Phase I/II Study of NORTHERA (DROXIDOPA) for Dysautonomia in Adult Survivors of Menkes Disease and Adults With Occipital Horn Syndrome: Double-blind Placebo-controlled Randomized Crossover Clinical Trial
Phase: PHASE1
Conditions: Menkes Disease, Occipital Horn Syndrome
Sponsor: Stephen G. Kaler, MD

Phase I/II Study of NORTHERA (DROXIDOPA) for Dysautonomia in Adult Survivors of Menkes Disease or Adults with Occipital Horn 
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STUDY PROTOCOL 
 
Phase I/II study of NORTHERA (DROXIDOPA)  for Dysautonomia in Adult 
Survivors of Menkes Disease and Adults with Occipital Horn Syndrome 
Double-blind Placebo-controlled Randomized Crossover Clinical Trial  
Protocol Version/Date:  1.7 Version (15MAR2022) 
Sponsor-Investigator (PI): Stephen G. Kaler, MD  
Center for Gene Therapy, Abigail Wexner Research Institute 
Nationwide Children’s Hospital (NCH)  
 
 
Co-Investigator(s):  
Mari Mori MD, MS 
Department of Genetic and Genomic Medicine, NCH 
 
Maryann M. Kaler MS, CNP 
Gene Therapy-Clinical Research Unit 
 
Margie A. Ream, MD, PhD  
Kimberly A. Hampton, CPNP-PC 
Department of Neurology, NCH 
 
Guy Brock, PhD  
Biostatistics, Epidemiology, and Research Design (BERD) Core,  
Center for Clinical Translational Science; OSU College of Medicine 
 
Kan Hor, MD 
Department of Cardiology, NCH 
 
Linda P. Lowes PhD 
Department of Physical Therapy, NCH 
 
 
 
 
 
 

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 PROTOCOL SYNOPSIS 
Title 
Phase I/II Study of NORTHERA (DROXIDOPA) for Dysautonomia in Adult Survivors 
of Menkes Disease or Adults with Occipital Horn Syndrome 
Study ID Number 
00001113 
Clinical Study Phase 
Phase I/II  
Number of Centers 
Single site (Nationwide Children’s Hospital) 
Study Design 
Double-blind placebo-controlled randomized crossover clinical trial 
Patient Population 
Inclusion Criteria 
1. Adult persons with Menkes disease who survived beyond the expected natural 
history, attained independent ambulation, attend (or attended) school, and 
reached adulthood after early CuHis treatment for three years or adults with 
Occipital Horn Syndrome, who manifest clinical signs and symptoms of 
dysautonomia, e.g., orthostatic hypotension: specifically, a decrease in systolic 
or diastolic blood pressure of at least 20 or 10 mm Hg, respectively, within 
three minutes after standing, and/or chronic diarrhea: production of loose 
stools with or without increased stool frequency for more than four weeks 
immediately preceding enrollment. 
2. History of at least thrice weekly occurrence of dizziness/feeling lightheaded 
while standing upright and/or thrice weekly episodes of diarrhea or an urgent 
need to defecate after food ingestion for more than four weeks immediately 
preceding enrollment. 
3. Documented mutation in ATP7A. 
4. Must sign and date an Informed Consent Form (ICF). 
5. Age ≥ 18 years of age. 
6. Ability to adhere to the prescribed oral Northera (Droxidopa) regimen. 
7. Willingness to comply with all study visits and procedures.  
Exclusion Criteria  
1. Pre-existing liver (e.g., hepatitis, biliary atresia, cirrhosis) or kidney disease 
(i.e., calculated glomerular filtration rate <30 ml/min). 
2. History of hypertension, anti-hypertensive therapy, heart failure (or decreased 
ejection fraction), cardiac arrhythmia, or bleeding diatheses.  
3. Any disease or condition that, in the opinion of the Investigator, has a high 
probability of precluding the subject from completing the study or where the 
subject cannot or will not appropriately comply with study requirements. 
4. Any alpha-1 adrenoreceptor agonist, beta-blocker, DOPA decarboxylase 
inhibitor, midodrine, ephedrine, or any triptan medication as a concomitant 
medication.   
 
Provide Northera (Droxidopa) treatment in a dose titration schedule (100mg, 200mg, 
300mg po b.i.d. for adults and a blinded placebo control crossover to evaluate safety 
and assess clinical (hemodynamic and gastrointestinal effects) and plasma 
neurochemical responses and effect on symptoms during a six-week period. Please see 
Protocol Schema p18 for detailed description of all study procedures. 
Primary Outcome 
Safety and Tolerability 
Secondary Outcomes 
 
 
 
1. Improved plasma neurochemical levels 
2. Improved systolic blood pressure  
3. Improved gastrointestinal symptoms 
4. Improved performance on tests of physical exertion  
Exploratory Outcome 
Improved scores on the Orthostatic Hypotension Symptom Assessment  Questionnaire  
Study Duration 
13 to 18 weeks per Subject (depending on cumulative visit interval) 

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Sample Size 
Six to 10 adult subjects 
Statistical Analysis 
The safety and effect(s) of Northera (Droxidopa) treatment will be assessed in a double 
blind, placebo-controlled, two-period, randomized, crossover design by comparing 
baseline to treatment and placebo-treatment data using paired t tests or a linear mixed-
effects model.  
Long-term follow-up 
After participation in this study, subjects will be followed up by their local physicians 
under a normal standard of care, and also will be seen annually in the NCH Menkes 
Disease Clinic. Subjects may also be followed by phone and/or medical records. 
                                                                        
2.0 Introduction 
Menkes disease is an X-linked recessive disorder of human copper metabolism with a predicted 
minimum birth prevalence of 1 in 34,810 live male births based on loss-of-function variant 
frequencies in the Genome Aggregation Database (gnomAD) [1] for ATP7A, which encodes an 
essential copper-transporting ATPase [2-4]. Abnormal plasma neurochemical levels due to 
deficiency of a copper-requiring enzyme, dopamine-β-hydroxylase, are diagnostic in affected 
Menkes newborns [5]. A brief window of therapeutic opportunity exists in the newborn period 
during which medical intervention can prevent the inexorable downhill course otherwise expected 
for this illness, as demonstrated with Copper Histidinate (CuHis) treatment [5,6]. Another emerging 
approach, adeno-associated virus-mediated ATP7A gene therapy, appears highly promising, 
demonstrating a synergistic treatment effect with CuHis in the Menkes mouse model [7,8]. 
 
Survivors of the profound central nervous system (CNS) effects of this illness, spared by their early 
diagnosis and successful responses to early subcutaneous CuHis treatment (daily injections for the 
first three years of life), sometimes develop symptoms of dysautonomia, including dizziness, 
lightheadedness, syncopal episodes, low blood pressure, and chronic diarrhea. This reflects a 
persistent defect in Cu delivery into the secretory pathway of cells, including sympathetic 
(dopaminergic) neurons that regulate the autonomic nervous system, resulting in diminished DBH 
activity and deficiency of norepinephrine (Fig. 1).  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Figure 1. Normal neuronal copper transport and catecholamine biosynthesis. A) In neuronal cells, Cu uptake is 
mediated by CTR1 and DMT1 and ferried to various intracellular destinations by a set of copper chaperones (CCS, 
ATOX1, Cox17, Cox11 and Sco1). The copper transporting ATPases ATP7B (Wilson disease) and ATP7A (Menkes 
disease, Occipital Horn syndrome) are both localized at the trans-Golgi network and required for maturation of 
ceruloplasmin (CP), and dopamine-b-hydroxylase (DBH) and peptidylglycine-a-amidating monooxygenase (PAM), 
respectively. Details of cytochrome c oxidase (CCO) subunit metalation are illustrated here. With an increase in Cu 
levels, ATP7A normally traffics from the somatodendritic to axonal (basolateral) region. (From Kaler SG. Nat Rev 
Neurol 2011). B) In dopaminergic neurons, the catecholamine biosynthetic pathway requires DBH to convert dopamine 
A 
 
B 

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to norepinephrine. Since DBH acquires its copper co-factor based on the activity of ATP7A, subjects with Menkes 
disease and Occipital Horn syndrome have diminished DBH activity. In contrast, DOPA decarboxylase converts L-
DOPS (Droxidopa) to norepinephrine and is not Cu-dependent.  
 
Early treatment with CuHis enhances delivery of copper to the developing brain in Menkes disease 
patients, who have all the other proper Cu-transport machinery, except for ATP7A. Without ATP7A, 
however, correction of DBH (and PAM, a cuproenzyme responsible for amidation of various 
neuropeptides) deficiency is not possible in Menkes disease subjects, whether or not under treatment 
with CuHis. The importance of CuHis in Menkes subjects is to enhance Cu delivery across the 
blood-CSF and blood-brain barriers. This facilitates restoring the activities of brain cuproenzymes 
such as SOD1 and CCO during the critical first three years of life, when brain growth and 
development is particularly rapid (Fig. 2). Our Phase I/II and Phase III studies limited CuHis   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      Figure 2. Growth velocity of head circumference  
      in first 3 years of life is steep especially in year 1. 
      Head growth reflects underlying brain growth.  
 
recessive disorder not associated with any neurodevelopmental problems in infancy or early child-
hood [9-11]. Menkes disease survivors typically first manifest these symptoms in mid-late childhood 
or early adolescence, when they grow taller. Advancing linear growth in children necessitates higher 
blood pressure to overcome gravity and enable adequate brain perfusion [12].   
 
