Ph 2B/3 Tafenoquine (TFQ) Study in Prevention of Vivax Relapse

NCT ID: NCT01376167

Last Updated: 2018-04-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 851 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-04-24
• Study Completion Date: 2016-11-18

Brief Summary

The purpose of this two part study is to test the safety and efficacy of Tafenoquine (with Cholorquine) as a radical cure for Plasmodium vivax (P.vivax) malaria relative to the control Chloroquine.Part 1 aims to select an efficacious and well tolerated dose that can be co-administered with Chloroquine. Part 2 will investigate the safety and efficacy of the selected dose (300 mg tafenoquine) in the treatment and radical cure of Plasmodium Vivax Malaria.

Detailed Description

Plasmodium vivax represents 50-80% of all malarial cases in Latin America and South East Asia. It is able to establish a dormant liver stage called the hypnozoite. Hypnozoite activation after initial infection can cause a relapse. Currently the only widely available drug is primaquine which requires administration over 14 days, resulting in poor compliance and treatment failure. Tafenoquine (an 8-aminoquinoline anti-malarial drug) has been shown to possess activity against all stages of the plasmodium life cycle, including the dormant stage in the liver. This is a multi-centre, double dummy, double blind, parallel group, randomized, active control study which is conducted in two parts. For both parts, subjects are treated with Chloroquine on days 1 to 3 (600mg, 600mg, and 300mg) to treat the blood stage vivax malaria. Part 1 will include at least 324 subjects and part 2 at least 600 subjects. Part 1 has 6 treatment arms, arms 1 to 4 contain different doses of Tafenoquine (50mg, 100mg, 300mg, and 600mg) dosed on day 1 or 2, arm 5 contains primaquine (15mg) dosing over 14 days (days 2-15 (15mg)) and arm 6 contains chloroquine only. The aim of this is to find a dose of Tafenoquine which meets the defined dose criteria. Based on Part 1 efficacy and safety, a single Tafenoquine dose (300 mg) will be studied in the pivotal Part 2. Part 2 contains 3 treatment arms one with the selected Tafenoquine dose (300 mg), the second arm will be 15mg Primaquine which will again be dosed over 14 days and the final arm contains chloroquine only dosed days 1-3 (600mg, 600mg, 300mg). Therefore as with Part 1, in Part 2 all subjects will receive Chloroquine. The aim of Part 2 is to investigate the safety and efficacy of the selected Tafenoquine/Chloroquine dose in the treatment and radical cure of Plasmodium vivax malaria. In addition to the Primary and Secondary endpoints stated below we will also be collecting; other efficacy endpoints (gametocyte clearance time, Recrudescence defined as any Plasmodium vivax parasitemia occurring on or before Day 29 (blood stage treatment failure), Incidence of Plasmodium falciparum malaria and Incidence of recrudescence and new Plasmodium vivax infection, determined by Polymerase Chain Reaction (PCR), safety endpoints (clinically relevant haemolysis leading to drops in haemoglobin / haematocrit or complications thereof (required transfusions, acute renal failure), changes in methaemoglobin, gastrointestinal (GI) tolerability - incidence of abdominal pain, heartburn, diarrhoea, constipation, nausea and vomiting and ophthalmic safety - incidence of corneal deposits, retinal and visual field abnormalities. Data collected at up to four centres . Additionally, the incidence and severity of adverse events and abnormal laboratory observations will be presented).Pharmacokinetic endpoints (Population pharmacokinetic parameters for tafenoquine including but not limited to oral clearance (CL/F) and volume of distribution (V/F)and Pharmacokinetic/Pharmacodynamic endpoints (e.g. tafenoquine plasma concentrations) and selected Pharmacodynamic endpoints (e.g. relapse efficacy, change in methaemoglobin) if appropriate, will be explored.

Conditions

Malaria, Vivax

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Tafenoquine 50mg

On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 50mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed.

Group Type: EXPERIMENTAL

Chloroquine 600mg

Intervention Type: DRUG

600mg Chloroquine given to each subject on Day 1 and Day2 of the trial

Chloroquine 300mg

Intervention Type: DRUG

300mg Chloroquine given to each subject on Day 3 of the trial

Tafenoquine 50mg

Intervention Type: DRUG

single dose 50mg Tafenoquine given to subject on treatment arm 1 on Days 1 or 2

Tafenoquine 100mg

On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 100mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed.

Group Type: EXPERIMENTAL

Chloroquine 600mg

Intervention Type: DRUG

600mg Chloroquine given to each subject on Day 1 and Day2 of the trial

Chloroquine 300mg

Intervention Type: DRUG

300mg Chloroquine given to each subject on Day 3 of the trial

Tafenoquine 100mg

Intervention Type: DRUG

single dose 100mg Tafenoquine given to subject on treatment arm 2 on Days 1 or 2

Tafenoquine 300mg

On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 300mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed.

