<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/NCT03278808</url>
  </required_header>
  <id_info>
    <org_study_id>S-16-06</org_study_id>
    <nct_id>NCT03278808</nct_id>
  </id_info>
  <brief_title>Chloroquine (CQ) and Azithromycin (AZ) Combination for Malaria Prophylaxis</brief_title>
  <official_title>A Phase 2a Open Label Study of the Safety and Efficacy of a Single Dose of Weekly Chloroquine (CQ) and Azithromycin (AZ) Administered in Combination for Malaria Prophylaxis in Healthy Adults Challenged With 7G8 Chloroquine-Resistant Plasmodium Falciparum in a Controlled Human Malaria Infection (CHMI) Model</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>U.S. Army Medical Research and Development Command</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>U.S. Army Medical Research and Development Command</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an open label, Phase 2 study with controlled human malaria infection (CHMI). Twenty&#xD;
      three subjects will be enrolled into 2 groups (15 subjects in the Chloroquine-Azithromycin&#xD;
      [CQ/AZ] Intervention Group, and 8 subjects in the Chloroquine [CQ] Group). The CQ/AZ Group&#xD;
      will receive experimental intervention of 300 mg of CQ and 2 g of azithromycin (AZ). The CQ&#xD;
      Group will receive 300 mg of CQ only. All subjects will participate in the CHMI and will be&#xD;
      required to stay at a hotel for evaluation for a maximum of 14 nights starting 7 days after&#xD;
      the challenge. A standard dose of atovaquone-proguanil (Malarone®) will be administered to&#xD;
      all symptomatic parasitemic subjects under directly observed treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study is a Phase 2, open-label study of the combination of a single dose-level of AZ&#xD;
      (Zithromax) plus CQ given weekly as a prophylaxis against CQ-resistant P falciparum in&#xD;
      healthy adults. After signing informed consent, subjects will undergo screening procedures&#xD;
      between Day -77 to Day -18. If enrolled, subjects who are still eligible at Study Day -18&#xD;
      will be randomized to either the CQ/AZ group (Group 1 of 15 subjects: 2 g AZ (Zithromax) plus&#xD;
      300 mg CQ base weekly for 6 weeks), or the CQ control group (Group 2 of 8 subjects: 300 mg&#xD;
      chloroquine base weekly for 6 weeks) and start intervention on Study Day -17. The rationale&#xD;
      for the CQ control group to receive CQ is to show that the strain utilized (7G8) is indeed&#xD;
      chloroquine resistant in humans: we expect all of the subjects in the CQ control group to&#xD;
      become symptomatically parasitemic. If 3 or more subjects in the CQ control group do not&#xD;
      become symptomatic with malaria, the CHMI will be considered uncontrolled either due to 7G8&#xD;
      not being CQ-resistant, or the parasite not being infective.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    The IND has been withdrawn from FDA&#xD;
  </why_stopped>
  <start_date type="Actual">September 17, 2018</start_date>
  <completion_date type="Actual">January 1, 2020</completion_date>
  <primary_completion_date type="Actual">December 30, 2019</primary_completion_date>
  <phase>Phase 2</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>Subjects will be randomized to either the CQ/AZ group (Group 1 of 15 subjects: 2 g AZ (Zithromax) plus 300 mg CQ base weekly for 6 weeks), or the CQ control group (Group 2 of 8 subjects: 300 mg chloroquine base weekly for 6 weeks)</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>Because placebo for both products is difficult to obtain and because the primary endpoint of symptomatic parasitemia is an objective measure, treatment will be open-label. Microscopists reading the smears will be blinded to the group, but will be aware of whether or not a particular sample is from a symptomatic subject.&#xD;
Although symptoms are a subjective measure and part of the primary endpoint of symptomatic parasitemia, subjects will not be told if they are parasitemic prior to treatment initiation thus making symptomatic complaints and this endpoint more reliable.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Efficacy: Proportion of subjects free from symptomatic parasitemic subjects</measure>
