Artesunate plus pyronaridine for treating uncomplicated Plasmodium falciparum malaria
Abstract
Background
The World Health Organization (WHO) recommends that people with uncomplicated Plasmodium falciparum malaria are treated using Artemisinin‐based Combination Therapy (ACT). ACT combines three‐days of a short‐acting artemisinin derivative with a longer‐acting antimalarial which has a different mode of action. Pyronaridine has been reported as an effective antimalarial over two decades of use in parts of Asia, and is currently being evaluated as a partner drug for artesunate.
Objectives
To evaluate the efficacy and safety of artesunate‐pyronaridine compared to alternative ACTs for treating people with uncomplicated P. falciparum malaria.
Search methods
We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; LILACS; ClinicalTrials.gov; the metaRegister of Controlled Trials (mRCT); and the WHO International Clinical Trials Search Portal up to 16 January 2014. We searched reference lists and conference abstracts, and contacted experts for information about ongoing and unpublished trials.
Selection criteria
Randomized controlled trials of artesunate‐pyronaridine versus other ACTs in adults and children with uncomplicated P. falciparum malaria.
For the safety analysis, we also included adverse events data from trials comparing any treatment regimen containing pyronaridine with regimens not containing pyronaridine.
Data collection and analysis
Two authors independently assessed trial eligibility and risk of bias, and extracted data. We combined dichotomous data using risk ratios (RR) and continuous data using mean differences (MD), and presented all results with a 95% confidence interval (CI). We used the GRADE approach to assess the quality of evidence.
Main results
We included six randomized controlled trials enrolling 3718 children and adults.
Artesunate‐pyronaridine versus artemether‐lumefantrine
In two multicentre trials, enrolling mainly older children and adults from west and south‐central Africa, both artesunate‐pyronaridine and artemether‐lumefantrine had fewer than 5% PCR adjusted treatment failures during 42 days of follow‐up, with no differences between groups (two trials, 1472 participants, low quality evidence). There were fewer new infections during the first 28 days in those given artesunate‐pyronaridine (PCR‐unadjusted treatment failure: RR 0.60, 95% CI 0.40 to 0.90, two trials, 1720 participants, moderate quality evidence), but no difference was detected over the whole 42 day follow‐up (two trials, 1691 participants, moderate quality evidence).
Artesunate‐pyronaridine versus artesunate plus mefloquine
In one multicentre trial, enrolling mainly older children and adults from South East Asia, both artesunate‐pyronaridine and artesunate plus mefloquine had fewer than 5% PCR adjusted treatment failures during 28 days follow‐up (one trial, 1187 participants, moderate quality evidence). PCR‐adjusted treatment failures were 6% by day 42 for these treated with artesunate‐pyronaridine, and 4% for those with artesunate‐mefloquine (RR 1.64, 95% CI 0.89 to 3.00, one trial, 1116 participants, low quality evidence). Again, there were fewer new infections during the first 28 days in those given artesunate‐pyronaridine (PCR‐unadjusted treatment failure: RR 0.35, 95% CI 0.17 to 0.73, one trial, 1720 participants, moderate quality evidence), but no differences were detected over the whole 42 days (one trial, 1146 participants, low quality evidence).
Adverse effects
Serious adverse events were uncommon in these trials, with no difference detected between artesunate‐pyronaridine and comparator ACTs. The analysis of liver function tests showed biochemical elevation were four times more frequent with artesunate‐pyronaridine than with the other antimalarials (RR 4.17, 95% CI 1.38 to 12.62, four trials, 3523 participants, moderate quality evidence).
Authors' conclusions
Artesunate‐pyronaridine performed well in these trials compared to artemether‐lumefantrine and artesunate plus mefloquine, with PCR‐adjusted treatment failure at day 28 below the 5% standard set by the WHO. Further efficacy and safety studies in African and Asian children are required to clarify whether this combination is an option for first‐line treatment.
PICOs
Plain language summary
Artesunate plus pyronaridine for treating uncomplicated Plasmodium falciparum malaria
What is uncomplicated malaria and how might artesunate‐pyronaridine work
Uncomplicated malaria is the milder form of malaria which usually causes fever, with or without headache, tiredness, muscle pains, abdominal pains, nausea, and vomiting. If left untreated, uncomplicated malaria can rapidly develop into severe malaria with kidney failure, fitting, unconsciousness, and eventually death. Plasmodium falciparum is the most common parasite causing malaria in sub‐Saharan Africa and causes most of the severe malaria worldwide.
The World Health Organization currently recommends countries use one of five different artemisinin‐based combination therapies (ACTs) to treat malaria. These combinations contain an artemisinin component (artemether, dihydroartemisinin, or artesunate), which works quickly to clear the parasite from the person's blood, and a longer‐acting drug which clears the remaining parasites from the blood and may prevent new Plasmodium infections for several weeks. Artesunate plus pyronaridine is a new combination and in this review we evaluate its effectiveness and safety compared to the other ACTs.
After examining the research published up to 16 January 2014, we included six randomized controlled trials, enrolling 3718 children and adults.
What the research says
Based on studies of mostly older children and adults living in Africa and Southeast Asia, artesunate‐pyronaridine is probably as effective as artemether‐lumefantrine at treating uncomplicated malaria and preventing further malaria infections after treatment (moderate quality evidence).
In a study primarily of older children and adults in Asia, artesunate‐pyronaridine is probably as effective as artesunate plus mefloquine at treating P. falciparum malaria and preventing recurrent parasitaemias (moderate quality evidence).
Serious adverse events were rare in people treated with either artesunate‐pyronaridine or other ACTs. However, short‐lasting liver toxicity was more frequent in people treated with artesunate‐pyronaridine than with the other antimalarials (moderate quality evidence).
Authors' conclusions
Artesunate‐pyronaridine performed well compared to the other two ACT with which it has been compared, but further studies in African and Asian children are required to help clarify whether this combination is an option for first‐line treatment.
Authors' conclusions
Summary of findings
| Artesunate‐pyronaridine compared to artemether‐lumefantrine for treating people with uncomplicated falciparum malaria | |||||
| Patient or population: Adults and children with uncomplicated falciparum malaria | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Artemether‐lumefantrine | Artesunate‐pyronaridine | ||||
| Treatment failure (day 28) | PCR‐unadjusted | RR 0.60 (0.40 to 0.90) | 1720 | ⊕⊕⊕⊝ | |
| 7 per 100 | 4 per 100 | ||||
| PCR‐adjusted | RR 1.69 | 1650 | ⊕⊕⊕⊝ | ||
| 1 per 100 | 1 per 100 | ||||
| Treatment failure (Day 42) | PCR‐unadjusted | RR 0.85 (0.53 to 1.36) | 1691 (2 trials) | ⊕⊕⊕⊝ | |
| 17 per 100 | 15 per 100 | ||||
| PCR‐adjusted | RR 1.53 | 1472 | ⊕⊕⊝⊝ | ||
| 2 per 100 | 3 per 100 | ||||
| The assumed risk is the mean risk across the trials in those treated with artemether‐lumefantrine. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 No serious risk of bias: Both trials were well conducted and at low risk of bias. | |||||
| Artesunate‐pyronaridine compared to artesunate plus mefloquine for treating people with uncomplicated P. falciparum malaria | |||||
| Patient or population: People with uncomplicatedP. falciparum malaria | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Artesunate‐mefloquine | Artesunate‐pyronaridine | ||||
| Treatment failure (Day 28) | PCR‐unadjusted | RR 0.35 | 1200 | ⊕⊕⊕⊝ | |
| 4 per 100 | 2 per 100 | ||||
| PCR‐adjusted | RR 0.38 | 1187 | ⊕⊕⊕⊝ | ||
| 2 per 100 | 1 per 100 | ||||
| Treatment failure (Day 42) | PCR‐unadjusted | RR 0.86 | 1146 | ⊕⊕⊕⊝ | |
| 8 per 100 | 7 per 100 | ||||
| PCR‐adjusted | RR 1.64 | 1116 | ⊕⊕⊝⊝ | ||
| 4 per 1000 | 6 per 100 | ||||
| The assumed risk is the risk in the group treated with artesunate plus mefloquine in the single trial. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 No serious risk of bias: This trial was well conducted with low risk of bias. | |||||
| Liver toxicity of pyronaridine compared to other antimalarials | |||||
| Patient or population: People with uncomplicated falciparum malaria | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Comparator antimalarial | Pyronaridine alone or with artesunate | ||||
| Elevated alanine aminotransaminase levels | 2 per 1000 | 10 per 1000 | RR 4.17 | 3523 | ⊕⊕⊕⊝ |
| Elevated aspartate aminotransferase levels Grade 3, 4 toxicity | 2 per 1000 | 8 per 1000 | RR 4.08 | 3528 | ⊕⊕⊕⊝ |
| Elevated alkaline phosphatase levels | 2 per 1000 | 1 per 1000 | RR 0.62 | 2606 | ⊕⊕⊕⊝ |
| Elevated bilirubin | 3 per 1000 | 6 per 1000 | RR 1.92 | 3067 | ⊕⊕⊝⊝ |
| *The basis for the assumed risk (for example, the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 No serious risk of bias: Trials were well conducted, although the data analysis was not clearly independent of the drug manufacturer in three trials. | |||||
Background
Description of the condition
Malaria continues to pose a serious global health challenge despite considerable progress over the past decade to control and eliminate malaria in some parts of the world. In 2010, there were an estimated 219 million malaria illness episodes, resulting in around 660,000 deaths (WHO 2012).
Five species of Plasmodium parasite cause malaria in humans; Plasmodium falciparum and P. vivax are the most common, and P. falciparum causes most of the severe disease cases (WHO 2012). Uncomplicated malaria is the mild form of the disease, typically characterized by fever with or without associated headache, tiredness, muscle pains, abdominal pains, rigors, nausea, and vomiting (WHO 2010a). If left untreated, uncomplicated malaria can rapidly develop into severe, life‐threatening forms of the disease, particularly in people that have not acquired immunity. Effective immunity generally requires repeated infections over five to 10 years, and is reduced during pregnancy. Consequently in highly endemic settings, as seen in many areas of rural sub‐Saharan Africa, young children and pregnant women are most at risk, while in settings with low or seasonal transmission, all age groups can be equally at risk (WHO 2010a).
In many parts of the world, P. falciparum has developed resistance to most antimalarial drugs used as monotherapy (White 2004; WHO 2010b). Consequently, the World Health Organization (WHO) now recommends that P. falciparum malaria is always treated with a combination of two drugs that act at different biochemical sites within the parasite (WHO 2010a). If a parasite mutation producing drug resistance arises spontaneously during treatment, the parasite should then be killed by the partner drug, thus reducing or delaying the development of resistance and increasing the useful lifetime of the individual drugs (White 1996; White 1999).
Five artemisinin‐based combination therapies (ACTs) are now recommended for the first‐line treatment of uncomplicated malaria; artemether‐lumefantrine (AL), artesunate plus amodiaquine (AS+AQ), artesunate plus mefloquine (AS+MQ), artesunate plus sulfadoxine‐pyrimethamine (AS+SP), and dihydroartemisinin‐piperaquine (DHA‐P) (WHO 2010a). The artemisinin components (artemether, artesunate, or dihydroartemisinin) are highly effective schizonticides, and over three days of treatment rapidly eliminate up to 90% of the blood stage asexual forms of P. falciparum. The partner drugs are longer‐acting and are used to clear any residual infection (Nosten 2007; Kurtzhals 2008; WHO 2010a). The combinations with very long half‐lives (AS+MQ and DHA‐P) can provide a period of post‐treatment prophylaxis which may last for up to six weeks (Sinclair 2009).