Occipital horn syndrome (OHS) is a milder allelic variant of Menkes disease in which the neurologic 
phenotype is far less severe; the diagnosis of occipital horn syndrome is not evident until late 
childhood or early teenage rather than during infancy [13-17]. Many subjects with the OHS 
phenotype at these ages also manifest dysautonomia in the form of frequent syncopal episodes [14-
17] and chronic diarrhea [13-17]. A recent review [18] indicated that symptoms of dysautonomia, 
including chronic diarrhea, temperature instability, and orthostatic hypotension are present in almost 
90% (13/15) of OHS patients and can be disabling. These symptoms reflect impaired sympathetic 
noradrenergic function related to DBH deficiency. 
 
treatment to three years based on this fact, as well as 
benefit-to-risk considerations related to potential renal 
toxicity (NCT00001262, NCT00811785). Importantly, 
three years of daily CuHis treatment was adequate to 
prevent premature death in a large majority of classic 
Menkes disease subjects treated from early infancy who 
now range in age from 3 to 27 years. In addition to 
prolonged survival, these individuals manifest impressive 
neurodevelopmental and neurocognitive outcomes. They 
have all attended school, including college in some 
instances, and are socially active. Some have learned to 
drive, voted in US national elections, and joined the work 
force. 
 
However, troubling symptoms of dysautonomia consistent 
with DBH deficiency and typically beginning at 7 to 10 
years of age as they grew taller, has inconvenienced the 
lives of these  Menkes survivors. They often experience 
dizziness, lightheadedness, syncopal or near-syncopal 
episodes, and chronic diarrhea, all symptoms reported in 
adults with congenital absence of DBH, an autosomal  

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Sympathoneural ablation with hydroxydopamine, and blockade of vesicular uptake with reserpine 
produce diarrhea in experimental animals [19,20]. The loose stools and chronic diarrhea in Menkes 
disease survivors appears to reflect increased gastrointestinal motility and poor rectal sphincter 
control caused by unopposed parasympathetic stimulation and are also reported in individuals with 
isolated DBH deficiency (21) and in OHS [17,18]. 
 
2.1 Background 
The synthetic amino acid L-threo-3,4-dihydroxyphenylserine (L-DOPS, Droxidopa) is highly 
effective in reversing neurogenic orthostatic hypotension and correcting abnormal neurochemical 
levels in patients with autosomal recessive congenital absence of dopamine-b-hydroxylase (DBH) 
[22-24]. DBH deficiency is, in fact, one of the labelled indications for Northera (Droxidopa) 
(Appendices 1, 1A, Full Prescribing Information). Northera (Droxidopa) is metabolized by the 
enzyme DOPA decarboxylase, which does not require copper to produce norepinephrine, bypassing 
the DBH enzymatic defect [22]. Individuals with the copper transport disorders Menke disease and 
occipital horn syndrome (OHS), an ATP7A-related variant of Menkes, have partial deficiency of 
DBH, show distinctive neurochemical abnormalities [5,13,25-27], and frequently symptoms of 
dysautonomia, such as syncope, dizziness, orthostatic hypotension, and bowel dysfunction (chronic 
diarrhea) [13-18]. As in patients with congenital absence of DBH [22,23], these problems in 
autonomic nervous system function seem potentially responsive to restoration of normal 
neurochemical levels by Northera (Droxidopa) treatment. 
 
Menkes disease is an X-linked recessive disease caused by diverse loss-of-function mutations in the 
gene encoding a copper-transporting ATPase, ATP7A [2-6,28]. One function of ATP7A is the 
delivery of intracellular copper to the trans-Golgi network (TGN) for incorporation into specific 
enzymes within the secretory pathway of cells. Dopamine-b-hydroxylase (DBH), the enzyme 
catalyzing the conversion of dopamine to norepinephrine (NE) is one such copper-dependent 
enzyme processed in the TGN. Patients with ATP7A mutations (Menkes, OHS) therefore show 
evidence of partial DBH deficiency [5,25-27]. 
 
Affected Menkes disease infants appear healthy at birth and develop normally for 6 to 8 weeks, 
after which hypotonia, seizures, failure to thrive, and connective tissue abnormalities occur, leading 
to premature death, often by three years of age [3]. Neonatal diagnosis, sometimes via 
neurochemical evidence of DBH deficiency, and early treatment with copper injections may 
improve survival and clinical outcomes [5,6].  
 
The complete pathophysiologic impact of decreased DBH activity in Menkes disease and OHS 
remains unknown. Mice with knockout of the DBH gene die in utero, implying a vital role of NE 
in neural development [29]. In contrast, humans with autosomal recessive congenital absence of 
DBH have no major neurodevelopmental consequences but manifest signs of autonomic 
dysfunction including syncope, dizziness, and orthostatic hypotension, symptoms which are 
relieved by oral L-DOPS (Droxidopa) treatment [22-24]. Furthermore, the abnormal neurochemical 
levels in these patients are improved by this treatment. 
 
2.1.1 Name of the Drug 
Northera™ (Droxidopa) (Treatment A; label known only to the NCH Pharmacy Investigational Drug 
Service) (please see Appendices 1, 1A) will be provided to adult subjects as a capsule with with 

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100mg, 200mg, or 300mg of Northera (Droxidopa) contained within gelatin color capsules (sky blue 
and white, size 0). These are physically indistinguishable from the Treatment B (placebo) capsules. 
The synthetic amino acid L-threo-3,4-dihydroxyphenylserine (Northera (Droxidopa)) is highly 
effective in reversing neurogenic orthostatic hypotension and correcting neurochemical abnormalities 
in patients with autosomal recessive congenital absence of dopamine-beta-hydroxylase (DBH) [22-
24]. 
 
Northera (Droxidopa) is metabolized by the enzyme DOPA decarboxylase to produce 
norepinephrine, thus bypassing the DBH enzymatic defect. Individuals with the copper transport 
disorders Menkes disease and occipital horn syndrome (OHS), have partial deficiency of DBH, which 
is copper-dependent, and show distinctive neurochemical abnormalities and sometimes symptoms 
of dysautonomia, such as syncope, dizziness, orthostatic hypotension, and chronic diarrhea. As in 
patients with congenital absence of DBH, these problems in autonomic nervous system function seem 
potentially responsive to restoration of normal neurochemical levels. 
 
 
Placebo (Treatment B; label known only to the NCH Pharmacy Investigational Drug Service):  
Empty gelatin color capsules (sky blue and white, size 0) filled with cellulose microcrystalline and   
 
physically indistinguishable from Treatment A capsules. 
  
 Clinical Information  
2.1. 
Clinical Trial and Principal Investigator 
This clinical trial will evaluate the safety of Northera (Droxidopa) treatment in young adults 
who survived the major neurodegenerative and neurocognitive effects of Menkes disease via 
early CuHis treatment. We hypothesize that Northera (Droxidopa) treatment in Menkes 
disease survivors with dysautonomia will improve blood neurochemical levels, raise systolic 
blood pressure, reduce diarrhea, improve performance on tests of physical exertion, and 
enhance overall quality of life. We will test this hypothesis, in six to 10 adult Menkes 
disease survivors or OHS patients, with symptoms of dysautonomia, by evaluating 
Northera (Droxidopa) treatment in a dose-ascending schedule (100 mg to 300 mg p.o. 
b.i.d) with a power of 95% at the proposed sample size [30]. Please also see Statistical 
Analysis Plan, Appendix 5). Primary outcome will establish safety and tolerability, and 
secondary outcomes will evaluate plasma norepinephrine and DHPG levels, systolic blood 
pressure, and performance on tests of physical exertion. We seek to understand whether 
Northera (Droxidopa) will engender a favorable effect on dysautonomia symptoms during a 
six-week period in comparison to a placebo treatment. Using a double-blind, placebo-
controlled randomized crossover design, we will gain a clear delineation of safety and 
tolerability, as well as preliminary efficacy data for Northera (Droxidopa) in this population. 
Since the half-life of Northera (Droxidopa) is approximately 2.5 hours [24], (Appendices 1, 
1A) after peaking at approximately 3 hours following a p.o. dose, carryover effects when 
transitioning between the drug and placebo arms are not anticipated, especially when a 7-10 
day washout between periods is included. We expect to complete this pilot study within five 
years. 
 

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The principal investigator has long-term experience and interest in Menkes disease, human 
copper metabolism, and conduct of clinical trials (please see NIH Biosketch for details 
specific to this project). 
2.2. 
Rationale for Using Drug(s) for indication 
The synthetic amino acid L-threo-3,4-dihydroxyphenylserine (Northera (Droxidopa) is 
effective in reversing neurogenic orthostatic hypotension and correcting neurochemical 
abnormalities in patients with autosomal recessive congenital absence of dopamine-beta-
hydroxylase (DBH) [22-24]. Northera (Droxidopa) is metabolized by the enzyme 
dihydroxyphenylalanine (DOPA) decarboxylase to produce norepinephrine, thus bypassing 
the DBH enzymatic defect [22]. Individuals with the copper transport disorder Menke disease 
who survive beyond early childhood due to very early diagnosis and three years of daily 
CuHis injections [5,6,28] often have evidence of persistent low DBH activity, with distinctive 
neurochemical abnormalities and symptoms of dysautonomia, such as syncope, dizziness, 
orthostatic hypotension, and gastrointestinal dysfunction. These subjects harbor a variety of 
ATP7A mutation types, including deletion/duplication, nonsense, splice junction, and 
missense (Table 1).  
 
