The study listed may include approved and nonapproved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: Tafenoquine (SB252263, WR238605) Study Number: TAF112582 Title: A multicentre, doubleblind, randomised, parallelgroup, activecontrolled study to evaluate the efficacy, safety and tolerability of tafenoquine (SB252263, WR238605) in subjects with Plasmodium vivax (P. vivax) malaria Rationale: Tafenoquine () is being developed for the radical cure of P. vivax, to be coadministered with standard doses of chloroquine (). Studies to date have shown to be well tolerated with preliminary efficacy following 1 to 3 days of dosing and a prolonged halflife of 15 to 19 days. However, with monotherapy at doses of 400 mg once daily for 3 days, parasite and fever clearance times were significantly slower relative to combination + primaquine (); in addition, safety concerns (haemoglobin decline, raised methaemoglobin and haemolysis in subjects with G6PD deficiency) were observed. Lower doses of and coadministration with may reduce these limitations. Exploratory studies have supported a 1 to 3 day treatment regimen when is coadministered with a second blood schizontocidal, such as ; results from a drugdrug interaction study suggest no clinically significant pharmacokinetic interaction with the concomitant administration of and. The aim of this study was to find a dose of which met the defined dose criteria. Based on Part 1 efficacy and safety, a single dose will be selected to be studied in the pivotal Part 2 study. Phase: 2 Study Period: 19Sep2011 to 25Mar2013 Study Design: This was a multicentre, doubleblind, doubledummy, parallelgroup, randomised, activecontrolled study conducted in two parts (Part 1 dose ranging and Part 2 pivotal); Part 1 is presented in this document. Following screening, subjects were treated with on Days 1 to 3 to treat the blood stage malaria infection; once all screening results were known, eligible subjects were randomised to one of six treatment groups. Following randomisation, the study consisted of a treatment period of 14 days. Subjects stayed in the clinic and received directly observed therapy for Days 1 to 3, and were treated as outpatients for the remainder of the study. Subjects were followed up to Day 180. Centres: Seven centres in four countries (Brazil, India, Peru and Thailand) Indication: P. vivax malaria Treatment: Subjects were treated with on Days 1 to 3 (600 mg, 600 mg, 300 mg). On completion of all screening procedures, eligible subjects were randomised to one of six treatment groups: 50 mg single dose (Day 1 or 2), 100 mg single dose (Day 1 or 2), 300 mg single dose (Day 1 or 2), 600 mg single dose (Day 1 or 2), 15 mg once daily for 14 days, and a only regimen. Objectives: The primary objective was to determine the efficacy of as a radical cure for P. vivax malaria, relative to control. Primary Outcome/Efficacy Variable: The primary endpoint was relapsefree efficacy 6 months post dosing. Subjects for whom initial clearance of parasitaemia was confirmed (parasite numbers fell below the limit of detection in thick blood smear and remained undetectable at the second smear collected 6 to 12 hours later) and who did not present with P. vivax asexual stage parasites within 6 months were considered treatment successes. Secondary Outcome/Efficacy Variable(s): The secondary endpoints were relapsefree efficacy 4 months post dosing, time to relapse, parasite clearance time, and fever clearance time. Statistical Methods: The study was designed to test superiority of + against in the prevention of relapse of P. vivax malaria. The null hypothesis for the primary endpoint was that the 6month relapse efficacy was not different between + and treatment groups. The alternative hypothesis was that the relapse efficacy of the treatments was different. The hypothesis test was twosided and tested at the 5% significance level. For dose selection purposes, this hypothesis was tested separately for each of the four dose groups against group in a stepdown approach, starting with the highest dose. No multiplicity adjustment was thus necessary to control the overall Type I error rate. The primary population for all efficacy analyses was the IntenttoTreat (ITT) population which consisted of all randomised subjects who received at least one dose of study medication, and who had at least one P. vivax parasite assessment after randomisation. Subjects were analysed according to their randomised treatment. The Safety population was defined as all randomised subjects who received at least one dose of study medication. If subjects received a treatment different to their randomised treatment, they were analysed according to the treatment actually received. This was the primary population for all safety analyses and data presentations. In this study, the Safety population was identical to the ITT population. Study Population: Subjects 16 years of age with a positive Giemsa smear for P. vivax and parasite density >100/ L 1
