<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/NCT03238131</url>
  </required_header>
  <id_info>
    <org_study_id>11-11-36</org_study_id>
    <nct_id>NCT03238131</nct_id>
  </id_info>
  <brief_title>IVM Alone vs ALB + IVM Against Onchocerciasis</brief_title>
  <official_title>Comparison of Ivermectin Alone With Albendazole (ALB) Plus Ivermectin (IVM) in Their Efficacy Against Onchocerciasis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospitals Cleveland Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospitals Cleveland Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Onchocerciasis is a vector-borne nematode parasitic disease that causes severe disability.&#xD;
      Onchocerciasis affects approximately 33 million people, mostly in 30 countries in sub-Saharan&#xD;
      Africa (with small foci in Latin America and Yemen) 1This disease causes blindness and severe&#xD;
      skin disease and it is spread by black flies. O. volvulus adult worms live in subcutaneous&#xD;
      nodules. O. volvulus adult worms are larger and less sensitive to available drug treatments&#xD;
      than those of the species that cause Lymphatic Filariasis (LF). They also have a longer&#xD;
      lifespan (approximately 14 years rather than the estimated 7 years for LF parasites). Several&#xD;
      programs and developments have greatly improved the Onchocerciasis. situation since the&#xD;
      1970's when the Onchocerciasis Control Programme (OCP) in West Africa (green countries in the&#xD;
      map) was initiated. OCP relied exclusively on vector (black fly) control in its early years.&#xD;
      However, following the appearance of Ivermectin (Mectizan) on the scene in the late 1980's,&#xD;
      OCP transitioned to become a drug distribution program with annual IVM MDA in 11 countries.&#xD;
      OCP ended in 2002. This was replaced by the African Program for Onchocerciasis Control (APOC)&#xD;
      which coordinates community directed distribution of IVM MDA in 28 African countries&#xD;
      (including the former OCP countries). OCP and APOC have done a good job of reducing parasite&#xD;
      infection intensities and Onchocerciasis disease rates in many endemic countries.&#xD;
      Unfortunately, there is no real end in sight for the APOC approach (apart from a funding&#xD;
      endpoint in 2015); while it may be possible to eliminate Onchocerciasis. In selected areas by&#xD;
      MDA with IVM (alone, or combined with vector control), disease control programs in most&#xD;
      African countries will require active maintenance for many years to come. While IVR has good&#xD;
      activity against the parasite larvae that cause disease in the skin and eye (microfilariae or&#xD;
      Mf), it does not kill O. volvulus adult worms, and they resume production of Mf that can lead&#xD;
      to transmission of new Onchocerciasis. Cases by black flies after a few months. APOC&#xD;
      activities are focused on areas with high infection rates (where disease risks are highest).&#xD;
      However, extensive areas in Africa where fewer than 20% of adult men have Onchocerciasis&#xD;
      nodules detectable by palpation are not receiving interventions for Onchocerciasis at this&#xD;
      time. These areas are not disease free. (Onchocerciasis dermatitis can be severe in&#xD;
      hypoendemic areas), and they also may serve as a source for reintroduction of the parasite&#xD;
      into previously controlled areas after interventions stop.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Onchocerciasis control programs have relied on annual MDA with IVM at a dose of 150-200&#xD;
      µg/kg. This regimen kills skin (and eye) Mf, thereby reducing disease and (in some areas)&#xD;
      transmission. However, standard IVM monotherapy has little macrofilaricidal activity against&#xD;
      adult O. volvulus, and it does not permanently sterilize adult worms, which have a&#xD;
      reproductive life span of 12-14 years. More effective drugs or dosing schedules that have&#xD;
      embryo-static or macrofilaricidal activity could drastically reduce the number of years&#xD;
      required to interrupt transmission of Onchocerciasis. IVM has activity against adult O.&#xD;
      volvulus when it is given at high doses four times per year for several years. This regimen&#xD;
      caused some adverse events, and is not practical for national control programs. By contrast,&#xD;
      whereas ALB has little effect on O. volvulus Mf, the drug has embryo-toxic effects at&#xD;
