Tafenoquine for preventing relapse in people with Plasmodium vivax malaria.

BACKGROUND: Plasmodium vivax malaria is widespread, and the persistent liver stage causes relapse of the disease which contributes to continued P. vivax transmission. Primaquine is currently the only drug that cures the parasite liver stage, but requires 14 days to be effective and can cause haemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In addition, there is some evidence of parasite resistance to the drug. Tafenoquine is a new alternative with a longer half-life.
OBJECTIVES: To assess the effects of tafenoquine in people with P. vivax infection. SEARCH
METHODS: We searched the following databases up to 13 April 2015: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; CINAHL; SCOPUS; and LILACS. We also searched the World Health Organization (WHO) International Clinical Trial Registry Platform and the metaRegister of Controlled Trials (mRCT) for ongoing trials using "tafenoquine" and "malaria" as search terms up to 13 April 2015. SELECTION CRITERIA: Randomized controlled trials (RCTs) in people with P. vivax malaria. Adverse effects of tafenoquine are assessed in populations where people with G6PD deficiency have been excluded, and in populations without screening for G6PD deficiency. DATA COLLECTION AND ANALYSIS: All review authors independently extracted data and assessed trial quality. Meta-analysis was carried out where appropriate, and estimates given as relative risk with 95% confidence intervals. We assessed the quality of the evidence using the GRADE approach. MAIN
RESULTS: Three RCTs met our inclusion criteria, with the asexual infection in both the tafenoquine and comparator arm treated with chloroquine, and in all trials G6PD deficiency patients were excluded. Tafenoquine dose comparisonsThree of the included trials compared eight different dosing regimens. Tafenoquine doses of 300 mg and above resulted in fewer relapses than no hypnozoite treatment over six months follow-up in adults (300 mg single dose: RR 0.19, 95% CI 0.08 to 0.41, one trial, 110 participants, moderate quality evidence; 500 to 600 mg single dose: RR 0.14, 95%CI 0.06 to 0.34, two trials, 122 participants, moderate quality evidence; 1800 mg to 3000 mg in divided doses: RR 0.05, 95% CI 0.01 to 0.23, two trials, 63 participants, low quality evidence).In people with normal G6PD status, there may be little or no difference in serious adverse events (three trials, 358 participants, low quality evidence); or any adverse event (one trial, 272 participants, low quality evidence). Tafenoquine versus primaquine Two of the included trials compared four different dosing regimens of tafenoquine against the standard primaquine regimen of 15 mg/day for 14 days. A single tafenoquine dose of 600 mg may be more effective than primaquine in relation to relapses at six months follow-up (RR 0.29, 95% CI 0.10 to 0.84, two trials, 98 participants, low quality evidence)In people with normal G6PD status, there may be little or no difference for serious adverse events (two trials, 323 participants, low quality evidence) or any adverse event (two trials, 323 participants, low quality evidence) between tafenoquine and primaquine. AUTHORS'
CONCLUSIONS: Tafenoquine prevents relapses after clinically and parasitologically confirmed P. vivax malaria. The drug is untested in pregnancy, children and in G6PD-deficient people. The shorter treatment course is an important practical advantage in people who do not have G6PD deficiency, but the longer half-life may have more substantive consequences if given inadvertently to people with G6PD deficiency.

Summary of findings

Background

Malaria remains an important cause of illness and death in many tropical countries. In 2011, 216 million cases of malaria were estimated to have occurred globally and in 2010 there were approximately 655,000 deaths due to malaria (WHO 2012). Global malaria eradication efforts have resulted in a decrease in mortality and morbidity, with global mortality from malaria falling by 25% since 2000 (WHO 2012). Most malaria cases are caused by the species Plasmodium falciparum and Plasmodium vivax. P. falciparum causes a more severe form of malaria with multi‐organ involvement (Fernando 2011a). P. vivax is less virulent than P. falciparum and seldom causes death. However, it causes substantive illness‐related burden in endemic areas. The incidence of P. vivax infection has become particularly important in countries aiming for malaria elimination. Currently, there are 32 such countries, of which, 25 are mainly targeting elimination (interruption of transmission without local cases) ofP. vivax. Another 67 countries are working towards reducing and controlling the high burden of malaria mortality and morbidity (Feachem 2010;Fernando 2011a). P. vivax infection has been treated with chloroquine (CQ) but resistance to this widely available drug has been reported on all continents in which malaria caused by P. vivax is endemic (Rieckmann 1989; WHO 2009). Eradication of liver stages of the disease is necessary to avoid relapses. Due to the large number of infections reported, malaria caused by P. vivax is increasingly being identified as an important public health problem in endemic areas (WHO 2009).

Description of the condition

The life cycles of P. falciparum and P. vivax differ. P. vivax can have dormant forms in the hepatocytes, known as hypnozoites, which can remain dormant for weeks or even months. Thus, a single infection with P. vivax can be responsible for a relapse or series of relapses after an apparent cure. Therefore, eradication of the dormant hepatic forms of the P. vivax parasite is necessary to prevent recurrences. Treatment of people infected with P. vivax with blood schizonticidal agents alone will not result in complete cure as these agents are not capable of clearing the hypnozoites.

Description of the intervention

Primaquine (PQ), an 8‐aminoquinoline, was first licensed for use in the 1950s by the Food and Drug Administration (FDA), United States (Hill 2006), for treatment of vivax malaria. It is the only licensed drug capable of eliminating the vivax hypnozoites. Without administration of PQ in adequate doses, complete cure of patients with P. vivax infection is difficult, and patients often have relapses of clinical disease (Baird 2004; Fernando 2011b). There are several potential alternatives to PQ but tafenoquine (TQ) has been the most extensively studied option over the last 15 years. TQ is an 8‐aminoquinoline (Wells 2010) and is a synthetic analogue of PQ (Walsh 2004a). It has potential to be useful in regimens for prophylaxis and radical cure of P. vivax malaria.

