<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/NCT04410406</url>
  </required_header>
  <id_info>
    <org_study_id>202005076</org_study_id>
    <nct_id>NCT04410406</nct_id>
  </id_info>
  <brief_title>Moxidectin for LF, Cote d'Ivoire (DOLF)</brief_title>
  <official_title>A Clinical Trial to Assess the Safety and Efficacy of Moxidectin Combination Treatments vs. Ivermectin Combination Treatments for Bancroftian Filariasis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Case Western Reserve University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Regional Hospital of Agboville, Southern Cote d'Ivoire</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Washington University School of Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine whether moxidectin (Mox) will be more effective&#xD;
      than ivermectin (IVM) when used in single-dose combination therapies for lymphatic filariasis&#xD;
      (LF).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study will test the hypothesis that Moxidectin combination therapies are superior to&#xD;
      ivermectin combination therapies for achieving sustained clearance of W. bancrofti&#xD;
      microfilaremia.&#xD;
&#xD;
      This trial is designed as single-site, Phase III, randomized, open-label, masked-observer&#xD;
      superiority trial with four treatment arms: ivermectin + albendazole (IA), moxidectin +&#xD;
      albendazole (MoxA), ivermectin + diethylcarbamazine + albendazole (IDA), and moxidectin +&#xD;
      diethylcarbamazine + albendazole (MoxDA). The primary endpoint is the proportion of&#xD;
      participants achieving complete clearance of microfilaremia at 12 months (IA vs. MoxA&#xD;
      comparison) or 24 months (IDA vs. MoxDA comparison). Block randomization by gender will be&#xD;
      used to assign treatment arms.&#xD;
&#xD;
      The first 48 participants (12 each arm) will be treated at Agboville Hospital in Cote&#xD;
      d'Ivoire at the Centre de Recherche de Filariose with inpatient AE monitoring and collection&#xD;
      of post-treatment plasma drug levels (Part 1). For Part 1, active AE surveillance will be&#xD;
      conducted in the hospital on days 1, 2, and 3, post-treatment, and in the participant's&#xD;
      village of residence on day 7 post-treatment and passive surveillance will be conducted by&#xD;
      trained village health workers on days 4-6. An interim safety analysis will take place after&#xD;
      Part 1. If no safety concerns are identified, the remainder of the participants will be&#xD;
      treated in their home villages, with active AE monitoring on days 1 and 2 post-treatment&#xD;
      (Part 2) with passive surveillance by trained village health workers on days 3-7. Any&#xD;
      participant in either Part 1 or Part 2 experiencing AEs of grade 2 or higher will be followed&#xD;
      until adverse event (AE) severity falls below grade 2. Follow-up assessments for efficacy of&#xD;
      treatments for all participants (Parts 1 and 2) will be conducted at 6, 12, 24, and 36&#xD;
      months.&#xD;
&#xD;
      The study includes both safety and efficacy analyses. The safety assessment (Part 1 only)&#xD;
      ends 7 days after treatment (unless AEs remain grade 2 or higher). The efficacy assessment&#xD;
      (Parts 1 and 2 combined) ends when participants are retested for filarial infection 36 months&#xD;
      post-treatment. Participants in the IA arm will receive IA annually (standard of care).&#xD;
      Participants in the other arms will receive the assigned treatment at baseline; those found&#xD;
      to be microfilaremic at 24 months post-treatment will be retreated with the same treatment&#xD;
      received at baseline. If clearance of microfilariae (Mf) at 12 months in the IA arm is&#xD;
      superior to Mf clearance in the MoxA arm, the MoxA group will be switched to annual IA&#xD;
      treatment.&#xD;
&#xD;
      The study design does not currently include stratification, nor do any sub-studies. However,&#xD;
      the study may stratify based on pre-treatment Mf levels if high variability among&#xD;
      pre-screening Mf counts is observed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 20, 2020</start_date>
  <completion_date type="Anticipated">September 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">September 1, 2023</primary_completion_date>
  <phase>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>
    <intervention_model_description>This trial is a single-site, Phase III, randomized, open-label, masked-observer superiority trial with four treatment arms (IA, MoxA, IDA, and MoxDA). Block randomization by gender will be used to assign treatment arms.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>Recognizing that number and appearance of tablets received in each study arm will be noticeably different, this study will not be completely masked to participants or care providers. To minimize bias, administration of study medications will be performed by a staff member with no role in assessing AEs. AE assessments and all other outcome measures will be assessed by observers masked to the treatment assignment as best as possible.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Clearance of microfilaremia (IA vs. MoxA)</measure>
    <time_frame>12 months</time_frame>
    <description>The proportion of participants in IA and MoxA study arms with complete clearance of W. bancrofti microfilaremia at 12 months after treatment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clearance of microfilaremia (IDA vs. MoxDA)</measure>
