ORIGINAL

Niger J Paed 2013; 40 (2): 145 –149

Meremikwu M

Odey F

Oringanje C

Oyo-Ita A

Udoh E

Effectiveness of a 6-dose regimen of

Artemether-Lumefantrine for

unsupervised treatment of

uncomplicated childhood malaria in

Calabar, Nigeria

Eyong K

Oduwole O

DOI:http://dx.doi.org/10.4314/njp.v40i2,7

Accepted: 17th September 2012

Abstract Background: The six

dose regimen of Artemether-

Lumefantrine (AL), has high effi-

cacy in clinical trials and is the first

home.

Results: Of the 1035 screened, 215

eligible children were enrolled and

193 completed the study. Twenty-

two (22) patients withdrew from the

study (18 were lost to follow-up, 3

violated protocol and 1 withdrew

consent). Adequate clinical and

parasitological response (ACPR)

was observed in 90.7%; late clinical

failure in 7 (3.6%) and late parasi-

tological failure in 11 (5.7%).

Conclusion: This study showed

high efficacy of AL in treating un-

complicated P. falciparum malaria

in under-fives in Nigeria. Adher-

ence by caregivers to the treatment

regimen was quite good and so,

should continue to be used in the

home setting.

Meremikwu M

(

)

Udoh E, Eyong K, Odey F

Department of Paediatrics,

Calabar Institute of Tropical Diseases

Research and Prevention

Email: mmeremiku@yahoo.co.uk

Tel: +2348036742377

-line drug for treating uncompli-

cated malaria in Nigeria. The com-

plex dosage schedule could militate

against its effectiveness.

Objective: To assess the effective-

ness of AL prescribed under rou-

tine outpatient conditions in the

treatment of uncomplicated ma-

laria.

Methods: An open label, non-

comparative trial to assess the ef-

fectiveness of AL in children 6 to

59 months with uncomplicated P.

falciparum and parasite density

between 1,000 and 250,000/ꢀL.

Enrolled children received 6-dose

course of AL (20/120mg tablets).

The first dose was administered in

the health facility and caregivers

were instructed on how to adminis-

ter the remaining five doses at

Oduwole O, Oringanje C

Calabar Institute of Tropical Diseases

Research and Prevention

Oyo-Ita A

Department of Community Medicine,

University of Calabar and University of

Calabar Teaching Hospital, Calabar,

Nigeria.

Key words: Artemether-

lumefantrine, effectiveness, adher-

ence, uncomplicated malaria.

5

-8

Introduction

ria, showed that artemisinin-based combination ther-

apy (ACT) are efficacious and safe . In line with the

recommendation of world health organization (WHO),

the Nigerian Federal Ministry of Health changed the

1

,2

The global burden of malaria is well described with

0% of global episodes of clinical malaria and mortality

9

occurring in sub-Sahara Africa. The malaria control

situation became worse following the emergence of anti-

malarial drug resistance and more recently by reports of

resistance to artemisinin product from South East Asia.

Early diagnosis and prompt treatment during malaria

episodes are the key components of the global strategy

malaria treatment policy in 2005, to artemisinin-based

combination therapy. Artemether-Lumefantrine (AL)

was the first ACT approved for use as first-line in the

treatment of uncomplicated falciparum malaria.

Artemeter-Lumefantrine is co-formulated hence it is less

likely to be misused as monotherapy unlike the co-

3

for malaria control.

8

packaged ACTs. However, its use as the drug of choice

In Nigeria, about 50% of the population suffers at least

one episode of malaria every year and malaria accounts

for over 45 per cent of all out-patient visits. The disease

accounts for 25 % infant and 30 % childhood mortality

in the country. Results of randomized control trials

conducted in different parts of the world including Nige-

in Nigeria can be limited by partial adherence with the

recommended 6 dose regimen and the interval of 8 hours

between the first and the second dose, 24 hours between

the first and the third dose, and 12 hourly intervals be-

tween the remaining doses. The main concern of AL use

is its timed dosage multi-dose schedule, raising the

4

1

46

question of whether it will remain effective when used

on an unsupervised basis in the community.

to enrolment.

