Studies of a Candidate Aminoquinoline Antimalarial (AQ-13)

NCT01614964 | Completed Phase 2 Results DMC

• 2 other identifiers: 2149FDA 1R01-FD-003373
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 1

Brief 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).

Conditions

Malaria

Keywords

Plasmodium falciparum; pharmacokinetics; antimalarials (antimalarial drugs); chloroquine (chloroquine-resistant); QT (QTc) interval

Outcome Measures

Primary Outcomes (1)

• Cure Rates of AQ-13 and Coartem for Uncomplicated Plasmodium Falciparum Malaria in Adult Malian Males.

  Cure rate is defined as a lack of recrudescence within 42 days PCR-corrected (correcting for new infections due to treatment failures). The investigators were looking for 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 to measure the cure rate. Failure is defined as lack of cure.

  Subjects are followed for 42 days after beginning treatment with either AQ-13 or Coartem..

Secondary Outcomes (11)

• Number of Participants With Adverse Events

  Within 4 weeks of beginning treatment with either AQ-13 or Coartem

• Parasite Clearance Time

  From the time of beginning treatment with either AQ-13 or Coartem to the first of 2 successive negative blood smears, assessed during the 1 week inpatient stay.

• Number of Participants With Recrudescence of Infection

  Within 42 days after beginning treatment with either AQ-13 or Coartem

• QTc Interval Response Following Antimalarial Treatment

  Between dosing and 4 hours after dosing

• Mean Fever Clearance Time in Days

  Days 1-7 after beginning treatment with either AQ-13 or Coartem

Study Arms (2)

AQ-13

EXPERIMENTAL

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

Coartem Treatment

ACTIVE COMPARATOR

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

Interventions

AQ-13 Treatment DRUG

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.

Also known as: N'-(7-Chloroquinolin-4-yl)-N,N-diethyl-propane-1,3-diamine.

AQ-13

Coartem Treatment DRUG

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.

Also known as: Tablets contain 20 (or 80) mg artemether and 120 (or 480) mg lumefantrine.

Coartem Treatment

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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).

Sponsors & Collaborators

• Tulane University: lead
• University of the Sciences, Techniques and Technologies of Bamako: collaborator

Study Sites (1)

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

Bamako, BP 1805, Mali

Location

Related Publications (8)

• 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.

  PMID: 9025680 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.

  PMID: 9836608 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.

  PMID: 15204721 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.

  PMID: 16520100 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.

  PMID: 21383099 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.

  PMID: 17213921 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.

  PMID: 15944738 BACKGROUND

• 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.

  PMID: 28916443 RESULT

MeSH Terms

Conditions

Malaria; Malaria, Falciparum

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Limitations and Caveats

The Principal Investigator, Dr. Donald Krogstad, died on August 14, 2020 (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543845/). The Results Point of Contact has been updated to list Jeffrey G. Shaffer, PhD.

Results Point of Contact

• Title: Jeffrey G Shaffer
• Organization: Tulane University

jshaffer@tulane.edu

504-988-1142

Study Officials

• Donald J. Krogstad, MD

  Tulane School of Public Health and Tropical Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 6, 2012
• First Posted: June 8, 2012
• Study Start: August 1, 2013
• Primary Completion: January 1, 2016
• Study Completion: February 1, 2017
• Last Updated: July 11, 2024
• Results First Posted: July 11, 2024

Record last verified: 2024-06

Locations

MA (1)