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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Medicines for Malaria Venture
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01376167
First received: June 16, 2011
Last updated: May 29, 2014
Last verified: January 2014
  Purpose

The purpose of this two part study is to test the safety and efficacy of Tafenoquine 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 in the treatment and radical cure of Plasmodium Vivax Malaria.

The key milestone and completion dates that have been entered into this summary only reflect the Part 1 of the study.


Condition Intervention Phase
Malaria, Vivax
Drug: Chloroquine 600mg
Drug: Chloroquine 300mg
Drug: Tafenoquine 50mg
Drug: Tafenoquine 100mg
Drug: Tafenoquine 300mg
Drug: Tafenoquine 600mg
Drug: Primaquine 15mg
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multi-centre, Double-blind, Randomised, Parallel-group, Active Controlled Study to Evaluate the Efficacy, Safety and Tolerability of Tafenoquine (SB-252263, WR238605) in Subjects With Plasmodium Vivax Malaria.

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Relapse Efficacy [ Time Frame: 6 months post dosing (180 days) ] [ Designated as safety issue: No ]
    Subjects for whom initial clearance of parasitaemia is confirmed (parasite numbers fall below the limit of detection in thick blood smear and remain undetectable at the second smear collected 6-12 hours later) and who do not present with Plasmodium vivax asexual stage parasites within six months will be considered treatment successes


Secondary Outcome Measures:
  • Relapse Efficacy [ Time Frame: 4 months post dosing ] [ Designated as safety issue: No ]
    First confirmed presence of Plasmodium Vivax asexual stage parasites after clearance of initial parasitemia following treatment.

  • Time to relapse [ Time Frame: Within 180 days post dosing ] [ Designated as safety issue: No ]
    Time from initial parasite clearance to time of relaspe

  • Parasite clearance time [ Time Frame: From first dose until Day 180 ] [ Designated as safety issue: No ]
    Time needed to clear asexual parasites from blood, parasites fall below limit of detection in thick blood smear and remains undetectable for at least 48 hours.

  • Fever clearance time [ Time Frame: From first dose until Day 180 ] [ Designated as safety issue: No ]
    Time from first dose of treatment to time when body temperature falls to normal and remains normal for at least 48 hours.


Enrollment: 329
Study Start Date: September 2011
Estimated Study Completion Date: September 2015
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: Chloroquine 600mg
600mg Chloroquine given to each subject on Day 1 and Day2 of the trial
Drug: Chloroquine 300mg
300mg Chloroquine given to each subject on Day 3 of the trial
Drug: Tafenoquine 50mg
single dose 50mg Tafenoquine given to subject on treatment arm 1 on Days 1 or 2
Experimental: 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.
Drug: Chloroquine 600mg
600mg Chloroquine given to each subject on Day 1 and Day2 of the trial
Drug: Chloroquine 300mg
300mg Chloroquine given to each subject on Day 3 of the trial
Drug: Tafenoquine 100mg
single dose 100mg Tafenoquine given to subject on treatment arm 2 on Days 1 or 2
Experimental: 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.
Drug: Chloroquine 600mg
600mg Chloroquine given to each subject on Day 1 and Day2 of the trial
Drug: Chloroquine 300mg
300mg Chloroquine given to each subject on Day 3 of the trial
Drug: Tafenoquine 300mg
single dose 300mg Tafenoquine given to subject on treatment arm 3 on Days 1 or 2
Experimental: 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.
Drug: Chloroquine 600mg
600mg Chloroquine given to each subject on Day 1 and Day2 of the trial
Drug: Chloroquine 300mg
300mg Chloroquine given to each subject on Day 3 of the trial
Drug: Tafenoquine 600mg
single dose 600mg Tafenoquine given to subject on treatment arm 4 on Days 1 or 2
Active Comparator: 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.
Drug: Chloroquine 600mg
600mg Chloroquine given to each subject on Day 1 and Day2 of the trial
Drug: Chloroquine 300mg
300mg Chloroquine given to each subject on Day 3 of the trial
Drug: Primaquine 15mg
15mg Primaquine given once daily to subject on treatment arm 5 on Days 2 to 15.
Placebo Comparator: Chloroquine only
On Day 1 and Day 2 600mg Chloroquine will be administered, on Day 3 300mg Chloroquine will be administered.
Drug: Chloroquine 600mg
600mg Chloroquine given to each subject on Day 1 and Day2 of the trial
Drug: Chloroquine 300mg
300mg Chloroquine given to each subject on Day 3 of the trial

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 will be selected to be studied in the pivotal Part 2. Part 2 contains 3 treatment arms one with the selected Tafenoquine dose, 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 (Pharmacokinetic (PK) (e.g. tafenoquine plasma concentrations) and selected Pharmacodynamic (PD) endpoints (e.g. relapse efficacy, change in methaemoglobin) if appropriate, will be explored.)

The key milestone and completion dates that have been entered into this summary only reflect the Part 1 of the study.

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 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
  • Use of an intrauterine device with a documented failure rate of <1% per year
  • 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 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:

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.

  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01376167

Locations
Bangladesh
GSK Investigational Site
Bandarban, Bangladesh
Brazil
GSK Investigational Site
Manaus, Amazonas, Brazil, 69040-000
India
GSK Investigational Site
Bikaner, India
GSK Investigational Site
Chennai, India, 600016
GSK Investigational Site
Lucknow, India, 226003
GSK Investigational Site
Secunderabad, India, 500 003
Thailand
GSK Investigational Site
Bangkok, Thailand, 10400
GSK Investigational Site
Tak, Thailand, 63110
Sponsors and Collaborators
GlaxoSmithKline
Medicines for Malaria Venture
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided by GlaxoSmithKline

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01376167     History of Changes
Other Study ID Numbers: 112582, TAF112582
Study First Received: June 16, 2011
Last Updated: May 29, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Malaria
Malaria, Vivax
Protozoan Infections
Parasitic Diseases
Tafenoquine
Primaquine
Chloroquine
Chloroquine diphosphate
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Amebicides
Antirheumatic Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Filaricides
Antinematodal Agents
Anthelmintics
Central Nervous System Agents

ClinicalTrials.gov processed this record on October 19, 2014