Biological Clock Dysfunction in Optic Nerve Hypoplasia

Biological Clock Dysfunction Clinical Trial

Official title:

Identification and Treatment of Biological Clock Dysfunction in Optic Nerve Hypoplasia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00825591
• Other study ID #: 0804003699
• Secondary ID: TRSH-SAR
• Status: Completed
• Phase: Early Phase 1
• Start date: October 2008
• Est. completion date: September 2011

Study information

• Verified date: September 2020
• Source: Yale University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: September 2011
• Est. primary completion date: September 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 10 Years

Eligibility

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

Related Conditions & MeSH terms

• Biological Clock Dysfunction
• Optic Nerve Hypoplasia

Intervention

Dietary Supplement:
• Melatonin
Oral administration before bed. We will test two doses (0.5 or 3.0 mg/m2. 6 week duration.)
• Placebo Comparator
Oral administration before bed. 6 week duration.

Locations

Country	Name	City	State
United States	Children's Hospital of Los Angeles	Los Angeles	California

Sponsors (2)

Lead Sponsor	Collaborator
Yale University	Children's Hospital Los Angeles

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Assessment of rest-activity patterns		two years