Table 1. Adult Menkes Disease Survivors and OHS Subjects at Risk for Dysautonomia 
 
Current Age 
(Years) 
 
ATP7A mutation 
 
Diagnosis 
Age enrolled in CuHis 
treatment trial 
[Reference] 
19 
G666R 
Menkes 
10 days [5] 
20 
IVS9; DS, +6, t>g 
Menkes 
9 days [5] 
25 
R201X 
Menkes 
8 days [6] 
27 
IVS8; AS, dup5  
Menkes 
8 days [6] 
31 
IVS14 DS, +4, a>g (c.2917-4a>g) 
OHS 
Not enrolled [18] 
41 
IVS11; DS, -2, A>G (S833G) 
OHS 
11 years [6,13] 
 
The occipital horn syndrome (OHS) is a neurologically milder allelic variant of Menkes 
disease [13]. This condition takes its name from the wedge-shaped calcifications that form 
bilaterally within the trapezius and sternocleidomastoid muscle tendons at their point of 
attachment to the occiput in affected individuals, generally by the second decade of life. Such 
protuberances can be palpated in some patients and are demonstrable radiographically on 
lateral and Towne’s view skull X-rays or appropriate sagittal images from CT or MRI 
[4,13,16,18]. OHS shares the hair and connective tissue abnormalities observed in classic 
Menkes disease, which are attributable to a lysyl oxidase deficiency [14]. However, since the 
neurological phenotype in OHS is mild (slight generalized muscle weakness, and 
dysautonomia that includes syncope, orthostatic hypotension and chronic diarrhea), affected 
individuals often escape detection until mid-childhood or later. Patients with this variant of 
Menkes disease manifest low-normal levels of serum copper and ceruloplasmin, and 
distinctively abnormal plasma and CSF catecholamine levels [13,27], reflecting deficiency of 
DBH activity, as in Menkes disease. We treated one OHS individual with CuHis [6,13] 
(Table 1) who has reached adulthood. A number of other adult OHS patients may be available 
for recruitment to this study from academic departments of medical genetics, neurology, and 
gastroenterology [18].  

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As in patients with deficiency of DBH unrelated to copper metabolism, these problems in 
autonomic nervous system function seem potentially responsive to restoration of normal 
neurochemical levels via Northera (Droxidopa) treatment [22-24]. Therefore, there is 
prospect of direct benefit from this treatment for adult Menkes survivors and adults with OHS.  
2.3. 
Preliminary Clinical Data 
One 11-year-old Menkes disease survivor with a large deletion (exons 2-19) in the ATP7A 
gene (which contains 23 exons) detected by DNA microarray in the first month of life who was 
referred for enrollment in the phase 3 early CuHis treatment protocol (NCT00811785) has 
experienced significant dysautonomia for the past six years. This young man attained normal 
gross motor, fine motor, personal-social, and language development, and attends school in 
normal classes. A significant issue affecting this patient’s life, however, is the need to stop and 
squat after walking short distances. After a few seconds squatting, he is able to resume walking 
before having to squat again. These episodes are attributed to orthostatic hypotension. He has 
also had numerous episodes of syncope and lightheadedness, especially on rising from prone or 
seated positions, as well as chronic diarrhea, all known manifestations of dysautonomia 
attributable to reduced DBH activity and NE deficiency [9,10,21]. 
 
This Menkes disease survivor was evaluated at 10 years of age in July 2019 at New York 
University Center for Dysautonomia (Jose-Alberto Palma MD PhD, a colleague of this 
project’s PI). During a two-day assessment, the following preliminary data were obtained 
before and after a 50 mg (1.9mg/kg) dose of Northera: Blood pressure in the supine position 
was 103/78 mmHg with a heart rate of 83 bpm. Fluctuations in heart rate in response to deep 
paced breathing were within the normal range for age, indicating preserved parasympathetic 
innervation of the heart. After 1-min of head-up tilt the blood pressure dropped to 47/32. After 
3-min of head-up tilt blood pressure was 36/33 mmHg. During this tilt table exercise, plasma 
concentration of norepinephrine was 122 pg/ml in supine position and increased only to 130 
when tilted (normal pediatric range: 500-1,056 pg/ml [25]), indicating impaired baroreflex-
mediated sympathetic activation. Epinephrine concentration remained stable at <10 pg/ml, and 
dopamine was high at 22 pg/ml in the supine position and increased to 37 in the head-up tilt 
position (normal pediatric range 0-22 pg/ml [25]).  
 
One hour after the 50 mg trial dose of Northera (measured by estimating 50% of the contents 
of a 100 mg capsule of the drug, Lundbeck Pharmaceuticals, Inc.), the patient’s blood pressure 
in the supine position rose to 126/95 mmHg. After 1-min of head-up tilt, his blood pressure 
was 73/66. After 3-min of head-up tilt, his blood pressure was 54/42 mmHg. After 6-min of 
head-up tilt, his blood pressure was 63/48 mmHg. After Northera, the plasma concentration of 
norepinephrine substantially increased to 237 pg/ml in supine position and 313 when tilted, 
consistent with conversion of Northera to norepinephrine. Off the tilt table, the patient 
demonstrated improved ability to remain standing, improved duration of walking, and an 
improved overall sense of well-being. 
 
In summary, this subject’s evaluation indicated impaired autonomic reflexes and impaired 
norepinephrine release with severe, symptomatic neurogenic orthostatic hypotension. After 50 

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mg of Northera, his systolic blood pressure rose, plasma norepinephrine levels increased, and 
his gross motor function and capacity, and psychological outlook all improved.  
 
 
 Other Preliminary Data 
3.1 Proof of Principle Studies 
In the mottled-brindled mouse model of Menkes disease, we previously documented that L-
threo-dihydroxyphenylserine (L-DOPS), the active ingredient in Northera (Droxidopa), 
crosses the blood-brain barrier and corrects brain neurochemical abnormalities, including 
norepinephrine concentration [31].   
 
In a single human subject (also mentioned in Section 2.3) who survived the most devastating 
neurodegenerative effects of Menkes disease through early diagnosis and CuHis treatment, a 
trial dose of Northera was associated with increased plasma norepinephrine levels, higher 
blood pressures, and improved clinical symptomatology. The subject was exquisitely sensitive 
to 50 mg doses of Northera however, and the drug was discontinued due to severe headaches 
and difficulty in precise measurement of doses from the commercially available 100mg, 200mg 
and 300mg capsules (Lundbeck Pharmaceuticals, Inc.)  
3.2     Safety of drug treatment 
Northera, approved by the FDA in 2014 and approved in Japan for orthostatic hypotension 
since 1989, is indicated for the treatment of orthostatic dizziness, lightheadedness, or the 
“feeling that you are about to black out” in adult patients with symptomatic neurogenic 
orthostatic hypotension caused by primary autonomic failure (Parkinson's disease), multiple 
system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and 
non-diabetic autonomic neuropathy. Headache and supine hypertension are known side effects 
of this product. The product may exacerbate existing ischemic heart disease, arrhythmias, and 
congestive heart failure (please see Appendix 1, Full Prescribing Information). Droxidopa, a 
generic version of Northera, was also approved in 2014. 
 
 Research 
4.1. 
Study Population 
The study population is comprised of six to ten adult survivors of classic Menkes disease or 
adult subjects with occipital horn syndrome, aged 18 to 50 years, who have signs and 
symptoms of dysautonomia including neurogenic orthostatic hypotension and chronic diarrhea. 
These represent subjects with Menkes disease or Occipital Horn Syndrome who completed 
three years of subcutaneous CuHis treatment in the Phase 1/2 clinical trial previously 
conducted by the PI at the NIH Clinical Center through the intramural research programs of 
NINDS and NICHD. The Menkes disease subjects were enrolled in this trial within 8 to 10 
days after birth, based on family histories of classic severe Menkes disease and one OHS 
patient began CuHis at age 11 years (Table 1). These subjects all completed three years of 
CuHis treatment with no significant adverse effects identified (5,6). Additional OHS Subjects 
may be referred from departments of Neurology, Gastroenterology, Genetics, or Metabolism, 

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at US or international academic medical centers. The study will be registered and posted on 
ClinicalTrials.gov website.  
4.2. 
Pre-Treatment Assessment: 
A) Inclusion Criteria 
1. Adult persons with Menkes disease who survived beyond the expected natural history, 
attained independent ambulation, attend (or attended) school, and reached adulthood after 
early CuHis treatment for three years or adults with Occipital Horn Syndrome, who manifest 
clinical signs and symptoms of dysautonomia, e.g., orthostatic hypotension: specifically, a 
decrease in systolic or diastolic blood pressure of at least 20 or 10 mm Hg, respectively, 
within three minutes after standing, and/or chronic diarrhea: production of loose stools with 
or without increased stool frequency for more than four weeks immediately preceding 
enrollment. 
2. History of at least thrice weekly occurrence of dizziness/feeling lightheaded while standing 
upright and/or thrice weekly episodes of diarrhea or an urgent need to defecate after food 
ingestion for more than four weeks immediately preceding enrollment. 
3. Documented pathogenic mutation in ATP7A 
4. Must sign and date an Informed Consent Form (ICF). 
5. Age ≥18 years. 
6. Ability to adhere to the prescribed oral Northera (Droxidopa) regimen. 
7. Willingness to comply with all study visits and procedures.  
 
B) Exclusion criteria  
1. Pre-existing liver (e.g., hepatitis, biliary atresia, cirrhosis) or kidney disease (i.e., calculated 
glomerular filtration rate <30 ml/min). 
2. History of hypertension, anti-hypertensive therapy, heart failure (or decreased ejection 
fraction), cardiac arrhythmia, or bleeding diatheses. 
3. Any disease or condition that, in the opinion of the Investigator, has a high probability of 
precluding the subject from completing the study or where the subject cannot or will not 
appropriately comply with study requirements.   
4. Any alpha-1 adrenoreceptor agonist, beta-blocker, DOPA decarboxylase inhibitor, 
midodrine, ephedrine, or any triptan medication as a concomitant medication.   
4.3. 
Dosing Plan 
The present study will evaluate the safety and efficacy of Northera (Droxidopa), in adult Menkes 
disease survivors or adults with Occipital Horn syndrome, who have symptoms of dysautonomia, by 
providing Northera (Droxidopa) treatment and assessing the neurochemical response (plasma 
catechol levels) and effect on hemodymanic and gastrointestinal symptoms, and exercise tolerance 
during a six-week period while receiving the study drug, or a placebo control.  
 
