<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/NCT03238846</url>
  </required_header>
  <id_info>
    <org_study_id>MMSD Study</org_study_id>
    <secondary_id>MRCZ/A/2168</secondary_id>
    <nct_id>NCT03238846</nct_id>
  </id_info>
  <brief_title>Operations Research of the 'Real World' Effectiveness of Multi-Month Dispensing of ART for Stable Patients in CARGs in Zimbabwe</brief_title>
  <official_title>Outcomes of Differentiated Models of Care: Multi-Month Dispensing (MMD) and Community ART Refill Groups (CARGs) in Stable ART Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Kheth'Impilo</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ministry of Health and Child Welfare, Zimbabwe</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>EQUIP Innovation for Health</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Organization for Public Health Interventions and Development (OPHID)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Family Health International (FHI 360)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Population Services International (PSI)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Kheth'Impilo</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study aims to evaluate the effectiveness of two strategies for multi-month dispensing&#xD;
      (MMD) of ART in Community ART Refill Groups (CARGs) on retention, virologic suppression, and&#xD;
      cost compared to standard of care.&#xD;
&#xD;
      This study is a three-arm cluster-randomized controlled trial conducted among 5,760 stable&#xD;
      HIV-positive patients) in Zimbabwe to compare outcomes of three antiretroviral therapy (ART)&#xD;
      dispensing models. Outcomes of retention in care, virologic suppression, and cost&#xD;
      effectiveness will be investigated in 30 purposively selected clusters (facilities) which are&#xD;
      randomized into three arms; standard of care (3 months dispensing at facilities), three-month&#xD;
      dispensing in CARGs, and six-month dispensing in CARGs. Each study arm will have 10 clusters&#xD;
      stratified into 2 urban and 8 rural. Study participants will be followed, and outcomes will&#xD;
      be measured at 12 months and 24 months. Qualitative research will be conducted at baseline,&#xD;
      12 months, and 24 months (20 participant Focus Group Discussion (FGDs) and 20 provider Key&#xD;
      Informant Interview (KII) at each interval) to understand patient and health provider&#xD;
      acceptability of multi-month dispensing of ART within CARGs. Other outcomes of interest&#xD;
      include measuring gains of facility decongestion and feasibility of multi-month dispensing of&#xD;
      ART within CARGs. Cost analysis will include comparisons of patient level costs, cost per&#xD;
      patient outcomes and cost effectiveness across the three study arms.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study will use a cluster (facility) randomized trial with 3 arms; patients receiving 3&#xD;
      monthly ART supply at facilities-standard of care (3MF) (Control group), patients receiving 3&#xD;
      monthly ART supply at newly formed CARGs (3MC) and patients receiving 6 monthly ART supply at&#xD;
      newly formed CARGs (6MC). Participants will be followed up for 24 months. A total of 30 study&#xD;
      clusters (facilities) will be randomization, into the three study arms; 10 clusters per arm&#xD;
      stratified 2 urban, 8 rural.&#xD;
&#xD;
      Study Setting and study population The study population is HIV-infected adults over the age&#xD;
      of 18 years recruited from health facilities in U.S. President's Emergency Plan for AIDS&#xD;
      Relief (PEPFAR) Zimbabwe scale-up districts (using existing national records of patients in&#xD;
      the ART registers) that have been stable on a standard first-line ART treatment regimen for&#xD;
      at least 6 months.&#xD;
&#xD;
      Facilities from Chitungwiza Municipality, Matebeleland South Province, Masvingo Province and&#xD;
      Mberengwa district will be purposively selected to be the urban/periurban and rural settings&#xD;
      in the study. These areas were selected as they have PEPFAR Zimbabwe scale-up priority&#xD;
      facilities, high numbers of patients on ART and have prioritized implementation of CARGs.&#xD;
      These locations are also viewed to be good representations of PEPFAR Zimbabwe scale-up&#xD;
      priority facilities, hence are likely to improve the generalizability of the study findings&#xD;
      to the study population. As contexts differ between rural and urban/periurban settings, it is&#xD;
      important to determine the effectiveness of MMD within CARGs within both contexts.&#xD;
&#xD;
      Sampling and Sample size Sample sizes were determined for a cluster-randomized noninferiority&#xD;
      trial, using PASS v.14 (TM) software. Sample size estimates were calculated for the primary&#xD;
      outcome of retention in care at 12 months. The probability of patient attrition twelve months&#xD;
      after study enrolment in the control group (3MF) is assumed to be 5%, derived from the&#xD;
      relative difference in patient retention between 12 and 24 months from the 2015 Zimbabwe&#xD;
      UNAIDS Global AIDS Response progress report. An intracluster correlation coefficient (ICC) of&#xD;
      0.01 for patient retention/attrition amongst stable ART patients is assumed. The&#xD;
      noninferiority limit is specified as 3.25%. Assuming α=0.05, power of 85%, using one-sided&#xD;