Resistance to the artemisinin‐derivatives was first reported among P. falciparum strains in 2008 along the Thai‐Cambodian border (Dondorp 2010; Lim 2010; WHO 2010b). This has led to global initiatives to contain the spread of artemisinin resistance, which includes the development of new drugs to partner and protect the artemisinin‐derivatives in ACT (WHO 2011).
Description of the intervention
Pyronaridine is a benzonaphthyridine derivative first synthesized in China in 1970 (Fu 1991). It was used extensively as a monotherapy to treat P. falciparum and P. vivax infections in the Hunan and Yunan provinces of China for more than 20 years (Chen 1992), and to treat P. falciparum in some parts of Africa during the 1980s. Between 1985 and 1995, some in vitro pyronaridine‐resistant strains of P. falciparum emerged along the China‐Lao and China‐Myanmar border areas (Yang 1997).
Elsewhere, in vitro studies using clinical isolates of P. falciparum from Africa, Cambodia, and Thailand in the 1990s demonstrated high activity of pyronaridine against chloroquine‐sensitive and chloroquine‐resistant P. falciparum strains (Childs 1988; Basco 1992; Chen 1992; Pradines 1998; Ringwald 1999), and more recent in vitro studies have also shown pyronaridine to be effective against multiple‐drug resistant P. falciparum schizonts and gametocytes in Thailand and Indonesia (Chavalitshewinkoon‐Petmitr 2000; Price 2010), and against chloroquine‐resistant P. falciparum strains in Gabon (Kurth 2009). However, almost half of 28 P. falciparum isolates tested in vitro in Abidjan, Cote d'Ivoire, were resistant to pyronaridine and also showed some evidence of cross resistance to dihydroartemisinin (Brice 2010).
Pyronaridine interferes with the glutathione‐dependent detoxification of haem and targeting of β‐haematin formation (Auparakittanon 2006). Its activity in multi‐drug resistant strains of P. falciparum is believed to be due to its ability to inhibit P‐glycoprotein function and reverse multi‐drug resistance in cell lines (Qi 2002; Pradines 2010).
Pyronaridine is structurally related to amodiaquine, leading to some concerns that pyronaridine may have similar toxicity related to the formation of a reactive metabolite (quinoneimine) in the liver and white blood cells. However, some studies suggest that pyronaridine and other bis‐Mannich compounds are structurally advantaged and do not form the bioactive quinoneimine metabolite (Naisbitt 1998; Ruscoe 1998).
Assessment of antimalarial drug efficacy
The WHO recommends that new antimalarials should have a treatment failure rate of less than 5%, and that failure rates greater than 10% with existing first‐line antimalarials should trigger a change in treatment policy (WHO 2010a).
Treatment failure can be classified as:
Early treatment failure:
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the development of danger signs or severe malaria on days 1, 2, or 3 in the presence of parasitaemia;
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parasitaemia on day 2 higher than on day 0;
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parasitaemia and axillary temperature > 37.5 °C on day 3;
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parasitaemia on day 3 > 20% of count on day 0.
Late treatment failure:
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development of danger signs, or severe malaria, after day 3 with parasitaemia;
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presence of P. falciparum parasitaemia and axillary temperature > 37.5 °C on or after day 4;
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presence of P. falciparum parasitaemia after day 7.
The late reappearance of P. falciparum parasites in the blood of an infected person can be due to failure of the drug to completely clear the original parasite (a recrudescence) or due to a new infection, which is especially common in areas of high transmission. A molecular genotyping technique called polymerase chain reaction (PCR) can be used in clinical trials to distinguish between recrudescence and new infection, giving a clearer picture of the efficacy of the drug and its post‐treatment prophylactic effect (White 2002; Cattamanchi 2003; WHO 2008).
The WHO recommends a minimum follow‐up period of 28 days for antimalarial efficacy trials, but longer periods of follow‐up may be required for antimalarials with long elimination half‐lives (White 2002; Bloland 2003). Treatment failure due to true recrudescence of malaria parasites may be delayed until the drug concentration falls below the minimum concentration required to inhibit parasite multiplication, which may be beyond 28 days. The WHO recommends 42 days follow‐up for trials involving lumefantrine and piperaquine and 63 days follow‐up for trials of mefloquine (WHO 2010a).
Why it is important to do this review
Early studies of pyronaridine monotherapy conducted in Africa showing efficacy against chloroquine‐resistant P. falciparum malaria (Ringwald 1999), and promising dose finding studies of the artesunate‐pyronaridine combination from the Gabon (Ramharter 2008), have led to the promotion of artesunate‐pyronaridine as a possible addition to the current list of recommended ACTs (Vivas 2008; Croft 2010).
This review aims to systematically evaluate the available trials on the effectiveness and safety of artemisinin plus pyronaridine for consideration by global and national policy makers.
Objectives
To evaluate the efficacy and safety of artesunate‐pyronaridine compared to alternative ACTs for treating people with uncomplicated P. falciparum malaria.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCTs).
Types of participants
Adults and children with uncomplicated P. falciparum malaria, as confirmed by either microscopy or rapid diagnostic tests.
Types of interventions
Intervention
Artesunate plus pyronaridine.
Control
WHO‐recommended ACTs for treating malaria.
For an additional safety analysis we extended the inclusion criteria to all RCTs comparing pyronaridine alone or in combination with any other antimalarial.
Types of outcome measures
We used current WHO recommendations to guide the selection of outcomes for this review (Bloland 2003; WHO 2008).
Primary outcomes
Total treatment failure at day 28, 42, or 63 (PCR‐unadjusted and PCR‐adjusted).
Secondary outcomes
-
Early treatment failure
-
Parasite clearance
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Fever clearance
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Gametocyte carriage
Adverse events
-
Serious adverse events (leading to death, requiring hospitalization or prolongation of existing hospitalization, are life threatening, or result in persistent or significant disability or incapacity)
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Adverse events leading to withdrawal from treatment (discontinuation of trial drug or withdrawal from trial)
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Patient reported symptoms
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Abnormal liver function tests (LFTs)
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Abnormal WBC counts
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Abnormal electrocardiogram (ECG) findings
Search methods for identification of studies
We attempted to find all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).
Electronic searches
We updated previous literature searches done in February 2007 and August 2012 of the following databases using the search terms and strategy described in Appendix 1 up to 16 January 2014: Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; and LILACS. We also searched ClinicalTrials.gov, the metaRegister of Controlled Trials (mRCT) and the WHO's International Clinical Trials Registry Platform Search Portal for ongoing or recently completed trials using 'pyronaridine' and 'malaria' as search terms.
Searching other resources
Conference proceedings
We searched the following conference proceedings for relevant abstracts: The American Society of Tropical Medicine and Hygiene Annual Meetings (2007, 2008, 2009, and 2010); The Third ASEAN Congress of Tropical Medicine and Parasitology (ACTMP3); the MIM Pan‐African Malaria Conference (2005 and 2009); the International Congress on Infectious Diseases (ICID) (2002, 2004, 2008, and 2010); the International Conference on Malaria: 125 years of Malaria Research 2005; the Keystone Symposia Global Health Series: and Malaria (Immunology, pathogenesis and perspectives) 2008.
Reference lists
We checked the reference lists of all trials identified by the above methods.
Contacting organizations and experts
We contacted the Medicines for Malaria Venture and the WHO for information about ongoing and unpublished trials.
Data collection and analysis
Selection of studies
Hasifa Bukirwa (HB) and Prathap Tharyan (PT) independently scanned the results of the search strategy and retrieved the full text articles of all potentially relevant trials, conscious of the possibility of multiple publications of the same trial. HB and PT independently assessed each potentially relevant trial for inclusion in the review using an eligibility form based on the inclusion criteria. There were no disagreements. We excluded studies that did not meet the eligibility criteria and listed the reasons for exclusion in the 'Characteristics of excluded studies' table.
Data extraction and management
HB and PT independently extracted the data from the trials using data extraction forms. We resolved disagreements through discussion. For dichotomous outcome measures, we recorded the number of participants experiencing the event and the number analysed in each group. For continuous outcome measures, we extracted arithmetic means and standard deviations for each group together with the numbers analysed in each group.
Primary outcome
Our primary analysis drew on the WHO's protocol for assessing and monitoring antimalarial drug efficacy (Bloland 2003). This protocol has been used to guide most efficacy trials since its publication in 2003, even though it was designed to assess the level of antimalarial resistance in the trial area rather than for comparative trials. As a consequence, a high number of randomized participants are excluded from the final efficacy outcome as losses to follow‐up or voluntary or involuntary withdrawals (see Table 1).
| Analysisa | Participants | PCRb‐unadjusted | PCR‐adjusted | ||
| Numerator | Denominator | Numerator | Denominator | ||
| Primary analysis | Exclusions after enrolment | Excludedc | Excluded | Excluded | Excluded |
| Missing or indeterminate PCR | Included as failures | Included | Excluded | Excluded | |
| New infections | Included as failures | Included | Excluded | Excluded | |
| Sensitivity analysis 1d | As 'Primary analysis' except: missing or indeterminate PCR | — | — | Included as failures | Included |
| Sensitivity analysis 2e | As 'Sensitivity analysis 1' except: new infections | — | — | Included as successes | Included |
| Sensitivity analysis 3f | As 'Sensitivity analysis 2' except: exclusions after enrolment | Included as failures | Included | Included as failures | Included |
| Sensitivity analysis 4g | As 'Sensitivity analysis 2' except: exclusions after enrolment | Included as successes | Included | Included as successes | Included |
aNote: we removed participants that did not satisfy the inclusion criteria after randomization from all calculations.
bPCR: polymerase chain reaction.
c'Excluded' means removed from the calculation.
dTo re‐classify all indeterminate or missing PCR results as treatment failures in the PCR‐adjusted analysis.
eTo re‐classify all PCR‐confirmed new infections as treatment successes in the PCR‐adjusted analysis. (This analysis may overestimate efficacy as PCR is not wholly reliable and some recrudescences may be falsely classified as new infections. Also some participants may have gone on to develop a recrudescence after the new infection).
fTo re‐classify all exclusions after enrolment (losses to follow‐up, withdrawn consent, other antimalarial use, or failure to complete treatment) as treatment failures. For PCR‐unadjusted total failure this represents a true worse‐case scenario.
gTo re‐classify all exclusions after enrolment (losses to follow‐up, withdrawn consent, other antimalarial use, or failure to complete treatment) as treatment successes.
PCR‐unadjusted total failure
We calculated PCR‐unadjusted total failure (P. falciparum) as the sum of early treatment failures and late treatment failures (without PCR adjustment). The denominator excludes participants for whom an outcome was not available (for example, those who were lost to follow‐up, withdrew consent, took other antimalarials, or failed to complete treatment) and those participants who did not to fulfil the inclusion criteria after randomization.