      standard doses manifest as partial suppression (by 66%) of skin Mf counts for at least one&#xD;
      year. ALB given at doses of 800 mg produced a more sustained reduction in Mf relative to a&#xD;
      dose of 400 mg, but higher doses did not improve efficacy. It is not known whether ALB&#xD;
      produces transient or permanent female worm sterility. Administration of a single 400 mg dose&#xD;
      of ALB combined with IVM 200 µg/kg failed to a show greater reduction in Mf or&#xD;
      macrofilaricidal activity compared to IVM alone; however, combination therapy suppressed&#xD;
      embryogenesis more than IVM alone. These studies involved small numbers of participants, used&#xD;
      ALB only at a dose of 400 mg, and followed the participants for just one year. Thus, IVM&#xD;
      combined with ALB at higher doses given more than once per year may generate more sustained&#xD;
      reduction in Mf by reducing female fertility or by killing adult worms.&#xD;
&#xD;
      IVM and ALB are very safe and highly effective anti-filarial drugs when given singly or in&#xD;
      combination.&#xD;
&#xD;
      ALB causes degenerative alterations in the tegument and intestinal cells of the worm by&#xD;
      binding to the colchicine-sensitive site of tubulin, thus inhibiting its polymerization or&#xD;
      assembly into microtubules. The loss of cytoplasmic microtubules leads to impaired uptake of&#xD;
      glucose by larval and adult stages of the parasite, and depletes glycogen stores.&#xD;
      Degenerative changes in endoplasmic reticulum and mitochondria of the germinal layer, and the&#xD;
      subsequent release of lysosomal enzymes result in decreased production of adenosine&#xD;
      triphosphate, which is the source of energy required for survival of the helminth. Due to&#xD;
      diminished energy production, the parasite is immobilized and eventually dies. The drug has&#xD;
      been shown to cause occasionally (&lt;1% of treated patients) reversible reductions in total&#xD;
      white blood cell count. It has also been associated with slight increases in liver&#xD;
      transaminases in ~16% of patients. The enzymes return to normal levels with cessation of&#xD;
      treatment. These abnormalities are associated primarily with prolonged treatment for such&#xD;
      diseases as neurocysticercosis and hydatid diseases, not single dose treatment which is being&#xD;
      proposed here. ALB given with fatty foods as proposed in the current protocol will increase&#xD;
      absorption and may increase the risk of adverse side effects.&#xD;
&#xD;
      IVMis an avermectin compound of macrocyclic lactones derived from the bacterium Streptomyces&#xD;
      avermitilis. The mechanism by which IVM kills LF microfilariae is not known with certainty,&#xD;
      but the drug interferes with glutamate gated ion channels that can affect parasite&#xD;
      contractility and release of immunomodulatory molecules by the parasite. IVM also has a&#xD;
      direct effect on the central nervous system and muscle function as it enhances strength of&#xD;
      inhibitory neurotransmission pathways. The main concern with use of IVM in animals and humans&#xD;
      is neurotoxicity, which can be manifest as ataxia. Neurotoxicity has not been observed in&#xD;
      humans given single dose IVM for LF or other parasitic infections, and the drug has been used&#xD;
      to treat millions of people with LF and Onchocerciasis. Peak IVM serum concentrations are&#xD;
      reached approximately 4-5 hours after administration. The half-life of IVM in various&#xD;
      populations ranges from 12 to 56 hours 12. There is no evidence of drug:drug interaction&#xD;
      between ALB and IVM.&#xD;
&#xD;
      IVM can cause nausea, dizziness and occasionally pruritus, but these are infrequent,&#xD;
      transient and usually mild. Major side effects occur with heavy infections of Loa loa;&#xD;
      however, this parasite is not endemic in Ghana.&#xD;
&#xD;
      In Ghana the chiefs and elders are the custodians of the land so they must first to be&#xD;
      contacted for permission to enter their communities. The study objectives and procedures are&#xD;
      then explained to them, and if they accept it then the research team is allowed to enter the&#xD;
      communities to explain the research aims and procedures to their subjects.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>April 2012</start_date>
  <completion_date type="Actual">October 2016</completion_date>