      Z-test (unpooled) test statistic, 182 participants per facility will be required with a total&#xD;
      sample size of 5460 participants. A sample size re-estimation during accrual will increase&#xD;
      the total sample size to approximately 5760; 192 enrolled participants per study site and&#xD;
      1,920 participants per arm. As retention in care is the primary outcome, no adjustment for&#xD;
      loss to follow-up needs to be made.&#xD;
&#xD;
      Study procedures As this is operational research, the study will not interfere with routine&#xD;
      patient management and will follow national guidelines. The health care worker assesses each&#xD;
      patient's clinical notes to establish stability and study inclusion. Once informed consent is&#xD;
      obtained, a baseline questionnaire will be applied to record demographic characteristics and&#xD;
      the patients clinical and ART history. Patients will receive care based on their study ARM&#xD;
      and relevant SOP. Patient files and CARG tools will be reviewed and data collected at each&#xD;
      ART refill. Viral loads will be repeated annually.&#xD;
&#xD;
      Data Collection The study will use both qualitative and quantitative methods. The data&#xD;
      sources will include patient clinic notes, electronic patient management system (ePMS), CARG&#xD;
      monitoring data collection tools. In addition, variables to control for confounding in the&#xD;
      analysis for outcomes of interest will be collected at baseline through a short&#xD;
      cross-sectional survey. A pre-and-24-month post survey time-flow evaluation of patient&#xD;
      waiting times to assess gains of facility decongestion will be conducted. Feasibility of MMD&#xD;
      of ART within CARGs will be measured prospectively at baseline, 12 and 24 months. To&#xD;
      understand the acceptability of CARGs by patients and service providers; patient&#xD;
      satisfaction, and improvement in quality of care at the facilities, 20 patient FGDs and 20&#xD;
      heath care provider KII will be conducted at baseline, 12 and 24 months. A micro-costing&#xD;
      approach supplemented by a macro-costing approach of fixed costs will be utilized to measure&#xD;
      cost outcomes. A resource use form will collect information per patient through retrospective&#xD;
      review of clinic records. Start up costs will be included under each arm. Data to assess&#xD;
      patient level costs will be collected from a randomly selected sub-sample of 365 patients per&#xD;
      arm at baseline, 12 months and 24 months.&#xD;
&#xD;
      Data analysis Quantitative data will be analyzed using STATA 14. An intention-to-treat&#xD;
      analysis will be performed for the primary outcome of retention in care, in which all&#xD;
      patients and clinics will be analyzed in the group to which they were originally assigned.&#xD;
      Risk differences between arms will be compared with binomial population averaged generalized&#xD;
      estimating equations using an identity link and an exchangeable correlation matrix,&#xD;
      specifying for clustering by facility. Viral load suppression analyzed using log-binomial&#xD;
      regression, generalized estimating equations will be used to estimate risk ratios between the&#xD;
      study arms, specifying for clustering by facility and using an exchangeable correlation&#xD;
      matrix. Average patient waiting times will be compared between study arms using linear&#xD;
      regression.&#xD;
&#xD;
      Content qualitative analysis will be conducted using Atlas Ti, A cost outcomes analysis will&#xD;
      be conducted from the provider perspective. Average cost per yield rates (cost per client&#xD;
      retained in care, cost per client virally suppressed, cost per patient per year) will be&#xD;
      calculated. An incremental cost-effectiveness ratio (ICER) for the will be calculated; ICER&#xD;
      threshold comparison as recommended by World Health Organisation (WHO) will be employed.&#xD;
      Average patient costs will be from the patient's perspective. Startup costs for each service&#xD;
      delivery model will also be analyzed.&#xD;
&#xD;
      RISKS / BENEFITS TO PARTICIPANTS There may be no direct benefit to participants who take part&#xD;
      in this study, beyond benefits related to their routine ART medication that would have been&#xD;
      achieved otherwise. Information learned in this study may be of benefit to participants and&#xD;
      others in the future, particularly information that may lead to optimized treatment&#xD;
      guidelines for HIV-infected stable patients on ART.&#xD;
&#xD;
      As this is operational research, study procedures are routine clinical care associated with&#xD;
      minimal risk to participants. All patients will attend routine clinic visits to be assessed&#xD;
      for new Opportunistic infections (OIs), pregnancy, drug-drug interactions or side effects of&#xD;
      medications. This will ensure that patients who develop co-morbidities or become pregnant&#xD;
      during the study receive standard care, although they will not be excluded from the study.&#xD;
&#xD;
      REIMBURSEMENTS AND COMPENSATION As participants of FGDs may use transport money to the&#xD;
      discussion venue, this will be reimbursed. Those who are part of a FGD will receive snacks&#xD;