    <time_frame>24 months</time_frame>
    <description>The proportion of participants in IDA and MoxDA study arms with complete clearance of W. bancrofti microfilaremia at 24 months after treatment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clearance of microfilaremia</measure>
    <time_frame>6, 12, 24, &amp; 36 months</time_frame>
    <description>The proportion of participants in each study arm with complete clearance of W. bancrofti microfilaremia at 6, 12, 24, &amp; 36 months after treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reduction in Mf counts</measure>
    <time_frame>Baseline, 6, 12, &amp; 24 months</time_frame>
    <description>Reduction in microfilariae counts (relative to baseline) at 6, 12, &amp; 24 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reduction in circulating filarial antigen (CFA) counts</measure>
    <time_frame>Baseline, 6, 12, &amp; 24 months</time_frame>
    <description>Reduction in circulating filarial antigen (CFA) counts (relative to baseline) at 6, 12, &amp; 24 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inactivation of adult worm nests</measure>
    <time_frame>6, 12, &amp; 24 months</time_frame>
    <description>Inactivation of adult worm nests as assessed by scrotal ultrasound at 6, 12, and 24 months after treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency and severity of AEs</measure>
    <time_frame>From baseline treatment to 7 days post-treatment</time_frame>
    <description>Frequency and severity of AEs during the first 7 days after treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma levels of drugs/metabolites post treatment</measure>
    <time_frame>Baseline, 2, 3, 4, 6, 12, 24, &amp; 48 hours post-treatment</time_frame>
    <description>Noncompartmental pharmacokinetic analyses of DEC, ABZ, ABZSO, ABZSO2, IVM and Mox concentrations will be conducted using WinNonlin (Pharsight Corporation; Cary, North Carolina, USA). Drug plasma concentrations and computed pharmacokinetic parameters will be listed by subject and summarized by drug or metabolite (geometric mean with coefficient of variation, arithmetic mean with standard deviation, minimum, maximum, number of observations). Individual and geometric mean (by time) concentrations versus time will be plotted for each treatment group on both linear and natural logarithm scales.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">164</enrollment>
  <condition>Lymphatic Filariasis</condition>
  <arm_group>
    <arm_group_label>IA (Ivermectin + Albendazole)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will receive one oral dose of Ivermectin (IVM) 200 µg/kg + Albendazole (ABZ) 400 mg (IA) annually for 24 months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>MoxA (Moxidectin + Albendazole)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will receive one oral dose of Mox 8 mg + ABZ 400 mg. Participants who are Mf positive at 24 months will be retreated with MoxA at the same dosage.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>IDA (Ivermectin + Diethylcarbamazine + Albendazole)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will receive one oral dose of IVM 200 µg/kg + Diethylcarbamazine (DEC) 6mg/kg + ABZ 400 mg. Participants who are Mf positive at 24 months will be retreated with IDA at the same dosage.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>MoxDA (Moxidectin + Diethylcarbamazine + Albendazole)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will receive one oral dose of Mox 8 mg + DEC 6mg/kg + ABZ 400 mg. Participants who are Mf positive at 24 months will be retreated with MoxDA at the same dosage.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ivermectin</intervention_name>
    <description>Ivermectin (IVM) 200 µg/kg</description>
    <arm_group_label>IA (Ivermectin + Albendazole)</arm_group_label>
    <arm_group_label>IDA (Ivermectin + Diethylcarbamazine + Albendazole)</arm_group_label>
    <other_name>Stromectol</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Diethylcarbamazine</intervention_name>
    <description>Diethylcarbamazine (DEC) 6mg/kg</description>
    <arm_group_label>IDA (Ivermectin + Diethylcarbamazine + Albendazole)</arm_group_label>
    <arm_group_label>MoxDA (Moxidectin + Diethylcarbamazine + Albendazole)</arm_group_label>
    <other_name>Diethylcarbamazine citrate</other_name>
    <other_name>Hetrazan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Albendazole</intervention_name>
    <description>Albendazole (ABZ) 400 mg</description>
    <arm_group_label>IA (Ivermectin + Albendazole)</arm_group_label>
    <arm_group_label>IDA (Ivermectin + Diethylcarbamazine + Albendazole)</arm_group_label>
    <arm_group_label>MoxA (Moxidectin + Albendazole)</arm_group_label>
    <arm_group_label>MoxDA (Moxidectin + Diethylcarbamazine + Albendazole)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Moxidectin</intervention_name>
    <description>Moxidectin (Mox) 8 mg</description>
    <arm_group_label>MoxA (Moxidectin + Albendazole)</arm_group_label>
    <arm_group_label>MoxDA (Moxidectin + Diethylcarbamazine + Albendazole)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Provision of signed and dated informed consent form&#xD;
&#xD;
          -  Male or female, aged 18-70 years&#xD;
&#xD;
          -  In good general health as evidenced by medical history&#xD;
&#xD;
          -  Peripheral night blood W. bancrofti Mf levels ≥40 Mf/mL&#xD;
&#xD;