    <time_frame>Days 1 thru 56</time_frame>
    <description>CQ/AZ Group will be compared to endpoint in CQ Group by Fisher's Exact Test. Symptomatic is defined as any one of the following solicited adverse events that first occurred concurrent with parasitemia: fever (temperature &gt; 100.4 °F), chills, headache, arthralgia, myalgia, nausea, vomiting, or abdominal pain. Subjects will only undergo malaria treatment after both criteria are met.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety: Solicited and unsolicited Adverse Events in each group</measure>
    <time_frame>Days 1 thru 56</time_frame>
    <description>Groups will be analyzed by descriptive statistics and safety monitoring will be conducted throughout the study</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Electrocardiogram baseline vs peak concentration for AZ</measure>
    <time_frame>Day 11 post challenge, 6 hours after dosing</time_frame>
    <description>QTcF will be analyzed for CQ/AZ Group subjects at presumed field-effective time point (Day 11 post challenge) 6 hours after dosing, which will coincide with time to peak concentration for AZ. This will be compared to baseline reading</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics: Cmax - comparison for CQ/AZ-Group subjects</measure>
    <time_frame>Days 11 thru 15</time_frame>
    <description>Cmax will be compared for CQ/AZ-Group subjects who become symptomatic and parasitemic to CQ/AZ-Group subjects who do not become parasitemic.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics: Tmax - comparison for CQ/AZ-Group</measure>
    <time_frame>Days 11 thru 15</time_frame>
    <description>Tmax will be compared for CQ/AZ-Group subjects who become symptomatic and parasitemic to CQ/AZ-Group subjects who do not become parasitemic.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokentics: T½ - comparison for CQ/AZ Group</measure>
    <time_frame>Days 11 thru 15</time_frame>
    <description>T½ will be compared for CQ/AZ-Group subjects who become symptomatic and parasitemic to CQ/AZ-Group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokentics: AUC - comparison for CQ/AZ Group</measure>
    <time_frame>Days 11 thru 15</time_frame>
    <description>Area under the curve (AUC) will be compared for CQ/AZ-Group subjects who become symptomatic and parasitemic to CQ/AZ-Group subjects who do not become parasitemic.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Malaria</condition>
  <arm_group>
    <arm_group_label>Chloroquine-Azithromycin (CQ/AZ ) Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive experimental intervention of 300mg of CQ orally (PO) and 2g of AZ PO weekly for 6 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Chloroquine (CQ) Group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Subjects will only receive 300mg of CQ orally (PO) weekly for 6 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CHMI Group - atovaquone-proguanil (Malarone®)</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>All subjects will participate in the Controlled Human Malaria Infection (CHMI) and will be required to stay at a hotel for evaluation for a maximum of 14 nights starting 7 days after the challenge. A standard dose of atovaquone-proguanil (Malarone®) will be administered to all symptomatic parasitemic subjects under directly observed treatment.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Chloroquine-Azithromycin (CQ/AZ)</intervention_name>
    <description>Chloroquine-Azithromycin (CQ/AZ); Chloroquine (CQ) 300mg and 2g of azithromycin (AZ) given orally</description>
    <arm_group_label>Chloroquine-Azithromycin (CQ/AZ ) Group</arm_group_label>
    <other_name>CQ/AZ</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Chloroquine (CQ)</intervention_name>
    <description>Chloroquine (CQ); 300 mg of CQ only given orally</description>
    <arm_group_label>Chloroquine (CQ) Group</arm_group_label>