      after the discussion. CARGs will receive a bag to carry drugs from the clinic back to their&#xD;
      communities. This will be made clear to all study participants during the informed consent&#xD;
      process.&#xD;
&#xD;
      CONFIDENTIALITY ASSURANCES Participant information will not be released without written&#xD;
      permission to do so except as necessary for review, monitoring, and/or auditing. All&#xD;
      study-related information will be stored securely. Participant research records will be&#xD;
      stored in locked areas with access limited to study staff. case record files (CRFs), and&#xD;
      other documents that may be transmitted off-site will be identified by patient identifier&#xD;
      only. Likewise, communications between study staff and the investigators regarding individual&#xD;
      participants will identify participants by patient identifier only. The patient identifier&#xD;
      will be an anonymized key to identify unique subjects and will be used for data pooling,&#xD;
      transfer, storage, manipulation and analysis. Personal identifying data will not be available&#xD;
      to the investigators. Study sites will store study records that bear participant names or&#xD;
      other personal identifiers separately from records identified by patient identifier. Lists,&#xD;
      logbooks, appointment books, and any other documents that link the patient identifier to&#xD;
      personal identifying information at the facilities should be stored in a separate, locked&#xD;
      location in an area with limited access. Electronic data will be stored on password secured&#xD;
      servers, which will be backed-up on a regular basis. Data will be presented in aggregate form&#xD;
      only.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">July 28, 2017</start_date>
  <completion_date type="Anticipated">September 30, 2019</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2019</primary_completion_date>
  <phase>N/A</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>A prospective, parallel, cluster randomized noninferiority trial with three study arms will be conducted. In this study, a health facility is a cluster or site. Study sites were purposively selected from Chitungwiza Municipality, Masvingo Provincial districts, Matebeleland South Provincial districts, and Mberengwa district where USAID partners are currently implementing CARGs. Thirty clusters were selected and randomized in two strata per geographic location (urban and rural) to the three study arms. Outcomes will be assessed after 12 and 24 months,</intervention_model_description>
    <primary_purpose>Health Services Research</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Retention in care</measure>
    <time_frame>12 months</time_frame>
    <description>To determine if stable ART patients receiving 3 monthly dispensing of ART within CARGs have noninferior retention in care than stable ART patients receiving 3 monthly dispensing at health facilities after 12 months.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Retention in care</measure>
    <time_frame>12 months</time_frame>
    <description>To determine if stable ART patients receiving 6 monthly dispensing of ART within CARGs have noninferior retention in care than stable ART patients receiving 3 monthly dispensing at health facilities after 12 months.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Measure change in retention in care</measure>
    <time_frame>12 and 24 months</time_frame>
    <description>To determine if stable ART patients within CARGs receiving 6 monthly dispensing of ART have noninferior retention in care than stable ART patients receiving 3 monthly dispensing within CARGs after 12 months</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Virologic suppression</measure>
    <time_frame>12 months</time_frame>
    <description>To determine if stable ART patients receiving 3 and 6 monthly dispensing of ART within CARGs have noninferior viral suppression than stable ART patients receiving 3 monthly dispensing at health facilities after 12 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure change in virologic suppression</measure>
    <time_frame>12 and 24 months</time_frame>
    <description>To determine if stable ART patients within CARGs receiving 6 monthly dispensing have noninferior viral suppression than stable ART patients receiving 3 monthly dispensing within CARGs after 12 months and 24 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure cost effectiveness at 2 time points</measure>
    <time_frame>12 and 24 months</time_frame>
    <description>To determine the cost-effectiveness of dispensing of ART for three and six months within CARGs compared to three months in facilities (standard of care). Cost-effectiveness will be estimated as the average cost per successful outcome (patient retained at 12 and 24 months)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure change in patient level benefits of implementing CARGs</measure>
    <time_frame>12 and 24 months</time_frame>
    <description>To determine patient-level benefits of implementing CARGs with 3 monthly and 6 monthly dispensing (effects on cost of accessing care, productivity benefits and informal care effects).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measuring change in feasibility of multi-month dispensing of ART within CARGs</measure>
    <time_frame>12 and 24 months</time_frame>
