<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/NCT02986802</url>
  </required_header>
  <id_info>
    <org_study_id>CN-16-2669</org_study_id>
    <nct_id>NCT02986802</nct_id>
  </id_info>
  <brief_title>Comparative Effectiveness of Treatment Options for Genital Herpes Infection to Reduce Adverse Pregnancy Outcomes</brief_title>
  <acronym>PCORIHSV</acronym>
  <official_title>Comparative Effectiveness of Treatment Options for Genital Herpes Infection in Pregnant Women to Reduce Adverse Pregnancy Outcomes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Kaiser Permanente</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Patient-Centered Outcomes Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Kaiser Permanente</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Preterm delivery (PTD), together with low birthweight (LBW), is the leading cause of infant&#xD;
      death and illness, affecting 500,000 births with annual medical costs of more than $26&#xD;
      billion in the U.S. each year. Identifying changeable risk factors to reduce PTD is&#xD;
      considered a top research priority. Recent research has shown genital herpes infection (HSV)&#xD;
      is associated with increased risks of PTD and LBW. More importantly, treating this infection,&#xD;
      including infection with no symptoms, using readily available antiviral medications can be&#xD;
      effective in removing the risk due to HSV. Thus, early identification and treatment of HSV in&#xD;
      pregnant women could be an effective way to prevent PTD and LBW. Currently, many pregnant&#xD;
      women with HSV infection, especially those with no symptoms, choose not to treat due to (a) a&#xD;
      lack of demonstrated benefit of treatment and (b) general hesitance to use medications during&#xD;
      pregnancy due to safety concerns for the fetus. Thus, emerging evidence of an increased risk&#xD;
      of PTD/LBW associated with HSV infection, if untreated, and treatment effectiveness by&#xD;
      anti-herpes medications has significantly changed current treatment paradigms among pregnant&#xD;
      women. This evidence also provides new hope that effectively treating HSV infection among&#xD;
      pregnant women, especially before the 3rd trimester, could lead to a new method to reduce PTD&#xD;
      and LBW and reduce racial/ethnic disparities in these risks due to high rates of the&#xD;
      infection in minority groups. To further examine the effectiveness of treating HSV in&#xD;
      pregnant women to reduce adverse pregnancy outcomes, the investigators propose to conduct a&#xD;
      prospective cohort study with a two-stage design combining the large pregnant women&#xD;
      population (N=90,000) in Stage I identified through Kaiser Permanente Northern California&#xD;
      (KPNC) electronic medical records (EMRs), with a Stage II sample to collect detailed&#xD;
      information on additional factors that might muddle our understanding of this issue. This&#xD;
      study will address the following: (1) Does treating HSV infection in pregnant women reduce&#xD;
      the risk of PTD or LBW? (2) Does timing of the treatment during pregnancy influence treatment&#xD;
      effectiveness? (3) Do other factors influence treatment effectiveness? and (4) Does HSV&#xD;
      infection in pregnancy, if untreated, increase the risk of PTD and LBW, compared to no&#xD;
      infection? Answers to these questions will be valuable to pregnant women and clinicians, and&#xD;
      directly address their concerns when making treatment decisions&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Preterm delivery (PTD), along with low birthweight (LBW), is the leading cause of perinatal&#xD;
      mortality and morbidity. In the U.S., 12% of livebirths are PTDs, resulting in more than $26&#xD;
      billion in medical costs annually. The impact on infant health and staggering costs makes PTD&#xD;
      one of the top research priorities of PCORI, AHRQ, the Institute of Medicine (IOM) and the&#xD;
      World Health Organization (WHO), due to a lack of effective interventions to reduce PTD.&#xD;
&#xD;
      Genital herpes infection is prevalent, with a recent WHO estimation of 500 million people&#xD;
      worldwide infected. Treating pregnant women with genital herpes infection, especially before&#xD;
      the 3rd trimester, has been shown to reduce the risk of PTD and LBW, thus it can be an&#xD;
      effective intervention to reduce PTD/LBW. However, the effectiveness and benefit of treating&#xD;
      genital herpes to reduce PTD and LBW needs to be further demonstrated in order to be&#xD;
      incorporated into the treatment decision making process. Currently, many pregnant women&#xD;
      choose not to treat genital herpes due to a general aversion to taking medications during&#xD;
      pregnancy for the safety of their fetuses, and a lack of demonstrated evidence of benefits.&#xD;
      Paradoxically, the choice of no treatment for genital herpes may adversely impact fetal&#xD;
      health, leading to PTD and LBW. Given that pregnant women frequently prefer no treatment,&#xD;
      studies are urgently needed to establish the risk-benefit profile between treatment and no&#xD;
