A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria

TY - JOUR

T1 - A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria

AU - Macintyre, Fiona

AU - Adoke, Yeka

AU - Tiono, Alfred B

AU - Duong, Tran Thanh

AU - Mombo-Ngoma, Ghyslain

AU - Bouyou-Akotet, Marielle

AU - Tinto, Halidou

AU - Bassat, Quique

AU - Issifou, Saadou

AU - Adamy, Marc

AU - Demarest, Helen

AU - Duparc, Stephan

AU - Leroy, Didier

AU - Laurijssens, Bart E

AU - Biguenet, Sophie

AU - Kibuuka, Afizi

AU - Tshefu, Antoinette Kitoto

AU - Smith, Melnick

AU - Foster, Chanelle

AU - Leipoldt, Illse

AU - Kremsner, Peter G

AU - Phuc, Bui Quang

AU - Ouedraogo, Alphonse

AU - Ramharter, Michael

AU - OZ-Piperaquine Study Group

AU - Groger, Mirjam

AU - Mischlinger, Johannes

PY - 2017/10/9

Y1 - 2017/10/9

N2 - BACKGROUND: The clinical development of a single encounter treatment for uncomplicated malaria has the potential to significantly improve the effectiveness of antimalarials. Exploratory data suggested that the combination of artefenomel and piperaquine phosphate (PQP) has the potential to achieve satisfactory cure rates as a single dose therapy. The primary objective of the study was to determine whether a single dose of artefenomel (800 mg) plus PQP in ascending doses is an efficacious treatment for uncomplicated Plasmodium falciparum malaria in the 'target' population of children ≤ 5 years of age in Africa as well as Asian patients of all ages.METHODS: Patients in six African countries and in Vietnam were randomised to treatment with follow-up for 42-63 days. Efficacy, tolerability, safety and pharmacokinetics were assessed. Additional key objectives were to characterise the exposure-response relationship for polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response at day 28 post-dose (ACPR28) and to further investigate Kelch13 mutations. Patients in Africa (n = 355) and Vietnam (n = 82) were included, with 85% of the total population being children < 5 years of age.RESULTS: ACPR28 in the per protocol population (95% confidence interval) was 70.8% (61.13-79.19), 68.4% (59.13-76.66) and 78.6% (70.09-85.67) for doses of 800 mg artefenomel with 640 mg, 960 mg and 1440 mg of PQP respectively. ACPR28 was lower in Vietnamese than in African patients (66.2%; 54.55-76.62 and 74.5%; 68.81-79.68) respectively. Within the African population, efficacy was lowest in the youngest age group of ≥ 0.5 to ≤ 2 years, 52.7% (38.80-66.35). Initial parasite clearance was twice as long in Vietnam than in Africa. Within Vietnam, the frequency of the Kelch13 mutation was 70.1% and was clearly associated with parasite clearance half-life (PCt1/2). The most significant tolerability finding was vomiting (28.8%).CONCLUSIONS: In this first clinical trial evaluating a single encounter antimalarial therapy, none of the treatment arms reached the target efficacy of > 95% PCR-adjusted ACPR at day 28. Achieving very high efficacy following single dose treatment is challenging, since > 95% of the population must have sufficient concentrations to achieve cure across a range of parasite sensitivities and baseline parasitaemia levels. While challenging, the development of tools suitable for deployment as single encounter curative treatments for adults and children in Africa and to support elimination strategies remains a key development goal.TRIAL REGISTRATION: ClinicalTrials.gov, NCT02083380 . Registered on 7 March 2014.

AB - BACKGROUND: The clinical development of a single encounter treatment for uncomplicated malaria has the potential to significantly improve the effectiveness of antimalarials. Exploratory data suggested that the combination of artefenomel and piperaquine phosphate (PQP) has the potential to achieve satisfactory cure rates as a single dose therapy. The primary objective of the study was to determine whether a single dose of artefenomel (800 mg) plus PQP in ascending doses is an efficacious treatment for uncomplicated Plasmodium falciparum malaria in the 'target' population of children ≤ 5 years of age in Africa as well as Asian patients of all ages.METHODS: Patients in six African countries and in Vietnam were randomised to treatment with follow-up for 42-63 days. Efficacy, tolerability, safety and pharmacokinetics were assessed. Additional key objectives were to characterise the exposure-response relationship for polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response at day 28 post-dose (ACPR28) and to further investigate Kelch13 mutations. Patients in Africa (n = 355) and Vietnam (n = 82) were included, with 85% of the total population being children < 5 years of age.RESULTS: ACPR28 in the per protocol population (95% confidence interval) was 70.8% (61.13-79.19), 68.4% (59.13-76.66) and 78.6% (70.09-85.67) for doses of 800 mg artefenomel with 640 mg, 960 mg and 1440 mg of PQP respectively. ACPR28 was lower in Vietnamese than in African patients (66.2%; 54.55-76.62 and 74.5%; 68.81-79.68) respectively. Within the African population, efficacy was lowest in the youngest age group of ≥ 0.5 to ≤ 2 years, 52.7% (38.80-66.35). Initial parasite clearance was twice as long in Vietnam than in Africa. Within Vietnam, the frequency of the Kelch13 mutation was 70.1% and was clearly associated with parasite clearance half-life (PCt1/2). The most significant tolerability finding was vomiting (28.8%).CONCLUSIONS: In this first clinical trial evaluating a single encounter antimalarial therapy, none of the treatment arms reached the target efficacy of > 95% PCR-adjusted ACPR at day 28. Achieving very high efficacy following single dose treatment is challenging, since > 95% of the population must have sufficient concentrations to achieve cure across a range of parasite sensitivities and baseline parasitaemia levels. While challenging, the development of tools suitable for deployment as single encounter curative treatments for adults and children in Africa and to support elimination strategies remains a key development goal.TRIAL REGISTRATION: ClinicalTrials.gov, NCT02083380 . Registered on 7 March 2014.

KW - Adolescent

KW - Adult

KW - Africa

KW - Antimalarials/administration & dosage

KW - Artemisinins/administration & dosage

KW - Asian Continental Ancestry Group

KW - Child

KW - Child, Preschool

KW - Dose-Response Relationship, Drug

KW - Double-Blind Method

KW - Drug Therapy, Combination

KW - Female

KW - Humans

KW - Infant

KW - Malaria, Falciparum/drug therapy

KW - Male

KW - Middle Aged

KW - Plasmodium falciparum/genetics

KW - Quinolines/administration & dosage

KW - Treatment Outcome

KW - Young Adult

U2 - 10.1186/s12916-017-0940-3

DO - 10.1186/s12916-017-0940-3

M3 - SCORING: Journal article

C2 - 28988541

VL - 15

SP - 181

JO - BMC MED

JF - BMC MED

SN - 1741-7015

IS - 1

ER -