PQ can precipitate haemolysis (which can be life‐threatening) in patients with glucose‐6‐phosphate dehydrogenase (G6PD) deficiency, an X‐linked recessive condition (Ramos Júnior 2010). In addition, it has other undesirable side effects such as methaemoglobinaemia and gastrointestinal disturbances (Carmona‐Fonseca 2009). PQ resistance has been reported as isolated cases from different areas even after it has been administered in adequate doses according to body weight (Ehrman 1944; Goller 2007; Hill 2006; Reddy 2006). PQ treatment has to be continued for 14 days, which often leads to poor compliance (Hill 2006).

A search for a replacement drug for PQ in its curative role has been ongoing for the last few decades. The characteristics of an ideal replacement would be: a) has a shorter duration of treatment, b) has better efficacy in clearing hypnozoites, c) is free from the significant side effects of PQ such as haemolysis in individuals with G6PD deficiency and d) lower chance of the parasite developing resistance to the drug. Several options have been explored in this regard, including TQ, bulaquine, tinidazole and imidazolidinone. Bulaquine is the pro‐drug of PQ and is currently not licensed for sale outside India (Wells 2010). Of other options, only TQ has been tested to show promising results for both prevention and radical cure in individual trials. Also, its shorter duration of therapy makes it an attractive option to improve adherence. It also causes haemolysis, and its longer half‐life makes any haemolytic effect more prolonged and thus potentially more serious. In 2013, the FDA designated TQ as a breakthrough therapy. This Cochrane review will pool the evidence from all RCTs on use of TQ for radical cure ofP. vivax malaria to answer key questions on its efficacy and adverse event profile as compared to no treatment or PQ.

How the intervention might work

The exact mechanism of action of TQ is not yet known. Based on early in vitro and animal studies, some believed it to be longer acting and more effective than PQ (Walsh 2004a). Preclinical studies showed better activity of TQ compared to PQ against both hepatic and erythrocytic forms of the parasite. Phase I and II trials have been conducted to evaluate its safety (Brueckner 1998a; Brueckner 1998b). It has been more than a decade since TQ has been studied for treating P. vivax malaria.

Why it is important to do this review

PQ is a unique drug in combating vivax malaria but has side effects, which can sometimes be serious in people with G6PD deficiency. The long duration of treatment also leads to poor adherence. TQ is a possible alternative that has shown promise in replacing PQ and it can be administered as a single dose or in much shorter treatment regimens. Therefore, it is important to establish the effects of TQ from available data for preventing relapses of vivax malaria after an acute infection.

Objectives

To assess the effects of tafenoquine in people with P. vivax infection.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled clinical trials (RCTs). We excluded quasiRCTs..

Types of participants

Adults and children with confirmed (clinical and parasitological) diagnosis of P. vivax malaria.

We included trials where people with G6PD deficiency have been excluded, and in populations without screening for G6PD deficiency.

Types of interventions

Intervention

Tafenoquine

Control

No drug or placebo;

Primaquine in standard WHO 14‐day regimen

Both intervention and control groups must have received the same treatment, either CQ or an ACT, for the blood‐borne stage of the P. vivax infection.

Types of outcome measures

Episodes of P. vivax parasitaemia during follow‐up

Serious adverse events:death, symptomatic haemolysis, symptomatic methaemoglobinaemia, any other potentially life threatening observation or complaint that required treatment and monitoring by further investigations.

Any adverse events: all adverse effects either reported by subjects or elicited by investigators during treatment and follow‐up.

Search methods for identification of studies

We identified all relevant trials regardless of language or publication status (published, unpublished, in press and in progress). There were no time limits for the search.

Electronic searches

We searched the following databases using the search terms detailed in Appendix 1: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; CINAHL; SCOPUS; and LILACS. We also searched the World Health Organization (WHO) International Clinical Trial Registry Platform and the metaRegister of Controlled Trials (mRCT) for ongoing trials using "tafenoquine" and "malaria" as search terms. The date of the last search for all databases was 13 April 2015 and included all entries within these databases up to this date.

Searching other resources

Conference proceedings

We searched relevant proceedings of the Multilateral Initiative on Malaria (MIM) Pan‐African Malaria Conference and the American Society of Tropical Medicine and Hygiene Annual Meeting from 1990 onwards for trial information. The date of the last search was 13 April 2015.

Researchers

We contacted researchers working in the field and the WHO for unpublished and ongoing trials.

Reference lists

We checked the reference lists of existing reviews and of all trials identified by the above methods.

Data collection and analysis

Selection of studies

We (SR, CR and SDF) independently screened all trials identified by the search strategy and obtained full reports of potentially relevant trials. We independently applied the inclusion criteria to the full reports using an eligibility form and scrutinized publications to ensure each trial was included in the review only once. If necessary, we contacted the trial authors for clarification. Any disagreement was resolved by consensus. We have listed the ineligible trials and the reasons for their exclusion in the 'Characteristics of excluded studies' table.

Data extraction and management

We (SR, CR and SDF) extracted data from the selected trials and independently recorded outcomes. We developed and used a data extraction and assessment form suited for the needs of this review according to the instructions provided by The Cochrane Collaboration (Higgins 2011). We used RevMan 2014 for data analysis and storage, and created 'Summary of findings' tables with GRADEpro 2014 software. In each of the selected trials, we identified key information such as demographic characteristics of selected populations, G6PD status of the subjects, trial design and measures taken to minimize bias, treatment offered in different trial arms (with respect to dose and duration), duration of follow‐up, adverse events and reported outcomes. We also noted the limitations in each of the trials.