Group Type: EXPERIMENTAL

Chloroquine 600mg

Intervention Type: DRUG

600mg Chloroquine given to each subject on Day 1 and Day2 of the trial

Chloroquine 300mg

Intervention Type: DRUG

300mg Chloroquine given to each subject on Day 3 of the trial

Tafenoquine 300mg

Intervention Type: DRUG

single dose 300mg Tafenoquine given to subject on treatment arm 3 on Days 1 or 2

Tafenoquine 600mg

On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 600mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed.

Group Type: EXPERIMENTAL

Chloroquine 600mg

Intervention Type: DRUG

600mg Chloroquine given to each subject on Day 1 and Day2 of the trial

Chloroquine 300mg

Intervention Type: DRUG

300mg Chloroquine given to each subject on Day 3 of the trial

Tafenoquine 600mg

Intervention Type: DRUG

single dose 600mg Tafenoquine given to subject on treatment arm 4 on Days 1 or 2

Primaquine 15mg

On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 15mg Primaquine once daily Days 2-15.

Group Type: ACTIVE_COMPARATOR

Chloroquine 600mg

Intervention Type: DRUG

600mg Chloroquine given to each subject on Day 1 and Day2 of the trial

Chloroquine 300mg

Intervention Type: DRUG

300mg Chloroquine given to each subject on Day 3 of the trial

Primaquine 15mg

Intervention Type: DRUG

15mg Primaquine given once daily to subject on treatment arm 5 on Days 2 to 15.

Chloroquine only

On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered.

Group Type: PLACEBO_COMPARATOR

Chloroquine 600mg

Intervention Type: DRUG

600mg Chloroquine given to each subject on Day 1 and Day2 of the trial

Chloroquine 300mg

Intervention Type: DRUG

300mg Chloroquine given to each subject on Day 3 of the trial

Tafenoquine 300mg (Part 2)

On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 300mg Tafenoquine will be administered on either Day 1 or Day2 depending on when eligibility is confirmed.

Group Type: EXPERIMENTAL

Chloroquine 600mg (Part 2 )

Intervention Type: DRUG

600mg Chloroquine given to each subject on Day 1 and Day2 of the trial.

Chloroquine 300mg (Part 2 )

Intervention Type: DRUG

300mg Chloroquine given to each subject on Day 3 of the trial.

Tafenoquine 300mg (Part 2)

Intervention Type: DRUG

single dose 300mg Tafenoquine given to subject on treatment arm 3 on Days 1 or 2.

Primaquine 15mg (Part 2)

On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered. 15mg Primaquine once daily Days 2-15

Group Type: ACTIVE_COMPARATOR

Chloroquine 600mg (Part 2 )

Intervention Type: DRUG

600mg Chloroquine given to each subject on Day 1 and Day2 of the trial.

Chloroquine 300mg (Part 2 )

Intervention Type: DRUG

300mg Chloroquine given to each subject on Day 3 of the trial.

Primaquine 15mg (Part2 )

Intervention Type: DRUG

15mg Primaquine given once daily to subject on treatment arm 3 on Days 2 to 15.

Chloroquine only (Part 2)

On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered

Group Type: PLACEBO_COMPARATOR

Chloroquine 600mg (Part 2 )

Intervention Type: DRUG

600mg Chloroquine given to each subject on Day 1 and Day2 of the trial.

Chloroquine 300mg (Part 2 )

Intervention Type: DRUG

300mg Chloroquine given to each subject on Day 3 of the trial.

Interventions

Chloroquine 600mg

600mg Chloroquine given to each subject on Day 1 and Day2 of the trial

Intervention Type: DRUG

Chloroquine 300mg

300mg Chloroquine given to each subject on Day 3 of the trial

Intervention Type: DRUG

Tafenoquine 50mg

single dose 50mg Tafenoquine given to subject on treatment arm 1 on Days 1 or 2

Intervention Type: DRUG

Tafenoquine 100mg

single dose 100mg Tafenoquine given to subject on treatment arm 2 on Days 1 or 2

Intervention Type: DRUG

Tafenoquine 300mg

single dose 300mg Tafenoquine given to subject on treatment arm 3 on Days 1 or 2

Intervention Type: DRUG

Tafenoquine 600mg

single dose 600mg Tafenoquine given to subject on treatment arm 4 on Days 1 or 2

Intervention Type: DRUG

Primaquine 15mg

15mg Primaquine given once daily to subject on treatment arm 5 on Days 2 to 15.

Intervention Type: DRUG

Chloroquine 600mg (Part 2 )

600mg Chloroquine given to each subject on Day 1 and Day2 of the trial.

Intervention Type: DRUG

Chloroquine 300mg (Part 2 )

300mg Chloroquine given to each subject on Day 3 of the trial.

Intervention Type: DRUG

Tafenoquine 300mg (Part 2)

single dose 300mg Tafenoquine given to subject on treatment arm 3 on Days 1 or 2.