Treatment A: Northera™ (Droxidopa) is provided as a tasteless white crystalline powder in capsules 
of 100mg, 200mg, or 300mg inside unlabeled gelatin color capsules (sky blue and white, size 0), 
which will accommodate the size 1, 2, and 3 Northera (Droxidopa) capsules (plus a variable quantity 
of cellulose microcrystalline to complete the fill). We will use a ProFill Capsule Filling System 
(Torpac; Fairfield, NJ) to generate the Treatment A capsules in the NCH Investigational Drugs 
Service.   

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Treatment B: The placebo control will be approximately 500 mg microcrystalline cellulose in 
unlabeled gelatin color capsules (sky blue and white, size 0). We will use a ProFill Capsule Filling 
System (Torpac; Fairfield, NJ) to generate the Treatment B capsules in the NCH Investigational 
Drugs Service. The Treatment B capsules used are indistinguishable in weight, taste, texture, 
consistency, and visible characteristics from Treatment A capsules.  
 
Figure 3. Northera (Droxidopa) ascending dose schedule. Visit 2 involves an initial open-label dose titration period to 
identify the ideal Northera (Droxidopa) dose for each adult subject. 
 
 
 
Figure 4. Algorithm for determining Northera (Droxidopa) dose during open-label dose titration period. Blood pressure 
greater than 140mm Hg systolic or 90mm Hg diastolic, or headache longer than 2hrs will be grounds to discontinue or 
lower the Northera (Droxidopa) dose. If hypertension persists despite discontinuation of Northera (Droxidopa), 
conventional medical treatment will be instituted or arranged by the research team in a timely fashion. Signs or symptoms 
of allergic-type reactions or malignant hyperthermia will be grounds for withdrawing the subject from the study.   
 
Figures 3 and 4 above, and the Protocol Visit Schedule and Protocol Schema below illustrate the 
approach we will take to identify and monitor a safe dose of Northera (Droxidopa) for individual 
subjects in this trial. Each participant will undergo a screening evaluation and, if qualified, will be 
assigned to Treatment A (Northera (Droxidopa)) or Treatment B (Placebo). An open-label dose 
titration will be used to determine a maximally tolerated dose of Northera (Droxidopa) (Figure 4). 

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Subjects will begin Treatment A or B after a 7-10 day washout period, followed by crossover to the 
alternative Treatment (A or B) for a second 6-week arm.  
 
In this pilot study, we are testing only the safety, tolerability, and preliminary efficacy of Northera 
(Droxidopa), and factors such as age, mutation type, or maximum tolerated dose cannot be 
considered due to the small patient population. Based on preliminary data in one 10 year old Menkes 
survivor that suggested adrenoreceptor hypersensitivity, and because the safety and effectiveness of 
Northera (Droxidopa) in subjects with Menkes disease has not been established, we will evaluate 
only adults (≥18 years of age) in this study. Furthermore, the optimal dose identified in the dose-
titration period (Visit 2) will be used in a b.i.d rather than t.i.d. regimen, to diminish the risk of supine 
hypertension while sleeping.  
 
As per the product Full Prescribing Information (Appendix 1), peak plasma concentration (Cmax) of 
Northera (Droxidopa) are reached by 1 to 4 hours post-dose (mean of approximately 2 hours) in 
healthy adult volunteers. Cmax was delayed by approximately 2 hours with a high-fat meal. The 
metabolism of Northera (Droxidopa) is mediated by catecholamine biosynthetic pathway (Figure 1) 
and not through the cytochrome P450 system. Northera (Droxidopa) is initially converted to 
methoxylated dihydroxyphenylserine (3-OM-DOPS), a major metabolite, by catechol-O-
methyltransferase (COMT), to norepinephrine by DOPA decarboxylase (DDC), or to 
protocatechualdehyde by DOPS aldolase. After oral dosing in humans, plasma norepinephrine levels 
peak within 3 to 4 hours but are generally very low (less than 1 ng/mL) and variable with no 
consistent relationship with dose. The contribution of the metabolites of Northera (Droxidopa) other 
than norepinephrine to its pharmacological effects is not well understood.  
 
The mean elimination half-life of Northera (Droxidopa) is approximately 2.5 hours in humans (24). 
The major route of elimination of Northera (Droxidopa) and its metabolites is via the kidneys in both 
animals and in humans. Studies in animals showed that ~75% of the radiolabeled dose was excreted 
in urine within 24 hours of oral dosing. There are no known clinically relevant effects of age, body 
mass index or sex on the pharmacokinetics of Northera (Droxidopa). A population pharmacokinetic 
analysis suggests that hepatic function, assessed by aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase, and total bilirubin, does not influence response to 
Northera (Droxidopa). The controlled clinical trials included patients with mild to moderate renal 
impairment (GFR>30 mL/min) and did not have a higher frequency of adverse reactions. No dose 
adjustments are required in patients with mild to moderate renal impairment (Northera (Droxidopa) 
Full Prescribing Information, Appendix 1). Statistical comparisons (see Statistical Analysis Plan) 
based on different dose regimens is not currently planned and may be added, if appropriate.  
 
PROTOCOL DESIGN SUMMARY 
Randomization: Schedule established by NCH Investigational Pharmacy (Statistical Analysis Plan).  
Visit 1: Patients are consented, screened, and randomized blindly to Treatment A (Northera 
(Droxidopa)) or Treatment B (Placebo). Contraception will be discussed with all post pubertal 
subjects during the informed consent process to ensure that women of child-bearing potential (no 
female enrollment is anticipated given X-linked recessive inheritance) or sexually active males whose 
partner is a women of child-bearing potential avoid pregnancy during the study. 
Visit 2: Patients have studies performed to test Northera (Droxidopa) tolerance and establish dose for 
clinical trial. Includes four days of testing, followed by assignment to Treatment A (Northera 

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(Droxidopa)) versus Treatment B (Placebo) based on prior randomization. Patients, their parents, the 
clinical staff, and the statistician will be blinded. Randomization codes will stored in sealed 
envelopes. A 7-10 day washout period will precede the start of the Arm 1 treatment period at home. 
Visit 3: Mid-way point of Arm 1.  
Visit 4: Conclusion of Arm 1; Washout period (7-10 days) and Crossover to Arm 2. 
Visit 5: Mid-way point of Arm 2. 
Visit 6: Conclusion of Arm 2 
Unblinding and Data Analysis: After all subjects have completed both Arms.  
Time Table 
Year 1: Enroll initial subjects and complete both Arms. IRB annual review. FDA annual report. 
Year 2: FDA and DSMC evaluation of initial results; Enroll additional subjects and complete both 
Arms; IRB annual review; FDA annual report. 
Year 3: DSMC evaluation of 6 to 10 total subjects; IRB annual review; FDA annual report. 
Year 4: Follow-up of all participants. Data analysis and publication of primary results in per-reviewed 
journal(s). IRB Annual review; FDA annual report. 
Year 5: Ongoing data analysis and publication of related information from study, e.g., cardiac 
findings, validation of Orthostatic Hypotension Symptoms Assessment questionnaire in peer-
reviewed journal(s); IRB annual review; FDA annual report. Report results to ClinicalTrials.gov. 
 
Protocol Visit Schedule: 
Visit 1: Screening Visit; Outpatient 
 
Informed Consent 
 OHSA Questionnaire (Appendix 2), FDA COA, and IBS-D report form completed 
 Orthostatics: Blood pressure (BP) and Pulse (P) (supine, sitting, standing)*  
 History and Physical 
 Physical Therapy Exercise Tolerance Test (walk-through) 
 Randomize blindly to Treatment A or Treatment B 
*Supine after approx. 5 mins. Sitting and standing: each after approx. 3 minutes. Measured with a 
DINAMAP PRO 100, or Omron 3 Series oscillometric Upper Arm Blood Pressure Monitor (Model 
BP7100).  
 
1 to 7-day interval 
 
Visit 2: Dose determination/Initial Dosing Visit  
Day 1  Inpatient Admission for acclimatization and rest/preparation for Day 2 schedule (below) 
History and Physical Exam 
EKG/ECHO 
Placement of saline lock IV 
Baseline laboratory work: CBC with diff/PLTs, CMP, Serum Copper and Ceruloplasmin,  
Urinalysis, Plasma Catechols (1) 
Review Concomitant Meds/Adverse Events  
  
Baseline Physical Therapy Exercise Tolerance Tests* 
* Time standing duration; Six-minute walk test; Up and Go test 
 
Day 2 (All hours and times are estimates) 

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Morning 
8am 
Tilt Table Testing (WR Medical S1 model; DINAMAP PRO 100 or Omron 3 
Series oscillometric Upper Arm Blood Pressure Monitor Model BP7100)  
Baseline: 
Supine for 5 minutes  
A) BP/P 
B) Plasma Catechols* (2) 
Head tilt 60˚ for 3 minutes 
A) BP/P 
B) Plasma Catechols (3) 
 
 
Off Tilt Table (Seated):  
A) BP/P 
  
NORTHERA (DROXIDOPA) Dose #1 (100 mg)  
Seated BP/P q15 mins x 4 
*Plasma catechols drawn from saline lock IV immediately after BP/P 
Repeat Tilt Table (75 to 90 minutes post-NORTHERA (DROXIDOPA)) 
Supine for 5 minutes  
A) BP/P 
B) Plasma Catechols (4) 
Head tilt 60˚ for 3 minutes 
A) BP/P 
B) Plasma Catechols (5) 
 
Rest off Tilt Table (10 mins) 
2h post-dose: Plasma Catechols (6) 
Physical Therapy Exercise Tolerance Tests 
4h post-dose: Plasma Catechols (7) 
6h post-dose: Plasma Catechols (8) 
 
Afternoon (All hours and times are estimates) 
2pm  NORTHERA (DROXIDOPA) Dose #2 (200 mg)† 
Orthostatics: BP and pulse (supine, sitting, standing)* 1h, 2h, 3h, 4h post-dose 
Plasma Catechols 2h post-dose (9) 
†Assumes that previous 100 mg dose was well-tolerated.  
*Supine after approx. 5 mins. Sitting and standing: each after approx. 3 minutes. 
 
