Molecular Bases of Response to Copper Treatment in Menkes Disease, Related Phenotypes, and Unexplained Copper Deficiency

Study Description:

The purpose of this study is to allow currently enrolled participants to complete their
three-year course of subcutaneous Copper Histidinate treatment under the protocol. We
hypothesize that subcutaneous injections of this drug will raise serum copper levels and
ceruloplasmin levels in enrolled participants, improve neurodevelopmental and neurological
outcomes, and reduce mortality compared to untreated affected subjects.

Objectives:

-Primary Objective: Evaluate responses to Copper Histidinate treatment for clinical care.

Endpoints:

-Completion of three years treatment by 13 remaining subjects

Study Population:

The 13 remaining subjects

Phase: Clinical Care/Treatment only

Description of Sites/Facilities Enrolling Participants: The study will occur at the NIH
Clinical Center

Description of Study Intervention:

The study intervention is administration of Copper Histidinate in dose(s) prescribed as
follows: 250 microgram sc b.i.d. in infants up to 12 months of age, and 250 microgram sc q.d.
for infants and children older than 12 months. The total duration of copper histidinate
treatment will not exceed three years.

Study Duration:

The estimated time from when the study opens to enrollment until completion is approximately
151 months (02/27/2009-09/30/2021). (May end sooner pending FDA new drug approval.)

Participant Duration:

The time it will take for each individual participant to complete all participant visits is
approximately 36 months. There are 13 subjects with a total of 31 visits to complete.

- INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the
following criteria:

1. Provision of signed and dated informed consent form by parent or legal guardian, or
the subject himself/herself.

2. Male or female, aged 0 to 80 years.

3. Diagnosed with classic Menkes disease, Occipital Horn Syndrome (OHS), or unexplained
copper deficiency.

4. Serum copper level results between 0 and 75 mg/dl (normal range 80-180 microgram/dl).

5. Ability to adhere to the prescribed subcutaneous Copper Histidinate injection regimen.

6. Willingness to comply with all study visits and procedures.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation
in this study:

1. Pre-existing liver (e.g., hepatitis, biliary atresia, cirrhosis) or kidney disease
(e.g., serum creatinine >1.0 mg/dL)

2. History of bleeding diatheses

3. Pregnancy or lactation

4. Diagnosis of Wilson disease

5. Any disease or condition that, in the opinion of the Investigator, has a high
probability of precluding the patient from completing the study or where the patient
cannot or will not appropriately comply with study requirements

6. Participation in any other investigational trial in which receipt of investigational
drug or device occurred within 30 days prior to screening for this study

7. History of diagnosed drug or alcohol dependence within the previous 3 years

8. Any disease process that may adversely affect gastrointestinal absorption, e.g. celiac
sprue

9. Chronic/severe cardiac disease (applies to adult subjects only) that could make
participating in a clinical trial physically demanding, including but not limited to
cardiac insufficiency, arrhythmias, bradycardia, or hypotension, unless associated
with other features of dysautonomia, as in OHS.

10. History of cerebrovascular accident (applies to adult subjects only) that could make
participating in a clinical trial difficult for the subject.

Adults who are, or who may be, unable to consent will not be allowed to participate in this
study. This is because we did not encounter subjects in this category for whom enrollment
would be necessary or appropriate in our previous studies (90-CH-0149, 90-N-0149) with this
IND. The main populations to be recruited are 1) pediatric subjects under 18 years of age
with inherited copper transport disorders, and 2) non-cognitively-impaired adults with
unexplained copper deficiency.

NIH employees are eligible to participate in this protocol if they meet the Inclusion
criteria and have no exclusion criteria. Recruitment, enrollment and compensation of NIH
employee subjects will be consistent with the Guidelines for the Inclusion of Employees in
NIH Intramural Research Studies (December 2015) and NIH Policy Manual Chapter 2300-630-3,
"Leave Policy for NIH Employees Participating in NIH Medical Research Studies". The
consenting research team member will make the NIH Information Sheet on Employee Research
Participation available to staff members who are considering enrolling.

If the individual requesting to participate in the protocol is a co-worker, the consent
from the NIH staff member (co-worker) will not be obtained by the staff member s direct
supervisor but by another research staff member approved for obtaining informed consent who
is not a co-worker.

Neither participation nor refusal to participate as a subject in this protocol will have an
effect, either beneficial or adverse, on the participant s employment or position at NIH.

Employee subjects' privacy and confidentiality will be respected by protocol and consenting
staff the same as for all subjects participating in research protocols. However, all
subjects will be made aware that there are limits to these protections.