<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/NCT02245022</url>
  </required_header>
  <id_info>
    <org_study_id>PK12</org_study_id>
    <nct_id>NCT02245022</nct_id>
  </id_info>
  <brief_title>Safety and Pharmacokinetics of Dolutegravir in Pregnant HIV Mothers and Their Neonates: A Pilot Study</brief_title>
  <acronym>DolPHIN1</acronym>
  <official_title>Safety and Pharmacokinetics of Dolutegravir in Pregnant HIV Mothers and Their Neonates: A Pilot Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Liverpool</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>ViiV Healthcare</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Makerere University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Liverpool</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>
      Aim: To evaluate dolutegravir (DTG) pharmacokinetics in pregnant HIV-infected women&#xD;
&#xD;
      Rationale: In developing countries many women present with a new HIV diagnosis in late&#xD;
      pregnancy, and are at high risk of transmitting infection during delivery. Moreover, women&#xD;
      may acquire NNRTI resistance from primary transmission, or use of nevirapine (NVP) in&#xD;
      previous pregnancies. In these circumstances, DTG is likely to be more effective in reducing&#xD;
      mother to child transmission of HIV than NNRTI-based regimens.&#xD;
&#xD;
      Study design: HIV positive pregnant women presenting with untreated HIV infection in late&#xD;
      (≥28 -36 weeks gestation) pregnancy will be randomised 1:1 to receive DTG (50mg once daily)&#xD;
      or standard of care (nevirapine or efavirenz) + 2 NRTIs. PK (0-24h) profile will be sampled&#xD;
      in third trimester and post-partum.&#xD;
&#xD;
      Although this is primarily a PK study (and has been powered as such) randomisation is&#xD;
      included to allow comparison of plasma HIV VL responses against standard of care (NVP or EFV)&#xD;
      and is essential for evaluation of secondary endpoints of safety and efficacy of DTG in&#xD;
      pregnancy.&#xD;
&#xD;
      Number recruited N=30 per group&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Antiretroviral therapy (ART) in pregnancy is able to effectively reduce mother-to-child&#xD;
      transmission (MTCT) of HIV. If untreated, the risk of transmission is around 25% (greater&#xD;
      with high viral loads) but ART administered optimally during pregnancy may reduce this risk&#xD;
      to 1-2%. In order to successfully prevent infection, ART should be started in the first or&#xD;
      second trimester, and should reduce maternal plasma viral load to undetectable levels.&#xD;
      Unfortunately throughout low-middle income countries, MTCT rates are unacceptably high with&#xD;
      an estimated 430 000 newborn children infected annually. The main causes for this are&#xD;
      undiagnosed or late diagnosis of maternal infection, suboptimal adherence to therapy and drug&#xD;
      resistance, particularly in mothers who have previously received single dose nevirapine.&#xD;
&#xD;
      In sub-Saharan Africa (SSA), women frequently engage with health services late in pregnancy,&#xD;
      and new HIV diagnoses in the third trimester (≥28 weeks of pregnancy) are not uncommon. Risk&#xD;
      of MTCT is high, especially as NNRTI-based therapy takes a median of 2 months to&#xD;
      significantly reduce the HIV viral load, making it unlikely that commencement of these drugs&#xD;
      in late pregnancy will offer protection of the infant from intrapartum transmission.&#xD;
&#xD;
      Vertical transmission of HIV remains a significant challenge in developing countries and&#xD;
      antiretroviral prophylaxis for PMTCT is an important tool towards elimination of paediatric&#xD;
      infections. Between 2009 and 2010, coverage of antiretroviral prophylaxis for prevention of&#xD;
      mother to child transmission was 42% and an estimated 1.48 million infants were born to women&#xD;
      living with HIV (WHO 2010). Global efforts are geared towards improving access to&#xD;
      antiretrovirals for PMTCT by simplifying antiretroviral treatment protocols while ensuring&#xD;
      optimal outcomes for HIV-infected women and their children (WHO 2010; WHO 2012).&#xD;
&#xD;
      Under consolidated antiretroviral guidelines issued by the WHO in 2013, efavirenz-based ART&#xD;
      is now recommended the preferred NNRTI option for HIV-1 infected patients, including among&#xD;
      women of childbearing age and pregnant women (WHO 2013). In 2012, Uganda adopted the Option&#xD;
      B+ strategy for PMTCT of HIV. Under this strategy, lifelong ART is offered to all pregnant&#xD;
      ART naïve women irrespective of CD4 count with efavirenz-based ART as the preferred treatment&#xD;
      option. However, the effectiveness of this regimen could be compromised in the event of large&#xD;
      populations of women who may have been either exposed to single dose nevirapine in the past&#xD;
      or among women with transmitted NNRTI resistance.&#xD;
&#xD;
      The justification for studying DTG in pregnancy includes:&#xD;
&#xD;
        1. Likely widespread availability of generic DTG in the coming years. The manufacturer has&#xD;
           indicated its willingness to make DTG available in low income countries, and is&#xD;
           currently engaging with generic manufacturers. Estimates from the Clinton Foundation&#xD;
           suggest that generic manufacture of DTG will make this drug affordable either as an&#xD;
           alternative first line, or else second line agent (Hill 2013). Clinical guidelines from&#xD;
           the US and Europe currently rank INSTIs such as raltegravir and elvitegravir alongside&#xD;
           NNRTIs as preferred first line agents. INSTIs may replace NNRTIs in first line regimens&#xD;
           due to their good safety and toxicity profile, lower propensity for drug interactions,&#xD;
           and superior efficacy. Large phase III RCTs comparing raltegravir (Rockstroh, Dejesus et&#xD;
           al. 2013), elvitegravir (Sax, DeJesus et al. 2012) and dolutegravir (van Lunzen,&#xD;
