Prednisolone Versus Vigabatrin in the First-line Treatment of Infantile Spasms

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Brief Title

Prednisolone Versus Vigabatrin in the First-line Treatment of Infantile Spasms

Official Title

Prednisolone vs. Vigabatrin in the First-line Treatment of Infantile Spasms

Brief Summary

      Infantile Spasms, is an rare age-specific epilepsy of early infancy. A 2012 American Academy
      Neurology/ Child Neurology Society practice parameter update on the medical treatment of
      infantile spasms concluded: adrenocorticotrophic hormone or vigabatrin may be offered for
      short-term treatment of infantile spasms. There was insufficient evidence to recommend the
      use of prednisolone, dexamethasone, and methylprednisolone. The cost of ACTH and the side
      effects of vigabatrin have led to the consideration of alternative medications to treat
      infantile spasms. The United Kingdom Infantile Spasms Study (UKISS) in 2004, comparing the
      efficacy of intramuscular synthetic ACTH to high dose oral prednisolone, showed a response
      rate of 74% for ACTH and 70% for prednisolone. Since the UKISS paper was published, many
      institutions in the United States and Australia have used oral prednisolone instead of ACTH,
      partly due to the exorbitant cost of intramuscular ACTH but also its ease of use and better
      adverse event profile compared to ACTH. Prednisolone and vigabatrin are both oral
      medications, which can be initiated promptly upon diagnosis of infantile spasms, expediting
      treatment and shortening treatment lag time. Because the UKISS trial is the only Class 3
      study providing evidence for oral prednisolone in the first-line treatment of infantile
      spasms, further prospective studies are needed.
    

Detailed Description

      Background and Rationale for the study:

      Infantile spasms (IS) is a rare, catastrophic age-specific epilepsy syndrome with onset
      within the first 12 months of life. The disorder is characterized clinically by epileptic
      spasms, often accompanied by developmental regression and a characteristic interictal
      electroencephalography (EEG) pattern called hypsarrhythmia. When all these three features are
      present, the term, "West syndrome" is commonly used. The catastrophic nature of the disorder
      is due to the frequent sequelae of severe global neurodevelopmental delay and medically
      refractory epilepsy.

      The initial age of onset in 90% of cases occur before 12 months of life, with peak onset at 6
      months. The incidence is 2 to 3 per 10,000 live births with a lifetime prevalence of 1.5 to 2
      per 10,000 children. It is slightly more common in males, and a family history exists in
      3%-6% of cases.1,2,3 The etiology of IS has conventionally been divided into symptomatic or
      cryptogenic, depending on whether the underlying cause is known. Conditions causing
      symptomatic IS are diverse and can include focal or multifocal brain injuries, chromosomal
      abnormalities and genetic mutations and inborn errors of metabolism. In about 20% of cases,
      the identifiable cause remains unknown and these are defined as cryptogenic.

      The spontaneous remission rate of IS in limited natural history studies is 30%.4,5 Although
      the clinical spasms and typical EEG pattern disappear by 3 to 4 years of age, up to 60% of
      children with IS will go on to develop other types of refractory seizures, including Lennox
      Gastaut syndrome. The poor developmental outcome in IS is primarily due to the underlying
      etiology, however, delay in diagnosis and treatment6 and the use of ineffective therapies are
      also contributory factors. The hypsarrhythmia EEG pattern is a pattern of epileptic
      encephalopathy and there is evidence that longer duration of epileptic encephalopathy
      contributes to developmental delay and to the development of autism, especially in infants
      with Down syndrome and tuberous sclerosis complex (TSC).7,8 Currently, there is still
      considerable variation in the management of IS, as evidenced by the US Consensus Report and a
      recent survey done on the current evaluation and treatment of IS among members of the Child
      Neurology Society (CNS). Most neurologists use adrenocorticotrophic hormone (ACTH) as their
      preferred, first-line treatment of IS, not caused by TSC and Vigabatrin (VGB) as the
      first-line treatment of IS caused by TSC. 9,10 The 2004 American Academy of Neurology (AAN)
      and CNS practice parameter on the medical treatment of IS and the 2012 update of this
      evidenced-based guideline concluded that ACTH or VGB may be useful for the short-term
      treatment of IS, with ACTH being more effective than VGB excluding cases with TSC. 11,12 The
      2012 update also concluded that there is insufficient evidence to determine whether other
      forms of corticosteroids are as effective as ACTH. There is also insufficient evidence to
      recommend other agents, or combination therapy in the short-term treatment of IS.