      treatment for genital herpes infection in the context of improving fetal health, including&#xD;
      the timing of treatment (before the 3rd trimester). This study is designed to provide clear&#xD;
      evidence of treatment effectiveness in real-world clinical practice, and risk-benefit&#xD;
      profiles to inform both treatment decisions by pregnant women and clinicians.&#xD;
&#xD;
      Study Aims:&#xD;
&#xD;
      This proposed comparative effectiveness study will address the following questions:&#xD;
&#xD;
        1. Does treating genital herpes infection in pregnant women reduce the risk of adverse&#xD;
           pregnancy outcomes including PTD or LBW? (treated vs. untreated)&#xD;
&#xD;
        2. Does the timing of the treatment during pregnancy influence the treatment effectiveness&#xD;
           on reducing adverse pregnancy outcomes (PTD and LBW)? (head-to-head comparison of&#xD;
           treatment timing: before the 3rd trimester vs. during the 3rd trimester).&#xD;
&#xD;
        3. Do other treatment metrics, including treatment duration, dosage, and compliance, impact&#xD;
           treatment effectiveness in reducing the risk of PTD and LBW?&#xD;
&#xD;
        4. Does treatment effectiveness vary depending on the type (or severity) of underlying&#xD;
           genital herpes infection? (e.g., treating symptomatic genital herpes infection vs.&#xD;
           treating latent/asymptomatic genital herpes)&#xD;
&#xD;
        5. Does genital herpes infection in pregnancy, if untreated, increase the risk of PTD and&#xD;
           LBW, compared to no genital herpes infection? (untreated vs. controls without genital&#xD;
           herpes) In addition, this study is especially relevant in addressing racial disparities,&#xD;
           given that minority pregnant women have higher rates of both genital herpes infection&#xD;
           and PTD: 3 times the infection rate and 150% higher PTD rate among African-Americans&#xD;
           compared to Whites. Thus, demonstrating the effectiveness of treating genital herpes in&#xD;
           reducing PTD could lead to a reduction in the existing racial disparity in PTD rates.&#xD;
&#xD;
      Study Description Overall study design: The investigators will conduct a prospective cohort&#xD;
      study with a two-stage design based on more than 90,000 pregnant KPNC members in real-world&#xD;
      clinical practice. Due to the increased fetal risk of untreated genital herpes infection,&#xD;
      randomizing pregnant women with the infection into treated and untreated groups presents&#xD;
      ethical problems, thus is not feasible. Our innovative two-stage prospective cohort design,&#xD;
      leveraging our large membership and comprehensive electronic medical record (EMR) data, is a&#xD;
      robust alternative option for examining the comparative effectiveness of treating genital&#xD;
      herpes infection in pregnant women to reduce PTD and LBW.&#xD;
&#xD;
      Comparators: Three comparisons will be made:&#xD;
&#xD;
        1. When assessing treatment effectiveness, women with the infection who choose not to&#xD;
           receive treatment will serve as the comparator (untreated). This comparator is a&#xD;
           frequently preferred treatment option chosen by pregnant women due to their reluctance&#xD;
           to use medications during pregnancy, based on their predominant concerns for the safety&#xD;
           of their developing fetus as well as a lack of evidence that treating genital herpes&#xD;
           infection is beneficial to their fetus. This comparator will also make the comparison&#xD;
           groups more comparable by controlling for confounding by indication.&#xD;
&#xD;
        2. When assessing the timing of treatment effectiveness (before vs. after the start of the&#xD;
           3rd trimester), those who receive treatment during the 3rd trimester will be used as the&#xD;
           comparator. Using this comparator will allow a head-to-head comparison between the&#xD;
           timing of the treatment.&#xD;
&#xD;
        3. When assessing the effect of choosing not to treat during pregnancy, women without an&#xD;
           underlying genital herpes infection or receipt of any treatment will serve as the&#xD;
           comparator (normal controls). This comparison will provide evidence of the increased&#xD;
           risk of PTD and LBW if genital herpes infection is not treated during pregnancy.&#xD;
&#xD;
      Our comparators will allow us to control for confounding by indication (genital herpes, its&#xD;
      type and severity). Our EMR contains extensive questions on risk factors, including lifestyle&#xD;
      factors, for all 90,000 mother-infant dyads. Through the unique two-stage study design,&#xD;
      investigators will collect additional information, through interviews, on a subsample of&#xD;
      women that will further allow controlling for additional confounders. Multiple statistical&#xD;
      methodologies, in accordance with PCORI's methodology standards, will be employed in the&#xD;
      analytic plan (e.g., propensity scores, instrumental variable methods) to ensure&#xD;
      compatibility between comparison groups.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 14, 2017</start_date>
