Atovaquone‐proguanil for treating uncomplicated Plasmodium falciparum malaria

Andrew Blanshard; Paul Hine

doi:10.1002/14651858.CD004529.pub3

. 2021 Jan 18;2021(1):CD004529. doi: 10.1002/14651858.CD004529.pub3

Atovaquone‐proguanil for treating uncomplicated Plasmodium falciparum malaria

Andrew Blanshard ¹, Paul Hine ^2,^✉

Editor: Cochrane Infectious Diseases Group

PMCID: PMC8094970 PMID: 33459345

Abstract

Background

The World Health Organization (WHO) in 2015 stated atovaquone‐proguanil can be used in travellers, and is an option in malaria‐endemic areas in combination with artesunate, as an alternative treatment where first‐line artemisinin‐based combination therapy (ACT) is not available or effective. This review is an update of a Cochrane Review undertaken in 2005.

Objectives

To assess the efficacy and safety of atovaquone‐proguanil (alone and in combination with artemisinin drugs) versus other antimalarial drugs for treating uncomplicated Plasmodium falciparum malaria in adults and children.

Search methods

The date of the last trial search was 30 January 2020. Search locations for published trials included the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, and LILACS. To include recently published and unpublished trials, we also searched ClinicalTrials.gov, the metaRegister of Controlled Trials and the WHO International Clinical Trials Registry Platform Search Portal.

Selection criteria

Randomized controlled trials (RCTs) reporting efficacy and safety data for atovaquone‐proguanil or atovaquone‐proguanil with a partner drug compared with at least one other antimalarial drug for treating uncomplicated Plasmodium falciparum infection.

Data collection and analysis

For this update, two review authors re‐extracted data and assessed certainty of evidence. We meta‐analyzed data to calculate risk ratios (RRs) with 95% confidence intervals (CI) for treatment failures between comparisons, and for safety outcomes between and across comparisons. Outcome measures include unadjusted treatment failures and polymerase chain reaction (PCR)‐adjusted treatment failures. PCR adjustment differentiates new infection from recrudescent infection.

Main results

Seventeen RCTs met our inclusion criteria providing 4763 adults and children from Africa, South‐America, and South‐East Asia. Eight trials reported PCR‐adjusted data to distinguish between new and recrudescent infection during the follow‐up period. In this abstract, we report only the comparisons against the three WHO‐recommended antimalarials which were included within these trials.

There were two comparisons with artemether‐lumefantrine, one trial from 2008 in Ethiopia with 60 participants had two failures with atovaquone‐proguanil compared to none with artemether‐lumefantrine (PCR‐adjusted treatment failures at day 28). A second trial from 2012 in Colombia with 208 participants had one failure in each arm (PCR‐adjusted treatment failures at day 42).

There was only one comparison with artesunate‐amodiaquine from a 2014 trial conducted in Cameroon. There were six failures with atovaquone‐proguanil at day 28 and two with artesunate‐amodiaquine (PCR‐adjusted treatment failures at day 28: 9.4% with atovaquone‐proguanil compared to 2.9% with artesunate‐amodiaquine; RR 3.19, 95% CI 0.67 to 15.22; 1 RCT, 132 participants; low‐certainty evidence), although there was a similar number of PCR‐unadjusted treatment failures (9 (14.1%) with atovaquone‐proguanil and 8 (11.8%) with artesunate‐amodiaquine; RR 1.20, 95% CI 0.49 to 2.91; 1 RCT, 132 participants; low‐certainty evidence).

There were two comparisons with artesunate‐mefloquine from a 2012 trial in Colombia and a 2002 trial in Thailand where there are high levels of multi‐resistant malaria. There were similar numbers of PCR‐adjusted treatment failures between groups at day 42 (2.7% with atovaquone‐proguanil compared to 2.4% with artesunate‐mefloquine; RR 1.15, 95% CI 0.57 to 2.34; 2 RCTs, 1168 participants; high‐certainty evidence). There were also similar PCR‐unadjusted treatment failures between groups (5.3% with atovaquone‐proguanil compared to 6.6% with artesunate‐mefloquine; RR 0.8, 95% CI 0.5 to 1.3; 1 RCT, 1063 participants; low‐certainty evidence).

When atovaquone‐proguanil was combined with artesunate, there were fewer treatment failures with and without PCR‐adjustment at day 28 (PCR‐adjusted treatment failures at day 28: 2.16% with atovaquone‐proguanil compared to no failures with artesunate‐atovaquone‐proguanil; RR 5.14, 95% CI 0.61 to 43.52; 2 RCTs, 375 participants, low‐certainty evidence) and day 42 (PCR‐adjusted treatment failures at day 42: 3.82% with atovaquone‐proguanil compared to 2.05% with artesunate‐atovaquone‐proguanil (RR 1.84, 95% CI 0.95 to 3.56; 2 RCTs, 1258 participants, moderate‐certainty evidence). In the 2002 trial in Thailand, there were fewer treatment failures in the artesunate‐atovaquone‐proguanil group compared to the atovaquone‐proguanil group at day 42 with PCR‐adjustment.

Whilst there were some small differences in which adverse events were more frequent in the atovaquone‐proguanil groups compared to comparator drugs, there were no recurrent associations to suggest that atovaquone‐proguanil is strongly associated with any specific adverse event.

Authors' conclusions

Atovaquone‐proguanil was effective against uncomplicated P falciparum malaria, although in some instances treatment failure rates were between 5% and 10%. The addition of artesunate to atovaquone‐proguanil may reduce treatment failure rates. Artesunate‐atovaquone‐proguanil and the development of parasite resistance may represent an area for further research.

Plain language summary

What are the benefits and risks of atovaquone‐proguanil for treating uncomplicated malaria caused by the Plasmodium falciparum parasite?

What is the aim of this review?

The most common, and most serious, type of malaria is caused by Plasmodium falciparum. In its mild (uncomplicated) form, the symptoms are fever, headaches, muscle pain, and vomiting. The disease can become severe and life‐threatening if it is not treated soon enough or with the right medicines.

This review aimed to find out whether atovaquone‐proguanil is effective and safe for treating uncomplicated cases of P falciparum malaria. We aimed to achieve this by comparing the results of studies that had compared atovaquone‐proguanil to other malaria treatments.

Key messages

Atovaquone‐proguanil is as effective for treating uncomplicated Plasmodium falciparum malaria as artesunate‐mefloquine. It may be less effective than artemether‐lumefantrine, artesunate‐amodiaquine, and artesunate‐atovaquone‐proguanil, though more robust evidence is needed to confirm this. Side effects seem similar with atovaquone‐proguanil.

What was studied in this review?

The World Health Organization (WHO) recommends treating uncomplicated malaria with oral (by mouth) artemisinin‐based combination medicines (called ACTs).

ACTs are not always available worldwide and, in some places, Plasmodium falciparum is becoming resistant to recommended treatments (the medicines stop working). We looked at the evidence about the benefits and harms of combinations of medicines that are not artemisinin‐based, but contain atovaquone‐proguanil. This is an oral treatment commonly used by people from non‐malaria areas to prevent them catching malaria when they travel to malaria areas. We wanted to find out whether it works as well for treating uncomplicated Plasmodium falciparum malaria as ACTs and other malaria treatments.

We searched for randomized controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) that compared atovaquone‐proguanil against other malaria treatments. These studies provide the most robust evidence about the effects of a treatment. We compared results, summarized the evidence, and rated our confidence in the evidence.

What are the main results of the review?

We found 17 studies involving 4763 adults and children in Africa, South America, and South East Asia. People were followed for 28 days to one year.

Fifteen studies compared atovaquone‐proguanil against 12 different antimalarial treatments (ACTs in five studies; other therapies that combined several medicines in two studies; single medicines in nine studies).

Five studies compared atovaquone‐proguanil plus another medicine (artesunate or chloroquine) against atovaquone‐proguanil alone (three studies); atovaquone‐proguanil plus a different medicine (one study); a combination of therapies that did not include atovaquone‐proguanil (one study); or single medicines (two studies).

In 15 studies, the researchers and people who were treated knew which medicines participants received. Pharmaceutical companies funded 10 studies.

Atovaquone‐proguanil against ACTs recommended by the WHO

Atovaquone‐proguanil may work less well to clear Plasmodiumfalciparum parasites from the blood or prevent them from returning (treatment success) than artemether‐lumefantrine (rates of success compared 28 and 42 days after treatment; one study). However this evidence was based on one small study.