           Maggiolo et al. 2012) against efavirenz-based therapy have shown superior virological&#xD;
           outcome at 48 weeks, faster time to undetectable viral load, lower incidence of adverse&#xD;
           events, and fewer treatment discontinuations, and these findings have recently been&#xD;
           confirmed in a meta-analysis (Messiaen, Wensing et al. 2013).&#xD;
&#xD;
        2. Low risk for serious drug-drug interactions. The potential for drug-drug interactions is&#xD;
           significantly less for INSTIs compared with other antiretrovirals (relative risk&#xD;
           compared with raltegravir: boosted protease inhibitors [RR = 4.96], non-nucleoside&#xD;
           reverse transcriptase inhibitors [RR = 2.48](Patel, Abdelsayed et al. 2011). These are&#xD;
           particularly important considerations for low/middle income country settings where&#xD;
           adults with newly diagnosed HIV infection often present with tuberculosis, or during&#xD;
           antenatal screening in late pregnancy. Here DTG may carry significant advantages over&#xD;
           NNRTIs, and other INSTIs. In the absence of alternatives to rifampicin-based TB therapy,&#xD;
           DTG and raltegravir exposures are only moderately reduced (Dooley, Sayre et al. 2013),&#xD;
           compared to larger (50-90%) reductions in concentrations of boosted PIs, nevirapine and&#xD;
           elvitegravir. Dolutegravir is metabolized by glucuronidation (UGT1A1) with some&#xD;
           contribution from CYP3A.&#xD;
&#xD;
        3. Rapid viral load drop potentially beneficial in late diagnosis during pregnancy. In&#xD;
           Sub-Saharan Africa, pregnant mothers tend to engage with health services later in&#xD;
           pregnancy compared with Europe, and new HIV diagnoses resulting from universal testing&#xD;
           at ≥28w gestation are frequent. DTG results in a very rapid reduction in viral load;&#xD;
           median time to undetectable viral load in the SINGLE study was 28 days vs. 84 days with&#xD;
           Atripla (P&lt;0.0001) (Walmsley, Antela et al. 2012). Use of DTG may lower risk of&#xD;
           mother-to-child transmission of HIV in late presenters. Although meta-analysis shows no&#xD;
           increase in birth defects with maternal efavirenz (Ford, Mofenson et al. 2010), there&#xD;
           has been recent suspicion of neurological toxicity in a large French registry (Sibiude,&#xD;
           Madelbrot et al. 2013) and neurodevelopmental delay in a South African cohort&#xD;
           (Westreich, Rubel et al. 2010)&#xD;
&#xD;
        4. Proven efficacy in patients with established drug resistance to other antiretrovirals.&#xD;
           In most resource-poor settings, options for anti-retroviral therapy are limited (2011),&#xD;
           and the emergence of HIV drug resistance gives cause for concern (Hedt, Wadonda-Kabondo&#xD;
           et al. 2008; WHO 2012). In a cross-sectional study conducted among HIV-1 antiretroviral&#xD;
           naïve patients in five African countries, the highest prevalence of transmitted&#xD;
           resistance was observed in Kampala, Uganda 12.3% (22 of 179; 7.5-17.1) (Hamers, Wallis&#xD;
           et al. 2011). In Malawi, the prevalence of primary drug resistance in new infections was&#xD;
           6.1% which is comparable with figures of ~3% for South Africa (Manasa, Katzenstein et&#xD;
           al. 2012), and 5.7% for Zambia (Hamers, Siwale et al. 2010), with over half of all&#xD;
           mutations conferring resistance to non-nucleoside reverse transcriptases (NNRTI)&#xD;
           (Wadonda-Kabondo, Banda et al. 2012). Studies across Africa have shown that treatment&#xD;
           response to NNRTIs in mothers and children exposed to nevirapine (particularly single&#xD;
           dose) during pregnancy is blunted (Musiime, Ssali et al. 2009). In this context, a novel&#xD;
           class of ARV which is safe, affordable and effective is an urgent need&#xD;
&#xD;
        5. Safety profile in pregnancy. DTG is classified as FDA pregnancy Category B. There are no&#xD;
           adequate and well-controlled studies in pregnant women. Because animal reproduction&#xD;
           studies are not always predictive of human response, and dolutegravir was shown to cross&#xD;
           the placenta in animal studies, the manufacturer recommends that this drug should be&#xD;
           used during pregnancy only if clearly needed (ViiV 2013).&#xD;
&#xD;
        6. Necessity of investigating DTG PK in pregnant women. Alongside the clinical and&#xD;
           humanitarian imperative to provide effective treatment for preventing HIV transmission&#xD;
           in pregnant mothers with NNRTI-resistant HIV, there is an equally important ethical&#xD;
           imperative to establish the safety, efficacy and pharmacokinetics of DTG in pregnant&#xD;
           mothers and their breastfed infants in SSA, especially given the implementation of WHO&#xD;
           Option B+, and the potential for widespread use of DTG in the forseeable future.&#xD;
           Previous experience suggests it is universally the case that pregnant women in SSA&#xD;
           receive new antiretrovirals (ARV) ahead of any proper evaluation, and clinical studies&#xD;
           (if undertaken at all) occur at a much later stage after many mothers and infants have&#xD;
           been exposed.&#xD;
&#xD;
        7. Importance of undertaking the study in SSA. Any pivotal study if undertaken in developed&#xD;
           countries would have limited generalizability to an African setting because i) ARVs tend&#xD;
           to be initiated later in gestation in newly presenting pregnant women, ii) the standard&#xD;
           of care across SSA is likely to be an efavirenz or nevirapine-based regimen iii) infant&#xD;
           breastfeeding is recommended in the presence of ARVs ii) host factors such as BMI,&#xD;
           ethnicity etc may impact on pharmacokinetics (PK) of ARVs.&#xD;
&#xD;
        8. Continued administration of DTG for 2 weeks post-partum (whilst breastfeeding) to&#xD;
