Studies of a Candidate Aminoquinoline Antimalarial (AQ-13)

Study Overview
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Brief Summary
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This is an initial efficacy study of a candidate antimalarial in human subjects with uncomplicated malaria caused by the most common and most important parasite in Africa (Plasmodium falciparum). This study will enroll 66 adult Malian males with uncomplicated P. falciparum malaria and randomize them to treatment with 1750 mg of the investigational drug (AQ-13) by mouth over 3 days or the current standard treatment, which is 2 doses of Coartem twice daily for 3 days. The hypothesis underlying this study is that AQ-13 will be similarly effective to Coartem for the treatment of uncomplicated P. falciparum malaria due to both chloroquine-susceptible and chloroquine-resistant parasites. Funding Source - FDA Office of Orphan Product Development (OOPD).

Detailed Description
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This is an initial efficacy study (Phase 2 Proof of Concept Study) of a candidate antimalarial in human subjects with uncomplicated malaria caused by the most common and most important parasite in Africa (Plasmodium falciparum). This study will enroll 66 adult Malian males with uncomplicated P. falciparum malaria and randomize them to treatment with 1750 mg of the investigational drug (AQ-13) by mouth over 3 days or the current standard treatment, which is 80 mg of artemether and 480 mg of lumefantrine twice daily for 3 days. The hypothesis underlying this study is that AQ-13 will be similarly effective to Coartem for the treatment of uncomplicated P. falciparum malaria due to both chloroquine-susceptible and chloroquine-resistant parasites.

Official Title
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Phase 2 Proof of Concept Study of a Candidate Aminoquinoline Antimalarial (AQ-13)