Atovaquone‐proguanil may work as well as, or less well than, artesunate‐amodiaquine depending on whether new infections appearing after the start of treatment were counted or not (rates of success compared three and 28 days after treatment; one study). However this evidence was based on one small study of children aged under five years.

When new infections after the start of treatment were excluded, there is strong evidence of little to no difference in treatment success between atovaquone‐proguanil and artesunate‐mefloquine after 42 days (two studies). When new infections were counted, atovaquone‐proguanil may be better than artesunate‐mefloquine, but this evidence was based on the imprecise results of one study.

Atovaquone‐proguanil against atovaquone‐proguanil plus artesunate

Compared to atovaquone‐proguanil plus artesunate, atovaquone‐proguanil may be less successful at treating uncomplicated malaria after three and 28 days, however this evidence is based on the results of two small studies. It is probably less successful at treating uncomplicated malaria after 42 days (two studies).

Side effects

Studies reported several side effects, such as nausea and vomiting, or headaches. Overall, they were similar between groups.

How‐up‐to date is this review?

The evidence is current to 30 January 2020.

Summary of findings

Background

Description of the condition

Plasmodium falciparum is the most important of all species of malaria. In 2016, it was responsible for 99% of malaria cases in the World Health Organization (WHO) African region, and 66% in the South‐East Asia region (WHO 2017).

Uncomplicated malaria is defined by the absence of clinical features that define severe malaria in the presence of an asexual P falciparum parasitaemia (WHO 2015). Severe malaria is defined as a P falciparum parasitaemia with one or more of: impaired consciousness, prostration, multiple convulsions, acidosis, hypoglycaemia, severe malarial anaemia, renal impairment, jaundice, pulmonary oedema, significant bleeding, shock, or a parasitaemia greater than 10%.

The first‐line treatment for uncomplicated P falciparum malaria is artemisinin‐based combination therapy (ACT) (WHO 2015). The artemisinin component rapidly clears parasites from the blood. It is active against some sexual stages of the parasite, particularly immature gametocytes. This property helps reduce post‐treatment malaria transmission. The partner drug is longer acting and protects the artemisinin component from resistance. Those with longer half‐lives also provide post‐treatment prophylaxis against reinfection.

Artemisinin resistance has emerged in South East Asia; initially in Western Cambodia (Noedl 2008), but has since become prevalent in Laos, Myanmar, Thailand, and Vietnam (the Greater Mekong subregion). Genetic mutations associated with artemisinin resistance in these areas have also been detected at significant prevalence (greater than 5%) in Guyana, Papua New Guinea, and Rwanda, although the clinical significance is uncertain (WHO 2019). Historically, chloroquine‐resistant malaria emerged in the Greater Mekong subregion, an area of low transmission. It has since spread through Asia and Africa. Further spread of artemisinin resistance could lead to higher mortality from malaria (Lubell 2014).

Description of the intervention

Atovaquone‐proguanil is commonly used to prevent malaria when travelling (ACMP 2017). It is a 'causal' prophylactic agent, meaning that it inhibits liver stage development of malaria. This means that it needs to be taken only for one week after travel to endemic areas (rather than four weeks, as for doxycycline or mefloquine).

The WHO also supports use of atovaquone‐proguanil outside malaria‐endemic areas and in combination with artesunate and primaquine as an alternative treatment where first‐line ACT is not available or effective (WHO 2015). It has been used in areas where there are high rates of treatment failure associated with artemisinins (WHO 2012), and as such it is important to understand how it compares to ACTs and other antimalarials. The high cost of atovaquone‐proguanil has limited its use for treatment, and a public‐private partnership to provide the drug for free was short‐lived due to concerns about poor use of resources (Oyediran 2002). While atovaquone‐proguanil was previously only available as Malarone, it is now available off‐licence in generic formulations.

How the intervention might work

Atovaquone selectively inhibits electron transport in the malarial cytochrome b complex. Proguanil hydrochloride mainly acts via the metabolite cycloguanil, a dihydrofolate reductase inhibitor. Proguanil's main effect is to potentiate atovaquone, rather than having direct antimalarial activity. As such, although it has two components, atovaquone‐proguanil is not a combination equivalent to ACT, in which two antimalarial drugs with different modes of action, are combined.

Resistance to atovaquone is a potential barrier to its widespread use. Resistance predominantly emerges rapidly via single point mutations in the malarial cytochrome b gene (Blasco 2017). Animal studies suggest that resistance may be non‐transmissible as the mutation significantly reduces parasite fitness (Goodman 2016). Therefore, it is likely that resistance usually originates in the parasite from de novo mutations, rather than being spread between mosquitoes and humans.

Atovaquone is poorly absorbed, though proguanil is rapidly absorbed from the gastrointestinal tract. The elimination half‐life of atovaquone is about two days to three days in adults, and of proguanil is 12 hours to 15 hours in adults (WHO 2015). These elimination half‐lives are longer than artemisinins, similar to lumefantrine and sulfadoxine‐pyrimethamine, but shorter than mefloquine or piperaquine.

Why it is important to do this review

This review is an update of a Cochrane Review first published in 2005 (Osei‐Akoto 2005). The previous review included 10 randomized controlled trials (RCTs) and concluded that there was some evidence that atovaquone‐proguanil was superior to chloroquine, mefloquine, and amodiaquine, but that there was insufficient data for other comparisons. The authors recommended larger trials comparing atovaquone‐proguanil with new combination therapies.

A 2017 non‐Cochrane systematic review aimed to estimate efficacy of atovaquone‐proguanil for treatment of uncomplicated malaria (including, but not limited to P falciparum) (Staines 2017). This included one study (Bustos 1999), which the original authors of this Cochrane Review excluded due to protocol amendments. Staines 2017 also excluded one study included in the previous Cochrane Review (Van Vugt 2002), but the reason for this was unclear. The analysis combined RCTs and observational studies, and used single‐arm weighted means to estimate atovaquone‐proguanil treatment efficacy. The authors used the outcome of 'treatment success at day 28', but it was unclear how this outcome was defined. Within their discussion, the authors state that "meta‐analysis suggests that atovaquone‐proguanil treatment success is equivalent to the use of ACT". Given the strength of this conclusion, we considered it would be useful to re‐evaluate the evidence using updated Cochrane methodology.

Since the last update in 2005, the Cochrane Review process has evolved. An updated review will benefit from GRADE methodology, which will allow greater clarity for the assessment of the certainty of evidence. Inclusion of 'Summary of findings' tables will help to frame conclusions with clear indications to the reader regarding the certainty of evidence presented.

This remains an important and relevant area, particularly in the context of evolving antimalarial drug resistance.

Objectives

Methods

Criteria for considering studies for this review

Types of studies

RCTs.

Types of participants

Children and adults with uncomplicated P falciparum malaria confirmed by microscopy or rapid diagnostic tests in all geographical locations.

Types of interventions

Intervention

Atovaquone‐proguanil, alone or in combination with other antimalarials.

Control

Other antimalarial drugs, alone or in combination with other antimalarials.

Types of outcome measures

We collected data on both primary and secondary outcome measures.

Primary outcomes

Total treatment failure at day 28 (polymerase chain reaction (PCR)‐adjusted and unadjusted).
Total treatment failure at day 42 (PCR‐adjusted and unadjusted).

We based these primary outcome measures on WHO recommendations (WHO 2003; WHO 2009), which advise a 28‐day follow‐up to capture most failures, and 42‐day follow‐up to capture failures for drugs with a longer elimination half‐life (mefloquine and piperaquine). PCR adjustment differentiates recrudescent infections from new infections during follow‐up but may misclassify. Unadjusted treatment failure helps indicate the post‐treatment prophylactic effect of partner drugs. Including both measures helps inform policy makers, and these outcomes are also consistent with previous Cochrane Reviews.

We did not use adequate clinical and parasitological response (ACPR) as this is defined as absence of failure and is, therefore, duplication.

Secondary outcomes

Early treatment failure (WHO 2009):
- danger signs or severe malaria on days one, two, or three in the presence of parasitaemia;
- parasitaemia on day two higher than on day zero, irrespective of axillary temperature;
- parasitaemia on day three with axillary temperature 37.5 °C or greater; and
- parasitaemia on day three 25% or greater of count on day 0.

It is important to include data for parasitaemia on day three as this is both part of the standardized definition for treatment response used for all levels of malaria transmission, and it is regarded as an indirect marker of artemisinin resistance (WHO 2009; WHO 2011).

Adverse events

Serious adverse events (including death, life‐threatening events, hospitalization, and disability).
Adverse events leading to withdrawal from the trial.
Other adverse events.

