Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT01640587 |
| Other study ID # |
SMRU1201 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
November 2013 |
| Est. completion date |
March 30, 2017 |
Study information
| Verified date |
June 2017 |
| Source |
University of Oxford |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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 numbers.The
proportion of patients with parasitaemia persisting on day-2 increased significantly from
4.5% before 2001 to 21.9% after 2002 (p<0.001). Delayed parasite clearance was associated
with increased risk of developing gametocytaemia (AOR = 2.29; 95% CI, 2.00-2.69, p = 0.002).
MAS3 efficacy declined slightly but significantly (Hazards ratio 1.13; 95% CI, 1.07-1.19,
p<0.001), although efficacy in 2007 remained well within acceptable limits: 96.5% (95% CI,
91.0-98.7). The proportion of infections caused by parasites with increased pfmdr1 copy
number rose from 30% (12/40) in 1996 to 53% (24/45) in 2006 (p = 0.012, 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
P.falciparum.
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 numbers.The proportion of
patients with parasitaemia persisting on day-2 increased significantly from 4.5% before 2001
to 21.9% after 2002 (p<0.001). Delayed parasite clearance was associated with increased risk
of developing gametocytaemia (AOR = 2.29; 95% CI, 2.00-2.69, p = 0.002). MAS3 efficacy
declined slightly but significantly (Hazards ratio 1.13; 95% CI, 1.07-1.19, p<0.001),
although efficacy in 2007 remained well within acceptable limits: 96.5% (95% CI, 91.0-98.7).
The proportion of infections caused by parasites with increased pfmdr1 copy number rose from
30% (12/40) in 1996 to 53% (24/45) in 2006 (p = 0.012, 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 mg/kg of artesunate
(AS) alone for 7 days or 4 mg/kg AS for 3 days plus 25 mg/kg 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 47.0% (95% CI 27.0-64.7), 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
P.falciparum 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.
