Artemisinin-naphthoquine combination versus chloroquine-primaquine to treat vivax malaria: an open-label randomized and non-inferiority trial in Yunnan Province, China
Artemisinin-naphthoquine combination versus chloroquine-primaquine to treat vivax malaria: an open-label randomized and non-inferiority trial in Yunnan Province, China
Hui Liu 0
Heng-lin Yang 0
Jian-Wei Xu 0
Jia-zhi Wang 1
Ren-hua Nie 0
Chun-fu Li 0
0 Yunan Institute of Parasitic Diseases , Puer 665000 , China
1 Tengchong County Center for Disease Control and Prevention , Tengchong , China
Background: Plasmodium vivax is the main malaria parasite in China, and China is now making efforts to eliminate malaria by 2020. Radical cure of vivax malaria is one of challenges for malaria elimination. The purpose is to evaluate the efficacy and safety of artemisinin-naphthoquine (ANQ) versus chloroquine-primaquine (CQ-PQ) in treatment of vivax malaria in Yunnan Province, China. Methods: An open-label randomized and non-inferiority design, eligible patients with monoinfections of P. vivax were randomly assigned to receive either a total target dose of ANQ 24.5 mg/kg (naphthoquine 7 mg/kg and artemisinin 17.5 mg/kg), once a day for three days, or a total CQ dose of 24 mg base/kg, once a day for three days plus a PQ dose of 0.45 mg base/kg/day, once a day for eight days. Patients were followed up for one year. The difference in efficacy between ANQ and CQ-PQ was compared via Wilson's test. Results: By day 42, the number of patients free of recurrence was 125 (98.4%; 95% Confidence interval, 94.4-99.8%) for ANQ arm and 123 (96.1%; 95%CI, 91.1-98.7%) for CQ-PQ, and non-significant (P = 0.4496). By day 365, the number was 101 (79.5%; 95%CI, 71.8-85.9%) for ANQ and 106 (82.8%; 95%CI, 75.1-88.9%) for CQ-PQ, and non-significant (P = 0.610). So the proportions of patients free of recurrence had no significant difference between ANQ and CQ-PQ groups by day 28, 42 and 365; compared with CQ-PQ, the side effect of ANQ was mild. Conclusion: ANQ is non-inferior to CQ-PQ in terms of patients free of recurrence, and safer than CQ-PQ.
Plasmodium vivax; Artemisinin-naphthoquine; Efficacy; Safety
Plasmodium vivax is the main malaria parasite in China.
Yunnan Province is a vivax and falciparum malaria
coendemic region and one of two provinces with endemic
falciparum malaria. China is now making efforts to
eliminate malaria by 2020 [1,2]. Radical cure of vivax
malaria is one of challenges for malaria elimination .
The treatment regimen, chloroquine (CQ) for blood
stage infection and 8-aminoquinoline for liver stage
parasite is often poorly adhered to [4,5]. Further, since
CQ-resistant P. vivax was first described in 1989 in
Papua New Guinea , the decline in the efficacy of
CQ has been reported in some geographical sites .
In general, the use of artemisinin-based combination
therapy (ACT) has been limited to patients with
falciparum malaria and showed advantages in terms of
adherence and safety [8-11]. However, with the high
number of misdiagnoses in routine practice and the
rise and spread of CQ-resistant P. vivax, there might
be a compelling rationale for a unified ACT strategy
for vivax and falciparum malaria in all co-endemic regions
. The use of ACT for patients with vivax malaria
has been evaluated in China , Papua, Indonesia
, Thailand  and Ethiopia . These study
results have documented that ACT was effective, safe
and well-tolerated in the treatment of vivax malaria. In
the context, an open-label randomized and non-inferiority
trial was conducted to assess whether
artemisininnaphthoquine (ANQ) is as effective as
chloroquineprimaquine (CQ-PQ), safer than CQ-PQ in treatment
of patients with P. vivax monoinfections in Yunnan
From February 2009 to December 2010, patients were
recruited into our open-label randomized study at
Tengchong County Center for Disease Control and
Prevention, and Tengchong County Hospitals at the
China-Myanmar border. The local transmission is from
June to September in most parts of Tengchong County.