  <completion_date type="Actual">February 28, 2021</completion_date>
  <primary_completion_date type="Actual">October 15, 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Preterm Delivery</measure>
    <time_frame>Up to 37 weeks</time_frame>
    <description>Participants who gave birth before 37 completed weeks of gestation</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With a Low Birthweight Child</measure>
    <time_frame>Through the end of pregnancy, an average of 40 weeks</time_frame>
    <description>Women having a child born with birthweight &lt;2500 grams</description>
  </primary_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Actual">89132</enrollment>
  <condition>HSV-2 Infection</condition>
  <condition>PreTerm Birth</condition>
  <condition>Pregnancy Complications</condition>
  <arm_group>
    <arm_group_label>Genital herpes treated before third trimester</arm_group_label>
    <description>Women with genital herpes receiving treatment before the 3rd trimester</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Genital herpes treated only during third trimester</arm_group_label>
    <description>Women with genital herpes receiving treatment during the 3rd trimester</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Genital herpes untreated</arm_group_label>
    <description>Women with untreated genital herpes</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <description>Women (controls) with neither genital herpes nor treatment</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Pregnant Kaiser Permanente Northern California members&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Kaiser Permanente Northern California members&#xD;
&#xD;
          -  Pregnant women&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Non Kaiser Permanente Northern California members&#xD;
&#xD;
          -  Non pregnant women&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>De-Kun Li, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Kaiser Permanente</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Division of Research</name>
      <address>
        <city>Oakland</city>
        <state>California</state>
        <zip>94612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>December 6, 2016</study_first_submitted>
  <study_first_submitted_qc>December 6, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 8, 2016</study_first_posted>
  <results_first_submitted>June 28, 2021</results_first_submitted>
  <results_first_submitted_qc>August 23, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">September 17, 2021</results_first_posted>
  <last_update_submitted>August 23, 2021</last_update_submitted>
  <last_update_submitted_qc>August 23, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 17, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Communicable Diseases</mesh_term>
    <mesh_term>Herpes Genitalis</mesh_term>
    <mesh_term>Herpesviridae Infections</mesh_term>
    <mesh_term>Premature Birth</mesh_term>
    <mesh_term>Pregnancy Complications</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 30, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/02/NCT02986802/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Genital Herpes Treated Before Third Trimester</title>
          <description>Women with genital herpes receiving treatment before the 3rd trimester</description>
        </group>
        <group group_id="P2">
          <title>Genital Herpes Treated Only During Third Trimester</title>
          <description>Women with genital herpes receiving treatment during the 3rd trimester</description>
        </group>
        <group group_id="P3">
          <title>Genital Herpes Untreated</title>
          <description>Women with untreated genital herpes</description>
        </group>
        <group group_id="P4">
          <title>Control Group</title>
          <description>Women (controls) with neither genital herpes nor treatment</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="1360"/>
                <participants group_id="P2" count="2839"/>
                <participants group_id="P3" count="1873"/>
                <participants group_id="P4" count="83060"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1360"/>
                <participants group_id="P2" count="2839"/>
                <participants group_id="P3" count="1873"/>
                <participants group_id="P4" count="83060"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Genital Herpes Treated Before Third Trimester</title>
          <description>Women with genital herpes receiving treatment before the 3rd trimester</description>
        </group>
        <group group_id="B2">
          <title>Genital Herpes Treated Only During Third Trimester</title>
          <description>Women with genital herpes receiving treatment during the 3rd trimester</description>
        </group>
        <group group_id="B3">
          <title>Genital Herpes Untreated</title>
          <description>Women with untreated genital herpes</description>
        </group>
        <group group_id="B4">
          <title>Control Group</title>
          <description>Women (controls) with neither genital herpes nor treatment</description>
        </group>
        <group group_id="B5">
          <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="1360"/>
