancing personal and social motivation and developing behavioural&#xD;
      skills that are key determinants of adherence and may improve adherence in this group. The&#xD;
      intervention will involve a structured interview in which the trial nurse and participant&#xD;
      will develop an action plan that includes personalised information, sources of motivation for&#xD;
      adherence and a treatment routine configured to be compatible with the participant's&#xD;
      lifestyle. Anticipating barriers to adherence and problem-solving will be included in the&#xD;
      treatment routine. The intervention will take place at the randomisation visit and last&#xD;
      approximately one hour. During the intervention, participants will be guided by their trial&#xD;
      nurse in the completion of a personalised booklet, &quot;Hepatitis C and Me&quot;. The booklet contains&#xD;
      general and personalised information on Hepatitis C, exercises designed to explore and&#xD;
      enhance personal and social motivation for treatment adherence and a behavioural action plan&#xD;
      (the skills element of the IMB model). The booklet uses the principles of node-link mapping&#xD;
      to structure the intervention. Node link mapping use a set of visual tools to structure and&#xD;
      guide therapeutic conversation and has been shown to enhance memory and compliance with&#xD;
      treatment in substance misusers. Participants in the other two arms of the trial, who are not&#xD;
      receiving the psychological intervention, will be given the current National Health Service&#xD;
      (NHS) Tayside hepatitis information booklet (&quot;Living with Hepatitis C&quot;) which provides&#xD;
      generalised information about HCV without personalised information or specific strategies to&#xD;
      enhance motivation and behavioural skills.&#xD;
&#xD;
      Reinfection follow up. Trial participants will be invited to also consent for access to&#xD;
      information from their annual clinic visits and HCV testing at any other contact with&#xD;
      clinical services for up to 5 years, to detect re-infection.&#xD;
&#xD;
      Illicit drug monitoring Illicit drug use will be recorded at baseline and at end of treatment&#xD;
      (week 8 for genotype 3, week 12 for genotype 1). One sample of urine for toxicology will be&#xD;
      taken during treatment. Those participants who fail to achieve SVR will be compared to&#xD;
      successful participants for any correlation with particular substance use. For any candidate&#xD;
      substance associated with failure to achieve SVR not explained by lack of adherence,&#xD;
      biological samples will be analysed for biological mechanisms.&#xD;
&#xD;
      Adherence monitoring Adherence of those participants randomised to DOT will be documented on&#xD;
      a daily log. Those randomised to fortnightly collection of medication will receive Zepatier&#xD;
      tablets in blister packaging. They will return their packets of medication every two weeks&#xD;
      and any remaining tablets will be counted. Participants infected with HCV genotype 3 will&#xD;
      additionally receive bottles containing Sovaldi tablets. These bottles will be fitted with&#xD;
      adherence aid caps that record time and date of each cap opening.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 19, 2018</start_date>
  <completion_date type="Actual">October 28, 2020</completion_date>
  <primary_completion_date type="Actual">August 31, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Randomised, un-blinded trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Comparison of Sustained Viral Response at 12 Weeks Post Treatment (SVR12) in the Three Treatment Groups.</measure>
    <time_frame>24 weeks for genotype 1 HCV, 20 weeks for genotype 3 HCV infection</time_frame>
    <description>SVR12 of participants in the directly observed therapy (DOT), fortnightly pick-up or fortnightly pick-up with a psychological adherence intervention group. SVR12 was measured by viral load of hepatitis c virus (HCV) in participant's blood at least 12 weeks after end of treatment. A viral load of less than 10IU/ml indicates no active infection and SVR12 has been achieved.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adherence as Assessed by the Total Percentage of Tablets Taken (Out of Those Dispensed) During the Treatment Period</measure>
    <time_frame>12 weeks for genotype 1 HCV, 8 weeks for genotype 3 HCV infection</time_frame>
    <description>Adherence of daily directly observed therapy group from daily logs Adherence measured by counting tablets returned after each 2 week treatment period (fortnightly pickup groups) Adherence of participants infected with genotype 3 and treated with Sovaldi measured using medication event monitoring system (MEMS®) cap.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of Reinfection Rates in Active PWIDs Treated With Oral DAA Regimes</measure>
    <time_frame>Not applicable. Not part of study data set.</time_frame>
    <description>Hepatitis C viral load by polymerase chain reaction (PCR) analysis. Any participants testing positive for reinfection post SVR12.&#xD;
This data will no longer be collected as part of this study and will be collected as part of standard clinical care.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of Resistance Profiles in Those Who do Not Achieve SVR</measure>
    <time_frame>Bloods collected at baseline, end of treatment and 12 weeks post end of treatment</time_frame>
    <description>Profiles of the HCV viral resistance proteins, NS5a and NS3 in participants who did not achieve SVR12, for reasons other than non-adherence to treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of the Types of Illicit Drugs Taken by Trial Participants and Identification of Any Interaction With the Directly Acting Therapies.</measure>
    <time_frame>At three timepoints; time zero (before treatment), time 2-8 weeks (during treatment) time 12 weeks (at the end of treatment)</time_frame>
    <description>Drug misuse history and urine toxicology to test for potential illicit drug interactions with the treatment in participants who did not achieve SVR12 for reasons that are not non-adherence to treatment.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">129</enrollment>
  <condition>Hepatitis C</condition>
  <arm_group>
    <arm_group_label>Daily observed therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a daily, observed basis by either the nurse or a community pharmacist.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Fortnightly pick-up</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Fortnightly pick-up +psych intervention</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse. In addition, this group will receive a one-off interview with the researcher to complete a psychological intervention designed to improve adherence to the medication regimen.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Elbasvir/Grazoprevir 50 MG-100 MG Oral Tablet</intervention_name>
    <description>Drugs will be given to participants to treat hepatitis C infection</description>
    <arm_group_label>Daily observed therapy</arm_group_label>
    <arm_group_label>Fortnightly pick-up</arm_group_label>
    <arm_group_label>Fortnightly pick-up +psych intervention</arm_group_label>
    <other_name>Zepatier</other_name>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Psychological intervention</intervention_name>
    <description>Participants randomised to fortnightly pick-up with psychological intervention will have an interview with the study nurse designed to aid their compliance with the drug regimen. During the intervention participants will be guided by their trial nurse in the completion of a personalised booklet, &quot;Hepatitis C and Me&quot;. The booklet uses the principles of node-link mapping to structure the intervention.</description>
    <arm_group_label>Fortnightly pick-up +psych intervention</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sofosbuvir 400 MG</intervention_name>
    <description>Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
    <arm_group_label>Daily observed therapy</arm_group_label>
    <arm_group_label>Fortnightly pick-up</arm_group_label>
    <arm_group_label>Fortnightly pick-up +psych intervention</arm_group_label>
    <other_name>Sovaldi</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or Female. (Age limit 18-70)&#xD;
&#xD;
          -  HCV PCR confirmed active infection, genotype 1 or 3.&#xD;
&#xD;
          -  If female, must have negative urine test results for pregnancy during initial&#xD;
             screening period (for trial inclusion) and be advised of limited safety data in&#xD;
             pregnancy.&#xD;
&#xD;
          -  Current illicit drug use established through participant history.&#xD;
&#xD;
          -  Able to provide informed consent, agreeing to trial and clinical monitoring criteria&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Aggressive or violent behaviour.&#xD;
&#xD;
          -  Platelet count &lt; 75000000000 /ml&#xD;
&#xD;
          -  Alanine transaminase &gt; 350 Units/l&#xD;
&#xD;
          -  Inability to provide informed consent.&#xD;
&#xD;
          -  Clinical history or abnormal valves for albumin&lt; 30 g/l, Bilirubin &gt;35 umol/l or&#xD;
             prothrombin time &gt;1.5 consistent with decompensated liver failure Childs-Pugh B or C&#xD;
&#xD;
          -  Clinical history of primary hepatocellular carcinoma&#xD;
&#xD;
          -  Pregnancy or breast feeding.&#xD;
&#xD;
          -  Participation in a drug trial within the previous 30 days&#xD;
&#xD;
          -  Hepatitis B surface antigen positive&#xD;
&#xD;
          -  HIV infection.&#xD;
&#xD;
          -  Hypersensitivity to elbasvir and grazoprevir&#xD;
&#xD;
          -  Hypersensitivity to sofosbuvir (genotype 3 infected-participants ony)&#xD;
&#xD;
          -  Currently being treated with an inhibitor of organic anion transporting polypeptide&#xD;
             1B, e.g. rifampicin, atazanavir, daruavir, lopinavir, saquinavir, tipranavir,&#xD;
             cobicistat or ciclosporin.&#xD;
&#xD;
          -  Currently being treated with inducers of cytochrome P450 3A or P-glycoprotein, such as&#xD;
             efavirenz, phenytoin, carbamazepine, bosentan, etravirine, modafinil or St John's Wort&#xD;
             (Hypericum perforatum)&#xD;
&#xD;
          -  Currently being treated with amiodarone (Participants infected with genotype 3 HCV&#xD;
             only)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>John Dillon, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Dundee</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Dundee</name>
      <address>
        <city>Dundee</city>
        <state>Tayside</state>
        <zip>DD1 9SY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NHS Tayside</name>
      <address>
        <city>Dundee</city>
        <zip>DD1 9SY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>July 4, 2017</study_first_submitted>