The intervention: was a co-formulated preparation of

Artemether (20mg) and Lumefantrine (120mg) in each

tablet presented in a blister form. The dosing schedule

requires intervals of 0, 8, 24, 36, 48 and 60 hours, the

interval between the first two doses are crucial to the

eventual outcome of treatment. The blister pack contains

pictures and instructions on how the drug should be ad-

ministered. The dosage is based on the child’s weight.

The detail of the dosage of AL is shown in Table 1.

The effectiveness of an intervention is the ability to

achieve the desired aim when used in an unsupervised

setting and it depends on compliance with the recom-

1

0

mended treatment regimen. Poor adherence is likely to

decrease treatment effectiveness and expose the parasite

to sub-therapeutic drug levels which may favour devel-

1

0

opment of resistance to the drug. Most clinical trials

assess the efficacy and safety of drugs under supervised

settings. The cure rate of a drug reported from clinical

trial may not be the same as that observed under routine

out patient conditions. Since there could be differences

between the efficacy of a drug during clinical trial and

its effectiveness on routine use, it is important to assess

the effectiveness of AL, the first line anti-malarial drug

presently in use in Nigeria.

Table 1: Dosage schedule of artemether-lumefantrine

Number of tablets/recommended time of administration

Day 0

Day 1

Day 2

Weight

(kg)

0

Hours

8

Hours

24

Hours

36

Hours

48

Hours

60

Hours

5

1

2

– 15

5 – 25

5 – 35

1

2

3

1

2

3

1

2

3

1

2

3

1

2

3

1

2

3

The aim of this study was to assess the effectiveness of

AL under routine outpatient conditions in the treatment

of uncomplicated malaria in under-five children.

> 35

4

Drug administration: Once a participant was enrolled,

the first dose of AL was administered to the patient in

the health facility under the supervision of the study

nurse. The child was then observed for 30 minutes in the

health facility. If the child vomited within this period,

another dose was given and the participant observed for

another 30 minutes. A child that vomited two or more

times within one hour of commencement of drug ad-

ministration was classified as repeated vomiting and

withdrawn from the study. Such participant was referred

to the next level of care for treatment with parenteral

antimalarial. Those that tolerated the first dose were sent

home with further instructions on how to administer the

remaining doses. Emphasis was laid on the importance

of giving the second dose eight hours after the first dose,

then two doses per day in the morning and evening for

the following two days. Parents/guardians were also

informed that the drug is best given with fatty foods or

shortly after breastfeeding for children that were still

breastfeeding.

Methods and Patients

Design: This was an open label non-randomized trial to

determine the effectiveness of AL for treating uncompli-

cated P. falciparum malaria in children aged 6 to 59

months.

Study Population: The study was conducted over 13

month period from June 2006 to June 2007. Children

with features suggestive of uncomplicated malaria, at-

tending the outpatient clinic at a Health Centre in Ikot

Ansa, Calabar Municipality, South Eastern Nigeria were

screened for inclusion.

Inclusion criteria: Participants were eligible for inclu-

sion if they were between 6 and 59 months old, had fe-

ver (axillary temperature ≥ 37.5°C) or history of fever in

the past 24 hours with P. falciparum asexual parasites

between 1000 and 250,000/ꢀL. In addition, participants

were resident in the study area to be eligible for enrol-

ment. Finally, a signed informed consent was mandatory

for inclusion in the study.

Clinical Assessments: Clinical assessments include

history of illness, measurement of axillary temperature

and weight of participants on day 0 and during follow up

visits on days 7, 14 and 28. Patients were not reviewed

on Days 1, 2 and 3 so as not to induce adherence to the

drug. Guardians/parents were advised to bring back the

participant to the health facility if the health condition

deteriorated. Participants that were not brought on

schedule for follow-up visits were visited at home the

same day and where that was not possible within two

days after the scheduled visit date. Rescue medication

for this study was quinine in line with the Nigerian na-

tional malaria treatment guidelines.

Exclusion criteria: Participants were excluded if there

was known allergy to any of the study drug components,

vomiting study drug two or more consecutive times;

packed cell volume <15%, other manifestation of com-

plicated malaria and any other danger sign of childhood

illness such as severe malnutrition, not able to sit, stand

or drink, recent history of convulsion, lethargic or un-

consciousness.

