Ignite Creation Date:
2024-05-06 @ 12:43 AM
Last Modification Date:
2024-10-26 @ 10:53 AM
Study NCT ID:
NCT01640587
Status:
TERMINATED
Last Update Posted:
2023-01-10
First Post:
2012-07-11
Brief Title:
Compare the Effectiveness Between Existing Treatment and New Treatment
Sponsor:
University of Oxford
Organization:
University of Oxford
Study Overview
Official Title:
Randomized Open-label Trial of Comparison Between DHA-Piperaquine and Mefloquine Artesunate Combinations 3 Day-regimens for the Treatment of Uncomplicated Plasmodium Falciparum Malaria on the Thai-Myanmar Border RDM
Status:
TERMINATED
Status Verified Date:
2017-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
No adequate malaria patient
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
RDM
Brief Summary:
In camps for displaced persons located along the Thai-Myanmar border mefloquine and artesunate combination therapy has been used since 1992 In vivo efficacy of a 3 day regimen of mefloquine artesunate MAS3 has been monitored regularly since its introduction in 1992 In 2009 Carrara et al summarised the in vivo PCR-adjusted cure rates at Day 42 and Day 63 in patients treated with MAS3 between 1995 and 2005 as well as the in-vitro parasite susceptibility to MAS3 during that same period and the changes in pfmdr1 copy numbersThe proportion of patients with parasitaemia persisting on day-2 increased significantly from 45 before 2001 to 219 after 2002 p0001 Delayed parasite clearance was associated with increased risk of developing gametocytaemia AOR 229 95 CI 200-269 p 0002 MAS3 efficacy declined slightly but significantly Hazards ratio 113 95 CI 107-119 p0001 although efficacy in 2007 remained well within acceptable limits 965 95 CI 910-987 The proportion of infections caused by parasites with increased pfmdr1 copy number rose from 30 1240 in 1996 to 53 2445 in 2006 p 0012 test for trend
Evidence of reduced susceptibility to artemisinins in Western Cambodia was first reported in January 2007 Artemisinin resistance was manifest by a marked slowing of parasite clearance A more recent analysis of parasite clearance data collected prospectively in patients with uncomplicated hyperparasitaemic malaria has shown a progressive decline in parasite clearance rates over the last decade suggesting a decline following the same trajectory as in Western Cambodia but with a time lag of a few years
Surveillance data collected in 2011 have shown a dramatic and worrying decline in efficacy of MAS3 albeit in a small number of patients This decline in efficacy of mefloquine artesunate is likely to be attributable to reduced parasite susceptibility to mefloquine The other fixed dose combinations available dihydroartemisinin-piperaquine DP is the best option to replace mefloquine-artesunate since it is thought that it remains effective in the presence of high pfmdr1 copy numbers In addition DP is administered once daily and needs no special dietary modification to ensure adequate absorption
In this study it is hypothesised that efficacy of DP estimated to be 95 will be significantly higher than that of MAS3 estimated to be 65 therefore the investigators propose to conduct a randomised controlled trial between DP and MAS3 for the treatment of Pfalciparum
Evidence of reduced susceptibility to artemisinins in Western Cambodia was first reported in January 2007 Artemisinin resistance was manifest by a marked slowing of parasite clearance A more recent analysis of parasite clearance data collected prospectively in patients with uncomplicated hyperparasitaemic malaria has shown a progressive decline in parasite clearance rates over the last decade suggesting a decline following the same trajectory as in Western Cambodia but with a time lag of a few years
Surveillance data collected in 2011 have shown a dramatic and worrying decline in efficacy of MAS3 albeit in a small number of patients This decline in efficacy of mefloquine artesunate is likely to be attributable to reduced parasite susceptibility to mefloquine The other fixed dose combinations available dihydroartemisinin-piperaquine DP is the best option to replace mefloquine-artesunate since it is thought that it remains effective in the presence of high pfmdr1 copy numbers In addition DP is administered once daily and needs no special dietary modification to ensure adequate absorption
In this study it is hypothesised that efficacy of DP estimated to be 95 will be significantly higher than that of MAS3 estimated to be 65 therefore the investigators propose to conduct a randomised controlled trial between DP and MAS3 for the treatment of Pfalciparum
Detailed Description:
In camps for displaced persons located along the Thai-Myanmar border mefloquine and artesunate combination therapy has been used since 1992 It was studied first in trials but by 1994 it became the first line treatment for all uncomplicated P falciparum malaria episodes in the non-pregnant population In vivo efficacy of a 3 day regimen of mefloquine artesunate MAS3 has been monitored regularly since its introduction in 1992 In 2009 Carrara et al summarised the in vivo PCR-adjusted cure rates at Day 42 and Day 63 in patients treated with MAS3 between 1995 and 2005 as well as the in-vitro parasite susceptibility to MAS3 during that same period and the changes in pfmdr1 copy numbersThe proportion of patients with parasitaemia persisting on day-2 increased significantly from 45 before 2001 to 219 after 2002 p0001 Delayed parasite clearance was associated with increased risk of developing gametocytaemia AOR 229 95 CI 200-269 p 0002 MAS3 efficacy declined slightly but significantly Hazards ratio 113 95 CI 107-119 p0001 although efficacy in 2007 remained well within acceptable limits 965 95 CI 910-987 The proportion of infections caused by parasites with increased pfmdr1 copy number rose from 30 1240 in 1996 to 53 2445 in 2006 p 0012 test for trend