    <other_name>CQ</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>atovaquone-proguanil (Malarone®)</intervention_name>
    <description>All subjects will participate in the Controlled Human Malaria Infection (CHMI) and will be required to stay at a hotel for evaluation for a maximum of 14 nights starting 7 days after the challenge. A standard dose of atovaquone-proguanil (Malarone®) will be administered to all symptomatic parasitemic subjects under directly observed treatment.</description>
    <arm_group_label>CHMI Group - atovaquone-proguanil (Malarone®)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy adults (male or non-pregnant, non-lactating female) 18 to 50 years of age&#xD;
             (inclusive) at the time of screening.&#xD;
&#xD;
          -  If the subject is female:&#xD;
&#xD;
               1. Non-childbearing potential (ie., either surgically sterilized (bilateral tubal&#xD;
                  ligation, tubes tied, hysterectomy, removal of the uterus, bilateral&#xD;
                  oophorectomy, removal of both ovaries) at least 6 months before dosing) or one&#xD;
                  year post menopausal), abstinent or using adequate contraceptive precautions (eg,&#xD;
                  intrauterine contraceptive device; oral contraceptives; diaphragm, cervical cap,&#xD;
                  or condom in combination with contraceptive jelly, cream or foam; Norplant® or&#xD;
                  Depo-Provera®) from 3 months prior to this study through 56 days after challenge&#xD;
&#xD;
               2. A negative pregnancy test at the time of enrollment&#xD;
&#xD;
          -  Free of significant health problems as established by medical history, laboratory, and&#xD;
             clinical examination before entering the study&#xD;
&#xD;
          -  Subjects must have low cardiac risk factors according to the NHANES I criteria,&#xD;
             medical history and family history, blood pressure measurements, and a normal or&#xD;
             normal variant ECG including QTcF no greater than 450 msec for males and 470 msec for&#xD;
             females.&#xD;
&#xD;
          -  Available to participate in all planned study visits and reachable by phone for&#xD;
             duration of study (approximately 4 months).&#xD;
&#xD;
          -  Willing to comply with all protocol procedures and time commitments&#xD;
&#xD;
          -  No plans to participate in another clinical research study for the duration of this&#xD;
             study.&#xD;
&#xD;
          -  Written informed consent must be obtained from the subject before screening procedures&#xD;
             are performed&#xD;
&#xD;
          -  If a subject is active duty military, he or she must obtain approval from his or her&#xD;
             supervisor per Walter Reed Army Institute of Research (WRAIR) Policy 11-45&#xD;
&#xD;
          -  Subjects must score at least 80% correct on a multiple-choice quiz that assesses their&#xD;
             understanding of this study&#xD;
&#xD;
               1. If they do not score 80% on the initial quiz, the protocol information will be&#xD;
                  reviewed with them, and they will have the opportunity to retest&#xD;
&#xD;
               2. If a subject fails to correctly answer 80% of the questions after 2 attempts, he&#xD;
                  or she will be excluded from the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects with a history or presence of gastrointestinal, hepatic or renal disease, or&#xD;
             other condition known to interfere with the absorption, distribution, metabolism or&#xD;
             excretion of drugs.&#xD;
&#xD;
          -  Subjects with a history of retinopathy, sickle cell disease or trait, psoriasis, or&#xD;
             porphyria.&#xD;
&#xD;
          -  Subjects who take certain prescribed or over the counter (OTC) concomitant medication&#xD;
             including: ampicillin, antacids (including kaolin), cimetidine, digoxin, ergot&#xD;
             alkaloids, statins (HMG-CoA reductase inhibitors), cyclosporine, warfarin,&#xD;
             fluconazole, nelfinavir, or rifabutin, within 2 weeks of dosing start, and during the&#xD;