Because of in malaria pre-elimination phase and an
altitude higher than 2,000 m, there was only imported
malaria and rarely local infection in recent years. Patients
older than five years of age who weighed more than 15 kg
and presented with single P. vivax malaria (parasite
density 400100,000 parasites per L) were enrolled
into the study. Patients were not admitted to the study if
any the following criteria present: (1) pregnancy, (2) severe
malaria, (3) having taken any anti-malarial drug within
the past 14 days, (4) history of hypersensitivity to any of
the study drugs, (5) severe dysfunction of kidney, liver
and heart, (6) residence living at an altitude lower than
2,000 m, (7) unable to follow up.
As soon as confirmed patients were enrolled into the
study, they were randomly assigned to receive either ANQ
or CQ-PQ regimens. A researcher, who did not have a role
in recruitment, put sealed envelopes in blocks of 50 (25
ANQ and CQ-PQ respectively) in a box, and an enrolled
patient drew an envelope from it to achieve treatment
allocations in equal numbers. When the box was empty,
another 50 envelopes were added.
ANQ was registered by Food and Drug Administration,
China as GYZZ H20050270 and licensed to Kunming
Pharmaceutical Corp to produce. A tablet of ANQ is
composed of 50 mg naphthoquine and 125 mg
artemisinin. CQ was registered as GYZZ H31020423 and PQ as
GYZZ H2005984 in China. CQ-PQ was produced and
pre-packed by Shanghai Sino-West Pharmaceutical Corp.
Both ANQ and CQ-PQ were administered following the
anti-malarial drug policy of China. Based on the
hypothesis that a three day dosing could reduce recurrence of
Plasmodium vivax, ANQ was given once a day for three
days, with a total target dose of 24.5 mg/kg (naphthoquine
7 mg/kg and artemisinin 17.5 mg/kg). CQ was given once a
day for three days with a total target dose of 24 mg base/kg
and PQ was offered once a day for eight days with a dose
of 0.45 mg base/kg/day.
The researchers visited all patients every 8 hrs for the first
three days. Axillary temperatures were measured every
8 hrs after treatment until after 48 hrs of fever clearance.
Thick and thin blood smears were taken and examined
every 8 hrs in each active visit, and then day 7, 14, 21 and
28 respectively. The subsequent PQ doses of CQ-PQ
groups were given under supervision of patient caretakers
one hour after supper and before going to bed from the
fourth day. Patients received the remaining PQ doses
packed by aluminium-plastic foil and were instructed
clearly about their subsequent treatment, emphasizing the
importance of taking drugs after food and before going to
bed, and taking their medicines even when their
symptoms had subsided. The patients were asked to return for
treatment in any case that they had dark urine; this was
done instead of testing for G6PD deficiency because of
shortage of reagent kit and equipment supplies. Patients
were visited and interviewed every month; meanwhile
blood smears were done during the monthly visits, and
asked to return for screening and treatment at any time, if
they became ill. If a patient had fever, blood smears were
prepared and examined for malaria at any time.
Microscopists examining blood films were unaware of treatment
allocation. If any patients were positive of P. vivax again,
they were retreated with CQ (24 mg base/kg) for three
days and PQ (0.25 mg base/kg/d) for 14 days. Patients
were observed and interviewed with semi-structured
questionnaires in depth for adverse reactions and compliance
during administering each dose and follow-up visits on
days 1, 2, 3, 7, 14, 21 and 28. Patients were followed up for
one year through monthly visits.
Malaria blood films were stained with Giemsa, and both
asexual parasites and gametocytaemia were counted per
500 white blood cells. The number of parasites was
calculated as per l of blood by the level of 8,000 of
leukocyte per l . Parasite clearance was defined as
no any parasite per 500 white blood cells by two
continuous every 8-hr microscopy and gametocyte
clearance defined by the same method. Fever clearance was
defined as axillary temperatures < 37.1C in duration of
24 hrs. Cure was defined as elimination of the
symptoms and asexual blood stages of the malaria parasites
that caused the patient to seek treatment. Recurrence
was defined as reappearance of asexual parasitaemia
following treatment caused by a recrudescence, a
relapse or a new infection .
Study end points
The primary end point was the proportion of patients
free of recurrence at day 42, and the secondary end
points included at day 28 and 365, the parasite and fever
clearance times, and the adverse events reported by
patients during follow-up.
