The integrated safety analysis included 2,815 adults and children treated with PA for uncomplicated P. falciparum or P. vivax infection. The PA group was well balanced for baseline clinical and demographic characteristics with respect to the combined comparator group. The safety profile for PA in this analysis was similar to that reported for pyronaridine and artemisinin monotherapy
[21, 32–35]. Comparator safety profiles were also consistent with previous reports for MQ + AS
[25, 43–46] and CQ
[23, 47, 48].
Overall, PA and comparators were generally well tolerated. Although the nature and incidence of adverse events were generally similar between PA and comparators overall, dizziness was more common with MQ + AS (6.6%) and myalgia with CQ (9.2%) than with PA (1.4% and 3.8%, respectively) (Table
4). Serious adverse events were uncommon in all treatment groups (0–0.7%). For PA, only one patient had serious adverse events thought to be related to drug treatment; hepatic enzymes increased and incomplete abortion.
The only significant laboratory finding in the PA group was a mean increase in ALT and AST on days 3 and 7, compared with decreases in these enzymes for comparators (Figure
2). As a result of this signal, an Independent Data Monitoring Committee (IDMC) comprising six members, including three experts in hepatotoxicity, examined the data from all of the studies. Increased transaminases have been observed consistently across all the Phase II/III PA clinical studies and two (of four) of the completed Phase I studies. When they occurred, rises in transaminases peaked by day 7 and levels had normalized or were decreasing by day 28 with no instances of Grade 3 or 4 toxicity at this time point. Increased transaminases were associated rarely with rises in total bilirubin, which was often high at baseline and subsequently fell during treatment. Overall, 0.2% (7/2,815) of patients in the PA group and 0.3% (2/603) in the AL group had ALT and/or AST >3x the upper limit of normal (ULN) plus peak total bilirubin >2xULN; one of these patients in the PA group had elevated ALP which precluded them as a Hy’s law case. Importantly, no patients had any clinical sequelae related to these liver function changes and as a result the IDMC concluded that whilst PA treatment is associated with transient elevated transaminases, the early onset (day 3–7) and rapid resolution are consistent with a direct low-level toxicity. Therefore, as PA is dosed for only three days, the risk of progressive liver injury is small. Additional studies are ongoing in healthy volunteers and in patients to assess the hepatic safety profile of PA when the treatment is administered more than once.
Electrocardiograph results did not suggest any cardiac safety concerns with PA. As would be expected, prolonged QT interval was uncommon with PA (0.07%) but occurred more frequently with the quinoline derivatives MQ (0.7%) and particularly CQ (2.7%)
. Bradycardia was observed as an adverse event in 1.1% of patients receiving PA and 0.8% with AL. However, the finding of bradycardia in a young and otherwise fit population is likely to be associated with the resolution of the tachycardia associated with fever as decreases in mean heart rate were noted across all treatment groups and have been observed in other studies of anti-malarial therapy as patients become afebrile and they return to their normal baseline heart rate
For the treatment of uncomplicated P. falciparum in children and adults, there was no difference between PA and comparators for day-28 PCR-corrected ACPR for the ITT or PP analyses (Figure
3). This reflects results from the three P. falciparum Phase III studies in which non-inferiority of PA day 28 PCR-corrected ACPR (PP population) was demonstrated versus MQ + AS or AL
[15, 22, 25]. Sub-group analysis showed similar day-28 PCR-corrected ACPR (ITT population) for PA by region, age group, gender, weight, previous malaria, malaria in the last 12 months, and baseline parasitemia versus efficacy with PA overall (Table
Kaplan-Meier analysis of the integrated efficacy analysis indicated a P. falciparum recrudescence rate for PA intermediate between the comparators (Figure
4A). For individual studies, recrudescence rate over the 42-day study period was marginally higher with PA versus MQ + AS (P = .049) in SP-C-004-06 and similar versus AL (P = .90) in SP-C-005-06 and in the paediatric study SP-C-007-07 (P = .53)
[15, 22, 25]. Similarly, Kaplan-Meier analysis of the integrated efficacy analysis indicated a P. falciparum re-infection rate for PA intermediate between the comparators (AL highest, MQ + AS lowest) (Figure
4B). However, in the individual Phase III studies, re-infection rate was higher with MQ + AS than PA at day 28 (P = .04), and similar at day 42 (P = .17)
. One difference in the integrated analysis was that there were more patients in the PA group who where under 18 years of age than in the MQ + AS group and this may have increased the re-infection rate for PA relative to MQ + AS. In support of this, in the Phase III study of PA versus AL that comprised mostly adults (SP-C-005-06), PA had a lower re-infection rate than AL (day 28 P = .004, day 42 P = .007)
, but this difference was not evident in the paediatric PA versus AL study (SP-C-007-07) (P = .77)
. In the integrated analysis, re-infection rate was lower with PA than AL and the patients in the AL group tended to be younger. An alternative explanation is that there were differences in transmission rates between the treatment groups given the imbalance in Asian versus African centres in the integrated analysis.
