Safety and Efficacy Study of Intravenous Immunoglobulin to Treat Japanese Encephalitis

NCT01856205 | Completed Phase 2 DMC

• 1 other identifier: IVIG607
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Japanese Encephalitis

Keywords

Japanese Encephalitis, Randomized Controlled Trial, intravenous immunoglobulin, safety, efficacy, Nepal

Outcome Measures

Primary Outcomes (1)

• Evidence of side effects of study drug such as infusion site reaction, diarrhea, rise in blood pressure and change in urinary output

  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.

  Every 12 hours after administration of study drug upto discharge, which is on average eigth day (192 hours) of hospital admission

Secondary Outcomes (1)

• Death or neurological sequelae

  At the time of discharge, an expected average of eighth day of admission and again at 6 months after discharge

Other Outcomes (1)

• Serum JEV PRNT50 level (immunological marker)

  Measured at 3 time points: pre-treatment (just before first dose of study drug on first day), mid-treatment (just prior to fourth dose on fourth day) and post-treatment (one hour after fifth dose on fifth day).

Study Arms (2)

IVIG in JE (JE-positive)

PLACEBO COMPARATOR

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.

Drug: Intravenous immunoglobulin [ImmunoRel™ (batch 20081217)]

IVIG in Non-JE(JE-negative)

PLACEBO COMPARATOR

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.

Drug: Intravenous immunoglobulin [ImmunoRel™ (batch 20081217)]

Interventions

Intravenous immunoglobulin [ImmunoRel™ (batch 20081217)] DRUG

IVIG group received 400mg/kg/day intravenous at the rate of 0.01 to 0.02 ml/kg body weight/minute for 5 days or appearance of side effect or adverse events. Placebo group received 0.9% saline intravenous at similar rate.

IVIG in JE (JE-positive); IVIG in Non-JE(JE-negative)

Eligibility Criteria

• Age: 1 Year - 14 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Liverpool: lead
• Kanti Children's Hospital: collaborator
• B.P. Koirala Institute of Health Sciences: collaborator

Study Sites (2)

Kanti Children's Hospital

Kathmandu, Bagmati, 44616, Nepal

Location

BP Koirala Institute of Health Sciences

Dharān, Koshi, Nepal

Location

Related Publications (107)

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MeSH Terms

Conditions

Encephalitis, Japanese

Interventions

Immunoglobulins, Intravenous

Condition Hierarchy (Ancestors)

Encephalitis, Arbovirus; Encephalitis, Viral; Central Nervous System Viral Diseases; Central Nervous System Infections; Infections; Infectious Encephalitis; Arbovirus Infections; Vector Borne Diseases; Mosquito-Borne Diseases; Virus Diseases; RNA Virus Infections; Flavivirus Infections; Flaviviridae Infections; Encephalitis; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuroinflammatory Diseases

Intervention Hierarchy (Ancestors)

Immunoglobulin G; Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Tom Solomon, MRCP, PhD

  Director,Institute of Infection and Global Health, University of Liverpool, Apex Building, 8 West Derby Street, Liverpool, L69 7BE, UK , Head- Liverpool Brain Infection Group

  STUDY CHAIR

• Ajit Rayamajhi, MBBS, MD

  Institute of Infection and Global Health, University of Liverpool, Liverpool, UK & Kanti Children's Hospital, Maharajgunj, Kathmandu, Nepal

  PRINCIPAL INVESTIGATOR

• Sam Nightingale, MRCP

  Institute of Infection and Global Health, University of Liverpool, Apex Building, 8 West Derby Street, Liverpool, L69 7BE, UK

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Research Fellow (PhD Student)

Study Record Dates

• First Submitted: May 5, 2013
• First Posted: May 17, 2013
• Study Start: May 1, 2009
• Primary Completion: August 1, 2009
• Study Completion: August 1, 2009
• Last Updated: May 21, 2013

Record last verified: 2013-05

Locations

NE (2)