Based on calculation recommended by literature , a
sample size of 120 patients per study group allowed a
cure rate of 90% per group to be estimated with 5%
precision, and allowed estimation of effectiveness equivalence
with a maximum allowable difference of 10% (90% power
and 95% confidence) between groups with a follow-up
drop-out rate of up to 10%.
The difference of patients free of recurrence and its
two-sided 95% confidence intervals between ANQ and
CQ-PQ arms were calculated via Wilsons test.
Proportions were compared by using Yates corrected x2 tests.
Mean fever and parasite clearance time were compared
The study was reviewed and approved by The Academic
Board of Yunnan Institute of Parasitic Diseases (YIPD)
in China as protocol 200807. Approval was also obtained
from YIPDs ethics committees. The purpose of the study
was explained and approval was sought from patients and
their caretakers. Informed written consent was obtained
from patient or caretakers of child patients. All results
were kept confidential and were unlinked to any
The patient proportion of rejecting enrolment was high
(35.2%). When these patients knew that they might take
CQ-PQ for eight days, they were not willing to be
involved in the trial. Of 17,619 fever patients screened
for malaria, 425 had P. vivax. 401 met the enrollment
criteria, but 141 did not agree to participate in the study.
260 were randomly assigned to one of treatment groups.
128 (49.2%) and 132 (50.8%) received ANQ and CQ-PQ
respectively. Three (1.2%) have not completed the 365 day
follow-up and two (0.8%) withdrew from the study on day
1 (Figure 1). Baseline characteristics were similar between
the two treatment groups. 228 (89%) of all patients
enrolled were male and 232 (91%) were older than 16 years
(Table 1). All patients were Chinese citizens. Most of them
went a neighbouring country and got infected there, and
then came back China for treatment. According to
exclusion criteria (6), patients who went go back and forth
Myanmar during the study period were not admitted to
the study because of being unable to follow up. So most
patients stayed in their homeland during the study period,
Figure 1 Trial profile.
Table 1 Baseline characteristics of patients in Yunnan
Age groups (years)
Mean (SD) weight, kg
Mean (SD) height, cm
52.6 (17.7) 56.6 (14.9)
167.6 (4.9) 159.8 (18.7) 163.6 (14.2)
127 (100%) 128 (100%) 255 (100%)
Duration of illness before presentation (hr)
Body temperature (C)
Haemoglobin values (g/l)
Pulse rates (/min)
140.3 (19.1) 145.5 (17.3) 142.7 (19.2)
three patients who are lost follow up might go back
The proportion of patients with recurrence in the
ANQ group were not significant (P = 0.4496) to that in
the CQ-PQ arm by day 42 (Table 2). Neither group had
any recurrence by day 28. The ANQ group had two
recurrences by day 42, respectively on day 36 and 38; the
CQ-PQ group had five recurrences, one respectively on
day 30, 35 and 41, and two on day 31. The ANQ group
had 26 (20.5%) recurrences by day 365, one patient had
two recurrences with a 69-day interval, and 25 had only
one. The CQ-PQ group had 22 (17.2%) recurrences, two
patients had two recurrences and 20 had only one; the
intervals of two recurrences for the two patients were
respectively 153 and 121 days. Most of recurrences
occurred between day 43 and 98, the median time of
ANQ to recurrence was 77 days (range, 29347 days)
and CQ-PQ arm 85 days (range, 24357 days) (Table 3).
All 255 patients cleared parasitaemia by day 3, ANQ
treatment group by hour 48 and CQ-PQ by hour 64.
50% parasite, full parasite, gametocyte clearance times of
ANQ were shorter than of CQ-PQ. ANQ cleared
parasitaemia very rapid, the proportion of patients with
parasitaemia at 24 hrs after therapy was significantly lower
than of CQ-PQ. The fever clearance time (FCT) of ANQ
was significantly shorter than of CQ-PQ group (Table 2).