 
Evening (All hours and times are estimates) 
6pm  Head-elevated (30˚) sleeping position: 
Supine BP* and Pulse measured every 3 hours (estimated 9pm, 12am, 3am, and 6am) 
Plasma Catechols 12am (≈10h post-dose) (10) 
  
*Measured with Philips Sure Signs VM4 inpatient unit monitor 
 
Day 3 Morning (All hours and times are estimates) 
8am 
Tilt Table Testing (WR Medical S1 model; DINAMAP PRO 100 or Omron 3 Series 
oscillometric Upper Arm Blood Pressure Monitor Model BP7100)  
Baseline: 
Supine for 5 minutes  
A) BP/P 
B) Plasma Catechols (11) 
Head tilt 60˚ for 3 minutes 
A) BP/P 
B) Plasma Catechols (12) 
 
 
Off Tilt Table (Seated):  
A) BP/P 
 
NORTHERA (DROXIDOPA) dose #3 (200 mg)†  
Seated BP/P q15 mins x 4 
Repeat Tilt Table (75 to 90 minutes post-NORTHERA (DROXIDOPA)) 
Supine for 5 minutes  
A) BP/P 
B) Plasma Catechols (13) 
Head tilt 60˚ for 3 minutes 
A) BP/P 
B) Plasma Catechols (14) 

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Rest off Tilt Table (10 mins) 
2h post-dose Plasma Catechols (15) 
Physical Therapy Exercise Tolerance Tests 
4h post-dose Plasma Catechols (16) 
6h post-dose Plasma Catechols (17)  
†Assumes that previous 200 mg dose was well-tolerated.  
 
Afternoon: (All hours and times are estimates) 
2pm 
NORTHERA (DROXIDOPA) Dose #4 (300 mg)† 
Orthostatics: BP and pulse (supine, sitting, standing) 1h, 2h, 3h, 4h post-dose* 
Plasma Catechols 2h post-dose (18) 
†Assumes that previous 200 mg dose was well-tolerated 
 
Evening (All hours and times are estimates) 
6pm 
Head-elevated sleeping position  
Supine BP* and Pulse every 3 hours (estimated 9pm, 12am, 3am, 6am) 
Plasma Catechols 12am (≈10h post-dose) (19) 
  
*Measured with Philips Sure Signs VM4 inpatient unit monitor 
 
Day 4 Morning (All hours and times are estimates) 
8am 
Laboratory work: Plasma Catechols (20)  
  
Remove saline lock IV 
Orthostatics: BP and Pulse measurements (supine, sitting, standing)* 
NORTHERA (DROXIDOPA) Dose #5 (300 mg)† 
*Supine after approx. 5 mins. Sitting and standing: each after approx. 3 minutes.  
 
†Assumes that previous 300 mg dose was well-tolerated 
If there is no clinical or biochemical response to the 300 mg dose, the PI and team of  
Co-Investigators may file a protocol amendment to prescribe a higher dose of 
NORTHERA (DROXIDOPA), based on clinical judgment and emerging data for the 
individual subject. 
 
Treatment A or Placebo (Treatment B) based on prior randomization 
Discharge to home with 1-month supply (60 capsules of NORTHERA (DROXIDOPA) or 
Placebo). Instructions: 100 mg, 200 mg, or 300 mg po b.i.d. (8am, 2pm) to begin after 
7 to 10 day washout. 
 
Teaching and practice with the Omron 3 Series Home BP monitoring device: The 
patients will be taught how to use the BP monitoring device and we will practice with 
them. The study team and all those that will be teaching and instructing the patients and 
families will have an in-service on proper usage of device prior to study initiation. The 
investigators and study team will review proper usage with the patient in a hands-on 
demonstration. We will demonstrate the proper use and then have patient/subject 
demonstrate proper use as many times as needed and will review again if necessary.     
We will also provide written instructions to take home and provide the study team 
members/investigator contact info for any questions or concerns. 

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3-week interval (+/- 7d) 
 
Visit 3: Initial Follow-up; Pill count. Consider Dose adjustment. See Schema for testing planned  
Outpatient 
(Default weekday: Any) 
History and Physical Exam 
Orthostatics: blood pressure (BP) and pulse (supine, sitting, standing)*  
EKG 
Placement of saline lock IV 
Baseline laboratory work: CBC with diff/PLTs, CMP, Urinalysis 
 
Tilt Table Testing (All times are estimates) 
Supine for 5 minutes  
A) BP/P 
B) Plasma Catechols 
Head tilt 60˚ for 3 minutes 
A) BP/P 
B) Plasma Catechols  
Physical Therapy Exercise Tolerance Tests  
*Supine after approx. 5 mins. Sitting and standing: each after approx. 3 minutes. Measured with a 
DINAMAP PRO 100, or Omron 3 Series oscillometric Upper Arm Blood Pressure Monitor (Model 
BP7100).  
. 
 
 
 
 
3-week interval (+/- 7d) 
 
Visit 4: Final Follow-up (Arm 1). Pill count  
Outpatient 
 
History and Physical Exam 
Orthostatics: blood pressure (BP) and Pulse measurements (supine, sitting, standing)*  
EKG/ECHO 
Placement of saline lock IV 
Baseline laboratory work: CBC with diff/PLTs, CMP, Serum Copper and Ceruloplasmin,  
Urinalysis 
 
Tilt Table Testing (All times are estimates) 
Supine for 5 minutes  
A) BP/P 
B) Plasma Catechols 
Head tilt 60˚ for 3 minutes 
A) BP/P 
B) Plasma Catechols  
Physical Therapy Exercise Tolerance Tests  
*Supine after approx. 5 mins. Sitting and standing: each after approx. 3 minutes. Measured with a 
DINAMAP PRO 100, or Omron 3 Series oscillometric Upper Arm Blood Pressure Monitor (Model 
BP7100).  
 
Reinforce Teaching and practice with the Omron 3 Series Home BP monitoring device 
Washout: 7-10 day washout period  
Cross-over to alternate arm (Treatment B or Treatment A) 
 
4-week interval (+/- 7d) includes wash-out period 
 
Visit 5: Initial Follow-up (Arm 2) 
Outpatient:  

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History and Physical Exam 
Orthostatics: blood pressure (BP) and pulse (supine, sitting, standing)*  
EKG 
Placement of saline lock IV 
Laboratory work: CBC with diff/PLTs, CMP, Urinalysis 
Tilt Table Testing (All times are estimates) 
Supine for 5 minutes  
A) BP/P 
B) Plasma Catechols 
Head tilt 60˚ for 3 minutes 
A) BP/P 
B) Plasma Catechols  
Physical Therapy Exercise Tolerance Tests  
*Supine after approx. 5 mins. Sitting and standing: each after approx. 3 minutes. Measured with a 
DINAMAP PRO 100, or Omron 3 Series oscillometric Upper Arm Blood Pressure Monitor (Model 
BP7100).  
 
 
 
 
3-week interval (+/- 7d) 
 
Visit 6: Final visit (Arm 2); Outpatient  
History and Physical Exam 
Orthostatics: blood pressure (BP) and pulse (supine, sitting, standing)*  
EKG/ECHO 
Placement of saline lock IV 
Baseline laboratory work: CBC with diff/PLTs, CMP, Serum Copper and Ceruloplasmin,  
Urinalysis 
Tilt Table Testing (All times are estimates) 
Supine for 5 minutes  
A) BP/P 
B) Plasma Catechols 
Head tilt 60˚ for 3 minutes 
A) BP/P 
B) Plasma Catechols  
Physical Therapy Exercise Tolerance Tests  
 
Detailed Protocol Schema (Please see next page) 
 
Daily Home Monitoring Between Visits 
1. Record Blood Pressure and Pulse (supine, after 3 minutes sitting, and after 3 minutes 
standing) b.i.d. (before and after school or work) via Omron 3 Series Home BP monitor. All 
times are estimates. 
2. Drug Administration/Headache/Other Side Effects Diaries 
3. Irritable Bowel Syndrome-Diarrhea Report 
 
Weekly Home Monitoring Between Visits:  
 
1. Orthostatic Hypotension Symptom Assessment (OHSA Questionnaire) 
2. FDA Clinical Outcomes Assessment (based on the Patient Global Impression of Severity) 
(Appendix 3) 
3. Telephone follow-up by a member of the Study Team re:  
a. Daily and weekly monitoring as described 
b. Subject diaries as described 
c. Concomitant medications 
d. Adverse events 
 

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Protocol Schema  
 
Visit # 
Visit 1 
Visit 2 
H 
Visit 3 
H 
Visit 4 
H 
Visit 5 
H 
Visit 6 
Weekday (Default) 
Monday 
Tues-Fri 
 
Any 
 
Any 
 
Any 
 
Any 
 
Time from 
Enrollment 
 
-1 to -7d 
 
0 
 
Approx. 3 
weeks 
± 7d 
 
Approx. 6 
weeks 
± 7d 
 
Approx. 10 
weeks 
± 7d 
 
Approx. 13 
weeks 
± 7d 
 
Purpose 
 
Screening 
Open label 
Dose 
Titration 
 
Initial 
Follow-up 
First Arm 
 
F/up 1st Arm; 
Plan Washout 
& Crossover 
 
Initial 
Follow-up 
Arm 2 
 
Final follow-up, 
Arm 2;  
End of Study 
Informed Consent 
ü 
 
 
 
 
 
 
 
 
 
Assent, if < 18yr 
ü 
 
 
 
 
 
 
 
 
 
Inpatient 
 
ü 
 
 
 
 
 
 
 
 
Outpatient  
ü 
 
 
ü 
 
ü 
 
ü 
 
ü 
OHSA 
Questionnaire 
 
ü 
 
 
ü 
 
 
ü 
 
 
ü 
 
 
ü 
 
FDA COA 
ü 
 
ü 
 
ü 
 
ü 
 
ü 
 
IBS-D report form 
ü 
 
ü 
 
ü 
 
ü 
 
ü 
 
Randomization  
ü 
 
 
 