          -  No history of taking antifilarial medications in past 12 months&#xD;
&#xD;
          -  Resident of the study area with no plans to change residence in the next 36 months&#xD;
&#xD;
          -  For women of childbearing potential, willing to use appropriate method of&#xD;
             contraception for one month following each treatment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy or currently breastfeeding&#xD;
&#xD;
          -  Known allergic reactions to any of the study medications&#xD;
&#xD;
          -  Evidence of severe or systemic comorbidities (aside from features of filarial&#xD;
             disease), as judged by the principal investigator&#xD;
&#xD;
          -  Baseline biochemical abnormalities, as indicated by AST, ALT, or creatinine &gt; 2 times&#xD;
             the upper limit of normal&#xD;
&#xD;
          -  Evidence of urinary tract infection as indicated by 3+ nitrites on dipstick&#xD;
             (individuals with 1+ or 2+ nitrites will not be excluded) or underlying chronic kidney&#xD;
             disease as indicated by 3+ protein or 3+ blood on urine dipstick exam&#xD;
&#xD;
          -  Hgb &lt; 7 gm/dL (any such individuals will be referred to the local health center for&#xD;
             evaluation and treatment)&#xD;
&#xD;
          -  Positive skin snip for onchocerciasis&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Philip Budge, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Washington University School of Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Catherine Bjerum, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Case Western Reserve University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Toki Pascal Gabo, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Regional Hospital of Agboville, Southern Cote d'Ivoire</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Benjamin Koudou, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Regional Hospital of Agboville, Southern Cote d'Ivoire</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Regional Hospital of Agboville, Southern Cote d'Ivoire</name>
      <address>
        <city>Agboville</city>
        <country>Côte D'Ivoire</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Côte D'Ivoire</country>
  </location_countries>
  <link>
    <url>https://tdr.who.int/newsroom/news/item/14-06-2018-first-new-treatment-for-river-blindness-approved-by-u-s-fda-in-20-years</url>
    <description>First new treatment for river blindness approved by U.S. FDA in 20 years 2018 [cited 2018 June 27].</description>
  </link>
  <reference>
    <citation>Opoku NO, Bakajika DK, Kanza EM, Howard H, Mambandu GL, Nyathirombo A, Nigo MM, Kasonia K, Masembe SL, Mumbere M, Kataliko K, Larbelee JP, Kpawor M, Bolay KM, Bolay F, Asare S, Attah SK, Olipoh G, Vaillant M, Halleux CM, Kuesel AC. Single dose moxidectin versus ivermectin for Onchocerca volvulus infection in Ghana, Liberia, and the Democratic Republic of the Congo: a randomised, controlled, double-blind phase 3 trial. Lancet. 2018 Oct 6;392(10154):1207-1216. doi: 10.1016/S0140-6736(17)32844-1. Epub 2018 Jan 18. Erratum In: Lancet. 2018 Oct 6;392(10154):1196.</citation>
    <PMID>29361335</PMID>
  </reference>
  <reference>
    <citation>Ichimori K, King JD, Engels D, Yajima A, Mikhailov A, Lammie P, Ottesen EA. Global programme to eliminate lymphatic filariasis: the processes underlying programme success. PLoS Negl Trop Dis. 2014 Dec 11;8(12):e3328. doi: 10.1371/journal.pntd.0003328. eCollection 2014 Dec. No abstract available.</citation>
    <PMID>25502758</PMID>
  </reference>
  <reference>
    <citation>Ottesen EA, Duke BO, Karam M, Behbehani K. Strategies and tools for the control/elimination of lymphatic filariasis. Bull World Health Organ. 1997;75(6):491-503.</citation>
    <PMID>9509621</PMID>
  </reference>
  <reference>
    <citation>Ottesen EA. Lymphatic filariasis: Treatment, control and elimination. Adv Parasitol. 2006;61:395-441. doi: 10.1016/S0065-308X(05)61010-X.</citation>
    <PMID>16735170</PMID>
  </reference>
  <reference>
    <citation>Thomsen EK, Sanuku N, Baea M, Satofan S, Maki E, Lombore B, Schmidt MS, Siba PM, Weil GJ, Kazura JW, Fleckenstein LL, King CL. Efficacy, Safety, and Pharmacokinetics of Coadministered Diethylcarbamazine, Albendazole, and Ivermectin for Treatment of Bancroftian Filariasis. Clin Infect Dis. 2016 Feb 1;62(3):334-341. doi: 10.1093/cid/civ882. Epub 2015 Oct 20.</citation>
    <PMID>26486704</PMID>
  </reference>
  <reference>
    <citation>King CL, Suamani J, Sanuku N, Cheng YC, Satofan S, Mancuso B, Goss CW, Robinson LJ, Siba PM, Weil GJ, Kazura JW. A Trial of a Triple-Drug Treatment for Lymphatic Filariasis. N Engl J Med. 2018 Nov 8;379(19):1801-1810. doi: 10.1056/NEJMoa1706854.</citation>
    <PMID>30403937</PMID>
  </reference>
  <reference>
    <citation>Edi C, Bjerum CM, Ouattara AF, Chhonker YS, Penali LK, Meite A, Koudou BG, Weil GJ, King CL, Murry DJ. Pharmacokinetics, safety, and efficacy of a single co-administered dose of diethylcarbamazine, albendazole and ivermectin in adults with and without Wuchereria bancrofti infection in Cote d'Ivoire. PLoS Negl Trop Dis. 2019 May 20;13(5):e0007325. doi: 10.1371/journal.pntd.0007325. eCollection 2019 May.</citation>
    <PMID>31107869</PMID>
  </reference>
  <reference>
    <citation>Irvine MA, Stolk WA, Smith ME, Subramanian S, Singh BK, Weil GJ, Michael E, Hollingsworth TD. Effectiveness of a triple-drug regimen for global elimination of lymphatic filariasis: a modelling study. Lancet Infect Dis. 2017 Apr;17(4):451-458. doi: 10.1016/S1473-3099(16)30467-4. Epub 2016 Dec 22.</citation>