Conditions
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Malaria

Intervention / Treatment
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* Drug: AQ-13 Treatment
* Drug: Coartem Treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Adult Malian males ≥ 18 years of age, Uncomplicated malaria with ≥ 2,000 asexual P. falciparum parasites per ul, and Informed consent obtained and signed. Exclusion Criteria Severe or complicated malaria (including temperature ≥ 40o C), ≥ 100,000 asexual parasites per ul of blood, Anemia or other laboratory results (other than malaria) that require treatment (e.g., Hb ≤ 7 gm/dL, K+ ≤ 3.5 millimolar (mM), BP ≥ 140/90), Seizures or impaired consciousness, Recent antimalarial treatment by history (within ≤ 2 weeks), Chronic medications (including inducers of Cytochrome P450 3A4 [CYP3A4] activity such as rifampin and nevirapine), Ventricular or atrial arrhythmias, or second or third degree heart block on the screening ECG or Holter recording, Infection with other plasmodial species on the blood smear (P. ovale, P. ovale, P. vivax).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AQ-13<br>Adult Malian males 18 years of age or older with uncomplicated P. falciparum malaria who agree to participate and provide their informed consent will be randomized to receive treatment with either AQ-13 or Coartem. Intervention 'AQ-13 Treatment' Participants randomized to the AQ-13 arm will be treated with two (350 mg) capsules on days 1 and 2 and one (350 mg) AQ-13 capsule on day 3 for a total oral dose of 1750 mg of AQ-13 (5 capsules containing 350 mg apiece) over 3 days. | Drug: AQ-13 Treatment<br>* Adult Malian males 18 years of age or older with uncomplicated P. falciparum malaria who agree to participate and provide their informed consent will be randomized to receive treatment with either AQ-13 or Coartem. Intervention 'AQ-13 Treatment' Participants randomized to the AQ-13 arm will be treated with two (350 mg) capsules on days 1 and 2 and one (350 mg) AQ-13 capsule on day 3 for a total oral dose of 1750 mg of AQ-13 (5 capsules containing 350 mg apiece) over 3 days.<br>* Other names: N'-(7-Chloroquinolin-4-yl)-N,N-diethyl-propane-1,3-diamine.;|
| Active Comparator: Coartem Treatment<br>Adult Malian males 18 years of age or older with uncomplicated P. falciparum malaria who agree to participate and provide their informed consent will be randomized to receive treatment with either AQ-13 or Coartem. Intervention: Active Comparator: Coartem. Participants randomized to the Coartem arm will be treated with 80 mg artemether and 480 mg lumefantrine at the time of diagnosis and 8 hours later on day 1, the same doses (80 mg artemether and 480 mg lumefantrine) twice on day 2 (24 and 36 hours after diagnosis) and twice more on day 3 (48 and 60 hours after diagnosis) for total oral doses of 480 mg artemether and 2880 mg lumefantrine over 3 days. | Drug: Coartem Treatment<br>* Adult Malian males 18 years of age or older with uncomplicated P. falciparum malaria who agree to participate and provide their informed consent will be randomized to receive treatment with either AQ-13 or Coartem. Intervention 'Coartem Treatment' Participants randomized to the Coartem arm will receive six doses of Coartem tablets over 3 days (each dose containing 80 mg artemether and 480 mg lumefantrine). Those six doses will be given at the time of diagnosis and 8 hours later on day 1, at 24 and 36 hours on day 2 and at 48 and 60 hours on day 3 for total doses of 480 mg artemether and 2880 mg lumefantrine over 3 days.<br>* Other names: Tablets contain 20 (or 80) mg artemether and 120 (or 480) mg lumefantrine.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary outcome of this study is a comparison of the cure rates of AQ-13 and Coartem for uncomplicated Plasmodium falciparum malaria in adult Malian males. | Cure is defined as a lack of recrudescence within 42 days (PCR-corrected) - no evidence of recurrent infection with the same parasite genotype after reduction of the asexual parasitemia to less than 25% of the admission value by day 3 and clearance of asexual parasites and fever by day 7. Failure is defined as lack of cure. | Subjects are followed for 42 days after beginning treatment with either AQ-13 or Coartem.. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse events | Adverse events (AEs) are defined as events possibly related to the study drug(s) as judged by blinded physician observers that occur within 4 weeks of beginning treatment with AQ-13 or Coartem. | within 4 weeks of beginning treatment with either AQ-13 or Coartem | 
| Parasite Clearance Time | Blood smears are performed at the time of diagnosis and then (for persons who have been enrolled after providing their informed consent to participate) twice daily until two successive negative smears have been obtained. | from the time of beginning treatment with either AQ-13 or Coartem to the first of 2 successive negative blood smears | 
| Time to recrudescence of reinfection | This is the time from the initiation of oral treatment with either AQ-13 or Coartem until the reappearance of asexual Plasmodium falciparum parasites on the blood smear. | within 42 days after beginning treatment with either AQ-13 or Coartem | 
| Effects of antimalarial treatment on the QT (QTc) interval. | Previous (Phase 1) studies of AQ-13 in comparison with chloroquine have shown that QT prolongation is greater with chloroquine than AQ-13, does not produce arrhythmias or other definable cardiac AEs and returns to normal (pre-treatment) levels within 2 weeks after treatment. QT intervals will be monitored daily during the 5-7 day inpatient stay and checked again during an outpatient visit in week 2 (on day 14). Although this is identified as a potential safety issue, there have been no definable cardiac AEs with AQ-13 doses up to 2100 mg in the Phase 1 studies. | within 14 days of beginning treatment with either AQ-13 or Coartem | 
| Pharmacokinetic parameters for AQ-13 | Based on serial blood levels (35 blood level determinations of AQ-13 and its metabolites over the 42 day study period) and urine collections (24 hour collections for the first four days after beginning treatment), it should be possible to define the pharmacokinetics of AQ-13 in febrile patients with uncomplicated malaria and to relate those results to the area under the curve, peak levels, clearance rates, previous data from uninfected subjects in the Phase 1 studies and the clinical outcome of treatment. | These studies will continue for the entire 42 day follow-up period. | 
| Fever Clearance Time | Body temperature will be measured twice daily with an electronic (digital) thermometer during the 5-7 day inpatient stay. Fever clearance time is defined as the time in hours from beginning treatment with AQ-13 or Coartem until the disappearance of fever for at least 24 hours. This is not a safety issue because patients with hyperthermia will be excluded from participation in this study. | Days 1-7 after beginning treatment with either AQ-13 or Coartem | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Plasmodium falciparum, pharmacokinetics, antimalarials (antimalarial drugs), chloroquine (chloroquine-resistant), QT (QTc) interval