UM27/189/ The study listed may iclude approved ad o-approved uses, formulatios or treatmet regimes. The results reported i ay sigle study may ot reflect the overall results obtaied o studies of a product. Before prescribig ay product metioed i this Register, healthcare professioals should cosult prescribig iformatio for the product approved i their coutry. Study No.: SB-71473-5 Title: A multicetre, radomised, double-blid, double-dummy study comparig the efficacy ad safety of chlorproguail-dapsoe-artesuate versus artemether-lumefatrie i the treatmet of acute, ucomplicated Plasmodium falciparum malaria i childre ad adolescets i Africa Ratioale: To demostrate oiferiority of chlorproguail-dapsoe-artesuate () to artemether-lumefatrie (; Coartem), the curret Gold Stadard artemesii-based combiatio therapy (ACT) for treatmet of P. falciparum malaria i sub-sahara Africa. If prove o-iferior to Coartem, it was believed that would offer a safe, effective, ad affordable atimalarial treatmet. Phase: III Study Period: 26 Jue 26 3 August 27 Study Desig: Radomised, parallel-group, double-blid, double-dummy, multicetre study that compared the efficacy ad safety of to i the treatmet of acute, ucomplicated P. falciparum malaria i childre ad adolescets i sub-sahara Africa. Cetres: Eleve sites amog 5 coutries i sub-sahara Africa, icludig 4 sites i Nigeria, 3 sites i Keya, 2 sites i Tazaia, ad 1 site each i Ghaa ad Burkia Faso. Idicatio: Acute, ucomplicated P. falciparum malaria i sub-sahara Africa Treatmet: was admiistered oce daily for 3 days at target doses of chlorproguail (CPG), dapsoe (DDS), ad artesuate (ART) of 2, 2.5, ad 4 mg/kg/day, respectively. The comparator drug,, was admiistered twice daily for 3 days, with the secod dose admiistered 8 hours after the first dose. Both treatmets were dosed accordig to body weight. Objectives: The primary objective of the study was to demostrate that is o-iferior to whe comparig parasitological cure rate at Day 28 of the study Primary Outcome/Efficacy Variable: The primary efficacy edpoit was parasitological cure rate (Polymerase Chai Reactio [PCR]-corrected) at Day 28, usig the Per Protocol (PP) populatio. Secodary Outcome/Efficacy Variable(s): Secodary efficacy edpoits icluded: 1) Parasitological cure rate (PCR-corrected) at Days 14 ad 42; 2) Adequate Cliical ad Parasitological Respose (ACPR), ad PCR-corrected ACPR at Days 14, 28, ad 42; 3) Asexual parasite desities; 4) Parasite Clearace Times (PCT); Fever Clearace Times (FCT); ad 5) Gametocyte desities. Statistical Methods: The ull hypothesis for the primary edpoit was that PCR-corrected parasitological cure rate at Day 28 is cliically iferior i subjects who received compared with those who received. The oe-sided alterative hypothesis was that the parasitological cure rate for subjects who received was oiferior to the parasitological cure rate for subjects who received. The pricipal efficacy aalysis was based o the treatmet group comparisos of the umber (percetage) of subjects i the PP populatio with PCR-corrected parasitological cure at Day 28. Two-sided 95% CIs were used to estimate the differece betwee the treatmet groups i the proportio of successes, calculated usig the ormal approximatio to the biomial distributio. A coclusio of o-iferiority of was to be draw if the lower boud of the CI was greater tha -7%. The Itet-to-Treat (ITT) populatio icluded all subjects who were radomised ad received at least oe dose of study medicatio, irrespective of whether they vomited after dosig. The ITT populatio was used as a supportive aalysis for assessmet of the primary efficacy edpoit, ad for the aalysis of the secodary efficacy edpoits, study populatio, ad safety data. 1