Assessment of risk of bias in included studies

We (SR, CR and SDF) independently assessed the risk of bias for each included trial using a 'Risk of bias' assessment form. We resolved any discrepancies between the results of the 'Risk of bias' analysis through discussion and consensus. If data were unclear or not reported, we wrote to the trial authors for clarification. We did not calculate quality scores for individual trials as it is not perceived by some authors as an objective measure of risk of bias (Greenland 1994).

We assessed the risk of bias for individual trials using the Cochrane 'Risk of bias' tool. This covers six domains of bias: allocation (selection bias), blinding (performance bias and detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias) and other potential sources of bias. Furthermore, we summarized the risk of bias for individual trials in a 'Risk of bias' table.

Measures of treatment effect

We expressed the effect of treatment within trials as risk ratio (RR) for dichotomous outcomes (for example, relapse of vivax malaria, new infections of vivax malaria). We defined the level of significance of differences according to the Chi2 statistic of P < 0.05. For all results, we calculated 95% confidence intervals (CIs) and performed meta‐analyses if sufficient data were available. We split the control groups between trial arms of a single trial where appropriate for meta‐analysis.

Unit of analysis issues

We did not identify any cluster‐RCTs in the search. Trials used different doses of TQ in multiple‐treatment arms against a control. If the doses were identical in certain trial groups, we combined them for pair‐wise comparison in a meta‐analysis. When comparing different TQ doses, we split the control group to avoid duplication in data entry.

Dealing with missing data

We contacted the corresponding author of one trial (Llanos‐Cuentas 2014) regarding data not reported in the paper and we obtained relevant data. No trials were excluded due to missing data.

Assessment of heterogeneity

We assessed heterogeneity using the I2 statistic (Higgins 2003), which examines the percentage of total variation across studies that are due to heterogeneity rather than chance. An I2 statistic value > 70% indicates a high level of heterogeneity.

Assessment of reporting biases

Since an insufficient number of RCTs met our inclusion criteria (< 10 trials) for each primary objective, we could not construct funnel plots to look for evidence of publication bias.

Data synthesis

We analysed data using RevMan 2014. CR conducted the initial analysis, and SR and SDF independently double checked and performed recalculations. We compared relapses following treatment between groups treated with TQ‐containing drug regimens against CQ alone or CQ plus PQ. Also, we compared the reported adverse events between TQ and controls. We used a fixed‐effect model for analysis (and rechecked for any differences of results in a random‐effects model).

Subgroup analysis and investigation of heterogeneity

When several trials were combined in a meta‐analysis, we calculated heterogeneity to express the treatment effect of TQ and CQ versus CQ alone or CQ plus PQ. We presented data in subgroups depending on the different doses of TQ used and whether single doses or split doses were used.

Sensitivity analysis

We did not perform a sensitivity analysis as only three trials were eligible for a valid comparison in a meta‐analysis.

Results

Description of studies

See: Characteristics of included studies, Characteristics of excluded studies and Characteristics of ongoing studies. We have given a summary of drug doses used in each trial arm of all included trials for ease of comparison (Table 5).

Table 1

Summary of doses of drugs used in each of the trial arms

Trial	Trial groups and tafenoquine doses	Comments
Llanos‐Cuentas 2014	50 mg single dose 100 mg single dose 300 mg single dose 600 mg as a single dose No TQ; CQ followed by PQ 15 mg/day for 14 days No TQ; CQ only	In all trials, all patients received the standard treatment of CQ 1500 mg over 3 days to clear the initial parasitaemia.There were no reports of CQ resistance.
Walsh 1999	300 mg/day for 7 days (total dose 2100 mg) 500 mg/day for 3 days, two courses separated by 1 week (total dose 3000 mg) 500 mg as a single dose No TQ; CQ only
Walsh 2004a	300 mg/day for 7 days (total dose 2100 mg) 600 mg/day for 3 days (total dose 1800 mg) 600 mg as a single dose No TQ; CQ only No TQ; CQ followed by PQ 15 mg/day for 14 days

CQ: Chloroquine; PQ: Primaquine; TQ: Tafenoquine

Results of the search

The results of the search, after excluding duplicate and irrelevant articles, yielded 15 papers that we deemed potentially useful for this Cochrane review (Figure 1). However, only three trials met the inclusion criteria.

Figure 1

PRISMA flow diagram indicating the process of inclusion and exclusion of studies.

Included studies

Three individually RCTs met the inclusion criteria (Llanos‐Cuentas 2014; Walsh 1999; Walsh 2004a). All patients received a full course of CQ to treat their P. vivax infection (1500 mg over three days). Comparisons included TQ + CQ versus CQ only (all three trials) and TQ + CQ versus CQ + PQ (two trials). No trials were conducted with ACTs as the background treatment.

All trials were in symptomatic patients with uncomplicated vivax malaria, and all trials excluded patients with G6PD deficiency, pregnant females and children.

Two trials were conducted in Bangkok, Thailand (Walsh 1999; Walsh 2004a) and the latest trial was a multicentre trial in Thailand, India, Peru and Brazil (Llanos‐Cuentas 2014). The earlier two trials examined comparatively high doses of TQ starting from 500 mg (Walsh 1999) or 600 mg (Walsh 2004a) administered as single doses and 1800 to 3000 mg administered as split doses over three to seven days. Llanos‐Cuentas 2014 tested single doses of TQ at strengths of 50, 100, 300 and 600 mg. The main outcomes assessed were: a) recurrences of vivax malaria up to six months follow‐up and b) adverse events. We contacted the authors of Llanos‐Cuentas 2014 for details not published in the paper (exact number of relapses during follow‐up) and we included the data in this analysis.

Excluded studies

We excluded randomized trials on prophylaxis, non‐controlled trials, case reports and pharmacokinetic studies (see Characteristics of excluded studies).