           characterize PK in non-pregnant state. Under standard of care, the infant will receive 6&#xD;
           weeks of nevirapine syrup, and would be exposed to the NNRTI/NRTI/NRTI combination&#xD;
           received by the mother under standard of care. In this study, infants will be exposed&#xD;
           DTG via the breastmilk for a 2 week period following birth. We believe this risk to be&#xD;
           acceptable given the potential benefits. Furthermore, the risk is unlikely to exceed any&#xD;
           potential risk of in utero exposure to DTG. Drug-drug interactions between directly&#xD;
           administered NVP and DTG ingested via the breastmilk are unlikely to have clinical&#xD;
           significance, although we will study this. The potential risks of breastfeeding are&#xD;
           fewer than those of giving formula feeding during the two week period that mothers&#xD;
           continue to receive DTG postpartum. Replacement of breast feeding with formula feeding&#xD;
           during the first two weeks post-partum would be unethical due to the loss of the immune&#xD;
           benefits of colostrum to the neonate, risks intrinsic to formula feeding in low resource&#xD;
           settings and increased risk of HIV transmission if mixed feeding occurs (Teasdale et al,&#xD;
           2011) The potential risks of low-level ARV causing drug-resistance in the infant should&#xD;
           the PMTCT fail exist for the standard of care NNRTIs and NRTIs; it is not anticipated&#xD;
           that DTG will carry a greater risk but nevertheless this is best monitored within a&#xD;
           clinical trial setting before widespread uptake without monitoring.&#xD;
&#xD;
      Study Design Open label randomized trial of DTG in late pregnancy. HIV+ pregnant women&#xD;
      (untreated at ≥28w gestation will be randomized 1:1 to receive a DTG-based regimen compared&#xD;
      with standard of care (regimen not containing INSTI).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 14, 2017</start_date>
  <completion_date type="Actual">December 6, 2018</completion_date>
  <primary_completion_date type="Actual">December 6, 2018</primary_completion_date>
  <phase>Phase 2/Phase 3</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>AUC0-24 of DTG in pregnant women in third trimester and 2 weeks postpartum</measure>
    <time_frame>In 3rd trimester and 2 weeks postpartum</time_frame>
    <description>Rich PK with sampling at t0, 1, 2, 4, 6, 8 and 24 hours relative to drug dose</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability of DTG</measure>
    <time_frame>Up to 6 months postpartum</time_frame>
    <description>Safety questionnaires at every scheduled and unscheduled study visit Infant safety questionnaires at all post-partum visits Self-reporting</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of women in each arm with VL &lt; 50 copies/mL, and &lt;400 copies/mL at delivery</measure>
    <time_frame>At delivery</time_frame>
    <description>HIV viral load will be measured at enrollment into the study and at delivery</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in viral load over the first 4 weeks of therapy</measure>
    <time_frame>4 weeks after treatment started</time_frame>
    <description>HIV viral load will be measured at enrollment and after 4 weeks of antiretroviral therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cord:maternal plasma DTG ratio</measure>
    <time_frame>At delivery</time_frame>
    <description>A maternal blood sample and a cord blood sample will be taken at delivery to calculate the transplacental transfer of Dolutegravir</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maternal plasma: breastmilk DTG ratio</measure>
    <time_frame>At 2 weeks postpartum, and after 1, 2 and 3 days after transfer back to standard of care medications</time_frame>
    <description>At the timepoints indicated, a single maternal blood sample and a sample of breast milk will be taken to measure Dolutegravir levels in both matrices and allow estimation of transmammary drug exposure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infant DTG levels</measure>
    <time_frame>At maternal steady state (2 weeks postpartum) and at 1, 2 and 3 days after transfer to standard of care</time_frame>
    <description>Infants from the Dolutegravir arm (N=30) will be randomised 1:1:1 to return for PK sampling 1, 2 or 3 days after the mother has discontinued Dolutegravir and changed to Standard of Care treatment. All infants will have a single capillary blood sample (heel prick) taken at 2 weeks postpartum, and then at the time point they have been randomised to.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence and severity of adverse events and laboratory abnormalities</measure>
    <time_frame>Up to 3 days after change to standard of care</time_frame>
    <description>Laboratory test measured routinely up until 3 days after change to standard of care. In addition, patients will remain under follow-up until 6 months postpartum, and laboratory tests will be performed if clinically indicated at any point. The routinely measured 'safety bloods' in this study are Full Blood Count, Urea and Electrolytes including eGFR, Liver Function Tests including Alanine Aminotransferase and Bilirubin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute values and changes over time in laboratory parameters</measure>
    <time_frame>Until 3 days after change back to standard of care</time_frame>
    <description>Laboratory tests will be performed routinely until 3 days after change to standard of care regime, but the study will continue to follow the women until 6 months postpartum. Lab tests will be performed if clinically indicated at any time point</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of subjects who discontinue treatment due to adverse events</measure>
    <time_frame>Until 2 weeks postpartum</time_frame>
    <description>Mothers will be switched to standard of care at 2 weeks postpartum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of mother to child transmission of HIV</measure>
    <time_frame>6 months postpartum</time_frame>
