Molecular Bases of Response to Copper Treatment in Menkes Disease, Related Phenotypes, and Unexplained Copper Deficiency
Molecular Bases of Response to Copper Treatment in Menkes Disease, Related Phenotypes, and Unexplained Copper Deficiency
Menkes disease and occipital horn syndrome are two forms of copper deficiency that must be
 diagnosed and treated very early in life to prevent serious developmental problems. However,
 these and other forms of copper deficiency are not very well understood, and further research
 is needed to determine whether certain treatments are useful in treating copper deficiency.
 One such treatment is copper histidine, a copper replacement that can be injected directly
 into the body to avoid absorption through the gastrointestinal tract. This study will
 investigate the effectiveness, side effects, and dosage of copper histidine treatment for
 patients with copper deficiency. It will also collect medical history information from
 patients to allow researchers to study possible genetic and nongenetic origins of copper
 deficiency.

 This study will include 100 subjects, all of whom will be children and adults who have been
 diagnosed with Menkes disease, occipital horn syndrome, or other unexplained copper
 deficiency.

 Patients will receive a prescribed dose of copper histidine, which will be administered daily
 as an injection.

 During the study, patients will be admitted to the NIH Clinical Center on an outpatient basis
 to evaluate their response to the copper histidine treatment. These evaluations will take
 place every 8 months, with a final evaluation performed after 3 years of treatment. During
 the outpatient visits, patients will be required to give blood and urine samples for testing
 and undergo ultrasound testing. They will also undergo brain MRI scans at the initial visit
 and at the 16-month and 36-month visits. Patients who agree will give additional blood
 samples for genetic research purposes.
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.