Risk of bias in included studies

For a summary of risk of bias please see the 'Characteristics of included studies' table and Figure 2.

Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.

All three included trials were described as randomized with computer generated sequence allocation. However in Walsh 2004a, some randomizations were eliminated and a few others were shifted between groups to balance the number of participants recruited in each group. Therefore we were unclear regarding the selection bias.

Both Walsh 1999 and Walsh 2004a were open label studies. However, the primary outcome of vivax parasitaemia was unlikely to be influenced by this fact as long as the microscopists were blinded. Walsh 1999 mentions that the microscopists were blinded but Walsh 2004a does not. So we judged that Walsh 1999 was at low risk of bias and Walsh 2004a was at unclear risk of bias. Llanos‐Cuentas 2014 was a double blind trial at low risk of bias. Walsh 1999 had a high attrition rate (27% of total sample during the first two months). It was lower but significant in Walsh 2004a (15% of total sample were lost to follow‐up during the first two months). The attrition rates were less than 6% for any of the trial arms in Llanos‐Cuentas 2014 which had a low risk of attrition bias.

All missing patients were accounted for and there was no reporting bias in all trials.

Effects of interventions

See: Table 1; Table 2

Summary of findings for the main comparison

Summary of findings table 1

Tafenoquine vs placebo/no hypnozoite treatment in people with Plasmodium vivax malaria
Patient or population: Adults and children withP. vivax malaria Settings:P. vivax endemic areas Intervention: Tafenoquine. Both intervention and control received chloroquine treatment. Comparison: No hypnozoite treatment.
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	CQ alone	TQ plus CQ
Recurrent P. vivax parasitaemia during six months of follow‐up	300 mg as a single dose		RR 0.19 (0.08 to 0.41)	110 (1 trial)	⊕⊕⊕⊝ moderate1,2,3
	57 per 100	11 per 100(5 to 23)
	500 mg or 600 mg as a single dose		RR 0.14 (0.06 to 0.34)	122 (2 trials)	⊕⊕⊕⊝ moderate4,5,6,7
	57 per 100	8 per 100(3 to 19)
	1800 mg to 3000 mg in divided doses		RR 0.05 (0.01 to 0.23)	63 (2 trials)	⊕⊕⊝⊝ low5,7,8,9
	57 per 100	3 per 100 (1 to 13)
Serious adverse events	6 per 100	6 per 100 (2 to 16)	RR 0.94 (0.34 to 2.59)	358 (3 trials)	⊕⊕⊝⊝ low10,11
*The basis for the assumed risk (for example, the median control group risk across studies) 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). CI: Confidence interval; CQ: Chloroquine; TQ: Tafenoquine; RR: Risk ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

1No serious risk of bias: This trial was at low risk of selection and reporting bias. 2No serious indirectness: This trial enrolled adults with P. vivax malaria in Peru, Thailand, India and Brazil. CQ was given in the standard adult dose to all participants. 3Downgraded by 1 for serious imprecision: This single trial is small and had few events during six months, as such this result is at high risk of being a chance finding or of overestimating the true effect. 4No serious risk of bias: One trial is at low risk of selection or detection bias. The second smaller trial is at unclear risk of selection bias. 5No serious inconsistency. 6No serious indirectness: These trials enrolled adults with P. vivax malaria in Peru, Thailand, India and Brazil. CQ was given in the standard adult dose to all participants. 7Downgraded by 1 for serious imprecision: These two trials are small with few events, as such this result is at high risk of being a chance finding or of overestimating the true effect. 8Downgraded by 1 for serious risk of bias: Both trials are at unclear risk of selection bias. 9No serious indirectness: These trials enrolled adults with P. vivax malaria in Thailand. CQ was given in the standard adult dose to all participants. 10Downgraded by 1 for serious indirectness: These trials excluded children, pregnant women and people with G6PD deficiency. 11Downgraded by 1 for serious imprecision.

Summary of findings 2

Summary of findings table 2

Tafenoquine vs primaquine in people with Plasmodium vivax malaria
Patient or population: Adults and children withP. vivax malaria Settings:P. vivax endemic areas Intervention: Tafenoquine. Both intervention and control received chloroquine treatment. Comparison: primaquine (standard 14 day regimen)
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	PQ and CQ	TQ and CQ
Recurrent P. vivax parasitaemia during six months of follow‐up	300 mg as a single dose		RR 0.41 (0.15 to 1.14)	79 (1 trial)	⊕⊕⊝⊝ low1,2,3
	26 per 100	11 per 100(4 to 30)
	600 mg as a single dose		RR 0.29 (0.1 to 0.84)	98 (2 trials)	⊕⊕⊝⊝ low4,5
	25 per 100	7 per 100(3 to 21)
	1800 mg to 2100 mg in divided doses		RR 0.06 (0.00 to 1.1)	38 (1 trial)	⊕⊕⊝⊝ low3,5
	25 per 100	2 per 100 (0 to 27)
Serious adverse events	12 per 100	5.5 per 100 (2 to 13)	RR 0.47 (0.2 to 1.08)	323 (2 trials)	⊕⊕⊝⊝ low6,7
*The basis for the assumed risk (for example, the median control group risk across studies) 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). CI: Confidence interval; CQ: Chloroquine; PQ: Primquine; TQ: Tafenoquine; RR: Risk ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

1No serious risk of bias: This trial was at low risk of selection and reporting bias. 2No serious indirectness: This trial enrolled adults with P. vivax malaria in Peru, Thailand, India and Brazil. CQ was given in the standard adult dose to all participants. 3Downgraded by 1 for serious imprecision: This single trial is small and had few events during six months, as such this result is at high risk of being a chance finding or of overestimating the true effect. Larger trials are needed to confirm this effect. 4Downgraded by 1 for serious imprecision: Both trials are small and had only a few events during six months, as such this result is at high risk of being a chance finding or of overestimating the true effect. Larger trials are needed to confirm this effect. 5Downgraded by 1 for serious risk of selection and detection bias in one trial. 6Downgraded by 1 for serious indirectness: These trials excluded children, pregnant women and people with G6PD deficiency. 7Downgraded by 1 for serious imprecision.