    <description>Infant HIV testing by PCR will be undertaken at six weeks and six months of age, as per Uganda National Policy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacogenomic factors affecting DTG PK in pregnancy and transfer to infant via placenta or breastmilk</measure>
    <time_frame>Single 5ml sample at rich PK visit</time_frame>
    <description>Blood sample for genomic testing will be taken at the same time as the rich PK sampling, either in the third trimester or at 2 weeks postpartum. A panel of known SNPs for the major drug metabolising enzymes known to alter the pharmacokinetics of efavirenz, lamivudine and tenofovir will be analysed (primarily SNPs affecting CYP2B6)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>HIV</condition>
  <condition>Pregnancy</condition>
  <arm_group>
    <arm_group_label>Dolutegravir 50mg od</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>30 patients who will receive dolutegravir 50mg once daily plus the same NRTI backbone as the active comparator group (lamivudine and tenofovir)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of Care</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients randomised to receive antiretroviral therapy as per Uganda national guidelines (Efavirenz 600mg od based plus Tenofovir 300mg od and Lamivudine 300mg od)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dolutegravir 50mg od</intervention_name>
    <description>Patients randomised to receive either Dolutegravir 50mg od or standard of care (Efavirenz 600mg od) plus Lamivudine 300mg od/ Tenofovir 300mg od</description>
    <arm_group_label>Dolutegravir 50mg od</arm_group_label>
    <other_name>Tivicay (ViiV Healthcare)</other_name>
    <other_name>GSK1349572</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Standard of Care</intervention_name>
    <description>Patients are randomised 1:1 to receive either Dolutegravir 50mg once daily in combination with Lamivudine 300mg od and tenofovir 300mg od or standard of care (Efavirenz 600mg plus Lamivudine 300mg od and tenofovir 300mg od)</description>
    <arm_group_label>Standard of Care</arm_group_label>
    <other_name>Efavirenz 600mg od</other_name>
    <other_name>Lamivudine 300mg od</other_name>
    <other_name>Tenofovir 300mg od</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Able to provide informed consent&#xD;
&#xD;
          -  Willing to participate,&#xD;
&#xD;
          -  Women age 18 years and above&#xD;
&#xD;
          -  Pregnant&#xD;
&#xD;
          -  Untreated HIV infection in late pregnancy at ≥28 - 36 weeks gestation&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Received antiretroviral drugs in previous 6 months&#xD;
&#xD;
          -  Ever received integrase inhibitors&#xD;
&#xD;
          -  Serum haemoglobin &lt; 8.0 g/dl&#xD;
&#xD;
          -  Elevations in serum levels of alanine aminotransferase (ALT) &gt;5 times the upper limit&#xD;
             of normal (ULN) or ALT &gt;3xULN and bilirubin &gt;2xULN (with &gt;35% direct bilirubin)&#xD;
&#xD;
          -  eGFR &lt; 50ml/min&#xD;
&#xD;
          -  Active Hepatitis B infection, history or clinical suspicion of unstable liver disease,&#xD;
             or subjects with severe liver disease (Class C by Childs-Hugh criteria)&#xD;
&#xD;
          -  Severe pre-eclampsia (e.g. HELLP), or other pregnancy related events such as renal or&#xD;
             liver abnormalities (e.g. grade 2 or above proteinuria, elevation in serum creatinine&#xD;
             (above 2.5 x ULN), total bilirubin ALT or AST)&#xD;
&#xD;
          -  Paternal non-consent (where disclosure to male partner has been made)&#xD;
&#xD;
          -  Clinical depression or clinical judgement suggests increased risk of suicidality&#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>Saye H Khoo, PhD, MBChB</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Liverpool</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Mohammed Lamorde, PhD, MBChB</last_name>
    <role>Principal Investigator</role>
    <affiliation>Infectious Diseases Institute, Makerere University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Desmond Tutu HIV Foundation</name>
      <address>
        <city>Cape Town</city>
        <state>Western Cape</state>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Infectious Diseases Institute</name>
      <address>
        <city>Kampala</city>
        <country>Uganda</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>South Africa</country>
    <country>Uganda</country>
  </location_countries>
  <link>
    <url>https://www.viivhealthcare.com/our-medicines/tivicay.aspx</url>
    <description>Product Information</description>
  </link>
  <verification_date>September 2019</verification_date>
  <study_first_submitted>September 12, 2014</study_first_submitted>
  <study_first_submitted_qc>September 16, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 19, 2014</study_first_posted>
  <last_update_submitted>September 24, 2019</last_update_submitted>
  <last_update_submitted_qc>September 24, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">September 25, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Liverpool</investigator_affiliation>
    <investigator_full_name>Catriona Waitt</investigator_full_name>
    <investigator_title>Site sub-investigator</investigator_title>
  </responsible_party>
  <keyword>HIV</keyword>
  <keyword>Prevention of mother to child transmission</keyword>
  <keyword>Africa</keyword>
  <keyword>Uganda</keyword>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Pregnancy</keyword>
  <keyword>Breastfeeding</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tenofovir</mesh_term>
    <mesh_term>Lamivudine</mesh_term>
    <mesh_term>Efavirenz</mesh_term>
    <mesh_term>Dolutegravir</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>December 13, 2022</submitted>
  </pending_results>
  <!-- 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/NCT02245022
org study id: PK12
nct id: NCT02245022
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Aim: To evaluate dolutegravir (DTG) pharmacokinetics in pregnant HIV-infected women