PCR‐adjusted total failure
We determined PCR‐adjusted total failure (P. falciparum) as the sum of early treatment failures, and late treatment failures due to PCR‐confirmed recrudescence. We treated participants with indeterminate PCR results, missing PCR results, or PCR‐confirmed new infections as involuntary withdrawals and excluded them from the calculation. The denominator excludes participants for whom an outcome was not available (for example, those who were lost to follow‐up, withdrew consent, took other antimalarials, or failed to complete treatment) and participants who did not fulfil the inclusion criteria after randomization.
These primary outcomes relate solely to failure due to P. falciparum. For both PCR‐unadjusted and PCR‐adjusted total failure, we retained in the calculation participants who developed P. vivax parasitaemia during follow‐up if they were treated with chloroquine and continued to be monitored by the trialists. We classified them as treatment successes provided they did not go on to develop P. falciparum parasitaemia. We excluded from the calculation participants who developed P. vivax parasitaemia and were removed from the trial's follow‐up at the time of P. vivax parasitaemia.
Assessment of risk of bias in included studies
For efficacy outcomes we assessed the risk of bias for each included trial using the Cochrane tool for assessing the risk of bias (Higgins 2011). For each of six domains; sequence generation; allocation concealment; blinding of participants, trial personnel and outcome assessors; incomplete outcome data; selective reporting; and other sources of bias, we assigned a judgment regarding the risk of bias. We classified these judgments as 'high risk', 'low risk ', or 'unclear risk' of bias. We recorded these assessments in the standard 'risk of bias' tables and summarized the risk of bias for each trial in a summary risk of bias graph.
For patient reported adverse events, we assessed the risk of bias by examining if monitoring was active or passive; whether participants and outcome assessors were blinded; whether the outcome data reporting was complete; whether all participants were included; and whether data analysis was independent of pharmaceutical companies (Table 2).
| Criterion | Assessment | Explanation |
| Patient‐reported symptoms | ||
| Was monitoring active or passive?
| Active Passive Unclear | We classified monitoring as 'active' when authors reviewed participants at set timepoints and enquired about symptoms. |
| Was blinding for participants and outcome assessors adequate? | Adequate Inadequate Unclear | We classified blinding as 'adequate' when both participants and outcome assessors were blinded to the intervention group, and the methods of blinding (including use of a placebo) were described. |
| Was outcome data reporting complete or incomplete? | Complete Incomplete Unclear | We classified outcome data reporting as 'complete' when data was presented for all the time‐points where it was collected. |
| Were all participants included in reporting? | We report the percentage of randomized participants included in adverse event reporting. | |
| Was theanalysis independent of study sponsor? | Yes No Unclear | We classified the analysis of trials sponsored by pharmaceutical companies as independent of the sponsor when it was clearly stated that the sponsor had no input to the trial analysis |
| Laboratory tests | ||
| Number of tests undertaken | — | We extracted the type and number of laboratory tests were taken. |
| Timing of tests Was number and timing of tests adequate? | Adequate Inadequate | We classified the number and timing of tests as 'adequate', when tests were taken at baseline, plus two other timepoints within the first week after treatment, plus the last day of the study. We classed the number of test taken as "inadequate", if either the laboratory controls in the first week or controls at four weeks were not performed. |
| Reporting of test results Was reporting of test results complete? | Complete Incomplete | We classified reporting as 'complete' when test results of all time points were reported. For the trials with inadequate number of tests taken, we considered completeness of reporting as inconsequential, and therefore did not record a judgement. |
| Independence of data analysis Was data analysis independent? | Yes No Unclear | We classified the analysis of trials sponsored by pharmaceutical companies as independent of the sponsor when it was clearly stated that the sponsor had no input to the trial analysis |
For laboratory reported adverse events, we assessed the risk of bias by examining which tests were performed, the timing of the tests, the completeness of reporting, and the independence of the data analysis (Table 2).
Measures of treatment effect
We extracted data from each included trial to calculate risk ratios, 95% confidence intervals (CIs) for dichotomous data, and mean differences with 95% CIs for continuous data.
Unit of analysis issues
We did not encounter any unit of analysis issues.
Dealing with missing data
If data from the trial reports were insufficient, unclear, or missing, we attempted to contact the trial authors for additional information. If we considered that the missing data rendered the result uninterpretable, we excluded the data from the meta‐analysis and clearly stated the reason for exclusion. We explored the potential effects of missing data through a series of sensitivity analyses (Table 1).
Assessment of heterogeneity
We assessed heterogeneity amongst trials by inspecting the forest plots, applying the Chi² test with a 10% level of statistical significance, and also using the I² statistic with a value of 50% used to denote moderate levels of heterogeneity.
Assessment of reporting biases
There were too few trials to examine funnel plot asymmetry for evidence of small trial effects or publication bias.
Data synthesis
We analysed data using Review Manager 2011.
For the primary analysis we stratified by comparator ACT, and when outcomes were assessed and reported at different time‐points, we also stratified the analyses by time point. We performed meta‐analysis where appropriate after assessment and investigation of heterogeneity. In the first instance, we used a fixed‐effect model and applied a random‐effects model when the Chi² test P value was < 0.1 or the I² statistic was > 50%.
Arithmetic means and standard deviations used to summarize continuous data are assumed to be normally distributed; however, sometimes these summary statistics are incorrectly used when the data are not normally distributed. Therefore, when arithmetic means were reported, we checked the normality of the data by calculating the ratio of the mean over the standard deviation. If this ratio (mean/standard) was < 2, then it is likely that the data are skewed as the mean cannot then lie in the centre of a normal distribution. It is possible to combine data with less severe degrees of skew in meta‐analyses and when ratio of the mean over the standard deviation was more than one (ratios less than one indicate that data were severely skewed), we combined data from these trials with normally distributed data.
Subgroup analysis and investigation of heterogeneity
There were too few trials to use subgroup analyses to explore the causes of heterogeneity. However, to explore the generalizability of the evidence we subgrouped the available data by age (< 5 years versus ≥ 5 years), country, and geographic region.
Sensitivity analysis
We assessed that all three trials were at low risk of bias so we did not perform a sensitivity analysis exploring effects of risk of bias.
To investigate the robustness of the methodology used in the primary analysis, we conducted a series of sensitivity analyses. The aim of this was to restore the integrity of the randomization process by adding excluded groups back into the analysis in a stepwise fashion (see Table 1 for details).
Quality of evidence
We assessed the quality of evidence across each outcome measure using the GRADE approach. The quality rating across studies has four levels: high, moderate, low, or very low. RCTs are initially categorized as high quality but can be downgraded after assessment of five criteria: risk of bias, consistency, directness, imprecision, and publication bias (Guyatt 2008).
Results
Description of studies
See Characteristics of included studies, and Characteristics of excluded studies sections.
Results of the search
Of the 52 reports we retrieved by the search, we identified 39 potentially relevant reports. Three trials comparing artesunate‐pyronaridine with other ACTs met the inclusion criteria for the main review (Tshefu 2010; Kayentao 2012; Rueangweerayut 2012). We included three additional trials for a further assessment of the effect of pyronaridine on liver function (Ringwald 1996; Ringwald 1998; Poravuth 2011). We described the results of the search in a flow diagram (Figure 1)
Flow diagram.
Included studies
Efficacy trials
The three efficacy trials were all Phase III non‐inferiority trials conducted by the public‐private partnership of Medicines for Malaria Venture (Switzerland) and Shin Poong Pharmaceuticals (Korea) for registration with the European Medicines Agency (Tshefu 2010; Kayentao 2012; Rueangweerayut 2012).
Artesunate‐pyronaridine versus artemether‐lumefantrine
Two multicentre trials that included 1807 participants evaluated this comparison (Tshefu 2010; Kayentao 2012).
Most participants (88.3%) were recruited from trial sites in Africa (Burkina Faso, Cote d'Ivoire, Democratic Republic of Congo, Gabon, The Gambia, Ghana, Kenya, Mali, Mozambique, and Senegal), with a small number (11.7%) from Southeast Asia (Indonesia and the Phillipines). All recruiting sites were endemic for P. falciparum malaria and most were reported as highly endemic.
Most participants were older children or adults, and only 232 children aged under five years, and 15 aged under one year were included.
Important exclusion criteria were severe malaria, cerebral malaria, severe anaemia, pregnant and lactating women, and people with hepatic, renal, or other disorders. Tshefu 2010 also excluded those with severe malnutrition and Kayentao 2012 excluded children with HIV infection.
In both trials, artesunate‐pyronaridine was administered once daily for three days, and artemether‐lumefantrine twice daily for three days in the standard dosing (see Table 3).
| Trial ID | Actual or target dose | Intervention | Comparator | ||
| Artesunate | Pyronaridine | Artemisinin‐derivative | Partner drug | ||
| Actual dose | 2.2 to 4.4 | 6.7 to 13.3 | 1.3 to 4.0 | 8.0 to 24.0 | |
| Target dose | 2.4 to 4.6 | 7.2 to 13.8 | NS | NS | |
| Actual dose | 2.4 to 4.7 | 7.1 to 14.0 | 2.5 to 5.0 | 6.2 to 12.5 | |
| Target dose | 2.4 to 4.6 | 7.2 to 13.8 | — | 10, 5, 5 | |
| Target dose | — | 16, 8, 8 | — | 10, 5, 5 | |
| Target dose | — | 8, 8, 8, 8 | — | 10, 10, 5 | |
NS = Not specified.
Artesunate‐pyronaridine versus artemether plus mefloquine
A single multicentre trial, enrolling 1271 participants evaluated this comparison (Rueangweerayut 2012).
Most participants (81.3%) were from Southeast Asia (Cambodia, India, Thailand, and Vietnam), with a smaller number (18.7%) from Africa (Burkina Faso, Ivory Coast, and Tanzania). Malaria endemicity was high in most sites.
Although the trial planned to recruit participants aged between 3 to 60 years, the youngest participant was five years old.
Important exclusion criteria were severe malaria, cerebral malaria, severe anaemia, severe malnutrition, pregnant and lactating women, and people with hepatic or renal disorders.
Both artesunate‐pyronaridine and artesunate plus mefloquine were administered once daily for three days (see Table 3).
Additional safety trials
The three additional safety trials compared artesunate‐pyronaridine versus chloroquine (Poravuth 2011), and pyronaridine alone versus chloroquine (Ringwald 1996; Ringwald 1998).
Poravuth 2011 was conducted in Asia and primarily evaluated the effects of artesunate‐pyronaridine on P. vivax malaria (Cambodia, India, Indonesia, and Thailand). Ringwald 1996 and Ringwald 1998 were conducted in Cameroon.
Poravuth 2011 randomized 456 participants aged seven years to 60 years; Ringwald 1996 randomized 96 adults aged 15 to 64 years, and Ringwald 1998 recruited 88 children only, aged five years to 15 years.
For further details of the included trials see the 'Characteristics of included studies' tables.
Excluded studies
We excluded 21 trials (22 records) for the reasons described in the 'Characteristics of excluded studies' table. In brief; 13 were not randomized, four were quasi‐randomized (used alternation), and five did not have populations, comparisons, or outcomes of relevance to this review (Figure 1).
One trial comparing pyronaridine alone for three days versus dihydroartemisinin alone for seven days versus a combination of pyronaridine and dihydroartemisinin for three days did not meet the inclusion criteria for the primary efficacy analysis due to the lack of an appropriate comparison arm with an ACT, and was not included in the safety analysis as LFTs were not reported (Liu 2002).
Risk of bias in included studies
See Figure 2.
