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

Study Overview
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Brief Summary
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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.

Detailed Description
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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 more than 6 weeks washout period before second admission visit. Second admission visit: Subject who receives Artemether-Lumefantrine from previous visit will receive amodiaquine in this visit and vice versa. This visit will required more than 6 weeks washout period before third admission visit. Third admission visit: Every subject will receive Artemether-lumefantrine and Amodiaquine with more than 6 weeks washout period before forth admission visit. Forth admission visit: Every subject will receive Primaquine with more than 1 week washout period before fifth admission visit. Fifth admission visit: Subject may randomize to receive either Artemether-Lumefantrine and Primaquine or Artemether-Lumefantrine and Amodiaquine and Primaquine in this visit with more than 6 weeks washout period before sixth admission visit. 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.

Official Title
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A Randomized, Open-Label Study to Evaluate Potential Pharmacokinetic Interactions of Orally Administered Artemether-lumefantrine, Amodiaquine and Primaquine in Healthy Adult Subjects

Conditions
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Pharmacokinetic, Drug Combination, Healthy

Intervention / Treatment
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* Drug: Artemether-lumefantrine
* Drug: Amodiaquine
* Drug: Artemether-lumefantrine
* Drug: Artemether-lumefantrine + Amodiaquine
* Drug: Primaquine
* Drug: Artemether-lumefantrine + Primaquine
* Drug: Artemether-lumefantrine + Amodiaquine + Primaquine
* Drug: Artemether-lumefantrine + Primaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy as judged by a responsible physician with no abnormality identified on a medical evaluation including medical history and physical examination. Male or female non-smoker aged between 18 years to 60 years. 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 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. Normal electrocardiogram (ECG) with QTc <450 msec. Willingness and ability to comply with the study protocol for the duration of the trial. Exclusion Criteria: Females who are pregnant, trying to get pregnant, or are lactating. The subject has evidence of active substance abuse that may compromise safety, pharmacokinetics, or ability to adhere with protocol instructions. A positive pre-study hepatitis B surface antigen, positive hepatitis C antibody, or positive human immunodeficiency virus-1 (HIV-1) antibody result at screening. 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. 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]. History of alcohol or substance abuse or dependence within 6 months of the study. 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. 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. 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. 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. 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. 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. AST or ALT >1.5 upper limit of normal (ULN) Subjects with history of renal disease, hepatic disease, and/or cholecystectomy G6PD deficient Abnormal methemoglobin level (more than 3 mg/dL). History of antimalarial drugs use including but not limited to mefloquine, chloroquine, primaquine, artesunate, piperaquine and pyronaridine treatment within 6 months. Subject who received quinacrine in last 30 days.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br> | Drug: Artemether-lumefantrine<br>* Artemether-lumefantrine on Day 0, 1 and 2 Washout period: more than 6 weeks<br>Drug: Amodiaquine<br>* Amodiaquine on Day 0, 1 and 2 Washout period: more than 6 weeks<br>Drug: Artemether-lumefantrine + Amodiaquine<br>* Artemether-lumefantrine + Amodiaquine on Day 0, 1 and 2 Washout period: more than 6 weeks<br>Drug: Primaquine<br>* Primaquine on Day 0 Washout period: more than 1 week<br>Drug: Artemether-lumefantrine + Primaquine<br>* Artemether-lumefantrine on Day 0, 1 and 2 + Primaquine on Day 0 Washout period: more than 6 weeks<br>Drug: Artemether-lumefantrine + Amodiaquine + Primaquine<br>* Artemether-lumefantrine Day 0, 1 and 2 + Amodiaquine on Day 0, 1 and 2 + Primaquine on Day 0 Washout period: more than 6 weeks<br>|
| Experimental: Group B<br> | Drug: Amodiaquine<br>* Amodiaquine on Day 0, 1 and 2 Washout period: more than 6 weeks<br>Drug: Artemether-lumefantrine<br>* Artemether-lumefantrine on Day 0, 1 and 2 Washout period: more than 6 weeks<br>Drug: Artemether-lumefantrine + Amodiaquine<br>* Artemether-lumefantrine + Amodiaquine on Day 0, 1 and 2 Washout period: more than 6 weeks<br>Drug: Primaquine<br>* Primaquine on Day 0 Washout period: more than 1 week<br>Drug: Artemether-lumefantrine + Amodiaquine + Primaquine<br>* Artemether-lumefantrine Day 0, 1 and 2 + Amodiaquine on Day 0, 1 and 2 + Primaquine on Day 0 Washout period: more than 6 weeks<br>Drug: Artemether-lumefantrine + Primaquine<br>* Artemether-lumefantrine on Day 0, 1 and 2 + Primaquine on Day 0<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve (AUC (0-∞) | for artemether, lumefantrine, amodiaquine and primaquine and their metabolites when given alone and in combination. | 1 year | 
| Area under the concentration-time curve AUC (0-last) | for artemether, lumefantrine, amodiaquine and primaquine and their metabolites when given alone and in combination. | 1 year | 
| Maximal concentration (Cmax) | for artemether, lumefantrine, amodiaquine and primaquine and their metabolites when given alone and in combination. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Elimination clearance (CL/F) | of artemether, lumefantrine, amodiaquine and primaquine and their metabolites when given alone and in combination. | 1 year | 
| Terminal elimination half-life (t1/2) | of artemether, lumefantrine, amodiaquine and primaquine and their metabolites when given alone and in combination. | 1 year | 
| Apparent volume of distribution (Vd) | of artemether, lumefantrine, amodiaquine and primaquine and their metabolites when given alone and in combination. | 1 year | 
| Number of adverse events | Safety and tolerability parameters including adverse events, electrocardiographic changes, vital signs and biochemical assessments. | 1 year | 
| Number of event concerning of abnormal electrocardiographic | Safety and tolerability parameters including adverse events, electrocardiographic changes, vital signs and biochemical assessments. | 1 year | 
| Number of event concerning of abnormal vital signs | Safety and tolerability parameters including adverse events, electrocardiographic changes, vital signs and biochemical assessments. | 1 year | 
| Number of event concerning of abnormal laboratory values | Safety and tolerability parameters including adverse events, electrocardiographic changes, vital signs and biochemical assessments. | 1 year | 
| Identify polymorphisms of cytochrome 450 | To identify polymorphisms of cytochrome 450 related to drug metabolism from individual subject. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Artemether-lumefantrine, Amodiaquine, Primaquine