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

NCT01795170 | Withdrawn

• 1 other identifier: H12-03481
• Study Type: observational
• Target: N/A
• Locations: 6 countries
• Sites: 7

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.

Conditions

Pyridoxine Dependant Epilepsy

Keywords

Pyridoxine Dependant Epilepsy; Antiquitin Deficiency; Lysine Restricted Diet

Outcome Measures

Primary Outcomes (2)

• Neurocognitive development at age 3 years

  defined by total developmental index measured using the Bayley Scales for Infant and Toddler Development, 3rd Edition (Bayley-III)

  3 years

• Level of biochemical marker-α- aminoadipicsemialdehyde (AASA) in plasma and urine

  3 years

Secondary Outcomes (3)

• Seizure frequency: clinical and electrical (EEG)

  3 years

• Quality of life

  3 years

• Neurological deficits

  3 years

Other Outcomes (4)

• Anthropometric measures

  3 years

• Plasma lysine and branched chain amino acid levels

  3 years

• Global nutritional assessment with plasma levels for albumin, prealbumin, total protein, iron parameters, zinc, selenium, CBC, folic acid, vitamin B12

  3 years

Study Arms (2)

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; Drug: Pyridoxine

Control Group

Patients on pyridoxine mono-therapy will be participants in the 'control' group

Drug: Pyridoxine

Interventions

Lysine Restricted Diet DIETARY_SUPPLEMENT

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.

Test Group

Pyridoxine DRUG

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; Test Group

Eligibility Criteria

• Age: 3 Months - 3 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

Study Population

Infants with pyridoxine-dependent epilepsy resulting from ATQ deficiency.

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of British Columbia: lead
• March of Dimes: collaborator
• British Columbia Childrens Hospital Foundation: collaborator

Study Sites (7)

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

BC Children's Hospital

Vancouver, British Columbia, V6H 3V4, Canada

Location

Hannover Medical School

Hanover, Hannover, Germany

Location

Maxima Medical Center

Veldhoven, Netherlands

Location

Kinderspital Zürich

Zurich, Switzerland

Location

University College London

London, United Kingdom

Location

Related Publications (1)

• van Karnebeek CD, Hartmann H, Jaggumantri S, Bok LA, Cheng B, Connolly M, Coughlin CR 2nd, Das AM, Gospe SM Jr, Jakobs C, van der Lee JH, Mercimek-Mahmutoglu S, Meyer U, Struys E, Sinclair G, Van Hove J, Collet JP, Plecko BR, Stockler S. Lysine restricted diet for pyridoxine-dependent epilepsy: first evidence and future trials. Mol Genet Metab. 2012 Nov;107(3):335-44. doi: 10.1016/j.ymgme.2012.09.006. Epub 2012 Sep 10.

  PMID: 23022070 BACKGROUND

MeSH Terms

Conditions

Pyridoxine-dependent epilepsy

Interventions

Pyridoxine

Intervention Hierarchy (Ancestors)

Vitamin B 6; Picolines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Clara van Karnebeek

  University of British Columbia

  PRINCIPAL INVESTIGATOR

• Sylvia Stockler

  University of British Columbia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 18, 2013
• First Posted: February 20, 2013
• Study Start: April 1, 2013
• Primary Completion: November 1, 2016
• Study Completion: November 1, 2016
• Last Updated: September 30, 2014

Record last verified: 2014-09

Locations

CH (1); CA (1); NL (1); US (2); DE (1); GB (1)