Risk of bias summary table (Methodological quality summary): review authors' judgements about each methodological quality item for each included trial.
Allocation
All trials were at low risk of selection bias.
Blinding
The four non‐inferiority trials were at low risk for performance and detection bias as they used double‐dummy techniques, or independent outcome assessors and trial personnel who were not aware of allocation (Tshefu 2010; Poravuth 2011; Kayentao 2012; Rueangweerayut 2012).
The additional two safety trials (Ringwald 1996; Ringwald 1998) were open label or inadequately masked but were at low risk of bias, since blinding would not affect detection of the adverse outcomes sought in this review.
Incomplete outcome data
All of the included trials reported attrition with details of all randomized participants.
Selective reporting
Tshefu 2010; Poravuth 2011; Kayentao 2012 and Rueangweerayut 2012 were prospectively registered and appeared free of selective reporting, as ascertained from the data presented in the reports, the registration documents, and where available, the trial protocols.
Other potential sources of bias
We considered that Ringwald 1996; Ringwald 1998; and Tshefu 2010 had other potential biases (see Risk of bias tables) but the effects on these on outcomes are uncertain.
For adverse events, we conducted additional assessments of the adequacy of safety monitoring and the completeness of reporting. For patient reported adverse events, the method for monitoring adverse events was unclear in all six trials, the days monitoring occurred was unclear in five trials, and the day of outcome reporting unclear in all six trials (see Table 4). For biochemical adverse events, the frequency of testing was adequate in three trials (Tshefu 2010; Poravuth 2011; Kayentao 2012), and reporting was complete in two trials (Tshefu 2010; Poravuth 2011; see Table 5).
| Trial ID | Monitoring active or passive? | Outcome data reporting | Blinding adequate? | % of participants included in AE reporting | Independent data analysis | ||||
| Days data collected | Days data reported | Patient | Clinician | Data analysis | AS‐Pyr | Control | |||
| Unclear | 0 to 3, 7, 14, 21, 28, 35, 42 | Unclear | Yes | Yes | Unclear | 100% | 100% | No | |
| Unclear | Unclear | Unclear | No | No | Yes | 100% | 100% | No | |
| Unclear | Unclear | Unclear | No | No | Unclear | 100% | 100% | No | |
| Unclear | Unclear | Unclear | Yes | Yes | Yes | 100% | 100% | Yes | |
| Unclear | Unclear | Unclear | No | No | Unclear | Unclear | Unclear | Yes | |
| Unclear | Unclear | Unclear | No | No | Unclear | 100% | 100% | Yes | |
| Trial ID | Number of tests | Days tested | Days reported | Days tested adequate? | For adequate testing, was reporting complete? | Data analysis independent of sponsor? |
| 41 | 0, 3, 7, 282 | 3, 7, 28 | Adequate | Complete | No | |
| 41 | 0, 3, 7, 28, 42 | 3, 7 | Adequate | Incomplete 3 | No | |
| 41 | 0, 28, 42 | 0, “post baseline” | Inadequate | ‐4 | No | |
| 41 | 0, 3, 7, 282 | 3, 7, 28 | Adequate | Complete | Yes | |
| 41 | 0, 7 | 0, 7 | Inadequate | — | Yes | |
| 51,5 | 0, 7 | 0, 7 | Inadequate | — | Yes |
1 Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TBIL).
2 Plus day 42 if clinically indicated.
3 Does not report the outcome data for day 28 in additional file 3.
4 The trial did not report ALP values for all participants (ALT and AST values for 848 patients in the artesunate pyronaridine arm and for 423 participants in the artesunate mefloquine arm at baseline; AST values only for 635 participants and 308 participants respectively at baseline).
5 Plus conjugated bilirubin in addition.
Effects of interventions
See: Summary of findings for the main comparison Artesunate‐pyronaridine compared to artemether‐lumefantrine for uncomplicated falciparum malaria; Summary of findings 2 Artesunate‐pyronaridine compared to artesunate plus mefloquine for treating uncomplicated P. falciparum malaria; Summary of findings 3 Liver toxicity of pyronaridine compared to other antimalarials
Comparison 1. Artesunate‐pyronaridine versus artemether‐lumefantrine
Two trials, including 1595 participants from Africa and 212 from Southeast Asia, compared artesunate‐pyronaridine with artemether‐lumefantrine (Tshefu 2010; Kayentao 2012). Only Kayentao 2012 included children aged under five years (232 children), of which only 15 were aged under one year. Follow‐up was until day 42.
Treatment failure
At day 28, the proportion of participants with recurrent parasitaemia was lower in those treated with artesunate‐pyronaridine compared to artemether‐lumefantrine (PCR‐unadjusted treatment failure; RR 0.60, 95% CI 0.40 to 0.90; two trials, 1720 participants, Analysis 1.1, Figure 3). However, after PCR‐adjustment treatment failure, it was below 5% with both ACTs, with no differences between groups (PCR‐adjusted treatment failure: two trials, 1650 participants, Analysis 1.1).
Forest plot of comparison: 1 Artesunate‐pyronaridine versus artemether‐lumefantrine, outcome: 1.1 Total failure (Day 28).
At day 42, there were no significant differences between artesunate‐pyronaridine and artemether‐lumefantrine for PCR‐unadjusted (two trials, 1691 participants, Analysis 1.2) or PCR‐adjusted treatment failure (two trials, 1472 participants, Analysis 1.2). PCR‐adjusted treatment failure with artesunate‐pyronaridine was marginally above 5% in one trial at this time‐point (6.8%).
Only two people on artesunate‐pyronaridine and one on artemether‐lumefantrine experienced early treatment failure (two trials, 1676 participants, Analysis 1.3).
Parasite clearance
Both trials reported that artesunate‐pyronaridine cleared parasites from the peripheral blood quicker than artemether‐lumefantrine. Tshefu 2010 reported a slightly lower mean clearance time (MD 3.2 hours, 95% CI 4.38 to 2.02; one trial, 1170 participants; Analysis 1.4), and Kayentao 2012 reported a slightly lower median clearance time (24.1 hours, 95% CI 24.0 to 24.1 with artesunate‐pyronaridine versus 24.2 hours, 95% CI 24.1 to 32.0 with artemether‐lumefantrine; P = 0.02, authors' own figures, one trial, 535 participants, Table 6). These differences are probably not clinically important.
| Trial ID | Outcome | Artesunate‐pyronaridine | Artemether‐lumefantrine | P value |
| Median parasite clearance time | 24.1 hours | 24.2 hours (95% CI 24.1 to 32.0) | 0.02 | |
| Median fever clearance time | 8.1 hours | 8.1 hours | 0.049 | |
| "Post‐baseline gametocytes" | 95/354 (26.8%) | 44/178 | 0.6 | |
| Gametocyte development | 53/354 | 20/178 | 0.24 |
Fever clearance
Fever clearance times were similar between groups in both trials. Tshefu 2010 reported mean fever clearance time as marginally shorter following treatment with artesunate‐pyronaridine than artemether‐lumefantrine (MD 1.2 hours, 95% CI 2.38 to 0.02 hours, one trial, 1170 participants, Analysis 1.5), while Kayentao 2012 reported equal median clearance times (8.1 hours with artesunate‐pyronaridine versus 8.1 hours with artemether‐lumefantrine, P = 0.049, authors' own figures, one trial, 535 participants, Table 6).
Gametocyte clearance and carriage
In Tshefu 2010, 8% of participants given artesunate‐pyronaridine and 5% of those given artemether‐lumefantrine had peripheral gametocytaemia at baseline. The mean time to gametocyte clearance was 10.5 hours shorter with artesunate‐pyronaridine (MD 10.5 hours, 95% CI 12.4 to 8.60; one trial, 1170 participants, Analysis 1.6).
In Kayentao 2012, 13% of participants had gametocytes at baseline. No subsequent statistically significant differences in gametocyte carriage, or gametocyte development were reported (one trial, 532 participants, Table 6).
Serious adverse events
Neither trial reported any deaths. There were six serious adverse events in total with no significant difference between groups (0.3% with artesunate‐pyronaridine versus 0.3% with artemether‐lumefantrine; two trials, 1787 participants, Analysis 1.7).
Adverse events leading to withdrawal from treatment
There was no significant difference between groups in the proportion of participants withdrawn from the trial due to adverse events (2.3% with artesunate‐pyronaridine versus 1.7% with artemether‐lumefantrine; two trials, 1787 participants, Analysis 1.8).
Patient‐reported symptoms
There were no significant differences in patient‐reported symptoms between the two ACTs (two trials, 1807 participants, Analysis 1.9, Analysis 1.10). The trial authors reported symptoms of vomiting, headache, abdominal pain, vertigo, haematuria, upper abdominal pain, and anorexia.
Biochemical monitoring and adverse events
Both trials measured biochemical LFTs in all participants at baseline and on days three and seven (Kayentao 2012 also measured LFTs on day 28), Although the two trials used slightly different grading scales, there were no significant differences between groups in grade 3 or 4 liver toxicity by any of the measures used (two trials, 1807 participants, Analysis 1.11, Analysis 1.12).
Haematological monitoring and adverse events
In both trials the mean haemoglobin fell compared to baseline during the first seven days after starting treatment, before recovering by day 28 (two trials, 1807 participants, Analysis 1.12). At day seven the reduction in haemoglobin was greater with artesunate‐pyronaridine but this is unlikely to be of clinical significance (MD ‐0.16, 95% CI ‐0.28 to ‐0.05; two trials, 1741 participants, Analysis 1.12).
Kayentao 2012 also reported the occurrence of anaemia as an adverse event with no differences between groups (one trial, 535 participants, Analysis 1.13).
ECG monitoring and adverse events
Both trials conducted ECG monitoring at baseline, days 2, 7, 14 and 28. Tshefu 2010 reported two participants in each group having abnormal ECG readings and reported these as "mild". Kayentao 2012 reported that there were "no post‐baseline clinically important abnormal ECG results" (see Table 7).
| Trial ID | Days tested | ECG results | |
| Pyronaridine arm | Comparator arm | ||
| 0, 2, 7, 14, and 28 | "no post baseline clinically important ECG results" | "no post baseline clinically important ECG results" | |
| 0, 2, 7, 14, and 28 | 1 patient with T‐wave inversion at day 2 1 patient with ventricular premature complexes and extended QTc (manual reading QTcB 461 ms, QTcF 458 ms) at day 21 | 1 patient with sinus bradycardia and sinus arrhythmia on day 2 1 patient with sinus bradycardia on day 2 | |
| Unclear | 6/848 (0.7%) patients with abnormal ECGs‐ "All were mild and resolved before study completion" | 3/423 (0.7%) patients with abnormal ECGs ‐ "All were mild and resolved before study completion" 3/423 with long or prolonged QT interval ‐ None had a QT interval that exceeded 480 msec | |
| 0, 2, 7, 14, and 42 | 1/226 (0.4%) patients with QTc prolongations | 6/222 (2.7%) patients with QTc prolongations (1/222 not drug‐related) | |
Subgroup analysis
We have presented a subgroup analysis of PCR‐adjusted treatment failure at day 28 by age of participants in Analysis 2.1. This demonstrates the paucity of data for the under‐five age group.
Further subgroup analyses by geographical region and country are in Analysis 2.2 and Analysis 2.3. Again, these demonstrate that the data remain severely underpowered to inform national decision‐making. Primary outcome data was available for only 194 participants from East Africa, compared to 816 from West Africa, 490 from South‐central Africa, and 175 from Asia.