Laboratory investigation: Thick and thin blood film

specimens were used to screen for presence of malaria

parasites. During each visit, blood smears were col-

lected, prepared and stained in 3% Giemsa solution for

The Ethical Review Committee of the University of

Calabar Teaching Hospital approved the protocol for the

study. A written informed consent was obtained from

each parent/legal guardian of eligible participants prior

3

0 minutes. Smears were read to 100 fields with quanti

1

47

quantification of P. falciparum asexual parasites on the

thick smear (per uL) and gametocytes (number per 1000

white cell count). Parasites were enumerated using thick

film as described by Shute. Parasite density was calcu-

lated, assuming a normal leucocyte level of 8,000/ꢀl.

The thin film was used to speciate the parasites. Packed

cell volume was determined on days 0, 14 and 28 with

sample collected in a heparinized capillary tube and cen-

trifuged for 5 minutes at 10,000 G.

Analysis: Endpoints were assessed based on intention to

treat analysis. Data generated were recorded in a log

book and individual patient’s case record files and later

double - entered into EPI-Info version 3.5.1 software.

Data was analyzed on the same software.

1

Results

General characteristics

Withdrawals: Participants who were lost to follow up

or those that withdrew consent were classified as with-

drawals from the study. Also, participants who took

other anti-malarial drugs during this period were with-

drawn from the study. All withdrawals were followed up

for safety except those that were lost to follow up.

One thousand and thirty five children were screened for

eligibility, of whom 215 (20.7%) were enrolled. Base-

line characteristics are shown in Table 3.

Table 3: Baseline Characteristics of patients

Characteristics

Mean (SD) N=215

Outcome measures: Therapeutic efficacy was assessed

on follow up visits using WHO guidelines for as₁s₂essing

therapeutic efficacy in intense transmission areas.

Primary outcome measures were

Age in years(mean ± SD)

Males (%)

Females (%)

Height in cm (Mean ± SD)

Weight in Kg (Mean ± SD)

2.50±1.70

123 (57.2)

92 (42.8)

91.7 (13.2)

12.7 (3.2)

•

Day 28 cure rate: adequate clinical and parasitologi-

cal cure rate (ACPR)

Treatment failures which could be

Axillary Temperature (Mean ± SD)ºC

Packed Cell Volume Day 0

Mean parasite density in µL (range)

37.6 (1.14)

28.0 (4.9)

35,312 (1,009-228,889)

1

2

3

.

Early treatment failure (ETF)

Late clinical failure (LCF)

Late parasitological failure (LPF)

Enrolment and follow-up: Figure 1 shows the patient

flow from screening, treatment, follow-up to comple-

tion. Four hundred and ten (50%) of the 820 excluded

patients were due to use of anti-malarial drug within two

weeks of screening. There were 22 withdrawals in this

study as follows; 18 were lost to follow up (traveled out

of study area), 3 violated protocol (took anti-malarials

outside study drug) and one withdrew consent. A total of

•

Adherence to recommended treatment schedule.

Secondary outcome measure was safety and tolerability.

Safety and tolerability was evaluated by the risk of

occurrence of an adverse event (AE), classified as mild,

moderate, severe or serious. A serious adverse event was

defined as any AE resulting in death or in persistent or

significant disability/incapacity, life-threatening, requir-

ing hospitalization or significant medical intervention to

prevent serious outcome. Presence of adverse events

was assessed based on the assessment given by the

mother or guardian.

1

93 (89%) participants completed the study and had

adequate data for analysis of the study outcomes.

Fig 1: Patient flow diagram for the study

Trial Flow Diagram

Enrollment

Assessed for eligibility (n=1035)

Table 2: Definition of therapeutic efficacy measures

Therapeutic

outcome meas-

ure

Definition of term

Excluded (n=820)

Not meeting inclusion criteria:

Adequate clini-

cal and parasi-

tological re-

sponse (ACPR)

Early treatment

failure (ETF)

Absence of parasitaemia on Day 28 irrespective of

axillary temperature without previously meeting any

of the criteria of Early Treatment Failure, Late

Clinical Failure and Late Parasitological Failure

Development of danger signs or severe malaria on

Days 1, 2 or 3 in the presence of parasitaemia, or

parasitaemia on Day 2 higher than Day 0 count

irrespective of axillary temperature, or parasitaemia

•Anti-malarial within 2 weeks = 410

•

low parasite density/others = 409

Allocated to intervention (n = 215)

Allocation

• Received allocated intervention (n= 214)

Did not receive allocated intervention

incomplete treatment dose) (n=1)

o

on Day 3 with axillary temperature ≥ 37.5 C, or

parasitaemia on Day 3 > 25%of Day 0 count irre-

spective of axillary temperature.

