Investigating the Role of Early Intravenous Immunoglobulin Treatment for Children With Encephalitis

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Brief Title

Investigating the Role of Early Intravenous Immunoglobulin Treatment for Children With Encephalitis

Official Title

A Phase III Multi-centre Randomised, Double Blind, Placebo Controlled Trial to Assess the Role of Intravenous Immunoglobulin in the Management of Children With Encephalitis

Brief Summary

      This is a phase III multi-centre randomised, double blind, placebo controlled trial to assess
      the role of intravenous immunoglobulin in the treatment of children with encephalitis. The
      primary objective is to find out whether early use of IVIG treatment improves neurological
      outcomes of children with encephalitis.

      308 children with encephalitis, aged 6 weeks to 16 years will be recruited in 30 hospitals in
      the United Kingdom. Participants will be randomised to receive two doses of IVIG or matching
      placebo in addition to other standard treatments, within the first five days of hospital
      admission.

      Each participant will be followed up for 12 months. During this period, information on
      clinical, radiological and laboratory investigations will be collected. Neurological outcomes
      will be assessed by the use of questionnaires at 6 and 12 months, and a neuropsychological
      assessment at 12 months.
    

Detailed Description

      Encephalitis is a syndrome of neurological dysfunction caused by inflammation of the brain
      parenchyma, resulting in altered mental status, seizures, and/or focal neurologic deficits,
      usually accompanied by laboratory and radiological evidence of brain inflammation. The
      worldwide annual incidence of encephalitis ranges from 3.5 to 7.4 per 100,000, rising to 16
      per 100,000 in children. In the United Kingdom, Public Health England (formerly the Health
      Protection Agency) reports an annual rate of 1.5 cases per 100,000 in the general population
      and 2.8 per 100,000 in children, with the highest incidence in infants under 1 year of age of
      8.7 per 100,000.

      Despite the use of current standard treatments, mortality of 7-10% and morbidity of up to 50%
      are still being reported. Encephalitis also imposes a substantial economic and resource
      burden on healthcare services. Strategies to reduce the disability in patients with
      encephalitis are therefore required.

      There is increasing evidence from case reports of a beneficial role of IVIG treatment in
      encephalitis. However, in clinical practice, the use of IVIG in encephalitis varies. The
      variation in practice is in most part due to a lack of class 1 evidence to support the use of
      IVIG in encephalitis. For the immune mediated forms of encephalitis, IVIG is typically used
      after inevitable delay (by weeks in some cases) while alternative diagnoses are being
      excluded, or a definitive diagnosis is obtained. In other cases, IVIG is used usually as a
      last treatment option where clinical improvement is slow. Again, this is usually after
      several days from hospital admission. Delays in the institution of appropriate treatment in
      encephalitis may contribute to the high rate of morbidity and mortality, prolonged
      hospitalisation and associated costs from encephalitis. In particular, it is currently
      unknown whether wider use of IVIG in infectious encephalitis and earlier use in
      immune-mediated encephalitis could alter the outcome of this group of conditions.

      This study will fill in the evidence gap on the potential benefit of IVIG in reducing disease
      burden in children with encephalitis. The trial also aims to generate evidence to inform
      clinical decision making in the National Health Service (NHS) and provide added value to the
      NHS by addressing healthcare, quality of life and productivity costs of this expensive and
      resource limited product.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

'Good recovery' defined by a score of 2 or lower, assessed using the Pediatric version of the Glasgow Outcome Scale Extended.

Secondary Outcome

 Neurological outcomes using age appropriate questionnaires and neuropsychology assessment

Condition

Encephalitis

Intervention

Immunoglobulins, Intravenous (Privigen)

Study Arms / Comparison Groups

 Intravenous immunoglobulin
Description:  Intravenous immunoglobulin: 1g/kg per day for 2 consecutive days

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

308

Start Date

January 2016

Completion Date

February 2020

Primary Completion Date

February 2019

Eligibility Criteria

        Inclusion Criteria:

          1. 6 weeks to 16 years of age (day before 17th birthday) AND

          2. Acute (within 24 hours) or sub-acute (between 24 hours and 4 weeks) onset of altered
             mental state (reduced or altered conscious level, irritability, altered personality or
             behaviour, lethargy) not attributable to a metabolic cause AND

          3. At least two of:

               1. fever > 38 degrees Celsius within 72 hours before or after presentation to
                  hospital

               2. brain imaging evidence consistent with encephalitis or immune-mediated
                  encephalopathy that is either new from prior studies or appears acute in onset

               3. CSF pleocytosis > 4 white blood cells per microlitre

               4. generalised or partial seizures not fully attributable to a pre-existing seizure
                  disorder

               5. new onset focal neurological signs (including movement disorders) for > 6 hours

               6. abnormality on EEG that is consistent with encephalitis and not clearly
                  attributable to another cause AND

          4. Parent/guardian/legal representative able to give informed consent

        Exclusion Criteria:

          -  high clinical suspicion of bacterial meningitis or TB meningitis (for example:
             presence of frankly purulent CSF; CSF WBCs >1000/microlitre; bacteria on Gram stain
             and/or culture)

          -  Traumatic brain injury

          -  Known metabolic encephalopathy

          -  toxic encephalopathy (i.e. encephalopathy secondary to exposure to intoxicants,
             including alcohol, prescription or recreational drugs)

          -  hypertensive encephalopathy/posterior reversible encephalopathy syndrome

          -  pre-existing demyelinating disorder; pre-existing antibody mediated CNS disorder;
             pre-existing CSF diversion

          -  ischaemic or haemorrhagic stroke

          -  children with a contra-indication to IVIG or albumin (i.e. history of anaphylactic
             reaction to IVIG or albumin, known IgA deficiency and history of hypersensitisation)

          -  Known hypercoagulable state

          -  significant renal impairment defined as GFR of 29mls/min/1.73m2 and below (Chronic
             Kidney Disease Stage 4)

          -  Known hyperprolinaemia

          -  Known to be pregnant

          -  Any other significant disease or disorder which, in the opinion of the Investigator,
             may either put the participants at risk because of participation in the trial, or may
             influence the result of the trial, or the participant's ability to participate in the
             trial

          -  participants who are being actively followed up in another research trial involving an
             investigational medicinal product

          -  Administration of study drug not feasible within 120 hours from hospital admission as
             determined by the study team

          -  Any other condition which, in the opinion of the investigator, may interfere with the
             ability to fulfil study requirements, especially relating to the primary objective of
             the study (this includes plans to be outside the UK for more than 12 months after
             enrolment)
      

Gender

All

Ages

6 Weeks - 16 Years

Accepts Healthy Volunteers

No

Contacts

Andrew J Pollard, FRCPCH, PhD, , 

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations


NCT ID

NCT02308982

Organization ID

OVG 2014/05


Responsible Party

Sponsor

Study Sponsor

University of Oxford

Collaborators

 National Institute for Health Research, United Kingdom

Study Sponsor

Andrew J Pollard, FRCPCH, PhD, Principal Investigator, University of Oxford


Verification Date

October 2018