Sensitivity analysis
We conducted a sensitivity analysis to explore the influence of different methods for analysing the primary outcome data. For PCR‐unadjusted treatment failure, our primary analysis following the WHO guidelines for analysing trials of antimalarials was the least conservative (Analysis 3.1). The per‐protocol and intention‐to‐treat analyses as presented by the trial authors, where missing data were considered treatment failure, were more conservative and the result did not reach statistical significance. For PCR‐adjusted treatment failure, there were no substantial differences (Analysis 3.2).
We did not undertake a sensitivity analysis by risk of bias criteria as both of the included trials were at low risk of bias.
Comparison 2. Artesunate‐pyronaridine versus artesunate plus mefloquine
Only one trial, enrolling 1033 participants from Asia and 238 from Africa, compared artesunate‐pyronaridine versus artemether‐lumefantrine (Rueangweerayut 2012). This trial excluded children under five years of age and follow‐up was until day 42.
Treatment failure
At day 28, the proportion of participants with recurrent parasitaemia was lower in those treated with artesunate‐pyronaridine compared to artesunate plus mefloquine (PCR‐unadjusted treatment failure: RR 0.35, 95% CI 0.17 to 0.73; one trial, 1200 participants, Analysis 4.1). However, after PCR‐adjustment treatment, failure was below 5% with both ACTs with no differences between groups (one trial, 1187 participants, Analysis 4.1).
At day 42, there were no statistically significant differences between artesunate‐pyronaridine and artesunate plus mefloquine for PCR‐unadjusted or PCR‐adjusted treatment failure (one trial, 1146 participants, Analysis 4.2). At this time point, PCR‐adjusted treatment failure was 5.8% with artesunate‐pyronaridine versus 3.6% with artesunate plus mefloquine.
One person treated with artesunate plus mefloquine experienced early treatment failure and developed cerebral malaria (one trial, 1103 participants, Analysis 4.3).
Parasite clearance
The mean parasite clearance time was slightly lower with artesunate‐pyronaridine compared to artesunate plus mefloquine (MD 2.60 hours, 95% CI 4.94 to 0.26, one trial, 1259 participants, Analysis 4.4).
Fever clearance
Fever clearance time was similar between treatment arms (one trial, 1051 participants, Analysis 4.5).
Gametocyte clearance and carriage
Rueangweerayut 2012 only reported the mean time to gametocyte clearance for the 27 participants (13 on artesunate‐pyronaridine versus 14 on artesunate plus mefloquine) who cleared their gametocytes within the first 72 hours. There was no difference between groups (one trial, 27 participants, Analysis 4.6).
Serious adverse events
Rueangweerayut 2012 did not report any deaths. There were nine serious adverse events in total with no significant difference between groups (0.7% with artesunate‐pyronaridine versus 0.7% with artesunate plus mefloquine; one trial, 1271 participants, Analysis 4.7).
Adverse events leading to withdrawal from treatment
There was no significant difference between groups in the proportion of participants withdrawn from the trial due to adverse events (0.6% with artesunate‐pyronaridine versus 0.9% with artesunate plus mefloquine; one trial, 1271 participants, Analysis 4.8).
Patient‐reported symptoms
Rueangweerayut 2012 only reported symptoms if they occurred in at least 2% of patients. Dizziness was twice as common in those treated with artesunate plus mefloquine than with artesunate‐pyronaridine (RR 0.46, 95% CI 0.28 to 0.78; one trial, 1271 participants, Analysis 4.9). The other reported symptoms were headache, cough, diarrhoea, vomiting, and myalgia.
Biochemical monitoring and adverse events
Biochemical tests for liver function monitoring were performed on all participants on days 0, 3, 7, 28, and 42.
Artesunate‐pyronaridine was associated with more participants recording elevated ALT and AST levels following treatment. For ALT, grade 2 toxicity (up to five times the upper limit of normal) was significantly higher with artesunate‐pyronaridine (21/843 versus 0/417; RR 21.30, 95% CI 1.29 to 350.7; one trial, 1260 participants, Analysis 4.10), and grade 3 or 4 toxicity (> five times the upper limit of normal) approached statistical significance (15/843 versus 0/417; RR 7.41, 95% CI 0.98 to 55.98; one trial, 1260 participants, Analysis 4.11). There were no significant differences for other liver enzymes or bilirubin. No patients developed signs or symptoms of liver disease.
Haematological monitoring and adverse events
The mean haemoglobin level fell in both groups during the first seven days after starting treatment (Analysis 4.12) This drop was slightly larger with artesunate‐pyronaridine compared to artesunate plus mefloquine (Day 3: MD ‐0.22 g/dL, 95% CI ‐0.36 to ‐0.08; one trial, participants, Analysis 4.12), but by day 28 mean haemoglobin levels were better than baseline in both groups. A similar pattern was observed with platelet counts (Analysis 4.13), and white cell counts (Analysis 4.14). However the differences were small and unlikely to be of clinical significance.
ECG monitoring and adverse events
Rueangweerayut 2012 conducted ECG monitoring on all participants in this trial but the timing and frequency of ECGs was unclear. The trial authors reported abnormal ECGs in under 1% of participants in both groups, and described all abnormalities as mild and transient (one trial, 1271 participants, Analysis 4.15).
Subgroup analysis
We did not conduct a subgroup analysis by age of participants as this trial did not include children aged under five years.
We have presented subgroup analyses by geographical region and country in Analysis 5.1 and Analysis 5.2. The majority of PCR‐adjusted treatment failures occurred in Thailand and Cambodia, with almost none elsewhere. They also demonstrate the paucity of data from Africa.
Trial authors noted that participants enrolled in Pailin, Cambodia (an area of low‐transmission forP. falciparum) had significantly longer parasite clearance times than people in the other trial sites; only 63% cleared parasites within 72 hours compared to 98% of participants in the other sites. Recrudescence at this site was reportedly higher with artesunate‐pyronaridine than with artesunate plus mefloquine (10.2% versus 0%, P = 0.04; authors' own figures).
Sensitivity analysis
We conducted a sensitivity analysis to explore the influence of different methods for analysing the primary outcome data. For PCR‐unadjusted treatment failure, our primary analysis following the WHO guidelines for analysing trials of antimalarials was similar to the per‐protocol analysis of the trial authors (Analysis 6.1). In the most conservative estimates the effect size was dramatically reduced and the estimate was no longer statistically significant (Analysis 6.1). For PCR‐adjusted treatment failure we did not observe any substantial differences (Analysis 6.2).
We did not perform any further sensitivity analyses as there was only one trial.
Part 3. Biochemical, haematological and ECG adverse events
In light of concerns about liver toxicity with pyronaridine, we included three additional RCTs of pyronaridine. Two trials compared pyronaridine alone to chloroquine (Ringwald 1996; Ringwald 1998) and one trial compared artesunate‐pyronaridine to chloroquine (Poravuth 2011).
Biochemical monitoring and adverse events
The six trials reported abnormalities in liver functions in different ways. We assessed the adequacy of monitoring and completeness of results reporting in Table 5.
Artesunate‐pyronaridine was associated with a four‐fold increase in the incidence of ALT and AST grade 3 or 4 toxicity (elevations > five times the upper limit of normal) (ALT: RR 4.17, 95% CI 1.38 to 12.62, AST: RR 4.08, 95% CI 1.17 to 14.26; four trials, 3528 participants, Analysis 7.1). Grade 3 or 4 toxicity measured with ALP and bilirubin were not substantially different.
The three main efficacy trials also reported cases with both raised ALT (3 x ULN) and raised bilirubin (2 x ULN) as an indicator for drug induced liver injury (Tshefu 2010; Kayentao 2012; Rueangweerayut 2012). Only five of the 2052 participants in the artesunate‐pyronaridine group and one of 1020 participants in the comparator groups had raised ALT and bilirubin. This difference was not statistically significant (three trials, 3072 participants, Analysis 7.2).
Ringwald 1996 reported that 5/40 participants given pyronaridine had elevated bilirubin levels compared to 0/41 with chloroquine but did not give any further details.
Renal function tests
Three trials reported serum creatinine levels as a measure of renal function. At day 7, creatinine values were marginally lower in the pyronaridine‐treated group than in those treated with comparator regimens (artemether‐lumefantrine, artesunate+mefloquine, chloroquine) (MD ‐2.76, 95% CI ‐4.58 to ‐0.94; three trials, 1808 participants, Analysis 7.3).
Haematological monitoring and adverse events
Four trials reported mean haemoglobin on days 0, 3, 7, and 28, and in all four trials the mean haemoglobin fell in both groups between day 0 and day 7 before recovering by day 28 (four trials, 3534 participants, Analysis 7.4). At day 7 the mean haemoglobin was ¼ gram lower in those treated with artesunate‐pyronaridine (MD ‐0.24 g/dL, 95% CI ‐0.32 to ‐0.16; four trials, 3394 participants, Analysis 7.4).
ECG monitoring and adverse events
Four trials conducted ECG monitoring and ECG adverse effects were rare in all four trials (see Table 7). Prolonged QT interval was less common with artesunate‐pyronaridine than comparators (RR 0.25, 95% CI 0.07 to 0.90; three trials, 2991 participants, Analysis 7.5).
Discussion
Summary of main results
Artesunate‐pyronaridine versus artemether‐lumefantrine
In two multicentre trials, enrolling mainly older children and adults from west and south‐central Africa, both artesunate‐pyronaridine and artemether‐lumefantrine had fewer than 5% PCR adjusted treatment failures during 42 days of follow‐up, with no differences between groups (low quality evidence). There were fewer new infections during the first 28 days in those given artesunate‐pyronaridine (moderate quality evidence), but no difference was detected over the whole 42 day follow‐up (moderate quality evidence).
Artesunate‐pyronaridine versus artesunate plus mefloquine
In one multicentre trial, enrolling mainly older children and adults from South East Asia, both artesunate‐pyronaridine and artesunate plus mefloquine had fewer than 5% PCR adjusted treatment failures during 28 days follow‐up (moderate quality evidence). PCR‐adjusted treatment failures had risen to 6% by day 42 in those treated with artesunate‐pyronaridine, but this was not substantially different to artesunate plus mefloquine (low quality evidence). Again, there were fewer new infections during the first 28 days in those given artesunate‐pyronaridine (moderate quality evidence), but no differences were detected over the whole 42 days (low quality evidence).
Adverse effects
Serious adverse events were rare in these trials with no statistically significant differences between artesunate‐pyronaridine and the comparator ACTs. However, biochemical elevation of LFTs occurred four times more frequently with artesunate‐pyronaridine than with the other antimalarials (moderate quality evidence).
Overall completeness and applicability of evidence
Artesunate‐pyronaridine performed well in all three efficacy trials included in this review, with low levels of PCR‐adjusted treatment failure at day 28 in all settings. All three trials were multicentre trials, with trial sites in 11 African countries and six countries in Asia, which broadens the applicability of the findings. However, the actual number of participants recruited from many trial sites was small and the trials were underpowered to evaluate either superiority or equivalence at country level. East Africa is particularly under represented, with only 232 participants from Kenya and Tanzania, and several of the West African countries recruited fewer than 100 participants.