             duration of the study.&#xD;
&#xD;
          -  Are known or suspected of drinking too much alcohol (for men, more than 28 standard&#xD;
             alcohol drinks and for women more than 21 standard alcohol drinks per week (standard&#xD;
             drink is defined as a 12 oz beer, 5 oz glass of wine, or 1.5 oz of distilled spirit)&#xD;
&#xD;
          -  Positive urine drug screen for amphetamine, methamphetamine, cocaine, and opioids at&#xD;
             screening.&#xD;
&#xD;
          -  Subjects who have donated more than 1500 mL (males) or 1000 mL (females) blood in the&#xD;
             previous 12 months, including the maximum volume of blood (328 mL) to be taken in this&#xD;
             study.&#xD;
&#xD;
          -  Subjects who are currently enrolled in another study involving an investigational&#xD;
             product, or if recently involved in another clinical trial which has ended, have not&#xD;
             received any investigational products within the past 3 months or 5 half-lives&#xD;
             (whichever is longer) from the time of screening.&#xD;
&#xD;
          -  Any history of malaria infection in the past 3 years.&#xD;
&#xD;
          -  History of travel to malaria endemic areas in the 3 months prior to day of challenge,&#xD;
             or plans to travel to malaria endemic areas during the duration of the study (56 days&#xD;
             post challenge).&#xD;
&#xD;
          -  Any history of receiving a malaria vaccine&#xD;
&#xD;
          -  History of receipt of malaria prophylaxis during the 2 months prior to day of&#xD;
             challenge&#xD;
&#xD;
          -  History of use of any antibiotics with significant antimalarial activity (examples&#xD;
             include tetracycline, doxycycline, clindamycin, azithromycin, and sulfa drugs) during&#xD;
             the course of the study period&#xD;
&#xD;
          -  Pregnant (positive β-human chorionic gonadotropin test, β-HCG) or lactating female at&#xD;
             screening or plans to become pregnant or breastfeed from the time of enrollment until&#xD;
             three months after challenge&#xD;
&#xD;
          -  Allergy to antimalarial drugs or use of medications known to interact with CQ&#xD;
&#xD;
          -  Significant (e.g., systemic) hypersensitivity reactions to mosquito bites (local&#xD;
             hypersensitivity reactions at the site of mosquito bites are not an exclusion&#xD;
             criterion)&#xD;
&#xD;
          -  History of splenectomy&#xD;
&#xD;
          -  Any confirmed or suspected immunodeficiency, including HIV infection, or taking&#xD;
             immunosuppressive medications&#xD;
&#xD;
          -  Acute or chronic, ally significant, pulmonary, cardiovascular, endocrine, hepatic, or&#xD;
             renal functional abnormality, as determined by history, physical examination, or&#xD;
             laboratory evaluation&#xD;
&#xD;
          -  Chronic or active neurologic disease including seizure disorder and chronic migraine&#xD;
             headaches&#xD;
&#xD;
          -  Any abnormal baseline laboratory screening tests listed below&#xD;
&#xD;
               1. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) above twice&#xD;
                  the upper limit of normal for the reference lab&#xD;
&#xD;
               2. Creatinine above normal range&#xD;
&#xD;
               3. Hemoglobin out of normal range&#xD;
&#xD;
               4. Platelet count out of normal range&#xD;
&#xD;
               5. Total white blood cell (WBC) count out of normal range Note: If screening lab&#xD;
                  values are out of the normal range but are expected to be temporary (e.g. due to&#xD;
                  dehydration), they may be re-assessed one time at the discretion of the&#xD;
                  investigator.&#xD;
&#xD;
          -  Seropositive for Human immunodeficiency virus (HIV) or Hepatitis C virus (HCV) or&#xD;
             hepatitis B surface antigen (HBsAg) positive&#xD;
&#xD;
          -  An abnormal baseline screening ECG suggestive of cardiac disease as determined by a&#xD;