Search methods for identification of studies

We aimed to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress). We searched for relevant trials on 10 January 2018, 14 January 2019 and 30 January 2020.

Electronic searches

The authors of the review and the Cochrane Infectious Disease Group information specialist Vittoria Lutje (VL) attempted to identify all relevant trials. We searched the following databases using the search terms and strategy described in Appendix 1:

Cochrane Infectious Diseases Group (CIDG) Specialized Register;
Cochrane Central Register of Controlled Trials (CENTRAL);
MEDLINE;
Embase;
LILACS.

We searched ClinicalTrials.gov, the metaRegister of Controlled Trials and the WHO International Clinical Trials Registry Platform Search Portal for ongoing or recently completed trials. The date of the last search was 30 January 2020.

Searching other resources

To identify additional published, unpublished, and ongoing studies, we checked the reference lists of all studies identified.

The original authors of this review circulated a list of identified studies to individual researchers working in the field and to the drug manufacturer to help identify additional trials and provide information on ongoing trials (Osei‐Akoto 2005). We did not do this and did not search conference abstracts or proceedings because improved trial methods and search methodology means that relevant trials are more readily found through electronic databases.

Data collection and analysis

Selection of studies

For this update, two review authors (AB and PH) independently screened newly identified articles by title and abstract to assess if they met the inclusion criteria. There were no disagreements. We documented the reason for excluding trials in the Characteristics of excluded studies table. We presented an adapted PRISMA flow diagram for review updates, following standard guidance (Mohor 2009; Stovold 2014).

Data extraction and management

Due to changes in the primary and secondary outcomes of the review compared to the previous version and to ensure consistency, two review authors (AB and PH) independently re‐extracted all data using a standardized form.

Unadjusted total failure rate day 28 and day 42

We extracted the following data and summed it to form the numerator.

Early treatment failure.
Late clinical failure.
Late parasitological failure.

We extracted the following data and subtracted it from the number of participants randomized. This formed the denominator.

Those found not to be fulfilling inclusion criteria after randomization.
Those voluntarily withdrawing consent.
Those lost to follow‐up.
Those violating protocol, including (but not limited to) missed or vomited doses, those failing to complete treatment, and those taking additional antimalarials.

Polymerase chain reaction‐adjusted total failure rate day 28 and day 42

We extracted the following data and summed it to form the numerator.

Early treatment failure due to PCR‐confirmed recrudescence.
Late clinical failure due to PCR‐confirmed recrudescence.
Late parasitological failure due to PCR‐confirmed recrudescence.

We extracted the following data and subtracted it from the number of participants randomized. This formed the denominator.

Those with indeterminate PCR results.
Those with missing PCR results.
Those with PCR‐confirmed new infections.
Those found not to be fulfilling inclusion criteria after randomization.
Those voluntarily withdrawing consent.
Those lost to follow‐up.
Those violating protocol, including (but not limited to) missed or vomited doses, those failing to complete treatment, and those taking additional antimalarials.

Adverse events

We extracted the number of people who had been reported as experiencing an adverse event to form the numerator. The denominator was formed from the number of people who had received at least one dose of the study drug, unless otherwise stated. We used the Medical Dictionary for Regulatory Activities to search for a 'higher level term' to group adverse events together and allow comparison between studies using different descriptors for similar and related symptoms (MedDRA 2018). Where a study reported multiple adverse events that had a common MedDRA term, we only included the most common adverse event to avoid double counting. Where more than one 'higher level term' was given for a symptom, we consistently applied the term that we considered most appropriate, and used footnotes in the forest plots to describe original terms where a 'higher level term' might be considered ambiguous.

Comment on efficacy denominators

This approach was based on standard WHO approaches for assessing and monitoring antimalarial drug efficacy (WHO 2003; WHO 2009). We adopted this approach within our review to ensure consistency with the WHO approach, and the analysis method used in previous Cochrane systematic reviews of malaria treatment. We recognize that this method excludes a high number of randomized participants from the denominator for the final efficacy outcome. In order to restore integrity of randomization, we had planned to conduct a series of sensitivity analyses (as described in Table 5), but, given the small number of trials included for each comparison, we did not pursue this as it was unlikely to alter conclusions.

1. Sensitivity analysis.

Numerator	Analysis	Participants	Denominator	Numerator	Denominator
Primary analysis^a	Exclusions after enrolment	Excluded^c	Excluded	Excluded	Excluded
	Missing or indeterminate PCR^b	Included as failures	Included	Excluded	Excluded
	New infections	Included as failures	Included	Excluded	Excluded
Sensitivity analysis 1^d	As 'Primary analysis' except missing or indeterminate PCR	—	—	Included as failures	Included
Sensitivity analysis 2^e	As 'Sensitivity analysis 1' except new infections	—	—	Included as successes	Included
Sensitivity analysis 3^f	As 'Sensitivity analysis 2' except exclusions after enrolment	Included as failures	Included	Included as failures	Included
Sensitivity analysis 4^g	As 'Sensitivity analysis 2' except exclusions after enrolment	Included as successes	Included	Included as successes	Included

	WHO‐recommended artemisinin‐based combination therapy				Other antimalarials
Study	AV+PG	AL	AS+AQ	AS+MQ	AS+AV+PG	Other combinations	Monotherapy
Anabwani 1999	√	—	—	—	—	—	HL
Borrmann 2003	√	—	—	—	—	—	AQ
Bouchaud 2000	√	—	—	—	—	—	HL
Carrasquilla 2012	√	√	—	√	—	—	—
De Alencar 1997	√	—	—	—	—	QN+TET	—
Giao 2004	√	—	—	—	—	CV8	—
Gurkov 2008	√	√	—	—	—	—	QN
Llanos‐Cuentas 2001	√	—	—	—	—	—	CQ, SP
Looareesuwan 1999	√	—	—	—	—	—	MQ
Mulenga 1999	√	—	—	—	—	—	SP
Mulenga 2006	√	—	—	—	—	—	SP
Radloff 1996	√	—	—	—	—	—	AQ
Tahar 2014	√	—	√	—	√	—	—
Van Vugt 2002	√	—	—	√	√	—	—
Wojnarski 2019	√	—	—	—	√	—	—
McGready 2005	—	—	—	—	√	—	QN
Laufer 2012	—	—	—	—	—	CQ+AS, CQ+AV+PG, CQ+AZ	CQ
Total number	15	2	1	2	4	3	11

Study	Cure/failure rate	Adverse events	Parasite clearance time	Fever clearance time	Gametocyte carriage rate	Audiological outcomes	Other
Anabwani 1999	√	√	√	√	—	—	—
Borrmann 2003	√	√	√	√	—	—	—
Bouchaud 2000	√	√	√	√	—	—	—
Carrasquilla 2012	√	√	—	—	—	√	—
De Alencar 1997	√	√	√	√	—	—	—
Giao 2004	√	√	√	√	—	—	—
Gurkov 2008	√	√	—	—	—	√	—
Laufer 2012	√	√	—	—	—	—	√
Llanos‐Cuentas 2001	√	√	√	√	—	—	—
Looareesuwan 1999	√	√	√	√	—	—	—
McGready 2005	√	√	√	√	√	—	√
Mulenga 1999	√	√	√	√	—	—	—
Mulenga 2006	√	√	—	√	—	—	—
Radloff 1996	√	√	√	√	—	—	—
Tahar 2014	√	√	√	√	—	—	√
Van Vugt 2002	√	√	√	√	√	—	—
Wojnarski 2019	√	√	√	√	√	—	√
Total number making comparison	17	17	13	14	3	2	4

Study	Trial dates	Region	Failure rate of AV+PG (+ partner drug)	Failure rate of comparators
Anabwani 1999	1994	Africa	6%	10%
Borrmann 2003	1999–2000	Africa	1–4%	4–47%
Bouchaud 2000	1994–1995	Returning travellers	0%	0%
Carrasquilla 2012	2007–2008	South America	2%	1–2%
De Alencar 1997	1995–1996	South America	0–1%	0%
Giao 2004	2001–2002	Asia	0–6%	0–5%
Gurkov 2008	2006	Africa	0–7%	0–23%
Laufer 2012	2007–2009	Africa	0% (+CQ)	0–1%
Llanos‐Cuentas 2001	1995–1996	South America	0%	0–54%
Looareesuwan 1999	1993–1994	Asia	0%	0–14%
McGready 2005	2001–2003	Asia	0–3% (+AS)	0–45%
Mulenga 1999	1993–1994	Africa	0%	1%
Mulenga 2006	2000–2002	Africa	0–5%	1–22%
Radloff 1996	1994–1995	Africa	2%	19%
Tahar 2014	2008–2009	Africa	2–15%	0–12%
Van Vugt 2002	1998–2000	Asia	3–5%	1–7%
Wojnarski 2019	2014–2015	Asia	0–9%	0–8%

