A Multicentre Randomized Controlled Trial of the Efficacy and Safety of Single-Dose Praziquantel at 40 mg/kg vs. 60 mg/kg for Treating Intestinal Schistosomiasis in the Philippines, Mauritania, Tanzania and Brazil

Abstract

BackgroundPraziquantel at 40 mg/kg in a single dose is the WHO recommended treatment for all forms of schistosomiasis, but 60 mg/kg is also deployed nationally.Methodology/Principal FindingsFour trial sites in the Philippines, Mauritania, Tanzania and Brazil enrolled 856 patients using a common protocol, who were randomised to receive praziquantel 40 mg/kg (n = 428) or 60 mg/kg (n = 428). While the sites differed for transmission and infection intensities (highest in Tanzania and lowest in Mauritania), no bias or heterogeneity across sites was detected for the main efficacy outcomes. The primary efficacy analysis was the comparison of cure rates on Day 21 in the intent-to-treat population for the pooled data using a logistic model to calculate Odd Ratios allowing for baseline characteristics and study site. Both doses were highly effective: the Day 21 cure rates were 91.7% (86.6%–98% at individual sites) with 40 mg/kg and 92.8% (88%–97%) with 60 mg/kg. Secondary parameters were eggs reduction rates (ERR), change in intensity of infection and reinfection rates at 6 and 12 months. On Day 21 the pooled estimate of the ERR was 91% in both arms. The Hazard Ratio for reinfections was only significant in Brazil, and in favour of 60 mg/kg on the pooled estimate (40 mg/kg: 34.3%, 60 mg/kg: 23.9%, HR = 0.78, 95%CI = [0.63;0.96]). Analysis of safety could not distinguish between disease- and drug-related events. 666 patients (78%) reported 1327 adverse events (AE) 4 h post-dosing. The risk of having at least one AE was higher in the 60 than in the 40 mg/kg group (83% vs. 73%, p<0.001). At 24 h post-dosing, 456 patients (54%) had 918 AEs with no difference between arms. The most frequent AE was abdominal pain at both 4 h and 24 h (40% and 24%).ConclusionA higher dose of 60 mg/kg of praziquantel offers no significant efficacy advantage over standard 40 mg/kg for treating intestinal schistosomiasis caused by either S. mansoni or S. japonicum. The results of this study support WHO recommendation and should be used to inform policy decisions in the countries.Trial Registration Controlled-Trials.com ISRCTN29273316 ClinicalTrials.gov NCT00403611

Schistosomiasis mass drug administration in the Philippines: lessons learnt and the global implications

“…A multicentre trial comparing the efficacy of 40 mg/kg PZQ against the higher dose of 60 mg/kg for the treatment of intestinal schistosomiasis was also conducted at one of the study sites. The study involved 10e19 year olds and showed no significant difference in the effect of the two doses of PZQ in terms of cure rates or egg reduction rates [43].…”

Advocacy, policies and practicalities of preventive chemotherapy campaigns for African children with schistosomiasis

“…Similarly, in those unable to mount an immunological response that fails to synergize with the effect of treatment will manifest itself in poor cure even though the drug-specific part was satisfactory, for example, this might explain poor drug performance in very young children [13,84]. It is also known that poor cure rates are reported in communities with a heavy intensity of infections [85], thus even if the drug is killing the vast majority of worms, there may still be residual worms that survive initial treatment [15]. Also different isolates of schistosomes have variable levels of tolerance to PZQ [86], likely due to extensive genetic variation within and between worms [66,67].…”

“…Throughout the 2010-2012 period there were several workshops, as coordinated by WHO-Geneva, that solicited expert opinions from those involved in worm control, inclusive of representatives from the veterinary sector (where anthelmintic resistance to nematodes is well-known) [55], to develop pragmatic in-field guidelines for programme managers. Novel treatment regimes using double PZQ treatment separated by 2-weeks to improve cure [71,87] were discussed, as was recourse to slightly higher dosing at 60 mg/kg, although recent findings from Cochrane Reviews appear to be equivocal in terms of increased performance [85]. While these research findings are important, it should not be forgotten that large-scale interventions have different programmatic bottlenecks.…”

Decades down the line: the viability of praziquantel for future schistosomiasis treatment

“…Clinical observation over many years has confirmed initial safety predictions. Unwanted side effects after treatment are not uncommon, but they are usually mild and short-lived [3]. Some of the more severe reactions are probably the consequence of a massive release of parasite material from dying worms rather than a direct effect of the drug on the host.…”