49 (19.2%) patients reported adverse events during the
study (Table 4). 9 (7.1%) in ANQ arm and 7 (5.5%) in
CQ-PQ group had nausea and anorexia within the first
hour respectively. However, whether the drugs caused
the side effect could not be confirmed. The proportion
with adverse events were similar (RR 1.05; 95%CI,
0.631.74; P = 0.97) between the two groups, but side effect of
the ANQ was mild. In CQ-PQ group, two patients
withdrew because of the serious adverse effect. They were
both male, 33 and 39 years of age. Their body
temperatures were respectively 37.3C and 37.0C (not at time of
malaria attack) when they presented, however, the
temperature of patient 1 climbed to 39C after four hrs
taking CQ-PQ and patient 2 to 38.6C after four and half
hrs. Their baseline hemoglobin was respectively 149 g/l
and 136 g/l. After the two patients took the first dose of
PQ (22.5 mg/person), they felt more uncomfortable than
prior to taking CQ-PQ for malaria treatment and their
urines were the color of black tea. The result of
haemoglobinuria test were respectively ++ ( 2 g/l) for patient
1 and +++ (3 g/l) for patient 2. Following the guideline
on treatment of G6PD deficiency, they stopped use of PQ.
They were treated with ANQ and excluded them from the
study. Their urines became normal without special
treatment after 24 hrs not taking PQ. The two patients were
Jingpo and Dai ethnical minority respectively. Their
personal or family history of haemolysis/haemoglobinuria
could not be investigated because they could not provide
related information. Based on the above, the two patients
were supposed to be G6PD deficiency and the primaquine
caused their haemoglobinuria.
The study results showed that ANQ had similar efficacy
to CQ-PQ in terms of patients free of recurrence, and
better tolerated and safer than CQ-PQ. Naphthoquine
has a half-life of 40.93 hrs. The cure rate of
naphthoquine phosphate (NP, 100%) was higher than CQ
(74.3%) by day 42, but longer fever clearance times
(FCT) and parasite clearance times (PCT) than of CQ
. ANQ was evaluated to overcome the shortage of
NP in FCT and PCT in Hainan Province of China from
May 1999 to October 2000. The cure rate of ANQ was
100% by day 42, and FCT and PCT was shorter than of
CQ . In Papua New Guinea, ANQ has been used for
P. vivax infections now. The study showed that the
lower single ANQ dose was associated with relatively
frequent recurrence of parasitaemia . In Thailand,
Fever clearance times (hr)
50% parasite clearance times (hr)
Parasite clearance times (hr)
Gametocyte clearance times
Table 2 Therapeutic responses of patients in Yunnan Province, China
ANQ (n = 127)
CQ-PQ (n = 128)
25 (19.7%; 95%CI, 13.2-27.7%)
76 (59.4%; 95%CI, 50.3-68.0%)
<0.0001 0.397 (95%CI, 0.281-0.498)
25 (19.7%; 95%CI, 13.2-27.7%)
58 (45.3%; 95%CI, 36.5-54.3%)
<0.0001 0.256 (95%CI, 0.142-0.361)
127 (100%; 95%CI, 97.1-100%)
128 (100%; 95%CI, 97.2-100%)
0 (95%CI, -0.029-0.029)
125 (98.4%; 95%CI, 94.4-99.8%) 123 (96.1%; 95%CI, 91.1-98.7%) 0.4496
0.0233 (95%CI, -0.022-0.074)
101 (79.5%; 95%CI,71.8-85.9%) 106 (82.8%; 95%CI, 75.1-88.9%) 0.610
0.0328 (95%CI, -0.064-0.129)
dihydroartemisinin-piperaquine (DP) was evaluated in
the treatment of vivax malaria. The results showed that
the cumulative risk of recurrence with P. vivax was
significant lower in DP recipients than in CQ . In southern
Papua, Indonesia, a study results showed that recurrence
of vivax malaria occurred in 38% of patients given
artemether-lumefantrine and 10% given DP . All the
studies showed that ACT cleared P. vivax very rapidly and
had high cure rates. This coincides with the viewpoint that
P. vivax is more sensitive than P. falciparum to the
artemisinin derivatives .
Table 3 Recurrence of patients in 365 day in Yunnan
(n = 127) (n = 128)
Patients with parasite 26 (20.5%; 95%CI, 22 (17.7%; 95%CI, 0.61
reappearance in 14.1-28.2%) 11.1-24.9%)
Artemisinin has a short half-life. A single dose or a
two-day dosing of ANQ is usually for treatment of
Plasmodium falciparum. The finding in Papua New
Guinea showed that the lower single ANQ dose was
associated with relatively frequent recurrence of P. vivax .