            <count group_id="B2" value="2839"/>
            <count group_id="B3" value="1873"/>
            <count group_id="B4" value="83060"/>
            <count group_id="B5" value="89132"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Age (years)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="1360"/>
                    <count group_id="B2" value="2839"/>
                    <count group_id="B3" value="1873"/>
                    <count group_id="B4" value="83060"/>
                    <count group_id="B5" value="89132"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>18-24</title>
                  <measurement_list>
                    <measurement group_id="B1" value="149"/>
                    <measurement group_id="B2" value="250"/>
                    <measurement group_id="B3" value="152"/>
                    <measurement group_id="B4" value="9170"/>
                    <measurement group_id="B5" value="9721"/>
                  </measurement_list>
                </category>
                <category>
                  <title>25-29</title>
                  <measurement_list>
                    <measurement group_id="B1" value="278"/>
                    <measurement group_id="B2" value="625"/>
                    <measurement group_id="B3" value="399"/>
                    <measurement group_id="B4" value="21155"/>
                    <measurement group_id="B5" value="22457"/>
                  </measurement_list>
                </category>
                <category>
                  <title>30-34</title>
                  <measurement_list>
                    <measurement group_id="B1" value="431"/>
                    <measurement group_id="B2" value="986"/>
                    <measurement group_id="B3" value="595"/>
                    <measurement group_id="B4" value="30900"/>
                    <measurement group_id="B5" value="32912"/>
                  </measurement_list>
                </category>
                <category>
                  <title>≥35</title>
                  <measurement_list>
                    <measurement group_id="B1" value="502"/>
                    <measurement group_id="B2" value="978"/>
                    <measurement group_id="B3" value="727"/>
                    <measurement group_id="B4" value="21835"/>
                    <measurement group_id="B5" value="24042"/>
                  </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="1360"/>
                    <count group_id="B2" value="2839"/>
                    <count group_id="B3" value="1873"/>
                    <count group_id="B4" value="83060"/>
                    <count group_id="B5" value="89132"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1360"/>
                    <measurement group_id="B2" value="2839"/>
                    <measurement group_id="B3" value="1873"/>
                    <measurement group_id="B4" value="83060"/>
                    <measurement group_id="B5" value="89132"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>White</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="1360"/>
                    <count group_id="B2" value="2839"/>
                    <count group_id="B3" value="1873"/>
                    <count group_id="B4" value="83060"/>
                    <count group_id="B5" value="89132"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="633"/>
                    <measurement group_id="B2" value="1338"/>
                    <measurement group_id="B3" value="758"/>
                    <measurement group_id="B4" value="28887"/>
                    <measurement group_id="B5" value="31616"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="1360"/>
                    <count group_id="B2" value="2839"/>
                    <count group_id="B3" value="1873"/>
                    <count group_id="B4" value="83060"/>
                    <count group_id="B5" value="89132"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="116"/>
                    <measurement group_id="B2" value="331"/>
                    <measurement group_id="B3" value="232"/>
                    <measurement group_id="B4" value="22591"/>
                    <measurement group_id="B5" value="23270"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>African American</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="1360"/>
                    <count group_id="B2" value="2839"/>
                    <count group_id="B3" value="1873"/>
                    <count group_id="B4" value="83060"/>
                    <count group_id="B5" value="89132"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="217"/>
                    <measurement group_id="B2" value="381"/>
                    <measurement group_id="B3" value="299"/>
                    <measurement group_id="B4" value="4660"/>
                    <measurement group_id="B5" value="5557"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hispanic</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="1360"/>
                    <count group_id="B2" value="2839"/>
                    <count group_id="B3" value="1873"/>
                    <count group_id="B4" value="83060"/>
                    <count group_id="B5" value="89132"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="302"/>