In the integrated analysis, the P. falciparum parasite clearance rate was 24.1 h with PA and 32.9 h with MQ + AS (Figure
6). However, this was not seen in the comparative Phase III trial of these treatments in which median parasite clearance time was approximately 32 h in both arms (P = .08)
. This is probably because of the greater proportion of patients from Africa in the PA group versus the MQ + AS group in the integrated analysis; median parasite clearance rates were longer in Asia than Africa for all comparators (Table
6). In particular, in Cambodia parasite clearance times were extended for PA and MQ + AS to around 64 h (Figure
5B). However, this did not seem to affect the day-28 PCR-corrected ACPR (ITT population) between Cambodia and Thailand for either PA or MQ + AS. Extended parasite clearance times indicate the presence of artemisinin resistance and the results presented here are consistent with other reports from the Cambodia–Thailand border area
[8–14, 53]. For example, mean parasite clearance times of around 65 h have been reported for artemisinin-piperaquine, dihydroartemisinin-piperaquine and AL in this region
Parasite clearance times were similar between PA and AL in the integrated analysis (Figure
5A). However, in the individual studies of PA versus AL, parasite clearance was faster with PA (P = .02) in study SP-C-007-07 conducted in children, and in study SP-C-005-06 including mostly adults (P < .001)
[22, 25]. As above, these differences are probably explained by the longer parasite clearance times in Asian versus African centres, there being a relative lack of patients recruited from Asian centres in the AL group compared with the PA group in the integrated analysis.
Fever clearance time for PA in the integrated analysis was approximately intermediate between AL (fastest) MQ + AS (slowest) (Figure
6). However, in the individual Phase III studies, fever clearance times were shorter with PA versus AL in the paediatric study (P = .049) and there was no difference in the study conducted versus AL mostly in adults (P = .55)
[22, 25]. This again probably reflects the greater proportion of patients recruited from Asian centres in the PA and MQ + AS groups versus the AL group in the integrated analysis.
In the integrated analysis, it appeared that AL more rapidly eradicated gametocytes versus PA and MQ + AS (Figure
7). However, this is also probably explained by the difference in baseline populations. To investigate further, gametocytes carriage was analysed in the two studies that enrolled both adults and children
[15, 25], using log10 AUC [gametocyte density]
[54, 55]. In patients with baseline gametocytes, MQ + AS did appear to more rapidly reduce gametocyte carriage versus PA, though in patients with no gametocytes at baseline PA appeared to more effectively suppress gametocyte emergence (Figure
8). There appeared to be no differences between AL and PA in respect to gametocyte clearance or suppression.
Children are the most important target group for anti-malarial therapy, having reduced immunity and consequently poorer outcomes. Despite this, until recently paediatric ACT formulations have been generally lacking
. Paediatric formulations are easier to administer and may be better tolerated, particularly in terms of vomiting, which may affect anti-malarial drug levels
. A granule formulation was included in the PA development plan to ensure early availability after drug registration. For the primary efficacy outcome used in the Phase III studies – day-28 PCR-corrected ACPR – the granule and tablet formulation had similar efficacy in this analysis. Efficacy outcomes at day 42 were also similar for the two pyronaridine-artesunate formulations.
For the efficacy analysis, this report is concerned with the integrated analysis of the PA Phase III P. falciparum clinical trials. However, the efficacy of PA in P. vivax has also been evaluated in one Phase III study in adults and children
. In summary, for the primary outcome – the day-14 crude cure rate (PP population) – PA efficacy was 99.5%, (217/218; 95% CI 97.5, 100). This was non-inferior to CQ 100% efficacy (209/209; 95% CI 98.3, 100); treatment difference −0.5% (95% CI −2.6, 1.4). Non-inferiority of PA to CQ was maintained throughout follow-up (days 21, 28, 35 and 42)
. Additional clinical trials will report PA safety and efficacy in young children with P. vivax malaria and PA efficacy in areas of chloroquine-resistant P. vivax.