      Rationale: In developing countries many women present with a new HIV diagnosis in late
      pregnancy, and are at high risk of transmitting infection during delivery. Moreover, women
      may acquire NNRTI resistance from primary transmission, or use of nevirapine (NVP) in
      previous pregnancies. In these circumstances, DTG is likely to be more effective in reducing
      mother to child transmission of HIV than NNRTI-based regimens.

      Study design: HIV positive pregnant women presenting with untreated HIV infection in late
      (≥28 -36 weeks gestation) pregnancy will be randomised 1:1 to receive DTG (50mg once daily)
      or standard of care (nevirapine or efavirenz) + 2 NRTIs. PK (0-24h) profile will be sampled
      in third trimester and post-partum.

      Although this is primarily a PK study (and has been powered as such) randomisation is
      included to allow comparison of plasma HIV VL responses against standard of care (NVP or EFV)
      and is essential for evaluation of secondary endpoints of safety and efficacy of DTG in
      pregnancy.

      Number recruited N=30 per group
Antiretroviral therapy (ART) in pregnancy is able to effectively reduce mother-to-child
      transmission (MTCT) of HIV. If untreated, the risk of transmission is around 25% (greater
      with high viral loads) but ART administered optimally during pregnancy may reduce this risk
      to 1-2%. In order to successfully prevent infection, ART should be started in the first or
      second trimester, and should reduce maternal plasma viral load to undetectable levels.
      Unfortunately throughout low-middle income countries, MTCT rates are unacceptably high with
      an estimated 430 000 newborn children infected annually. The main causes for this are
      undiagnosed or late diagnosis of maternal infection, suboptimal adherence to therapy and drug
      resistance, particularly in mothers who have previously received single dose nevirapine.

