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Study of Artemether-lumefantrine, Amodiaquine and Primaquine in Healthy Subjects (ALAQPQ)

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ClinicalTrials.gov Identifier: NCT02696954
Recruitment Status : Recruiting
First Posted : March 2, 2016
Last Update Posted : August 24, 2017
Sponsor:
Collaborators:
Mahidol University
Mahidol Oxford Tropical Medicine Research Unit
Information provided by (Responsible Party):
University of Oxford

Brief Summary:

Primary Objective

  • To characterize the potential pharmacokinetic interactions of artemether -lumefantrine, amodiaquine and primaquine in healthy adult subjects.

Secondary Objectives

  • To characterize the pharmacokinetic properties of artemether-lumefantrine, amodiaquine and primaquine when given alone and in combination.
  • To evaluate the safety and tolerability of co-administered artemether-lumefantrine, amodiaquine and primaquine.
  • To investigate pharmacogenetic polymorphisms affecting drug levels of artemether-lumefantrine, amodiaquine and primaquine and their metabolites.

Condition or disease Intervention/treatment Phase
Pharmacokinetic Drug Combination Healthy Drug: Artemether-lumefantrine Drug: Amodiaquine Drug: Artemether-lumefantrine + Amodiaquine Drug: Primaquine Drug: Artemether-lumefantrine + Primaquine Drug: Artemether-lumefantrine + Amodiaquine + Primaquine Phase 1 Phase 2

Detailed Description:

The study design is an open-label pharmacokinetic study in healthy G6PD normal Thai subjects. This study will enroll 16 healthy subjects. Participants who pass the screening process will have 6 admissions in the hospital to receive 6 drug regimens as below

First admission visit: The subject may be randomized to receive either Artemether-Lumefantrine or Amodiaquine with 6-10 weeks washout period.

Second admission visit: Subject who receives Artemether-Lumefantrine from previous visit will receive amodiaquine in this visit and vice versa. This visit will required 6-10 weeks washout period.

Third admission visit: Every subject will receive Artemether-lumefantrine and Amodiaquine with 6-10 weeks washout period.

Forth admission visit: Every subject will receive Primaquine with 1-5 weeks washout period.

Fifth admission visit: Subject may randomize to receive either Artemether-Lumefantrine and Primaquine or Artemether-Lumefantrine and Amodiaquine and Primaquine in this visit with 6-10 weeks washout period.

Sixth admission visit: Subject who receives Artemether-Lumefantrine and Amodiaquine and primaquine from previous visit will receive Artemether-Lumefantrine and Primaquine in this visit and vice versa.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Open-Label Study to Evaluate Potential Pharmacokinetic Interactions of Orally Administered Artemether-lumefantrine, Amodiaquine and Primaquine in Healthy Adult Subjects
Study Start Date : November 2016
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Group A Drug: Artemether-lumefantrine
Artemether-lumefantrine on Day 0, 1 and 2 Washout period: 6-10 weeks

Drug: Amodiaquine
Amodiaquine on Day 0, 1 and 2 Washout period: 6-10 weeks

Drug: Artemether-lumefantrine + Amodiaquine
Artemether-lumefantrine + Amodiaquine on Day 0, 1 and 2 Washout period: 6-10 weeks

Drug: Primaquine
Primaquine on Day 0 Washout period: 1-5 weeks

Drug: Artemether-lumefantrine + Primaquine
Artemether-lumefantrine on Day 0, 1 and 2 + Primaquine on Day 0 Washout period: 6-10 weeks

Drug: Artemether-lumefantrine + Amodiaquine + Primaquine
Artemether-lumefantrine Day 0, 1 and 2 + Amodiaquine on Day 0, 1 and 2 + Primaquine on Day 0 Washout period: 6-10 weeks

Experimental: Group B Drug: Amodiaquine
Amodiaquine on Day 0, 1 and 2 Washout period: 6-10 weeks