                    <measurement group_id="B2" value="615"/>
                    <measurement group_id="B3" value="460"/>
                    <measurement group_id="B4" value="22026"/>
                    <measurement group_id="B5" value="23403"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Other/multiple/unknown</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="1360"/>
                    <count group_id="B2" value="2839"/>
                    <count group_id="B3" value="1873"/>
                    <count group_id="B4" value="83060"/>
                    <count group_id="B5" value="89132"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="92"/>
                    <measurement group_id="B2" value="174"/>
                    <measurement group_id="B3" value="124"/>
                    <measurement group_id="B4" value="4896"/>
                    <measurement group_id="B5" value="5286"/>
                  </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 States</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="1360"/>
                    <count group_id="B2" value="2839"/>
                    <count group_id="B3" value="1873"/>
                    <count group_id="B4" value="83060"/>
                    <count group_id="B5" value="89132"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1360"/>
                    <measurement group_id="B2" value="2839"/>
                    <measurement group_id="B3" value="1873"/>
                    <measurement group_id="B4" value="83060"/>
                    <measurement group_id="B5" value="89132"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Parity</title>
          <population>Women who were missing parity data are not included.</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="1345"/>
                    <count group_id="B2" value="2798"/>
                    <count group_id="B3" value="1808"/>
                    <count group_id="B4" value="82257"/>
                    <count group_id="B5" value="88208"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>0</title>
                  <measurement_list>
                    <measurement group_id="B1" value="639"/>
                    <measurement group_id="B2" value="1249"/>
                    <measurement group_id="B3" value="664"/>
                    <measurement group_id="B4" value="38369"/>
                    <measurement group_id="B5" value="40921"/>
                  </measurement_list>
                </category>
                <category>
                  <title>1</title>
                  <measurement_list>
                    <measurement group_id="B1" value="428"/>
                    <measurement group_id="B2" value="954"/>
                    <measurement group_id="B3" value="659"/>
                    <measurement group_id="B4" value="27965"/>
                    <measurement group_id="B5" value="30006"/>
                  </measurement_list>
                </category>
                <category>
                  <title>2 or more</title>
                  <measurement_list>
                    <measurement group_id="B1" value="278"/>
                    <measurement group_id="B2" value="595"/>
                    <measurement group_id="B3" value="485"/>
                    <measurement group_id="B4" value="15923"/>
                    <measurement group_id="B5" value="17281"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Preterm Delivery</title>
        <description>Participants who gave birth before 37 completed weeks of gestation</description>
        <time_frame>Up to 37 weeks</time_frame>
        <population>Women who could not be classified into any of the designed Arms/Groups as listed due to their starting treatment too late for examining preterm delivery (&lt; 37 weeks of gestation) were considered as ineligible and therefore excluded from the analyses related to preterm delivery. They did not contribute to the results or conclusions related to preterm delivery.</population>
        <group_list>
          <group group_id="O1">
            <title>Genital Herpes Treated Before Third Trimester</title>
            <description>Women with genital herpes receiving treatment before the 3rd trimester</description>
          </group>
          <group group_id="O2">
            <title>Genital Herpes Treated Only During Third Trimester</title>
            <description>Women with genital herpes receiving treatment during the 3rd trimester</description>
          </group>
          <group group_id="O3">
            <title>Genital Herpes Untreated</title>
            <description>Women with untreated genital herpes</description>
          </group>
          <group group_id="O4">
            <title>Control Group</title>
            <description>Women (controls) with neither genital herpes nor treatment</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Preterm Delivery</title>
          <description>Participants who gave birth before 37 completed weeks of gestation</description>
          <population>Women who could not be classified into any of the designed Arms/Groups as listed due to their starting treatment too late for examining preterm delivery (&lt; 37 weeks of gestation) were considered as ineligible and therefore excluded from the analyses related to preterm delivery. They did not contribute to the results or conclusions related to preterm delivery.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1360"/>
