Studies of AQ-13, a Candidate Aminoquinoline Antimalarial, in Comparison With Chloroquine
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this protocol is to perform Phase 1 (safety/toxicity and pharmacokinetic)
      Studies of an investigational aminoquinoline antimalarial (AQ-13) in human subjects. The
      compound to be studied (AQ-13) is being examined because it is active in vitro against
      Plasmodium falciparum malaria parasites resistant to chloroquine (CQ) and other antimalarials
      (multi-resistant P. falciparum), and because its safety was similar to that of CQ in
      preclinical studies performed by SRI International (IND 55,670). AQ-13 was also selected for
      study because it is active in vivo in two monkey models of human malaria: 1] P. cynomolgi in
      the rhesus monkey (Macaca mulatta), a model of human infection with P. vivax, and 2]
      CQ-resistant P. falciparum in the squirrel monkey, a model of human infection with
      CQ-resistant P. falciparum.
    

Detailed description: 
      Study Population:

      Healthy young men and women 21-45 years of age who are taking no chronic medications with the
      exception of birth control pills will be invited to participate in this Phase 1 Study at the
      Tulane/LSU/Charity Hospital General Clinical Research Center (GCRC) in New Orleans. Exclusion
      criteria include pregnancy, breast feeding, abnormal liver or kidney function tests, anemia
      (Hb < 12 gm per dL), chronic medications other than birth control pills, and an abnormal
      baseline ECG or Holter recording. Because the purpose of this testing is to determine whether
      AQ-13 is likely to have significant toxicity in Africans (Malians), ≥ 25% of the volunteers
      studied in New Orleans will be African-Americans.

      Randomization:

      Drug allocation codes will be generated by the study biostatistician in blocks of size 4 and
      6, using computer software, and will be sealed in numbered, opaque envelops. Block sizes will
      be determined at random so that they will not be known to the study personnel. The envelopes
      containing the randomization codes will be hand-delivered to the study pharmacist and kept in
      the Research Pharmacy, which is outside the GCRC.

      Blinding:

      The study participants, investigators and staff will be blinded to the type of the drug
      administered throughout the study. The interim reports to the DSMB after completion of each
      dose level will be presented without breaking the code, unless deemed necessary by the DSMB.
      The envelope containing the drug allocation code will be opened by the study pharmacist and
      the appropriate drug will be dispensed to the GCRC on the morning of its administration. With
      the exception of the 600 mg CQ tablets (Aralen™) tablets, the two drugs (AQ-13 and CQ) will
      be administered in identical capsular form and number.

      Informed Consent:

      Informed consent will be obtained from each participant before screening. As per the IRB
      regulations, the informed consent form will be updated and reviewed at yearly intervals or
      whenever new pertinent information on the study drugs or their side effects becomes
      available.

      Baseline Screening:

      To determine their eligibility, each volunteer will have a complete physical exam, including
      an eye examination (visual acuity, visual fields, indirect ophthalmoscopy), panels of
      standard chemical tests (BUN, Creatinine, AST, ALT, LDH, Alkaline Phosphatase, Glucose,
      Bilirubin, Creatine Kinase) and hematologic tests (Hematocrit, Hemoglobin, White Cell Count
      and Platelet Count), and a cardiac examination (physical exam, baseline ECG and 24-hour
      Holter recording) for arrhythmias and other evidence of cardiac disease.

      In-patient Studies at the Tulane-LSU-Charity Hospital GCRC:

      Volunteers will be hospitalized the night before drug administration at the GCRC, prior to
      randomization to receive either AQ-13 or CQ capsules orally (po) the next morning. Doses will
      begin at 10 mg base with 8 volunteers per drug x dose group, and will escalate in subsequent
      groups to 100, 300 and 600 mg base (8 subjects per drug x dose group for the 10, 100 and 300
      mg doses [subtotal of 48 subjects]; 12 subjects per drug x dose group at the 600 mg dose in
      order to compare the pharmacokinetics of CQ and AQ-13 before proceeding to the equivalent
      therapeutic dose). At the request of FDA, a third group will be added at the 600 mg dose to
      determine whether the blood levels obtained with CQ capsules are equivalent to the blood
      levels obtained with commercially available FDA-approved Sanofi-Winthrop CQ tablets (Aralen™,
      i.e., 12 subjects per drug x dose group at 600 mg x 3 drug groups [AQ-13 capsules, CQ
      capsules and Aralen™ CQ tablets] = subtotal of 36 subjects]).

