A Randomized, Double-Blind, Placebo-Controlled Trial of Safety and Efficacy of Combined Praziquantel and Artemether Treatment for Acute Schistosomiasis Japonica in China/Essai Controle Randomise En Double Aveugle, Portant Sur L'innocuite et L'efficacite De L'association Praziquantel/artemether Dans le B'aitement De la Schistosomiase Asiatique Aigue En Chine/Ensayo Aleatorizado a Doble

Article excerpt

Introduction

Schistosomiasis japonica, caused by Schistosoma japonicum, was highly prevalent in China (1,2) but an effective control programme has substantially decreased its endemicity, prevalence, intensity and associated morbidity. (3-5) Elimination, however, is a major challenge. (1,6-9) Chemotherapy remains the main tool for control. (1,2,10) The clinical features of schistosomiasis japonica can be severe. (6) Recent evidence suggests that the burden of disease attributable to S. japonicum (and other human schistosomes) has been under-recognized. (11)

Schistosomiasis japonica can be divided into three disease stages: acute, chronic and advanced. Acute S. japonicum infection (Katayama syndrome), (12) which appears 14-84 days after non-immune individuals are exposed to a primary infection or heavy reinfection, is common in high transmission areas in China. (2,7) Disease onset is related to migrating schistosomula larvae and egg deposition by adult female worms, with individuals typically presenting with nocturnal fever, cough, myalgia, headache and abdominal tenderness. (12)

Treatment for acute schistosomiasis in China is praziquantel (PZQ) at a dose of 120 mg/kg body weight over a 6-day period. (6,13,14) However, this is only effective on adult worms and early (3-8 hour) skin-stage schistosomula. (15) The co-existence of mature and immature worms in infected subjects may prolong fever after PZQ treatment, necessitating additional chemotherapy. (16) Furthermore, some individuals do not respond well to PZQ, especially if they have had repeated water exposure before the onset of disease. (12)

Artemether (AM), used for the treatment of malaria, is also effective against juvenile schistosomes in animals (17-21) and humans, (22-27) and it has been developed as a prophylactic for the prevention of patent schistosome infections. (26,27) In animals, combination therapy with PZQ plus AM is safe and results in higher worm reduction rates than pZQ alone, (28,29) a finding that has yet to be confirmed in human studies.

Here, we assessed the safety and efficacy of combining PZQ plus AM in different doses to treat acute schistosomiasis japonica in a randomized, double-blind, placebo-controlled trial carried out in a hospital setting in China.

Methods

Study objectives

The main objective of the study was to determine the safety and efficacy of combination therapy with AM and PZQ for acute cases of schistosomiasis japonica. Secondary objectives were to assess the safety and efficacy of PZQ in varying doses, either alone or in combination with AM, in the treatment of acute disease.

Study design

A randomized, double-blind, placebo-controlled trial, within four specialized schistosomiasis hospitals in the Dongting Lake region Hunan province, China, was carried out between May 2003 and December 2005. Study participants were randomized into one of four treatment regimens (Table 1) and were followed up over a 45-day period. The primary endpoint of the trial was human infection status. Secondary endpoints included haemoglobin and alanine aminotransferase (ALT) levels over time.

Study participants

Patients were admitted to the study based on the following inclusion criteria: (i) diagnosed to have acute schistosomiasis japonica, (ii) aged 10-60 years, (iii) weighed > 25 kg, (iv) willing to be followed up for 45 days post-treatment, and (v) provided informed consent. A confirmed case of acute schistosomiasis japonica was based on the following criteria formulated by the Ministry of Public Health in China (13): (i) positive stool examination for S. japonicum eggs by the Kato--Katz method, (ii) positive serology for schistosomiasis, (iii) recent history of water exposure, (iv) fever and/ or other relevant symptoms, and (v) peripheral blood eosinophilia comprising [greater than or equal to] 15% of the total leukocyte count.

Exclusion criteria included any of the following: (i) pregnancy confirmed by a positive pregnancy test, (ii) known hypersensitivity to PZQor AM, (iii) had received anti-schistosomal treatment before hospitalization, (iv) had water contact within the 45-day post-AM/ placebo treatment, or (v) had severe clinical signs/symptoms of disease such as jaundice, caput medusae, ascites, hepatosplenomegaly or telangiectasias as determined by haematological, biochemical, radiological and physiological assessment that included a full blood count, liver function tests, including measurement of ALT, renal function tests, chest X-ray, abdominal ultrasound and electrocardiography (ECG). …