*Atovaquone‐proguanil compared to artemether‐lumefantrine for treating uncomplicated Plasmodium falciparum* malaria**
Patient or population: children and adults Setting: Colombia and Ethiopia Intervention: AV+PG Comparison: AL
Outcomes	Study event rates*		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	With AL	With AV+PG
Total failure day 28 PCR‐adjusted	0/30 (0%)	2/30 (6.7%)	RR 5.00 (0.25 to 99.95)	60 (1 RCT)	⊕⊕⊝⊝ Low^a,b	Compared to AL, AV+PG may have more PCR‐adjusted treatment failures at day 28.
Total failure day 42 PCR‐unadjusted	0/30 (0%)	2/30 (6.7%)	RR 5.00 (0.25 to 99.95)	60 (1 RCT)	⊕⊕⊝⊝ Low^a,b	Compared to AL, AV+PG may have more PCR‐unadjusted treatment failures at day 28.
Total failure day 42 PCR‐adjusted	Anticipated absolute effects^† (95% CI)		RR 3.00 (0.19 to 47.12)	208 (1 RCT)	⊕⊕⊝⊝ Low^a,b	Compared to AL, AV+PG may have more PCR‐adjusted treatment failures at day 42.
	Risk with AL	Risk with AV+PG
	6 per 1000	19 per 1000 (1 to 302)
We presented study event rates rather than anticipated absolute effects as there were no events in the AL group. ^†The risk in the intervention group* (and its 95% confidence interval) was based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AL: artemether‐lumefantrine; AV+PG: atovaquone‐proguanil; CI: confidence interval; PCR: polymerase chain reaction; RCT: randomized controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

*Atovaquone‐proguanil compared to artesunate‐amodiaquine for treating uncomplicated Plasmodium falciparum* malaria**
Patient or population: children under the age of 5 years Setting: Cameroon Intervention: AV+PG Comparison: AS+AQ
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with AS+AQ	Risk with AV+PG
Total failure day 28 PCR‐adjusted	29 per 1000	94 per 1000 (20 to 448)	RR 3.19 (0.67 to 15.22)	132 (1 RCT)	⊕⊕⊝⊝ Low^a,b	Compared to AS+AQ, AV+PG may have more PCR‐adjusted failures at day 28.
Total failure day 28 PCR‐unadjusted	118 per 1000	141 per 1000 (58 to 342)	RR 1.20 (0.49 to 2.91)	132 (1 RCT)	⊕⊕⊝⊝ Low^a,b	There may be little or no difference in PCR‐adjusted failures at day 28 between AS+AQ and AV+PG.
Early treatment failure	Study event rates^†		RR 13.80 (0.79 to 240.11)	132 (1 RCT)	⊕⊕⊝⊝ Low^a,b	Compared to AS+AQ, AV+PG may have more early treatment failures.
	With AS+AQ	With AV+PG
	0/68 (0%)	6/64 (9.4%)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ^†We presented study event rates rather than anticipated absolute effects as there were no events in the AL group for two of the outcomes. AS+AQ: artesunate‐amodiaquine; AV+PG: atovaquone‐proguanil; CI: confidence interval; PCR: polymerase chain reaction; RCT: randomized controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Study	Total treatment failure day 28 PCR‐adjusted		Observed rate
Study	Events	Total	Observed rate
Gurkov 2008	2	30	6.67%
Tahar 2014	6	64	9.38%
Mulenga 2006	0	97	0%
Wojnarski 2019	1	93	1.08%
Study	Total treatment failure day 42 PCR‐adjusted		Observed rate
Study	Events	Total	Observed rate
Carrasquilla 2012	1	152	0.66%
Van Vugt 2002	15	530	2.83%
Wojnarski 2019	9	98	9.18%

Comparator	Studies	Efficacy findings	Adverse events
CV8	Giao 2004	Little or no difference between AV+PG and CV8 in PCR‐unadjusted treatment failures day 28 (Analysis 5.1; Analysis 5.2).	Few adverse events reported.
QN+TET	De Alencar 1997	1 PCR‐unadjusted treatment failure at day 28 reported (Analysis 6.1).	Auditory problems reported in QN group.
SP	Mulenga 1999; Llanos‐Cuentas 2001; Mulenga 2006	3 RCTs contributed data to analysis. Little or no difference for PCR‐adjusted treatment failures at day 28 (Analysis 7.1). Greater PCR‐unadjusted treatment failures at day 28 for SP (Analysis 7.2).	Large numbers of adverse events reported, but little or no difference between AV+PG and SP.
QN	Gurkov 2008	Study reported PCR adjusted data at day 28, and unadjusted data at day 42. Little or no difference for PCR‐adjusted treatment failures at day 28 (Analysis 8.1) or PCR‐unadjusted treatment failures at day 42 (Analysis 8.2).	Small numbers of adverse events reported. Little or no difference between AV+PG and QN.
MQ	Looareesuwan 1999	Fewer PCR‐unadjusted treatment failures at day 28 for AV+PG compared to MQ (Analysis 9.1).	Several adverse events reported. Both nausea and vomiting symptoms and abnormal liver function tests more frequent with AV+PG versus MQ (Analysis 9.3).
AQ	Radloff 1996; Borrmann 2003	2 RCTs contributed data to analysis. Fewer failures PCR‐unadjusted failures at day 28 for AV+PG compared to AQ (Analysis 10.1).	Several adverse events reported. Asthenic conditions, pruritis, sleep disturbance, and dizziness more common in the AQ group. Nausea and vomiting more common in AV+PG group.
CQ	Llanos‐Cuentas 2001	1 small RCT (27 participants). Fewer PCR‐unadjusted failures at day 28 for AV‐PG compared to CQ (Analysis 11.1).	Several adverse events reported with little or no difference between groups. Headaches more common in CQ group.
HL	Anabwani 1999; Bouchaud 2000	2 RCTs contributed data to analysis. Little or no difference between AV+PG and HL in PCR‐unadjusted treatment failures day 28 (Analysis 12.1).	Nausea and vomiting seen more frequently with AV+PG compared to HL.

Date	Event	Description
14 January 2021	New search has been performed	We aligned the outcomes with the emerging core outcome set used by the Cochrane Infectious Diseases Group. This led us to remove the following secondary outcomes from the original protocol. Treatment failure by day 14: we replaced this with early treatment failure. Parasite clearance time: we omitted this as there is commonly heterogeneity in measures of parasite clearance time between studies, as encountered in previous Cochrane Reviews (see Esu 2014). The preferred measure would be parasite clearance rate using the WWARN calculator (Flegg 2011), but we did not include as the frequent sampling required may be too demanding for trials in resource‐limited settings. Fever clearance time: we omitted this as there was overlap with early treatment failure. Progression to severe malaria: we omitted this as there was overlap with early treatment failure and treatment failure at day 28 and day 42. An updated protocol was approved by the CIDG editorial team on 27 April 2018, and the changes are described in Appendix 3. In a change to the protocol, we focused comparisons on WHO‐approved ACT, and presented the other comparisons in narrative format as we consider this will be of more relevance to current clinical practice.
14 January 2021	New citation required and conclusions have changed	A new author team (Andrew Blanshard and Paul Hine) prepared this review. We have rewritten the protocol, updated the background to reflect changes in the field, updated the outcomes of the review, and used newer Cochrane methodology.
5 August 2008	Amended	Converted to new review format with minor editing.