The other major limitation on the applicability of these trials is the age of the participants. The trials predominantly recruited older children and adults. The combination appeared to be effective in these groups but little is known about the main target group; children aged under five years. These trials included only 232 children aged below five years compared to over 7000 in trials of dihydroartemisinin‐piperaquine.
Notably, all three efficacy trials excluded people with known pre‐existing liver disease, and one trial explicitly excluded those with raised LFTs at baseline. Screening of this kind may not be feasible in many malaria‐endemic settings.
Quality of the evidence
We assessed the quality of the evidence in this review using the GRADE approach and presented it in two summary of findings tables for efficacy (summary of findings Table for the main comparison; summary of findings Table 2).
The evidence that artesunate‐pyronaridine is equivalent to established ACTs at preventing PCR‐adjusted treatment failures was of moderate quality due to two main concerns:
-
Indirectness: The trials to date have largely been conducted in older children and adults, with exclusion of young children who bear the greatest burden and risks of malaria infection and illness.
-
Imprecision: The trials were not powered to examine the efficacy of artesunate‐pyronaridine in individual regions or countries. This is problematic for national decision‐making, and limits the wider generalizability of these results. Larger trials would be required to have full confidence in these results.
We also assessed the quality of evidence on comparative adverse effects and presented these in Appendix 2 and Appendix 3. In general the evidence was of moderate to low quality, and downgraded for similar reasons.
Potential biases in the review process
The objectives of the review changed significantly between the published protocol and final review. The basis for the change was to focus on only interventions of relevance to current malaria treatment policies (see Differences between protocol and review). We used standard methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and complied with the Cochrane Collaboration's methodological standards for the conduct of new reviews of interventions (MECIR 2011).
We believe that we have identified all pyronaridine trials relevant to inform clinical decisions and policy regarding the use of pyronaridine combinations for the treatment of uncomplicated P. falciparum malaria. The three trials were all conducted under the auspices of the public‐private partnership, Medicines for Malaria Venture, and Poong Pharmaceutical Company Ltd, Seoul, Republic of Korea.
Agreements and disagreements with other studies or reviews
We found one further systematic review of artesunate‐pyronaridine published by authors from the Medicines for Malaria Venture (MMV), the co‐developers of the artesunate‐pyronaridine combination (Duparc 2013). The authors include four of the studies included here, plus one study we excluded as it was not randomized (Ramharter 2008), and one unpublished study. The authors conclude that 'Pyronaridine‐artesunate was well tolerated with no safety concerns with the exception of mostly mild transient rises in transaminases. Efficacy was high and met the requirements for use as first‐line therapy'. While we agree that artesunate‐pyronaridine shows promise as a further addition to the ACT combinations, we think it requires further studies in the main target group, children aged less than five years, before countries consider this as a first‐line treatment.
Risk of bias summary table (Methodological quality summary): review authors' judgements about each methodological quality item for each included trial.
Forest plot of comparison: 1 Artesunate‐pyronaridine versus artemether‐lumefantrine, outcome: 1.1 Total failure (Day 28).
Comparison 1 Artesunate‐pyronaridine versus artemether‐lumefantrine, Outcome 1 Total failure (Day 28).
Comparison 1 Artesunate‐pyronaridine versus artemether‐lumefantrine, Outcome 2 Total failure (Day 42).
Comparison 1 Artesunate‐pyronaridine versus artemether‐lumefantrine, Outcome 3 Early treatment failure.
Comparison 1 Artesunate‐pyronaridine versus artemether‐lumefantrine, Outcome 4 Parasite clearance time (hours).
Comparison 1 Artesunate‐pyronaridine versus artemether‐lumefantrine, Outcome 5 Fever clearance time (hours).
Comparison 1 Artesunate‐pyronaridine versus artemether‐lumefantrine, Outcome 6 Gametocyte clearance time.
Comparison 1 Artesunate‐pyronaridine versus artemether‐lumefantrine, Outcome 7 Serious adverse events.
Comparison 1 Artesunate‐pyronaridine versus artemether‐lumefantrine, Outcome 8 Adverse events leading to withdrawal from treatment.
Comparison 1 Artesunate‐pyronaridine versus artemether‐lumefantrine, Outcome 9 Patient reported symptoms.
Comparison 1 Artesunate‐pyronaridine versus artemether‐lumefantrine, Outcome 10 Patient reported symptoms judged as drug‐related.
Comparison 1 Artesunate‐pyronaridine versus artemether‐lumefantrine, Outcome 11 Abnormal LFTs; grade 3 and 4 toxicity.
Comparison 1 Artesunate‐pyronaridine versus artemether‐lumefantrine, Outcome 12 Change in haemoglobin.
Comparison 1 Artesunate‐pyronaridine versus artemether‐lumefantrine, Outcome 13 Anaemia as an adverse event.
Comparison 2 Artesunate‐pyronaridine versus artemether‐lumefantrine; subgroup analysis, Outcome 1 Total failure PCR‐adjusted (Day 28); subgrouped by age.
Comparison 2 Artesunate‐pyronaridine versus artemether‐lumefantrine; subgroup analysis, Outcome 2 Total failure PCR‐adjusted (Day 28); subgrouped by region.
Comparison 2 Artesunate‐pyronaridine versus artemether‐lumefantrine; subgroup analysis, Outcome 3 Total failure PCR‐adjusted (Day 28); subgrouped by country.
Comparison 3 Artesunate‐pyronaridine versus artemether‐lumefantrine; sensitivity analysis, Outcome 1 Total failure PCR‐unadjusted (Day 28); Sensitivity analysis.
Comparison 3 Artesunate‐pyronaridine versus artemether‐lumefantrine; sensitivity analysis, Outcome 2 Total failure PCR‐adjusted (Day 28); Sensitivity analysis.
Comparison 4 Artesunate‐pyronaridine versus artesunate‐mefloquine, Outcome 1 Total failure (Day 28).
Comparison 4 Artesunate‐pyronaridine versus artesunate‐mefloquine, Outcome 2 Total failure (Day 42).
Comparison 4 Artesunate‐pyronaridine versus artesunate‐mefloquine, Outcome 3 Early treatment failures.
Comparison 4 Artesunate‐pyronaridine versus artesunate‐mefloquine, Outcome 4 Parasite clearance time (hours).
Comparison 4 Artesunate‐pyronaridine versus artesunate‐mefloquine, Outcome 5 Fever clearance time (hours).
Comparison 4 Artesunate‐pyronaridine versus artesunate‐mefloquine, Outcome 6 Gametocyte clearance time (hours).
Comparison 4 Artesunate‐pyronaridine versus artesunate‐mefloquine, Outcome 7 Serious adverse events.
Comparison 4 Artesunate‐pyronaridine versus artesunate‐mefloquine, Outcome 8 Adverse events leading to withdrawal from treatment.
Comparison 4 Artesunate‐pyronaridine versus artesunate‐mefloquine, Outcome 9 Patient reported symptoms.
Comparison 4 Artesunate‐pyronaridine versus artesunate‐mefloquine, Outcome 10 Abnormal LFTs; Grade 2 toxicity.
Comparison 4 Artesunate‐pyronaridine versus artesunate‐mefloquine, Outcome 11 Abnormal LFTs; Grade 3 or 4 toxicity.
Comparison 4 Artesunate‐pyronaridine versus artesunate‐mefloquine, Outcome 12 Haemoglobin (g/dL).
Comparison 4 Artesunate‐pyronaridine versus artesunate‐mefloquine, Outcome 13 Platelet counts (x 109/L).
Comparison 4 Artesunate‐pyronaridine versus artesunate‐mefloquine, Outcome 14 White blood counts (x 109/L).
Comparison 4 Artesunate‐pyronaridine versus artesunate‐mefloquine, Outcome 15 Abnormal ECG finding.
Comparison 5 Artesunate‐pyronaridine versus artesunate‐mefloquine; subgroup analysis, Outcome 1 Total failure PCR‐adjusted (Day 28); subgrouped by region.
Comparison 5 Artesunate‐pyronaridine versus artesunate‐mefloquine; subgroup analysis, Outcome 2 Total failure PCR‐adjusted (Day 28); subgrouped by country.
Comparison 6 Artesunate‐pyronaridine versus artesunate‐mefloquine; sensitivity analysis, Outcome 1 Total failure PCR‐unadjusted (Day 28); Sensitivity analysis.
Comparison 6 Artesunate‐pyronaridine versus artesunate‐mefloquine; sensitivity analysis, Outcome 2 Total failure PCR‐adjusted (Day 28); Sensitivity analysis.
Comparison 7 Pyronaridine alone or with artesunate versus another antimalarial: laboratory findings, Outcome 1 Abnormal LFTs; Grade 3 or 4 toxicity.
Comparison 7 Pyronaridine alone or with artesunate versus another antimalarial: laboratory findings, Outcome 2 Combined abnormal LFTs.
Comparison 7 Pyronaridine alone or with artesunate versus another antimalarial: laboratory findings, Outcome 3 Renal function tests.
Comparison 7 Pyronaridine alone or with artesunate versus another antimalarial: laboratory findings, Outcome 4 Haemoglobin.
Comparison 7 Pyronaridine alone or with artesunate versus another antimalarial: laboratory findings, Outcome 5 Abnormal ECG findings.