      In sub-Saharan Africa (SSA), women frequently engage with health services late in pregnancy,
      and new HIV diagnoses in the third trimester (≥28 weeks of pregnancy) are not uncommon. Risk
      of MTCT is high, especially as NNRTI-based therapy takes a median of 2 months to
      significantly reduce the HIV viral load, making it unlikely that commencement of these drugs
      in late pregnancy will offer protection of the infant from intrapartum transmission.

      Vertical transmission of HIV remains a significant challenge in developing countries and
      antiretroviral prophylaxis for PMTCT is an important tool towards elimination of paediatric
      infections. Between 2009 and 2010, coverage of antiretroviral prophylaxis for prevention of
      mother to child transmission was 42% and an estimated 1.48 million infants were born to women
      living with HIV (WHO 2010). Global efforts are geared towards improving access to
      antiretrovirals for PMTCT by simplifying antiretroviral treatment protocols while ensuring
      optimal outcomes for HIV-infected women and their children (WHO 2010; WHO 2012).

      Under consolidated antiretroviral guidelines issued by the WHO in 2013, efavirenz-based ART
      is now recommended the preferred NNRTI option for HIV-1 infected patients, including among
      women of childbearing age and pregnant women (WHO 2013). In 2012, Uganda adopted the Option
      B+ strategy for PMTCT of HIV. Under this strategy, lifelong ART is offered to all pregnant
      ART naïve women irrespective of CD4 count with efavirenz-based ART as the preferred treatment
      option. However, the effectiveness of this regimen could be compromised in the event of large
      populations of women who may have been either exposed to single dose nevirapine in the past
      or among women with transmitted NNRTI resistance.

      The justification for studying DTG in pregnancy includes:

        1. Likely widespread availability of generic DTG in the coming years. The manufacturer has
           indicated its willingness to make DTG available in low income countries, and is
           currently engaging with generic manufacturers. Estimates from the Clinton Foundation
           suggest that generic manufacture of DTG will make this drug affordable either as an
           alternative first line, or else second line agent (Hill 2013). Clinical guidelines from
           the US and Europe currently rank INSTIs such as raltegravir and elvitegravir alongside
           NNRTIs as preferred first line agents. INSTIs may replace NNRTIs in first line regimens
           due to their good safety and toxicity profile, lower propensity for drug interactions,
           and superior efficacy. Large phase III RCTs comparing raltegravir (Rockstroh, Dejesus et
           al. 2013), elvitegravir (Sax, DeJesus et al. 2012) and dolutegravir (van Lunzen,
           Maggiolo et al. 2012) against efavirenz-based therapy have shown superior virological
           outcome at 48 weeks, faster time to undetectable viral load, lower incidence of adverse
           events, and fewer treatment discontinuations, and these findings have recently been
           confirmed in a meta-analysis (Messiaen, Wensing et al. 2013).

        2. Low risk for serious drug-drug interactions. The potential for drug-drug interactions is
           significantly less for INSTIs compared with other antiretrovirals (relative risk
           compared with raltegravir: boosted protease inhibitors [RR = 4.96], non-nucleoside
           reverse transcriptase inhibitors [RR = 2.48](Patel, Abdelsayed et al. 2011). These are
           particularly important considerations for low/middle income country settings where
           adults with newly diagnosed HIV infection often present with tuberculosis, or during
           antenatal screening in late pregnancy. Here DTG may carry significant advantages over
           NNRTIs, and other INSTIs. In the absence of alternatives to rifampicin-based TB therapy,
           DTG and raltegravir exposures are only moderately reduced (Dooley, Sayre et al. 2013),
           compared to larger (50-90%) reductions in concentrations of boosted PIs, nevirapine and
           elvitegravir. Dolutegravir is metabolized by glucuronidation (UGT1A1) with some
           contribution from CYP3A.

        3. Rapid viral load drop potentially beneficial in late diagnosis during pregnancy. In
           Sub-Saharan Africa, pregnant mothers tend to engage with health services later in
           pregnancy compared with Europe, and new HIV diagnoses resulting from universal testing
           at ≥28w gestation are frequent. DTG results in a very rapid reduction in viral load;
           median time to undetectable viral load in the SINGLE study was 28 days vs. 84 days with
           Atripla (P<0.0001) (Walmsley, Antela et al. 2012). Use of DTG may lower risk of
           mother-to-child transmission of HIV in late presenters. Although meta-analysis shows no
           increase in birth defects with maternal efavirenz (Ford, Mofenson et al. 2010), there
           has been recent suspicion of neurological toxicity in a large French registry (Sibiude,
           Madelbrot et al. 2013) and neurodevelopmental delay in a South African cohort
           (Westreich, Rubel et al. 2010)