  <study_first_submitted_qc>July 27, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 2, 2017</study_first_posted>
  <results_first_submitted>August 24, 2021</results_first_submitted>
  <results_first_submitted_qc>October 25, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">November 18, 2021</results_first_posted>
  <last_update_submitted>October 25, 2021</last_update_submitted>
  <last_update_submitted_qc>October 25, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 18, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Dundee</investigator_affiliation>
    <investigator_full_name>John Dillon</investigator_full_name>
    <investigator_title>Professor John Dillon</investigator_title>
  </responsible_party>
  <keyword>Illicit drug</keyword>
  <keyword>Injecting drug</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis C</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sofosbuvir</mesh_term>
    <mesh_term>Grazoprevir</mesh_term>
    <mesh_term>Elbasvir-grazoprevir drug combination</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 2, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/06/NCT03236506/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 29, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/06/NCT03236506/SAP_002.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>135 participants were recruited. 6 withdrew by choice prior to randomisation. One randomised participant had to be withdrawn prior to starting treatment due to elevated Alanine Aminotransferase (ALT) levels, over the limit for inclusion in this study. Hence 128 participants who initiated treatment.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Daily Observed Therapy</title>
          <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a daily, observed basis by either the nurse or a community pharmacist.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
        </group>
        <group group_id="P2">
          <title>Fortnightly Pick-up</title>
          <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
        </group>
        <group group_id="P3">
          <title>Fortnightly Pick-up +Psych Intervention</title>
          <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse. In addition, this group will receive a one-off interview with the researcher to complete a psychological intervention designed to improve adherence to the medication regimen.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Psychological intervention: Participants randomised to fortnightly pick-up with psychological intervention will have an interview with the study nurse designed to aid their compliance with the drug regimen. During the intervention participants will be guided by their trial nurse in the completion of a personalised booklet, &quot;Hepatitis C and Me&quot;. The booklet uses the principles of node-link mapping to structure the intervention.&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="39"/>
                <participants group_id="P2" count="42"/>
                <participants group_id="P3" count="47"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="33"/>
                <participants group_id="P2" count="37"/>
                <participants group_id="P3" count="40"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="5"/>
                <participants group_id="P3" count="7"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Did not initiate treatment</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Daily Observed Therapy</title>
          <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a daily, observed basis by either the nurse or a community pharmacist.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
        </group>
        <group group_id="B2">
          <title>Fortnightly Pick-up</title>
          <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
        </group>
        <group group_id="B3">
          <title>Fortnightly Pick-up +Psych Intervention</title>
          <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse. In addition, this group will receive a one-off interview with the researcher to complete a psychological intervention designed to improve adherence to the medication regimen.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Psychological intervention: Participants randomised to fortnightly pick-up with psychological intervention will have an interview with the study nurse designed to aid their compliance with the drug regimen. During the intervention participants will be guided by their trial nurse in the completion of a personalised booklet, &quot;Hepatitis C and Me&quot;. The booklet uses the principles of node-link mapping to structure the intervention.&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="39"/>
            <count group_id="B2" value="42"/>
            <count group_id="B3" value="47"/>
            <count group_id="B4" value="128"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="39"/>
                    <count group_id="B2" value="42"/>
                    <count group_id="B3" value="47"/>
                    <count group_id="B4" value="128"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="36.2" spread="8.20"/>
                    <measurement group_id="B2" value="35.7" spread="7.33"/>
                    <measurement group_id="B3" value="37.7" spread="7.53"/>
                    <measurement group_id="B4" value="36.6" spread="7.67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="39"/>
                    <count group_id="B2" value="42"/>
                    <count group_id="B3" value="47"/>
                    <count group_id="B4" value="128"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="15"/>
                    <measurement group_id="B4" value="36"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="29"/>
                    <measurement group_id="B2" value="31"/>
                    <measurement group_id="B3" value="32"/>
                    <measurement group_id="B4" value="92"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                    <count group_id="B4" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United Kingdom</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="39"/>
                    <count group_id="B2" value="42"/>
                    <count group_id="B3" value="47"/>
                    <count group_id="B4" value="128"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="39"/>
                    <measurement group_id="B2" value="42"/>
                    <measurement group_id="B3" value="47"/>
                    <measurement group_id="B4" value="128"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Living Situation</title>
          <description>Type of living accommodation used by participants</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="39"/>
                    <count group_id="B2" value="42"/>
                    <count group_id="B3" value="47"/>
                    <count group_id="B4" value="128"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Owned/rented</title>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                    <measurement group_id="B2" value="24"/>
                    <measurement group_id="B3" value="31"/>
                    <measurement group_id="B4" value="79"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Supported accommodation (drug related)</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Homeless</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="12"/>
                    <measurement group_id="B4" value="38"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Other</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Source of income</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="39"/>
                    <count group_id="B2" value="42"/>
                    <count group_id="B3" value="47"/>
                    <count group_id="B4" value="128"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Unemployed on government benefit</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="23"/>
                    <measurement group_id="B3" value="30"/>
                    <measurement group_id="B4" value="73"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unemployed on government benefit and at least one other source of income</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="14"/>
                    <measurement group_id="B4" value="47"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Casual work and government benefit</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No government benefit but other source of income</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Alcohol consumption</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="39"/>
                    <count group_id="B2" value="42"/>
                    <count group_id="B3" value="47"/>
                    <count group_id="B4" value="128"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>None</title>
                  <measurement_list>
                    <measurement group_id="B1" value="32"/>
                    <measurement group_id="B2" value="33"/>
                    <measurement group_id="B3" value="37"/>
                    <measurement group_id="B4" value="102"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 1-20 units</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Over 20 units</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Drug injecting history</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="39"/>
                    <count group_id="B2" value="42"/>
                    <count group_id="B3" value="47"/>
                    <count group_id="B4" value="128"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Injected within last week</title>
                  <measurement_list>
                    <measurement group_id="B1" value="27"/>
                    <measurement group_id="B2" value="28"/>
                    <measurement group_id="B3" value="33"/>
                    <measurement group_id="B4" value="88"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Injected within last month</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Injected within last 3 months</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Comparison of Sustained Viral Response at 12 Weeks Post Treatment (SVR12) in the Three Treatment Groups.</title>
        <description>SVR12 of participants in the directly observed therapy (DOT), fortnightly pick-up or fortnightly pick-up with a psychological adherence intervention group. SVR12 was measured by viral load of hepatitis c virus (HCV) in participant's blood at least 12 weeks after end of treatment. A viral load of less than 10IU/ml indicates no active infection and SVR12 has been achieved.</description>
        <time_frame>24 weeks for genotype 1 HCV, 20 weeks for genotype 3 HCV infection</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Daily Observed Therapy</title>
            <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a daily, observed basis by either the nurse or a community pharmacist.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
          </group>
          <group group_id="O2">
            <title>Fortnightly Pick-up</title>
            <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
          </group>
          <group group_id="O3">
            <title>Fortnightly Pick-up +Psych Intervention</title>
            <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse. In addition, this group will receive a one-off interview with the researcher to complete a psychological intervention designed to improve adherence to the medication regimen.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Psychological intervention: Participants randomised to fortnightly pick-up with psychological intervention will have an interview with the study nurse designed to aid their compliance with the drug regimen. During the intervention participants will be guided by their trial nurse in the completion of a personalised booklet, &quot;Hepatitis C and Me&quot;. The booklet uses the principles of node-link mapping to structure the intervention.&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
          </group>
        </group_list>
        <measure>
          <title>Comparison of Sustained Viral Response at 12 Weeks Post Treatment (SVR12) in the Three Treatment Groups.</title>
          <description>SVR12 of participants in the directly observed therapy (DOT), fortnightly pick-up or fortnightly pick-up with a psychological adherence intervention group. SVR12 was measured by viral load of hepatitis c virus (HCV) in participant's blood at least 12 weeks after end of treatment. A viral load of less than 10IU/ml indicates no active infection and SVR12 has been achieved.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="33"/>
                <count group_id="O2" value="37"/>
                <count group_id="O3" value="40"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>SVR test positive for virus</title>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="5"/>
                    <measurement group_id="O3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>SVR test negative for virus</title>
                  <measurement_list>
                    <measurement group_id="O1" value="30"/>
                    <measurement group_id="O2" value="32"/>
                    <measurement group_id="O3" value="37"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>Assuming a 95% SVR rate (based on published studies) in the DOT arm of the trial in this population and a non-inferiority limit of 14% (which would be likely to maintain cost-effectiveness) then at a 5% significance level and 90% power we would need a sample size of 42 in each group 126 in total. To allow for drop-outs we will aim to recruit 135 individuals, 45 per group.</non_inferiority_desc>
            <p_value>0.67</p_value>
            <method>Logistic</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>0.64</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.14</ci_lower_limit>
            <ci_upper_limit>3.00</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>Described in Statistical Analysis 1.</non_inferiority_desc>
            <p_value>0.41</p_value>
            <method>logistic</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>0.53</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.11</ci_lower_limit>
            <ci_upper_limit>2.45</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>Described in Statistical Analysis 1.</non_inferiority_desc>
            <p_value>0.82</p_value>
            <method>logistic</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.22</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.23</ci_lower_limit>
            <ci_upper_limit>6.61</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Adherence as Assessed by the Total Percentage of Tablets Taken (Out of Those Dispensed) During the Treatment Period</title>
        <description>Adherence of daily directly observed therapy group from daily logs Adherence measured by counting tablets returned after each 2 week treatment period (fortnightly pickup groups) Adherence of participants infected with genotype 3 and treated with Sovaldi measured using medication event monitoring system (MEMS®) cap.</description>
        <time_frame>12 weeks for genotype 1 HCV, 8 weeks for genotype 3 HCV infection</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Daily Observed Therapy</title>
            <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a daily, observed basis by either the nurse or a community pharmacist.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
          </group>
          <group group_id="O2">
            <title>Fortnightly Pick-up</title>
            <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
          </group>
          <group group_id="O3">
            <title>Fortnightly Pick-up +Psych Intervention</title>
            <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse. In addition, this group will receive a one-off interview with the researcher to complete a psychological intervention designed to improve adherence to the medication regimen.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Psychological intervention: Participants randomised to fortnightly pick-up with psychological intervention will have an interview with the study nurse designed to aid their compliance with the drug regimen. During the intervention participants will be guided by their trial nurse in the completion of a personalised booklet, &quot;Hepatitis C and Me&quot;. The booklet uses the principles of node-link mapping to structure the intervention.&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
          </group>
        </group_list>
        <measure>
          <title>Adherence as Assessed by the Total Percentage of Tablets Taken (Out of Those Dispensed) During the Treatment Period</title>
          <description>Adherence of daily directly observed therapy group from daily logs Adherence measured by counting tablets returned after each 2 week treatment period (fortnightly pickup groups) Adherence of participants infected with genotype 3 and treated with Sovaldi measured using medication event monitoring system (MEMS®) cap.</description>
          <units>percentage of medication taken</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="39"/>
                <count group_id="O2" value="42"/>
                <count group_id="O3" value="47"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="69" spread="0.32"/>
                    <measurement group_id="O2" value="96" spread="0.09"/>
                    <measurement group_id="O3" value="98" spread="0.05"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of Reinfection Rates in Active PWIDs Treated With Oral DAA Regimes</title>
        <description>Hepatitis C viral load by polymerase chain reaction (PCR) analysis. Any participants testing positive for reinfection post SVR12.&#xD;
This data will no longer be collected as part of this study and will be collected as part of standard clinical care.</description>
        <time_frame>Not applicable. Not part of study data set.</time_frame>
        <population>Data not collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Daily Observed Therapy</title>
            <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a daily, observed basis by either the nurse or a community pharmacist.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
          </group>
          <group group_id="O2">
            <title>Fortnightly Pick-up</title>
            <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
          </group>
          <group group_id="O3">
            <title>Fortnightly Pick-up +Psych Intervention</title>
            <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse. In addition, this group will receive a one-off interview with the researcher to complete a psychological intervention designed to improve adherence to the medication regimen.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Psychological intervention: Participants randomised to fortnightly pick-up with psychological intervention will have an interview with the study nurse designed to aid their compliance with the drug regimen. During the intervention participants will be guided by their trial nurse in the completion of a personalised booklet, &quot;Hepatitis C and Me&quot;. The booklet uses the principles of node-link mapping to structure the intervention.&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of Reinfection Rates in Active PWIDs Treated With Oral DAA Regimes</title>
          <description>Hepatitis C viral load by polymerase chain reaction (PCR) analysis. Any participants testing positive for reinfection post SVR12.&#xD;
This data will no longer be collected as part of this study and will be collected as part of standard clinical care.</description>
          <population>Data not collected.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of Resistance Profiles in Those Who do Not Achieve SVR</title>
        <description>Profiles of the HCV viral resistance proteins, NS5a and NS3 in participants who did not achieve SVR12, for reasons other than non-adherence to treatment.</description>
        <time_frame>Bloods collected at baseline, end of treatment and 12 weeks post end of treatment</time_frame>
        <population>Viral resistance would be tested for in instances where a positive HCV blood test at the SVR12 stage could not be explained by non-adherence to medication. No participants met this criteria.</population>
        <group_list>
          <group group_id="O1">
            <title>Daily Observed Therapy</title>
            <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a daily, observed basis by either the nurse or a community pharmacist.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
          </group>
          <group group_id="O2">
            <title>Fortnightly Pick-up</title>
            <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
          </group>
          <group group_id="O3">
            <title>Fortnightly Pick-up +Psych Intervention</title>
            <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse. In addition, this group will receive a one-off interview with the researcher to complete a psychological intervention designed to improve adherence to the medication regimen.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Psychological intervention: Participants randomised to fortnightly pick-up with psychological intervention will have an interview with the study nurse designed to aid their compliance with the drug regimen. During the intervention participants will be guided by their trial nurse in the completion of a personalised booklet, &quot;Hepatitis C and Me&quot;. The booklet uses the principles of node-link mapping to structure the intervention.&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of Resistance Profiles in Those Who do Not Achieve SVR</title>