Search set	CIDG SR^a	CENTRAL	MEDLINE^b	Embase^b	LILACS^b
1	atovaquone	atovaquone	malaria	malaria	malaria
2	proguanil	proguanil	Exp MALARIA	Exp MALARIA	proguanil
3	Malarone	Malarone	1 or 2	1 or 2	atovaquone
4	malaria	malaria	atovaquone	atovaquone	Malarone
5	—	—	proguanil	proguanil	—
6	—	—	Atovaquone‐proguanil	Atovaquone‐proguanil	—
7	—	—	chloriguane	chloriguane	—
8	—	—	Chlorguanid*	cycloguanil	—
9	—	—	cycloguanil	7 or 8	—
10	—	—	7 or 8 or 9	5 or 9	—
11	—	—	5 or 10	4 and 10	—
12	—	—	4 and 10	6 or 11	—
13	—	—	6 or 12	Malarone	—
14	—	—	Malarone	12 or 13	—
15	—	—	13 or 14	3 and 14	—
16	—	—	3 and 15	—	—
17	—	—	—	—	—

Monotherapy abbreviation	Name of antimalarial	Combination therapy abbreviation	Name of antimalarial
AQ	Amodiaquine	AL	Artemether‐lumefantrine
AM	Artemether	AS+AQ	Artesunate‐amodiaquine
ART	Artemisinin	AS+AV+PG	Artesunate‐atovaquone‐proguanil
AS	Artesunate	AS+MQ	Artesunate‐mefloquine
AV	Atovaquone	AV+PG	Atovaquone‐proguanil
AZ	Azithromycin	CV8	Dihydroartemisinin‐piperaquine‐trimethoprim‐primaquine
CL	Clindamycin	SP	Sulfadoxine‐Pyrimethamine
CQ	Chloroquine	QN+TET	Quinine‐Tetracycline
DHA	Dihydroartemisinin	CQ+AV+PG	Chloroquine‐Atovaquone‐Proguanil
HL	Halofantrine	CQ+AS	Chloroquine‐Artesunate
LUM	Lumefantrine	CQ+AZ	Chloroquine‐Azithromycin
MQ	Mefloquine
NQ	Naphthoquine
PIP	Piperaquine
PQ	Primaquine
PG	Proguanil
SX	Sulfadoxine
QN	Quinine
TET	Tetracycline

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Total failure day 28 PCR‐adjusted	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	5.00 [0.25, 99.95]
1.2 Total failure day 42 PCR‐adjusted	1	208	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.19, 47.12]
1.3 Total failure day 42 PCR‐unadjusted	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	5.00 [0.25, 99.95]
1.4 Adverse events	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.4.1 Serious adverse events	2	272	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.4.2 Adverse events leading to withdrawal	2	272	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.4.3 Headaches	2	272	Risk Ratio (M‐H, Fixed, 95% CI)	2.54 [1.17, 5.51]
1.4.4 Diarrhoea	2	272	Risk Ratio (M‐H, Fixed, 95% CI)	2.25 [0.48, 10.54]
1.4.5 Gastrointestinal and abdominal pains	1	212	Risk Ratio (M‐H, Fixed, 95% CI)	2.00 [0.34, 11.65]
1.4.6 Nausea and vomiting	2	272	Risk Ratio (M‐H, Fixed, 95% CI)	10.00 [2.73, 36.60]
1.4.7 Dizziness	1	212	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.58, 4.75]
1.4.8 Hearing problem	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.87]
1.4.9 Inner ear signs and symptoms	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.04, 3.03]
1.4.10 Feelings and sensations	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.33, 27.23]
1.4.11 Febrile disorders	2	272	Risk Ratio (M‐H, Fixed, 95% CI)	2.25 [0.77, 6.60]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Total failure day 28 PCR‐adjusted	1	132	Risk Ratio (M‐H, Fixed, 95% CI)	3.19 [0.67, 15.22]
2.2 Total failure day 28 PCR‐unadjusted	1	132	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.49, 2.91]
2.3 Early treatment failure	1	132	Risk Ratio (M‐H, Fixed, 95% CI)	13.80 [0.79, 240.11]
2.4 Adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.4.1 Serious adverse events	1	139	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.4.2 Adverse events leading to withdrawal	1	139	Risk Ratio (M‐H, Fixed, 95% CI)	3.04 [0.13, 73.43]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Total failure day 42 PCR‐adjusted	2	1168	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.57, 2.34]
3.2 Total failure day 42 PCR‐unadjusted	1	1063	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.50, 1.30]
3.3 Adverse events	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.3.1 Serious adverse events	2	1275	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.10, 4.22]
3.3.2 Adverse events leading to withdrawal	2	1275	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.04, 23.89]
3.3.3 Headaches	1	212	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [1.10, 8.16]
3.3.4 Diarrhoea	1	212	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.18, 4.00]
3.3.5 Gastrointestinal and abdominal pains	1	212	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [0.28, 7.96]
3.3.6 Nausea and vomiting	2	896	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.44, 0.89]
3.3.7 Disturbances in initiating and maintaining sleep	1	212	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.02, 6.02]
3.3.8 Feelings and sensations	1	594	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.34, 1.02]
3.3.9 Dizziness	1	212	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.41, 2.83]
3.3.10 Febrile disorders	1	212	Risk Ratio (M‐H, Fixed, 95% CI)	6.00 [1.13, 31.83]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Total failure day 28 PCR‐adjusted	2	375	Risk Ratio (M‐H, Fixed, 95% CI)	5.14 [0.61, 43.52]
4.2 Total failure day 28 PCR‐unadjusted	1	187	Risk Ratio (M‐H, Fixed, 95% CI)	15.48 [0.90, 267.27]
4.3 Total failure day 42 PCR‐adjusted	2	1258	Risk Ratio (M‐H, Fixed, 95% CI)	1.84 [0.95, 3.56]
4.4 Total failure day 42 PCR‐unadjusted	1	1063	Risk Ratio (M‐H, Fixed, 95% CI)	1.56 [0.88, 2.79]
4.5 Early treatment failure	2	395	Risk Ratio (M‐H, Fixed, 95% CI)	5.11 [0.25, 104.94]
4.6 Adverse events	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
4.6.1 Serious adverse events	3	1455	Risk Ratio (M‐H, Fixed, 95% CI)	1.66 [0.22, 12.49]
4.6.2 Adverse events leading to withdrawal	2	1250	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
4.6.3 Nausea and vomiting	1	664	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.34, 0.80]
4.6.4 Gastrointestinal and abdominal pains	1	752	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.33, 1.04]
4.6.5 Feelings and sensations	1	611	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.35, 1.04]

