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Studies of a Candidate Aminoquinoline Antimalarial (AQ-13)

Primary Purpose

Malaria

Status

Completed

Phase

Phase 2

Locations

Mali

Study Type

Interventional

Intervention

AQ-13 Treatment

Coartem Treatment

About this trial

This is an interventional treatment trial for Malaria focused on measuring Plasmodium falciparum, pharmacokinetics, antimalarials (antimalarial drugs), chloroquine (chloroquine-resistant), QT (QTc) interval

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)MaleDoes not accept healthy volunteers

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).

Sites / Locations

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

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

AQ-13

Coartem Treatment

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT01614964

First Posted

June 6, 2012

Last Updated

August 11, 2017

Sponsor

Donald Krogstad

Collaborators

University of the Sciences, Techniques and Technologies of Bamako

1. Study Identification

Unique Protocol Identification Number

NCT01614964

Brief Title

Studies of a Candidate Aminoquinoline Antimalarial (AQ-13)

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2017

Overall Recruitment Status

Completed

Study Start Date

August 2013 (Actual)

Primary Completion Date

January 2016 (Actual)

Study Completion Date

February 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Donald Krogstad

Collaborators

University of the Sciences, Techniques and Technologies of Bamako

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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).

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Malaria

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

66 (Actual)

8. Arms, Groups, and Interventions

Arm Title

AQ-13

Arm Type

Experimental

Arm Description

Arm Title

Coartem Treatment

Arm Type

Active Comparator

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

AQ-13 Treatment

Other Intervention Name(s)

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

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Coartem Treatment

Other Intervention Name(s)

Tablets contain 20 (or 80) mg artemether and 120 (or 480) mg lumefantrine.

Intervention Description

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.

Primary Outcome Measure Information:

Title

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.

Description

Time Frame

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

Secondary Outcome Measure Information:

Title

Frequency of adverse events

Description

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.

Time Frame

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

Title

Parasite Clearance Time

Description

Time Frame

from the time of beginning treatment with either AQ-13 or Coartem to the first of 2 successive negative blood smears

Title

Time to recrudescence of reinfection

Description

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.

Time Frame

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

Title

Effects of antimalarial treatment on the QT (QTc) interval.

Description

Time Frame

within 14 days of beginning treatment with either AQ-13 or Coartem

Title

Pharmacokinetic parameters for AQ-13

Description

Time Frame

These studies will continue for the entire 42 day follow-up period.

Title

Fever Clearance Time

Description

Time Frame

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

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

99 Years

Accepts Healthy Volunteers

Eligibility Criteria

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).

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Donald J. Krogstad, MD

Organizational Affiliation

Tulane School of Public Health and Tropical Medicine

Official's Role

Principal Investigator

Facility Information:

Facility Name

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

City

Bamako

ZIP/Postal Code

BP 1805

Country

Mali

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

9025680

Citation

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.

Results Reference

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PubMed Identifier

9836608

Citation

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.

Results Reference

background

PubMed Identifier

15204721

Citation

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.

Results Reference

background

PubMed Identifier

16520100

Citation

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.

Results Reference

background

PubMed Identifier

21383099

Citation

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.

Results Reference

background

PubMed Identifier

17213921

Citation

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.

Results Reference

background

PubMed Identifier

15944738

Citation

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 Reference

background

PubMed Identifier

28916443

Citation

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.

Results Reference

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Studies of a Candidate Aminoquinoline Antimalarial (AQ-13)

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