          <description>Profiles of the HCV viral resistance proteins, NS5a and NS3 in participants who did not achieve SVR12, for reasons other than non-adherence to treatment.</description>
          <population>Viral resistance would be tested for in instances where a positive HCV blood test at the SVR12 stage could not be explained by non-adherence to medication. No participants met this criteria.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of the Types of Illicit Drugs Taken by Trial Participants and Identification of Any Interaction With the Directly Acting Therapies.</title>
        <description>Drug misuse history and urine toxicology to test for potential illicit drug interactions with the treatment in participants who did not achieve SVR12 for reasons that are not non-adherence to treatment.</description>
        <time_frame>At three timepoints; time zero (before treatment), time 2-8 weeks (during treatment) time 12 weeks (at the end of treatment)</time_frame>
        <population>Toxicological analysis of participant's urine for potential interacting illicit drugs would be tested for in instances where a positive HCV blood test at the SVR12 stage could not be explained by non-adherence to medication. No participants met this criteria.</population>
        <group_list>
          <group group_id="O1">
            <title>Daily Observed Therapy</title>
            <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a daily, observed basis by either the nurse or a community pharmacist.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
          </group>
          <group group_id="O2">
            <title>Fortnightly Pick-up</title>
            <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
          </group>
          <group group_id="O3">
            <title>Fortnightly Pick-up +Psych Intervention</title>
            <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse. In addition, this group will receive a one-off interview with the researcher to complete a psychological intervention designed to improve adherence to the medication regimen.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Psychological intervention: Participants randomised to fortnightly pick-up with psychological intervention will have an interview with the study nurse designed to aid their compliance with the drug regimen. During the intervention participants will be guided by their trial nurse in the completion of a personalised booklet, &quot;Hepatitis C and Me&quot;. The booklet uses the principles of node-link mapping to structure the intervention.&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of the Types of Illicit Drugs Taken by Trial Participants and Identification of Any Interaction With the Directly Acting Therapies.</title>
          <description>Drug misuse history and urine toxicology to test for potential illicit drug interactions with the treatment in participants who did not achieve SVR12 for reasons that are not non-adherence to treatment.</description>
          <population>Toxicological analysis of participant's urine for potential interacting illicit drugs would be tested for in instances where a positive HCV blood test at the SVR12 stage could not be explained by non-adherence to medication. No participants met this criteria.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>31 months</time_frame>
      <desc>Recorded but not reported as Serious Adverse Events:&#xD;
Death or hospitalisation for assault or accidental injury&#xD;
Hospitalisation for abscesses due to drugs use&#xD;
Hospitalisation for wound management due to drugs use&#xD;
Death or hospitalisation due to infection&#xD;
Hospitalisation for elective or planned investigation or treatment&#xD;
Death or hospitalisation for deteriorating renal function, high or low potassium levels&#xD;
Hospitalisation due to nausea, vomiting, constipation or diarrhea</desc>
      <group_list>
        <group group_id="E1">
          <title>Daily Observed Therapy</title>
          <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a daily, observed basis by either the nurse or a community pharmacist.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
        </group>
        <group group_id="E2">
          <title>Fortnightly Pick-up</title>
          <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
        </group>
        <group group_id="E3">
          <title>Fortnightly Pick-up +Psych Intervention</title>
          <description>Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse. In addition, this group will receive a one-off interview with the researcher to complete a psychological intervention designed to improve adherence to the medication regimen.&#xD;
Zepatier Pill: Drugs will be given to participants to treat hepatitis C infection&#xD;
Psychological intervention: Participants randomised to fortnightly pick-up with psychological intervention will have an interview with the study nurse designed to aid their compliance with the drug regimen. During the intervention participants will be guided by their trial nurse in the completion of a personalised booklet, &quot;Hepatitis C and Me&quot;. The booklet uses the principles of node-link mapping to structure the intervention.&#xD;
Sofosbuvir Pill: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 21.1</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="47"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="42"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="42"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Arthritis bacterial</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="42"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="47"/>
              </event>
              <event>
                <sub_title>Staphylococcal bacteraemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="42"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="47"/>
              </event>
              <event>
                <sub_title>Lower respiratory tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="42"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="47"/>
              </event>
              <event>
                <sub_title>Groin abcess</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="42"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="47"/>
              </event>
              <event>
                <sub_title>Intervertebral discitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="42"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="47"/>
              </event>
              <event>
                <sub_title>Community acquired pneumonia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="42"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="47"/>
              </event>
              <event>
                <sub_title>Septic emboli</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="42"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="47"/>
              </event>
              <event>
                <sub_title>Streptococcus bacteraemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="42"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Intentional self harm</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="42"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="47"/>
              </event>
              <event>
                <sub_title>Vascular psuedoaneurysm</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="42"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="47"/>
              </event>
              <event>
                <sub_title>Illicit drug overdose</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="39"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="42"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Neck pain secondary to fall</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="42"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="47"/>
              </event>
              <event>
                <sub_title>Joint swelling</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="42"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Mania</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="42"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="47"/>
              </event>
              <event>
                <sub_title>Loss of consciousness due to drug use</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="42"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Renal colic</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="42"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>vaginal haemorrhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="42"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Aspiration pneumonia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="42"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Social circumstances</title>
            <event_list>
              <event>
                <sub_title>Physical assault</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="42"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Left mild cerebral infarct</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="42"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="47"/>
              </event>
              <event>
                <sub_title>Deep vein thrombosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="42"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 21.1</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="42"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="42"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Injection site infection/abscess</sub_title>
                <description>Infection or abscess related to injecting drug use</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="39"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="42"/>
                <counts group_id="E3" events="9" subjects_affected="3" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Illicit drug overdose</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="39"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="42"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Menorrhagia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="42"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Professor John Dillon</name_or_title>
      <organization>University of Dundee</organization>
      <phone>01382 383017</phone>
      <email>j.f.dillon@dundee.ac.uk</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03236506
org study id: 2016GA03
secondary id: 2017-001039-38
nct id: NCT03236506
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Hepatitis C is a blood borne virus that can seriously damage the liver. An estimated 50,000
      Scots have been infected with Hepatitis C virus (HCV). The main driver for spread of HCV
      infection is intravenous drug use. As HCV is highly infectious by the blood borne route
      through needle sharing, it can infect the person who injects drugs (PWID) early in their
      habit.

