A Randomized Double Blind Placebo Controlled Trial to Assess the Safety and Efficacy of Intravenous Immunoglobulin (IVIG) in Children With Japanese Encephalitis in Nepal
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 22
- 试验地点
- 2
- 主要终点
- Evidence of side effects of study drug such as infusion site reaction, diarrhea, rise in blood pressure and change in urinary output
研究概览
简要总结
Japanese encephalitis is caused by a viral infection of the brain transmitted by the bite of an infected mosquito. Patients with Japanese encephalitis can rapidly develop worsening conscious level and seizures. Around a third will die from the infection and half of survivors have serious long-term neurological disability. The majority of those affected are children. There are many causes of viral encephalitis, however Japanese encephalitis virus is the most common cause worldwide with over 60,000 cases annually. It occurs over much of Asia and the geographical range is expanding. There is no specific treatment for Japanese encephalitis virus, although several have been trialed. In this study we examined the effect of a new treatment, called intravenous immunoglobulin, on children with Japanese encephalitis in Nepal. Prior studies have suggested intravenous immunoglobulin may neutralize Japanese encephalitis virus and suppress damaging inflammation in the brain. It has previously been used in individual cases but never examined in a randomized trial. There was recently a trial of IVIG in West Nile encephalitis in the United States, in which Professor Solomon was on the Scientific Advisory Committee. In this study we will look if intravenous immunoglobulin is safe in this context, and that this treatment may alter the way the immune system manages the infection. Therefore, in this pilot study we will test the hypothesis that IVIG can be safely given to children with suspected JE, with no increased risk of serious adverse events compared with placebo. The aim of this proposal is to conduct a pilot safety and tolerability randomized placebo controlled trial of intravenous immunoglobulin (IVIG) in patients with Japanese encephalitis, to explore the relationship between JEV viral load, pro-inflammatory markers called cytokines and blood brain barrier markers, and the effect of IVIG on these relationships.
详细描述
Japanese encephalitis (JE) is the most important epidemic encephalitis worldwide, causing approximately 35-50,000 cases and 10-15,000 deaths annually. Half of the survivors have severe neuropsychiatric sequelae, posing a large socio-economic burden on communities that can ill afford it. JE virus (JEV, genus flavivirus, family Flaviviridae) has a 50 nm lipoprotein envelope surrounding a nucleocapsid comprised of core protein and 11 KB of single-stranded positive-sense RNA. The genome has 5' and 3' untranslated regions (UTR), and a single open reading frame encoding genes for three structural proteins (core - C, pre-membrane - prM and envelope - E) and 7 non-structural (NS) proteins. The E protein is critical for viral attachment and entry into cells, and along with NS1 and NS3 is a major target of the immune response.
JEV is an arthropod-borne virus (arbovirus), transmitted in an enzootic cycle between birds, pigs and other vertebrates by mosquitoes, especially Culex species. Almost all of the population in affected parts of Asia is infected by early adulthood, but only a small proportion (about 1 in 300) develops clinical features. These may range from a non-specific febrile illness to a severe meningoencephalitis, in which seizures and clinical signs of raised intracranial pressure are common, and carry a poor prognosis. In addition JEV causes a poliomyelitis-like flaccid paralysis. The distribution of the four genotypes of JEV across Asia was thought to explain the clinical epidemiology, but is now thought to be a reflection of the virus' origin in Southeast Asia, and spread from here. However subtle differences in the genome may be important in determining neurological presentations of flaviviruses.
Although there are vaccines against JEV, they are not available for many of the people that need them, because of issues over cost and production. Progress is being made to overcome these difficulties, and newer vaccines are being used increasingly. In fact Nepal has been at the forefront of the use of a single dose of live attenuated SA14-14-2 vaccine for JE. However, continues to spread across Asia, and there is no treatment. Interferon-α (IFN-α), which is produced as part of the innate response to JEV infection, and which has antiviral activity against the virus, was thought to be the most promising treatment. However, a randomized placebo-controlled trial showed recombinant IFN-α2a at 10 million units/m2/day did not improve the outcome. The pathogenesis of JE is incompletely understood, but by comparison with other positive sense RNA viral encephalitides, is likely to involve a mixture of viral cytopathology and immunopathology .The role of steroids in JEV has been examined in one randomized-placebo controlled trial in Thailand, which failed to show any benefit.