| Artesunate‐pyronaridine compared to artemether‐lumefantrine for treating people with uncomplicated falciparum malaria | |||||
| Patient or population: Adults and children with uncomplicated falciparum malaria | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Artemether‐lumefantrine | Artesunate‐pyronaridine | ||||
| Treatment failure (day 28) | PCR‐unadjusted | RR 0.60 (0.40 to 0.90) | 1720 | ⊕⊕⊕⊝ | |
| 7 per 100 | 4 per 100 | ||||
| PCR‐adjusted | RR 1.69 | 1650 | ⊕⊕⊕⊝ | ||
| 1 per 100 | 1 per 100 | ||||
| Treatment failure (Day 42) | PCR‐unadjusted | RR 0.85 (0.53 to 1.36) | 1691 (2 trials) | ⊕⊕⊕⊝ | |
| 17 per 100 | 15 per 100 | ||||
| PCR‐adjusted | RR 1.53 | 1472 | ⊕⊕⊝⊝ | ||
| 2 per 100 | 3 per 100 | ||||
| The assumed risk is the mean risk across the trials in those treated with artemether‐lumefantrine. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 No serious risk of bias: Both trials were well conducted and at low risk of bias. | |||||
| Artesunate‐pyronaridine compared to artesunate plus mefloquine for treating people with uncomplicated P. falciparum malaria | |||||
| Patient or population: People with uncomplicatedP. falciparum malaria | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Artesunate‐mefloquine | Artesunate‐pyronaridine | ||||
| Treatment failure (Day 28) | PCR‐unadjusted | RR 0.35 | 1200 | ⊕⊕⊕⊝ | |
| 4 per 100 | 2 per 100 | ||||
| PCR‐adjusted | RR 0.38 | 1187 | ⊕⊕⊕⊝ | ||
| 2 per 100 | 1 per 100 | ||||
| Treatment failure (Day 42) | PCR‐unadjusted | RR 0.86 | 1146 | ⊕⊕⊕⊝ | |
| 8 per 100 | 7 per 100 | ||||
| PCR‐adjusted | RR 1.64 | 1116 | ⊕⊕⊝⊝ | ||
| 4 per 1000 | 6 per 100 | ||||
| The assumed risk is the risk in the group treated with artesunate plus mefloquine in the single trial. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 No serious risk of bias: This trial was well conducted with low risk of bias. | |||||
| Liver toxicity of pyronaridine compared to other antimalarials | |||||
| Patient or population: People with uncomplicated falciparum malaria | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Comparator antimalarial | Pyronaridine alone or with artesunate | ||||
| Elevated alanine aminotransaminase levels | 2 per 1000 | 10 per 1000 | RR 4.17 | 3523 | ⊕⊕⊕⊝ |
| Elevated aspartate aminotransferase levels Grade 3, 4 toxicity | 2 per 1000 | 8 per 1000 | RR 4.08 | 3528 | ⊕⊕⊕⊝ |
| Elevated alkaline phosphatase levels | 2 per 1000 | 1 per 1000 | RR 0.62 | 2606 | ⊕⊕⊕⊝ |
| Elevated bilirubin | 3 per 1000 | 6 per 1000 | RR 1.92 | 3067 | ⊕⊕⊝⊝ |
| *The basis for the assumed risk (for example, the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 No serious risk of bias: Trials were well conducted, although the data analysis was not clearly independent of the drug manufacturer in three trials. | |||||
| Analysisa | Participants | PCRb‐unadjusted | PCR‐adjusted | ||
| Numerator | Denominator | Numerator | Denominator | ||
| Primary analysis | Exclusions after enrolment | Excludedc | Excluded | Excluded | Excluded |
| Missing or indeterminate PCR | Included as failures | Included | Excluded | Excluded | |
| New infections | Included as failures | Included | Excluded | Excluded | |
| Sensitivity analysis 1d | As 'Primary analysis' except: missing or indeterminate PCR | — | — | Included as failures | Included |
| Sensitivity analysis 2e | As 'Sensitivity analysis 1' except: new infections | — | — | Included as successes | Included |
| Sensitivity analysis 3f | As 'Sensitivity analysis 2' except: exclusions after enrolment | Included as failures | Included | Included as failures | Included |
| Sensitivity analysis 4g | As 'Sensitivity analysis 2' except: exclusions after enrolment | Included as successes | Included | Included as successes | Included |
| aNote: we removed participants that did not satisfy the inclusion criteria after randomization from all calculations. | |||||
| Criterion | Assessment | Explanation |
| Patient‐reported symptoms | ||
| Was monitoring active or passive?
| Active Passive Unclear | We classified monitoring as 'active' when authors reviewed participants at set timepoints and enquired about symptoms. |
| Was blinding for participants and outcome assessors adequate? | Adequate Inadequate Unclear | We classified blinding as 'adequate' when both participants and outcome assessors were blinded to the intervention group, and the methods of blinding (including use of a placebo) were described. |
| Was outcome data reporting complete or incomplete? | Complete Incomplete Unclear | We classified outcome data reporting as 'complete' when data was presented for all the time‐points where it was collected. |
| Were all participants included in reporting? | We report the percentage of randomized participants included in adverse event reporting. | |
| Was theanalysis independent of study sponsor? | Yes No Unclear | We classified the analysis of trials sponsored by pharmaceutical companies as independent of the sponsor when it was clearly stated that the sponsor had no input to the trial analysis |
| Laboratory tests | ||
| Number of tests undertaken | — | We extracted the type and number of laboratory tests were taken. |
| Timing of tests Was number and timing of tests adequate? | Adequate Inadequate | We classified the number and timing of tests as 'adequate', when tests were taken at baseline, plus two other timepoints within the first week after treatment, plus the last day of the study. We classed the number of test taken as "inadequate", if either the laboratory controls in the first week or controls at four weeks were not performed. |
| Reporting of test results Was reporting of test results complete? | Complete Incomplete | We classified reporting as 'complete' when test results of all time points were reported. For the trials with inadequate number of tests taken, we considered completeness of reporting as inconsequential, and therefore did not record a judgement. |
| Independence of data analysis Was data analysis independent? | Yes No Unclear | We classified the analysis of trials sponsored by pharmaceutical companies as independent of the sponsor when it was clearly stated that the sponsor had no input to the trial analysis |
| Trial ID | Actual or target dose | Intervention | Comparator | ||
| Artesunate | Pyronaridine | Artemisinin‐derivative | Partner drug | ||
| Actual dose | 2.2 to 4.4 | 6.7 to 13.3 | 1.3 to 4.0 | 8.0 to 24.0 | |
| Target dose | 2.4 to 4.6 | 7.2 to 13.8 | NS | NS | |
| Actual dose | 2.4 to 4.7 | 7.1 to 14.0 | 2.5 to 5.0 | 6.2 to 12.5 | |
| Target dose | 2.4 to 4.6 | 7.2 to 13.8 | — | 10, 5, 5 | |
| Target dose | — | 16, 8, 8 | — | 10, 5, 5 | |
| Target dose | — | 8, 8, 8, 8 | — | 10, 10, 5 | |
| NS = Not specified. | |||||
| Trial ID | Monitoring active or passive? | Outcome data reporting | Blinding adequate? | % of participants included in AE reporting | Independent data analysis | ||||
| Days data collected | Days data reported | Patient | Clinician | Data analysis | AS‐Pyr | Control | |||
| Unclear | 0 to 3, 7, 14, 21, 28, 35, 42 | Unclear | Yes | Yes | Unclear | 100% | 100% | No | |
| Unclear | Unclear | Unclear | No | No | Yes | 100% | 100% | No | |
| Unclear | Unclear | Unclear | No | No | Unclear | 100% | 100% | No | |
| Unclear | Unclear | Unclear | Yes | Yes | Yes | 100% | 100% | Yes | |
| Unclear | Unclear | Unclear | No | No | Unclear | Unclear | Unclear | Yes | |
| Unclear | Unclear | Unclear | No | No | Unclear | 100% | 100% | Yes | |
| Trial ID | Number of tests | Days tested | Days reported | Days tested adequate? | For adequate testing, was reporting complete? | Data analysis independent of sponsor? |
| 41 | 0, 3, 7, 282 | 3, 7, 28 | Adequate | Complete | No | |
| 41 | 0, 3, 7, 28, 42 | 3, 7 | Adequate | Incomplete 3 | No | |
| 41 | 0, 28, 42 | 0, “post baseline” | Inadequate | ‐4 | No | |
| 41 | 0, 3, 7, 282 | 3, 7, 28 | Adequate | Complete | Yes | |
| 41 | 0, 7 | 0, 7 | Inadequate | — | Yes | |
| 51,5 | 0, 7 | 0, 7 | Inadequate | — | Yes | |
| 1 Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TBIL). | ||||||
| Trial ID | Outcome | Artesunate‐pyronaridine | Artemether‐lumefantrine | P value |
| Median parasite clearance time | 24.1 hours | 24.2 hours (95% CI 24.1 to 32.0) | 0.02 | |
| Median fever clearance time | 8.1 hours | 8.1 hours | 0.049 | |
| "Post‐baseline gametocytes" | 95/354 (26.8%) | 44/178 | 0.6 | |
| Gametocyte development | 53/354 | 20/178 | 0.24 |
| Trial ID | Days tested | ECG results | |
| Pyronaridine arm | Comparator arm | ||
| 0, 2, 7, 14, and 28 | "no post baseline clinically important ECG results" | "no post baseline clinically important ECG results" | |
| 0, 2, 7, 14, and 28 | 1 patient with T‐wave inversion at day 2 1 patient with ventricular premature complexes and extended QTc (manual reading QTcB 461 ms, QTcF 458 ms) at day 21 | 1 patient with sinus bradycardia and sinus arrhythmia on day 2 1 patient with sinus bradycardia on day 2 | |
| Unclear | 6/848 (0.7%) patients with abnormal ECGs‐ "All were mild and resolved before study completion" | 3/423 (0.7%) patients with abnormal ECGs ‐ "All were mild and resolved before study completion" 3/423 with long or prolonged QT interval ‐ None had a QT interval that exceeded 480 msec | |
| 0, 2, 7, 14, and 42 | 1/226 (0.4%) patients with QTc prolongations | 6/222 (2.7%) patients with QTc prolongations (1/222 not drug‐related) | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total failure (Day 28) Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 PCR‐unadjusted | 2 | 1720 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.40, 0.90] |
| 1.2 PCR‐adjusted | 2 | 1650 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.69 [0.56, 5.10] |
| 2 Total failure (Day 42) Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.1 PCR‐unadjusted | 2 | 1691 | Risk Ratio (M‐H, Random, 95% CI) | 0.85 [0.53, 1.36] |
| 2.2 PCR‐adjusted | 2 | 1472 | Risk Ratio (M‐H, Random, 95% CI) | 1.53 [0.73, 3.19] |
| 3 Early treatment failure Show forest plot | 2 | 1676 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.12, 4.42] |
| 4 Parasite clearance time (hours) Show forest plot | 1 | 1170 | Mean Difference (IV, Fixed, 95% CI) | ‐3.20 [‐4.38, ‐2.02] |
| 5 Fever clearance time (hours) Show forest plot | 1 | 1170 | Mean Difference (IV, Fixed, 95% CI) | ‐1.20 [‐2.38, ‐0.02] |
| 6 Gametocyte clearance time Show forest plot | 1 | 1170 | Mean Difference (IV, Fixed, 95% CI) | ‐10.5 [‐12.40, ‐8.60] |
| 7 Serious adverse events Show forest plot | 2 | 1787 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.20, 4.28] |
| 8 Adverse events leading to withdrawal from treatment Show forest plot | 2 | 1787 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.37 [0.67, 2.82] |
| 9 Patient reported symptoms Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 9.1 Headache | 1 | 1272 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.60, 1.24] |
| 9.2 Cough | 2 | 1807 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.62, 1.17] |
| 9.3 Abdominal pain | 1 | 1272 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.67, 1.75] |
| 9.4 Vomiting | 1 | 535 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.58 [0.73, 3.44] |
| 9.5 Pyrexia | 1 | 535 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.46 [0.67, 3.19] |
| 9.6 Influenza‐ like illness | 1 | 535 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.20 [0.54, 2.70] |
| 10 Patient reported symptoms judged as drug‐related Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 10.1 Vomiting | 2 | 1807 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.25 [0.68, 2.31] |
| 10.2 Headache | 1 | 1272 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.57, 1.85] |
| 10.3 Abdominal pain | 1 | 1272 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.25 [0.60, 2.57] |
| 10.4 Vertigo | 1 | 1272 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.49 [0.48, 4.61] |
| 10.5 Haematuria | 1 | 1272 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.49 [0.55, 11.32] |
| 10.6 Upper abdominal pain | 1 | 1272 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.35, 3.62] |
| 10.7 Anorexia | 1 | 1272 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.09, 1.17] |
| 11 Abnormal LFTs; grade 3 and 4 toxicity Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 11.1 Alanine aminotransferase (ALT) | 2 | 1807 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.00 [0.43, 9.42] |
| 11.2 Asparatate aminotransferase (AST) | 2 | 1807 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.85 [0.70, 21.09] |
| 11.3 Alkaline phosphatase (ALP) | 1 | 1272 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.10 [0.00, 2.07] |
| 11.4 Bilirubin | 2 | 1807 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.30 [0.30, 5.62] |
| 12 Change in haemoglobin Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 12.1 Haemoglobin at baseline | 2 | 1807 | Mean Difference (IV, Fixed, 95% CI) | ‐0.03 [‐0.19, 0.13] |
| 12.2 Haemoglobin day 3 | 2 | 1755 | Mean Difference (IV, Fixed, 95% CI) | ‐0.01 [‐0.13, 0.11] |
| 12.3 Haemoglobin day 7 | 2 | 1741 | Mean Difference (IV, Fixed, 95% CI) | ‐0.16 [‐0.28, ‐0.05] |
| 12.4 Haemoglobin day 28 | 2 | 1702 | Mean Difference (IV, Fixed, 95% CI) | 0.04 [‐0.09, 0.18] |
| 13 Anaemia as an adverse event Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 13.1 Anaemia (AE of any cause) | 1 | 535 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.23 [0.68, 2.23] |