Protocol section	Refreshed protocol
Background	We updated the title to reflect that the review pertains to Plasmodium falciparum malaria, and follows Cochrane title conventions. We updated information in the background to follow the advised Cochrane/MECIR subheading structure. We updated the background to reflect the current global policy setting on malaria. The main review question has acquired a new relevance in the context of emerging artemisinin resistance; we reflected this in the updated protocol.
Research question	The existing PICO (population, intervention, comparison, outcome) remained relevant. We updated the protocol to incorporate WHO standards on reporting of malaria trials. These are in harmony with other Cochrane Reviews of malaria. Our protocol did not incorporate participant‐reported outcomes. In accordance with Cochrane guidelines, we restricted the number of primary and secondary outcomes. The inclusion criteria remain limited to randomized controlled trials.
Methods	We updated the description of the 'Risk of bias' tool. We added a plan to summarize the evidence using the GRADE approach.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Total failure day 28 PCR‐unadjusted	1	161	Risk Ratio (M‐H, Fixed, 95% CI)	1.30 [0.36, 4.66]
5.2 Early treatment failure	1	161	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
5.3 Adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5.3.1 Serious adverse events	1	165	Risk Ratio (M‐H, Fixed, 95% CI)	5.18 [0.25, 106.33]
5.3.2 Adverse events leading to withdrawal	1	165	Risk Ratio (M‐H, Fixed, 95% CI)	5.18 [0.25, 106.33]
5.3.3 Nausea and vomiting	1	165	Risk Ratio (M‐H, Fixed, 95% CI)	5.18 [0.25, 106.33]
5.3.4 Diarrhoea	1	165	Risk Ratio (M‐H, Fixed, 95% CI)	3.11 [0.13, 75.24]
5.3.5 Headaches	1	165	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.01, 8.36]
5.3.6 Oral dryness and saliva altered	1	165	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.01, 8.36]
5.3.7 Pruritis	1	165	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.07, 16.30]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Total failure day 28 PCR‐unadjusted	1	142	Risk Ratio (M‐H, Fixed, 95% CI)	2.84 [0.12, 68.51]
6.2 Early treatment failure	1	142	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.3 Adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
6.3.1 Serious adverse events	1	154	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.3.2 Adverse events leading to withdrawal	1	154	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
6.3.3 Gastrointestinal and abdominal pains	1	154	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.64, 1.93]
6.3.4 Nausea and vomiting	1	154	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.29, 1.02]
6.3.5 Asthenic conditions	1	154	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.28, 1.29]
6.3.6 Diarrhoea	1	154	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.20, 1.58]
6.3.7 Headaches	1	154	Risk Ratio (M‐H, Fixed, 95% CI)	1.89 [0.90, 3.97]
6.3.8 Dizziness	1	154	Risk Ratio (M‐H, Fixed, 95% CI)	0.26 [0.14, 0.48]
6.3.9 Pruritis	1	154	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [0.44, 5.11]
6.3.10 Auditory nerve disorders	1	154	Risk Ratio (M‐H, Fixed, 95% CI)	0.05 [0.02, 0.17]
6.3.11 Appetite disorders	1	154	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.14, 1.03]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Total failure day 28 PCR‐adjusted	1	192	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.92]
7.2 Total failure day 28 PCR‐unadjusted	3	364	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.10, 0.59]
7.3 Early treatment failure	2	172	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.06]
7.4 Adverse events	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
7.4.1 Serious adverse events	3	447	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.35, 1.41]
7.4.2 Adverse events leading to withdrawal	3	447	Risk Ratio (M‐H, Fixed, 95% CI)	5.95 [0.73, 48.75]
7.4.3 Gastrointestinal and abdominal pains	2	192	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.78, 2.18]
7.4.4 Diarrhoea	2	418	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [0.65, 2.96]
7.4.5 Nausea and vomiting	2	192	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.47, 1.74]
7.4.6 Headaches	2	192	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.56, 1.42]
7.4.7 Hypotensive disorders	1	163	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.17, 1.05]
7.4.8 Seizure and seizure disorders	2	284	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.08, 5.43]
7.4.9 Appetite disorders	2	192	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [0.52, 5.00]
7.4.10 Hepatobiliary signs and symptoms	1	163	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.30, 3.28]
7.4.11 Pruritis	2	192	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [0.35, 5.67]
7.4.12 Spleen disorders	1	163	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [0.25, 8.64]
7.4.13 Cardiac signs and symptoms	1	163	Risk Ratio (M‐H, Fixed, 95% CI)	6.92 [0.36, 131.79]
7.4.14 Disturbances in initiating and maintaining sleep	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.09, 1.21]
7.4.15 Feelings and sensations	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.06, 32.05]
7.4.16 Rubeola viral infections	1	255	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.11, 3.89]
7.4.17 Hypoglycaemic conditions	1	255	Risk Ratio (M‐H, Fixed, 95% CI)	4.96 [0.24, 102.33]
7.4.18 Lower respiratory tract and lung infections	1	255	Risk Ratio (M‐H, Fixed, 95% CI)	2.48 [0.49, 12.55]
7.4.19 Anaemias	1	255	Risk Ratio (M‐H, Fixed, 95% CI)	2.98 [0.12, 72.39]
7.4.20 Sepsis, bacteraemia, viraemia, fungaemia	1	255	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.03, 3.14]
7.4.21 Breathing abnormalities	1	255	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.01, 1.61]
7.4.22 Muscle pains	1	163	Risk Ratio (M‐H, Fixed, 95% CI)	1.58 [0.54, 4.63]
7.4.23 Asthenic conditions	2	418	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.68, 2.28]
7.4.24 Dizziness	2	192	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.28, 1.81]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Total failure day 28 PCR‐adjusted	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.12, 3.71]
8.2 Total failure day 42 PCR‐unadjusted	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.06, 1.26]
8.3 Early treatment failure	1	66	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.4 Adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
8.4.1 Serious adverse events	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.4.2 Adverse events leading to withdrawal	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
8.4.3 Inner ear signs and symptoms	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.87]
8.4.4 Febrile disorders	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.16, 2.29]
8.4.5 Feelings and sensations	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.33, 27.23]
8.4.6 Headaches	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.41, 3.51]
8.4.7 Nausea and vomiting	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.05, 5.22]
8.4.8 Diarrhoea	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.13, 70.83]
8.4.9 Appetite disorders	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.87]
8.4.10 Hearing problem	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.87]
8.4.11 Auditory nerve disorders	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.04, 3.03]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Total failure day 28 PCR‐unadjusted	1	158	Risk Ratio (M‐H, Fixed, 95% CI)	0.04 [0.00, 0.73]
9.2 Early treatment failure	1	158	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.3 Adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
9.3.1 Serious adverse events	1	182	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
9.3.2 Adverse events leading to withdrawal	1	182	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.08]
9.3.3 Diarrhoea	1	182	Risk Ratio (M‐H, Fixed, 95% CI)	2.50 [0.50, 12.56]
9.3.4 Gastrointestinal and abdominal pains	1	182	Risk Ratio (M‐H, Fixed, 95% CI)	5.00 [0.24, 102.72]
9.3.5 Nausea and vomiting	1	182	Risk Ratio (M‐H, Fixed, 95% CI)	4.50 [1.00, 20.26]
9.3.6 Appetite disorders	1	182	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.01, 4.11]
9.3.7 Headaches	1	182	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.01, 4.11]
9.3.8 Dizziness	1	182	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.01, 4.11]
9.3.9 Anaemias	1	182	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.23, 1.29]
9.3.10 Abnormal liver function tests	1	182	Risk Ratio (M‐H, Fixed, 95% CI)	2.50 [1.02, 6.16]
9.3.11 Disturbances in initiating and maintaining sleep	1	182	Risk Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 2.73]
9.3.12 Oral soft tissue signs and symptoms	1	182	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.37, 2.74]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Total failure day 28 PCR‐unadjusted	2	296	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.04, 0.22]
10.2 Early treatment failure	1	170	Risk Ratio (M‐H, Fixed, 95% CI)	0.28 [0.03, 2.66]
10.3 Adverse events	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
10.3.1 Serious adverse events	2	326	Risk Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 2.73]
10.3.2 Adverse events leading to withdrawal	2	326	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.12, 72.77]
10.3.3 Diarrhoea	2	326	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.57, 1.61]
10.3.4 Nausea and vomiting	2	326	Risk Ratio (M‐H, Fixed, 95% CI)	1.87 [1.05, 3.33]
10.3.5 Asthenic conditions	2	326	Risk Ratio (M‐H, Fixed, 95% CI)	0.12 [0.02, 0.64]
10.3.6 Respiratory tract infections	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	9.00 [0.49, 165.00]
10.3.7 Pruritis	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.04, 0.35]
10.3.8 Disturbances in initiating and maintaining sleep	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.12, 0.75]
10.3.9 Gastrointestinal and abdominal pains	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	2.80 [1.07, 7.31]
10.3.10 Appetite disorders	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.30, 3.29]
10.3.11 Coughing and associated symptoms	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.53, 2.17]
10.3.12 Upper respiratory tract infections	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.03, 2.20]
10.3.13 Dizziness	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.27 [0.08, 0.93]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 Total failure day 28 PCR‐unadjusted	1	27	Risk Ratio (M‐H, Fixed, 95% CI)	0.06 [0.00, 0.99]
11.2 Early treatment failure	1	27	Risk Ratio (M‐H, Fixed, 95% CI)	0.08 [0.01, 1.40]
11.3 Adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
11.3.1 Serious adverse events	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
11.3.2 Adverse events leading to withdrawal	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	2.14 [0.09, 49.08]
11.3.3 Gastrointestinal and abdominal pains	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	1.75 [0.39, 7.77]
11.3.4 Nausea and vomiting	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.44, 3.40]
11.3.5 Dizziness	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	2.14 [0.09, 49.08]
11.3.6 Asthenic conditions	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	0.06 [0.00, 1.09]
11.3.7 Appetite disorders	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	1.40 [0.14, 13.98]
11.3.8 Pruritis	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	0.10 [0.01, 1.83]
11.3.9 Cardiac signs and symptoms	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	0.10 [0.01, 1.83]
11.3.10 Feelings and sensations	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.04, 3.50]
11.3.11 Seizures and seizure disorders	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	2.14 [0.09, 49.08]
11.3.12 Headaches	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	0.23 [0.05, 0.99]
11.3.13 Disturbances in initiating and maintaining sleep	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.20, 5.49]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 Total failure day 28 PCR‐unadjusted	2	205	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.22, 1.88]
12.2 Early treatment failure	2	54	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
12.3 Adverse events	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
12.3.1 Serious adverse events	2	216	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
12.3.2 Adverse events leading to withdrawal	2	216	Risk Ratio (M‐H, Fixed, 95% CI)	5.75 [0.71, 46.65]
12.3.3 Headaches	2	216	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.36, 1.50]
12.3.4 Nausea and vomiting	2	216	Risk Ratio (M‐H, Fixed, 95% CI)	2.93 [1.36, 6.30]
12.3.5 Gastrointestinal and abdominal pains	2	216	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.27, 1.08]
12.3.6 Diarrhoea	2	216	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.23, 1.38]
12.3.7 Appetite disorders	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.10, 1.36]
12.3.8 Disturbances in initiating and maintaining sleep	2	216	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.22, 1.53]
12.3.9 Rashes, eruptions and exanthems	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.15, 2.43]
12.3.10 Feelings and sensations	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.11, 3.89]
12.3.11 Haemorrhages	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.02, 1.68]
12.3.12 Asthenic conditions	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.03, 2.19]
12.3.13 Muscle pains	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 2.72]
12.3.14 Cardiac signs and symptoms	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.05, 5.41]
12.3.15 Pruritis	2	216	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.52, 2.90]
12.3.16 Coughing and associated symptoms	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.34, 1.52]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
13.1 Total failure day 28 PCR‐adjusted	1	81	Risk Ratio (M‐H, Fixed, 95% CI)	0.05 [0.00, 0.77]
13.2 Total failure day 42 PCR‐adjusted	1	81	Risk Ratio (M‐H, Fixed, 95% CI)	0.08 [0.01, 0.56]
13.3 Total failure day 28 PCR‐unadjusted	1	81	Risk Ratio (M‐H, Fixed, 95% CI)	0.03 [0.00, 0.56]
13.4 Total failure day 42 PCR‐unadjusted	1	81	Risk Ratio (M‐H, Fixed, 95% CI)	0.06 [0.01, 0.40]
13.5 Early treatment failure	1	81	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.01, 4.34]
13.6 Adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
13.6.1 Serious adverse events	1	81	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
13.6.2 Adverse events leading to withdrawal	1	81	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
13.6.3 Auditory nerve disorders	1	58	Risk Ratio (M‐H, Fixed, 95% CI)	0.30 [0.16, 0.60]
13.6.4 Anaemias	1	81	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.91, 1.14]