UM27/189/ The Per Protocol (PP) populatio cosisted of all subjects i the ITT populatio who did ot violate the protocol i a way that could impact the efficacy aalyses ivolvig o-iferiority comparisos. The PP populatio was the primary populatio for the aalysis of efficacy. Study Populatio: Male or female subjects betwee the ages of 12 moths ad 14 years with acute, ucomplicated P. falciparum malaria ad microscopically-cofirmed ifectio of 2 to 2, parasites/µl. Eligible subjects also had to have either a tympaic temperature of 37.5 C at Screeig or a cofirmed history of fever withi the previous 24 hours. I additio, subjects had to have a screeig haemoglobi (Hb) value 7 g/dl (or haematocrit 25% if Hb measuremet was ot available at Screeig. Number of Subjects: Plaed, N 93 465 Radomised, N 914 (1) 458 (1) Completed, 87 (95) 442 (97) Total Number Subjects Withdraw, 44 (5) 16 (3) Withdraw due to Adverse Evets 3 1 Withdraw due to Lack of Efficacy Withdraw for other reasos 41 (5) 56 (12) Demographics N (ITT) 914 458 Females: Males 457:457 213:245 Mea Age, years (SD) 4.2 (2.96) 4. (2.85) Africa/Africa America, 914 (1) 458 (1) Glucose-6- phosphate dehydroge ase (G6PD) Geotype N = 914 N = 458 A 11 (11) 59 (13) B 395 (43) 231 (5) A/B 11 (11) 32 (7) A- 8 (9) 36 (8) A/A- 41 (4) 13 (3) B/A- 82 (9) 3 (7) Missig 114 (12) 57 (12) G6PD Status N = 914 Pheotype Geotype Normal Iter. Def. Missi g Males: Normal Deficiet Missig Females: Normal Heterozygo 155 (76) 5 (2) 8 14 (55) 8 (4) 1 (5) 5 7 (3) 19 (9) 4 154 3 52 Norma l 83 (76) 3 (3) 3 N = 458 Pheotype Iter. Def. Missi g 2 (2) 3 (3) 1 4 (4) 14 (13) 1 11 (6) 8 (4) 15 52 (58) 5 (6) 4 (4) 76 96 1 25 2
UM27/189/ us deficiet Homozygous deficiet Missig 38 (2 2 (1) 7 1 (5) 5 (3) 3 7 (4) 3 (2) 4 68 6 31 21 (24) 2 (2) 5 1 (1) 3 (3) 1 (1) 1 18 3 21 Primary Efficacy Results: Parasitological Cure at Day 28 - Per Protocol (PP) Populatio N = 4 PCR-ucorrected, 623 (78.3%) 33 (82.5%) PCR-corrected, 73 (94.1%) 369 (97.4%) Treatmet differece -3.3% 95% Cofidece Iterval (CI) (-5.6%, -.9%) Secodary Outcome Variable(s): Subjects with Parasitological Cure at Day 14 PP Populatio N = 4 PCR-ucorrected, 753 (94.6) 374 (93.5) PCR-corrected, 758 (96.3) 376 (95.7) Treatmet differece.6% 95% CI (-1.8%, 3.%) Subjects with Parasitological Cure at Day 42 PP Populatio N = 4 PCR-ucorrected, 528 (66.3) 281 (7.3) PCR-corrected, 591 (89.4) 311 (93.7) Treatmet differece -4.3% 95% CI (-7.8%, -.7%) Subjects with Adequate Cliical ad Parasitological Respose (ACPR) at Day 28 P P Populatio Assessable a ETF LCF LPF ACPR 8/76 (1) 41/796 (5) 112/796 (14) 64/765 (79) N = 4 6/381 (2) 16/4 (4) 44/4 (11) 315/381 (83) ACPR (p) b 78/765 (93) 36/381 (94) ETF = Early Treatmet Failure; LCF = Late Cliical Failure; LPF = Late Parasitological Failure; ACPR = Adequate Cliical ad Parasitological Respose (derived usig 22/23 WHO defiitios) a. Icludes subjects with sufficiet data to categorise treatmet respose uder the WHO defiitios b. Icludes subjects who had ACPR at Day 28 plus subjects who met LCF or LPF criteria, but accordig to PCR data, had a ew ifectio rather tha a recrudescece Subjects with ACPR at Day 14 P P Populatio N = 4 Assessable a ETF LCF LPF ACPR 8/76 (1) 1/796 14/796 (2) 737/76 (97) 6/381 (2) 8/399 (2) 366/38 (96) ACPR (p) b 743/76 (98) 368/38 (97) 3