 
(Crossover) 
 
 
 
 
History and 
Physical 
 
ü 
 
ü 
 
 
ü 
 
 
ü 
 
 
ü 
 
 
ü 
EKG 
 
ü 
 
ü 
 
ü 
 
ü 
 
ü 
Cardiac ECHO 
 
ü 
 
 
 
ü 
 
 
 
ü 
Saline Lock 
 
ü 
 
ü 
 
ü 
 
ü 
 
ü 
ATP7A test (+/-) 
ü 
 
 
 
 
 
 
 
 
 
CBC with diff/Plts 
 
ü 
 
ü 
 
ü 
 
ü 
 
ü 
CMP 
 
ü 
 
ü 
 
ü 
 
ü 
 
ü 
Copper/CP 
 
ü 
 
 
 
ü 
 
 
 
ü 
Urinalysis 
 
ü 
 
ü 
 
ü 
 
ü 
 
ü 
Plasma Catechols 
 
N=20 
 
N=2 
 
N=2 
 
N=2 
 
N=2 
Tilt Table Test  
 
ü(4) 
 
ü 
 
ü 
 
ü 
 
ü 
PT Exertion tests 
Walk-thru 
ü(3) 
 
ü 
 
ü 
 
ü 
 
ü 
*Orthostatics 
Seated BP/P 
Supine BP/P 
1 set 
 
 
3 sets 
N=8 
N=8 
 
1 set 
 
1 set 
 
1 set 
 
1 set 
Teaching: Med,  
BP monitoring 
 
 
 
ü 
 
 
 
 
 
ü 
 
 
 
 
 
 
Omron 3 Series 
Home BP Log 
 
 
 
ü 
 
 
ü 
 
 
ü 
 
 
ü 
 
Medication Log 
 
 
ü  
ü  
ü  
ü  
Phone call q wk 
 
 
ü  
ü  
ü  
ü  
Side Effects Diary 
 
 
ü  
ü  
ü  
ü  
Total Blood (ml) 
0-4 
48 
 
8 
 
12 
 
8 
 
12 
 
H= home; BP= blood pressure; P=pulse; CMP= comprehensive metabolic panel (includes albumin, total bilirubin, calcium, electrolytes,    
creatinine, glucose, alk phos, AST, BUN, ALT, total protein ; CP=serum ceruloplasmin; OHSA=orthostatic hypotension symptom 
assessment questionnaire (Appendix 2); FDA COA= US Food & Drug Administration Clinical Outcomes Assessment (Appendix 3); IBS-
D=Irritable Bowel Syndrome-Diarrhea form (Appendix 4); N=Number of times tested; PT=Physical Therapy; *Supine after 5 min. Sitting 
and standing: each after 3 min, measured with a DINAMAP PRO 100, or Omron 3 Series oscillometric Upper Arm Blood Pressure 
Monitor (Model BP7100). All times are estimates. 
 
 
 

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Rationale for Study Procedures 
Plasma catechols: Levels of these neurochemicals and ratios of proximal: distal metabolites (Figure 1) 
are directly influenced by DBH deficiency [9-11] and are distinctively abnormal in Menkes disease 
patients [25-27]. Preliminary data in one Menkes subject indicated that Northera (Droxidopa) treatment 
raises plasma norepinephrine levels (see p.8), suggesting that plasma catechols represent a rational 
parameter for serial measurement in this study.   
Plasma L-DOPS levels: Levels of L-threo-3,4-dihydroxyphenylserine (L-DOPS, droxidopa) may also be 
measured during Visit 2 for comparison to the known pharmacokinetic (PK) profile of Northera 
(Droxidopa) (peak level at approximately 3 hrs). The assay for plasma L-DOPS and plasma 
catecholamines (High Performance Liquid Chromatography with electrochemical detection) is the same 
[32]. Measurements of L-DOPS may permit correlation between plasma L-DOPS and plasma 
norepinephrine levels. 
Tilt Table Test: This testing will enable us to quantify the baseline levels of neurogenic orthostatic 
hypotension in this unique population. The Tilt Table test is typically used to assess adult and pediatric 
subjects with dysautonomia of various causes. In February 2020 (before COVID-related travel 
precautions), the PI visited Jose-Alberto Palma MD PhD, Associate Professor of Neurology at the NYU 
Dysautonomia Center of NYU Grossman School of Medicine/Langone Health in New York, NY to 
become acquainted with the procedure and equipment. Tilt Table testing involves gently strapping a 
patient onto the tilt table with feet resting on footplates. Continuous heart rate and blood pressure 
monitors are then attached to the subject. The entire table can be tilted to move from 0˚ to 60˚angle in 
approximately 45s, allowing determination of changes in pulse and blood pressure based on supine (0˚) 
and standing (60˚) positions. 
Tilt Table Stopping Rules: If a subject indicates that fainting is imminent, if measured systolic blood 
pressure drops more than 90 mm Hg when moved from supine (0˚) to upright (60˚), or if any other 
untoward medical event, e.g., EKG arrhythmia, seizure, vomiting occurs, the Tilt Table Test will be 
stopped immediately.  
Routine Laboratory tests: including CBC with diff/PLTs, CMP and urinalysis will be performed as 
safety labs to ensure no adverse general hematological or biochemical effects of Northera (Droxidopa). 
If a subject has not had their ATP7A mutation identified, 4 ml of blood will be collected for DNA to 
perform ATP7A mutation analysis at screening (Visit 1). 
Physical Therapy Exercise Tolerance tests: These outcome measures will reflect the effect(s) of 
Northera (Droxidopa) on physical activity, e.g., timed duration of standing or walking without the 
need to change posture due to dizziness or lightheadedness. Dr. Lowes and her colleagues have 
extensive knowledge and experience in devising meaningful outcome measures for unique populations 
based on specific clinical considerations. In conjunction with Dr. Lowes and members of the Menkes 
survivor community (parents and subjects), we determined that assessing duration of time standing, as 
well as performance on two formal tests: Six-minute Walk, and Up and Go, will be appropriate 
endpoints for this study. The duration of time standing will be assessed using a timer. The Subject will 
rise from a chair and, when standing up straight, the time (minutes: seconds) the Subject can remain 
standing will be recorded by a member of the study team using a hand-held stopwatch for up to 5 mins. 
The case report form (CRF) for this component of the study will includes notes to explain delays in 
performing for tests for specific reasons, e.g., postural hypotension, need to rest, etc.  
EKG and Cardiac ECHO: A higher than normal rate of congenital heart defects has been reported for 
Menkes disease [33]. In Menkes disease survivors, the natural history of cardiac function has never been 

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evaluated formally. Abnormalities including mitral valve prolapse, mitral regurgitation, aortic and 
pulmonary artery dilatation, RV compression, and wandering atrial pacemaker have been noted in some 
Menkes survivors. Serial EKGs and ECHOs will primarily contribute to establishing the safety profile of 
Northera (Droxidopa) in Menkes survivors and may also yield information concerning baseline cardiac 
function in this population. These tests will also be used to screen subjects at Visit 1 for hypertension, 
heart failure (or decreased ejection fraction), and cardiac arrhythmia (Exclusion criteria). 
Seven to ten day washout period: Although norepinephrine is rapidly eliminated from the blood (t1/2= 2 
to 2.5 minutes), as is Northera (Droxidopa) (t1/2= 2.5 hours), dysautonomia experts suggest that 
cumulative dosing may result in prolonged action of Northera (Droxidopa). Pharmacokinetic studies (in 
adults) suggest 75% elimination of Northera (Droxidopa) in urine within 24 hours (Appendix 1). A 
seven to ten day washout period will eliminate any significant risk of overlap between Northera 
(Droxidopa) and placebo treatments. The 7-10 day window for washout will also facilitate scheduling 
such that all follow-up visits/assessments occur while Subjects are receiving the study drug or placebo.   
4.4. Clinical Trial Monitoring Plan 
The trial will be monitored by a Clinical Research Monitor from the NCH Office of Research 
Compliance & Integrity, with activities to include: monitoring plan creation, subject record review, 
pharmacy review, regulatory review, and lab/supplies review.  
 
 Study Drug    Please see Northera (Droxidopa) Full Prescribing Information (Appendix 1) 
5.1. 
Storage 
Please see Northera (Droxidopa) Full Prescribing Information (Appendix 1) 
5.2. 
Preparation 
Please see Northera (Droxidopa) Full Prescribing Information (Appendix 1) and description 
of NCH IDS oral suspension (2.1.1, page 5) 
5.3. 
Drug Accountability and disposal 
Subjects and their families will maintain a daily log to record time of dose and will return 
used bottles and any remaining suspension at time of each follow-up visit.  
5.4. 
Risks associated  
Please see Northera (Droxidopa) Full Prescribing Information (Appendix 1) 
5.5. 
Randomization 
Randomization to either Northera (Droxidopa) treatment (A) or placebo (B) will occur at the 
conclusion or the screening visit (Visit 1). To ensure a balanced allocation of patients to each 
randomization sequence, the study will employ a permuted block randomization scheme with 
block sizes randomly alternating between 1 and 2. Block length will be unknown to the clinic 
personnel. The permuted randomization scheme is designed to effectively conceal the 
allocation. The technique assures a balanced allocation in the groups and also reduces the 
chance that testing personnel will be able to discern the next intervention group assignment. 
After the initial open-label dose titration period and after completion of one treatment arm 
(Visit 4), subjects will receive no treatment for seven to ten days (washout period).  
 