IVIG currently offers one of the best possibilities for improving the outcome in JE. It has been used presumptively in patients with flavivirus encephalitis, including JE, and is postulated to act in two ways: IVIG produced in countries where flaviviruses are endemic contains high titers of specific neutralizing antibody, because most of the population have been exposed to the virus, and thus have antibodies. In addition IVIG has non-specific anti-inflammatory properties, particularly through the suppression of pro-inflammatory cytokines (e.g. in Kawasaki disease). We aim to examine the role of IVIG in JE, and also look at its effects on pro-inflammatory cytokines.
The role of antibody in protection against severe disease in Japanese encephalitis: The humoral immune response in JE has been well characterized. When disease is due to primary infection (i.e. when JEV is the first flavivirus with which an individual has been infected) a rapid and potent IgM response occurs in serum and CSF within days of infection. By day 7 most patients have elevated titers. Attempts to isolate virus are usually negative in such patients. However, the failure to mount an IgM response is associated with positive virus isolation and a fatal outcome. Antibody to JEV probably protects the host by restricting viral replication during the viraemic phase, before the virus crosses the blood brain barrier. Evidence from other flaviviruses suggests it may also limit damage during established encephalitis by neutralizing extracellular virus and facilitating lysis of infected cells by antibody-dependent cellular cytotoxicity.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 1 Year 至 14 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Children aged between 1 and 14 years who had clinically diagnosed encephalitis on the basis of history of fever that lasted less than 14 days, altered consciousness with or without a history of new onset seizures with CSF finding of white cell count less than 1000 cells/mm3 with no organisms on Gram stain and a CSF: plasma glucose ratio > 40% admitted in Kanti Children's Hospital and BP Koirala Institute of Health Sciences, Nepal.
排除标准
- •Asexual Plasmodium falciparum parasites in blood
- •Coma appears secondary to other systemic condition, eg hepatic failure, cardiac failure, toxins.
- •Patients who have documented antibiotic treatment before admission and in whom partially treated bacterial meningitis appears more likely than encephalitis
- •Children with simple febrile convulsions, defined as a single seizure lasting less than 15 minutes followed by full recovery of consciousness within 60 minutes.
- •Pregnant or breastfeeding females
- •Children with a GCS of 3/15, who were receiving artificial ventilation without signs of spontaneous respiration, and with absent oculocephalic reflex.
研究组 & 干预措施
IVIG in JE (JE-positive)
We randomly allocated patients to treatment with IVIG or placebo. Children received either saline or intravenous immunoglobulin (IVIG) [ImmunoRel™ (batch 20081217)] at a dose of 400mg/kg/day for 5 days or an equivalent volume of 0.9% normal saline given intravenous at the rate of 0.01 to 0.02 ml/kg body weight/minute. All investigators, care providers and participants were blinded of the study drug. A second sealed envelope was kept with the patient's notes in case a physician urgently needed to know which drug a patient had received.
干预措施: Intravenous immunoglobulin [ImmunoRel™ (batch 20081217)] (Drug)
IVIG in Non-JE(JE-negative)
We randomly allocated patients to treatment with IVIG or placebo. Children received either saline or intravenous immunoglobulin (IVIG) [ImmunoRel™ (batch 20081217)] at a dose of 400mg/kg/day for 5 days or an equivalent volume of 0.9% normal saline given intravenous at the rate of 0.01 to 0.02 ml/kg body weight/minute. All investigators, care providers and participants were blinded of the study drug. A second sealed envelope was kept with the patient's notes in case a physician urgently needed to know which drug a patient had received.
干预措施: Intravenous immunoglobulin [ImmunoRel™ (batch 20081217)] (Drug)
结局指标
主要结局
Evidence of side effects of study drug such as infusion site reaction, diarrhea, rise in blood pressure and change in urinary output
时间窗: Every 12 hours after administration of study drug upto discharge, which is on average eigth day (192 hours) of hospital admission
Patients will be monitored for side effects such as infusion site reaction, diarrhea, rise in blood pressure (in mm Hg) and change in urinary output (in ml/Kg/hour) every 12 hours from first day of commencing treatment until until death or discharge. Patient on average are administered the study drug on the first day of admission. The study drug is administered daily for 5 days. Patients are discharged on an average on eighth day (192 hours) of hospital admission.
次要结局
- Death or neurological sequelae(At the time of discharge, an expected average of eighth day of admission and again at 6 months after discharge)
研究者
Ajit Rayamajhi
Clinical Research Fellow (PhD Student)
University of Liverpool