| 13.2 Anaemia (drug‐ related AE) | 1 | 535 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.32, 1.47] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total failure PCR‐adjusted (Day 28); subgrouped by age Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Age > 5 years | 2 | 1469 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.25, 4.03] |
| 1.2 Age < 5 years | 1 | 216 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.37 [0.43, 26.38] |
| 2 Total failure PCR‐adjusted (Day 28); subgrouped by region Show forest plot | 2 | 1675 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.44, 2.76] |
| 2.1 West Africa | 2 | 816 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.42 [0.29, 6.92] |
| 2.2 East Africa | 2 | 194 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.64 [0.13, 53.14] |
| 2.3 South‐central Africa | 2 | 490 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.15, 2.92] |
| 2.4 Asia | 2 | 175 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.09, 10.99] |
| 3 Total failure PCR‐adjusted (Day 28); subgrouped by country Show forest plot | 2 | 1675 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.41, 2.18] |
| 3.1 Burkina Faso | 1 | 25 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.05, 22.91] |
| 3.2 DR Congo | 2 | 369 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.5 [0.10, 2.43] |
| 3.3 Gabon | 1 | 78 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.17 [0.01, 4.03] |
| 3.4 Ivory Coast | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.25 [0.27, 18.43] |
| 3.5 Kenya | 2 | 194 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.64 [0.13, 53.14] |
| 3.6 Mali | 2 | 318 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3.7 The Gambia | 1 | 90 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3.8 Ghana | 1 | 7 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3.9 Mozambique | 1 | 121 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.5 [0.06, 36.02] |
| 3.10 Senegal | 1 | 198 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3.11 Phillipines | 2 | 107 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3.12 Indonesia | 1 | 68 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.09, 9.32] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total failure PCR‐unadjusted (Day 28); Sensitivity analysis Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Primary analysis (Cochrane review) | 2 | 1720 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.40, 0.90] |
| 1.2 Missing data included as failures | 2 | 1807 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.58, 1.03] |
| 1.3 Missing data included as successes | 2 | 1807 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.61 [0.41, 0.90] |
| 1.4 Intention to treat analysis (of trial authors) | 2 | 1807 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.58, 1.03] |
| 1.5 Per‐protocol analysis (of trial authors) | 2 | 1683 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.66 [0.43, 1.01] |
| 2 Total failure PCR‐adjusted (Day 28); Sensitivity analysis Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Primary analysis (Cochrane review) | 2 | 1650 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.69 [0.56, 5.10] |
| 2.2 Missing or indeterminate PCR results included as failures | 2 | 1651 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.35 [0.49, 3.73] |
| 2.3 New infections included as successes | 2 | 1720 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.41 [0.51, 3.88] |
| 2.4 Missing data included as failures | 2 | 1807 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.06 [0.71, 1.57] |
| 2.5 Missing data included as successes | 2 | 1807 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.41 [0.51, 3.89] |
| 2.6 Intention to treat analysis (by trial authors) | 2 | 1807 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.60, 1.24] |
| 2.7 Per‐protocol analysis (by trial authors) | 2 | 1676 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.38 [0.50, 3.81] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total failure (Day 28) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 PCR‐unadjusted | 1 | 1200 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.35 [0.17, 0.73] |
| 1.2 PCR adjusted | 1 | 1187 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.14, 1.02] |
| 2 Total failure (Day 42) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 PCR‐unadjusted | 1 | 1146 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.57, 1.31] |
| 2.2 PCR adjusted | 1 | 1116 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.64 [0.89, 3.00] |
| 3 Early treatment failures Show forest plot | 1 | 1103 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.16 [0.01, 3.96] |
| 4 Parasite clearance time (hours) Show forest plot | 1 | 1259 | Mean Difference (IV, Fixed, 95% CI) | ‐2.60 [‐4.94, ‐0.26] |
| 5 Fever clearance time (hours) Show forest plot | 1 | 1051 | Mean Difference (IV, Fixed, 95% CI) | 0.10 [‐1.52, 1.72] |
| 6 Gametocyte clearance time (hours) Show forest plot | 1 | 27 | Mean Difference (IV, Fixed, 95% CI) | ‐5.40 [‐21.80, 11.00] |
| 7 Serious adverse events Show forest plot | 1 | 1271 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.25, 3.97] |
| 8 Adverse events leading to withdrawal from treatment Show forest plot | 1 | 1271 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.17, 2.31] |
| 9 Patient reported symptoms Show forest plot | 1 | 7626 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.80, 1.22] |
| 9.1 Vomiting | 1 | 1271 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.45, 2.20] |
| 9.2 Diarrhea | 1 | 1271 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.44 [0.17, 1.14] |
| 9.3 Headache | 1 | 1271 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.15 [0.82, 1.60] |
| 9.4 Dizziness | 1 | 1271 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.46 [0.28, 0.78] |
| 9.5 Cough | 1 | 1271 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.50 [0.74, 3.03] |
| 9.6 Myalgia | 1 | 1271 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.39 [0.83, 2.32] |
| 10 Abnormal LFTs; Grade 2 toxicity Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 10.1 Alanine aminotransferase (ALT) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.2 Aspartate aminotransferase (AST) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.3 Alkaline phosphatase (ALP) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.4 Bilirubin | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 11 Abnormal LFTs; Grade 3 or 4 toxicity Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 11.1 Alanine aminotransferase (ALT) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 11.2 Aspartate aminotransferase (AST) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 11.3 Alkaline phosphatase (ALP) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 11.4 Bilirubin | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 12 Haemoglobin (g/dL) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 12.1 Haemoglobin at baseline | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 12.2 Haemoglobin day 3 | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 12.3 Haemoglobin day 7 | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 12.4 Haemoglobin day 28 | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 13 Platelet counts (x 109/L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 13.1 baseline | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 13.2 day 3 | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 13.3 day 7 | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 13.4 day 28 | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 14 White blood counts (x 109/L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 14.1 baseline | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 14.2 day 3 | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 14.3 day 7 | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 14.4 day 28 | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 15 Abnormal ECG finding Show forest plot | 1 | 2542 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.58 [0.20, 1.73] |
| 15.1 QT prolongation | 1 | 1271 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.17 [0.02, 1.59] |
| 15.2 ECG abnormalities | 1 | 1271 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.25, 3.97] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total failure PCR‐adjusted (Day 28); subgrouped by region Show forest plot | 1 | 1117 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.14, 1.03] |
| 1.1 East Africa | 1 | 38 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 1.2 West Africa | 1 | 192 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.48 [0.06, 35.75] |
| 1.3 South central Africa | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 1.4 Asia | 1 | 887 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.31 [0.10, 0.93] |
| 2 Total failure PCR‐adjusted (Day 28); subgrouped by country Show forest plot | 1 | 1117 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.14, 1.03] |
| 2.1 Thailand | 1 | 551 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.12 [0.03, 0.57] |
| 2.2 Vietnam | 1 | 159 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 2.3 Cambodia | 1 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.31 [0.17, 62.62] |
| 2.4 India | 1 | 45 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 2.5 Burkina Faso | 1 | 118 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 2.6 Ivory Coast | 1 | 74 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.65 [0.07, 39.20] |
| 2.7 Tanzania | 1 | 38 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Total failure PCR‐unadjusted (Day 28); Sensitivity analysis Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Primary analysis (Cochrane review) | 1 | 1200 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.35 [0.17, 0.73] |
| 1.2 Missing data included as failures | 1 | 1271 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.72 [0.49, 1.05] |
| 1.3 Missing data included as successes | 1 | 1271 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.35 [0.17, 0.73] |
| 1.4 Intention to treat analysis (of trial authors) | 1 | 1271 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.72 [0.49, 1.05] |
| 1.5 Per‐protocol analysis (of trial authors) | 1 | 1120 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.17, 0.78] |
| 2 Total failure PCR‐adjusted (Day 28); Sensitivity analysis Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Primary analysis (Cochrane review) | 1 | 1187 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.14, 1.02] |
| 2.2 Missing or indeterminate PCR results included as failures | 1 | 1187 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.14, 1.02] |
| 2.3 New infections included as successes | 1 | 1200 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.39 [0.15, 1.03] |
| 2.4 Missing data included as failures | 1 | 1271 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.54, 1.24] |
| 2.5 Missing data included as successes | 1 | 1271 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.39 [0.15, 1.03] |
| 2.6 Intention to treat analysis (by trial authors) | 1 | 1271 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.76 [0.51, 1.14] |
| 2.7 Per‐protocol analysis (by trial authors) | 1 | 1117 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.37 [0.13, 1.05] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Abnormal LFTs; Grade 3 or 4 toxicity Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Alanine aminotransferase (ALT) | 4 | 3523 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.17 [1.38, 12.62] |
| 1.2 Aspartate aminotransferase (AST) | 4 | 3528 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.08 [1.17, 14.26] |
| 1.3 Alkaline phosphatase (ALP) | 3 | 2606 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.15, 2.51] |
| 1.4 Bilirubin | 3 | 3067 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.92 [0.59, 6.24] |
| 2 Combined abnormal LFTs Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 ALT > 3 x ULN and Bilirubin > 2 x ULN (Hy's Law case) | 3 | 3072 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.50 [0.30, 7.42] |
| 3 Renal function tests Show forest plot | 3 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.1 Baseline | 3 | 1878 | Mean Difference (IV, Fixed, 95% CI) | ‐0.12 [‐2.07, 1.84] |
| 3.2 Day 3 | 2 | 1764 | Mean Difference (IV, Fixed, 95% CI) | ‐1.72 [‐3.54, 0.10] |
| 3.3 Day 7 | 3 | 1808 | Mean Difference (IV, Fixed, 95% CI) | ‐2.76 [‐4.58, ‐0.94] |
| 4 Haemoglobin Show forest plot | 4 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 4.1 Haemoglobin at baseline | 4 | 3534 | Mean Difference (IV, Fixed, 95% CI) | 0.08 [‐0.04, 0.21] |
| 4.2 Haemoglobin day 3 | 4 | 3461 | Mean Difference (IV, Fixed, 95% CI) | ‐0.12 [‐0.20, ‐0.04] |
| 4.3 Haemoglobin day 7 | 4 | 3394 | Mean Difference (IV, Fixed, 95% CI) | ‐0.24 [‐0.32, ‐0.16] |
| 4.4 Haemoglobin day 28 | 4 | 3294 | Mean Difference (IV, Fixed, 95% CI) | ‐0.09 [‐0.19, 0.01] |
| 5 Abnormal ECG findings Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.1 ECG abnormalities | 2 | 2543 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.26, 2.43] |
| 5.2 QT prolongation | 3 | 2991 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.25 [0.07, 0.90] |