             clinical investigator. QTcF of &gt;450 msec for males and &gt;470 msec for females.&#xD;
&#xD;
          -  Any other significant finding that in the opinion of the PI would increase the risk of&#xD;
             having an adverse outcome from participating in this study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jeffrey R Livezey, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Walter Reed Army Institute of Research (WRAIR)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Clinical Research Unit, Uniformed Services University of Health Sciences</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20814</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>WRAIR</name>
      <address>
        <city>Silver Spring</city>
        <state>Maryland</state>
        <zip>20910</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Heppner DG Jr, Walsh DS, Uthaimongkol N, Tang DB, Tulyayon S, Permpanich B, Wimonwattrawatee T, Chuanak N, Laoboonchai A, Sookto P, Brewer TG, McDaniel P, Eamsila C, Yongvanitchit K, Uhl K, Kyle DE, Keep LW, Miller RE, Wongsrichanalai C. Randomized, controlled, double-blind trial of daily oral azithromycin in adults for the prophylaxis of Plasmodium vivax malaria in Western Thailand. Am J Trop Med Hyg. 2005 Nov;73(5):842-9.</citation>
    <PMID>16282291</PMID>
  </reference>
  <reference>
    <citation>Pereira MR, Henrich PP, Sidhu AB, Johnson D, Hardink J, Van Deusen J, Lin J, Gore K, O'Brien C, Wele M, Djimde A, Chandra R, Fidock DA. In vivo and in vitro antimalarial properties of azithromycin-chloroquine combinations that include the resistance reversal agent amlodipine. Antimicrob Agents Chemother. 2011 Jul;55(7):3115-24. doi: 10.1128/AAC.01566-10. Epub 2011 Apr 4.</citation>
    <PMID>21464242</PMID>
  </reference>
  <reference>
    <citation>Taylor WR, Richie TL, Fryauff DJ, Picarima H, Ohrt C, Tang D, Braitman D, Murphy GS, Widjaja H, Tjitra E, Ganjar A, Jones TR, Basri H, Berman J. Malaria prophylaxis using azithromycin: a double-blind, placebo-controlled trial in Irian Jaya, Indonesia. Clin Infect Dis. 1999 Jan;28(1):74-81. doi: 10.1086/515071.</citation>
    <PMID>10028075</PMID>
  </reference>
  <reference>
    <citation>Yeo AE, Rieckmann KH. Increased antimalarial activity of azithromycin during prolonged exposure of Plasmodium falciparum in vitro. Int J Parasitol. 1995 Apr;25(4):531-2. doi: 10.1016/0020-7519(94)00119-9.</citation>
    <PMID>7635629</PMID>
  </reference>
  <results_reference>
    <citation>Andersen SL, Oloo AJ, Gordon DM, Ragama OB, Aleman GM, Berman JD, Tang DB, Dunne MW, Shanks GD. Successful double-blinded, randomized, placebo-controlled field trial of azithromycin and doxycycline as prophylaxis for malaria in western Kenya. Clin Infect Dis. 1998 Jan;26(1):146-50. doi: 10.1086/516281.</citation>
    <PMID>9455524</PMID>
  </results_reference>
  <results_reference>
    <citation>Biswas S. In-vitro antimalarial activity of azithromycin against chloroquine sensitive and chloroquine resistant Plasmodium falciparum. J Postgrad Med. 2001 Oct-Dec;47(4):240-3.</citation>
    <PMID>11832638</PMID>
  </results_reference>
  <results_reference>
    <citation>Dunne MW, Singh N, Shukla M, Valecha N, Bhattacharyya PC, Dev V, Patel K, Mohapatra MK, Lakhani J, Benner R, Lele C, Patki K. A multicenter study of azithromycin, alone and in combination with chloroquine, for the treatment of acute uncomplicated Plasmodium falciparum malaria in India. J Infect Dis. 2005 May 15;191(10):1582-8. doi: 10.1086/429343. Epub 2005 Apr 11.</citation>
    <PMID>15838784</PMID>
  </results_reference>
  <results_reference>
    <citation>Mzayek F, Deng H, Mather FJ, Wasilevich EC, Liu H, Hadi CM, Chansolme DH, Murphy HA, Melek BH, Tenaglia AN, Mushatt DM, Dreisbach AW, Lertora JJ, Krogstad DJ. Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers. PLoS Clin Trials. 2007 Jan 5;2(1):e6. doi: 10.1371/journal.pctr.0020006.</citation>
    <PMID>17213921</PMID>
  </results_reference>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>August 24, 2017</study_first_submitted>