1. Tafenoquine versus no hypnozoite treatment

All three trials included arms that evaluated TQ against no specific anti‐hypnozoite drug. The TQ doses varied from 50 to 600 mg in single doses and from 1800 to 3000 mg in spilt doses over three to seven days. All patients in all included arms received CQ 1500 mg for three days.

Recurrent P. vivax parasitaemia during six months follow‐up

We first analysed the data for this outcome for four groups based on the total dose of TQ used in the trials; 50 to 100 mg, 300 mg, 500 to 600 mg and 1800 to 3000 mg. The analysis indicate that low doses (50 to 100 mg) had outcomes comparable to no treatment (one trial, 162 participants, Analysis 1.1) and hence we did not use these groups for further analysis. A repeat analysis of all trials after excluding the low dose groups showed that TQ reduced the P. vivax recurrences compared to no treatment during a six month follow‐up (RR 0.13, 95% CI 0.08 to 0.22, three trials, 250 participants, moderate quality evidence; Analysis 1.2; Figure 3).

Analysis 1.1

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 1 Recurrent P. vivax parasitaemia by 6 months.

Analysis 1.2

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 2 Recurrent P. vivax parasitaemia by 6 months (excluding tafenoquine doses < 300 mg).

Figure 3

Forest plot of comparison: 1 TQ and CQ versus CQ alone, outcome: 1.2 Recurrent P. vivax parasitaemia by six months (excluding TQ doses < 300 mg).

Adverse events

Serious adverse events: We included the low dose TQ groups in the adverse event analysis.There was no difference between TQ groups and controls regarding serious adverse events (three trials, 358 participants, Analysis 1.3). No deaths were reported in any of the trials during treatment or follow‐up.

Analysis 1.3

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 3 Serious adverse events.

Any adverse events: There was no difference for any reported adverse events between the two groups (one trial, 272 participants, Analysis 1.4).

Analysis 1.4

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 4 Any adverse event by tafenoquine dose.

We also carried out a dose‐wise comparison (TQ 300 mg and 600 mg) for each type of adverse event reported and found no difference between TQ groups and controls except for a fewer number of chills in the TQ group (Analysis 1.5; Analysis 1.6).

Analysis 1.5

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 5 Comparison by type of adverse event for tafenoquine 300 mg.

Analysis 1.6

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 6 Comparison by type of adverse event for tafenoquine 600 mg.

There was also a dose‐dependent rise in methaemoglobin (MHb) levels in TQ treated groups, which was asymptomatic. In Walsh 1999 peak levels of MHb were 13.5%, 14.7% and 6.4% in treatment groups with total doses of 2100 mg, 3000 mg and 500 mg, respectively (normal value: 1 to 3%). Similarly, in Walsh 2004a the highest mean MHb level (12.1%) was reported from the trial arm which had the highest total TQ dose (2100 mg).

All trials screened and excluded patients with G6PD deficiency prior to randomization. Therefore, data on safety of TQ in G6PD‐deficient individuals are currently not available. The longer half‐life of TQ can potentially make it more harmful for patients with G6PD deficiency.

2. Tafenoquine versus primaquine

Two trials included this comparison (Llanos‐Cuentas 2014; Walsh 2004a). Both trials used the same dose of PQ (15 mg/day for 14 days). All patients received CQ 1500 mg for three days. Walsh 1999 did not have a PQ arm.

Recurrent P. vivax parasitaemia at six months

For purposes of analysis we divided the TQ groups to three subgroups based on the dose (300 mg single dose, 600 mg single dose, and 1800 to 2100 mg in split doses). A single TQ dose of 600 mg may be more effective than PQ in reducing relapses over six months follow‐up (RR 0.29, 95% CI 0.1 to 0.84, two trials, 98 participants, low quality evidence; Analysis 2.1; Table 2). The number of events in the higher dose category was too few to draw a firm conclusion. Overall, TQ may be better than PQ (15 mg/day over 14 days) in preventing relapses of vivax malaria during a six month follow‐up (RR 0.3, 95% CI 0.15 to 0.59, two trials, 215 participants, moderate quality evidence; Analysis 2.1; Figure 4).

Analysis 2.1

Comparison 2 Tafenoquine versus primaquine, Outcome 1 Recurrent P. vivax parasitaemia by 6 months (excluding tafenoquine doses < 300 mg).

Figure 4

Forest plot of comparison: 2 TQ versus PQ (both received CQ), outcome: 2.1 Recurrent P. vivax parasitaemia by six months (excluding TQ doses < 300 mg).

Serious adverse events: the low dose TQ groups were included in the adverse event analysis. There was no difference between TQ and PQ groups with regard to serious adverse events (two trials, 323 participants, low quality evidence; Analysis 2.2).

Analysis 2.2

Comparison 2 Tafenoquine versus primaquine, Outcome 2 Serious adverse events.

Any adverse events: There was also no difference detected between the two groups with regard to any reported adverse events (two trials, 323 participants, low quality evidence; Analysis 2.3). We carried out a dose wise comparison (TQ 300, 600, 1800, 3000 mg) for each type of adverse event reported and still found no difference between TQ and PQ groups (two trials, 323 participants, Analysis 2.4; Analysis 2.5; Analysis 2.6).

Analysis 2.3

Comparison 2 Tafenoquine versus primaquine, Outcome 3 Any adverse event by tafenoquine dose.

Analysis 2.4

Comparison 2 Tafenoquine versus primaquine, Outcome 4 Comparison by type of adverse event for tafenoquine 300 mg.