      Around two thirds of people who are infected are unaware of it, and often show no symptoms
      over a long period of time. While there is presently no vaccination for Hepatitis C, improved
      treatments with shorter duration are now available. This raises the possibility of using
      therapy as prevention, turning the epidemic off at source, by targeting active PWID who are
      the main source of new infections. Modelling work illustrates the startling possibility and
      impact of treating drug users to reduce the prevalence of HCV.

      The focus of this trial will be to ascertain whether oral treatment regimens are effective in
      the treatment as prevention scenario in an active PWID population where illicit drug taking
      and poor adherence may reduce treatment efficacy. The investigators will trial 3 different
      methods of delivering treatment and will trial an unlicensed combined treatment against HCV
      genotype 3 infection of shortened duration since current regimens for this genotype are
      limited.

      The investigators will recruit 135 participants and randomise them to one of three arms:
      daily, directly observed therapy; fortnightly dispensing of drugs; fortnightly dispensing of
      drugs with a psychological adherence intervention. Randomisation will be stratified according
      to HCV genotype. Participants will be treated for 12 or 8 weeks depending on genotype and
      followed up 12 weeks post treatment for the measurement of sustained viral response (SVR).
      The primary outcome measure will be SVR at 12 weeks post treatment (SVR12), as this measure
      of cure is the determinant of sufficient compliance and efficacy within the 3 treatment arms.
      Analysis will be by modified intention to treat of all participants who receive one dose of
      therapy, to show non-inferiority fortnightly dispensing is easier to deliver than daily
      dispensing.
Hepatitis C is a blood borne virus that can seriously damage the liver. An estimated 50,000
      Scots have been infected with Hepatitis C virus (HCV). The main driver for spread of HCV
      infection is intravenous drug use. As HCV is highly infectious by the blood borne route
      through needle sharing, it can infect the PWID early in their habit. With the advent of more
      effective therapies of shortening duration, it raises the possibility of using therapy as
      prevention, turning the epidemic off at source, by targeting active infected drug users who
      are the main source of new infections.