        4. Proven efficacy in patients with established drug resistance to other antiretrovirals.
           In most resource-poor settings, options for anti-retroviral therapy are limited (2011),
           and the emergence of HIV drug resistance gives cause for concern (Hedt, Wadonda-Kabondo
           et al. 2008; WHO 2012). In a cross-sectional study conducted among HIV-1 antiretroviral
           naïve patients in five African countries, the highest prevalence of transmitted
           resistance was observed in Kampala, Uganda 12.3% (22 of 179; 7.5-17.1) (Hamers, Wallis
           et al. 2011). In Malawi, the prevalence of primary drug resistance in new infections was
           6.1% which is comparable with figures of ~3% for South Africa (Manasa, Katzenstein et
           al. 2012), and 5.7% for Zambia (Hamers, Siwale et al. 2010), with over half of all
           mutations conferring resistance to non-nucleoside reverse transcriptases (NNRTI)
           (Wadonda-Kabondo, Banda et al. 2012). Studies across Africa have shown that treatment
           response to NNRTIs in mothers and children exposed to nevirapine (particularly single
           dose) during pregnancy is blunted (Musiime, Ssali et al. 2009). In this context, a novel
           class of ARV which is safe, affordable and effective is an urgent need

        5. Safety profile in pregnancy. DTG is classified as FDA pregnancy Category B. There are no
           adequate and well-controlled studies in pregnant women. Because animal reproduction
           studies are not always predictive of human response, and dolutegravir was shown to cross
           the placenta in animal studies, the manufacturer recommends that this drug should be
           used during pregnancy only if clearly needed (ViiV 2013).

        6. Necessity of investigating DTG PK in pregnant women. Alongside the clinical and
           humanitarian imperative to provide effective treatment for preventing HIV transmission
           in pregnant mothers with NNRTI-resistant HIV, there is an equally important ethical
           imperative to establish the safety, efficacy and pharmacokinetics of DTG in pregnant
           mothers and their breastfed infants in SSA, especially given the implementation of WHO
           Option B+, and the potential for widespread use of DTG in the forseeable future.
           Previous experience suggests it is universally the case that pregnant women in SSA
           receive new antiretrovirals (ARV) ahead of any proper evaluation, and clinical studies
           (if undertaken at all) occur at a much later stage after many mothers and infants have
           been exposed.

        7. Importance of undertaking the study in SSA. Any pivotal study if undertaken in developed
           countries would have limited generalizability to an African setting because i) ARVs tend
           to be initiated later in gestation in newly presenting pregnant women, ii) the standard
           of care across SSA is likely to be an efavirenz or nevirapine-based regimen iii) infant
           breastfeeding is recommended in the presence of ARVs ii) host factors such as BMI,
           ethnicity etc may impact on pharmacokinetics (PK) of ARVs.

        8. Continued administration of DTG for 2 weeks post-partum (whilst breastfeeding) to
           characterize PK in non-pregnant state. Under standard of care, the infant will receive 6
           weeks of nevirapine syrup, and would be exposed to the NNRTI/NRTI/NRTI combination
           received by the mother under standard of care. In this study, infants will be exposed
           DTG via the breastmilk for a 2 week period following birth. We believe this risk to be
           acceptable given the potential benefits. Furthermore, the risk is unlikely to exceed any
           potential risk of in utero exposure to DTG. Drug-drug interactions between directly
           administered NVP and DTG ingested via the breastmilk are unlikely to have clinical
           significance, although we will study this. The potential risks of breastfeeding are
           fewer than those of giving formula feeding during the two week period that mothers
           continue to receive DTG postpartum. Replacement of breast feeding with formula feeding
           during the first two weeks post-partum would be unethical due to the loss of the immune
           benefits of colostrum to the neonate, risks intrinsic to formula feeding in low resource
           settings and increased risk of HIV transmission if mixed feeding occurs (Teasdale et al,
           2011) The potential risks of low-level ARV causing drug-resistance in the infant should
           the PMTCT fail exist for the standard of care NNRTIs and NRTIs; it is not anticipated
           that DTG will carry a greater risk but nevertheless this is best monitored within a
           clinical trial setting before widespread uptake without monitoring.