  <primary_completion_date type="Actual">April 2015</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>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The percent fertile female O.volvulus worms in nodules</measure>
    <time_frame>36 months</time_frame>
    <description>Total number of live versus dead female worms in nodules</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percent reduction in skin Mf/mg</measure>
    <time_frame>0 months</time_frame>
    <description>Percent of live female worms in nodules</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent reduction in skin Mf/mg</measure>
    <time_frame>6 months</time_frame>
    <description>Total number of live versus dead female worms in nodules compared to time point zero</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent reduction in skin Mf/mg</measure>
    <time_frame>18 months</time_frame>
    <description>Total number of live versus dead female worms in nodules compared to time point zero</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent reduction in skin Mf/mg</measure>
    <time_frame>36 months</time_frame>
    <description>Total number of live versus dead female worms in nodules compared to time point zero</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of nodules with intact Mf</measure>
    <time_frame>36 months</time_frame>
    <description>number of nodules with intact Mf at 36 months following initial therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Soil Transmitted Helminth (STH) infections</measure>
    <time_frame>36 months</time_frame>
    <description>Assessment of the different treatment regimens on STH infections based on presence of intensity of ova in stools.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">272</enrollment>
  <condition>Onchocerciasis</condition>
  <arm_group>
    <arm_group_label>IVM annually (standard treatment)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The comparator (standard treatment) IVM 200 µg/kg body weight given at 0, 12 and 24 months plus vitamin pills at 6 and 18 months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>IVM plus ALB twice annually</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>IVM 200 µg/kg plus ALB 800 mg (regardless of weight) given at 0, 6, 12, 18, 24 months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>IVM plus ALB once annually</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>IVM 200 µg/kg plus ALB 800 mg given at 0, 12, 24 months plus vitamin pills at 6 and 18 months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>IVM twice annually</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>IVM 200 µg/kg given 0, 6, 12, 18, and 24 months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ivermectin</intervention_name>
    <description>Participants are either given Ivermectin alone or Ivermectin in combination with Albendazole</description>
    <arm_group_label>IVM annually (standard treatment)</arm_group_label>
    <arm_group_label>IVM plus ALB once annually</arm_group_label>
    <arm_group_label>IVM plus ALB twice annually</arm_group_label>
    <arm_group_label>IVM twice annually</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Albendazole</intervention_name>
    <description>Albendazole will be given to participants in Arm 2 and 3 in combination with Ivermectin at varying time points.</description>
    <arm_group_label>IVM plus ALB once annually</arm_group_label>
    <arm_group_label>IVM plus ALB twice annually</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Men and women 18-60 years residing in Ashanti and Central Region of Ghana&#xD;
&#xD;
          -  ≥1 accessible nodules&#xD;
&#xD;
          -  any Mf/mg based on skin snips&#xD;
&#xD;
          -  Willingness to give informed consent to participation in the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Last IVM treatment &lt; 7 months&#xD;
&#xD;
          -  Pregnant (do pregnancy test) + breastfeeding&#xD;
&#xD;
          -  Permanent disability, serious medical illnesses such as a stroke, advanced heart&#xD;
             disease, uncontrolled diabetes, emphysema, etc that prevents or impedes study&#xD;
             participation and/or comprehension&#xD;
&#xD;
          -  Weight of &lt;40kg suggesting malnourishment&#xD;
&#xD;
          -  AST/ALT, γ-GT &gt; 1.5 upper limit of normal&#xD;
&#xD;
          -  Significant glycosuria or proteinuria (2+ or 3+ protein or glucose)&#xD;
&#xD;
          -  Any one or more of the previous criteria is sufficient to exclude study participation&#xD;
