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

GlaxoSmithKline851 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

851

Conditions

Malaria, Vivax

Interventions

Chloroquine 600mgDRUG

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

Chloroquine 300mgDRUG

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

Tafenoquine 50mgDRUG

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

Eligibility

Sex: ALLMin age: 16 Years

Medical Language ↔ Plain English

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

Locations (14)

GSK Investigational Site

Bāndarban, Bangladesh

GSK Investigational Site

Manaus, Amazonas, Brazil

GSK Investigational Site

Porto Velho, Rondônia, Brazil

Outcomes

Primary Outcomes

Number of Participants With Recurrence-free Efficacy at 6 Months Post Dose

A participant was considered to have demonstrated recurrence-free efficacy at 6 months if: a) Participant had non-zero P vivax asexual parasite count at Baseline. b) Participant showed initial clearance of P vivax parasitemia defined as two negative asexual P vivax parasite counts, with at least 6 hours between the counts, and no positive counts in the interval. c) Participant had no positive asexual P vivax parasite count at any assessment prior to or on Study Day 201 following initial parasite clearance. d) Participant did not take a concomitant medication with anti-malarial activity at any point between Study Day 1 and their last parasite assessment. e) Participant is parasite-free at 6 months. Participants were censored if they did not have P.vivax at Baseline, or took a drug with anti-malarial action despite not having malaria parasites, or did not have a 6 month assessment. The number of participants with recurrence-free efficacy at 6 months has been summarized.

Time frame: 6 months post dose

Secondary Outcomes

Number of Participants With Recurrence-free Efficacy at 4 Months Post Dose

A participant (par) was considered to have demonstrated recurrence-free efficacy at 4 months if: a) Par had non-zero P vivax asexual parasite count at Baseline. b) Par showed initial clearance of P vivax parasitemia. c) Par had no positive asexual P vivax parasite count at any assessment prior to or on Study Day 130 following initial parasite clearance. d) Par did not take a concomitant medication with anti-malarial activity at any point between Study Day 1 and their last parasite assessment after Study Day 109 (up to and including Study Day 130). e) Par is parasite-free at 4 months defined as a negative asexual P vivax parasite count at the first parasite assessment performed after Study Day 109 (up to and including Study Day 130). Par were censored if they did not have P.vivax at Baseline, or took a drug with anti-malarial action despite not having malaria parasites or did not have a 4 month assessment. The number of par with recurrence-free efficacy at 4 months has been summarized.

Time frame: 4 months post dose

Time to Recurrence of P Vivax Malaria

Data from ClinicalTrials.gov

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

Tafenoquine 300mgDRUG

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

Tafenoquine 600mgDRUG

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

Primaquine 15mgDRUG

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

Chloroquine 600mg (Part 2 )DRUG

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

Chloroquine 300mg (Part 2 )DRUG

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

Tafenoquine 300mg (Part 2)DRUG

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

Primaquine 15mg (Part2 )DRUG

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

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

...and 4 more locations

Recurrence was defined as the first confirmed presence of P vivax asexual stage parasites after clearance of initial parasitemia following CQ treatment. Time to recurrence was defined as the time (in days) from initial parasite clearance to recurrence. The time to recurrence was analyzed by the Kaplan-Meier method. NA indicates data was not available due to insufficient number of participants with events during the follow up period in the study. The median number of days to recurrence along with 95% confidence interval has been presented for each treatment group.

Time frame: Up to Day 180

Time to Parasite Clearance

Parasite clearance time was defined as time needed to clear asexual parasite from the blood that is, parasite numbers falling below the limit of detection in the thick blood smear and remaining undetectable after 6 to 12 hours. The time taken to achieve parasite clearance was analyzed using Kaplan Meier Methodology. The median parasite clearance time along with 95% confidence interval has been presented for each treatment group.

Time frame: Up to Day 180

Time to Fever Clearance

Fever clearance time was defined as time from first dose of treatment to the time when body temperature falls to normal within Study Days 1-4 and remains normal for at least 48 hours up to the Day 8 visit. Fever clearance was considered to have been achieved once an initial temperature of more than 37.40 degree Celsius is reduced to a value less than or equal to 37.40 degree Celsius and in the absence of value more than 37.40 degree Celsius in the following 48 hours up to the Day 8 visit. The time taken to achieve fever clearance was analyzed using Kaplan Meier Methodology. The median fever clearance time along with 95% confidence interval has been presented for each treatment group.