    <description>To determine the feasibility of the introduction of multi-month dispensing of ART within CARGs and distribution in Zimbabwe (policy, supply chain management, and implementation).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure change in acceptability of CARGs</measure>
    <time_frame>12 and 24 months</time_frame>
    <description>To determine the acceptability of 3 and 6 monthly dispensing of ART within CARGs by patients and service providers.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measuring change in gains of facility decongestion</measure>
    <time_frame>12 and 24 months</time_frame>
    <description>To assess if there are any measurable gains made by decongesting facilities following the introduction of multi-month dispensing of ART within CARGs.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">4676</enrollment>
  <condition>HIV/AIDS</condition>
  <arm_group>
    <arm_group_label>3MF: 3-month ART dispensing at facilities</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Ten sites at which patients will receive standard of care where ART is dispensed three monthly from the facility based on usual practice at the clinic. The approach will be consistent with applicable country guidelines at the time of study.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>3MC: 3-month ART dispensing in CARGs</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ten sites at which patients will receive ART dispensed three monthly in CARGs. Providers at facilities will assist in the formation of CARGs and will provide all enrolled patients with a 3 month supply of ART and associated HIV medications. All other aspects of care will be as per standard of care for the enrolling clinic.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>6MC: 6-month ART dispensing in CARGs</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ten sites at which patients will receive ART dispensed six monthly in CARGs. Providers at facilities will assist in the formation of CARGs and will provide all enrolled patients with a 6 month supply of ART and associated HIV medications. All other aspects of care will be as per standard of care for the enrolling clinic.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Three month dispensing of ART in CARGs</intervention_name>
    <description>Patients enrolled in the three-month ART dispensing arm will receive a 90-day supply of ART in CARGs from their provider for the duration of the study. Each CARG will consist of 6-12 stable patients on ART and will meet in the community and select a group member to collect their ART at the facility every 3 months. Patients can have unscheduled clinic visits when unwell. Viral loads for the group will be collected at 12 and 24 months at the facility.</description>
    <arm_group_label>3MC: 3-month ART dispensing in CARGs</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Six month dispensing of ART in CARGs</intervention_name>
    <description>Patients enrolled in the three-month ART dispensing arm will receive a 90-day supply of ART in CARGs from their provider for the duration of the study. Each CARG will consist of 6-12 stable patients on ART and will meet in the community and select a group member to collect their ART at the facility every 6 months. Patients can have unscheduled clinic visits when unwell. Viral loads for the group will be collected at 12 and 24 months at the facility.</description>
    <arm_group_label>6MC: 6-month ART dispensing in CARGs</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  At least 18 years of age and willing and able to provide written informed consent for&#xD;
             participation in this study&#xD;
&#xD;
          -  Willing to be part of a CARG if in a facility that has been randomized to 3MC or 6MC,&#xD;
&#xD;
          -  Confirmed HIV-1 infection based on the Zimbabwe National HIV testing algorithm.&#xD;
&#xD;
          -  On ART ≥ 6 months&#xD;
&#xD;
          -  On first line ART regimen&#xD;
&#xD;
          -  No drug toxicity/tolerability issues within the prior 6 months&#xD;
&#xD;
          -  No active opportunistic infection suspected (including TB) and not treated for an&#xD;
             opportunistic infection in the last 30 days&#xD;
&#xD;
          -  Viral load &lt; 1000 copies/ml done at baseline of the study&#xD;
&#xD;
          -  Weight ≥ 35kgs&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Unwilling or unable to provide informed consent&#xD;
&#xD;
          -  On alternative first line or second line regimen&#xD;
&#xD;
          -  ARV toxicity or tolerability issue within the prior 6 months&#xD;
&#xD;
          -  Co-morbidities requiring facility visits more often than 3 months if in the 3MC/3MF&#xD;
             ARMS and 6 monthly if in the 6MC ARM&#xD;
&#xD;
          -  Viral load &gt; lower limit of standard assay (&gt;1000) within the prior 6 months&#xD;
&#xD;
          -  Confirmed pregnancy, or less than 18 months postpartum.&#xD;
&#xD;
          -  Weight criteria is less than 35kgs&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nicoletta Ngorima-Mabhena, MBChB, MSc Epidemiology</last_name>
    <role>Principal Investigator</role>
    <affiliation>Kheth'Impilo</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Seke North Clinic</name>
      <address>
        <city>Chitungwiza</city>
        <state>Harare</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seke South Clinic</name>
      <address>
        <city>Chitungwiza</city>