                <count group_id="O2" value="1411"/>
                <count group_id="O3" value="1873"/>
                <count group_id="O4" value="83060"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Preterm</title>
                  <measurement_list>
                    <measurement group_id="O1" value="100"/>
                    <measurement group_id="O2" value="83"/>
                    <measurement group_id="O3" value="247"/>
                    <measurement group_id="O4" value="5407"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Preterm</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1260"/>
                    <measurement group_id="O2" value="1328"/>
                    <measurement group_id="O3" value="1626"/>
                    <measurement group_id="O4" value="77653"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With a Low Birthweight Child</title>
        <description>Women having a child born with birthweight &lt;2500 grams</description>
        <time_frame>Through the end of pregnancy, an average of 40 weeks</time_frame>
        <population>Participants with birth weight data were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Genital Herpes Treated Before Third Trimester</title>
            <description>Women with genital herpes receiving treatment before the 3rd trimester</description>
          </group>
          <group group_id="O2">
            <title>Genital Herpes Treated Only During Third Trimester</title>
            <description>Women with genital herpes receiving treatment during the 3rd trimester</description>
          </group>
          <group group_id="O3">
            <title>Genital Herpes Untreated</title>
            <description>Women with untreated genital herpes</description>
          </group>
          <group group_id="O4">
            <title>Control Group</title>
            <description>Women (controls) with neither genital herpes nor treatment</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With a Low Birthweight Child</title>
          <description>Women having a child born with birthweight &lt;2500 grams</description>
          <population>Participants with birth weight data were included.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1353"/>
                <count group_id="O2" value="2829"/>
                <count group_id="O3" value="1845"/>
                <count group_id="O4" value="83052"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Low Birth Weight</title>
                  <measurement_list>
                    <measurement group_id="O1" value="66"/>
                    <measurement group_id="O2" value="59"/>
                    <measurement group_id="O3" value="153"/>
                    <measurement group_id="O4" value="4068"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Low Birth Weight</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1287"/>
                    <measurement group_id="O2" value="2770"/>
                    <measurement group_id="O3" value="1692"/>
                    <measurement group_id="O4" value="78984"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Through the end of pregnancy, an average of 40 weeks.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Genital Herpes Treated Before Third Trimester</title>
          <description>Women with genital herpes receiving treatment before the 3rd trimester</description>
        </group>
        <group group_id="E2">
          <title>Genital Herpes Treated Only During Third Trimester</title>
          <description>Women with genital herpes receiving treatment during the 3rd trimester</description>
        </group>
        <group group_id="E3">
          <title>Genital Herpes Untreated</title>
          <description>Women with untreated genital herpes</description>
        </group>
        <group group_id="E4">
          <title>Control Group</title>
          <description>Women (controls) with neither genital herpes nor treatment</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="1360"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2839"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1873"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="83060"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="1360"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2839"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1873"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="83060"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="1360"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2839"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1873"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="83060"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>De-Kun Li, MD, PhD</name_or_title>
      <organization>Kaiser Permanente Division of Research</organization>
      <phone>510.891.3755</phone>
      <email>De-Kun.Li@kp.org</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/NCT02986802
org study id: CN-16-2669
nct id: NCT02986802
lead sponsor: 
collaborator: 
has dmc: No