Considering these factors and that patients can easily
adhere to three-day regimens, dosing ANQ for three
days was chosen in the study.
Table 4 Number of patients reporting side-effects at any
time point after drug administration in Yunnan Province,
The efficacy of CQ in the treatment of P. vivax
infections was declining on the Thai-Myanmar border 
and in Vietnam . The cumulative risk of recurrence
with P. vivax at nine weeks was 79.1% in patients treated
with only CQ and 54.9% treated with
dihydroartemisininpiperaquine on the Thai-Myanmar border . As a
primary result of the study, the proportions of patients free
of recurrence between ANQ and CQ-PQ groups had no
difference even by day 365. The cumulative recurrence
rates with P. vivax at 365 days were respectively 21.05% in
patients treated with ANQ and 17.2% treated with
CQPQ. This indicated that PQ and NP significantly reduced
recurrence with P. vivax. This might attribute to two
reasons. One is that NP has a long half-life despite
ANQ cannot kill the liver stages, whereas CQ-PQ can;
the other is that no evidence documented that less than
14 days PQ can radically cure P. vivax . Despite the
total dose of PQ with the 0.45 8 day (=3.6 mg)
regimen is similar to the 0.25 mg/kg qd 14 days (=3.5 mg)
regimen recommended by WHO, the longer time of
treatment seems to be important for killing
hypnozoites. As a limitation, the subsequent PQ doses from
day 4 to 8 were given under supervision of patient
caretakers, not under supervision of researchers; despite the
patients or/and their caretakers said the patients
completed taking PQ regimen, the researcher could ensure
that they really took PQ completely. It is possible that
the people with relapse took a smaller dose of total PQ.
As one of exclusion criteria for both ANQ and CQ-PQ
groups, patients who went go back and forth Myanmar
during the study period were not admitted to the study
because of being unable to follow up, so it is not
necessary to keep on at the effect of re-infection on the study
ANQ had a mild side effect. However, two patients
could not complete the treatment because of PQ toxicity.
2064 persons were screened for G6PD deficiency in
China-Myanmar border region in July 2009. The result
was 2.3% (95%CI, 1.7-3.0%) of prevalence of G6PD
deficiency (not published). These showed that using CQ-PQ
has an intrinsic problem in the region. Patients of vivax
malaria can obtain 8-day CQ-PQ regimen free from public
health sector in China. As a reality, malaria patients want
to get rid of symptoms as quick as possible. They
commonly seek artemether or pyronaridine injection by
selfmedication or from private clinics because they considered
injection working better and faster than oral tablets, and
intolerability of the 8-day CQ-PQ regimen. All the update
studies showed that ACT was well tolerated with no
serious adverse events [7-14,20]. There is rarely local malaria
transmission in the study area due to low temperature
attributed to high altitude, malaria patients are from
migrants, most of them are adult male, so the issue of
re-infection was omitted during study period.
In terms of efficacy, the three-day ANQ regimen is as
effective as the 8-day CQ-PQ, safer and more acceptable
than CQ-PQ, but ANQ does not prevent relapse
completely. ANQ is a great blood schizonticide for P. vivax
infections and is a good option for Yunnan Province of
China if people do not want to take PQ.
The authors declare that they have no competing interests.
HL, H-L Y designed the study and developed the protocol. J-W X and HL
analyzed and interpreted the data. HL supervised the clinical trial. HL, J-Z W,
R-H N and C-F L conducted the clinical trial, and entered the data. J-WX and
HL wrote the first draft of the paper. All authors read and approved the final
This study was supported by Yunnan Provincial Department of Science and
Technology (YDST), China. Artemisinin-naphthoquine was provided by
Kunming Pharmaceutical Corp. We thank all participants for their contribution
of time and patience in the study. We also thank staff of Yunnan Institute of
Parasitic Diseases (YIPD) for logistic support, and clinical and laboratory staff of
Tengchong County Center for Disease Control and prevention, and Tengchong
County Hospitals for their hard work. The opinions expressed are those of
the authors and do not necessarily reflect those of YIPD and YDST.
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