        <state>Harare</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St Mary's Clinic</name>
      <address>
        <city>Chitungwiza</city>
        <state>Harare</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Zengeza Clinic</name>
      <address>
        <city>Chitungwiza</city>
        <state>Harare</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chimombe Rural Hospital</name>
      <address>
        <city>Gutu</city>
        <state>Masvingo</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chinyika Rural Hospital</name>
      <address>
        <city>Gutu</city>
        <state>Masvingo</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Gutu Mission Hospital</name>
      <address>
        <city>Gutu</city>
        <state>Masvingo</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Gutu Rural Hospital</name>
      <address>
        <city>Gutu</city>
        <state>Masvingo</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bota Rural Hospital</name>
      <address>
        <city>Zaka</city>
        <state>Masvingo</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bvukururu Clinic</name>
      <address>
        <city>Zaka</city>
        <state>Masvingo</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chiredzana Clinic</name>
      <address>
        <city>Zaka</city>
        <state>Masvingo</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Harava Rural Health Centre</name>
      <address>
        <city>Zaka</city>
        <state>Masvingo</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Siyawareva Clinic</name>
      <address>
        <city>Zaka</city>
        <state>Masvingo</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beitbridge Hospital</name>
      <address>
        <city>Beitbridge</city>
        <state>Matebeleland South</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chamnangana</name>
      <address>
        <city>Beitbridge</city>
        <state>Matebeleland South</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chaswingo</name>
      <address>
        <city>Beitbridge</city>
        <state>Matebeleland South</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dulibadzimu</name>
      <address>
        <city>Beitbridge</city>
        <state>Matebeleland South</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Makakabule</name>
      <address>
        <city>Beitbridge</city>
        <state>Matebeleland South</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Shabwe</name>
      <address>
        <city>Beitbridge</city>
        <state>Matebeleland South</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chidembeko Mission Hospital</name>
      <address>
        <city>Mberengwa</city>
        <state>Midlands</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jeka Mission Hospital</name>
      <address>
        <city>Mberengwa</city>
        <state>Midlands</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Masase Mission Hospital</name>
      <address>
        <city>Mberengwa</city>
        <state>Midlands</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mataga RHC</name>
      <address>
        <city>Mberengwa</city>
        <state>Midlands</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mberengwa Hospital</name>
      <address>
        <city>Mberengwa</city>
        <state>Midlands</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mnene Mission Hospital</name>
      <address>
        <city>Mberengwa</city>
        <state>Midlands</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mposi Mission Hospital</name>
      <address>
        <city>Mberengwa</city>
        <state>Midlands</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Musume Mission Hospital</name>
      <address>
        <city>Mberengwa</city>
        <state>Midlands</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mwanezi RHC</name>
      <address>
        <city>Mberengwa</city>
        <state>Midlands</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Negove Clinic</name>
      <address>
        <city>Mberengwa</city>
        <state>Midlands</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Svuure Clinic</name>
      <address>
        <city>Zaka</city>
        <state>Midlands</state>
        <country>Zimbabwe</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Zimbabwe</country>
  </location_countries>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>July 27, 2017</study_first_submitted>
  <study_first_submitted_qc>July 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2017</study_first_posted>
  <last_update_submitted>October 16, 2018</last_update_submitted>
  <last_update_submitted_qc>October 16, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">October 17, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Kheth'Impilo</investigator_affiliation>
    <investigator_full_name>Dr Nicoletta Mabhena</investigator_full_name>
    <investigator_title>EQUIP Technical Lead</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acquired Immunodeficiency Syndrome</mesh_term>
    <mesh_term>HIV Infections</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03238846
org study id: MMSD Study
secondary id: MRCZ/A/2168
nct id: NCT03238846
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This study aims to evaluate the effectiveness of two strategies for multi-month dispensing
      (MMD) of ART in Community ART Refill Groups (CARGs) on retention, virologic suppression, and
      cost compared to standard of care.

