Efficacy and Safety Study of Tafenoquine (TQ) Co-administered With Dihydroartemisinin-piperaquine (DHA-PQP) for the Radical Cure of Plasmodium Vivax (P. Vivax) Malaria

A participant was considered to have demonstrated relapse-free efficacy at 6 months if: a) Participant had non-zero P. vivax asexual parasite count at Baseline (Day 1), b) Participant demonstrated initial clearance of P.vivax parasitemia, c) Participant had no positive asexual P.vivax parasite count at any assessment prior to or on study Day 180 following initial parasite clearance, d) Participants did not take a concomitant medication with anti-malarial activity (excluding study treatment) at any point between Study Day 1 and their last parasite assessment, e) Participant was parasite-free at 6 months. The percentage of participants who were relapse-free at 6 months post dose has been presented.

A participant was considered to have demonstrated relapse-free efficacy at 6 months if: a) Participant had non-zero P. vivax asexual parasite count at Baseline (Day 1), b) Participant demonstrated initial clearance of P.vivax parasitemia, c) Participant had no positive asexual P.vivax parasite count at any assessment prior to or on study Day 180 following initial parasite clearance, d) Participants did not take a concomitant medication with anti-malarial activity (excluding study treatment) at any point between Study Day 1 and their last parasite assessment, e) Participant was parasite-free at 6 months. The percentage of participants who were relapse-free at 6 months post dose has been presented.

A participant was considered to have demonstrated recurrence-free efficacy at 4 months if: a) Participant had non-zero P. vivax asexual parasite count at Baseline, b) Participant demonstrated initial clearance of P.vivax parasitemia, c) Participant had no positive asexual P.vivax parasite count at any assessment prior to or on Study Day 135 following initial parasite clearance, d) Participants did not take a concomitant medication with anti-malarial activity (excluding study treatment) at any point between Study Day 1 and their first parasite assessment after Study Day 105 (up to and including Study Day 135), e) Participant was parasite-free at 4 months. The rate of relapse-free efficacy was estimated by Kaplan-Meier methodology. The percentage of participants who were relapse-free at 4 months post dose has been presented.

Relapse is defined by a positive blood smear with or without vivax symptoms. Relapse is described as any recurrence of P. vivax malaria after clearance of the initial infection. The time to relapse (number of days between the date of first positive count and date of Study Day 1) was analyzed by the Kaplan-Meier method. The median number of days to relapse along with 95 percent (%) confidence interval (CI) has been presented for each treatment group.

Time to fever clearance is defined as time from first dose of treatment to the time when body temperature falls to normal and remains normal for at least 48 hours up to the Day 7 visit. Fever clearance is considered to have been achieved once an initial temperature of greater than 37.4 degree Celsius is reduced to a value less than or equal to 37.4 degree Celsius, in the absence of value greater than 37.4 degree Celsius in the following 48 hours up to Day 7 visit. The time taken to achieve fever clearance was analyzed by Kaplan-Meier method.

Parasite clearance time is 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 hours later. The time to achieve parasite clearance was analyzed by Kaplan-Meier method.

Recrudescence was defined as blood stage treatment failure. A participant was considered to have had a recrudescence if both of the following were true: 1) if participant had a positive P. vivax asexual parasite count at Baseline and demonstrated clearance (i.e. two negative asexual P. vivax parasite counts, with at least 6 hours between the counts, and no positive counts in the interval); 2) Participant had a positive genetically homologous asexual P. vivax parasite count on or before Study Day 14, after their zero count in days 1 to 5.

An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as 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, is associated with liver injury and impaired liver function, other important medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before.

Blood samples were collected at indicated time points to analyze following chemistry parameters: alanine aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), Bilirubin, Creatine Kinase, Creatinine, Indirect Bilirubin and Urea. Clinical concern range for the parameters included ALT and AST (high: >3 times Upper Limit of Normal [ULN]), ALP (high: >2.5 times ULN), bilirubin and indirect bilirubin (high: >1.5 times ULN), creatine kinase (high: >5 times ULN), creatinine (high: >3 times ULN) and urea (high: >11.067 millimoles per Liter [mmol/L]. Data for any time on treatment has been presented.

Blood samples were collected to analyze the following hematology parameters: Hemoglobin, lymphocytes and Platelet count. The clinical concern ranges for the parameters included: hemoglobin (low: <7 grams per deciliter), lymphocytes: (low: <0.5x10^9 cells per liter and high: >4x10^9 cells per liter),and platelets (low: <50x10^9 cells per liter). Data for any time on treatment has been presented.

