Ignite Creation Date:
2024-05-06 @ 1:00 AM
Last Modification Date:
2024-10-26 @ 10:57 AM
Study NCT ID:
NCT01707199
Status:
COMPLETED
Last Update Posted:
2020-10-14
First Post:
2012-10-11
Brief Title:
SPK Study in Afghanistan
Sponsor:
University of Oxford
Organization:
University of Oxford
Study Overview
Official Title:
Efficacy and Safety of ArtesunateSulphadoxine-Pyrimethamine for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Malaria Control Center Asadabad in Kunar Province of Afghanistan
Status:
COMPLETED
Status Verified Date:
2020-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
In Afghanistan studies over the past 15 years have shown a high degree of Plasmodium falciparum resistance to chloroquine In 2003 the high failure rate of chloroquine against falciparum malaria led the national malaria treatment programme to switch its recommended first line drug treatment for uncomplicated Plasmodium falciparum malaria to artemisinin-based combination therapy ACT in the form of ArtesunateSulphadoxine-Pyrimethamine ASSP Second line drug treatment is oral quinine 7 days
For operational reasons prior to recent studies manuscript in preparation there have been no molecular data on P falciparum SP resistance markers from within the borders of Afghanistan These studies have revealed early evidence of increasing SP resistance resistance polymorphisms with double DHFR triple DHPS mutations The aim of this study is to conduct a focused prospective study in Kunar for monitoring of the efficacy of the ASSP combination in this province along with molecular studies of isolates from recruited patients
For operational reasons prior to recent studies manuscript in preparation there have been no molecular data on P falciparum SP resistance markers from within the borders of Afghanistan These studies have revealed early evidence of increasing SP resistance resistance polymorphisms with double DHFR triple DHPS mutations The aim of this study is to conduct a focused prospective study in Kunar for monitoring of the efficacy of the ASSP combination in this province along with molecular studies of isolates from recruited patients
Detailed Description:
Afghanistan is a poor country that remains largely dependent on foreign aid Life expectancy remains in the order of 60 years with 30 of mortality due to communicable diseases
Malaria is a large health burden and antimalarial drug resistance poses a considerable threat to malaria control Resistance to chloroquine was evident in Afghanistan by the late-1990s with failure rates more than 60 for the country as a whole and as high as 90 for Jalalabad Nangarhar province The combination of artesunate with amodiaquine also proved to have low efficacy In 2004 failure rates for SP for the treatment of P falciparum were 10-15 consistent with comparable clinical data in Afghan refugees residing in Pakistan Given this efficacy the Ministry of Public Health in consultation with WHO and other international partners has implemented ASSP as first-line treatment of slide confirmed P falciparum malaria in Afghanistan Quinine 7 days po is second line treatment CQSP has been the recommended treatment for patients with a presumptive diagnosis of malaria since 2003 Both artesunate and sulphadoxine-pyrimethamine are safe and well tolerated drugs and there is no evidence of an interaction between them
Artesunate AS has been reported to be associated with mild gastrointestinal disturbances dizziness and tinnitus although none of these associations are convincing The only potentially serious adverse effect that has been reported with the artemisinin class of drugs in clinical trials is type I hypersensitivity reactions about 13000 patients Transient reticulocytopenia neutropenia and elevated liver enzyme values have been reported but none have been clinically significant The weight of evidence suggests these drugs have no significant adverse cardiovascular effects A variety of clinical neurophysiological and pathologic studies in humans have not shown evidence of neurological toxicity Because these drugs have not been evaluated extensively in early pregnancy in humans they should be avoided in patients in the first trimester of pregnancy with uncomplicated malaria until more information is available WHO guidelines 2006
Sulphadoxine-pyrimethamine SP is a fixed combination of a long-acting sulfonamide and the antifolate pyrimethamine These are synergistic against sensitive parasites Minor adverse effects are unusual and serious sulfonamide toxicity is very unusual with a single-dose treatment of malaria The anti-folate properties of pyrimethamine rarely produce toxicity
The combination of AS SP has been evaluated extensively in adults and children with uncomplicated malaria and is sufficiently efficacious in areas where 28-day cure rates with sulphadoxine-pyrimethamine alone exceed 80 This ACT is currently being used in parts of South America the Middle East and South Asia where SP susceptibility remains high Studies conducted between 2004-2006 to evaluate the efficacy of artesunate plus sulphadoxine-pyrimethamine ASSP against P falciparum showed high efficacy in terms of adequate clinical and parasitological response Afghanistan National Malaria Strategic Plan