•

(

Late clinical

failure (LCF)

Development of danger signs or severe malaria and /

or axillary temperature ≥ 37.5 C on any day from

Day 4 to Day 28 in the presence of parasitaemia

without previously meeting any of the criteria for

Early Treatment Failure

o

Lost to follow-up (travelled out of area) = 18

Discontinued intervention (withdrew consent) =1

Follow-Up

Analysis

Late parasi-

tological failure

The presence of parasitaemia from Day 4 to Day 28

o

and axillary temperature < 37.5 C without previ-

Analysed (n= 193)

(

LPF)

ously meeting any of the criteria for Early Treatment

Failure or Late Clinical Failure

•Excluded from analysis (had other anti-malarial

drug during follow-up) (n=3)

1

48

Treatment outcome: Table 4 shows the results of the

8-day therapeutic efficacy of AL. The number of evalu-

able participants with adequate clinical and parasitologi-

cal response (ACPR) was 175 (90.7%). Late clinical

failure (LCF) was observed in 5 participants. There were

In this study, 97.6% of the caregivers adhered to the

dosage recommendation. Since the effectiveness of any

drug combination therapy is dependent on adherence

2

1

0

with the treatment regimen, it is assumed that the effi-

cacy reported in this study is as a result of acceptable

compliance with the treatment regimen. It therefore ap-

pears that majority of caregivers in this locality adhere

to the 6 doses of AL although it is difficult to say

whether they observe the 8 hours interval between the

1

2

1 late parasitological failures; 2 on Day 14, 2 on Day

5 and 7 on Day 28.

Assessment of patient adherence to treatment: Out of

the 215 enrolled participants empty blisters were re-

turned for 210 suggesting that most of the participants

1

3

first and the second doses. In the study by Ajayi et al ,

average adherence for the 3 countries that participate₁₆d in

the study was 94%. However, Depoortere et al in

southern Sudan reported that 18.3% of the participants

were ‘not adherent’ to the dosage schedule. However, in

their study emphasis was placed on giving the drug with

milk or fatty foods and some of the caregivers did not

administer the drug because of lack of milk or fatty food

to precede the drug. In this study, emphasis was not

placed on giving drug with milk or fatty food because an

earlier efficacy test in the same centre did not lay em-

phasis on the dietary component and the cure rate ob-

tained₈in this study is similar to that of the previous

study.

(

97.6%) adhered to the recommended dosage schedule.

Caregivers were interviewed to ascertain how and when

drugs were given to child. Four caregivers reported that

they had misplaced the empty blisters hence did not re-

turn them. One parent did not return the blister becaus_te_h

the child improved so she reserved the last 2 doses (5

th

and 6 dose) for next episode of malaria attack.

Table 4: Effectiveness of unsupervised artemether-

lumefantrine

Number of

Treatment Outcome

Participants

Percent

Day-28 cure (Adequate clinical and

parasitological response - ACPR)*

Late clinical failure (LCF)

Several factors may have contributed to the high adher-

ence observed in this study. Firstly, the fact that caregiv-

ers were required to return the empty blisters on day 7

may have played an indirect role in enhancing adher-

ence. Secondly, the packaging of the drug might also

have promoted adherence. The sealed-blister design

contains visual depictions of time inte₁r₆v_,₁a₇ls and number

175

7

11

90.7%

3.6%

5.7%

Late parasitological failure (LPF)

*PCR confirmation not used.

Adverse Events: There were 48 mild adverse events

during the study; the most common were cough (7.0%)

and vomiting study drug at least once (7.0%). Others

were catarrh (2.3%), headache (2.3%), abdominal pain

of tablets to be taken by the patients.

However, the

packaging is universal and available to non-study par-

ents, hence it is considered an important aid by the

manufacturers to promote adherence. Also the added

verbal explanation by the team membe₁r₇s to caregivers

have been shown to improve adherence.