and <100,000/ L were eligible for enrolment. Nonpregnant and nonlactating females were eligible. All subjects were required to be willing to be hospitalised for 3 days and return to clinic for all followup visits including Day 180. Any subjects with mixed malaria infections (e.g., identified by Giemsastained smear or rapid diagnostic test), severe vivax malaria (as defined by WHO criteria), severe vomiting (no food or inability to take food during previous 8 hours), screening haemoglobin concentration <7 g/dl, any clinically significant concurrent illness, or who had taken antimalarials within the past 30 days were not eligible for enrolment. In addition, subjects with G6PD deficiency, assessed by a quantitative spectrophotometric phenotype assay were excluded from the study: Males: Any subject with an enzyme level <70% of the site median value for G6PD normals were excluded. Females: (i) Those females with a screening Hb 10 g/dl were only excluded if their enzyme level was <70% of the site median value for G6PD normals. (ii) Those females with Hb 7 but <10 g/dl were excluded if an enzyme level was not >90% of the site median value for G6PD normals. Total Number of Subjects: Planned, N 54 54 54 54 54 54 324 Randomised, N 55 57 57 56 50 54 329 Completed, n 54 (98) 54 (95) 56 (98) 54 (96) 47 (94) 54 (100) 319 (97) Total Number Subjects Withdrawn from 3 (5) 2 (4) 3 (6) 0 10 (3) Study, n Withdrawn due to Adverse Events, n 0 0 0 0 0 0 0 Withdrawn due to Lack of Efficacy, n 0 0 0 0 0 0 0 Withdrawn for Other Reasons, n 3 (5) 2 (4) 3 (6) 0 10 (3) Demographics N (ITT) 55 57 57 56 50 54 329 Females: Males 18:37 13:44 14:43 11:45 15:35 15:39 86:243 Mean Age, years (SD) 36.3 (13.28) Race, n American Indian or Alaska Native 27 (49) Asian Central/South Asian Heritage 11 (20) Asian South East Asian Heritage 16 (29) Mixed Race Mean G6PD enzyme activity, IUg/Hb (SD) 9.9 (2.98) 34.6 (14.09) 28 (49) 11 (19) 16 (28) 2 (4) (2.89) 36.2 (13.49) 29 (51) 9 (16) 19 (33) 0 9.2 (2.36) 35.7 (15.06) 29 (52) 10 (18) 16 (29) (2.65) 36.0 (13.91) 25 (50) 6 (12) 16 (32) 3 (6) 9.5 (2.55) 33.6 (14.16) 27 (50) 10 (19) 16 (30) 9.2 (2.49) 35.4 (13.94) 165(50) 57 (17) 99 (30) 8 (2) (2.65) 2
Primary Efficacy Results: Analysis of RelapseFree Efficacy at Six Months (KaplanMeier Methodology) Subjects observed to relapse prior to Day 180, n Censored prior to 6 month assessment, n Censored relapsefree at 6 months, n Relapsefree efficacy rate at 6 months, estimate, % (95% CI) Difference from at 6 months, estimated difference, % (95% CI) 22 (40) 25 (44) 6 (11) 4 (7) 12 (24) 31 (57) 4 (7) 3 (5) 3 (5) 9 (16) 4 (8) 2 (4) 29 (53) 29 (51) 48 (84) 43 (77) 34 (68) 21 (39) 57.7 (43, 70) 54.1 (40, 66) 89.2 (77, 95) 91.9 (80, 97) 77.3 (63, 87) 37.5 (23, 52) 20.3 16.6 51.7 54.5 39.9 (0, 40) (3, 36) (35, 69) (38, 71) (21, 59) Log rank test, pvalue 0.158 <0.0001 <0.0001 0.0004 Secondary Outcome Results: Analysis of RelapseFree Efficacy at Four Months (KaplanMeier Methodology) Subjects observed to relapse prior to 19 (35) 22 (39) 5 (9) 2 (4) 10 (20) 28 (52) Day 120, n Censored prior to 4 month assessment, n 3 (5) 3 (5) 8 (14) 6 (12) 2 (4) Censored relapsefree at 4 months, n 33 (60) 32 (56) 51 (89) 46 (82) 34 (68) 24 (44) Relapsefree efficacy rate at 4 months, estimate, % (95% CI) 62.3 (46, 75) 60.3 (46, 72) 8 (75, 96) 98.1 (87,100) 78.4 (64, 88) 46.5 (32, 60) Difference from at 4 months, 15.8 13.8 42.9 51.6 32.0 estimated difference, % (95% CI) (5, 36) (6, 33) (26, 60) (37, 66) (13, 50) Time to P. vivax Relapse Subjects observed to relapse, n 22 (40) 25 (44) 6 (11) 4 (7) 12 (24) 31 (57) Subjects censored, n 33 (60) 32 (56) 51 (89) 52 (93) 38 (76) 23 (43) Hazard ratio estimate (95% CI) 0.581 (0.336, 1.005) 0.685 (0.404, 1.161) 0.129 (0.054, 0.310) 0.091 (0.032, 0.257) 0.309 (0.155, 0.616) Time to Fever Clearance Subjects with fever clearance, n 20 (36) 24 (42) 19 (33) 21 (38) 14 (28) 21 (39) Subjects censored, n 35 (64) 33 (58) 38 (67) 35 (63) 36 (72) 33 (61) Hazard ratio estimate compared to (95% CI) 0.873 (0.469, 1.626) 1.163 (0.638, 2.122) 0.870 (0.462, 1.636) 0.664 (0.356, 1.238) 0.528 (0.250, 1.115) Time to Parasite Clearance Subjects with parasite clearance, n 46 (84) 51 (89) 50 (88) 45 (80) 44 (88) 51 (94) Subjects censored, n 9 (16) 6 (11) 7 (12) 11 (20) 6 (12) 3 (6) Hazard ratio estimate compared to (95% CI) 0.755 (0.506, 1.128) 0.902 (0.612, 1.331) 0.961 (0.650, 1.421) 0.638 (0.426, 0.956) 0.889 (0.594, 1.332) 3