Drug: Artemether-lumefantrine
Artemether-lumefantrine on Day 0, 1 and 2 Washout period: 6-10 weeks

Drug: Artemether-lumefantrine + Amodiaquine
Artemether-lumefantrine + Amodiaquine on Day 0, 1 and 2 Washout period: 6-10 weeks

Drug: Primaquine
Primaquine on Day 0 Washout period: 1-5 weeks

Drug: Artemether-lumefantrine + Amodiaquine + Primaquine
Artemether-lumefantrine Day 0, 1 and 2 + Amodiaquine on Day 0, 1 and 2 + Primaquine on Day 0 Washout period: 6-10 weeks

Drug: Artemether-lumefantrine + Primaquine
Artemether-lumefantrine on Day 0, 1 and 2 + Primaquine on Day 0 Washout period: 6-10 weeks




Primary Outcome Measures :
  1. Area under the concentration-time curve (AUC (0-∞) [ Time Frame: 1 year ]
    for artemether, lumefantrine, amodiaquine and primaquine and their metabolites when given alone and in combination.

  2. Area under the concentration-time curve AUC (0-last) [ Time Frame: 1 year ]
    for artemether, lumefantrine, amodiaquine and primaquine and their metabolites when given alone and in combination.

  3. Maximal concentration (Cmax) [ Time Frame: 1 year ]
    for artemether, lumefantrine, amodiaquine and primaquine and their metabolites when given alone and in combination.


Secondary Outcome Measures :
  1. Elimination clearance (CL/F) [ Time Frame: 1 year ]
    of artemether, lumefantrine, amodiaquine and primaquine and their metabolites when given alone and in combination.

  2. Terminal elimination half-life (t1/2) [ Time Frame: 1 year ]
    of artemether, lumefantrine, amodiaquine and primaquine and their metabolites when given alone and in combination.

  3. Apparent volume of distribution (Vd) [ Time Frame: 1 year ]
    of artemether, lumefantrine, amodiaquine and primaquine and their metabolites when given alone and in combination.

  4. Number of adverse events [ Time Frame: 1 year ]
    Safety and tolerability parameters including adverse events, electrocardiographic changes, vital signs and biochemical assessments.

  5. Number of event concerning of abnormal electrocardiographic [ Time Frame: 1 year ]
    Safety and tolerability parameters including adverse events, electrocardiographic changes, vital signs and biochemical assessments.

  6. Number of event concerning of abnormal vital signs [ Time Frame: 1 year ]
    Safety and tolerability parameters including adverse events, electrocardiographic changes, vital signs and biochemical assessments.

  7. Number of event concerning of abnormal laboratory values [ Time Frame: 1 year ]
    Safety and tolerability parameters including adverse events, electrocardiographic changes, vital signs and biochemical assessments.

  8. Identify polymorphisms of cytochrome 450 [ Time Frame: 1 year ]
    To identify polymorphisms of cytochrome 450 related to drug metabolism from individual subject.



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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Healthy as judged by a responsible physician with no abnormality identified on a medical evaluation including medical history and physical examination.
  2. Male or female non-smoker aged between 18 years to 60 years.
  3. A female is eligible to enter and participate in this study if she is:

    • of non-childbearing potential including pre-menopausal females with documented (medical report verification) hysterectomy or double oophorectomy
    • or postmenopausal defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone levels >40 mIU/mL or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy
    • or of childbearing potential, has a negative serum pregnancy test at screening and prior to start the study drug in each period, and abstain from sexual intercourse or agrees to using effective contraceptive methods (e.g., intrauterine device, hormonal contraceptive drug, tubal ligation or female barrier method with spermicide) during the study until completion of the follow-up procedures
  4. A male is eligible to enter and participate in this study if he: agrees to abstain from sexual intercourse with females of childbearing potential or lactating females; or is willing to use a condom/spermicide, during the study until completion of the follow-up procedures.
  5. Normal electrocardiogram (ECG) with QTc <450 msec.
  6. Willingness and ability to comply with the study protocol for the duration of the trial.

