Studies of a Candidate Aminoquinoline Antimalarial (AQ-13)

Summary

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).

Timeline

Start

2013-08

Primary completion

2016-01

Completion

2017-02

Outcome

Missed primary endpoint

paper did not meet the criterion for non-inferiority of AQ-13 PMID 28916443 ↗

paper the upper bound of the 95% CI exceeded the 15% non-inferiority margin PMID 28916443 ↗

Publications

• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Results 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.

Drugs

Evaluation	Drug	Modality	Dose	Route
Subject	AQ-13	Small molecule	1750 mg	Oral
Subject	Artemether	Small molecule	80 mg	Oral
Subject	lumefantrine	Small molecule	480 mg	Oral

Indications