    <PMID>28012943</PMID>
  </reference>
  <reference>
    <citation>Kyelem D, Biswas G, Bockarie MJ, Bradley MH, El-Setouhy M, Fischer PU, Henderson RH, Kazura JW, Lammie PJ, Njenga SM, Ottesen EA, Ramaiah KD, Richards FO, Weil GJ, Williams SA. Determinants of success in national programs to eliminate lymphatic filariasis: a perspective identifying essential elements and research needs. Am J Trop Med Hyg. 2008 Oct;79(4):480-4.</citation>
    <PMID>18840733</PMID>
  </reference>
  <reference>
    <citation>Molyneux DH, Hopkins A, Bradley MH, Kelly-Hope LA. Multidimensional complexities of filariasis control in an era of large-scale mass drug administration programmes: a can of worms. Parasit Vectors. 2014 Aug 15;7:363. doi: 10.1186/1756-3305-7-363.</citation>
    <PMID>25128408</PMID>
  </reference>
  <reference>
    <citation>Horton J. Albendazole: a broad spectrum anthelminthic for treatment of individuals and populations. Curr Opin Infect Dis. 2002 Dec;15(6):599-608. doi: 10.1097/00001432-200212000-00008.</citation>
    <PMID>12821837</PMID>
  </reference>
  <reference>
    <citation>Horton J, Witt C, Ottesen EA, Lazdins JK, Addiss DG, Awadzi K, Beach MJ, Belizario VY, Dunyo SK, Espinel M, Gyapong JO, Hossain M, Ismail MM, Jayakody RL, Lammie PJ, Makunde W, Richard-Lenoble D, Selve B, Shenoy RK, Simonsen PE, Wamae CN, Weerasooriya MV. An analysis of the safety of the single dose, two drug regimens used in programmes to eliminate lymphatic filariasis. Parasitology. 2000;121 Suppl:S147-60. doi: 10.1017/s0031182000007423.</citation>
    <PMID>11386686</PMID>
  </reference>
  <reference>
    <citation>Kitzman D, Cheng KJ, Fleckenstein L. HPLC assay for albendazole and metabolites in human plasma for clinical pharmacokinetic studies. J Pharm Biomed Anal. 2002 Oct 15;30(3):801-13. doi: 10.1016/s0731-7085(02)00382-5.</citation>
    <PMID>12367706</PMID>
  </reference>
  <reference>
    <citation>Geary TG. Ivermectin 20 years on: maturation of a wonder drug. Trends Parasitol. 2005 Nov;21(11):530-2. doi: 10.1016/j.pt.2005.08.014. Epub 2005 Aug 26.</citation>
    <PMID>16126457</PMID>
  </reference>
  <reference>
    <citation>Moreno Y, Nabhan JF, Solomon J, Mackenzie CD, Geary TG. Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi. Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):20120-5. doi: 10.1073/pnas.1011983107. Epub 2010 Nov 1.</citation>
    <PMID>21041637</PMID>
  </reference>
  <reference>
    <citation>Awadzi K, Edwards G, Opoku NO, Ardrey AE, Favager S, Addy ET, Attah SK, Yamuah LK, Quartey BT. The safety, tolerability and pharmacokinetics of levamisole alone, levamisole plus ivermectin, and levamisole plus albendazole, and their efficacy against Onchocerca volvulus. Ann Trop Med Parasitol. 2004 Sep;98(6):595-614. doi: 10.1179/000349804225021370.</citation>
    <PMID>15324466</PMID>
  </reference>
  <reference>
    <citation>Kitzman D, Wei SY, Fleckenstein L. Liquid chromatographic assay of ivermectin in human plasma for application to clinical pharmacokinetic studies. J Pharm Biomed Anal. 2006 Mar 3;40(4):1013-20. doi: 10.1016/j.jpba.2005.08.026. Epub 2005 Oct 19.</citation>
    <PMID>16242280</PMID>
  </reference>
  <reference>
    <citation>Awadzi K, Edwards G, Duke BO, Opoku NO, Attah SK, Addy ET, Ardrey AE, Quartey BT. The co-administration of ivermectin and albendazole--safety, pharmacokinetics and efficacy against Onchocerca volvulus. Ann Trop Med Parasitol. 2003 Mar;97(2):165-78. doi: 10.1179/000349803235001697.</citation>
    <PMID>12803872</PMID>
  </reference>
  <reference>
    <citation>Bolla S, Boinpally RR, Poondru S, Devaraj R, Jasti BR. Pharmacokinetics of diethylcarbamazine after single oral dose at two different times of day in human subjects. J Clin Pharmacol. 2002 Mar;42(3):327-31. doi: 10.1177/00912700222011247.</citation>
    <PMID>11865970</PMID>
  </reference>
  <reference>
    <citation>Geary TG, Woo K, McCarthy JS, Mackenzie CD, Horton J, Prichard RK, de Silva NR, Olliaro PL, Lazdins-Helds JK, Engels DA, Bundy DA. Unresolved issues in anthelmintic pharmacology for helminthiases of humans. Int J Parasitol. 2010 Jan;40(1):1-13. doi: 10.1016/j.ijpara.2009.11.001. Epub 2009 Nov 20.</citation>
    <PMID>19932111</PMID>
  </reference>
  <reference>
    <citation>McGarry HF, Plant LD, Taylor MJ. Diethylcarbamazine activity against Brugia malayi microfilariae is dependent on inducible nitric-oxide synthase and the cyclooxygenase pathway. Filaria J. 2005 Jun 2;4:4. doi: 10.1186/1475-2883-4-4.</citation>
    <PMID>15932636</PMID>
  </reference>
  <reference>
    <citation>Weil GJ, Bogus J, Christian M, Dubray C, Djuardi Y, Fischer PU, Goss CW, Hardy M, Jambulingam P, King CL, Kuttiat VS, Krishnamoorthy K, Laman M, Lemoine JF, O'Brian KK, Robinson LJ, Samuela J, Schechtman KB, Sircar A, Srividya A, Steer AC, Supali T, Subramanian S; DOLF IDA Safety Study Group. The safety of double- and triple-drug community mass drug administration for lymphatic filariasis: A multicenter, open-label, cluster-randomized study. PLoS Med. 2019 Jun 24;16(6):e1002839. doi: 10.1371/journal.pmed.1002839. eCollection 2019 Jun.</citation>
    <PMID>31233507</PMID>
  </reference>
  <reference>
    <citation>Budge PJ, Herbert C, Andersen BJ, Weil GJ. Adverse events following single dose treatment of lymphatic filariasis: Observations from a review of the literature. PLoS Negl Trop Dis. 2018 May 16;12(5):e0006454. doi: 10.1371/journal.pntd.0006454. eCollection 2018 May.</citation>
    <PMID>29768412</PMID>
  </reference>
  <reference>
    <citation>Weil GJ, Lammie PJ, Richards FO Jr, Eberhard ML. Changes in circulating parasite antigen levels after treatment of bancroftian filariasis with diethylcarbamazine and ivermectin. J Infect Dis. 1991 Oct;164(4):814-6. doi: 10.1093/infdis/164.4.814.</citation>
    <PMID>1894943</PMID>
  </reference>
  <reference>
    <citation>Chhonker YS, Sleightholm RL, Murry DJ. Bioanalytical method development and validation of moxidectin in plasma by LC-MS/MS: Application to in vitro metabolism. Biomed Chromatogr. 2019 Feb;33(2):e4389. doi: 10.1002/bmc.4389. Epub 2018 Oct 30.</citation>
    <PMID>30238696</PMID>
  </reference>
  <reference>
    <citation>Hertz MI, Nana-Djeunga H, Kamgno J, Jelil Njouendou A, Chawa Chunda V, Wanji S, Rush A, Fischer PU, Weil GJ, Budge PJ. Identification and characterization of Loa loa antigens responsible for cross-reactivity with rapid diagnostic tests for lymphatic filariasis. PLoS Negl Trop Dis. 2018 Nov 16;12(11):e0006963. doi: 10.1371/journal.pntd.0006963. eCollection 2018 Nov.</citation>
    <PMID>30444866</PMID>
  </reference>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>May 27, 2020</study_first_submitted>
  <study_first_submitted_qc>May 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 1, 2020</study_first_posted>
  <last_update_submitted>October 3, 2022</last_update_submitted>
  <last_update_submitted_qc>October 3, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 6, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>moxidectin</keyword>
  <keyword>ivermectin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Filariasis</mesh_term>
    <mesh_term>Elephantiasis, Filarial</mesh_term>
    <mesh_term>Elephantiasis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ivermectin</mesh_term>
    <mesh_term>Albendazole</mesh_term>
    <mesh_term>Moxidectin</mesh_term>
    <mesh_term>Diethylcarbamazine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>De-identified datasets used for published results will be shared publically through a journal or other open source data repository so that the broader scientific community can access it. Datasets used for published results will be shared publically through a journal or other open source data repository so that the broader scientific community can access it. Only de-identified data will be shared outside of the study team.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04410406
org study id: 202005076
nct id: NCT04410406
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The purpose of this study is to determine whether moxidectin (Mox) will be more effective
      than ivermectin (IVM) when used in single-dose combination therapies for lymphatic filariasis
      (LF).
This study will test the hypothesis that Moxidectin combination therapies are superior to
      ivermectin combination therapies for achieving sustained clearance of W. bancrofti
      microfilaremia.

      This trial is designed as single-site, Phase III, randomized, open-label, masked-observer
      superiority trial with four treatment arms: ivermectin + albendazole (IA), moxidectin +
      albendazole (MoxA), ivermectin + diethylcarbamazine + albendazole (IDA), and moxidectin +
      diethylcarbamazine + albendazole (MoxDA). The primary endpoint is the proportion of
      participants achieving complete clearance of microfilaremia at 12 months (IA vs. MoxA
      comparison) or 24 months (IDA vs. MoxDA comparison). Block randomization by gender will be
      used to assign treatment arms.

      The first 48 participants (12 each arm) will be treated at Agboville Hospital in Cote
      d'Ivoire at the Centre de Recherche de Filariose with inpatient AE monitoring and collection
      of post-treatment plasma drug levels (Part 1). For Part 1, active AE surveillance will be
      conducted in the hospital on days 1, 2, and 3, post-treatment, and in the participant's
      village of residence on day 7 post-treatment and passive surveillance will be conducted by
      trained village health workers on days 4-6. An interim safety analysis will take place after
      Part 1. If no safety concerns are identified, the remainder of the participants will be
      treated in their home villages, with active AE monitoring on days 1 and 2 post-treatment
      (Part 2) with passive surveillance by trained village health workers on days 3-7. Any
      participant in either Part 1 or Part 2 experiencing AEs of grade 2 or higher will be followed
      until adverse event (AE) severity falls below grade 2. Follow-up assessments for efficacy of
      treatments for all participants (Parts 1 and 2) will be conducted at 6, 12, 24, and 36
      months.

      The study includes both safety and efficacy analyses. The safety assessment (Part 1 only)
      ends 7 days after treatment (unless AEs remain grade 2 or higher). The efficacy assessment
      (Parts 1 and 2 combined) ends when participants are retested for filarial infection 36 months
      post-treatment. Participants in the IA arm will receive IA annually (standard of care).
      Participants in the other arms will receive the assigned treatment at baseline; those found
      to be microfilaremic at 24 months post-treatment will be retreated with the same treatment
      received at baseline. If clearance of microfilariae (Mf) at 12 months in the IA arm is
      superior to Mf clearance in the MoxA arm, the MoxA group will be switched to annual IA
      treatment.