Safety Results: All adverse events (AEs) reported up to and including the Day 180 visit following enrolment of a subject into the study were documented. Treatmentemergent AEs were defined as AEs with an onset date and time on or after that of the start of first dose of study medication (including ). Most Frequent TreatmentEmergent Adverse Events Subjects with any AE(s), n 37 (67) 42 (74) 38 (67) 37 (66) 32 (64) 41 (76) Pyrexia 18 (33) 16 (28) 5 (9) 7 (13) 12 (24) 21 (39) Headache 14 (25) 17 (30) 10 (18) 16 (29) 14 (28) 20 (37) Chills 16 (29) 16 (28) 5 (9) 9 (16) 10 (20) 20 (37) Diarrhoea 4 (7) 3 (5) 9 (16) 4 (8) 4 (7) Pruritis 4 (7) 8 (14) 8 (14) 2 (4) 3 (6) 7 (13) Abdominal pain upper 6 (11) 5 (9) 6 (11) 6 (11) 7 (14) 5 (9) Dizziness 7 (13) 2 (4) 5 (9) 4 (7) 5 (10) 5 (9) Nausea 7 (13) 3 (5) 5 (9) 5 (9) 4 (8) 3 (6) Electrocardiogram QT prolonged 3 (5) 2 (4) 3 (5) 5 (10) 4 (7) Vomiting 3 (5) 2 (4) 2 (4) 3 (5) 5 (10) 0 Insomnia 2 (4) 3 (5) 5 (9) 3 (5) 3 (6) Back pain 2 (4) 0 5 (9) 4 (7) 2 (4) 2 (4) TreatmentEmergent Serious Adverse Events n [n considered by the investigator to be related to study medication] Subjects with nonfatal SAEs, n [n considered by the investigator to be related to study medication] 2 (4) [0] 6 (11) [1] 2 (4) [1] 4 (7) [1] 7 (14) [4] 4 (7) [1] Electrocardiogram QT prolonged 2 (4) [0] 2 (4) [1] [0] 0 4 (8) [2] 2 (4) [0] Haemoglobin decreased 0 0 0 [1] [1] [1] Anaemia 0 [0] [1] 0 0 0 Alanine aminotransferase increased 0 0 0 0 0 [0] Methaemoglobinaemia 0 0 0 0 [1] 0 Pyelonephritis 0 0 0 [0] 0 0 Scrub typhus 0 0 0 [0] 0 0 Pyrexia 0 [0] 0 0 0 0 Hepatitis acute 0 0 0 0 [0] 0 Dehydration 0 [0] 0 0 0 0 Haemarthrosis 0 0 0 [0] 0 0 Abortion induced 0 [0] 0 0 0 0 Subjects with fatal SAEs, n 0 0 0 0 0 0 4
Conclusion: This study shows statistically significant differences in favour of both 300 mg and 600 mg when compared with alone for the primary efficacy outcome. The relapsefree efficacy rates at 6 months were 37.5% on, 89.2% on 300 mg, and 91.9% on 600 mg. 50 mg and 100 mg did not show statistically significant results versus : the relapsefree efficacy rates in these treatment groups were 57.7% and 54.1%, respectively. In the 50 mg group, 37 subjects reported nonserious AEs with the most frequently reported being pyrexia, chills and headache. In the 100 mg group, 42 subjects reported nonserious AEs with the most frequently reported being pyrexia, chills and headache. In the 300 mg group, 38 subjects reported nonserious AEs with the most frequently reported being headache, pruritis and upper abdominal pain. In the 600 mg group, 37 subjects reported nonserious AEs with the most frequently reported being headache, chills and diarrhoea. In the group, 32 subjects reported nonserious AEs with the most frequently reported being pyrexia, chills and headache. In the group, 41 subjects reported nonserious AEs with the most frequently reported being pyrexia, chills and headache. Two subjects reported nonfatal serious adverse events (SAEs) in the 50 mg group, both of which were QT prolongations. Six subjects reported nonfatal SAEs in the 100 mg group (two QT prolongations, one anaemia, one pyrexia, one dehydration, and one abortion induced). Two subjects reported nonfatal SAEs in the 300 mg group (one QT prolongation, and one anaemia). Four subjects reported nonfatal SAEs in the 600 mg group (one haemoglobin decrease, one pyelonephritis, one scrub typhus, and one haemarthrosis). Seven subjects reported nonfatal SAEs in the group (four QT prolongations, one haemoglobin decrease, one methaemoglobinaemia, and one acute hepatitis). Four subjects reported nonfatal SAEs in the group (two QT prolongations, one haemoglobin decrease, and one alanine aminotransferase increase). No fatal adverse events were reported on any treatment arm. 5