      Although many conditions can cause IS, several hypotheses regarding the underlying mechanisms
      have been proposed. The corticotrophin releasing hormone (CRH) hypothesis is one of the most
      studied. Children with IS, have the common characteristic of excessive release of CRH.
      Elevated CRH can cause seizures and neuronal death within the hippocampus and amygdala of
      immature brains in animal studies. Elevated CRH also cause desensitization of CRH receptors
      leading to decreased ACTH release and resulting in reduced ACTH levels in the cerebrospinal
      fluid (CSF). ACTH treatment, most likely suppresses the excessive production of CRH via
      direct action on melanocortin receptors eliciting an antiepileptic effect.13 Prednisolone is
      a primary metabolite of a synthetic glucocorticoid, prednisone. Corticosteroids can reduce
      hippocampal excitability in vitro, increases gamma-aminobutyric acid (GABA) and antagonize
      5-hydroxytryptophan.14 VGB is an irreversible, enzyme-activated, selective inhibitor of
      GABA-transaminase. By inhibiting its catabolism, there is increased availability of GABA
      within the synaptic cleft, increasing its inhibitory effect.15 The mammalian target of
      rapamycin (mTOR) pathway is a key signaling pathway that is dysregulated in TSC. Animal
      studies have shown that VGB partially inhibited mTOR pathway activity and glial proliferation
      in the knock-out mice in vitro, as well as reduced mTOR pathway activation in cultured
      astrocytes from both knock-out and control mice. This may account for the unique efficacy of
      VGB in TSC.16

      At our institution, VGB is the preferred first-line treatment for all newly diagnosed IS due
      to its relative ease of use and fewer acute adverse events compared to ACTH. However,
      concerns regarding retinal toxicity17 require regular monitoring with electroretinograms
      (ERGs) performed under sedation.18 Also, VGB-related MRI changes are seen in 22-32% of
      children treated for IS and although these changes are mostly asymptomatic and may resolve
      even when VGB is continued, there is concern that the changes reflect a medication-related
      neurotoxic effect.19,20 For patients who fail VGB, we use a 6-week course of synthetic ACTH
      (Synacthen) given intramuscularly (IM) every other day as second-line agent. However, it is
      associated with significant adverse events, which include infections from immunosuppression,
      arterial hypertension, weight gain, severe irritability, gastric irritation, hyperglycemia,
      electrolyte disturbances, cerebral atrophy, and behavioral changes.

      The United Kingdom Infantile Spasms Study (UKISS) demonstrated the superiority of hormonal
      therapy over VGB for cessation of spasms at 14 days in infants without TSC. The hormonal
      therapy arm included patients allocated high-dose oral prednisolone and intramuscular ACTH
      and the study showed that prednisolone was as effective as ACTH.21 Because this is the only
      Class 3 study providing evidence for oral prednisolone in the first-line treatment of IS,
      further prospective studies are needed.

      Since 2010, the Hospital for Sick Children (SickKids) started providing the option of either
      IM ACTH or high-dose oral prednisolone as second-line treatments when patient failed VGB. Our
      previous retrospective case review of twenty IS patients who had failed a 2-week course of
      VGB showed an 80% response rate (12/15) to ACTH and only 20% (1/5) to prednisolone. 22. This
      seemingly low response to prednisolone may be due to the underlying etiology, which made the
      condition refractory to VGB in the first place.

      Since the UKISS paper was published, many institutions in the US and Australia have used oral
      prednisolone instead of ACTH, partly due to the exorbitant cost of intramuscular ACTH
      (US$70,000 per course for natural ACTH) but also its ease of use and better adverse event
      profile compared to ACTH.23,24 A retrospective case series of 17 newly diagnosed IS given
      high-dose oral prednisolone as first-line treatment showed clinical response of 100% in the
      cryptogenic group, and 64% in the symptomatic (non-TSC) group.24 A retrospective case series
      of 27 newly diagnosed IS given high dose prednisolone (8mg/kg/day) with a maximum daily dose
      of 60 mg showed a 63% response rate (17/27) to prednisolone within 2 weeks. 25

      The selection of the starting dose and 4 week, duration of treatment was based on the
      previous studies, which used a dose range of 4-8 mg/kg/day and 8mg/kg/day respectively with 4
      - 6 weeks duration of therapy. 21.23.24.25.

      We elected to use the higher end of the dose range previously reported to ensure maximum
      efficacy, with the shorter length of 4 weeks of treatment to reduce the risk of medication
      side effects.

      The relapse rate for infantile spasms in retrospective studies has ranged between 12-40%,
      with time to relapse between 2-25 months. 24,25. We do not envisage using long-term treatment
      or recurrent intermittent treatment with prednisolone.

      Prednisolone and VGB are both oral medications, which can be initiated promptly upon
      diagnosis of IS, expediting treatment and shortening treatment lag time. We propose that oral
      prednisolone may be more effective than VGB when used as a first-line treatment in newly
      diagnosed non-TSC IS patients.

      and Objective of the study: Aim To compare the efficacy of prednisolone and VGB as 1st line
      short-term treatment of IS as measured by clinical and EEG response at 2 weeks.