(

1.3%) and rashes (1%). No serious adverse event was

observed in any of the study participants.

Change in Haemoglobin: The packed cell volume in-

creased in all participants by the end of the follow up

period. The mean haematocrit value increased from 28%

at baseline (Day 0) to 33% on Day 28.

AL was well-tolerated with no serious adverse events

and only few mild adverse events in this study further

confirms the safety of the c₈o_,₁m₈ bination. This has been

documented by other studies.

The limitations of this study include the non-randomized

design, and the absence of a comparator. Also, the small

sample size of the study makes generalization difficult.

On the other hand, polymerase chain reaction was not

used to differentiate actual parasitological failures

Discussion

This study has shown that Artemeter-Lumefantrine is

effective with a cure rate of 90.7% when administered in

unsupervised setting. Reports from a multicentre study

on the effectiveness of home management of malaria in

which Nigeria was one of the s₃tudy sites gave a PCR-

(

recrudescence) from new infections hence day-28 cure

rate could have been higher than reported. Finally, the

adherence observed in this semi-urban setting cannot be

generalized to the typical rural communities.

1

corrected cure rate of 90.9%, The cure rate of this

study though uncorrected for reinfection is similar to the

PCR –corrected cure rate of the multi-centre study. In a

randomized ₄trial of effectiveness of AL in Ghana,

1

Kobbe et al reported parasitological cure rate of 88.3%

Conclusion

for AL, which is similar to the findings of this study.

However, in a report from Uganda, higher cure rate of

Despite the complexity of the 6 dose AL regimen, the

high day 28 parasitological cure in this and other studies

shows that the drug is effective when used in unsuper-

vised outpatient settings in Nigeria, even among care-

givers with low level of education. It is important for

9

8.0% was ob₅served when AL was given in unsuper-

1

vised setting. It therefore appears that the drug has

satisfac₁t₃o_-₁r₅y_.efficacy even when used in an unsupervised

setting.

1

49

healthcare providers to give sufficient explanation on the

correct method of administering drugs to caregivers. We

recommend multicentre, randomized trials with larger

sample sizes across the country to confirm the effective-

ness of artemether-lumefantrine as this is essential to

help ensure long-term treatment efficacy for the popula-

tion.

OO: Data collection and manuscript writing

All authors read and approved the final version of

manuscript

Conflict of interest: None

Funding: The project was funded by the Institute of

Tropical Diseases Research and prevention, University

of Calabar Teaching Hospital

Authors contributions

FO: Contributed in protocol writing, coordi nated da

collection and writing of manuscript.

Acknowledgements

MM: Conceptualized and directed the study, supervised

the analysis, preparation of manuscript.

CO: Data collection and wrote initial draft of manuscript

AO: Data analysis and input to manuscript writing

EU: Data collection and contributed to manuscript

writing

The contribution of the following is acknowledged: Mi-

croscopist (Vivian Asiegbu), Nurses (Nnanke Okoi,

Ofonime Akpabio and Esther Ibe), Clinician (Emmanuel

Onyenuche, Elemi Iwasam), Follow up (Friday Odey,

Asa Martins). With fond memory, we acknowledge the

contribution of Late Mr. Ime Mkpang to this study, He

was a committed and experienced microscopist.

KE: Contributed in manuscript development

References

1

.

The World Bank Group: African

Region Findings. The Roll Back

Malaria Partnership: Defining the

role of the World Bank, No. 44.

8. Meremikwu M, Alaribe A, Ejemot

R, Oyo-ita A, Ekenjoku J,

Nwachukwu C, Ordu D,

14. Kobbe R, Klein P, Adjei S, Ame-

masor S, Thompson WN, Heide-

mann H, Nielsen MV, Vohwinkel

J, Hogan B, Kreuels B, Bührlen M,

Loag W, Ansong D, May J. A

randomized trial on effectiveness

of artemether-lumefantrine versus

artesunate plus amodiaquine for

unsupervised treatment of uncom-

plicated Plasmodium falciparum

malaria in Ghanaian children. Ma-

laria J. 2008, 7:261. http://

Ezedinachi E. Artemether-

1

999

lumefantrine versus Artesunate

plus Amodiaqune for treating

uncomplicated childhood malaria

in Nigeria: Randomized controlled

trial. Malaria J. 2006; 5: 43-49

9. FMOH. Federal Ministry of Health

national antimalarial treatment

Policy. Abuja. 2005

2

3

.