      The modelling work of Martin et al, raises the startling possibility of the profound impact
      of treating small numbers of drug users on the prevalence of HCV, the work shows that
      treating as few as 10-20 per 1000 drug users per year can reduce HCV prevalence by 50-90%
      over 10 years. This has generated in the HCV field, the concept of treatment as prevention.
      The scale of the benefit is exponentially related to prevalence of HCV in the population, the
      lower the prevalence the bigger the impact. The model has some limitations, it groups all
      drug users together and assumes a similar risk of infection for those on methadone and those
      actively injecting and assumes a high rate of turn over from methadone back to active
      injecting and further assumes treatment is only possible during the opiate substitution
      phase.

      Oral anti-HCV regimens that are interferon free and have virtually no side-effects are now
      the standard of care in conventional treatment populations. The medication should be taken
      daily to optimise therapeutic success, and if adherence is poor in the actively injecting
      population it is possible that the effectiveness of the new oral drugs will be reduced. It is
      key to know if all oral directly acting antivirals (DAA) regimens are robust and maintain SVR
      rates in this population. The real world SVR rate combined with drug cost, re-infection rate
      and emergence of viral resistance will determine if this treatment as prevention model is
      cost-effective with DAAs. Directly observed therapy (DOT) is the ultimate adherence aid, but
      it is more costly and draconian so that it may discourage participants, especially this
      group, from taking up therapy. Therefore the investigators need to demonstrate that treatment
      uptake and adherence is sufficient to maintain the SVR rate at a level which makes treatment
      as prevention cost effective. Three means of delivery will be compared: daily DOT vs
      fortnightly pick up of therapy vs. fortnightly pick-up of therapy with a psychological
      intervention for adherence. The DOT method of treatment has not been explored in this
      difficult to find and engage population previously. Contingency management in the form of
      protein drinks for successful completion of each fortnight of treatment will be provided in
      all three arms of the trial. A comparison of the three pathways mentioned above will show
      which pathway shows best acceptability to participants and greatest compliance