      The study design does not currently include stratification, nor do any sub-studies. However,
      the study may stratify based on pre-treatment Mf levels if high variability among
      pre-screening Mf counts is observed.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This trial is a single-site, Phase III, randomized, open-label, masked-observer superiority trial with four treatment arms (IA, MoxA, IDA, and MoxDA). Block randomization by gender will be used to assign treatment arms.
primary purpose: Treatment
masking: None (Open Label)
masking description: Recognizing that number and appearance of tablets received in each study arm will be noticeably different, this study will not be completely masked to participants or care providers. To minimize bias, administration of study medications will be performed by a staff member with no role in assessing AEs. AE assessments and all other outcome measures will be assessed by observers masked to the treatment assignment as best as possible.
measure: Clearance of microfilaremia (IA vs. MoxA)
time frame: 12 months
description: The proportion of participants in IA and MoxA study arms with complete clearance of W. bancrofti microfilaremia at 12 months after treatment.
measure: Clearance of microfilaremia (IDA vs. MoxDA)
time frame: 24 months
description: The proportion of participants in IDA and MoxDA study arms with complete clearance of W. bancrofti microfilaremia at 24 months after treatment.
measure: Clearance of microfilaremia
time frame: 6, 12, 24, & 36 months
description: The proportion of participants in each study arm with complete clearance of W. bancrofti microfilaremia at 6, 12, 24, & 36 months after treatment.
measure: Reduction in Mf counts
time frame: Baseline, 6, 12, & 24 months
description: Reduction in microfilariae counts (relative to baseline) at 6, 12, & 24 months
measure: Reduction in circulating filarial antigen (CFA) counts
time frame: Baseline, 6, 12, & 24 months
description: Reduction in circulating filarial antigen (CFA) counts (relative to baseline) at 6, 12, & 24 months
measure: Inactivation of adult worm nests
time frame: 6, 12, & 24 months
description: Inactivation of adult worm nests as assessed by scrotal ultrasound at 6, 12, and 24 months after treatment
measure: Frequency and severity of AEs
time frame: From baseline treatment to 7 days post-treatment
description: Frequency and severity of AEs during the first 7 days after treatment.
measure: Plasma levels of drugs/metabolites post treatment
time frame: Baseline, 2, 3, 4, 6, 12, 24, & 48 hours post-treatment
description: Noncompartmental pharmacokinetic analyses of DEC, ABZ, ABZSO, ABZSO2, IVM and Mox concentrations will be conducted using WinNonlin (Pharsight Corporation; Cary, North Carolina, USA). Drug plasma concentrations and computed pharmacokinetic parameters will be listed by subject and summarized by drug or metabolite (geometric mean with coefficient of variation, arithmetic mean with standard deviation, minimum, maximum, number of observations). Individual and geometric mean (by time) concentrations versus time will be plotted for each treatment group on both linear and natural logarithm scales.
arm group label: IA (Ivermectin + Albendazole)
arm group type: Active Comparator
description: Participants will receive one oral dose of Ivermectin (IVM) 200 µg/kg + Albendazole (ABZ) 400 mg (IA) annually for 24 months.
arm group label: MoxA (Moxidectin + Albendazole)
arm group type: Active Comparator
description: Participants will receive one oral dose of Mox 8 mg + ABZ 400 mg. Participants who are Mf positive at 24 months will be retreated with MoxA at the same dosage.
arm group label: IDA (Ivermectin + Diethylcarbamazine + Albendazole)
arm group type: Active Comparator
description: Participants will receive one oral dose of IVM 200 µg/kg + Diethylcarbamazine (DEC) 6mg/kg + ABZ 400 mg. Participants who are Mf positive at 24 months will be retreated with IDA at the same dosage.
arm group label: MoxDA (Moxidectin + Diethylcarbamazine + Albendazole)
arm group type: Active Comparator
description: Participants will receive one oral dose of Mox 8 mg + DEC 6mg/kg + ABZ 400 mg. Participants who are Mf positive at 24 months will be retreated with MoxDA at the same dosage.
intervention type: Drug
intervention name: Ivermectin
description: Ivermectin (IVM) 200 µg/kg
arm group label: IA (Ivermectin + Albendazole)
arm group label: IDA (Ivermectin + Diethylcarbamazine + Albendazole)
other name: Stromectol
intervention type: Drug
intervention name: Diethylcarbamazine
description: Diethylcarbamazine (DEC) 6mg/kg
arm group label: IDA (Ivermectin + Diethylcarbamazine + Albendazole)
arm group label: MoxDA (Moxidectin + Diethylcarbamazine + Albendazole)
other name: Diethylcarbamazine citrate
other name: Hetrazan
intervention type: Drug
intervention name: Albendazole
description: Albendazole (ABZ) 400 mg
arm group label: IA (Ivermectin + Albendazole)
arm group label: IDA (Ivermectin + Diethylcarbamazine + Albendazole)
arm group label: MoxA (Moxidectin + Albendazole)
arm group label: MoxDA (Moxidectin + Diethylcarbamazine + Albendazole)
intervention type: Drug
intervention name: Moxidectin
description: Moxidectin (Mox) 8 mg
arm group label: MoxA (Moxidectin + Albendazole)
arm group label: MoxDA (Moxidectin + Diethylcarbamazine + Albendazole)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Philip Budge, MD, PhD
role: Principal Investigator
affiliation: Washington University School of Medicine
last name: Catherine Bjerum, MD, MPH
role: Principal Investigator
affiliation: Case Western Reserve University
last name: Toki Pascal Gabo, MD
role: Principal Investigator
affiliation: Regional Hospital of Agboville, Southern Cote d'Ivoire
last name: Benjamin Koudou, PhD
role: Principal Investigator
affiliation: Regional Hospital of Agboville, Southern Cote d'Ivoire
facility: 
country: Côte D'Ivoire
url: https://tdr.who.int/newsroom/news/item/14-06-2018-first-new-treatment-for-river-blindness-approved-by-u-s-fda-in-20-years
description: First new treatment for river blindness approved by U.S. FDA in 20 years 2018 [cited 2018 June 27].
