Studies of a Candidate Aminoquinoline Antimalarial (AQ-13)

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

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).

Study Overview

• Status: Completed
• Conditions: Malaria
• Intervention / Treatment: Drug: AQ-13 Treatment; Drug: Coartem Treatment

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 2

Contacts and Locations

Study Locations

• Mali
  • Bamako, Mali, BP 1805
    • Clinical Research Center (Hopital Point G, University of the Sciences, Techniques and Technologies of Bamako)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria

1. Adult Malian males ≥ 18 years of age,
2. Uncomplicated malaria with ≥ 2,000 asexual P. falciparum parasites per ul, and
3. Informed consent obtained and signed.

Exclusion Criteria

1. Severe or complicated malaria (including temperature ≥ 40o C),
2. ≥ 100,000 asexual parasites per ul of blood,
3. 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),
4. Seizures or impaired consciousness,
5. Recent antimalarial treatment by history (within ≤ 2 weeks),
6. Chronic medications (including inducers of Cytochrome P450 3A4 [CYP3A4] activity such as rifampin and nevirapine),
7. Ventricular or atrial arrhythmias, or second or third degree heart block on the screening ECG or Holter recording,
8. Infection with other plasmodial species on the blood smear (P. ovale, P. ovale, P. vivax).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AQ-13; 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; 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.; Other Names: N'-(7-Chloroquinolin-4-yl)-N,N-diethyl-propane-1,3-diamine.
Active Comparator: Coartem Treatment; 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; 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.; Other Names: Tablets contain 20 (or 80) mg artemether and 120 (or 480) mg lumefantrine.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Donald Krogstad
• Collaborators: University of the Sciences, Techniques and Technologies of Bamako
• Investigators: Principal Investigator: Donald J. Krogstad, MD, Tulane School of Public Health and Tropical Medicine

Publications and helpful links

General Publications

• De D, Krogstad FM, Cogswell FB, Krogstad DJ. Aminoquinolines that circumvent resistance in Plasmodium falciparum in vitro. Am J Trop Med Hyg. 1996 Dec;55(6):579-83. doi: 10.4269/ajtmh.1996.55.579.
• De D, Krogstad FM, Byers LD, Krogstad DJ. Structure-activity relationships for antiplasmodial activity among 7-substituted 4-aminoquinolines. J Med Chem. 1998 Dec 3;41(25):4918-26. doi: 10.1021/jm980146x.
• Ramanathan-Girish S, Catz P, Creek MR, Wu B, Thomas D, Krogstad DJ, De D, Mirsalis JC, Green CE. Pharmacokinetics of the antimalarial drug, AQ-13, in rats and cynomolgus macaques. Int J Toxicol. 2004 May-Jun;23(3):179-89. doi: 10.1080/10915810490471352.
• Deng H, Liu H, Krogstad FM, Krogstad DJ. Sensitive fluorescence HPLC assay for AQ-13, a candidate aminoquinoline antimalarial, that also detects chloroquine and N-dealkylated metabolites. J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Apr 3;833(2):122-8. doi: 10.1016/j.jchromb.2005.12.011. Epub 2006 Jan 18.
• Hocart SJ, Liu H, Deng H, De D, Krogstad FM, Krogstad DJ. 4-aminoquinolines active against chloroquine-resistant Plasmodium falciparum: basis of antiparasite activity and quantitative structure-activity relationship analyses. Antimicrob Agents Chemother. 2011 May;55(5):2233-44. doi: 10.1128/AAC.00675-10. Epub 2011 Mar 7.
• 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.
• Lakshmanan V, Bray PG, Verdier-Pinard D, Johnson DJ, Horrocks P, Muhle RA, Alakpa GE, Hughes RH, Ward SA, Krogstad DJ, Sidhu AB, Fidock DA. A critical role for PfCRT K76T in Plasmodium falciparum verapamil-reversible chloroquine resistance. EMBO J. 2005 Jul 6;24(13):2294-305. doi: 10.1038/sj.emboj.7600681. Epub 2005 Jun 9.
• Koita OA, Sangare L, Miller HD, Sissako A, Coulibaly M, Thompson TA, Fongoro S, Diarra Y, Ba M, Maiga A, Diallo B, Mushatt DM, Mather FJ, Shaffer JG, Anwar AH, Krogstad DJ. AQ-13, an investigational antimalarial, versus artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria: a randomised, phase 2, non-inferiority clinical trial. Lancet Infect Dis. 2017 Dec;17(12):1266-1275. doi: 10.1016/S1473-3099(17)30365-1. Epub 2017 Sep 12.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2013
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): February 1, 2017

Study Registration Dates

• First Submitted: June 6, 2012
• First Submitted That Met QC Criteria: June 7, 2012
• First Posted (Estimate): June 8, 2012

Study Record Updates

• Last Update Posted (Actual): August 15, 2017
• Last Update Submitted That Met QC Criteria: August 11, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Plasmodium falciparum; pharmacokinetics; antimalarials (antimalarial drugs); chloroquine (chloroquine-resistant); QT (QTc) interval
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Lumefantrine; Artemether; Artemether, Lumefantrine Drug Combination
• Other Study ID Numbers: 2149; FDA 1R01-FD-003373 (Other Grant/Funding Number: FDA Office of Orphan Products Development)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED