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Neurodevelopmental Outcome of Early Dietary Lysine Restriction in Pyridoxine Dependent Epilepsy Patients (NOEL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01795170
Recruitment Status : Withdrawn (The study couldn't be initiated as we did not secure funding.)
First Posted : February 20, 2013
Last Update Posted : September 30, 2014
March of Dimes
British Columbia Childrens Hospital Foundation
Information provided by (Responsible Party):
University of British Columbia

Brief Summary:
Restricting dietary lysine intake in infants from age 3 months or less with confirmed diagnosis of pyridoxine-dependent epilepsy due to Antiquitin (ATQ) deficiency will: reduce the accumulation of neurotoxic substratesα-aminoadipicsemialdehydeandits cyclic equivalent 1-piperideine-6-carboxylate;and will improve overall neurodevelopmental outcome at 3 years of age by acting as an effective intervention into the complex pathophysiology of the condition.

Condition or disease Intervention/treatment
Pyridoxine Dependant Epilepsy Dietary Supplement: Lysine Restricted Diet Drug: Pyridoxine

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Study Type : Observational
Actual Enrollment : 0 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Neurodevelopmental Outcome of Early Dietary Lysine Restriction in Pyridoxine
Study Start Date : April 2013
Estimated Primary Completion Date : November 2016
Estimated Study Completion Date : November 2016

Group/Cohort Intervention/treatment
Test Group
Patients receiving a lysine restricted diet adjunct to pyridoxine therapy will be considered as participants in the 'exposure'/test group
Dietary Supplement: Lysine Restricted Diet
Daily lysine intake will be managed to maintain a plasma lysine level of 50-80 µmol/L (normal range: 52-196 µmol/L). Diet prescriptions will be based on international guidelines for glutaricaciduria type I, another inborn error of lysine catabolism. In order to meet the recommended daily protein intake (DRI) [23,24], the diet may include commercially available lysine-free amino acid formulas approved for use in conditions affecting lysine metabolism, as well as commercially available low-protein products based on the participant's taste.

Drug: Pyridoxine
All participants will be on 15-30 mg/kg/day of pyridoxine therapy up to a maximum of 500mg/day divided in 2-3 doses enterally

Control Group
Patients on pyridoxine mono-therapy will be participants in the 'control' group
Drug: Pyridoxine
All participants will be on 15-30 mg/kg/day of pyridoxine therapy up to a maximum of 500mg/day divided in 2-3 doses enterally

Primary Outcome Measures :
  1. Neurocognitive development at age 3 years [ Time Frame: 3 years ]
    defined by total developmental index measured using the Bayley Scales for Infant and Toddler Development, 3rd Edition (Bayley-III)

  2. Level of biochemical marker-α- aminoadipicsemialdehyde (AASA) in plasma and urine [ Time Frame: 3 years ]

Secondary Outcome Measures :
  1. Seizure frequency: clinical and electrical (EEG) [ Time Frame: 3 years ]
  2. Quality of life [ Time Frame: 3 years ]
  3. Neurological deficits [ Time Frame: 3 years ]

Other Outcome Measures:
  1. Anthropometric measures [ Time Frame: 3 years ]
  2. Plasma lysine and branched chain amino acid levels [ Time Frame: 3 years ]
  3. Global nutritional assessment with plasma levels for albumin, prealbumin, total protein, iron parameters, zinc, selenium, CBC, folic acid, vitamin B12 [ Time Frame: 3 years ]
  4. Peripheral sensory neuropathy (relevant because the lysine restriction is expected to reduce chemical inactivation of pyridoxine, thus potentially increasing the risk of toxicity) [ Time Frame: 3 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   3 Months to 3 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Infants with pyridoxine-dependent epilepsy resulting from ATQ deficiency.

Inclusion Criteria:

  • Diagnosis of pyridoxine-dependent epilepsy based on clinical symptoms and elevated levels of plasma or urine AASA. Confirmation by at least one known disease causing mutation in the ALDH7A1 gene to be obtained within one month of enrollment.
  • Participant is male or female <3 years of age.

    • Participants in the test arm have to be less than 3 months of age when the dietary restriction was started.
    • Participants in the control arm may be older than 3 months of age but must not be older than 3 years of age when they are enrolled into the study and must have been on pyridoxine treatment prior to age 3 months and not treated with dietary lysine restriction at any time during their life.
  • Participant is managed with a vitamin B6 dose of 15-30 mg/kg/day continuously beginning at < 3 months age, and willing to maintain this dose for the study duration.
  • Participants must have been offered dietary lysine restriction as adjunct therapy as part of standard clinical care.
  • Parent(s) or guardian(s) is willing and able to provide written informed consent after the nature of the study has been explained, and prior to any research-related procedures.

Exclusion Criteria:

  • Diagnosis is not confirmed: Participant does not have a mutation in the ALDH7A1 gene.
  • Participant was treated prenatally for PDE with pyridoxine (i.e. mother was on pyridoxine)
  • Timing of dietary restriction: Participant is on a lysine-restricted diet from an age > 3months.
  • Confounding factors:

    • Participant is a pre-term with a gestational age < 32 weeks
    • The participant has a birth weight less than the 2nd percentile or weighs less than 2nd percentile at study entrance (on age appropriate growth chart).
    • Participant shows an intracranial malformation or abnormality unrelated to ATQ deficiency, as diagnosed on the cranial ultrasound and/or MRI brain scan
    • Participant has any other disorder identified that can affect the cognitive function in the opinion of the coordinating principal investigators.
  • A known allergy or sensitivity to any component of the products commonly used in a lysine-restricted diet or to other products associated with lysine restriction or any other products associated with general study procedures.
  • Participant is on oral folinic acid and/or pyridoxal phosphate treatment at study entrance.
  • Participant has any condition or situation which, in the investigator's opinion, places the patient at significant risk of adverse events, or may interfere significantly with their participation and compliance in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01795170

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United States, Colorado
Children's Hospital Colorado
Aurora, Colorado, United States, 80045
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105
Canada, British Columbia
BC Children's Hospital
Vancouver, British Columbia, Canada, V6H 3V4
Hannover Medical School
Hannover, Germany
Maxima Medical Center
Veldhoven, Netherlands
Kinderspital Zürich
Zürich, Switzerland
United Kingdom
University College London
London, United Kingdom
Sponsors and Collaborators
University of British Columbia
March of Dimes
British Columbia Childrens Hospital Foundation
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Principal Investigator: Clara van Karnebeek University of British Columbia
Principal Investigator: Sylvia Stockler University of British Columbia
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Responsible Party: University of British Columbia Identifier: NCT01795170    
Other Study ID Numbers: H12-03481
First Posted: February 20, 2013    Key Record Dates
Last Update Posted: September 30, 2014
Last Verified: September 2014
Keywords provided by University of British Columbia:
Pyridoxine Dependant Epilepsy
Antiquitin Deficiency
Lysine Restricted Diet
Additional relevant MeSH terms:
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Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vitamin B Complex
Physiological Effects of Drugs