Studies of a Candidate Aminoquinoline Antimalarial (AQ-13)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Tulane University Health Sciences Center
Sponsor:
Collaborator:
University of the Sciences, Techniques and Technologies of Bamako
Information provided by (Responsible Party):
Donald Krogstad, Tulane University Health Sciences Center
ClinicalTrials.gov Identifier:
NCT01614964
First received: June 6, 2012
Last updated: April 1, 2014
Last verified: April 2014
  Purpose

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 4 tablets 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).


Condition Intervention Phase
Malaria
Drug: AQ-13 Treatment
Drug: Coartem Treatment
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase 2 Proof of Concept Study of a Candidate Aminoquinoline Antimalarial (AQ-13)

Resource links provided by NLM:


Further study details as provided by Tulane University Health Sciences Center:

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. [ Time Frame: Subjects are followed for 42 days after beginning treatment with either AQ-13 or Coartem.. ] [ Designated as safety issue: No ]
    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 [ Time Frame: within 4 weeks of beginning treatment with either AQ-13 or Coartem ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: from the time of beginning treatment with either AQ-13 or Coartem to the first of 2 successive negative blood smears ] [ Designated as safety issue: No ]
    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 [ Time Frame: within 42 days after beginning treatment with either AQ-13 or Coartem ] [ Designated as safety issue: No ]
    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. [ Time Frame: within 14 days of beginning treatment with either AQ-13 or Coartem ] [ Designated as safety issue: Yes ]
    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 below, 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 [ Time Frame: These studies will continue for the entire 42 day follow-up period. ] [ Designated as safety issue: No ]
    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 three 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 [ Time Frame: Days 1-7 after beginning treatment with either AQ-13 or Coartem ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 66
Study Start Date: June 2013
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 four tablets (containing 20 mg artemether, 120 mg lumefantrine) at the time of diagnosis and 8 hours later on day 1, four tablets twice daily on day 2 (24 and 36 hours after diagnosis) and again on day 3 (48 and 60 hours after diagnosis) for a total oral dose of 24 tablets (containing 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 4 tablets over 3 days (each tablet containing 20 mg artemether and 120 mg lumefantrine). Those 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.
Other Name: Tablets contain 20 mg artemether and 120 mg lumefantrine.

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 4 tablets 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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,
  8. Infection with other plasmodial species on the blood smear (P. ovale, P. ovale, P. vivax).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01614964

Contacts
Contact: Ousmane A. Koita, PharmD, PhD 011-223-6363-8888 okoita@icermali.org
Contact: Aliou Sissako, MD 011-223-6673-4992 drsissakoaliou@yahoo.fr

Locations
Mali
Clinical Research Center (Hopital Point G, University of the Sciences, Techniques and Technologies of Bamako) Recruiting
Bamako, Mali, BP 1805
Contact: Ousmane A. Koita, PharmD, PhD    011-223-6363-8888    okoita@icermali.org   
Contact: Aliou Sissako, MD    011-223-6673-4992    drsissakoaliou@yahoo.fr   
Principal Investigator: Ousmane A. Koita, PharmD, PhD         
Sponsors and Collaborators
Donald Krogstad
University of the Sciences, Techniques and Technologies of Bamako
Investigators
Principal Investigator: Donald J. Krogstad, MD Tulane School of Public Health and Tropical Medicine
  More Information

Publications:

Responsible Party: Donald Krogstad, Henderson Professor of Tropical Medicine, Tulane University Health Sciences Center
ClinicalTrials.gov Identifier: NCT01614964     History of Changes
Other Study ID Numbers: 2149, FDA 1R01-FD-003373-01A2
Study First Received: June 6, 2012
Last Updated: April 1, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by Tulane University Health Sciences Center:
Plasmodium falciparum
pharmacokinetics
antimalarials (antimalarial drugs)
chloroquine (chloroquine-resistant)
QT (QTc) interval

Additional relevant MeSH terms:
Malaria
Protozoan Infections
Parasitic Diseases
Antimalarials
Artemether
Lumefantrine
Artemether-lumefantrine combination
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antifungal Agents
Coccidiostats
Schistosomicides
Antiplatyhelmintic Agents
Anthelmintics

ClinicalTrials.gov processed this record on August 25, 2014