      The advent of DAAs with their reduced side effect profiles, shorter treatment duration and
      high SVR rates have the potential to reduce the burden of treatment providing high levels of
      adherence can be maintained. However, the use of DAAs alone are unlikely to be sufficient to
      achieve the required levels of adherence. In addition, the use of DAAs will not address the
      psychosocial factors known to influence adherence. This trial will therefore investigate the
      effectiveness of a nurse-led educational intervention for adherence to DAAs in a PWID
      population.

      Whilst the combination of Grazoprevir and Elbasvir is licensed for treatment of HCV genotype
      1, treatment of HCV genotype 3 is more problematic. The C-SWIFT trial has recently shown that
      the combination of Grazoprevir, Elbasvir and Sofosbuvir is an effective and safe 8 week
      treatment for HCV genotype 3, resulting in high SVR rates. Whilst all 3 drugs are licensed
      for treatment of HCV, the combination is not yet licensed. This combination will be used to
      treat HCV genotype 3 infections in this trial.

      Hepatitis C virus is prone to develop resistance to DAAs since it has a high replication rate
      and therefore forms large numbers of genetically-distinct viral variants. The investigators
      will investigate whether participants who do not achieve SVR are infected with a drug
      resistant strain of HCV by sequencing the NS3 and NS5A regions of viral nonstructural (NS)
      protein present within their blood. The proteins of these genes are targeted by the DAA
      medications and if their structure is altered the DAA may no longer be effective.

      The trial will also explore whether the taking of illicit drugs affects the efficacy of
      treatment. While the main effect is likely to be via adherence, it is also possible that some
      of the illicit drugs may interact with the DAAs. A log of illicit drugs used by the
      participants will be kept and used to identify any candidate interactions for further
      investigation.

      This is a randomised, un-blinded trial which will be conducted in the needle exchange
      services and pharmacies across Tayside, designed to evaluate the efficacy and feasibility of
      DAA therapy, in HCV positive, genotype 1 and 3, active PWIDs, administered via three
      different routes:

        1. DOT,

        2. Fortnightly pick-up

        3. Fortnightly pick-up with psychological intervention.

      Participants included in the trial will have a reactive Dry Blood Spot (DBS) test to confirm
      HCV infection, polymerase chain reaction (PCR) test to confirm active infection and will
      currently be using illicit drugs, as confirmed by the participant. Drug screening (by urine
      sample) will not be tested at that time.

      Participants will be stratified by the genotype of their HCV infection; genotype 1 vs
      genotype 3 and randomised to one of three groups; DOT, fortnightly pick-up, or fortnightly
      pick-up with psychological adherence intervention.

      All PWID are encouraged to have a DBS test annually as part of clinical practice in Tayside.
      Upon receipt of a reactive DBS test, potential participants will be briefed about the trial
      by the specialist nurse or other trained member of staff and given a participant information
      sheet (PIS) informing them of what is involved. Willing individuals will provide written
      informed consent and will then have safety bloods drawn to determine eligibility to proceed.

      Participants in all three arms of the trial will attend a baseline visit, a randomisation
      visit either one (genotype 3) or two (genotype 1) visits during treatment, an end of
      treatment visit and an SVR visit.

      All participants will be given incentives to continue with their treatment in the trial.
      These will consist of protein drinks and will be given at each study visit.

      Psychological intervention Participants randomised to fortnightly pick-up with psychological
      intervention will have an interview with the study nurse, prior to beginning their treatment,
      which will cover the educational intervention designed to aid their compliance with the drug
      regimen. The intervention will be based on the Information-Motivation-Behavioural (IMB)
      Skills Model of Adherence12 which was originally developed to explain adherence behaviour in
      HIV. Recent research suggests this model may have applicability in understanding the
      facilitator and barriers to adherence in HCV patients. The model suggests that provision of
      medication information, enhancing personal and social motivation and developing behavioural
      skills that are key determinants of adherence and may improve adherence in this group. The
      intervention will involve a structured interview in which the trial nurse and participant
      will develop an action plan that includes personalised information, sources of motivation for
      adherence and a treatment routine configured to be compatible with the participant's
      lifestyle. Anticipating barriers to adherence and problem-solving will be included in the
      treatment routine. The intervention will take place at the randomisation visit and last
      approximately one hour. During the intervention, participants will be guided by their trial
      nurse in the completion of a personalised booklet, "Hepatitis C and Me". The booklet contains
      general and personalised information on Hepatitis C, exercises designed to explore and
      enhance personal and social motivation for treatment adherence and a behavioural action plan
      (the skills element of the IMB model). The booklet uses the principles of node-link mapping
      to structure the intervention. Node link mapping use a set of visual tools to structure and
      guide therapeutic conversation and has been shown to enhance memory and compliance with
      treatment in substance misusers. Participants in the other two arms of the trial, who are not
      receiving the psychological intervention, will be given the current National Health Service
      (NHS) Tayside hepatitis information booklet ("Living with Hepatitis C") which provides
      generalised information about HCV without personalised information or specific strategies to
      enhance motivation and behavioural skills.