      Hypothesis:

      More patients allocated to prednisolone therapy will have cessation of spasms and resolution
      of hypsarrhythmia at 2 weeks.

      METHODS:

      Study design:

      Single center, prospective, observational, open trial using high-dose oral prednisolone as
      first-line treatment for newly diagnosed IS (non-Tuberous Sclerosis), with follow up at 2
      weeks, the end of treatment and then 5 months later. All patients will undergo thorough
      history, physical and neurological examination, metabolic, genetic, EEG and neuroimaging
      studies as per the Hospital for Sick Children (HSC) Infantile Spasms Guidelines. 25 These
      patients will be compared to our historical controls, composed of our cohort of non-TSC IS
      patients from January 2010- September 2013 who received VGB as first-line treatment, met the
      inclusion criteria and were followed up for at least 6 months from diagnosis and treatment
      initiation.

      The patients and their families are under no obligation to be involved in the study and will
      continue to receive care from their primary neurologists should they choose not to
      participate in the study.

      Study Duration: The length of the study for each patient will be approximately 6 months. The
      total duration of the study is estimated at 3 years.

      Sample size: A sample population of 70 patients in the retrospective VGB cohort and 35
      patients in the prospective Prednisolone cohort with a 2:1 match are required to demonstrate
      a statistically significant difference in efficacy of 25% between Prednisolone and
      Vigabatrin.

      Patient Population: Children between the ages of 2-24 months with a clinical spasms and
      hypsarrhythmia or modified hypsarrhythmia on initial EEG referred to the outpatient Neurology
      clinic at Sickkids.

      Control Population: Historical controls will be composed of our cohort of non-TSC IS patients
      from 2010-2013 who received VGB as first-line treatment and fulfill the inclusion criteria
      for the study.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Resolution of Infantile spasms and Hypsarrhythmia

Secondary Outcome

 Clinical or EEG relapse of Infantile Spasms

Condition

Infantile Spasms

Intervention

Prednisolone

Study Arms / Comparison Groups

 Prednisolone
Description:  Single center, prospective, observational, open trial using high-dose oral prednisolone as first-line treatment for newly diagnosed Infantile Spasms (non-Tuberous Sclerosis)

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

0

Start Date

September 5, 2017

Completion Date

March 6, 2019

Primary Completion Date

March 6, 2019

Eligibility Criteria

        Inclusion Criteria: Inclusion criteria:

          1. Age 2-24 months

          2. Clinical spasms

          3. Initial EEG with hypsarrhythmia or modified hypsarrhythmia

        The inclusion criteria do not quantify the initial severity or frequency of infantile
        spasms. Infantile spasms is a unique epileptic disorder characterized by clusters of brief
        infantile spasms, where each one lasts a few seconds and cluster may last minutes. The
        diagnosis of infantile spasms and response to medication depends on the presence or absence
        of these events and the frequency of infantile spasms has not been used to determine
        medication efficacy in previous studies. A seizure diary will be used to quantify the
        seizure burden, however efficacy will depend on complete resolution of clinical spasms and
        resolution of hypsarrhythmia on EEG -

        Exclusion Criteria:

          1. Age <2months or older than 24 months

          2. Tuberous sclerosis (if known at the time of enrolment)

          3. Previous treatment (within 28 days) with VGB or hormonal treatments

          4. Contraindications to hormonal therapy: This includes untreated systemic fungal
             infections, known hypersensitivity to prednisolone or other corticosteroids, or to any
             of the non-medicinal ingredients present in the solution. Active or latent
             tuberculosis, ocular herpes simplex, hypothyroidism, hepatic cirrhosis, nonspecific
             ulcerative colitis, abscess or other pyogenic infection, fresh intestinal anastomoses,
             active or latent peptic ulcer, renal insufficiency, hypertension, osteoporosis,
             cardiac disease, thromboembolic disorders and diabetes mellitus. All patients with
             cardiac risk factors will receive an electrocardiogram (ECG), chest xray (CXR) and
             cardiology referral if indicated. Patients diagnosed with cardiac disorders will be
             excluded from the study since high dose steroids may exacerbate arrhythmias.

          5. Inability of parents or guardians to give consent

          6. Enrolment in a concurrent treatment trial that might affect outcome measures of this
             trial -
      

Gender

All

Ages

2 Months - 24 Months

Accepts Healthy Volunteers

No

Contacts

Carter Snead, MD, , 

Location Countries

Canada

Location Countries

Canada

Administrative Informations


NCT ID

NCT02299115

Organization ID

1000045463


Responsible Party

Principal Investigator

Study Sponsor

The Hospital for Sick Children


Study Sponsor

Carter Snead, MD, Principal Investigator, The Hospital for Sick Children


Verification Date

November 2019