Analysis 2.5

Comparison 2 Tafenoquine versus primaquine, Outcome 5 Comparison by type of adverse event for tafenoquine 600 mg.

Analysis 2.6

Comparison 2 Tafenoquine versus primaquine, Outcome 6 Comparison by type of adverse event for tafenoquine doses > 600 mg.

Discussion

Summary of main results

Please see Table 1 and Table 2.

TQ reduced recurrence of vivax malaria (up to six months of observation) when combined with a standard dose of CQ compared to controls who received CQ only (moderate quality evidence; further research is likely to have an important impact on our confidence in the estimate of effect). TQ and CQ combination may be superior to PQ and CQ combination at a TQ dose of 600 mg or greater (low quality evidence; further research is very likely to have an important impact on this effect and confidence estimates). There was no difference of adverse events (serious or any event) between TQ groups and the controls. The trials that assessed comparable outcomes were consistent in their findings.

Overall completeness and applicability of evidence

Llanos‐Cuentas 2014 is a multicentre, double blind RCT with a larger sample size than other included trials and gives moderate quality evidence to arrive at dosing recommendations of TQ for relapse prevention in patients with vivax parasitaemia. Llanos‐Cuentas 2014 showed that TQ in single low doses (50 and 100 mg) is ineffective in relapse prevention compared to CQ monotherapy and hence should not be used. When the data for higher doses in this trial is pooled with the other two trials (which are open label trials), a benefit is seen for relapse prevention by addition of TQ compared to CQ monotherapy. All trials are consistent in this regard.

The pooled results of the two trials comparing TQ with PQ indicate that TQ may be more effective, but numbers are small.

The dose of PQ used in the control arm in both trials was 15 mg/day for 14 days. More data from further clinical trials are needed to confirm the superiority (if any) of TQ over PQ at this PQ dosage. Current recommendations in some guidelines are for higher doses of PQ (for example, 30 mg/day for 14 days) (Hill 2006) and efficacy of TQ is untested against such doses of PQ. Similarly, G6PD deficient and pregnant individuals were excluded prior to enrolment in all trials and therefore safety of TQ under these circumstances is not explored. Therefore the major disadvantages with PQ, such as haemolysis with G6PD deficiency and methaemoglobinaemia, are still a risk with the structurally similar TQ and same cautions apply for its administration.

Quality of the evidence

Recurrent P. vivax parasitaemia at six months

All included trials were randomized prospective well designed clinical trials. However, two were open label trials (Walsh 1999; Walsh 2004a). Still, given the fact that the primary outcome was objectively defined (microscopically definedP. vivax parasitaemia), it would have offset any performance or detection bias as long as the microscopists were blinded. Only Walsh 1999 mentioned that microscopists were blinded. As mentioned previously, the sample size in individual trials was small and specially when the recruits were categorized into four or five treatment arms, the numbers in each arm were even fewer. Several of these arms had high attrition rates at two months. Considering the overall picture, we conclude that further evidence is needed to confirm these findings in larger clinical trials for the TQ versus PQ comparison . Furthermore, the maximum follow‐up was six months in both trials. Relapses of vivax malaria can occur even later, probably up to one year.

Adverse events

Two trials were open label trials (Walsh 1999; Walsh 2004a) which might have caused bias in reporting adverse events. There is no foolproof method of differentiating whether an adverse reaction is actually related to the trial drug. This decision was at the discretion of the investigator and was subjective. The definition of seriousness of an adverse event is also subjective and one trial (Llanos‐Cuentas 2014) had clearly reported more serious adverse events than the other two trials (Walsh 1999; Walsh 2004a) which had used much higher doses of TQ. Therefore, we have downgraded the quality of evidence to "low" with regard to this outcome. The safety of TQ in pregnancy, children and in G6PD deficient patients is untested.

Potential biases in the review process

The trial registries mentioned above were searched with specific search strategies to uncover any unpublished trials with negative results. None were identified.

Agreements and disagreements with other studies or reviews

There were no other reviews to compare with this Cochrane review on the efficacy of TQ in preventing relapses of vivax malaria. On adverse events we agree with the conclusion of individual trial investigators and other reviewers (Prashar 2009) that TQ is a well‐tolerated drug in non‐pregnant, non‐G6PD deficient individuals in the dose ranges tested.

Authors' conclusions

TQ has good efficacy in preventing relapses up to six months by clearing vivax hypnozoites when used at a total dose of 300 mg or more (moderate quality evidence). Evidence from two studies also suggest that it may be better than PQ (15 mg/day for 14 days) for hypnozoite clearance (low quality evidence). The ability to administer TQ as single doses or a shorter course of split doses is a significant advantage.

People with G6PD deficiency were excluded from the studies so recommendations for its use derived from trials to date can only be in people in whom G6PD deficiency has been excluded.

Further randomized controlled clinical trials will help establish whether TQ is better in relapse prevention compared to PQ. Such trials should test TQ at doses ≥ 300 mg compared to PQ in standard doses(15 mg/day for 14 days). Preferably patients should have a longer follow‐up period (extending to one year).

There is a greater potential risk of haemolysis with TQ than with PQ because of the longer half‐life. This is important to consider researching further before deployment of the drug widely in primary care.