12-lead ECG was obtained at indicated time points using an automated ECG machine that measured QTcF. Clinical concern range included:absolute QTcF interval (upper: >480 milliseconds) and increase from Baseline in QTcF (upper: >=60 milliseconds). Data for maximum post-Baseline increase >=60 and >480 milliseconds has been presented.

12-lead ECG was obtained at indicated time points using an automated ECG machine that measured QTcF interval. Change from Baseline is calculated as Post-Dose Visit Value minus Baseline value. Day 1 was considered as Baseline.

Body temperature was measured with participants in semi-supine position after 5 minutes of rest. Data was categorized as: body temperature 'low: <36.5 degrees celsius', 'high: >37.3 degrees celsius' and 'To Normal or No change'. Participants were counted in the worst case category that their value changes to (low, normal or high), unless there was no change in their category. Participants whose vital sign value category was unchanged (e.g.,High to High), or whose value became normal, are recorded in the "To Normal or No Change" category. Participants were counted twice if the participant had values that changed 'To Low' and 'To High', so the percentages may not add to 100%. Day 1 was considered as Baseline.

SBP and DBP were measured with participants in semi-supine position after 5 minutes of rest. Data was categorized as: systolic blood pressure (SBP) (low: <90 and high: >120 millimeters of mercury [mmHg]); diastolic blood pressure (DBP) (low: <60 and high: >80 mmHg); and 'To Normal or No change'. Participants were counted in the worst case category that their value changes to (low, normal or high), unless there was no change in their category. Participants whose vital sign value category was unchanged (e.g.,High to High), or whose value became normal, are recorded in the "To Normal or No Change" category. Participants were counted twice if the participant had values that changed 'To Low' and 'To High', so the percentages may not add to 100%. Day 1 was considered as Baseline.

Pulse rate was measured with participants in semi-supine position after 5 minutes of rest. Data was categorized as: pulse rate low: <60 beats per minute [bpm], high: >100 bpm and 'To normal or No change'. Participants were counted in the worst case category that their value changes to (low, normal or high), unless there was no change in their category. Participants whose vital sign value category was unchanged (e.g.,High to High), or whose value became normal, are recorded in the "To Normal or No Change" category. Participants were counted twice if the participant had values that changed 'To Low' and 'To High', so the percentages may not add to 100%. Day 1 was considered as Baseline.

Respiratory rate was measured with participants in semi-supine position after 5 minutes of rest. Data was categorized as: respiratory rate low: <12 breaths per minute', high: >18 breaths per minute and 'To normal or No change'. Participants were counted in the worst case category that their value changes to (low, normal or high), unless there was no change in their category. Participants whose vital sign value category was unchanged (e.g.,High to High), or whose value became normal, are recorded in the "To Normal or No Change" category. Participants were counted twice if the participant had values that changed 'To Low' and 'To High', so the percentages may not add to 100%.Day 1 was considered as Baseline. Day 1 was considered as Baseline.

The number of participants with gastrointestinal AEs: nausea, vomiting, diarrhea, dyspepsia, abdominal distension, abdominal discomfort and constipation has been presented.

Blood samples were collected for the assessment of methemoglobin/Total Hemoglobin (Hb). Methemoglobin is a type of Hb in the form of metalloprotein that cannot bind with oxygen, measured as percentage of methemoglobin in total hemoglobin. Change from Baseline is calculated as Post-Dose Visit Value minus Baseline value. Day 1 was considered as Baseline.

Blood samples were collected at indicated time points to analyze the hemoglobin level. Hemoglobin drop is defined as any one of the following occurring in the first 15 days of the study: a relative hemoglobin decrease of >=30% from Baseline, or an absolute hemoglobin decrease of >3 grams per liter from Baseline, or a drop in absolute hemoglobin to <7.0 grams per decilter (g/dL). Number of participants with a protocol-defined hemoglobin SAEs has been presented.

Blood samples were collected at the indicated time points for the determination of oral clearance following tefenoquine co-administered with DHA-PQP and was to be calculated by covariate analysis.

Blood samples were collected at the indicated time points for the determination of volume of distribution following tefenoquine co-administered with DHA-PQP and was to be calculated by covariate analysis.