Intervention Type: DRUG

Primaquine 15mg (Part2 )

15mg Primaquine given once daily to subject on treatment arm 3 on Days 2 to 15.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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

• Minimum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Medicines for Malaria Venture

OTHER

Sponsor Role: collaborator

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Bāndarban, , Bangladesh

GSK Investigational Site

Manaus, Amazonas, Brazil

GSK Investigational Site

Porto Velho, Rondônia, Brazil

GSK Investigational Site

Oddar Meancheay Province, , Cambodia

GSK Investigational Site

Gonder, , Ethiopia

GSK Investigational Site

Jimma, , Ethiopia

GSK Investigational Site

Bikaner, , India

GSK Investigational Site

Chennai, , India

GSK Investigational Site

Lucknow, , India

GSK Investigational Site

Secunderabad, , India

GSK Investigational Site

Iquitos, Loreto, Peru

GSK Investigational Site

Rio Tuba, Bataraza, , Philippines

GSK Investigational Site

Bangkok, , Thailand

GSK Investigational Site

Tak, , Thailand

Countries

Bangladesh; Brazil; Cambodia; Ethiopia; India; Peru; Philippines; Thailand

References

Roper DR, De la Salle B, Soni V, Fletcher K, Green JA. Abrogation of red blood cell G6PD enzyme activity through Heat treatment: development of survey material for the UK NEQAS G6PD scheme. Int J Lab Hematol. 2017 Jun;39(3):308-316. doi: 10.1111/ijlh.12627. Epub 2017 Mar 20.

Reference Type: DERIVED

PMID: 28318100 (View on PubMed)

Beck HP, Wampfler R, Carter N, Koh G, Osorio L, Rueangweerayut R, Krudsood S, Lacerda MV, Llanos-Cuentas A, Duparc S, Rubio JP, Green JA. Estimation of the Antirelapse Efficacy of Tafenoquine, Using Plasmodium vivax Genotyping. J Infect Dis. 2016 Mar 1;213(5):794-9. doi: 10.1093/infdis/jiv508. Epub 2015 Oct 23.

Reference Type: DERIVED

PMID: 26500351 (View on PubMed)

Tenero D, Green JA, Goyal N. Exposure-Response Analyses for Tafenoquine after Administration to Patients with Plasmodium vivax Malaria. Antimicrob Agents Chemother. 2015 Oct;59(10):6188-94. doi: 10.1128/AAC.00718-15. Epub 2015 Jul 27.

Reference Type: DERIVED

PMID: 26248362 (View on PubMed)

Llanos-Cuentas A, Lacerda MV, Rueangweerayut R, Krudsood S, Gupta SK, Kochar SK, Arthur P, Chuenchom N, Mohrle JJ, Duparc S, Ugwuegbulam C, Kleim JP, Carter N, Green JA, Kellam L. Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study. Lancet. 2014 Mar 22;383(9922):1049-58. doi: 10.1016/S0140-6736(13)62568-4. Epub 2013 Dec 19.

Reference Type: DERIVED

PMID: 24360369 (View on PubMed)

Lacerda MVG, Llanos-Cuentas A, Krudsood S, Lon C, Saunders DL, Mohammed R, Yilma D, Batista Pereira D, Espino FEJ, Mia RZ, Chuquiyauri R, Val F, Casapia M, Monteiro WM, Brito MAM, Costa MRF, Buathong N, Noedl H, Diro E, Getie S, Wubie KM, Abdissa A, Zeynudin A, Abebe C, Tada MS, Brand F, Beck HP, Angus B, Duparc S, Kleim JP, Kellam LM, Rousell VM, Jones SW, Hardaker E, Mohamed K, Clover DD, Fletcher K, Breton JJ, Ugwuegbulam CO, Green JA, Koh GCKW. Single-Dose Tafenoquine to Prevent Relapse of Plasmodium vivax Malaria. N Engl J Med. 2019 Jan 17;380(3):215-228. doi: 10.1056/NEJMoa1710775.

Reference Type: DERIVED

PMID: 30650322 (View on PubMed)

Study Documents

Document Type: Informed Consent Form

For additional information about this study please refer to the GSK Clinical Study Register

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Document Type: Clinical Study Report

For additional information about this study please refer to the GSK Clinical Study Register

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Document Type: Study Protocol

For additional information about this study please refer to the GSK Clinical Study Register

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Document Type: Dataset Specification

For additional information about this study please refer to the GSK Clinical Study Register

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Document Type: Statistical Analysis Plan

For additional information about this study please refer to the GSK Clinical Study Register

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Document Type: Individual Participant Data Set

For additional information about this study please refer to the GSK Clinical Study Register

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Other Identifiers

TAF112582

Identifier Type: -

Identifier Source: secondary_id

112582

Identifier Type: -

Identifier Source: org_study_id