PERMALINK

Atovaquone‐proguanil for treating uncomplicated Plasmodium falciparum malaria

Andrew Blanshard

Paul Hine

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Intervention

Control

Types of outcome measures

Primary outcomes

Secondary outcomes

Adverse events

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Unadjusted total failure rate day 28 and day 42

Polymerase chain reaction‐adjusted total failure rate day 28 and day 42

Adverse events

Comment on efficacy denominators

1. Sensitivity analysis.

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

Included studies

2. Comparison of Interventions.

3. Outcome reporting.

4. Trial dates, global region, and drug failure rates.

Studies comparing atovaquone‐proguanil to WHO‐recommended artemisinin‐based combination therapy

Other comparisons

Studies comparing atovaquone‐proguanil to artesunate‐atovaquone‐proguanil

Studies comparing atovaquone‐proguanil to other combinations or to monotherapy

Excluded studies

Risk of bias in included studies

2.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings 1. Atovaquone‐proguanil compared to artemether‐lumefantrine for treating uncomplicated Plasmodium falciparum malaria.

Summary of findings 2. Atovaquone‐proguanil compared to artesunate‐amodiaquine for treating uncomplicated Plasmodium falciparum malaria.

Summary of findings 3. Atovaquone‐proguanil compared to artesunate‐mefloquine for treating uncomplicated Plasmodium falciparum malaria.

Summary of findings 4. Atovaquone‐proguanil compared to artesunate‐atovaquone‐proguanil for treating uncomplicated Plasmodium falciparum malaria.

Abbreviations

Crude treatment failure rates

5. Crude PCR‐adjusted failures for atovaquone‐proguanil.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
14.1 Total failure day 28 PCR‐unadjusted	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
14.2 Early treatment failure	1	268	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
14.3 Adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
14.3.1 Serious adverse events	1	320	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.06, 1.35]
14.3.2 Adverse events leading to withdrawal	1	320	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
15.1 Total failure day 28 PCR‐adjusted	1	277	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.01, 8.78]
15.2 Total failure day 28 PCR‐unadjusted	1	277	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.01, 8.78]
15.3 Early treatment failure	1	277	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
15.4 Adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
15.4.1 Serious adverse events	1	320	Risk Ratio (M‐H, Fixed, 95% CI)	5.00 [0.24, 103.33]
15.4.2 Adverse events leading to withdrawal	1	320	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
16.1 Total failure day 28 PCR‐adjusted	1	271	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
16.2 Total failure day 28 PCR‐unadjusted	1	271	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.01, 8.41]
16.3 Early treatment failure	1	271	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
16.4 Adverse events	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
16.4.1 Serious adverse events	1	320	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.14, 7.01]
16.4.2 Adverse events leading to withdrawal	1	320	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
17.1 Serious adverse events	15	3222	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.40, 1.28]
17.2 Adverse events leading to withdrawal	14	2969	Risk Ratio (M‐H, Fixed, 95% CI)	3.13 [1.29, 7.62]
17.3 Anaemias	2	437	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.28, 1.43]
17.4 Appetite disorders	7	887	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.37, 1.03]
17.5 Asthenic conditions	7	1100	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.39, 0.88]
17.6 Auditory nerve disorders	2	214	Risk Ratio (M‐H, Fixed, 95% CI)	0.07 [0.03, 0.18]
17.7 Hypotensive disorders	1	163	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.17, 1.05]
17.8 Breathing abnormalities	1	255	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.01, 1.61]
17.9 Cardiac signs and symptoms	3	365	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.24, 2.29]
17.10 Coughing and associated symptoms	2	368	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.53, 1.48]
17.11 Diarrhoea	11	1733	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.70, 1.35]
17.12 Disturbances in initiating and maintaining sleep	6	765	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.20, 0.64]
17.13 Dizziness	6	871	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.25, 0.57]
17.14 Febrile disorders	2	272	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.47, 2.67]
17.15 Feelings and sensations	4	856	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.39, 1.05]
17.16 Gastrointestinal and abdominal pains	9	1834	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.76, 1.28]
17.17 Haemorrhages	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.02, 1.68]
17.18 Headaches	9	1186	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.77, 1.38]
17.19 Hearing problems	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.87]
17.20 Hepatobiliary signs and symptoms	1	163	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.30, 3.28]
17.21 Hypoglycaemic conditions	1	255	Risk Ratio (M‐H, Fixed, 95% CI)	4.96 [0.24, 102.33]
17.22 Inner ear signs and symptoms	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.04, 3.03]
17.23 Liver function tests abnormal	1	182	Risk Ratio (M‐H, Fixed, 95% CI)	2.50 [1.02, 6.16]
17.24 Lower respiratory tract and lung infections	1	255	Risk Ratio (M‐H, Fixed, 95% CI)	2.48 [0.49, 12.55]
17.25 Muscle pains	2	331	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.39, 2.49]
17.26 Nausea and vomiting	12	2196	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.79, 1.23]
17.27 Oral dryness and saliva altered	1	165	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.01, 8.36]
17.28 Oral soft tissue signs and symptoms	1	182	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.37, 2.74]
17.29 Pruritis	7	858	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.34, 0.87]
17.30 Rashes, eruptions, and exanthems	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.15, 2.43]
17.31 Rubeola viral infections	1	255	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.11, 3.89]
17.32 Seizures and seizure disorders	2	289	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.11, 6.26]
17.33 Spleen disorders	1	163	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [0.25, 8.64]
17.34 Sepsis, bacteraemia, viraemia, fungaemia	1	255	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.03, 3.14]
17.35 Upper respiratory tract infections	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.03, 2.20]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
18.1 Total failure day 28 PCR‐adjusted	2	192	Risk Ratio (M‐H, Fixed, 95% CI)	3.56 [0.89, 14.19]
18.2 Total failure day 28 PCR‐unadjusted	1	132	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.49, 2.91]
18.3 Total failure day 42 PCR‐adjusted	2	1271	Risk Ratio (M‐H, Fixed, 95% CI)	3.02 [1.17, 7.78]
18.4 Total failure day 42 PCR‐unadjusted	2	1123	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.54, 1.38]

*Study characteristics*
Methods	Randomized controlled trial Duration: 6 months; June 1994 to November 1994
Participants	Children with uncomplicated P falciparum malaria Number: 168 Inclusion criteria: aged 3–12 years; fever; tolerate oral therapy; weight > 10 kg Exclusion criteria: severe malaria; QTc interval > 0.44 seconds; mixed infections Diagnosis: parasitaemia 1000–200,000 parasites/μL
Interventions	Atovaquone‐proguanil (atovaquone 60 mg/kg + proguanil 24 mg/kg for 3 days) Halofantrine (24 mg/kg for 12 hours)
Outcomes	28‐day cure rate (parasite clearance within 7 days without recrudescence during the 28‐day follow‐up period) Parasite clearance time (initiation of treatment to smear negative for asexual parasites)^a Fever clearance time (initiation of treatment until temperature < 37.2 °C and remained < 37.2 °C for 24 hours)^a Adverse events ^aNot assessed in quantitative synthesis in this review.
Notes	Follow‐up: 28 days Countries (codes): Kenya (KEN) Setting: district hospital Malaria endemicity: high transmission (> 1 case per 1000 population) Source of funding: grant from Glaxo Wellcome Additional correspondence: we emailed the authors on 11 July 2018 but did not receive a reply.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Random assignment of study number".
Allocation concealment (selection bias)	Unclear risk	No allocation concealment described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open label.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Open label.
Incomplete outcome data (attrition bias) All outcomes	Low risk	164/168 (97%) participants evaluable.
Selective reporting (reporting bias)	Low risk	No reporting bias detected.
Other bias	Unclear risk	No assurance given regarding independence of authors.