Time frame: Up to Day 180

Number of Participants With Hemoglobin Decline From Baseline Over First 29 Days

Glucose-6-phosphate dehydrogenase deficiency (G6PD) deficiency is known to be a risk factor for hemolysis in participants treated with 8-aminoquinolines. Blood samples were collected for the evaluation of hemoglobin levels. Hemoglobin decreases of \>=30% or \>3 grams/deciliter (g/dL) from Baseline; or, an overall drop in hemoglobin below 6.0 g/dL in the first 15 days of the study were considered as protocol defined serious adverse events (SAEs). Number of participants with maximum hemoglobin decline from Baseline over first 29 days of study has been summarized. Safety Population consisted of all randomized participants who received at least one dose of study medication.

Time frame: Baseline and up to Day 29

Number of Participants With Treatment Emergent Adverse Events (TEAEs) Potentially Related to Hemoglobin Decrease

TEAEs are defined as adverse events (AEs) with an onset date and time on or after that of the start of first dose of study medication (including CQ). The number of participants with TEAEs potentially related to hemoglobin decrease has been presented.

Time frame: Up to Day 180

Number of Participants Who Received Blood Transfusion

The number of participants who received blood transfusion as a result of hemoglobin decline has been summarized.

Time frame: Up to Day 180

Number of Participants With Acute Renal Failure

There were no participants with acute renal failure in the study.

Time frame: Up to Day 180

Change From Baseline in Percent Methemoglobin

Methemoglobin assessment was made with the aid of a non-invasive signal extraction pulse CO-Oximeter handheld machine (Masimo). The change from Baseline in percent methemoglobin by treatment, time and sex has been summarized. The last assessment performed prior to the first dose of study medication (CQ or randomized treatment) was considered as Baseline. Change from Baseline was calculated as the post baseline assessment minus the Baseline assessment for percent methemoglobin. Only those participants with data available at the specified data points were analyzed.

Time frame: Baseline and up to Day 120

Number of Participants With Gastrointestinal Disorders

Gastrointestinal tolerability was analyzed by the number of par experiencing gastrointestinal disorders such as abdominal pain, heartburn, diarrhea, constipation, nausea, and vomiting. The number of participants with gastrointestinal disorders for each treatment group has been summarized.

Time frame: Up to Day 180

Number of Participants With Keratopathy

Ophthalmic assessments were carried out at pre-qualified sites (Manaus) prior to randomization and at Days 29 and 90 and at withdrawal. Assessments were carried out at Day 180 if the Day 90 assessments showed abnormalities. The last assessment performed on the day of randomization or earlier was considered Baseline. The number of participants displaying keratopathy in each eye was summarized for each visit. The number of participants with new keratopathy at any time post Baseline was also reported. Ophthalmic Safety Population comprised of all participants in the Safety Population who have results from any eye assessments. Only those participants with data available at the specified data points were analyzed.

Time frame: Up to Day 180

Incidence of Visual Field Abnormalities Based on Best Corrected Visual Acuity Test Scores

Ophthalmic assessments were carried out at pre-qualified sites (Manaus) prior to randomization and at Days 29 and 90 and at withdrawal. Assessments were carried out at Day 180 if the Day 90 assessments showed abnormalities. The last assessment performed on the day of randomization or earlier was considered Baseline. Best corrected visual acuity was assessed individually for each eye. Scores were recorded as a ratio. The values were used to derive a logMAR score for statistical analysis where logMAR=-1x log10 (ratio score). The mean and standard deviation of logMAR score for each treatment group has been summarized. High scores were associated with worse vision, and low scores with better vision. Only those participants with data available at the specified data points were analyzed.

Time frame: Up to Day 180

Number of Participants With Retinal Changes From Baseline

Ophthalmic assessments were carried out at pre-qualified sites (Manaus) prior to randomization and at Days 29 and 90 and at withdrawal. Assessments were carried out at Day 180 if the Day 90 assessments showed abnormalities. The last assessment performed on the day of randomization or earlier was considered Baseline. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment. The number of participants with definite retinal change and questionable (ques) retinal change from Baseline was presented. Only those participants with data available at the specified data points were analyzed.