Exclusion Criteria:

  1. Females who are pregnant, trying to get pregnant, or are lactating.
  2. The subject has evidence of active substance abuse that may compromise safety, pharmacokinetics, or ability to adhere with protocol instructions.
  3. A positive pre-study hepatitis B surface antigen, positive hepatitis C antibody, or positive human immunodeficiency virus-1 (HIV-1) antibody result at screening.
  4. Subjects with a personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or additional risk factors for torsades de pointes (heart failure, hypokalemia) or with a family history of sudden cardiac death.
  5. A creatinine clearance <70 mL/min as determined by Cockcroft-Gault equation:

    CLcr (mL/min) = (140 - age) * Wt / (72 * Scr) (multiply answer by 0.85 for females) Where age is in years, weight (wt) is in kg, and serum creatinine (Scr) is in units of mg/dL [Cockcroft, 1976].

  6. History of alcohol or substance abuse or dependence within 6 months of the study.
  7. Use of prescription or non-prescription drugs except paracetamol at doses of up to 2 grams/day, including vitamins, herbal and dietary supplements (including St. John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 times the drug half-life (whichever is longer) prior to the first dose of study medication until the completion of the follow-up procedure, unless in the opinion of investigator, the medication will not interfere with the study procedures or compromise subject safety; the investigator will take advice from the manufacturer representative as necessary.
  8. The subject has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 x half-life, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of study medication.
  9. The subject is unwilling to abstain from ingesting alcohol within 48 hours prior to the first dose of study medication until collection of the final pharmacokinetic sample during each regimen.
  10. Subjects who have donated blood to the extent that participation in the study would result in more than 300 mL blood donated within a 30-day period. Note: This does not include plasma donation.
  11. Subjects who have a history of allergy to the study drug or drugs of this class, or a history of drug or other allergy that, in the opinion of the investigator, contraindicates participation in the trial. In addition, if heparin is used during pharmacokinetic sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled.
  12. Lack of suitability for participation in this study, including but not limited to, unstable medical conditions, systemic disease manifested by tendency to granulocytopenia e.g. rheumatoid arthritis and lupus erythematosus that in the opinion of the investigator would compromise their participation in the trial.
  13. AST or ALT >1.5 upper limit of normal (ULN)
  14. Subjects with history of renal disease, hepatic disease, and/or cholecystectomy
  15. G6PD deficient
  16. Abnormal methemoglobin level (more than 3 mg/dL).
  17. History of antimalarial drugs use including but not limited to mefloquine, chloroquine, primaquine, artesunate, piperaquine and pyronaridine treatment within 6 months.
  18. Subject who received quinacrine in last 30 days.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02696954


Contacts
Contact: Borimas Hanboonkunupakarn, MD 662-354-9168 ext 3160 Borimas@tropmedres.ac
Contact: Salwaluk Panapipat 662-203-6375 Salwaluk@tropmedres.ac

Locations
Thailand
Faculty of Tropical Medicine, Mahidol University Recruiting
Bangkok, Thailand, 10400
Contact: Borimas Hanboonkunupakarn, MD    662-354-9100 ext 3160-62    borimas@tropmedres.ac   
Contact: Salwaluk Panapipat    662-203-6375    salwaluk@tropmedres.ac   
Sponsors and Collaborators
University of Oxford
Mahidol University
Mahidol Oxford Tropical Medicine Research Unit

Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT02696954     History of Changes
Other Study ID Numbers: ALAQPQ
First Posted: March 2, 2016    Key Record Dates
Last Update Posted: August 24, 2017
Last Verified: December 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

Keywords provided by University of Oxford:
Artemether-lumefantrine
Amodiaquine
Primaquine

Additional relevant MeSH terms:
Lumefantrine
Artemether
Artemisinins
Primaquine
Artemether-lumefantrine combination
Amodiaquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antifungal Agents
Coccidiostats
Schistosomicides
Antiplatyhelmintic Agents
Anthelmintics