&#xD;
          -  Not willing or able to give informed consent to participate in the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Committee on Human Research Publications and Ethics</name>
      <address>
        <city>Kumasi</city>
        <state>Ashanti</state>
        <country>Ghana</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Ghana</country>
  </location_countries>
  <reference>
    <citation>Basanez MG, Pion SD, Churcher TS, Breitling LP, Little MP, Boussinesq M. River blindness: a success story under threat? PLoS Med. 2006 Sep;3(9):e371. doi: 10.1371/journal.pmed.0030371.</citation>
    <PMID>17002504</PMID>
  </reference>
  <reference>
    <citation>Gardon J, Boussinesq M, Kamgno J, Gardon-Wendel N, Demanga-Ngangue, Duke BO. Effects of standard and high doses of ivermectin on adult worms of Onchocerca volvulus: a randomised controlled trial. Lancet. 2002 Jul 20;360(9328):203-10. doi: 10.1016/S0140-6736(02)09456-4.</citation>
    <PMID>12133654</PMID>
  </reference>
  <reference>
    <citation>Zahner H, Schares G. Experimental chemotherapy of filariasis: comparative evaluation of the efficacy of filaricidal compounds in Mastomys coucha infected with Litomosoides carinii, Acanthocheilonema viteae, Brugia malayi and B. pahangi. Acta Trop. 1993 Jan;52(4):221-66. doi: 10.1016/0001-706x(93)90010-9.</citation>
    <PMID>8094587</PMID>
  </reference>
  <reference>
    <citation>Awadzi K, Hero M, Opoku O, Buttner DW, Gilles HM. The chemotherapy of onchocerciasis. XV. Studies with albendazole. Trop Med Parasitol. 1991 Dec;42(4):356-60.</citation>
    <PMID>1796233</PMID>
  </reference>
  <reference>
    <citation>Awadzi K, Addy ET, Opoku NO, Plenge-Bonig A, Buttner DW. The chemotherapy of onchocerciasis XX: ivermectin in combination with albendazole. Trop Med Parasitol. 1995 Dec;46(4):213-20.</citation>
    <PMID>8826100</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>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>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>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>Cringoli G, Rinaldi L, Maurelli MP, Utzinger J. FLOTAC: new multivalent techniques for qualitative and quantitative copromicroscopic diagnosis of parasites in animals and humans. Nat Protoc. 2010 Mar;5(3):503-15. doi: 10.1038/nprot.2009.235. Epub 2010 Feb 25.</citation>
    <PMID>20203667</PMID>
  </reference>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>July 25, 2017</study_first_submitted>
  <study_first_submitted_qc>July 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2017</study_first_posted>
  <last_update_submitted>August 28, 2017</last_update_submitted>
  <last_update_submitted_qc>August 28, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 29, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Case Western Reserve University</investigator_affiliation>
    <investigator_full_name>Christopher L. King, MD, PhD</investigator_full_name>
    <investigator_title>Professor of International Health, Medicine and Pathology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Onchocerciasis</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>
  </intervention_browse>
  <!-- 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/NCT03238131
org study id: 11-11-36
nct id: NCT03238131
lead sponsor: 
collaborator: 
has dmc: No
Onchocerciasis is a vector-borne nematode parasitic disease that causes severe disability.
      Onchocerciasis affects approximately 33 million people, mostly in 30 countries in sub-Saharan
      Africa (with small foci in Latin America and Yemen) 1This disease causes blindness and severe
      skin disease and it is spread by black flies. O. volvulus adult worms live in subcutaneous
      nodules. O. volvulus adult worms are larger and less sensitive to available drug treatments
      than those of the species that cause Lymphatic Filariasis (LF). They also have a longer
      lifespan (approximately 14 years rather than the estimated 7 years for LF parasites). Several
      programs and developments have greatly improved the Onchocerciasis. situation since the
      1970's when the Onchocerciasis Control Programme (OCP) in West Africa (green countries in the
      map) was initiated. OCP relied exclusively on vector (black fly) control in its early years.
      However, following the appearance of Ivermectin (Mectizan) on the scene in the late 1980's,
      OCP transitioned to become a drug distribution program with annual IVM MDA in 11 countries.
      OCP ended in 2002. This was replaced by the African Program for Onchocerciasis Control (APOC)
      which coordinates community directed distribution of IVM MDA in 28 African countries
      (including the former OCP countries). OCP and APOC have done a good job of reducing parasite
      infection intensities and Onchocerciasis disease rates in many endemic countries.
      Unfortunately, there is no real end in sight for the APOC approach (apart from a funding
      endpoint in 2015); while it may be possible to eliminate Onchocerciasis. In selected areas by
      MDA with IVM (alone, or combined with vector control), disease control programs in most
      African countries will require active maintenance for many years to come. While IVR has good
      activity against the parasite larvae that cause disease in the skin and eye (microfilariae or
      Mf), it does not kill O. volvulus adult worms, and they resume production of Mf that can lead
      to transmission of new Onchocerciasis. Cases by black flies after a few months. APOC
      activities are focused on areas with high infection rates (where disease risks are highest).
      However, extensive areas in Africa where fewer than 20% of adult men have Onchocerciasis
      nodules detectable by palpation are not receiving interventions for Onchocerciasis at this
      time. These areas are not disease free. (Onchocerciasis dermatitis can be severe in
      hypoendemic areas), and they also may serve as a source for reintroduction of the parasite
      into previously controlled areas after interventions stop.
Onchocerciasis control programs have relied on annual MDA with IVM at a dose of 150-200
      µg/kg. This regimen kills skin (and eye) Mf, thereby reducing disease and (in some areas)
      transmission. However, standard IVM monotherapy has little macrofilaricidal activity against
      adult O. volvulus, and it does not permanently sterilize adult worms, which have a
      reproductive life span of 12-14 years. More effective drugs or dosing schedules that have
      embryo-static or macrofilaricidal activity could drastically reduce the number of years
      required to interrupt transmission of Onchocerciasis. IVM has activity against adult O.
      volvulus when it is given at high doses four times per year for several years. This regimen
      caused some adverse events, and is not practical for national control programs. By contrast,
      whereas ALB has little effect on O. volvulus Mf, the drug has embryo-toxic effects at
      standard doses manifest as partial suppression (by 66%) of skin Mf counts for at least one
      year. ALB given at doses of 800 mg produced a more sustained reduction in Mf relative to a
      dose of 400 mg, but higher doses did not improve efficacy. It is not known whether ALB
      produces transient or permanent female worm sterility. Administration of a single 400 mg dose
      of ALB combined with IVM 200 µg/kg failed to a show greater reduction in Mf or
      macrofilaricidal activity compared to IVM alone; however, combination therapy suppressed
      embryogenesis more than IVM alone. These studies involved small numbers of participants, used
      ALB only at a dose of 400 mg, and followed the participants for just one year. Thus, IVM
      combined with ALB at higher doses given more than once per year may generate more sustained
      reduction in Mf by reducing female fertility or by killing adult worms.

      IVM and ALB are very safe and highly effective anti-filarial drugs when given singly or in
      combination.

      ALB causes degenerative alterations in the tegument and intestinal cells of the worm by
      binding to the colchicine-sensitive site of tubulin, thus inhibiting its polymerization or
      assembly into microtubules. The loss of cytoplasmic microtubules leads to impaired uptake of
      glucose by larval and adult stages of the parasite, and depletes glycogen stores.
      Degenerative changes in endoplasmic reticulum and mitochondria of the germinal layer, and the
      subsequent release of lysosomal enzymes result in decreased production of adenosine
      triphosphate, which is the source of energy required for survival of the helminth. Due to
      diminished energy production, the parasite is immobilized and eventually dies. The drug has
      been shown to cause occasionally (<1% of treated patients) reversible reductions in total
      white blood cell count. It has also been associated with slight increases in liver
      transaminases in ~16% of patients. The enzymes return to normal levels with cessation of
      treatment. These abnormalities are associated primarily with prolonged treatment for such
      diseases as neurocysticercosis and hydatid diseases, not single dose treatment which is being
      proposed here. ALB given with fatty foods as proposed in the current protocol will increase
      absorption and may increase the risk of adverse side effects.