World Health Organization. The

Africa Malaria Report, Geneva:

World Health Organization 2003.

WHO, 2001: Anti-malarial drug

combination therapy: Report of a

WHO technical consultation

[document Who/CDS/

RBM/2001.35]. Geneva.

10. White NJ, Olliaro PL. Strategies

for prevention of antimalarial drug

resistance: rationale for combina-

tion therapy for malaria. Parasitol

Today. 1996; 12:399-401

11. Shute GT. The microscopic diag-

nosis of malaria. In principle and

practice of malariology, Edited by:

Wernsdorfer, McGregor L. Edin-

burgh: Churchhill Livingstone.

1998:781-814.

12. WHO 2003. Assessment and

monitoring of antimalarial drug

efficacy for the treatment of un-

complicated falciparum malaria

WHO/HTM/RBM. 2003. 50. Ge-

neva

13. Ajayi IO, Browne EN, Bateganya

F, Yar D, Happi C, Falade CO,

Gbotosho GO, Yusuf B, Boateng

S, Mugittu K, Cousens S,

www.malariajournal.com/

content/7/1/261

4

5

.

Federal Ministry of Health. Na-

tional Strategic Plan for Roll Back

Malaria in Nigeria-Abuja 2001.

Hutagalong R, Paiphun L, Ashley

EA, McGready R, Brockman A,

Thwai KL, Singhasivanon P,

Jelinek T, White NJ, Nosten FH. A

randomized trial of artemether-

lumefantrine for treating of un-

complicated multi-resistant Plas-

modium falciparum on the western

border of Thailand. Malaria J.

15. Piola P, Frogg C, Bajuniwe F,

Biraro S, Grandesso F, Ruzagira E,

Babigumira J, Kigozi I, Kiguli J,

Kyomuhendo J, Ferradini L, Tay-

lor W, Checchi F, Guthman J.

Supervised versus unsupervised

intake of six dose artemether-

lumefantrine for treating of acute

uncomplicated Plasmodium falci-

parum in Mbara, Uganda. A ran-

domized trial. Lancet. 2005; 363:

1467-1473

16. Depoortere E, Salvador ET, Sti-

vanello E, Bisoffi Z, Guthmann JP.

Adherence to a combination of

artemether and lumefantrine

(Coartem) in Kajo Keji, southern

Sudan. Ann Trop Med Parasitol.

2004; 98, 635–637

17. Qingiun L, Jihui D, Laiyi T, Xian-

giun Z, Jun L, Hay A, Shires S,

Navaratnam V. The effect of drug

packaging on patient’s adherence

with treatment for plasmodium

vivax malaria in china. Bull World

Health Organization. 1998; 76: 21-27

8. Bakshi R, Hermeling-Fritz I, Gath-

mann I, Alteri E. An integrated

assessment of the clinical safety of

artemether-lumefantrine: a new oral

fixed-dose combination antimalarial

drug. Trans R Soc Trop Med Hyg.

2

005; 4:46-52

6

7

.

Van Vugt M, Looareesuwan S,

Wilairatana P, McGready R,

Villegas L, Gathmann L, Mull R,

Brockman A, White NJ, Nosten F.

Artemether-lumefantrine for the

treatment of multidrug-resistant

falciparum malaria. Trans R Soc

Trop Med Hyg. 2000; 94: 545-548

Martensson A, Stromberg J, Siso-

wath C, Msellem MI, Gil JP,

Montgomery SM, Olliaro P, Ali

AS, Bjorkman A. Efficacy of ar-

tesunate plus amodiaquine versus

that of artemether-lumefantrine for

the treatment of uncomplicated

childhood Plasmodium falciparum

malaria in Zanibar, Tanzania. Clin

Infect Dis. 2005; 41: 1079-1086

Nanyunja M, Pagnoni F. Effective-

ness of artemisinin-based combi-

nation therapy used in the context

of home management of malaria:

A report from three study sites in

sub-Saharan Africa. Malaria J.

2008, 7:190. http://

1

www.malariajournal.com/

content/7/1/190

2

000; 94: 419–24.