  <study_first_submitted_qc>September 8, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 12, 2017</study_first_posted>
  <last_update_submitted>February 25, 2020</last_update_submitted>
  <last_update_submitted_qc>February 25, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 27, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Malaria</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Azithromycin</mesh_term>
    <mesh_term>Chloroquine</mesh_term>
    <mesh_term>Chloroquine diphosphate</mesh_term>
    <mesh_term>Atovaquone</mesh_term>
    <mesh_term>Proguanil</mesh_term>
    <mesh_term>Atovaquone, proguanil drug combination</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03278808
org study id: S-16-06
nct id: NCT03278808
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is an open label, Phase 2 study with controlled human malaria infection (CHMI). Twenty
      three subjects will be enrolled into 2 groups (15 subjects in the Chloroquine-Azithromycin
      [CQ/AZ] Intervention Group, and 8 subjects in the Chloroquine [CQ] Group). The CQ/AZ Group
      will receive experimental intervention of 300 mg of CQ and 2 g of azithromycin (AZ). The CQ
      Group will receive 300 mg of CQ only. All subjects will participate in the CHMI and will be
      required to stay at a hotel for evaluation for a maximum of 14 nights starting 7 days after
      the challenge. A standard dose of atovaquone-proguanil (Malarone®) will be administered to
      all symptomatic parasitemic subjects under directly observed treatment.
This study is a Phase 2, open-label study of the combination of a single dose-level of AZ
      (Zithromax) plus CQ given weekly as a prophylaxis against CQ-resistant P falciparum in
      healthy adults. After signing informed consent, subjects will undergo screening procedures
      between Day -77 to Day -18. If enrolled, subjects who are still eligible at Study Day -18
      will be randomized to either the CQ/AZ group (Group 1 of 15 subjects: 2 g AZ (Zithromax) plus
      300 mg CQ base weekly for 6 weeks), or the CQ control group (Group 2 of 8 subjects: 300 mg
      chloroquine base weekly for 6 weeks) and start intervention on Study Day -17. The rationale
      for the CQ control group to receive CQ is to show that the strain utilized (7G8) is indeed
      chloroquine resistant in humans: we expect all of the subjects in the CQ control group to
      become symptomatically parasitemic. If 3 or more subjects in the CQ control group do not
      become symptomatic with malaria, the CHMI will be considered uncontrolled either due to 7G8
      not being CQ-resistant, or the parasite not being infective.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Subjects will be randomized to either the CQ/AZ group (Group 1 of 15 subjects: 2 g AZ (Zithromax) plus 300 mg CQ base weekly for 6 weeks), or the CQ control group (Group 2 of 8 subjects: 300 mg chloroquine base weekly for 6 weeks)
primary purpose: Treatment
masking: None (Open Label)
masking description: Because placebo for both products is difficult to obtain and because the primary endpoint of symptomatic parasitemia is an objective measure, treatment will be open-label. Microscopists reading the smears will be blinded to the group, but will be aware of whether or not a particular sample is from a symptomatic subject.
Although symptoms are a subjective measure and part of the primary endpoint of symptomatic parasitemia, subjects will not be told if they are parasitemic prior to treatment initiation thus making symptomatic complaints and this endpoint more reliable.
measure: Efficacy: Proportion of subjects free from symptomatic parasitemic subjects
time frame: Days 1 thru 56
description: CQ/AZ Group will be compared to endpoint in CQ Group by Fisher's Exact Test. Symptomatic is defined as any one of the following solicited adverse events that first occurred concurrent with parasitemia: fever (temperature > 100.4 °F), chills, headache, arthralgia, myalgia, nausea, vomiting, or abdominal pain. Subjects will only undergo malaria treatment after both criteria are met.