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This is a double-blind study, in which both Menkes survivor participants and the clinical staff 
conducting the study will be blinded to the treatment administered. Only the NCH IDS 
Pharmacy staff will be unblinded as to the contents of the Treatment dispensed. The IDS 
Pharmacy will maintain the codes in sealed envelopes for each participant. At the conclusion of 
the study, identification of Treatment and Placebo arms for each subject will be revealed to the 
PI, biostatistician, protocol clinical staff, the subjects, and their families. The code(s) will be 
revealed sooner only upon request of the Data Safety Monitoring Committee or if there is an 
emergency indication. The PI will designate a 24hr/7d unblinding contact in case of such an 
emergency who will have access to the sealed unblinding codes. 
 
5.6. 
Subject Compensation 
Subjects in this pilot study will receive a Participant Incentive of $750 ($250 at completion of 
Visit 2, and $125 after completion of Visits 3 to 6). In addition, travel and lodging expenses for 
the subjects and one parent will be reimbursed, using the Greenphire ClinCard system. 
5.7. 
Study Variables 
This study involves specific clinical and neurochemical variables, including systolic blood 
pressure, plasma norepinephrine and dihydroxyphenylglycol levels, adequate measures of 
treatment effect on gastrointestinal symptoms, and defined measures of physical exertion, e.g., 
distance and time able to walk without need to squat or rest.  
 
Quality of life effects will be tracked by scores on the Orthostatic Hypotension Symptom 
Assessment questionnaire (Appendix 2) and the FDA Clinical Outcomes Assessment 
(Appendix 3).  
5.8. 
Outcome Measures 
The primary outcome of this study will be the safety of Northera (Droxidopa) in adult 
patients with an ATP7A genotype predictive of classic Menkes disease and who were spared 
the severe CNS effects of this illness but now suffer with dysautonomia, or adults with an 
ATP7A genotype predictive of Occipital Horn Syndrome and who suffer with dysautonomia. 
Safety will be determined by the rates of side effects and adverse events recorded in the 
treatment and placebo arms.  
 
Secondary outcomes will include: change in plasma norepinephrine and dihydroxyphenyl-
glycol levels after Northera (Droxidopa) compared to baseline and placebo; changes in systolic 
blood pressure after Northera (Droxidopa) compared to baseline and placebo; changes in 
gastrointestinal symptoms as reflected in the Irritable Bowel Syndrome-Diarrhea report 
(Appendix 4) compared to baseline and placebo, changes in physical therapy tests of exertion 
parameters, e.g., time able to stand without need to squat or rest; distance traveled on the 6 min 
walk test, and time to complete the Up and Go test after Northera (Droxidopa) compared to 
baseline and placebo. Breaks in timed tests will be documented if related to drops in blood 
pressure, dizziness, syncope or near-syncope, or possible Northera (Droxidopa) side effects.  
 
An exploratory outcome involves an improved score on the Orthostatic Hypotension Symptom 
Assessment questionnaire (Appendix 2) for Menkes Disease adult survivors or adult Occipital 
Horn syndrome subjects after Northera (Droxidopa), compared to baseline and placebo. We 

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also seek to validate the OHSAQ in this patient population by correlation to the FDA Clinical 
Outcomes Assessment (Appendix 3).  
 
5.8.1       Primary Outcome/Anticipated Results 
1. Safety and tolerability, as reflected in the type and incidence of serious adverse 
events in the Northera (Droxidopa) treatment versus placebo arms.  
5.8.2 
Secondary Outcomes: 
1. Change in level of plasma norepinephrine and dihydroxyphenylglycol after 
Northera (Droxidopa) compared to baseline and placebo  
2. Change in systolic blood pressure (mm Hg) Standing, and between supine and 
head-up tilt table positions after Northera (Droxidopa) compared to baseline and 
placebo 
 
3. Improved gastrointestinal symptoms: Irritable Bowel Syndrome-Diarrhea report 
4. Improvement in performance of Physical Exertion tests: Time Standing, Six-minute 
Walk test, Up and Go test 
5.8.3 
Exploratory Outcome: 
1. Change in scores on the Orthostatic Hypotention Symptom Assessment 
questionnaire (Appendix 2) after Northera (Droxidopa), compared to baseline and 
placebo 
5.9. 
Statistical Analysis  
For analysis of the Primary Outcome, time-to-event and proportions of serious adverse events 
(SAEs) and adverse events (AEs) between treatment and placebo arms will be compared using 
paired t tests or McNemar’s test, and the relative risks and 95% confidence intervals for each 
type of adverse event will be reported. The planned design in which subjects are treated and 
followed up for the same period of time will minimize bias in this safety assessment.  
 
For analysis of the Secondary Outcomes, age-matched normal values are available for the 
neurochemical evaluations planned [25]. The effect of Northera (Droxidopa) treatment will be 
measured by comparing the changes in secondary endpoints between Northera (Droxidopa) 
and placebo using a linear mixed-effects model to account for within- and between-person 
variability in repeated measurements over time, including patient-specific random intercepts. A 
similar approach will be applied to assess Treatment/Placebo differences for systolic blood 
pressure, gastrointestinal symptoms, and performance on the Physical Therapy Exercise 
Tolerance tests. The reference time point for each treatment period for computation of changes 
in secondary endpoints will be the time of the baseline assessments (Visit 1 or 2). The primary 
time point for comparison between Northera (Droxidopa) and placebo will be at final follow-
up (i.e., at Week 6 +/- 7 d) of each treatment period. If any of the statistical methods described 
herein prove unsuitable during analysis, more appropriate methods may be applied. All 

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changes in methodology will be documented in the clinical study report. Additional ad hoc 
analyses may be conducted as deemed suitable.  
 
Power calculation to determine sample size was based on the ability to observe a peak increase 
in neurochemical levels within three hours of Northera (Droxidopa) administration [18]. Based 
on our previous data on plasma catechol levels in untreated Menkes disease subjects [25], and 
assigning an absolute effect size of 150 pg/ml between plasma dihydroxyphenylglycol levels 
pre-treatment versus 6 hours post-treatment, a sample size of six provides 95% power with a 
two-tailed significance level of 0.05 [30]. 
 
For gastrointestinal symptoms, we will follow FDA Guidance for Industry on Irritable Bowel 
Syndrome and define a positive response as a decrease in weekly average of worst abdominal 
pain in past 24 hours score of at least 30% compared with baseline or placebo, and a decrease 
at least 50% in the number of days per week with at least one stool with consistency of Bristol 
Type 6 or 7 compared with baseline (please see Appendix 4). 
 
If any of the statistical methods described herein prove unsuitable during analysis, more 
appropriate methods may be applied. All changes in methodology will be documented in the 
clinical study report. Additional ad hoc analyses may be conducted as deemed suitable.  
 
As an exploratory outcome measure, we will undertake validation of the Orthostatic 
Hypotension Symptom Assessment questionnaire in a young adult population of Menkes 
disease survivors using data from this study. The OSHAQ was previously validated in older 
adults with neurogenic orthostatic hypotension [34]. We will determine whether worsening or 
improvement in the subjects’ secondary outcome measures are associated with commensurate 
changes in weekly OHSAQ scores. In addition, we will correlate OHSAQ scores with an 
independent Clinical Outcomes Assessment, the Patient Global Impression of Severity Scale 
(Appendix 3) using Cohen’s kappa coefficient, due to that both scores are four to six items on 
an ordinal scale. Additional correlation analysis such as Spearman’s correlation coefficient will 
be performed but the main validation is through kappa statistic. Hypothesis testing will be 
conducted at the two-tailed 0.05 significance level. by telephone each week, and compare 
responses to the OHSAQ. 
 
Appendix 5 outlines a detailed Statistical Analysis Plan for this study and includes a linear 
mixed-effects model to account for within- and between-person variability in repeated 
measurements obtained over time. 
 
 Dose Limiting Toxicity 
In reporting adverse events, we will follow the final regulations issued by the Food and Drug 
Administration addressing the safety reporting requirements for investigational new drug applications 
(INDs) found in 21 CFR part 312 and for bioavailability and bioequivalence studies found in 21 CFR 
part 320. “Safety Reporting Requirements for INDs and BA/BE Studies”. 
6.1. 
The classification for adverse events to be used is the following: 
Grade 1. Mild adverse event; did not require treatment 
Grade 2. Moderate adverse event; resolved with treatment 

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Grade 3. Severe adverse event; inability to carry on normal activities; required professional  
         medical attention 
Grade 4. Life-threatening or permanently disabling adverse event 
Grade 5. Fatal adverse event 
 
In this grading system, severity is not equivalent to seriousness. The definitions to be employed will 
follow the final regulations issued by the FDA in December 2012 “Safety Reporting Requirements 
for INDs and BA/BE Studies”, and described in section 8.0 of this protocol. 
6.2. 
Dose limiting toxicity (DLT) 
DLT is defined as any adverse event that is possibly, probably, or definitely related to the study 
agent. This would include any grade 3 according to the classification given above. Any treatment 
dose associated with a Grade 3, or higher adverse event toxicity that is possibly, probably, or 
definitely related to the study drug will be reviewed by the responsible physicians and a lower dose 
substituted, or all treatment stopped. 
 
The PI will fulfill the reporting responsibilities under 21 CFR 312.32(c), to notify the FDA in 
an IND safety report of potentially serious risks, as soon as possible, but no later than 15 
calendar days after the investigator receives the safety information and determines that the 
information qualifies for reporting. The principal investigator will report to the IRB, FDA, and 
DSMC before continuing enrollment. 
6.3. 
Stopping/Discontinuation Rules 
The Principal Investigator (PI) will monitor safety data on a continual basis throughout the trial. The 
PI, in conjunction with the DSMC (and with IRB approval), can recommend early termination of the 
trial for reasons of safety. Study enrollment will be halted by the investigators if any subject 
experiences a Grade 4, or higher adverse event that is possibly, probably, or definitely related to 
the study drug. This will include any patient death, important clinical laboratory finding, or any 
severe local complication related to the study agent. If after review by the IRB and FDA, the 
decision is made to continue, the study will proceed. 
 
