Study to Evaluate the Efficacy and Safety of Tafenoquine for the Treatment of Plasmodium Vivax in Adults

Study Overview
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Brief Summary
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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.

Detailed Description
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This was a randomized, active-control, double-blind, double-dummy study to be conducted in 2 sequential cohorts. Cohort 1 was randomized 2:1 to receive tafenoquine, 400mg/day for 3 days, or the standard blood schizontocidal dosing regimen of chloroquine (1000mg for 2 days followed by 500mg for 1 day) followed by a standard hypnozoite eradication dosing regimen for primaquine (15mg base per day for 14 days). Cohort 2 was to be randomized 2:1 to receive a single 600mg dose of tafenoquine or the standard blood schizontocidal dosing regimen of chloroquine (1000mg for 2 days followed by 500mg for 1 day) followed by a standard hypnozoite eradication dosing regimen for primaquine (15mg base per day for 14 days). A planned interim analysis was performed after all subjects in Cohort 1 had completed the day 28 assessment and an Independent Data Monitoring Committee (IDMC) convened to evaluate the efficacy and safety of the tafenoquine dosing regimen (400mg once per day for 3 days) used in Cohort 1. Only if the results from Cohort 1 met pre-defined efficacy and safety criteria was enrollment to begin for Cohort 2. The efficacy criterion for achieving the primary endpoint was that the lower limit of the one-sided 95% confidence interval was no less than 85%, and for safety that a review of trends in all AEs, tolerability, medical observations, methemoglobin and other lab data for all subjects indicated the dose was well tolerated. During the IDMC review it was determined that Cohort 1 failed to meet the pre-specified endpoint for the day 28 cure rate and therefore Cohort 2 should not be initiated and follow-up in Cohort 1 should be completed according to protocol. Following last subject last visit for Cohort 1 the study was terminated.

Official Title
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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

Conditions
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Malaria, Plasmodium Vivax

Intervention / Treatment
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* Drug: Tafenoquine
* Drug: Chloroquine + Primaquine
* Drug: tafenoquine
* Drug: Chloroquine + Primaquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Positive smear for P. vivax. Parasite density > 500 and < 200,000/μl Age: 20-60 years old Willing to sign consent form Willing to be hospitalized for 29 days and remain in a malaria free region for 60 days thereafter for follow-up. 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: Mixed malaria infections by Field's stain. 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. Symptoms of severe vomiting (no food or inability to take food during the previous 8 hours). Demonstrated glucose-6-phosphate dehydrogenase deficiency. Subject has taken other anti-malarials (mefloquine, primaquine, chloroquine) within the past 30 days by history 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). 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. History of allergy to chloroquine, mefloquine, tafenoquine, primaquine or any other 8-aminoquinolines. Subject has taken another investigational drug within 30 days or 5 half lives (whichever is longer), of study start. History of previous eye surgery or have evidence of corneal or retinal abnormalities identified in baseline ophthalmological examination. 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). Subjects whom, after examination by the study ophthalmologist, are judged to be at risk for acute angle closure glaucoma. Females who are pre-menarchal.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Only if Cohort 1 met specified endpoint criteria would Cohort 2 begin enrollment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 Tafenoquine<br>Tafenoquine: 2 capsules (200mg base/capsule for a total of 400mg base) and 4 chloroquine placebo capsules for 2 days, followed by 2 tafenoquine capsules and 2 chloroquine placebo capsules for 1 day, followed by 1 primaquine placebo capsule/day for 14 days. | Drug: Tafenoquine<br>* Tafenoquine: 2 capsules (200mg base/capsule for a total of 400mg base) and 4 chloroquine placebo capsules for 2 days, followed by 2 tafenoquine capsules and 2 chloroquine placebo capsules for 1 day, followed by 1 primaquine placebo capsule/day for 14 days.<br>|
| Active Comparator: Cohort 1-Chloroquine<br>Chloroquine (1000 mg chloroquine phosphate) and tafenoquine placebo x 2 day, followed by chloroquine (500 mg chloroquine phosphate) and tafenoquine placebo x 1day, followed by primaquine, 15 mg/day for 14 days. | Drug: Chloroquine + Primaquine<br>* Chloroquine (1000 mg chloroquine phosphate) and tafenoquine placebo x 2 day, followed by chloroquine (500 mg chloroquine phosphate) and tafenoquine placebo x 1day, followed by primaquine, 15 mg/day for 14 days.<br>|
| Experimental: Cohort 2 Tafenoquine<br>Tafenoquine (600 mg base) and chloroquine placebo x 1d, chloroquine placebo x 2 days, followed by primaquine placebo for 14 days. | Drug: tafenoquine<br>* Tafenoquine (600 mg base) and chloroquine placebo x 1d, chloroquine placebo x 2 days, followed by primaquine placebo for 14 days.<br>|
| Active Comparator: Cohort 2 Chloroquine<br>Chloroquine (1000 mg chloroquine phosphate) and tafenoquine placebo x 1 day, followed by chloroquine (1000 mg chloroquine phosphate) x 1 day, followed by chloroquine (500 mg chloroquine phosphate) x 1day, followed by primaquine, 15 mg/day for 14 days. | Drug: Chloroquine + Primaquine<br>* Chloroquine (1000 mg chloroquine phosphate) and tafenoquine placebo x 1 day, followed by chloroquine (1000 mg chloroquine phosphate) x 1 day, followed by chloroquine (500 mg chloroquine phosphate) x 1day, followed by primaquine, 15 mg/day for 14 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adequate Clinical Response (ACR) of Tafenoquine: 28 Day Cure Rate | A subject will be considered a success (cure) if they have an Adequate Clinical Response (ACR). Tafenoquine was efficacious if the lower bound of the two-sided 90% confidence interval for the day 28 cure rate was not less than 85% | 28 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Without Relapse of P. Vivax | Number of subjects without relapse of P. vivax at 2, 3 and 4 months - Blood smears were obtained at Days 28, 60, 90 and 120 to confirm the continued absence of P. vivax parasitemia | Day 28, Months 2, 3 and 4 | 
| Safety and Tolerability of Tafenoquine as Defined by Most Common Adverse Events (AEs) | To evaluate the safety and tolerability of the tafenoquine dosing regimens as defined by the most common AE's overall, occurring in >10% of subjects in either treatment group | 90 Days | 
| Parasite and Gametocyte Clearance Time (PCT and GCT) | Serial blood smears to detect the presence of P. vivax parasites and gametocytes, conducted every 12 hours up to and including day 7, until blood smear became negative were utilized to determine the time to clearance. PCT and GCT were considered cleared if 2 consecutive blood smears were negative. | up to day 7 after baseline smear | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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malaria, Plasmodium vivax, adults, treatment, tafenoquine