measure: Safety: Solicited and unsolicited Adverse Events in each group
time frame: Days 1 thru 56
description: Groups will be analyzed by descriptive statistics and safety monitoring will be conducted throughout the study
measure: Electrocardiogram baseline vs peak concentration for AZ
time frame: Day 11 post challenge, 6 hours after dosing
description: QTcF will be analyzed for CQ/AZ Group subjects at presumed field-effective time point (Day 11 post challenge) 6 hours after dosing, which will coincide with time to peak concentration for AZ. This will be compared to baseline reading
measure: Pharmacokinetics: Cmax - comparison for CQ/AZ-Group subjects
time frame: Days 11 thru 15
description: Cmax will be compared for CQ/AZ-Group subjects who become symptomatic and parasitemic to CQ/AZ-Group subjects who do not become parasitemic.
measure: Pharmacokinetics: Tmax - comparison for CQ/AZ-Group
time frame: Days 11 thru 15
description: Tmax will be compared for CQ/AZ-Group subjects who become symptomatic and parasitemic to CQ/AZ-Group subjects who do not become parasitemic.
measure: Pharmacokentics: T½ - comparison for CQ/AZ Group
time frame: Days 11 thru 15
description: T½ will be compared for CQ/AZ-Group subjects who become symptomatic and parasitemic to CQ/AZ-Group
measure: Pharmacokentics: AUC - comparison for CQ/AZ Group
time frame: Days 11 thru 15
description: Area under the curve (AUC) will be compared for CQ/AZ-Group subjects who become symptomatic and parasitemic to CQ/AZ-Group subjects who do not become parasitemic.
arm group label: Chloroquine-Azithromycin (CQ/AZ ) Group
arm group type: Experimental
description: Subjects will receive experimental intervention of 300mg of CQ orally (PO) and 2g of AZ PO weekly for 6 weeks
arm group label: Chloroquine (CQ) Group
arm group type: Active Comparator
description: Subjects will only receive 300mg of CQ orally (PO) weekly for 6 weeks
arm group label: CHMI Group - atovaquone-proguanil (Malarone®)
arm group type: Other
description: All subjects will participate in the Controlled Human Malaria Infection (CHMI) and will be required to stay at a hotel for evaluation for a maximum of 14 nights starting 7 days after the challenge. A standard dose of atovaquone-proguanil (Malarone®) will be administered to all symptomatic parasitemic subjects under directly observed treatment.
intervention type: Drug
intervention name: Chloroquine-Azithromycin (CQ/AZ)
description: Chloroquine-Azithromycin (CQ/AZ); Chloroquine (CQ) 300mg and 2g of azithromycin (AZ) given orally
arm group label: Chloroquine-Azithromycin (CQ/AZ ) Group
other name: CQ/AZ
intervention type: Drug
intervention name: Chloroquine (CQ)
description: Chloroquine (CQ); 300 mg of CQ only given orally
arm group label: Chloroquine (CQ) Group
other name: CQ
intervention type: Drug
intervention name: atovaquone-proguanil (Malarone®)
description: All subjects will participate in the Controlled Human Malaria Infection (CHMI) and will be required to stay at a hotel for evaluation for a maximum of 14 nights starting 7 days after the challenge. A standard dose of atovaquone-proguanil (Malarone®) will be administered to all symptomatic parasitemic subjects under directly observed treatment.
arm group label: CHMI Group - atovaquone-proguanil (Malarone®)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Jeffrey R Livezey, MD
role: Principal Investigator
affiliation: Walter Reed Army Institute of Research (WRAIR)
facility: 
facility: 
country: United States
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responsible party type: Sponsor
mesh term: Malaria
mesh term: Azithromycin
mesh term: Chloroquine
mesh term: Chloroquine diphosphate
mesh term: Atovaquone
mesh term: Proguanil
mesh term: Atovaquone, proguanil drug combination
sharing ipd: No