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Efficacy of combined antiparasitic therapy with praziquantel and albendazole for neurocysticercosis: a double-blind, randomised controlled trial

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Summary

Background

Neurocysticercosis causes a substantial burden of seizure disorders worldwide. Treatment with either praziquantel or albendazole has suboptimum efficacy. We aimed to establish whether combination of these drugs would increase cysticidal efficacy and whether complete cyst resolution results in fewer seizures. We added an increased dose albendazole group to establish a potential effect of increased albendazole concentrations.

Methods

In this double-blind, placebo-controlled, phase 3 trial, patients with viable intraparenchymal neurocysticercosis were randomly assigned to receive 10 days of combined albendazole (15 mg/kg per day) plus praziquantel (50 mg/kg per day), standard albendazole (15 mg/kg per day), or increased dose albendazole (22·5 mg/kg per day). Randomisation was done with a computer generated schedule balanced within four strata based on number of cysts and concomitant antiepileptic drug. Patients and investigators were masked to group assignment. The primary outcome was complete cyst resolution on 6-month MRI. Enrolment was stopped after interim analysis because of parasiticidal superiority of one treatment group. Analysis excluded patients lost to follow-up before the 6-month MRI. This trial is registered with ClinicalTrials.gov, number NCT00441285.

Findings

Between March 3, 2010 and Nov 14, 2011, 124 patients were randomly assigned to study groups (41 to receive combined albendazole plus praziquantel [39 analysed], 43 standard albendazole [41 analysed], and 40 increased albendazole [38 analysed]). 25 (64%) of 39 patients in the combined treatment group had complete resolution of brain cysts compared with 15 (37%) of 41 patients in the standard albendazole group (rate ratio [RR] 1·75, 95% CI 1·10–2·79, p=0·014). 20 (53%) of 38 patients in the increased albendazole group had complete cyst resolution at 6-month MRI compared with 15 (37%) of 41 patients in the standard albendazole group (RR 1·44, 95% CI 0·87–2·38, p=0·151). No significant differences in adverse events were reported between treatment groups (18 in combined treatment group, 11 in standard albendazole group, and 19 in increased albendazole group).

Interpretation

Combination of albendazole plus praziquantel increases the parasiticidal effect in patients with multiple brain cysticercosis cysts without increased side-effects. A more efficacious parasiticidal regime without increased treatment-associated side-effects should improve the treatment and long term prognosis of patients with neurocysticercosis.

Funding

National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health.

Introduction

Neurocysticercosis caused by Taenia solium is regarded as the most frequent cause of acquired epilepsy worldwide.1, 2 In the lifecycle of this parasite, human beings harbour the adult tapeworm in their intestines and are the only definitive host. Both human beings and pigs can act as intermediate hosts by harbouring the larvae or cysticerci in their tissues.3 The infection and resulting disease is highly endemic in all developing countries where pigs are raised as a food source.1 Neurocysticercosis is now also increasingly diagnosed in industralised countries because of migration and travel from endemic zones.4

Cyst death after antiparasitic treatment is a result of not only the direct action of the drug, but also of an attack by the host immune system in response to the release of antigens caused by treatment-associated damage, which is most pronounced during the initial days or weeks after the start of antiparasitic treatment.5 Antiparasitic treatment of patients with viable intraparenchymal brain cysts seems to improve the prognosis of their seizure disorders.6, 7, 8, 9 However, antiparasitic treatment has suboptimum efficacy, killing roughly 65% of parasites and obtaining complete cyst resolution (no viable parasites remaining) in less than 40% of patients after a course of praziquantel or albendazole.10, 11

Praziquantel is a pyrazinoisoquinoline derivative, of which the main pharmacological effects include muscle contractions, paralysis, and tegumentary damage, whereas albendazole is a benzimidazole, of which the main method of action is through selective degeneration of cytoplasmic microtubules resulting in energy depletion, disrupted cell division, and altered glucose intake.12, 13 We postulated that combinination of these two antiparasitic drugs would improve the destruction of brain cysts without affecting patient safety, and designed a clinical study to compare treatment with albendazole alone with combined albendazole plus praziquantel. An initial pharmacokinetic substudy showed increased serum albendazole concentrations in patients receiving combination treatment compared with concentrations in those receiving albendazole alone.14 This difference in concentrations was presumed to be due to a pharmacokinetic interaction between praziquantel and albendazole. Hence, the question arose whether any reported superiority of the albendazole–praziquantel combination in elimination of viable cysts would be due to an additional cysticidal effect of praziquantel or due to increased albendazole concentrations arising from an interaction with praziquantel. Therefore, in response to a suggestion by our data and safety monitoring board, we added an increased dose albendazole study group so that we could establish whether any recorded increase in efficacy was a result of increased albendazole concentrations or to the direct action of praziquantel. We also compared seizure rates during periods before and after complete cyst resolution, to assess whether complete cyst resolution resulted in a decrease in seizure frequency.

Section snippets

Study design and participants

For this double-blind, placebo-controlled, randomised phase 3 clinical trial, we recruited patients from the Instituto Nacional de Ciencias Neurologicas, and the national hospitals Cayetano Heredia, Eduardo Rebagliati, and Guillermo Almenara, Lima, Peru. We did the study at the CNS Parasitic Diseases Research Unit, Universidad Peruana Cayetano Heredia, Lima, Peru.

Inclusion criteria were age between 16 and 65 years; one to 20 viable neurocysticercosis cysts; serological confirmation on western

Results

Between March 3, 2010 and Nov 14, 2011, 124 patients were randomly assigned to study groups (41 to receive combined albendazole plus praziquantel, 43 standard albendazole, and 40 increased albendazole). Enrolment was halted by the study data and safety monitoring board after interim analyses showed parasiticidal superiority of one of the treatment groups. Up to this point, 167 patients (100 men, 67 women) had entered the screening phase in whom 43 patients were excluded (figure 1). Of 124

Discussion

Findings from this randomised controlled trial have shown the increased antiparasitic efficacy of an albendazole plus praziquantel regimen, and that further seizures are less frequent in individuals with complete cyst resolution after antiparasitic treatment (panel). Neurocysticercosis, particularly intraparenchymal brain cysticercosis, is associated with seizures and epilepsy in most of the world.1, 22 The parasitic larvae establish and survive in the brain for a variable period (often years

References (33)

  • HH Garcia et al.

    A trial of antiparasitic treatment to reduce the rate of seizures due to cerebral cysticercosis

    N Engl J Med

    (2004)
  • OH Del Brutto et al.

    Metaanalysis: cysticidal drugs for neurocysticercosis: albendazole and praziquantel

    Ann Intern Med

    (2006)
  • G Singh et al.

    A diagnostic and therapeutic scheme for a solitary cysticercus granuloma

    Neurology

    (2010)
  • WM Otte et al.

    Drug therapy for solitary cysticercus granuloma: a systematic review and metaanalysis

    Neurology

    (2013)
  • J Sotelo et al.

    Comparison of therapeutic regimen of anticysticercal drugs for parenchymal brain cysticercosis

    J Neurol

    (1990)
  • P Venkatesan

    Albendazole

    J Antimicrob Chemother

    (1998)
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