Randomized Controlled Trial of Levamisole Hydrochloride as Adjunctive Therapy in Severe Falciparum Malaria With High Parasitemia

Abstract

Background. Cytoadherence and sequestration of erythrocytes containing mature stages of Plasmodium falciparum are central to the pathogenesis of severe malaria. The oral anthelminthic drug levamisole inhibits cytoadherence in vitro and reduces sequestration of late-stage parasites in uncomplicated falciparum malaria treated with quinine.Methods. Fifty-six adult patients with severe malaria and high parasitemia admitted to a referral hospital in Bangladesh were randomized to receive a single dose of levamisole hydrochloride (150 mg) or no adjuvant to antimalarial treatment with intravenous artesunate.Results. Circulating late-stage parasites measured as the median area under the parasite clearance curves were 2150 (interquartile range [IQR], 0–28 025) parasites/µL × hour in patients treated with levamisole and 5489 (IQR, 192–25 848) parasites/µL × hour in controls (P = .25). The “sequestration ratios” at 6 and 12 hours for all parasite stages and changes in microvascular blood flow did not differ between treatment groups (all P > .40). The median time to normalization of plasma lactate (<2 mmol/L) was 24 (IQR, 12–30) hours with levamisole vs 28 (IQR, 12–36) hours without levamisole (P = .15).Conclusions. There was no benefit of a single-dose of levamisole hydrochloride as adjuvant to intravenous artesunate in the treatment of adults with severe falciparum malaria. Rapid parasite killing by intravenous artesunate might obscure the effects of levamisole.

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria

“…In a similar fashion, dichloracetate may be effective at reducing plasma lactate levels [34], however, it seems unlikely to be an effective adjuvant reducing the underlying causes of tissue hypoxia and mortality. Several of the current experimental adjuvant or supporting treatments are aiming at an improvement of the microcirculation in severe malaria, including nitric oxide donors [35, 36], and compounds affecting cytoadhesion and sequestration [15, 37]. Our results suggest that improvement in blood or plasma lactate concentrations over time is an adequate endpoint for trials evaluating these interventions.…”

“…Serial GCS (assessed 6 hourly) and lactate (assessed 6 hourly) data from adult patients with severe malaria enrolled in studies at Chittagong Medical College Hospital (CMCH), Chittagong, Bangladesh between 2005 and 2012. The Bangladeshi patients were enrolled in observational and treatment studies including studies on levamisole, timing of enteral feeding, N-acetylcysteine and paracetamol [15, 18, 20, 22]. These randomized clinical trials were monitored internally as well as by an outside monitor.…”

Management of severe paediatric malaria in resource-limited settings

“…Only one patient died (control) arm.Maude et al . [126]Chittagong, Bangladesh>or = 16 years P. falciparum (>2%) plus modified WHO severe malaria criteria N = 60Phase II Controlled RCT Levamisole 150 mg po or ng stat dose immediately vs control plus artesunateComposite: Clinical Death or coma recovery Parasite clearance and lactate Pharmacodynamics Microvascular flowDeath 5/29 (17%) Levamisole vs 9/27 (33%) P  = 0.22Levamisole inhibits cytoadherence in vitro and reduces sequestration of late-stage parasites.No differences in proportions of trophozoites, measures of parasite clearance in blood over 30 hours or effects sequestrationSpeculated whether rapid clearance of malaria parasites by artesunate may obscure beneficial effects of levamisole. Seizure prophylaxis White et al [127]ThailandChildren >6 years and adultsCerebral malaria N = 46Double blind RCT: 3.5 mg/kg single dose given IM phenobarbitone (Pb) n = 24 Control (n. saline) n = 241 0 Seizure prevention1 0 Convulsions in Pb arm 3/24 (12-5%), vs 13/24 (54%) placebo ( P  = 0-006).Seizures prevention superior2 0 Death2 0 Deaths 8 (33%) in Pb arm 5 (20.8) placebo arm ( P  = 0.5)Small numbers in trial not able to assess effect on mortality.Kochar et al [130]Rajasthan, IndiaAdults age 14 to 74 yearsCerebral malaria N = 185Randomly assigned:Not specified3/102 (3%) developed seizures after admission in Pb arm vs 19/83 (22.9%) controlReported as a correspondence not formally reported as a peer reviewed manuscript.10 mg/kg im one dose of phenobabitone (Pb) (n = 102) Control (n = 83)Deaths Pb: 29/102 (28.4% vs control 33/83 (39.8%)PbCrawley et al [128]Kilifi, KenyaChildren 9 months to 13 yearsCerebral malaria N = 340Placebo controlled trial1 0 Seizure prevention1 0 Seizure frequency lower in the Pb arm vs placebo group (18 (11%) vs 46 (27%) children had 3 or more seizures OR: 0.32 (95% CI 0.18 to 0.58)Frequency of respiratory arrest was higher in the phenobarbital arm vs placebo arm170 Pb arm/170 placebo armA single intramuscular dose of phenobarbital (Pb) (20 mg/kg) or identical placebo plus quinine2 0 Death2 0 Mortality higher in phenobarbitone arm (30 (18%) vs 14 (8%) deaths; OR 2.39 (1.28–4.64)).Mortality substantially increased in children who received phenobarbital plus three or more doses of diazepam (OR 31.7 (1.2 to 814))Not recommended in CM.Gwer et al [129]two centres Kilifi and Kisumu hospitals, Kenya…”

Editorial: CD36: Russian roulette of host and parasites during malaria infection

“…Although the manifestations of this phenomenon have been described extensively, the underlying mechanisms are not fully elucidated, and therefore, efficient therapeutic interventions have not yet been developed. The host scavenger receptor CD36 is thought to play a central role in malaria-induced ALI/ARDS [2], and the targeting of this molecule has been proposed as an adjunctive therapy for severe malaria [3]. The study by Lagassé et al [4] in this issue of the Journal of Leukocyte Biology shows why, despite its importance in ALI/ARDS, CD36 may not be a good therapeutic target.…”

“…The effect of CD36-blocking therapies on malariainduced lung injuries would thus be uncertain. In fact, they have been shown to induce no improvement when used as adjunctive therapy for severe P. falciparum malaria [3]. Therefore, the use of CD36-blocking molecules for therapeutic intervention in malaria should be reconsidered.…”