      To compare the absorption and metabolism of AQ-13 with the absorption and metabolism of CQ,
      blood samples will be obtained for AQ-13, CQ and metabolite blood levels immediately before
      and 1, 2, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 84, 96 and 120 hours after the 600 and the
      1500 mg doses using a heparin lock. At the 1500 mg dose, three 24-hour urine collections will
      be obtained on days 1-3 after beginning dosing on day 1 to compare the urinary excretion of
      AQ-13, CQ and their metabolites. Volunteers receiving 600 and 1500 mg doses of AQ-13 or CQ
      will return for blood samples twice weekly during the ensuing 4 weeks to define the terminal
      half-lives of AQ-13, CQ and their metabolites. After measurement of AQ-13, CQ and metabolite
      levels following the 600 mg dose, the doses given in the second set of studies (equivalent
      therapeutic course - i.e., 1500 mg CQ) will be adjusted (Dose Adjustment, see below) to
      obtain blood levels of AQ-13 similar to those obtained with CQ. In these studies, volunteers
      will receive the equivalent of 600 mg CQ base on the mornings of days 1 and 2, and an
      additional 300 mg CQ base equivalent on day 3.

      Previous experience with CQ (a structurally similar aminoquinoline) suggests that massive
      overdoses of AQ-13 may produce arrhythmias, although there has been no previous human
      experience with AQ-13. Although the arrhythmiagenic effects of CQ have been reported only
      with massive ingestions or rapid intravenous infusions, these Phase 1 Studies will provide an
      excellent opportunity to test for this potential toxicity. Therefore, investigators will use
      Holter monitoring during the Phase 1 Studies in New Orleans to ensure that there is no
      evidence of arrhythmias with AQ-13. Conventional electrocardiograms will be used to test for
      the T wave flattening and QTc prolongation, typically seen in persons receiving therapeutic
      courses of CQ. Continuous Holter monitoring will be performed to evaluate the effects of
      AQ-13 and CQ on the QT interval after the 1500 mg dose.

      Participants' Out-patient Follow-ups:

      After discharge from their in-patient stay at the GCRC (2½ days for the 10, 100, 300 and 600
      mg doses; 3½ days for the 1500 mg dose), participants will be asked to return to the GCRC
      twice weekly for a total of 4 weeks after discharge in order to obtain blood for drug and
      metabolite blood levels, and for the evaluation of adverse events (AEs). An ECG and chemistry
      and hematology lab tests will be repeated at the 2 week and 4 week follow-up visits.

      Dose Adjustment for AQ-13:

      The data obtained by SRI International during GLP preclinical toxicologic and pharmacokinetic
      studies indicate that the oral bioavailability of AQ-13 is less than that of CQ in rats and
      monkeys. Therefore, it is possible (perhaps likely) that the oral bioavailability of AQ-13 in
      humans will be less than that of CQ, and thus that it may be necessary to increase the oral
      dose of AQ-13 in order to provide molar blood levels of AQ-13 similar to those produced by
      the established oral doses of CQ. To estimate the amount of AQ-13 necessary to obtain similar
      oral bioavailability, investigators will compare blood levels and areas under the curve
      (AUCs) for AQ-13 and CQ at the 600 mg dose. Based on these results, researchers will estimate
      the dose adjustment (increment or decrement) necessary for AQ-13 and test that adjustment in
      12 additional volunteers. After the dose of AQ-13 necessary to produce equimolar blood levels
      and AUCs has been established, investigators will compare that adjusted dose to 1500 mg CQ
      base for the equivalent therapeutic dose of AQ-13.
    

Intervention name(s): AQ-13; Chloroquine (CQ) Treatment
Intervention type(s): Drug; Drug
Intervention description(s): A treatment dose of AQ-13 (1750 mg base) was administered orally to subjects randomized to AQ-13 over 3 days (as two capsules on days 1 and 2, plus one capsule on day 3).; A treatment dose of CQ (1500 mg CQ base) was administered orally to subjects randomized to CQ over 3 days (as two capsules on days 1 and 2, and one capsule on day 3).
Other intervention name(s): Aralen
Intervention MeSH terms: Chloroquine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Individual subjects were randomized to receive either the investigational candidate 4-aminoquinoline (AQ-13) or the control 4-aminoquinoline which has been used to treat malaria for decades and is known to be safe (chloroquine=CQ).
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Basic Science
Keywords: Malaria; Aminoquinolines; Drug Resistance; Chloroquine Resistance