UM27/189/ ETF = Early Treatmet Failure; LCF = Late Cliical Failure; LPF = Late Parasitological Failure; ACPR = Adequate Cliical ad Parasitological Respose (derived usig 22/23 WHO defiitios) a. Icludes subjects with sufficiet data to categorise treatmet respose uder the WHO defiitios b. Icludes subjects who are ACPR at Day 14 plus subjects who met LCF or LPF criteria, but accordig to PCR data, had a ew ifectio rather tha a recrudescece Subjects with ACPR at Day 42 P P Populatio Assessable a ETF LCF LPF ACPR 8/76 (1) 69/796 (9) 167/796 (21) 527/771 (68) N = 4 6/381 (2) 28/4 (7) 75/4 (19) 275/384 (72) ACPR (p) b 697/771 (9) 358/384 (93) ETF = Early Treatmet Failure; LCF = Late Cliical Failure; LPF = Late Parasitological Failure; ACPR = Adequate Cliical ad Parasitological Respose (derived usig 22/23 WHO defiitios) c. Icludes subjects with sufficiet data to categorise treatmet respose uder the WHO defiitios. d. Icludes subjects who are ACPR at Day 42 plus subjects who met LCF or LPF criteria, but accordig to PCR data, had a ew ifectio rather tha a recrudescece Asexual Parasite Desities P P Populatio Parasite Cout (per µl) Pre-dose 8h post-dose 16h post-dose 24h post-dose Day 7 Day 14 796 2271.9 26641 793 2199.6 6364 794 36.6 71. 796 3.7 78 1. 772 1.1 N = 4 4 2558.8 2581 4 387 9529.5 4 173.2 544.5 4 7.9 391 1. 385 1.1 4
UM27/189/ Day 28 Day 42 786 3.3 775 2.7 397 2.7 391 2.7 Parasite Clearace Time PP Populatio: Parasite Clearace Time (hours) Descriptive Statistics N = 4 796 4 Mea (SD) 23.11 (1.62) 25.49 (1.61) 24. 24. Rage 7. 7 2. 7. 7 2. Time of parasite clearace, : 8 hours 84 (11) 32 (8) >8 to 16 hours 25 (31) 84 (21) >16 to 24 hours 267 (34) 143 (36) >24 to 32 hours 117 (15) 88 (22) >32 to 4 hours 41 (5) 33 (8) >4 to 48 hours 24 (3) 13 (3) >48 to 56 hours 4 4 (1) >56 to 64 hours 5 >64 to 72 hours 3 1 Not cleared by 72 hours 1 2 Subjects with o parasites at Baselie Fever Clearace Time P P Populatio: Fever Clearace Time (hours) Descriptive Statistics N = 4 463 219 Mea (SD) 27.98 (22.91) 25.43 (21.57) 16. 16. Rage 7. 7 2. 7. 7 2. Time of fever clearace, : 8 hours 167 (36) 92 (42) >8 to 16 hours 83 (18) 3 (14) >16 to 24 hours 48 (1) 22 (1) >24 to 32 hours 32 (7) 26 (12) >32 to 4 hours 14 (3) 5 (2) >4 to 48 hours 15 (3) 6 (3) >48 to 56 hours 27 (6) 11 (5) >56 to 64 hours 24 (5) 5 (2) >64 to 72 hours 1 (2) 2 Not cleared by 72 hours 43 (9) 2 (9) Subjects with o fever at Baselie, /N (%) 333/796 (42) 18/4 (45) Safety Results: Recordig of AEs was to be performed at Screeig, Baselie, post-treatmet o Day, ad o Days 1, 2, 3, 7, 14, 28, 42, ad Follow-up. A treatmet-emerget AE was defied as a AE with oset after the first dose of study medicatio or a AE that was preset at baselie, but worseed i severity after the start of dosig. As with AEs, serious adverse evets 5
UM27/189/ were to be recorded through Day 42 ad ay Follow-up visits. The ITT Populatio was used for summarizatio of safety data. N = 914 N = 458 Most Frequet Adverse Evets O-Therapy Subjects with ay AE(s), (%) 476 (52) 22 (48) Reticulocyte cout decreased 81 (9) 45 (1) Aaemia 78 (9) 26 (6) Upper respiratory tract ifectio 74 (8) 36 (8) Helmithic ifectio 37 (4) 24 (5) Cough 4 (4) 2 (4) Diarrhoea 32 (4) 16 (3) Pyrexia 36 (4) 13 (3) Haemoglobi decreased 32 (4) 8 (2) Aorexia 25 (3) 14 (3) Thrombocytopeia 3 (3) 9 (2) Vomitig 31 (3) 8 (2) Malaria 21 (2) 9 (2) Parasite blood test positive 16 (2) 8 (2) Abdomial pai 15 (2) 9 (2) Serious Adverse Evets - O-Therapy [ cosidered by the ivestigator to be related to study medicatio] Preferred Term [related] [related] Subjects with SAEs (both fatal ad o-fatal), 63 (7) [23] 15 (3) [2] Aaemia 26 (3) [7] 1 [] Malaria 9 [] 7 (2) [1] Hemoglobi decreased 15 (2%) [11] 1 [] Peumoia 6 [] 2 [] Haematuria 5 [5] 1 [1] Haemolysis 2 [] Haemoglobiuria 2 [2] Haemolytic aaemia 2 [1] Typhoid fever 2 [] Meigitis 2 [] Febrile covulsio 2 [] Uriary tract ifectio 1 [] 2 [] Alaie amiotrasferase icreased 1 [] 1 [] Aspartate amiotrasferase icreased 1 [] 1 [] Itravascular haemolysis 1 [1] Cerebral malaria 1 [] Blood methaemoglobi preset 1 [1] Drug toxicity 1 [] Aspiratio peumoia 1 [] Pyrexia 2 [] Vomitig 1 [] Subjects with fatal SAEs, [related] [related] Total umber of subjects who died 2 (.22) [] 1 (.22) [] Malaria 1 (.11) [] Herbal itoxicatio 1 (.11) [] Sepsis 1 (.11) [] 6
UM27/189/ Sickle cell aaemia 1 (.11) [] Pyrexia 1 (.22) [] 7
UM27/189/ Abormal Decreases from Baselie i Haemoglobi, by G6PD Geotype Number (%) of Subjects Study Day Hb Alert Threshold N = 914 N = 458 Normal N=597 Deficie t N=23 Missig N=114 Normal N=322 Deficie t N=79 Missi g N=57 Total umber (%) of subjects with adverse Hb levels a at ay time durig the study 18 (3) 35 (17) 11 (1) 5 (2) 1 (1) 3 (5) Day 1 2g/L 51/585 13/198 11/16 3/311 8/79 (1) 4/52 (8) (9) (7) (1) (1) 4g/L 2/585 1/198 1/16 <5g/L 1/585 1/198 Day 2 2g/L 59/574 34/199 14/11 32/39 1/77 4/52 (8) (1) (17) (13) (1) (13) 4g/L 3/199 (2) 2/11 (2) <5g/L 1/199 1/11 1/77 (1) Day 3 2g/L 69/58 56/196 19/112 33/312 8/74 (11) 3/55 (5) (12) (29) (17) (11) 4g/L 5/58 6/196 (3) 4/112 1/55 (2) (4) <5g/L 2/58 1/196 2/112 1/55 (2) (2) Day 7 2g/L 87/567 66/191 19/11 23/38 6/75 (8) 5/54 (9) (15) (35) (17) (7) 4g/L 2/567 2/191 5/11 1/38 2/54 (4) (1) (5) <5g/L 5/191 (3) 1/11 1/54 (2) Day 14 2g/L 32/551 23/184 6/11 15/298 1/54 (2) (6) (13) (5) (5) 4g/L 1/551 2/184 (1) 2/11 1/298 1/54 (2) (2) <5g/L 1/54 (2) Day 28 2g/L 22/55 7/183 (4) 5/11 8/299 (3) 1/51 (2) (4) (5) 4g/L 2/55 <5g/L Day 42 2g/L 16/54 2/187 (1) 12/292 3/75 (4) 1/51 (2) (3) (4) 4g/L 1/54 3/292 (1) <5g/L 1/54 1/292 a. A adverse Hb level was defied as a decrease of 4g/L or >4% from Baselie, a Hb value <5g/L, or a value that ecessitated a blood trasfusio. 8
UM27/189/ Coclusio: This study demostrated that was o-iferior to (Coartem) for the assessmet of parasitological cure rate at Day 28 ad Day 14. Clearace of the parasite from the blood was rapid after the start of dosig, as demostrated by a 9% reductio i asexual parasite cout i the group (compared with 81% i the group) withi the first 8h after the iitial dose of study treatmet. The results of this study demostrated that has a uacceptable safety risk i patiets with G6PD deficiecy, due to the propesity of the DDS compoet to cause severe haemolytic aaemia i such patiets. Sice the prevalece of G6PD deficiecy i sub-sahara Africa is relatively high (approximately 1-2%) ad it would be impractical to scree patiets for the deficiecy prior to treatmet, is usuitable for use i a public health settig i sub-sahara Africa. As a result, further developmet of has bee discotiued. Malaria is a haemolytic disease ad to our kowledge, previous studies of atimalarial agets for the treatmet of ucomplicated P. falciparum malaria have ot characterised Hb chages attributable to the uderlyig disease. As Coartem is o-haemolytic, the Hb chages observed i the Coartem arm i this study have served to elucidate the degree of Hb declie that ca be expected durig the treatmet of malaria. Both G6PD-ormal ad G6PD-deficiet subjects who received Coartem were observed to have miimal decreases i Hb ( 5 g/l) followig the start of treatmet. This importat iformatio will be of beefit i providig a bechmark i determiig the haemolytic potetial of future atimalarials i developmet. Publicatios: Noe Date Updated: 13 Nov 28 9