      Reinfection follow up. Trial participants will be invited to also consent for access to
      information from their annual clinic visits and HCV testing at any other contact with
      clinical services for up to 5 years, to detect re-infection.

      Illicit drug monitoring Illicit drug use will be recorded at baseline and at end of treatment
      (week 8 for genotype 3, week 12 for genotype 1). One sample of urine for toxicology will be
      taken during treatment. Those participants who fail to achieve SVR will be compared to
      successful participants for any correlation with particular substance use. For any candidate
      substance associated with failure to achieve SVR not explained by lack of adherence,
      biological samples will be analysed for biological mechanisms.

      Adherence monitoring Adherence of those participants randomised to DOT will be documented on
      a daily log. Those randomised to fortnightly collection of medication will receive Zepatier
      tablets in blister packaging. They will return their packets of medication every two weeks
      and any remaining tablets will be counted. Participants infected with HCV genotype 3 will
      additionally receive bottles containing Sovaldi tablets. These bottles will be fitted with
      adherence aid caps that record time and date of each cap opening.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomised, un-blinded trial
primary purpose: Treatment
masking: None (Open Label)
measure: Comparison of Sustained Viral Response at 12 Weeks Post Treatment (SVR12) in the Three Treatment Groups.
time frame: 24 weeks for genotype 1 HCV, 20 weeks for genotype 3 HCV infection
description: SVR12 of participants in the directly observed therapy (DOT), fortnightly pick-up or fortnightly pick-up with a psychological adherence intervention group. SVR12 was measured by viral load of hepatitis c virus (HCV) in participant's blood at least 12 weeks after end of treatment. A viral load of less than 10IU/ml indicates no active infection and SVR12 has been achieved.
measure: Adherence as Assessed by the Total Percentage of Tablets Taken (Out of Those Dispensed) During the Treatment Period
time frame: 12 weeks for genotype 1 HCV, 8 weeks for genotype 3 HCV infection
description: Adherence of daily directly observed therapy group from daily logs Adherence measured by counting tablets returned after each 2 week treatment period (fortnightly pickup groups) Adherence of participants infected with genotype 3 and treated with Sovaldi measured using medication event monitoring system (MEMS®) cap.
measure: Assessment of Reinfection Rates in Active PWIDs Treated With Oral DAA Regimes
time frame: Not applicable. Not part of study data set.
description: Hepatitis C viral load by polymerase chain reaction (PCR) analysis. Any participants testing positive for reinfection post SVR12.
This data will no longer be collected as part of this study and will be collected as part of standard clinical care.
measure: Assessment of Resistance Profiles in Those Who do Not Achieve SVR
time frame: Bloods collected at baseline, end of treatment and 12 weeks post end of treatment
description: Profiles of the HCV viral resistance proteins, NS5a and NS3 in participants who did not achieve SVR12, for reasons other than non-adherence to treatment.
measure: Assessment of the Types of Illicit Drugs Taken by Trial Participants and Identification of Any Interaction With the Directly Acting Therapies.
time frame: At three timepoints; time zero (before treatment), time 2-8 weeks (during treatment) time 12 weeks (at the end of treatment)
description: Drug misuse history and urine toxicology to test for potential illicit drug interactions with the treatment in participants who did not achieve SVR12 for reasons that are not non-adherence to treatment.
arm group label: Daily observed therapy
arm group type: Experimental
description: Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a daily, observed basis by either the nurse or a community pharmacist.
arm group label: Fortnightly pick-up
arm group type: Active Comparator
description: Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse.
arm group label: Fortnightly pick-up +psych intervention
arm group type: Active Comparator
description: Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse. In addition, this group will receive a one-off interview with the researcher to complete a psychological intervention designed to improve adherence to the medication regimen.
intervention type: Drug
intervention name: Elbasvir/Grazoprevir 50 MG-100 MG Oral Tablet
description: Drugs will be given to participants to treat hepatitis C infection
arm group label: Daily observed therapy
arm group label: Fortnightly pick-up
arm group label: Fortnightly pick-up +psych intervention
other name: Zepatier
intervention type: Behavioral
intervention name: Psychological intervention
description: Participants randomised to fortnightly pick-up with psychological intervention will have an interview with the study nurse designed to aid their compliance with the drug regimen. During the intervention participants will be guided by their trial nurse in the completion of a personalised booklet, "Hepatitis C and Me". The booklet uses the principles of node-link mapping to structure the intervention.
arm group label: Fortnightly pick-up +psych intervention
intervention type: Drug
intervention name: Sofosbuvir 400 MG
description: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection
arm group label: Daily observed therapy
arm group label: Fortnightly pick-up
arm group label: Fortnightly pick-up +psych intervention
other name: Sovaldi
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: John Dillon, MD
role: Principal Investigator
affiliation: University of Dundee
facility: 
facility: 
country: United Kingdom
responsible party type: Principal Investigator
investigator affiliation: University of Dundee
investigator full name: John Dillon
investigator title: Professor John Dillon
mesh term: Hepatitis C
mesh term: Sofosbuvir
mesh term: Grazoprevir
mesh term: Elbasvir-grazoprevir drug combination
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 