Evidence of reduced susceptibility to artemisinins in Western Cambodia was first reported in January 2007 Artemisinin resistance was manifest by a marked slowing of parasite clearance In Pailin Cambodia the median parasite clearance time was 84 hours compared to 48 hours on the Thai side of the international border with Myanmar following either 2 mgkg of artesunate AS alone for 7 days or 4 mgkg AS for 3 days plus 25 mgkg of mefloquine at both locations A more recent analysis of parasite clearance data collected prospectively in patients with uncomplicated hyperparasitaemic malaria has shown a progressive decline in parasite clearance rates over the last decade suggesting a decline following the same trajectory as in Western Cambodia but with a time lag of a few years
Clinic experience data collected in 2011 have shown a steady decline in efficacy of MAS3 albeit in a small number of patients We have observed this trend over the past 10 years It appears to be related to the increased copies of the gene Pfmdr1 in adult males The PCR corrected efficacy in 43 patients was 470 95 CI 270-647 well below the 90 threshold at which WHO recommends changing to an alternative treatment This decline in efficacy of mefloquine artesunate is likely to be attributable to reduced parasite susceptibility to mefloquine The other fixed dose combinations available dihydroartemisinin-piperaquine DP is the best option to replace mefloquine-artesunate since it is thought that it remains effective in the presence of high pfmdr1 copy numbers In addition DP is administered once daily and needs no special dietary modification to ensure adequate absorption
However other groups in the area have documented a good efficacy of MAS3 In other words we think there is a decline in efficacy but we do not feel confident to say what the magnitude of this drop is Changing policy is a difficult task and we need more and stronger evidence of the current efficacy of MAS3 The best design to avoid selection bias is to do an adequately powered randomized control trial and we would like to compare MAS3 with the next generation ACT DP We have already conducted studies with DP and we know it is safe and effective In laboratory studies we found that this treatment DP is more effective against Pfalciparum when it exhibits resistance to mefloquine via increased expression of the Pfmdr1 gene We think it is timely to compare MAS3 and DP again and carefully monitor for the treatment response in patients with signs of mefloquine resistant parasites Therefore we propose a study to evaluate in an adequately powered RCT MAS3 the current national policy for Thailand and routinely use along the border to a potential replacement DP
Due to a lack of malaria patients at clinics the trial was terminated There will be no further analysis and or publication of the results
Evidence of reduced susceptibility to artemisinins in Western Cambodia was first reported in January 2007 Artemisinin resistance was manifest by a marked slowing of parasite clearance In Pailin Cambodia the median parasite clearance time was 84 hours compared to 48 hours on the Thai side of the international border with Myanmar following either 2 mgkg of artesunate AS alone for 7 days or 4 mgkg AS for 3 days plus 25 mgkg of mefloquine at both locations A more recent analysis of parasite clearance data collected prospectively in patients with uncomplicated hyperparasitaemic malaria has shown a progressive decline in parasite clearance rates over the last decade suggesting a decline following the same trajectory as in Western Cambodia but with a time lag of a few years
Clinic experience data collected in 2011 have shown a steady decline in efficacy of MAS3 albeit in a small number of patients We have observed this trend over the past 10 years It appears to be related to the increased copies of the gene Pfmdr1 in adult males The PCR corrected efficacy in 43 patients was 470 95 CI 270-647 well below the 90 threshold at which WHO recommends changing to an alternative treatment This decline in efficacy of mefloquine artesunate is likely to be attributable to reduced parasite susceptibility to mefloquine The other fixed dose combinations available dihydroartemisinin-piperaquine DP is the best option to replace mefloquine-artesunate since it is thought that it remains effective in the presence of high pfmdr1 copy numbers In addition DP is administered once daily and needs no special dietary modification to ensure adequate absorption
However other groups in the area have documented a good efficacy of MAS3 In other words we think there is a decline in efficacy but we do not feel confident to say what the magnitude of this drop is Changing policy is a difficult task and we need more and stronger evidence of the current efficacy of MAS3 The best design to avoid selection bias is to do an adequately powered randomized control trial and we would like to compare MAS3 with the next generation ACT DP We have already conducted studies with DP and we know it is safe and effective In laboratory studies we found that this treatment DP is more effective against Pfalciparum when it exhibits resistance to mefloquine via increased expression of the Pfmdr1 gene We think it is timely to compare MAS3 and DP again and carefully monitor for the treatment response in patients with signs of mefloquine resistant parasites Therefore we propose a study to evaluate in an adequately powered RCT MAS3 the current national policy for Thailand and routinely use along the border to a potential replacement DP
Due to a lack of malaria patients at clinics the trial was terminated There will be no further analysis and or publication of the results
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