      IVMis an avermectin compound of macrocyclic lactones derived from the bacterium Streptomyces
      avermitilis. The mechanism by which IVM kills LF microfilariae is not known with certainty,
      but the drug interferes with glutamate gated ion channels that can affect parasite
      contractility and release of immunomodulatory molecules by the parasite. IVM also has a
      direct effect on the central nervous system and muscle function as it enhances strength of
      inhibitory neurotransmission pathways. The main concern with use of IVM in animals and humans
      is neurotoxicity, which can be manifest as ataxia. Neurotoxicity has not been observed in
      humans given single dose IVM for LF or other parasitic infections, and the drug has been used
      to treat millions of people with LF and Onchocerciasis. Peak IVM serum concentrations are
      reached approximately 4-5 hours after administration. The half-life of IVM in various
      populations ranges from 12 to 56 hours 12. There is no evidence of drug:drug interaction
      between ALB and IVM.

      IVM can cause nausea, dizziness and occasionally pruritus, but these are infrequent,
      transient and usually mild. Major side effects occur with heavy infections of Loa loa;
      however, this parasite is not endemic in Ghana.

      In Ghana the chiefs and elders are the custodians of the land so they must first to be
      contacted for permission to enter their communities. The study objectives and procedures are
      then explained to them, and if they accept it then the research team is allowed to enter the
      communities to explain the research aims and procedures to their subjects.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: The percent fertile female O.volvulus worms in nodules
time frame: 36 months
description: Total number of live versus dead female worms in nodules
measure: Percent reduction in skin Mf/mg
time frame: 0 months
description: Percent of live female worms in nodules
measure: Percent reduction in skin Mf/mg
time frame: 6 months
description: Total number of live versus dead female worms in nodules compared to time point zero
measure: Percent reduction in skin Mf/mg
time frame: 18 months
description: Total number of live versus dead female worms in nodules compared to time point zero
measure: Percent reduction in skin Mf/mg
time frame: 36 months
description: Total number of live versus dead female worms in nodules compared to time point zero
measure: Number of nodules with intact Mf
time frame: 36 months
description: number of nodules with intact Mf at 36 months following initial therapy
measure: Soil Transmitted Helminth (STH) infections
time frame: 36 months
description: Assessment of the different treatment regimens on STH infections based on presence of intensity of ova in stools.
arm group label: IVM annually (standard treatment)
arm group type: Active Comparator
description: The comparator (standard treatment) IVM 200 µg/kg body weight given at 0, 12 and 24 months plus vitamin pills at 6 and 18 months.
arm group label: IVM plus ALB twice annually
arm group type: Experimental
description: IVM 200 µg/kg plus ALB 800 mg (regardless of weight) given at 0, 6, 12, 18, 24 months
arm group label: IVM plus ALB once annually
arm group type: Active Comparator
description: IVM 200 µg/kg plus ALB 800 mg given at 0, 12, 24 months plus vitamin pills at 6 and 18 months.
arm group label: IVM twice annually
arm group type: Active Comparator
description: IVM 200 µg/kg given 0, 6, 12, 18, and 24 months
intervention type: Drug
intervention name: Ivermectin
description: Participants are either given Ivermectin alone or Ivermectin in combination with Albendazole
arm group label: IVM annually (standard treatment)
arm group label: IVM plus ALB once annually
arm group label: IVM plus ALB twice annually
arm group label: IVM twice annually
intervention type: Drug
intervention name: Albendazole
description: Albendazole will be given to participants in Arm 2 and 3 in combination with Ivermectin at varying time points.
arm group label: IVM plus ALB once annually
arm group label: IVM plus ALB twice annually
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
facility: 
country: Ghana
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responsible party type: Principal Investigator
investigator affiliation: Case Western Reserve University
investigator full name: Christopher L. King, MD, PhD
investigator title: Professor of International Health, Medicine and Pathology
mesh term: Onchocerciasis
mesh term: Ivermectin
mesh term: Albendazole