      This study is a three-arm cluster-randomized controlled trial conducted among 5,760 stable
      HIV-positive patients) in Zimbabwe to compare outcomes of three antiretroviral therapy (ART)
      dispensing models. Outcomes of retention in care, virologic suppression, and cost
      effectiveness will be investigated in 30 purposively selected clusters (facilities) which are
      randomized into three arms; standard of care (3 months dispensing at facilities), three-month
      dispensing in CARGs, and six-month dispensing in CARGs. Each study arm will have 10 clusters
      stratified into 2 urban and 8 rural. Study participants will be followed, and outcomes will
      be measured at 12 months and 24 months. Qualitative research will be conducted at baseline,
      12 months, and 24 months (20 participant Focus Group Discussion (FGDs) and 20 provider Key
      Informant Interview (KII) at each interval) to understand patient and health provider
      acceptability of multi-month dispensing of ART within CARGs. Other outcomes of interest
      include measuring gains of facility decongestion and feasibility of multi-month dispensing of
      ART within CARGs. Cost analysis will include comparisons of patient level costs, cost per
      patient outcomes and cost effectiveness across the three study arms.
This study will use a cluster (facility) randomized trial with 3 arms; patients receiving 3
      monthly ART supply at facilities-standard of care (3MF) (Control group), patients receiving 3
      monthly ART supply at newly formed CARGs (3MC) and patients receiving 6 monthly ART supply at
      newly formed CARGs (6MC). Participants will be followed up for 24 months. A total of 30 study
      clusters (facilities) will be randomization, into the three study arms; 10 clusters per arm
      stratified 2 urban, 8 rural.

      Study Setting and study population The study population is HIV-infected adults over the age
      of 18 years recruited from health facilities in U.S. President's Emergency Plan for AIDS
      Relief (PEPFAR) Zimbabwe scale-up districts (using existing national records of patients in
      the ART registers) that have been stable on a standard first-line ART treatment regimen for
      at least 6 months.

      Facilities from Chitungwiza Municipality, Matebeleland South Province, Masvingo Province and
      Mberengwa district will be purposively selected to be the urban/periurban and rural settings
      in the study. These areas were selected as they have PEPFAR Zimbabwe scale-up priority
      facilities, high numbers of patients on ART and have prioritized implementation of CARGs.
      These locations are also viewed to be good representations of PEPFAR Zimbabwe scale-up
      priority facilities, hence are likely to improve the generalizability of the study findings
      to the study population. As contexts differ between rural and urban/periurban settings, it is
      important to determine the effectiveness of MMD within CARGs within both contexts.

      Sampling and Sample size Sample sizes were determined for a cluster-randomized noninferiority
      trial, using PASS v.14 (TM) software. Sample size estimates were calculated for the primary
      outcome of retention in care at 12 months. The probability of patient attrition twelve months
      after study enrolment in the control group (3MF) is assumed to be 5%, derived from the
      relative difference in patient retention between 12 and 24 months from the 2015 Zimbabwe
      UNAIDS Global AIDS Response progress report. An intracluster correlation coefficient (ICC) of
      0.01 for patient retention/attrition amongst stable ART patients is assumed. The
      noninferiority limit is specified as 3.25%. Assuming α=0.05, power of 85%, using one-sided
      Z-test (unpooled) test statistic, 182 participants per facility will be required with a total
      sample size of 5460 participants. A sample size re-estimation during accrual will increase
      the total sample size to approximately 5760; 192 enrolled participants per study site and
      1,920 participants per arm. As retention in care is the primary outcome, no adjustment for
      loss to follow-up needs to be made.

      Study procedures As this is operational research, the study will not interfere with routine
      patient management and will follow national guidelines. The health care worker assesses each
      patient's clinical notes to establish stability and study inclusion. Once informed consent is
      obtained, a baseline questionnaire will be applied to record demographic characteristics and
      the patients clinical and ART history. Patients will receive care based on their study ARM
      and relevant SOP. Patient files and CARG tools will be reviewed and data collected at each
      ART refill. Viral loads will be repeated annually.

      Data Collection The study will use both qualitative and quantitative methods. The data
      sources will include patient clinic notes, electronic patient management system (ePMS), CARG
      monitoring data collection tools. In addition, variables to control for confounding in the
      analysis for outcomes of interest will be collected at baseline through a short
      cross-sectional survey. A pre-and-24-month post survey time-flow evaluation of patient
      waiting times to assess gains of facility decongestion will be conducted. Feasibility of MMD
      of ART within CARGs will be measured prospectively at baseline, 12 and 24 months. To
      understand the acceptability of CARGs by patients and service providers; patient
      satisfaction, and improvement in quality of care at the facilities, 20 patient FGDs and 20
      heath care provider KII will be conducted at baseline, 12 and 24 months. A micro-costing
      approach supplemented by a macro-costing approach of fixed costs will be utilized to measure
      cost outcomes. A resource use form will collect information per patient through retrospective
      review of clinic records. Start up costs will be included under each arm. Data to assess
      patient level costs will be collected from a randomly selected sub-sample of 365 patients per
      arm at baseline, 12 months and 24 months.

