Biological Clock Dysfunction in Optic Nerve Hypoplasia

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: NCT00825591
Recruitment Status : Unknown
Verified February 2011 by Yale University.
Recruitment status was:  Recruiting
First Posted : January 21, 2009
Last Update Posted : February 8, 2011
Children's Hospital Los Angeles
Information provided by:
Yale University

Brief Summary:

Background: Optic Nerve Hypoplasia (ONH) is a leading cause of blindness in children. For unclear reasons, the incidence of ONH is increasing, with ONH affecting about 1 in 10,000 live-born infants. In addition to visual deficits, ONH is associated with varying degrees of hypopituitarism, developmental delay, brain malformations and obesity. Although genetic mutations have been rarely observed to result in ONH, the causes of ONH are largely not known. In limited anatomical observations, the suprachiasmatic nuclei (SCN) located in the anterior hypothalamus, which generate circadian rhythms, have been observed to be abnormal in children with ONH. Thus, children with ONH may have biological clock dysfunction.

In collaborative studies with Dr. Mark Borchert of Childrens Hospital Los Angeles (CHLA), we have recently discovered that one-half of children with ONH have grossly abnormal sleep-wake patterns, as assessed by actigraphy. Although not known for children with ONH, abnormal sleep-wake patterns have been observed to be associated with neurocognitive impairment and obesity. We also observe that nocturnal melatonin administration can improve abnormal sleep-wake cycles in these children, raising the possibility that it will be possible to treat abnormal rhythmicity in children with ONH.

Condition or disease Intervention/treatment Phase
Biological Clock Dysfunction Optic Nerve Hypoplasia Dietary Supplement: Melatonin Dietary Supplement: Placebo Comparator Early Phase 1

Detailed Description:

Objectives and Hypotheses. Our objectives are to define the scope and problems related to biological clock disorders in children with ONH and to develop effective treatments for this condition. Based on our observations, we hypothesize: (1) Daily rest-activity patterns and sleep will be abnormal in up to 50% of children with ONH. (2) It is possible to identify risk factors for abnormal circadian system function and sleep problems in ONH. (3) Nocturnal melatonin administration will improve abnormal sleep and activity patterns in children with ONH.

Design: These studies will involve collaborative efforts between Yale University and Dr. Mark Borchert of Childrens Hospital Los Angeles, who follows the largest population of children with ONH in the world. We will study children ages 2-10 years with documented ONH using standard criteria. Based on these criteria, we have more than 100 eligible patients.

To test our hypotheses, we will: (1) examine expressed rhythmicity in children with ONH. These studies will use actigraphy, sleep questionnaires, and assessment of melatonin secretory profiles. (2) We will correlate hypothalamic anatomical abnormalities and the degree endocrine dysfunction with sleep and expressed rhythmicity. (3) We will test if short-term administration of melatonin improves sleep-wake patterns in children with abnormally-expressed rhythmicity.

Potential Impact: Our preliminary data raise the possibility that children with ONH will have circadian system dysfunction resulting in abnormal rhythmicity and sleep. However, to date there have been no formal attempts to identify children with ONH who are at risk for such problems, nor have there been efforts aimed at developing potential treatments. The proposed prospective clinical study will represent an important attempt to identify a group of children with circadian system dysfunction.

At the completion of this study, we anticipate having determined risk factors for circadian system dysfunction in children with ONH. Insights gained from these studies should lead to the development of new approaches for treating circadian clock lesions in ONH, with the hope of improving the well-being of circadian system function in the boys and girls with this condition.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Diagnostic
Official Title: Identification and Treatment of Biological Clock Dysfunction in Optic Nerve Hypoplasia
Study Start Date : October 2008
Estimated Primary Completion Date : September 2011
Estimated Study Completion Date : September 2011

Resource links provided by the National Library of Medicine

Drug Information available for: Melatonin

Arm Intervention/treatment
Active Comparator: 1
Individuals with abnormal rhythmicity will be treated with melatonin to assess if sleep patterns are improved.
Dietary Supplement: Melatonin
Oral administration before bed. We will test two doses (0.5 or 3.0 mg/m2. 6 week duration.)

Placebo Comparator: 2 Dietary Supplement: Placebo Comparator
Oral administration before bed. 6 week duration.

Primary Outcome Measures :
  1. Assessment of rest-activity patterns [ Time Frame: two years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 10 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Confirmed diagnosis of ONH (Diagnosis will be confirmed by ocular fundus photography.Disc-macula distance 0.35 or below. In eyes without ONH, the DD/DM ratio is greater than 0.3581.)
  • Ages 2-10 years
  • Ability to ambulate independently
  • Under care of endocrinologist if on pituitary hormone replacement therapy.

Exclusion Criteria:

  • Non-ambulatory
  • Active malignancy
  • Cardio-respiratory disorder

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): NCT00825591

United States, California
Children's Hospital of Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Joyce Sutedja    323-361-6219   
Sponsors and Collaborators
Yale University
Children's Hospital Los Angeles
Study Director: Casandra Fink Children's Hospital Los Angeles

Responsible Party: Esther Nakamura-Reyes, Childrens Hospital of Los Angeles Identifier: NCT00825591     History of Changes
Other Study ID Numbers: 0804003699
First Posted: January 21, 2009    Key Record Dates
Last Update Posted: February 8, 2011
Last Verified: February 2011

Keywords provided by Yale University:
optic nerve hypoplasia
septo-optic dysplasia
circadian rhythm

Additional relevant MeSH terms:
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Central Nervous System Depressants