Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Active-control, Double-blind, Double-dummy Study to Evaluate the Efficacy and Safety of Tafenoquine for the Treatment of Plasmodium Vivax in Adults
Brief Summary: This Phase II study is designed to determine whether a single 600 mg dose or 400mg/day for 3 days of tafenoquine is efficacious, and well tolerated for clearing P. vivax malaria infection (blood schizontocidal and gametocytocidal activity) and preventing P. vivax relapse (hypnozoite eradication). It will also further establish the safety and tolerability of these doses of tafenoquine.


Options:
A: Inclusion Criteria:

* Between 18 and 45 years of age inclusive, at the time of signing the informed consent.
* Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, brief physical examination, and laboratory tests.
* Participant values for haematology and chemistry within the normal range. A participant with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
* Body weight between \>=35 kilogram (kg) and =\<100kg
* Male OR Female. Female participant is eligible to participate if she is not pregnant (as confirmed by a negative \[serum or urine, according to site standard\] human chorionic gonadotrophin \[hCG\] test), not lactating, and at least one of the following conditions applies:

Non-reproductive potential defined as Pre-menopausal females with one of the following: Documented tubal ligation or Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion or Hysterectomy or Documented Bilateral Oophorectomy or Postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to site specific laboratory reference ranges for confirmatory levels). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.

Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from screening until completion of the Day 90 follow-up visit.

* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

Exclusion Criteria:

* Alanine Aminotransferase (ALT) and bilirubin \>1.5 times Upper Limit of Normal (ULN) (isolated bilirubin \>1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* The QT interval corrected (QTc) for heart rate according to Fridericia's formula (QTcF). QTcF \> 450 milli second (msec). Other calculation methods (e.g. QT interval corrected for heart rate according to Bazett's formula \[QTcB\], individually corrected QT interval \[QTcI\]) machine-read or manually over-read are not acceptable.
* Use of prescription (except female contraception and acetaminophen at doses of =\<2 grams(g)/day) or non-prescription drugs, 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 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise participant safety.
* History of regular alcohol consumption within 30 days of the study defined as: an average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 millilitre \[mL\]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
* Positive results for drugs of abuse
* Cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 30 days prior to screening.
* History of sensitivity to TQ, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
* History of thalassaemia; or current or past history of methemoglobinemia or methemoglobin percentage above the reference range at screening.
* Lactating females.
* Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. A positive pre-study drug/alcohol screen.
* A positive test for human immunodeficiency virus (HIV) antibody.
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 15 days of dosing with TQ or matched-placebo.
* The participant has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Exposure to more than four new chemical entities within 12 months prior to the first dosing day
* Participants with a hemoglobin values outside the lower limit of normal range. A single repeat is allowed for eligibility determination.
* Documented phenotypic Glucose-6-phosphate dehydrogenase (G6PD) deficiency, determined by a quantitative assay of enzyme activity. Defined as \<70% of locally defined median.
* A BCVA (bilateral) at screening of =\<72 letters
* Eye disease that could compromise assessment of BCVA or imaging of the posterior pole by fundus photography, or spectral domain OCT, FAF, or is likely to require intervention during the 4 month (approximately) study participation (e.g. cataract, glaucoma with documented visual field loss, ischemic optic neuropathy, retinitis pigmentosa)
* History of retinal vascular disease, retinal detachment, inflammatory disease, central serous chorioretinopathy, or other retinal disease that may affect posterior retinal function or architecture.
* Vitreo-retinal interface disorders (e.g. epiretinal membrane, vitreo-macular traction) that may affect posterior retinal function or architecture
* Intraocular surgery within 3 months of dosing
* Laser photocoagulation within 3 months of dosing
* High Myopia (defined as equal to, or worse than, -6.00 diopters)
* Anterior, intermediate or posterior uveitis (active or history of) or history of significant intraocular infectious disease (e.g., conjunctivitis is not acceptable to include) or another active inflammatory disease
* An OCT central subfield thickness \<250 microns or \>290 microns
* Presence of significant abnormal patterns on FAF or ocular abnormalities on fundus photography at screening.
* Uncontrolled intraocular pressure \>22millimetre of mercury (mmHg).
B: Inclusion Criteria:

* A female is eligible to enter and participate in the study if she is non-pregnant, nonlactating and if she is of: a. Non-childbearing potential defined as: post-menopausal (12 months of spontaneous amenorrhea or \<6 months of spontaneous amenorrhea with serum follicle-stimulating hormone \>40 milli-International units per milliliter \[mIU/mL\]), or pre-menopausal and has had a hysterectomy or a bilateral oophorectomy (removal of the ovaries) or a bilateral tubal ligation, negative pregnancy test or, b. Child-bearing potential, has a negative pregnancy test at screening, and agrees to comply with one of the following during the treatment stage of the study and for a period of 90 days after stopping study medication: Use of oral contraceptive, either combined or progestogen alone used in conjunction with double barrier method as defined below. Use of an intrauterine device with a documented failure rate of \<1% per year; Use of depo provera injection; Double barrier method consisting of spermicide with either condom or diaphragm; Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female. Complete abstinence from intercourse for 2 weeks prior to administration of study medication, throughout the study and for a period of 90 days after stopping study medication.
* The subject has a glucose 6-phosphate dehydrogenase (G6PD) value (measured by a quantitative spectrophotometric phenotype assay) as follows: Female subjects must have an enzyme level \>= 40 percent of the site median value for G6PD normal males. Male subjects must have an enzyme level \>= 70 percent of the site median value for G6PD normal males.
* The subject has a screening hemoglobin (Hb) value as follows: Any subject with a G6PD value \>=70 percent of the site median value must have a screening Hb value \>=7 g/dL; Female subjects with a G6PD value is \>=40 - \<70 percent of the site median value must have a screening Hb value \>=8 g/dL.
* The subject has a QT duration corrected for heart rate by Fridericia's Formula (QTcF) \<450 milisecond (msec). Reading based on an average of triplicate Electrocardiograms (ECGs) obtained over a brief recording period by machine or manual over-read.
* The subject has a positive malarial smear for P. vivax .
* The subject has a parasite density of \>100 and \<100,000 per microliter (μL).
* Male or female subject aged 16 years or older (18 years or older in Ethiopia) at the time of signing the informed consent.
* The subject agrees to G6PD genotyping.
* The subject is willing and able to comply with the study protocol.
* The subject or parent/legal guardian, as applicable, has given written informed, dated consent; and the subject has given written assent, if applicable, to participate in the study.

Exclusion Criteria:

* The subject has a mixed malaria infection (identified by a malarial smear or rapid diagnostic test).
* The subject has severe P. vivax malaria as defined by World Health Organization (WHO) criteria.
* The subject has a history of allergy to chloroquine, mefloquine, tafenoquine, primaquine, or to any other 4- or 8-aminoquinoline.
* The subject has a liver alanine aminotransferase (ALT) \>2 x upper limit of normal (ULN).
* The subject has severe vomiting (no food or inability to take food during the previous 8 hours).
* The subject has a clinically significant concurrent illness (e.g., pneumonia, septicemia), pre-existing condition (e.g., renal disease, malignancy), condition that may affect absorption of study medication (e.g., vomiting, severe diarrhea), or clinical signs and symptoms of severe cardiovascular disease (e.g., uncontrolled congestive heart failure, severe coronary artery disease).
* The subject has a history of porphyria, psoriasis, or epilepsy.
* The subject has a history of significant ocular disease (e.g. surgery to the globe, glaucoma, diabetic retinopathy) or has evidence of corneal or retinal abnormalities identified in the clinical screening ophthalmologic examination.
* The subject has taken anti-malarials (e.g., artemisinin-based combination therapies, mefloquine, primaquine, or any other 4- or 8-aminoquinoline) within 30 days prior to study entry.
* The subject has taken or will likely require during the study the use of medications from the following classes: Histamine-2 blockers and antacids; Drugs with hemolytic potential; Drugs known to prolong the QTcF interval; The biguanides phenformin and buformin (but excluding metformin); Drugs that are substrates of the renal transporters OCT2, MATE1 AND MATE-2K and have a narrow therapeutic index (for example, the anti-arrhythmic agents dofetilide, procainamide and pilsicainide)
* The subject has received treatment with any investigational drug within 30 days of study entry, or within 5 half-lives, whichever is longer.
* The subject has a recent history of illicit drug abuse or heavy alcohol intake, such that full participation in the study could be compromised.
C: Inclusion Criteria:

1. Positive smear for P. vivax.
2. Parasite density \> 500 and \< 200,000/μl
3. Age: 20-60 years old
4. Willing to sign consent form
5. Willing to be hospitalized for 29 days and remain in a malaria free region for 60 days thereafter for follow-up.
6. A female is eligible to enter and participate in this study if she is of:

a non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who is post-menopausal or, b child-bearing potential, has a negative pregnancy (urine or serum) test at screen, and agrees to comply with recognized contraceptive methods during the treatment stage of the study and for a period of 12 weeks after stopping study drug. Recognized contraceptive methods include, abstinence, implants of levonorgestrel, injectable progestogen, or appropriate double barrier methods using licensed contraceptives such as diaphragm and condom (by the partner) or intrauterine device and condom. The use of oral/patch contraceptives during the study is not considered sufficient contraceptive protection.

Exclusion Criteria:

1. Mixed malaria infections by Field's stain.
2. Female subjects who are pregnant, lactating or unwilling/unable to comply with recognized contraceptive methods during the treatment stage of the study and for a period of 12 weeks after stopping study drug.
3. Symptoms of severe vomiting (no food or inability to take food during the previous 8 hours).
4. Demonstrated glucose-6-phosphate dehydrogenase deficiency.
5. Subject has taken other anti-malarials (mefloquine, primaquine, chloroquine) within the past 30 days by history
6. Clinically significant illness (intercurrent illness e.g. pneumonia, pre-existing condition e.g. renal disease, malignancy or conditions that may affect absorption of study medication e.g. severe diarrhea or any signs of malnutrition as defined clinically).
7. Clinically significant abnormal laboratory values as determined by history, physical examination or routine blood chemistries and hematology values (laboratory guideline values for exclusion are hemoglobin \<7 gm/dL, platelets \< 50,000/μl, White Blood Cell count (WBC) \< 2000/μl, serum creatinine \>2.0mg/dL, or ALT or AST more than 3 times the upper limit of normal for age.
8. History of allergy to chloroquine, mefloquine, tafenoquine, primaquine or any other 8-aminoquinolines.
9. Subject has taken another investigational drug within 30 days or 5 half lives (whichever is longer), of study start.
10. History of previous eye surgery or have evidence of corneal or retinal abnormalities identified in baseline ophthalmological examination.
11. Subjects taking concomitant medications likely to affect renal or ophthalmic function or that are known to be metabolized primarily by the cytochrome P450 isoforms 3A4/5 and 2C9 and whose therapeutic effect occurs within a narrow plasma concentration range (e.g. warfarin, ketoconazole).
12. Subjects whom, after examination by the study ophthalmologist, are judged to be at risk for acute angle closure glaucoma.
13. Females who are pre-menarchal.
D: Inclusion Criteria: - Positive Giemsa smear for P. vivax

* Parasite density \>100 and \<200,000/μL
* ≥16 years
* A female is eligible if she is non-pregnant, nonlactating and if she is of: - non-child bearing potential defined as: post-menopausal (12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone \>40 mIU/mL), pre-menopausal and has had a hysterectomy or a bilateral oophorectomy (removal of the ovaries) or a bilateral tubal ligation with medical report verification, negative pregnancy test or,
* child-bearing potential, has a negative serum pregnancy test at screening, and agrees to comply with one of the following during the treatment stage of the study and for a period of 90 days after stopping study drug:
* Use of oral contraceptive, either combined or progestogen alone used in conjunction with double barrier method as defined below
* Use of an intrauterine device with a documented failure rate of \<1% per year
* Use of depo provera injection (part 2)
* Double barrier method consisting of spermicide with either condom or diaphragm
* Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female.
* Complete abstinence from intercourse for 2 weeks prior to administration of study drug, throughout the study and for a period of 90 days after stopping study drug.
* A signed and dated informed consent is obtained from the subject or the subject's legal representative prior to screening.

NB Assent is obtained from subjects \<18 years, where applicable and written or oral witnessed consent has been obtained from parent or guardian.

* The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is likely to complete the study as planned.
* Willing to be hospitalized for 3 days and return to clinic for all follow-up visits including Day 180
* QTc \<450 msec at screening, based on a single QTcF value at screening (part 1 only) or as an average of triplicate Electrocardiogram obtained over a brief recording period by machine or manual over-read if first is \>450 msec.- Exclusion Criteria: - Mixed malaria infections (e.g. identified by Giemsa-stained smear or rapid diagnostic test)
* Severe vivax malaria as defined by World Health Organisation criteria.
* Severe vomiting (no food or inability to take food during previous 8 hours)
* Screening haemoglobin concentration \<7 g/dL.
* Glucose 6-phosphate dehydrogenase deficiency, assessed by a quantitative spectrophotometric phenotype assay:

Part 1 - Males: Any subject with an enzyme level \<70% of the site median value for Glucose 6-phosphate dehydrogenase normals will be excluded. Females: Those females with a screening Hb ≥ 10 g/dL will only be excluded if their enzyme level is \<70% of the site median value for Glucose 6-Phosphate dehydrogenase normals. hose females with Hb ≥7 but \< 10 g/dL will be excluded if an enzyme level is not \> 90% of the site median value for Glucose 6-Phosphate dehydrogenase normals.

Part 2 - Any subject with enzyme level \<70% of the site median value for Glucose 6-phosphate dehydrogenase normals will be excluded

* Liver function test alanine transaminase \>2x Upper Limit of Normal
* Any clinically significant concurrent illness (e.g. pneumonia, septicaemia), pre-existing conditions (e.g. renal disease, malignancy), conditions that may affect absorption of study medication (e.g. vomiting or severe diarrhea) or clinical signs and symptoms of severe cardiovascular disease (e.g. uncontrolled congestive heart failure or severe coronary artery disease). These abnormalities may be identified on the screening history and physical or laboratory examination.
* Subject has taken antimalarials (e.g. ACT, mefloquine, primaquine, chloroquine) or drugs with anti-malarial activity within the past 30 days by history.
* History of allergy to chloroquine, mefloquine, tafenoquine, primaquine or to any other 4- or 8-aminoquinolines.
* Any contraindications to chloroquine or primaquine administration including a history of porphyria, psoriasis or epilepsy (please refer to chloroquine and primaquine locally approved prescribing information).
* Subject who has previously received study medication for this protocol (all parts) or has received treatment with any other investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.
* History of illicit drug abuse or heavy alcohol intake within 6 months of the study.
* Subjects who have taken or will likely require the use of medications from the prohibited medication list which include the following classes: Histamine-2 blockers and antacids.
* Drugs with haemolytic potential.
* Drugs known to prolong the QTc interval

Answer: C