      Data analysis Quantitative data will be analyzed using STATA 14. An intention-to-treat
      analysis will be performed for the primary outcome of retention in care, in which all
      patients and clinics will be analyzed in the group to which they were originally assigned.
      Risk differences between arms will be compared with binomial population averaged generalized
      estimating equations using an identity link and an exchangeable correlation matrix,
      specifying for clustering by facility. Viral load suppression analyzed using log-binomial
      regression, generalized estimating equations will be used to estimate risk ratios between the
      study arms, specifying for clustering by facility and using an exchangeable correlation
      matrix. Average patient waiting times will be compared between study arms using linear
      regression.

      Content qualitative analysis will be conducted using Atlas Ti, A cost outcomes analysis will
      be conducted from the provider perspective. Average cost per yield rates (cost per client
      retained in care, cost per client virally suppressed, cost per patient per year) will be
      calculated. An incremental cost-effectiveness ratio (ICER) for the will be calculated; ICER
      threshold comparison as recommended by World Health Organisation (WHO) will be employed.
      Average patient costs will be from the patient's perspective. Startup costs for each service
      delivery model will also be analyzed.

      RISKS / BENEFITS TO PARTICIPANTS There may be no direct benefit to participants who take part
      in this study, beyond benefits related to their routine ART medication that would have been
      achieved otherwise. Information learned in this study may be of benefit to participants and
      others in the future, particularly information that may lead to optimized treatment
      guidelines for HIV-infected stable patients on ART.

      As this is operational research, study procedures are routine clinical care associated with
      minimal risk to participants. All patients will attend routine clinic visits to be assessed
      for new Opportunistic infections (OIs), pregnancy, drug-drug interactions or side effects of
      medications. This will ensure that patients who develop co-morbidities or become pregnant
      during the study receive standard care, although they will not be excluded from the study.

      REIMBURSEMENTS AND COMPENSATION As participants of FGDs may use transport money to the
      discussion venue, this will be reimbursed. Those who are part of a FGD will receive snacks
      after the discussion. CARGs will receive a bag to carry drugs from the clinic back to their
      communities. This will be made clear to all study participants during the informed consent
      process.

      CONFIDENTIALITY ASSURANCES Participant information will not be released without written
      permission to do so except as necessary for review, monitoring, and/or auditing. All
      study-related information will be stored securely. Participant research records will be
      stored in locked areas with access limited to study staff. case record files (CRFs), and
      other documents that may be transmitted off-site will be identified by patient identifier
      only. Likewise, communications between study staff and the investigators regarding individual
      participants will identify participants by patient identifier only. The patient identifier
      will be an anonymized key to identify unique subjects and will be used for data pooling,
      transfer, storage, manipulation and analysis. Personal identifying data will not be available
      to the investigators. Study sites will store study records that bear participant names or
      other personal identifiers separately from records identified by patient identifier. Lists,
      logbooks, appointment books, and any other documents that link the patient identifier to
      personal identifying information at the facilities should be stored in a separate, locked
      location in an area with limited access. Electronic data will be stored on password secured
      servers, which will be backed-up on a regular basis. Data will be presented in aggregate form
      only.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: A prospective, parallel, cluster randomized noninferiority trial with three study arms will be conducted. In this study, a health facility is a cluster or site. Study sites were purposively selected from Chitungwiza Municipality, Masvingo Provincial districts, Matebeleland South Provincial districts, and Mberengwa district where USAID partners are currently implementing CARGs. Thirty clusters were selected and randomized in two strata per geographic location (urban and rural) to the three study arms. Outcomes will be assessed after 12 and 24 months,
primary purpose: Health Services Research
masking: None (Open Label)
measure: Retention in care
time frame: 12 months
description: To determine if stable ART patients receiving 3 monthly dispensing of ART within CARGs have noninferior retention in care than stable ART patients receiving 3 monthly dispensing at health facilities after 12 months.
measure: Retention in care
time frame: 12 months
description: To determine if stable ART patients receiving 6 monthly dispensing of ART within CARGs have noninferior retention in care than stable ART patients receiving 3 monthly dispensing at health facilities after 12 months.