The genetic determinants of in vitro resistance to the two drug components of SP individually are shown to be point mutations at seven sites in the dihydrofolate reductase gene dhfr causing resistance to pyrimethamine and five sites in the dihydropteroate synthase dhps gene causing resistance to sulphadoxine Different combinations of mutations within each gene confer differing degrees of insensitivity Due to administrative instability until recently few molecular data relating to P falciparum SP resistance markers have been available from within the borders of Afghanistan However the investigators have obtained recent submitted data showing that in addition to two resistance polymorphisms in DHFR C59R and S108N that are well known to be at high frequency in the region a small number of parasites in the Kunar province have three mutations A437G K540E and A581G in DHPS
This study is a prospective open label single arm clinical trial to test the PCR confirmed efficacy and tolerability of ASSP for the treatment of uncomplicated falciparum malaria in Afghanistan Follow-up will be for 42 days in order to sensitively detect recrudescence Recrudescence will be distinguished from re-infection by molecular techniques based on well characterized microsatellite markers msp1 msp2 and glurp will be used Baseline and any recurrent parasites will be tested for DHFR and DHPS polymorphisms by RFLP as well as sequencing if indicated The proposed study will provide accurate data and accurate evidences on efficacy of the current malaria treatment regimen in Afghanistan
Malaria is a large health burden and antimalarial drug resistance poses a considerable threat to malaria control Resistance to chloroquine was evident in Afghanistan by the late-1990s with failure rates more than 60 for the country as a whole and as high as 90 for Jalalabad Nangarhar province The combination of artesunate with amodiaquine also proved to have low efficacy In 2004 failure rates for SP for the treatment of P falciparum were 10-15 consistent with comparable clinical data in Afghan refugees residing in Pakistan Given this efficacy the Ministry of Public Health in consultation with WHO and other international partners has implemented ASSP as first-line treatment of slide confirmed P falciparum malaria in Afghanistan Quinine 7 days po is second line treatment CQSP has been the recommended treatment for patients with a presumptive diagnosis of malaria since 2003 Both artesunate and sulphadoxine-pyrimethamine are safe and well tolerated drugs and there is no evidence of an interaction between them
Artesunate AS has been reported to be associated with mild gastrointestinal disturbances dizziness and tinnitus although none of these associations are convincing The only potentially serious adverse effect that has been reported with the artemisinin class of drugs in clinical trials is type I hypersensitivity reactions about 13000 patients Transient reticulocytopenia neutropenia and elevated liver enzyme values have been reported but none have been clinically significant The weight of evidence suggests these drugs have no significant adverse cardiovascular effects A variety of clinical neurophysiological and pathologic studies in humans have not shown evidence of neurological toxicity Because these drugs have not been evaluated extensively in early pregnancy in humans they should be avoided in patients in the first trimester of pregnancy with uncomplicated malaria until more information is available WHO guidelines 2006
Sulphadoxine-pyrimethamine SP is a fixed combination of a long-acting sulfonamide and the antifolate pyrimethamine These are synergistic against sensitive parasites Minor adverse effects are unusual and serious sulfonamide toxicity is very unusual with a single-dose treatment of malaria The anti-folate properties of pyrimethamine rarely produce toxicity
The combination of AS SP has been evaluated extensively in adults and children with uncomplicated malaria and is sufficiently efficacious in areas where 28-day cure rates with sulphadoxine-pyrimethamine alone exceed 80 This ACT is currently being used in parts of South America the Middle East and South Asia where SP susceptibility remains high Studies conducted between 2004-2006 to evaluate the efficacy of artesunate plus sulphadoxine-pyrimethamine ASSP against P falciparum showed high efficacy in terms of adequate clinical and parasitological response Afghanistan National Malaria Strategic Plan
The genetic determinants of in vitro resistance to the two drug components of SP individually are shown to be point mutations at seven sites in the dihydrofolate reductase gene dhfr causing resistance to pyrimethamine and five sites in the dihydropteroate synthase dhps gene causing resistance to sulphadoxine Different combinations of mutations within each gene confer differing degrees of insensitivity Due to administrative instability until recently few molecular data relating to P falciparum SP resistance markers have been available from within the borders of Afghanistan However the investigators have obtained recent submitted data showing that in addition to two resistance polymorphisms in DHFR C59R and S108N that are well known to be at high frequency in the region a small number of parasites in the Kunar province have three mutations A437G K540E and A581G in DHPS
This study is a prospective open label single arm clinical trial to test the PCR confirmed efficacy and tolerability of ASSP for the treatment of uncomplicated falciparum malaria in Afghanistan Follow-up will be for 42 days in order to sensitively detect recrudescence Recrudescence will be distinguished from re-infection by molecular techniques based on well characterized microsatellite markers msp1 msp2 and glurp will be used Baseline and any recurrent parasites will be tested for DHFR and DHPS polymorphisms by RFLP as well as sequencing if indicated The proposed study will provide accurate data and accurate evidences on efficacy of the current malaria treatment regimen in Afghanistan
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None