citation: Opoku NO, Bakajika DK, Kanza EM, Howard H, Mambandu GL, Nyathirombo A, Nigo MM, Kasonia K, Masembe SL, Mumbere M, Kataliko K, Larbelee JP, Kpawor M, Bolay KM, Bolay F, Asare S, Attah SK, Olipoh G, Vaillant M, Halleux CM, Kuesel AC. Single dose moxidectin versus ivermectin for Onchocerca volvulus infection in Ghana, Liberia, and the Democratic Republic of the Congo: a randomised, controlled, double-blind phase 3 trial. Lancet. 2018 Oct 6;392(10154):1207-1216. doi: 10.1016/S0140-6736(17)32844-1. Epub 2018 Jan 18. Erratum In: Lancet. 2018 Oct 6;392(10154):1196.
PMID: 29361335
citation: Ichimori K, King JD, Engels D, Yajima A, Mikhailov A, Lammie P, Ottesen EA. Global programme to eliminate lymphatic filariasis: the processes underlying programme success. PLoS Negl Trop Dis. 2014 Dec 11;8(12):e3328. doi: 10.1371/journal.pntd.0003328. eCollection 2014 Dec. No abstract available.
PMID: 25502758
citation: Ottesen EA, Duke BO, Karam M, Behbehani K. Strategies and tools for the control/elimination of lymphatic filariasis. Bull World Health Organ. 1997;75(6):491-503.
PMID: 9509621
citation: Ottesen EA. Lymphatic filariasis: Treatment, control and elimination. Adv Parasitol. 2006;61:395-441. doi: 10.1016/S0065-308X(05)61010-X.
PMID: 16735170
citation: Thomsen EK, Sanuku N, Baea M, Satofan S, Maki E, Lombore B, Schmidt MS, Siba PM, Weil GJ, Kazura JW, Fleckenstein LL, King CL. Efficacy, Safety, and Pharmacokinetics of Coadministered Diethylcarbamazine, Albendazole, and Ivermectin for Treatment of Bancroftian Filariasis. Clin Infect Dis. 2016 Feb 1;62(3):334-341. doi: 10.1093/cid/civ882. Epub 2015 Oct 20.
PMID: 26486704
citation: King CL, Suamani J, Sanuku N, Cheng YC, Satofan S, Mancuso B, Goss CW, Robinson LJ, Siba PM, Weil GJ, Kazura JW. A Trial of a Triple-Drug Treatment for Lymphatic Filariasis. N Engl J Med. 2018 Nov 8;379(19):1801-1810. doi: 10.1056/NEJMoa1706854.
PMID: 30403937
citation: Edi C, Bjerum CM, Ouattara AF, Chhonker YS, Penali LK, Meite A, Koudou BG, Weil GJ, King CL, Murry DJ. Pharmacokinetics, safety, and efficacy of a single co-administered dose of diethylcarbamazine, albendazole and ivermectin in adults with and without Wuchereria bancrofti infection in Cote d'Ivoire. PLoS Negl Trop Dis. 2019 May 20;13(5):e0007325. doi: 10.1371/journal.pntd.0007325. eCollection 2019 May.
PMID: 31107869
citation: Irvine MA, Stolk WA, Smith ME, Subramanian S, Singh BK, Weil GJ, Michael E, Hollingsworth TD. Effectiveness of a triple-drug regimen for global elimination of lymphatic filariasis: a modelling study. Lancet Infect Dis. 2017 Apr;17(4):451-458. doi: 10.1016/S1473-3099(16)30467-4. Epub 2016 Dec 22.
PMID: 28012943
citation: Kyelem D, Biswas G, Bockarie MJ, Bradley MH, El-Setouhy M, Fischer PU, Henderson RH, Kazura JW, Lammie PJ, Njenga SM, Ottesen EA, Ramaiah KD, Richards FO, Weil GJ, Williams SA. Determinants of success in national programs to eliminate lymphatic filariasis: a perspective identifying essential elements and research needs. Am J Trop Med Hyg. 2008 Oct;79(4):480-4.
PMID: 18840733
citation: Molyneux DH, Hopkins A, Bradley MH, Kelly-Hope LA. Multidimensional complexities of filariasis control in an era of large-scale mass drug administration programmes: a can of worms. Parasit Vectors. 2014 Aug 15;7:363. doi: 10.1186/1756-3305-7-363.
PMID: 25128408
citation: Horton J. Albendazole: a broad spectrum anthelminthic for treatment of individuals and populations. Curr Opin Infect Dis. 2002 Dec;15(6):599-608. doi: 10.1097/00001432-200212000-00008.
PMID: 12821837
citation: Horton J, Witt C, Ottesen EA, Lazdins JK, Addiss DG, Awadzi K, Beach MJ, Belizario VY, Dunyo SK, Espinel M, Gyapong JO, Hossain M, Ismail MM, Jayakody RL, Lammie PJ, Makunde W, Richard-Lenoble D, Selve B, Shenoy RK, Simonsen PE, Wamae CN, Weerasooriya MV. An analysis of the safety of the single dose, two drug regimens used in programmes to eliminate lymphatic filariasis. Parasitology. 2000;121 Suppl:S147-60. doi: 10.1017/s0031182000007423.
PMID: 11386686
citation: Kitzman D, Cheng KJ, Fleckenstein L. HPLC assay for albendazole and metabolites in human plasma for clinical pharmacokinetic studies. J Pharm Biomed Anal. 2002 Oct 15;30(3):801-13. doi: 10.1016/s0731-7085(02)00382-5.