Preterm delivery (PTD), together with low birthweight (LBW), is the leading cause of infant
      death and illness, affecting 500,000 births with annual medical costs of more than $26
      billion in the U.S. each year. Identifying changeable risk factors to reduce PTD is
      considered a top research priority. Recent research has shown genital herpes infection (HSV)
      is associated with increased risks of PTD and LBW. More importantly, treating this infection,
      including infection with no symptoms, using readily available antiviral medications can be
      effective in removing the risk due to HSV. Thus, early identification and treatment of HSV in
      pregnant women could be an effective way to prevent PTD and LBW. Currently, many pregnant
      women with HSV infection, especially those with no symptoms, choose not to treat due to (a) a
      lack of demonstrated benefit of treatment and (b) general hesitance to use medications during
      pregnancy due to safety concerns for the fetus. Thus, emerging evidence of an increased risk
      of PTD/LBW associated with HSV infection, if untreated, and treatment effectiveness by
      anti-herpes medications has significantly changed current treatment paradigms among pregnant
      women. This evidence also provides new hope that effectively treating HSV infection among
      pregnant women, especially before the 3rd trimester, could lead to a new method to reduce PTD
      and LBW and reduce racial/ethnic disparities in these risks due to high rates of the
      infection in minority groups. To further examine the effectiveness of treating HSV in
      pregnant women to reduce adverse pregnancy outcomes, the investigators propose to conduct a
      prospective cohort study with a two-stage design combining the large pregnant women
      population (N=90,000) in Stage I identified through Kaiser Permanente Northern California
      (KPNC) electronic medical records (EMRs), with a Stage II sample to collect detailed
      information on additional factors that might muddle our understanding of this issue. This
      study will address the following: (1) Does treating HSV infection in pregnant women reduce
      the risk of PTD or LBW? (2) Does timing of the treatment during pregnancy influence treatment
      effectiveness? (3) Do other factors influence treatment effectiveness? and (4) Does HSV
      infection in pregnancy, if untreated, increase the risk of PTD and LBW, compared to no
      infection? Answers to these questions will be valuable to pregnant women and clinicians, and
      directly address their concerns when making treatment decisions
Preterm delivery (PTD), along with low birthweight (LBW), is the leading cause of perinatal
      mortality and morbidity. In the U.S., 12% of livebirths are PTDs, resulting in more than $26
      billion in medical costs annually. The impact on infant health and staggering costs makes PTD
      one of the top research priorities of PCORI, AHRQ, the Institute of Medicine (IOM) and the
      World Health Organization (WHO), due to a lack of effective interventions to reduce PTD.

      Genital herpes infection is prevalent, with a recent WHO estimation of 500 million people
      worldwide infected. Treating pregnant women with genital herpes infection, especially before
      the 3rd trimester, has been shown to reduce the risk of PTD and LBW, thus it can be an
      effective intervention to reduce PTD/LBW. However, the effectiveness and benefit of treating
      genital herpes to reduce PTD and LBW needs to be further demonstrated in order to be
      incorporated into the treatment decision making process. Currently, many pregnant women
      choose not to treat genital herpes due to a general aversion to taking medications during
      pregnancy for the safety of their fetuses, and a lack of demonstrated evidence of benefits.
      Paradoxically, the choice of no treatment for genital herpes may adversely impact fetal
      health, leading to PTD and LBW. Given that pregnant women frequently prefer no treatment,
      studies are urgently needed to establish the risk-benefit profile between treatment and no
      treatment for genital herpes infection in the context of improving fetal health, including
      the timing of treatment (before the 3rd trimester). This study is designed to provide clear
      evidence of treatment effectiveness in real-world clinical practice, and risk-benefit
      profiles to inform both treatment decisions by pregnant women and clinicians.

      Study Aims:

      This proposed comparative effectiveness study will address the following questions:

        1. Does treating genital herpes infection in pregnant women reduce the risk of adverse
           pregnancy outcomes including PTD or LBW? (treated vs. untreated)

        2. Does the timing of the treatment during pregnancy influence the treatment effectiveness
           on reducing adverse pregnancy outcomes (PTD and LBW)? (head-to-head comparison of
           treatment timing: before the 3rd trimester vs. during the 3rd trimester).

        3. Do other treatment metrics, including treatment duration, dosage, and compliance, impact
           treatment effectiveness in reducing the risk of PTD and LBW?