measure: Measure change in retention in care
time frame: 12 and 24 months
description: To determine if stable ART patients within CARGs receiving 6 monthly dispensing of ART have noninferior retention in care than stable ART patients receiving 3 monthly dispensing within CARGs after 12 months
measure: Virologic suppression
time frame: 12 months
description: To determine if stable ART patients receiving 3 and 6 monthly dispensing of ART within CARGs have noninferior viral suppression than stable ART patients receiving 3 monthly dispensing at health facilities after 12 months.
measure: Measure change in virologic suppression
time frame: 12 and 24 months
description: To determine if stable ART patients within CARGs receiving 6 monthly dispensing have noninferior viral suppression than stable ART patients receiving 3 monthly dispensing within CARGs after 12 months and 24 months.
measure: Measure cost effectiveness at 2 time points
time frame: 12 and 24 months
description: To determine the cost-effectiveness of dispensing of ART for three and six months within CARGs compared to three months in facilities (standard of care). Cost-effectiveness will be estimated as the average cost per successful outcome (patient retained at 12 and 24 months)
measure: Measure change in patient level benefits of implementing CARGs
time frame: 12 and 24 months
description: To determine patient-level benefits of implementing CARGs with 3 monthly and 6 monthly dispensing (effects on cost of accessing care, productivity benefits and informal care effects).
measure: Measuring change in feasibility of multi-month dispensing of ART within CARGs
time frame: 12 and 24 months
description: To determine the feasibility of the introduction of multi-month dispensing of ART within CARGs and distribution in Zimbabwe (policy, supply chain management, and implementation).
measure: Measure change in acceptability of CARGs
time frame: 12 and 24 months
description: To determine the acceptability of 3 and 6 monthly dispensing of ART within CARGs by patients and service providers.
measure: Measuring change in gains of facility decongestion
time frame: 12 and 24 months
description: To assess if there are any measurable gains made by decongesting facilities following the introduction of multi-month dispensing of ART within CARGs.
arm group label: 3MF: 3-month ART dispensing at facilities
arm group type: No Intervention
description: Ten sites at which patients will receive standard of care where ART is dispensed three monthly from the facility based on usual practice at the clinic. The approach will be consistent with applicable country guidelines at the time of study.
arm group label: 3MC: 3-month ART dispensing in CARGs
arm group type: Experimental
description: Ten sites at which patients will receive ART dispensed three monthly in CARGs. Providers at facilities will assist in the formation of CARGs and will provide all enrolled patients with a 3 month supply of ART and associated HIV medications. All other aspects of care will be as per standard of care for the enrolling clinic.
arm group label: 6MC: 6-month ART dispensing in CARGs
arm group type: Experimental
description: Ten sites at which patients will receive ART dispensed six monthly in CARGs. Providers at facilities will assist in the formation of CARGs and will provide all enrolled patients with a 6 month supply of ART and associated HIV medications. All other aspects of care will be as per standard of care for the enrolling clinic.
intervention type: Other
intervention name: Three month dispensing of ART in CARGs
description: Patients enrolled in the three-month ART dispensing arm will receive a 90-day supply of ART in CARGs from their provider for the duration of the study. Each CARG will consist of 6-12 stable patients on ART and will meet in the community and select a group member to collect their ART at the facility every 3 months. Patients can have unscheduled clinic visits when unwell. Viral loads for the group will be collected at 12 and 24 months at the facility.
arm group label: 3MC: 3-month ART dispensing in CARGs
intervention type: Other
intervention name: Six month dispensing of ART in CARGs
description: Patients enrolled in the three-month ART dispensing arm will receive a 90-day supply of ART in CARGs from their provider for the duration of the study. Each CARG will consist of 6-12 stable patients on ART and will meet in the community and select a group member to collect their ART at the facility every 6 months. Patients can have unscheduled clinic visits when unwell. Viral loads for the group will be collected at 12 and 24 months at the facility.
arm group label: 6MC: 6-month ART dispensing in CARGs
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nicoletta Ngorima-Mabhena, MBChB, MSc Epidemiology
role: Principal Investigator
affiliation: Kheth'Impilo
facility: 
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country: Zimbabwe
responsible party type: Principal Investigator
investigator affiliation: Kheth'Impilo
investigator full name: Dr Nicoletta Mabhena
investigator title: EQUIP Technical Lead
mesh term: Acquired Immunodeficiency Syndrome
mesh term: HIV Infections
sharing ipd: No