PMID: 12367706
citation: Geary TG. Ivermectin 20 years on: maturation of a wonder drug. Trends Parasitol. 2005 Nov;21(11):530-2. doi: 10.1016/j.pt.2005.08.014. Epub 2005 Aug 26.
PMID: 16126457
citation: Moreno Y, Nabhan JF, Solomon J, Mackenzie CD, Geary TG. Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi. Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):20120-5. doi: 10.1073/pnas.1011983107. Epub 2010 Nov 1.
PMID: 21041637
citation: Awadzi K, Edwards G, Opoku NO, Ardrey AE, Favager S, Addy ET, Attah SK, Yamuah LK, Quartey BT. The safety, tolerability and pharmacokinetics of levamisole alone, levamisole plus ivermectin, and levamisole plus albendazole, and their efficacy against Onchocerca volvulus. Ann Trop Med Parasitol. 2004 Sep;98(6):595-614. doi: 10.1179/000349804225021370.
PMID: 15324466
citation: Kitzman D, Wei SY, Fleckenstein L. Liquid chromatographic assay of ivermectin in human plasma for application to clinical pharmacokinetic studies. J Pharm Biomed Anal. 2006 Mar 3;40(4):1013-20. doi: 10.1016/j.jpba.2005.08.026. Epub 2005 Oct 19.
PMID: 16242280
citation: Awadzi K, Edwards G, Duke BO, Opoku NO, Attah SK, Addy ET, Ardrey AE, Quartey BT. The co-administration of ivermectin and albendazole--safety, pharmacokinetics and efficacy against Onchocerca volvulus. Ann Trop Med Parasitol. 2003 Mar;97(2):165-78. doi: 10.1179/000349803235001697.
PMID: 12803872
citation: Bolla S, Boinpally RR, Poondru S, Devaraj R, Jasti BR. Pharmacokinetics of diethylcarbamazine after single oral dose at two different times of day in human subjects. J Clin Pharmacol. 2002 Mar;42(3):327-31. doi: 10.1177/00912700222011247.
PMID: 11865970
citation: Geary TG, Woo K, McCarthy JS, Mackenzie CD, Horton J, Prichard RK, de Silva NR, Olliaro PL, Lazdins-Helds JK, Engels DA, Bundy DA. Unresolved issues in anthelmintic pharmacology for helminthiases of humans. Int J Parasitol. 2010 Jan;40(1):1-13. doi: 10.1016/j.ijpara.2009.11.001. Epub 2009 Nov 20.
PMID: 19932111
citation: McGarry HF, Plant LD, Taylor MJ. Diethylcarbamazine activity against Brugia malayi microfilariae is dependent on inducible nitric-oxide synthase and the cyclooxygenase pathway. Filaria J. 2005 Jun 2;4:4. doi: 10.1186/1475-2883-4-4.
PMID: 15932636
citation: Weil GJ, Bogus J, Christian M, Dubray C, Djuardi Y, Fischer PU, Goss CW, Hardy M, Jambulingam P, King CL, Kuttiat VS, Krishnamoorthy K, Laman M, Lemoine JF, O'Brian KK, Robinson LJ, Samuela J, Schechtman KB, Sircar A, Srividya A, Steer AC, Supali T, Subramanian S; DOLF IDA Safety Study Group. The safety of double- and triple-drug community mass drug administration for lymphatic filariasis: A multicenter, open-label, cluster-randomized study. PLoS Med. 2019 Jun 24;16(6):e1002839. doi: 10.1371/journal.pmed.1002839. eCollection 2019 Jun.
PMID: 31233507
citation: Budge PJ, Herbert C, Andersen BJ, Weil GJ. Adverse events following single dose treatment of lymphatic filariasis: Observations from a review of the literature. PLoS Negl Trop Dis. 2018 May 16;12(5):e0006454. doi: 10.1371/journal.pntd.0006454. eCollection 2018 May.
PMID: 29768412
citation: Weil GJ, Lammie PJ, Richards FO Jr, Eberhard ML. Changes in circulating parasite antigen levels after treatment of bancroftian filariasis with diethylcarbamazine and ivermectin. J Infect Dis. 1991 Oct;164(4):814-6. doi: 10.1093/infdis/164.4.814.
PMID: 1894943
citation: Chhonker YS, Sleightholm RL, Murry DJ. Bioanalytical method development and validation of moxidectin in plasma by LC-MS/MS: Application to in vitro metabolism. Biomed Chromatogr. 2019 Feb;33(2):e4389. doi: 10.1002/bmc.4389. Epub 2018 Oct 30.
PMID: 30238696
citation: Hertz MI, Nana-Djeunga H, Kamgno J, Jelil Njouendou A, Chawa Chunda V, Wanji S, Rush A, Fischer PU, Weil GJ, Budge PJ. Identification and characterization of Loa loa antigens responsible for cross-reactivity with rapid diagnostic tests for lymphatic filariasis. PLoS Negl Trop Dis. 2018 Nov 16;12(11):e0006963. doi: 10.1371/journal.pntd.0006963. eCollection 2018 Nov.
PMID: 30444866
responsible party type: Sponsor
mesh term: Filariasis
mesh term: Elephantiasis, Filarial
mesh term: Elephantiasis
mesh term: Ivermectin
mesh term: Albendazole
mesh term: Moxidectin
mesh term: Diethylcarbamazine
sharing ipd: Yes
ipd description: De-identified datasets used for published results will be shared publically through a journal or other open source data repository so that the broader scientific community can access it. Datasets used for published results will be shared publically through a journal or other open source data repository so that the broader scientific community can access it. Only de-identified data will be shared outside of the study team.