NCT02216123

Trial name or title	A Randomized, Double‐Blind, Double Dummy, Comparative, Multicenter Study to Assess the Incidence of Hemolysis, Safety, and Efficacy of Tafenoquine (SB‐252263, WR238605) Versus Primaquine in the Treatment of Subjects With Plasmodium Vivax Malaria
Methods	Randomized, double‐blind, double dummy, comparative, multicentre study
Participants	Inclusion criteria: Age > 16 years Positive GIEMSA smear for P. vivax with parasite density between 100 to 100,000/µL Willing to follow study protocol Hb level > 7 g/dL (for those with a G6PD level > 70% of site median) or > 8 g/dL (or those with a G6PD level 40 to 70% of site median) Exclusion criteria: Lactating, pregnant and sexually active females not using a contraceptive method Any patient with 4‐ or 8‐aminoquinoline allergy, liver impairment or any other significant illness including QT prolongation on ECG, severe vivax malaria, mixed malaria infection and substance abuse
Interventions	CQ and TQ (trial arm) compared with CQ and primaquine and CQ and placebo (control arms)
Outcomes	Primary outcome(s): Proportion of all subjects with P. vivax experiencing clinically relevant haemolysis up to 180 days. Proportion of female subjects with P. vivax who are moderately (40 to 70 percent) G6PD deficient experiencing clinically relevant haemolysis. Secondary outcomes: Adverse events caused by treatment. P. vivax relapses within 6 months post treatment. Fever clearance time Gametocyte clearance time Total parasite clearance time Correlation between plasma TQ levels and haemoglobin MHb levels Treatment efficacy
Starting date	September 2014
Contact information	US GSK Clinical Trials Call Center
Notes	Location: Not mentionedFunding: GlaxoSmithKline Pharmaceuticals Ltd and Medicines for Malaria Venture

Comparison 1

Tafenoquine versus no hypnozoite treatment

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 1 Recurrent P. vivax parasitaemia by 6 months.

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 2 Recurrent P. vivax parasitaemia by 6 months (excluding tafenoquine doses < 300 mg).

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 3 Serious adverse events.

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 4 Any adverse event by tafenoquine dose.

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 5 Comparison by type of adverse event for tafenoquine 300 mg.

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 6 Comparison by type of adverse event for tafenoquine 600 mg.

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 1 Recurrent P. vivax parasitaemia by 6 months.

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 2 Recurrent P. vivax parasitaemia by 6 months (excluding tafenoquine doses < 300 mg).

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 3 Serious adverse events.

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 4 Any adverse event by tafenoquine dose.

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 5 Comparison by type of adverse event for tafenoquine 300 mg.

Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 6 Comparison by type of adverse event for tafenoquine 600 mg.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Recurrent P. vivax parasitaemia by 6 months Analysis 1.1
3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1 Tafenoquine 50 to 100 mg single dose	1	162	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.55, 1.04]
1.2 Tafenoquine 300 mg single dose	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.08, 0.41]
1.3 Tafenoquine 500 to 600 mg single dose	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	0.14 [0.06, 0.34]
1.4 Tafenoquine 1800 to 3000 mg split doses	2	63	Risk Ratio (M‐H, Fixed, 95% CI)	0.05 [0.01, 0.23]
2 Recurrent P. vivax parasitaemia by 6 months (excluding tafenoquine doses < 300 mg) Analysis 1.2
3	250	Risk Ratio (M‐H, Fixed, 95% CI)	0.13 [0.08, 0.22]
3 Serious adverse events Analysis 1.3
3	358	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.34, 2.56]
4 Any adverse event by tafenoquine dose Analysis 1.4
1	272	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.78, 1.10]
5 Comparison by type of adverse event for tafenoquine 300 mg Analysis 1.5
1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5.1 Abdominal pain	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.38, 3.57]
5.2 Nausea	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [0.40, 6.40]
5.3 Vomiting	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	4.82 [0.24, 98.24]
5.4 Diarrhoea	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.17, 3.08]
5.5 Chills	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.10, 0.60]
5.6 Vertigo/dizziness	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.30, 3.14]
5.7 Headache	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.25, 0.93]
5.8 Myalgia	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.03, 3.00]
5.9 Rash/pruritus	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.43, 2.83]
5.10 Weakness/asthenia	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	2.89 [0.12, 69.55]
5.11 Cough	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.25, 3.66]
5.12 Arthralgia	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	1.93 [0.18, 20.65]
5.13 Insomnia	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	4.82 [0.58, 39.94]
5.14 Anaemia/drop in Hb	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.06, 15.03]
5.15 QT prolongation	1	110	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.17, 3.08]
6 Comparison by type of adverse event for tafenoquine 600 mg Analysis 1.6
1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
6.1 Abdominal pain	1	108	Risk Ratio (M‐H, Fixed, 95% CI)	1.2 [0.39, 3.70]
6.2 Nausea	1	108	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.42, 6.63]
6.3 Vomiting	1	108	Risk Ratio (M‐H, Fixed, 95% CI)	7.0 [0.37, 132.35]
6.4 Diarrhoea	1	108	Risk Ratio (M‐H, Fixed, 95% CI)	2.25 [0.74, 6.87]
6.5 Chills	1	108	Risk Ratio (M‐H, Fixed, 95% CI)	0.45 [0.23, 0.90]
6.6 Vertigo/dizziness	1	108	Risk Ratio (M‐H, Fixed, 95% CI)	0.8 [0.23, 2.82]
6.7 Headache	1	108	Risk Ratio (M‐H, Fixed, 95% CI)	0.8 [0.47, 1.37]
6.8 Myalgia	1	108	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.21, 4.74]
6.9 Rash/pruritus	1	108	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.06, 1.31]
6.10 Weakness/asthenia	1	108	Risk Ratio (M‐H, Fixed, 95% CI)	11.0 [0.62, 194.17]
6.11 Cough	1	108	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.03, 2.16]
6.12 Arthralgia	1	108	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.32, 27.94]
6.13 Insomnia	1	108	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.32, 27.94]
6.14 Anaemia/drop in Hb	1	108	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.06, 15.58]
6.15 QT prolongation	1	108	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.03, 2.16]

Comparison 2

Tafenoquine versus primaquine

Comparison 2 Tafenoquine versus primaquine, Outcome 1 Recurrent P. vivax parasitaemia by 6 months (excluding tafenoquine doses < 300 mg).