Time frame: Baseline and up to Day 180

Number of Participants With TEAEs and Serious TEAEs

An AE is defined as any untoward medical occurrence in a participant under clinical investigation, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/ birth defect, other situations and is associated with possible drug induced liver injury with hyperbilirubinemia. TEAEs is defined as AEs with an onset date and time on or after that of the start of first dose of study medication (including CQ). Number of participants with TEAEs and serious TEAEs have been presented.

Time frame: Up to Day 180

Number of Participants With TEAEs by Maximum Intensity

An AE is defined as any untoward medical occurrence in a participant under clinical investigation, temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAE is defined as AEs with an onset date and time on or after that of the start of first dose of study medication (including CQ). Number of participants with AEs based on severity has been presented.

Time frame: Up to Day 180

Number of Participants With Hematology Laboratory Data Outside the Reference Range

Blood samples were collected for the evaluation of hematology parameters including eosinophils, leukocytes, lymphocytes, neutrophils, platelets, reticulocytes and methemoglobin. The number of participants with hematology laboratory data outside the extended normal range (F3) was presented. The upper and lower limits for F3 range were defined by multiplying the normal range limits by different factors. High and low indicated that the participants had values flagged as high and low respectively for the particular parameter any time on-treatment. Only those participants with data available at the specified data points were analyzed.

Time frame: Up to Day 120

Number of Participants With Clinical Chemistry Laboratory Data Outside the Reference Range

Blood samples were collected for the evaluation of clinical chemistry parameters including Alanine Aminotransferase (ALT), Alkaline Phosphatase (Alk. Phos), Aspartate Aminotransferase (AST), bilirubin, creatine kinase, creatinine, glomerular filtration rate (GFR), indirect bilirubin and urea. The number of participants with clinical chemistry laboratory data outside the extended normal range (F3) was presented. The upper and lower limits for F3 range were defined by multiplying the normal range limits by different factors. High and low indicated that the participants had values flagged as high and low respectively for the particular parameter any time on-treatment. Only those participants with data available at the specified data points were analyzed.

Time frame: Up to Day 120

Cost Associated With Recurrence Episode of P Vivax Malaria

Health outcomes were evaluated based on the total costs spent on treatment, transport, medication and tests. The cost was summarized according to the place at which the participant went to for care (drug shop, trial clinic, other clinic, hospital (inpatient/outpatient), traditional healer, other). The reported costs by type and by site has been summarized. Where costs have not been reported at a visit, the number of participants analyzed is given as 0. Only those participants with data available at the specified data points were analyzed.

Time frame: Up to Day 180

Cost Incurred With Purchase of Medications Associated With Recurrence Episode of Malaria

Health outcomes were evaluated based on the cost of medications purchased. The reported total medication cost for paracetamol associated with recurrence episode of P vivax malaria has been reported by site. Where costs have not been reported at a visit, the number of participants analyzed is given as 0. Medications recorded as "Other" and medications without costs are excluded from the analysis. Only those participants with data available at the specified data points were analyzed.

Time frame: Up to Day 180

Time Lost by Participants or Care Givers From Normal Occupation

Health outcomes were evaluated based on total time lost by participants or care givers due to an episode of malaria. The reported time lost due to recurrence episode of P vivax malaria has been summarized by category and by site. Where categories by site have not been reported at a visit, the number of participants analyzed is given as 0. Only those participants with data available at the specified data points were analyzed.

Time frame: Up to Day 180

Number of Participants With Action Taken to Treat Recurrence Episode of P Vivax Malaria

Health outcomes were evaluated based on the actions taken by the participants to treat recurrence episode of P vivax malaria. The reported action taken by site is summarized. Where no action by site have been reported at a visit, the number of participants analyzed is given as 0. Only those participants with data available at the specified data points were analyzed.

Time frame: Up to Day 180

Oral Clearance (CL/F) of TQ

Apparent population oral clearance of TQ

Time frame: Day 2, Day 8, Day 15, Day 29 and Day 60

Volume of Distribution (Vc/F) of TQ

Apparent population central volume of distribution of TQ

Time frame: Day 2, Day 8, Day 15, Day 29 and Day 60