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

NCT02696954 | Terminated Phase 1

• 1 other identifier: ALAQPQ
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

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.

Conditions

Pharmacokinetic; Drug Combination; Healthy

Keywords

Artemether-lumefantrine; Amodiaquine; Primaquine

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (8)

• Elimination clearance (CL/F)

  1 year

• Terminal elimination half-life (t1/2)

  1 year

• Apparent volume of distribution (Vd)

  1 year

• Number of adverse events

  1 year

• Number of event concerning of abnormal electrocardiographic

  1 year

Study Arms (2)

Group A

EXPERIMENTAL

Drug: Artemether-lumefantrine; Drug: Amodiaquine; Drug: Artemether-lumefantrine + Amodiaquine; Drug: Primaquine; Drug: Artemether-lumefantrine + Primaquine; Drug: Artemether-lumefantrine + Amodiaquine + Primaquine

Group B

EXPERIMENTAL

Drug: Amodiaquine; Drug: Artemether-lumefantrine; Drug: Artemether-lumefantrine + Amodiaquine; Drug: Primaquine; Drug: Artemether-lumefantrine + Amodiaquine + Primaquine; Drug: Artemether-lumefantrine + Primaquine

Interventions

Artemether-lumefantrine DRUG

Artemether-lumefantrine on Day 0, 1 and 2 Washout period: more than 6 weeks

Group A

Amodiaquine DRUG

Amodiaquine on Day 0, 1 and 2 Washout period: more than 6 weeks

Group A; Group B

Artemether-lumefantrine + Amodiaquine DRUG

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

Group A; Group B

Primaquine DRUG

Primaquine on Day 0 Washout period: more than 1 week

Group A; Group B

Artemether-lumefantrine + Primaquine DRUG

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

Group A

Artemether-lumefantrine + Amodiaquine + Primaquine DRUG

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

Group A; Group B

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Oxford: lead
• Mahidol University: collaborator
• Mahidol Oxford Tropical Medicine Research Unit: collaborator

Study Sites (1)

Faculty of Tropical Medicine, Mahidol University

Bangkok, 10400, Thailand

Location

MeSH Terms

Interventions

Artemether, Lumefantrine Drug Combination; Amodiaquine; Primaquine

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 18, 2016
• First Posted: March 2, 2016
• Study Start: November 18, 2016
• Primary Completion: March 1, 2019
• Study Completion: March 1, 2019
• Last Updated: June 28, 2019

Record last verified: 2019-05

Data Sharing

• IPD Sharing: Will share

Locations

TH (1)