Comparison 2 Tafenoquine versus primaquine, Outcome 2 Serious adverse events.

Comparison 2 Tafenoquine versus primaquine, Outcome 3 Any adverse event by tafenoquine dose.

Comparison 2 Tafenoquine versus primaquine, Outcome 4 Comparison by type of adverse event for tafenoquine 300 mg.

Comparison 2 Tafenoquine versus primaquine, Outcome 5 Comparison by type of adverse event for tafenoquine 600 mg.

Comparison 2 Tafenoquine versus primaquine, Outcome 6 Comparison by type of adverse event for tafenoquine doses > 600 mg.

Comparison 2 Tafenoquine versus primaquine, Outcome 1 Recurrent P. vivax parasitaemia by 6 months (excluding tafenoquine doses < 300 mg).

Comparison 2 Tafenoquine versus primaquine, Outcome 2 Serious adverse events.

Comparison 2 Tafenoquine versus primaquine, Outcome 3 Any adverse event by tafenoquine dose.

Comparison 2 Tafenoquine versus primaquine, Outcome 4 Comparison by type of adverse event for tafenoquine 300 mg.

Comparison 2 Tafenoquine versus primaquine, Outcome 5 Comparison by type of adverse event for tafenoquine 600 mg.

Comparison 2 Tafenoquine versus primaquine, Outcome 6 Comparison by type of adverse event for tafenoquine doses > 600 mg.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Recurrent P. vivax parasitaemia by 6 months (excluding tafenoquine doses < 300 mg) Analysis 2.1
2	215	Risk Ratio (M‐H, Fixed, 95% CI)	0.30 [0.15, 0.59]
1.1 Tafenoquine 300 mg single dose	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	0.41 [0.15, 1.14]
1.2 Tafenoquine 600 mg single dose	2	98	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.10, 0.84]
1.3 Tafenoquine 1800 to 2100 mg split doses	1	38	Risk Ratio (M‐H, Fixed, 95% CI)	0.06 [0.00, 1.10]
2 Serious adverse events Analysis 2.2
2	323	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.20, 1.08]
3 Any adverse event by tafenoquine dose Analysis 2.3
2	323	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.87, 1.28]
4 Comparison by type of adverse event for tafenoquine 300 mg Analysis 2.4
1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
4.1 Abdominal pain	1	103	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.26, 1.99]
4.2 Nausea	1	103	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.30, 3.68]
4.3 Vomiting	1	103	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.07, 1.65]
4.4 Diarrhoea	1	103	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.15, 2.67]
4.5 Chills	1	103	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.15, 1.14]
4.6 Vertigo/dizziness	1	103	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.26, 2.72]
4.7 Headache	1	103	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.29, 1.22]
4.8 Myalgia	1	103	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.04, 4.48]
4.9 Rash/pruritus	1	103	Risk Ratio (M‐H, Fixed, 95% CI)	2.24 [0.63, 7.96]
4.10 Weakness/asthenia	1	103	Risk Ratio (M‐H, Fixed, 95% CI)	2.53 [0.11, 60.60]
4.11 Cough	1	103	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.22, 3.18]
4.12 Arthralgia	1	103	Risk Ratio (M‐H, Fixed, 95% CI)	1.68 [0.16, 17.94]
4.13 Insomnia	1	103	Risk Ratio (M‐H, Fixed, 95% CI)	1.40 [0.35, 5.55]
4.14 Anaemia/drop in Hb	1	103	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.05, 13.06]
4.15 QT prolongation	1	103	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.13, 2.00]
5 Comparison by type of adverse event for tafenoquine 600 mg Analysis 2.5
2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5.1 Abdominal pain	2	129	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.27, 2.06]
5.2 Nausea	2	129	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.39, 3.90]
5.3 Vomiting	2	129	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.21, 2.32]
5.4 Diarrhoea	2	129	Risk Ratio (M‐H, Fixed, 95% CI)	1.70 [0.62, 4.68]
5.5 Chills	2	129	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.35, 1.76]
5.6 Vertigo/dizziness	2	129	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.33, 2.01]
5.7 Headache	2	129	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.49, 1.48]
5.8 Myalgia	2	129	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.23, 7.48]
5.9 Rash/pruritus	2	129	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.18, 3.11]
5.10 Weakness/asthenia	2	129	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.41, 1.92]
5.11 Cough	1	101	Risk Ratio (M‐H, Fixed, 95% CI)	0.22 [0.03, 1.88]
5.12 Arthralgia	1	101	Risk Ratio (M‐H, Fixed, 95% CI)	2.61 [0.28, 24.26]
5.13 Insomnia	1	101	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.18, 4.11]
5.14 Anaemia/drop in Hb	1	101	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.06, 13.53]
5.15 QT prolongation	1	101	Risk Ratio (M‐H, Fixed, 95% CI)	0.17 [0.02, 1.44]
6 Comparison by type of adverse event for tafenoquine doses > 600 mg Analysis 2.6
1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
6.1 Abdominal pain	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	3.77 [0.22, 65.19]
6.2 Nausea	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	3.77 [0.22, 65.19]
6.3 Vomiting	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.4 Diarrhoea	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	1.6 [0.20, 12.89]
6.5 Chills	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.05, 28.90]
6.6 Vertigo/dizziness	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	2.13 [0.76, 6.01]
6.7 Headache	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	0.8 [0.30, 2.17]
6.8 Myalgia	1	46	Risk Ratio (M‐H, Fixed, 95% CI)	1.65 [0.07, 38.22]
6.9 Rash/pruritus	1	46	Risk Ratio (M‐H, Fixed, 95% CI)	1.60 [0.18, 14.16]
6.10 Weakness/asthenia	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	0.9 [0.55, 1.48]