        4. Does treatment effectiveness vary depending on the type (or severity) of underlying
           genital herpes infection? (e.g., treating symptomatic genital herpes infection vs.
           treating latent/asymptomatic genital herpes)

        5. Does genital herpes infection in pregnancy, if untreated, increase the risk of PTD and
           LBW, compared to no genital herpes infection? (untreated vs. controls without genital
           herpes) In addition, this study is especially relevant in addressing racial disparities,
           given that minority pregnant women have higher rates of both genital herpes infection
           and PTD: 3 times the infection rate and 150% higher PTD rate among African-Americans
           compared to Whites. Thus, demonstrating the effectiveness of treating genital herpes in
           reducing PTD could lead to a reduction in the existing racial disparity in PTD rates.

      Study Description Overall study design: The investigators will conduct a prospective cohort
      study with a two-stage design based on more than 90,000 pregnant KPNC members in real-world
      clinical practice. Due to the increased fetal risk of untreated genital herpes infection,
      randomizing pregnant women with the infection into treated and untreated groups presents
      ethical problems, thus is not feasible. Our innovative two-stage prospective cohort design,
      leveraging our large membership and comprehensive electronic medical record (EMR) data, is a
      robust alternative option for examining the comparative effectiveness of treating genital
      herpes infection in pregnant women to reduce PTD and LBW.

      Comparators: Three comparisons will be made:

        1. When assessing treatment effectiveness, women with the infection who choose not to
           receive treatment will serve as the comparator (untreated). This comparator is a
           frequently preferred treatment option chosen by pregnant women due to their reluctance
           to use medications during pregnancy, based on their predominant concerns for the safety
           of their developing fetus as well as a lack of evidence that treating genital herpes
           infection is beneficial to their fetus. This comparator will also make the comparison
           groups more comparable by controlling for confounding by indication.

        2. When assessing the timing of treatment effectiveness (before vs. after the start of the
           3rd trimester), those who receive treatment during the 3rd trimester will be used as the
           comparator. Using this comparator will allow a head-to-head comparison between the
           timing of the treatment.

        3. When assessing the effect of choosing not to treat during pregnancy, women without an
           underlying genital herpes infection or receipt of any treatment will serve as the
           comparator (normal controls). This comparison will provide evidence of the increased
           risk of PTD and LBW if genital herpes infection is not treated during pregnancy.

      Our comparators will allow us to control for confounding by indication (genital herpes, its
      type and severity). Our EMR contains extensive questions on risk factors, including lifestyle
      factors, for all 90,000 mother-infant dyads. Through the unique two-stage study design,
      investigators will collect additional information, through interviews, on a subsample of
      women that will further allow controlling for additional confounders. Multiple statistical
      methodologies, in accordance with PCORI's methodology standards, will be employed in the
      analytic plan (e.g., propensity scores, instrumental variable methods) to ensure
      compatibility between comparison groups.
observational model: Cohort
time perspective: Prospective
measure: Number of Participants With Preterm Delivery
time frame: Up to 37 weeks
description: Participants who gave birth before 37 completed weeks of gestation
measure: Number of Participants With a Low Birthweight Child
time frame: Through the end of pregnancy, an average of 40 weeks
description: Women having a child born with birthweight <2500 grams
arm group label: Genital herpes treated before third trimester
description: Women with genital herpes receiving treatment before the 3rd trimester
arm group label: Genital herpes treated only during third trimester
description: Women with genital herpes receiving treatment during the 3rd trimester
arm group label: Genital herpes untreated
description: Women with untreated genital herpes
arm group label: Control group
description: Women (controls) with neither genital herpes nor treatment
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: De-Kun Li, MD
role: Principal Investigator
affiliation: Kaiser Permanente
facility: 
country: United States
responsible party type: Sponsor
mesh term: Infections
mesh term: Communicable Diseases
mesh term: Herpes Genitalis
mesh term: Herpesviridae Infections
mesh term: Premature Birth
mesh term: Pregnancy Complications
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 