*Study characteristics*
Methods	Randomized controlled trial Duration: 2 years; January 1999 to December 2000
Participants	Children with uncomplicated P falciparum malaria Number: 200 Inclusion criteria: weight 5–11 kg (age not in inclusion criteria) Exclusion criteria: antimalarials within previous 7 days; underlying severe disease; concomitant infection; mixed infection; allergy to study drugs; severe malaria Diagnosis: parasitaemia 1000–200,000 parasites/μL
Interventions	Atovaquone‐proguanil (atovaquone 62.5 mg + proguanil 25 mg for 3 days) Amodiaquine (amodiaquine chlorohydrate 10 mg/kg of a 1% suspension once daily for 3 days)
Outcomes	28‐day cure rate (absence of early or late treatment failure, no PCR adjustment) Parasite clearance time (treatment initiation until temperature < 37.5 °C and remained at 37.5 °C for > 24 hour)^a Fever clearance time (treatment initiation until first negative blood smear)^a Adverse events (including haematological/biochemical) ^aNot assessed in quantitative synthesis in this review.
Notes	Follow‐up: 28 days Countries (codes): Gabon (GAB) Setting: hospital Malaria endemicity: high transmission (> 1 case per 1000 population) Source of funding: GlaxoSmithKline Additional correspondence: we received email correspondence from S Borrmann on 18 January 2019.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Blocks of 10 and sequentially assigned to groups.
Allocation concealment (selection bias)	Low risk	Sealed envelopes.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label; no reported blinding of outcome assessors (confirmed by S Borrmann in email correspondence).
Incomplete outcome data (attrition bias) All outcomes	High risk	92/100 participants in atovaquone/proguanil group with day 28 data; 78/100 participants in amodiaquine group with day 28 data.
Selective reporting (reporting bias)	Low risk	No reporting bias detected.
Other bias	Unclear risk	Email correspondence from S Borrmann: GlaxoSmithKline sponsored the flights and accommodation for presentation of the study results. 1 author was an employee of GlaxoSmithKline.

*Study characteristics*
Methods	Randomized controlled trial Duration: 1 year; October 1994 to September 1995
Participants	Adults and adolescents with imported uncomplicated P falciparum malaria Number: 48 Inclusion criteria: aged > 16 years; imported malaria from short stay; non‐immune Exclusion criteria: severe malaria; QTc > 0.44 seconds; mixed infection; concomitant disease; inability to take oral treatment; syncope; pregnancy/breastfeeding; weight < 40 kg; resided in an endemic area for the previous year Diagnosis: parasitaemia 1000–100,000 parasites/μL
Interventions	Atovaquone‐proguanil (atovaquone 1 g + proguanil 400 mg as single daily dose for 3 days) Halofantrine (3 doses of 500 mg 6 hours apart)
Outcomes	Cure rate (defined as clinical and parasitological cure at day 7 without recrudescence at day 35) Parasite clearance time (treatment initiation until no asexual forms on thick films)^a Fever clearance (treatment initiation until temperature of 37.2 ºC maintained for > 24 hours)^a Adverse events (including QT elongation) ^aNot assessed in quantitative synthesis in this review
Notes	Follow‐up: 35 days Countries (codes): France (FRA) Setting: not specified Malaria endemicity: imported Source of funding: Glaxo Wellcome Research and Development Additional correspondence: we did not contact the authors.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Open‐label; no blinding of outcome assessors described.
Incomplete outcome data (attrition bias) All outcomes	Low risk	85% of participants assessable.
Selective reporting (reporting bias)	Low risk	No reporting bias detected.
Other bias	Unclear risk	No assurance given regarding independence of authors.

*Study characteristics*
Methods	Randomized controlled trial Duration: 10 months; April 1995 to January 1996
Participants	Adult men with P falciparum malaria Number: 175 Inclusion criteria: men; aged 18–65 years Exclusion criteria: grossly abnormal laboratory results; refusal to be hospitalized for 28 days; inability to tolerate study medication; missing study medication Diagnosis: smear positive with parasitaemia 1000–100,000 parasites/μL
Interventions	Atovaquone‐proguanil (atovaquone 1 g + proguanil 400 mg daily for 3 days) Quinine‐tetracycline (quinine 600 mg 3 times a day + tetracycline 250 mg 4 times a day for 7 days)
Outcomes	28‐day cure rate (based on weekly thick smears) Parasite clearance time (time to last positive blood smear before 3 negatives)^a Fever clearance time (time to last temperature of > 37.8 °C followed by 3 normal temperatures)^a Adverse events ^aNot assessed in quantitative synthesis in this review.
Notes	Follow‐up: 28 days Countries (codes): Brazil (BRA) Setting: National Health Foundation posts Malaria endemicity: high transmission rate (as described in study) Source of funding: Wellcome Diagnostics Additional correspondence: we received email correspondence from F De Alencar on 12 July 2018.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Email correspondence: "The sequence was generated by statisticians of Wellcome Diagnostics and sent to the study sites".
Allocation concealment (selection bias)	Low risk	Email correspondence: "The sequence was kept locked in a cabin and was conferred always by the same investigator at each enrolment as to define the group in where the participant was to be allocated".
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open label.
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding of outcome assessors.
Incomplete outcome data (attrition bias) All outcomes	Low risk	154 analyzed/175 randomized (88%).
Selective reporting (reporting bias)	Low risk	No evidence to suggest selective reporting.
Other bias	Low risk	Financial support from Wellcome Diagnostics. Email correspondence: members of Wellcome did not have any participation in the organization, execution, data collection, or data analysis, being restricted to observe if the study was being performed in a way methodologically sound.

*Study characteristics*
Methods	Randomized controlled trial Duration: 5 months; April 2006 to August 2006
Participants	Adults and children with uncomplicated P falciparum malaria Number: 97 Inclusion criteria: aged > 5 years; temperature ≥ 37.5 °C or history of fever within 24 hours; tolerate oral therapy; residence in study area, suitable for complete audio‐vestibular testing Exclusion criteria: known/suspected hearing deficits; antimalarials within 7 days; mixed infection; severe malaria; severe underlying disease; concomitant disease masking assessment of response; allergy to study medications; pregnancy Diagnosis: thick and thin blood smears
Interventions	Artemether‐lumefantrine (80 mg/480 mg (adults and children ≥ 35 kg bodyweight), at 0, 8, 24, 36, 48, and 60 hours; dose adjusted by weight for younger children. Quinine (~ 8 mg/kg quinine base, 3 times daily for 7 days) Atovaquone‐proguanil (20 mg/8 mg/kg (children < 40 kg bodyweight) or 1000 mg/400 mg (adults and children ≥ 40 kg bodyweight) per day for 3 days (3 doses)
Outcomes	Day 7 treatment failure Total treatment failure at day 28 (PCR adjusted and unadjusted) Tolerability and ototoxicity
Notes	Follow‐up: 90 days Countries (codes): Ethiopia (ETH) Setting: university hospital Malaria endemicity: high transmission (> 1 case per 1000 population) Source of funding: Friedrich‐Baur‐Stiftung, Munich, Germany Additional correspondence: we received email correspondence from T Löscher and N Berens‐Riha on 13 July 2018.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated, stratified by gender and age.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "Open‐label".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The microbiology examiners (parasitology, PCR testing) were blinded to treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Day 28: 90 analyzed/97 randomized (92.7%).
Selective reporting (reporting bias)	Low risk	Email correspondence: trial was registered before study at Ethiopian MOH. Delayed registration at international registry due to 'communication problems'.
Other bias	Low risk	No other bias detected.