      Study Design Open label randomized trial of DTG in late pregnancy. HIV+ pregnant women
      (untreated at ≥28w gestation will be randomized 1:1 to receive a DTG-based regimen compared
      with standard of care (regimen not containing INSTI).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: AUC0-24 of DTG in pregnant women in third trimester and 2 weeks postpartum
time frame: In 3rd trimester and 2 weeks postpartum
description: Rich PK with sampling at t0, 1, 2, 4, 6, 8 and 24 hours relative to drug dose
measure: Safety and tolerability of DTG
time frame: Up to 6 months postpartum
description: Safety questionnaires at every scheduled and unscheduled study visit Infant safety questionnaires at all post-partum visits Self-reporting
measure: Proportion of women in each arm with VL < 50 copies/mL, and <400 copies/mL at delivery
time frame: At delivery
description: HIV viral load will be measured at enrollment into the study and at delivery
measure: Change in viral load over the first 4 weeks of therapy
time frame: 4 weeks after treatment started
description: HIV viral load will be measured at enrollment and after 4 weeks of antiretroviral therapy
measure: Cord:maternal plasma DTG ratio
time frame: At delivery
description: A maternal blood sample and a cord blood sample will be taken at delivery to calculate the transplacental transfer of Dolutegravir
measure: Maternal plasma: breastmilk DTG ratio
time frame: At 2 weeks postpartum, and after 1, 2 and 3 days after transfer back to standard of care medications
description: At the timepoints indicated, a single maternal blood sample and a sample of breast milk will be taken to measure Dolutegravir levels in both matrices and allow estimation of transmammary drug exposure
measure: Infant DTG levels
time frame: At maternal steady state (2 weeks postpartum) and at 1, 2 and 3 days after transfer to standard of care
description: Infants from the Dolutegravir arm (N=30) will be randomised 1:1:1 to return for PK sampling 1, 2 or 3 days after the mother has discontinued Dolutegravir and changed to Standard of Care treatment. All infants will have a single capillary blood sample (heel prick) taken at 2 weeks postpartum, and then at the time point they have been randomised to.
measure: Incidence and severity of adverse events and laboratory abnormalities
time frame: Up to 3 days after change to standard of care
description: Laboratory test measured routinely up until 3 days after change to standard of care. In addition, patients will remain under follow-up until 6 months postpartum, and laboratory tests will be performed if clinically indicated at any point. The routinely measured 'safety bloods' in this study are Full Blood Count, Urea and Electrolytes including eGFR, Liver Function Tests including Alanine Aminotransferase and Bilirubin
measure: Absolute values and changes over time in laboratory parameters
time frame: Until 3 days after change back to standard of care
description: Laboratory tests will be performed routinely until 3 days after change to standard of care regime, but the study will continue to follow the women until 6 months postpartum. Lab tests will be performed if clinically indicated at any time point
measure: Proportion of subjects who discontinue treatment due to adverse events
time frame: Until 2 weeks postpartum
description: Mothers will be switched to standard of care at 2 weeks postpartum
measure: Proportion of mother to child transmission of HIV
time frame: 6 months postpartum
description: Infant HIV testing by PCR will be undertaken at six weeks and six months of age, as per Uganda National Policy
measure: Pharmacogenomic factors affecting DTG PK in pregnancy and transfer to infant via placenta or breastmilk
time frame: Single 5ml sample at rich PK visit
description: Blood sample for genomic testing will be taken at the same time as the rich PK sampling, either in the third trimester or at 2 weeks postpartum. A panel of known SNPs for the major drug metabolising enzymes known to alter the pharmacokinetics of efavirenz, lamivudine and tenofovir will be analysed (primarily SNPs affecting CYP2B6)
arm group label: Dolutegravir 50mg od
arm group type: Experimental
description: 30 patients who will receive dolutegravir 50mg once daily plus the same NRTI backbone as the active comparator group (lamivudine and tenofovir)
arm group label: Standard of Care
arm group type: Active Comparator
description: Patients randomised to receive antiretroviral therapy as per Uganda national guidelines (Efavirenz 600mg od based plus Tenofovir 300mg od and Lamivudine 300mg od)
intervention type: Drug
intervention name: Dolutegravir 50mg od
description: Patients randomised to receive either Dolutegravir 50mg od or standard of care (Efavirenz 600mg od) plus Lamivudine 300mg od/ Tenofovir 300mg od
arm group label: Dolutegravir 50mg od
other name: Tivicay (ViiV Healthcare)
other name: GSK1349572
intervention type: Drug
intervention name: Standard of Care
description: Patients are randomised 1:1 to receive either Dolutegravir 50mg once daily in combination with Lamivudine 300mg od and tenofovir 300mg od or standard of care (Efavirenz 600mg plus Lamivudine 300mg od and tenofovir 300mg od)
arm group label: Standard of Care
other name: Efavirenz 600mg od
other name: Lamivudine 300mg od
other name: Tenofovir 300mg od
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Saye H Khoo, PhD, MBChB
role: Principal Investigator
affiliation: University of Liverpool
last name: Mohammed Lamorde, PhD, MBChB
role: Principal Investigator
affiliation: Infectious Diseases Institute, Makerere University
facility: 
facility: 
country: South Africa
country: Uganda
url: https://www.viivhealthcare.com/our-medicines/tivicay.aspx
description: Product Information
responsible party type: Principal Investigator
investigator affiliation: University of Liverpool
investigator full name: Catriona Waitt
investigator title: Site sub-investigator
mesh term: Tenofovir
mesh term: Lamivudine
mesh term: Efavirenz
mesh term: Dolutegravir
sharing ipd: No
submitted: December 13, 2022