 Adverse Event Monitoring and Reporting 
7.1. 
Definition of an Adverse Event 
As stated above this protocol will follow the final regulations issued by the Food and Drug 
Administration addressing the safety reporting requirements for investigational new drug 
applications (INDs) found in 21 CFR part 312.  
Adverse Event (AE): Adverse event means any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related. 
 
Adverse events will be graded by the investigator accordingly: 1 = mild, 2 = moderate, 3 = severe,   
4 = life threatening or debilitating, and 5 = fatal. 
 
Association or relatedness to the study agent, study procedures and the subject's pre-existing disease 
will be graded as follows: 5 = unrelated, 4 = unlikely, 3 = possibly, 2 = probably, and 1 = definitely 
related. 

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Adverse reaction: An adverse reaction means any adverse event caused by a drug. Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude that the 
drug caused the event. 
 
Suspected adverse reaction (21 CFR 312.32(a)) Suspected adverse reaction means any adverse 
event for which there is a reasonable possibility that the drug caused the adverse event. For the 
purposes of IND safety reporting, “reasonable possibility” means there is evidence to suggest a 
causal relationship between the drug and the adverse event. A suspected adverse reaction implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
7.2. Serious adverse event (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: Death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
 
To reiterate, an SAE is an event in categories 3, 4, and 5. Category 3 Severe adverse event; inability 
to carry on normal activities; required professional medical attention Category 4 Life-threatening or 
permanently disabling adverse event Category 5 Fatal adverse event. 
7.3. 
Life-threatening (21 CFR 312.32(a)) 
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. The PI will fulfill the reporting responsibilities to FDA 
on behalf of Nationwide Children’s Hospital, by completing a Form FDA 3500 either online, by fax 
(1-800-FDA-0178) or calling the FDA at 1-800-FDA-1088.  
7.4. 
Obligations of the Investigator 
The Principal Investigator will submit a voluntary Form FDA 3500 by one of the methods 
mentioned above for any serious adverse event that is both unexpected and possibly, probably, or 
definitely associated with the use of the study drug(s). The Principal Investigator will adhere to any 
other serious adverse event reporting requirements in accordance with federal regulations, state laws, 
and the local institutional policies and procedures, as applicable. 
 
The Principal Investigator also will be responsible for ensuring that the reporting requirements are 
fulfilled and will be held accountable for any reporting lapses. 

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7.5. 
Adverse Event Reporting 
The investigator or his designee will report all serious and unexpected adverse events to the IRB, 
according to regulatory requirements described as follows: Any serious adverse event that is 
unexpected and related/probably related to the study drug(s) will be reported to the IRB within 5 
business days from notification. 
 
Any serious adverse event that is fatal or life-threatening, that is unexpected, and associated with the 
use of the study drug(s) will be reported to the FDA as soon as possible, but not later than 7 calendar 
days after the sponsor’s initial receipt of the information. 
 
Serious adverse events that are unexpected and associated with the use of the study drug(s), but are 
not fatal or life-threatening, will be reported to the FDA as soon as possible, but not later than 15 
calendar days after the sponsor’s initial receipt of the information.  
 
If, after further evaluation, an adverse event initially considered not to be associated with the use of 
the study drug(s) is subsequently determined to be associated, then the event will be reported to the 
FDA within 15 days of the determination. Relevant additional clinical and laboratory data will 
become available following the initial serious adverse event report. Any follow-up information 
relevant to a serious adverse event will be reported within 15 calendar days of the sponsor’s receipt 
of the information. If a serious adverse event occurs after the end of a clinical trial and is determined 
to be associated with the study drug(s), that event will be reported to the FDA within 15 calendar 
days of the determination. 
7.5.1. Serious Adverse Event Reporting: Content and Format 
The serious adverse event report will include, but need not be limited to: (1) the date of the 
event; (2) designation of the report as an initial report or a follow-up report, identification of all 
safety reports previously filed for the clinical protocol concerning a similar adverse event, and an 
analysis of the significance of the adverse event in light of previous similar reports; (3) clinical site; 
(4) the Principal Investigator; (5) protocol number; (6) FDA’s Investigational New Drug (IND) 
application number; (7) dosing schedule; (8) a complete description of the event; (9) relevant clinical 
observations; (10) relevant clinical history; (11) relevant tests that were or are planned to be 
conducted; (12) date of any treatment of the event; and (13) the suspected cause of the event. 
7.6. 
Unexpected Adverse Events 
Unexpected adverse events are those which are not previously reported with the study drug(s), 
commonly not seen in association with the subject's underlying disease or are related to a known 
toxicity but differ because of greater severity or specificity. 
7.7. 
Follow-up of Adverse Events 
All adverse events will be followed until resolution or stabilization. 
7.8. 
Adverse Event Reporting from Primary Care Physician 
Close communication will be established with the primary care physician of all study participants 
and will be maintained throughout the study. The important hallmarks of the study along with the 
proposed reporting plan will be explained. We will request that the primary care physician provide 
information regarding every routine visit and any potential adverse event taking place. Laboratory 

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reports, hospitalizations, clinical notes and any other relevant medical records will be requested at 
the time of their occurrence. If non-routine visits are reported to us by the primary care physician, 
the study investigator will initiate an investigation to determine the possibility of an adverse event 
related to the study drug(s) and will adhere to the adverse event reporting requirements in 
accordance with federal regulations, state laws, and the local institutional policies and procedures, as 
applicable. 
 
 Study Reports 
8.1. 
Sharing of Results with Subjects:  
Visit-to-visit results will be shared with participants verbally by Dr. Kaler and/or other members of 
the Study Team. Final results, and recommendations, if any, will be given to Subjects in a letter at the 
end of the study. We will also share the overall results from this study with the participants, including 
a copy of the medical-scientific paper describing it, if requested.  
8.2. 
Final Study Report 
The final study report will include data through the final study visit and will not necessarily include 
long-term follow-up information, such as normal standard of care communications from local 
physicians, or information from telephone conferences and/or medical records. Information from 
annual post-study follow-up visits at the NCH Menkes Disease Clinic will be included when 
available.  
8.3. 
Annual Study Reports 
Within 60 days after the one-year anniversary of the date on which the investigational new 
drug (IND) application went into effect, and after each subsequent anniversary until the trial 
is completed, the Principal Investigator will submit information set forth in 21 CFR 312. 
8.4. 
Safety Monitoring of the Study 
The Data and Safety Monitoring Committee (DSMC) will act in an advisory capacity to review 
participant safety and study progress. The DSMC membership will consist of persons completely 
independent of the investigator who have no financial, scientific, or other conflicts of interest with 
the trial.  Current or past collaborators or associates of the Principal Investigator must note any 
conflict of interest before their eligibility to serve on the DSMC is approved.  
 
The DSMC will include experts in or representatives of the fields of: catecholamine metabolism, 
dysautonomia, Menkes disease/Occipital Horn Syndrome, and DBH deficiency. 
  
Individuals invited to serve on the DSMC as either voting or non-voting members must disclose any 
potential conflicts of interest, whether real or perceived.  Conflicts of interest can include 
professional, proprietary, and miscellaneous interests as described in the NIH Grant Policy 
Statement and 45 CFR Part 94.  Potential conflicts that develop during a member’s tenure on a 
DSMC must also be disclosed.  Written documentation attesting to an absence of conflict of interest 
is required annually.  
 
DSMC Responsibilities 
Responsibilities of the DSMC are to   

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• Review the research protocol, informed consent documents and plans for data and safety 
monitoring; 
• Evaluate the progress of the trial, including periodic assessments of data quality and timelines, 
participant recruitment, accrual and retention, participant risk versus benefit, trial site 
performance, and other factors that can affect study outcome; 
• Consider factors external to the study when relevant information becomes available, such as 
scientific or therapeutic developments that may have an impact on participant safety or the ethics 
of the trials; 
• Review study performance, make recommendations and assist in the resolution of problems 
reported by the Principal Investigator; 
• Protect the safety of the study participants; 
• Ensure the confidentiality of the trial data and the results of monitoring; and  
• Assist by commenting on any problems with study conduct, enrollment, and sample size and/or 
data collection. 
 
DSMC Reporting and Meetings 
Reports describing the status of the study will be prepared by the PI’s staff and sent to the DSMC 
prior to a meeting, or at the DSMC’s request.  A meeting (either by teleconference or webcast) with 
the DSMC will be scheduled prior to study initiation and after three subjects have completed Visit 
#2, or after one subject has completed three visits.  
 
DSMC reports will include the following: 
• 
A brief narrative of the study status, including the target enrollment, current and 
projected time to completing enrollment. Any significant events and/or difficulties should 
be briefly described in this narrative. 
• 
A brief narrative for each participant describing gender, age, race and ethnicity and other 
relevant demographic characteristics. The narrative for each participant should briefly 
describe his/her study status (i.e., dose level, visit number, adverse event information); 
• 
A timeline outlining the study progress relative to visit number for each participant, as 
well as time points for each SAE/Dose Limiting Toxicity. A total for Adverse Events 
(AEs) for each participant should be included.  
• 
A summary of AEs by severity levels; 
• 
A listing of AE details grouped by participant; 
• 
A listing of SAE details grouped by participant; 
• 
A listing of deaths 
• 
A summary of clinically significant laboratory test results 
 
The study will be monitored in compliance with the relevant parts of 21 CFR and according to the 
ICH GCP Guidelines. The procedures outlined in the protocol and case report forms will be carefully 
reviewed by the PI and staff prior to study initiation to ensure appropriate interpretation and 
implementation. No deviations from the protocol shall be made except in emergency situations 
where alternative treatment is necessary for the protection, proper care and wellbeing of subjects. 
 
Amendments will be submitted to the Nationwide Children’s Hospital IRB for their review and 
approval prior to implementation. When an amendment to a protocol substantially alters the study 
design or increases potential risk to the study subject, the Informed Consent Form will be revised 

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and if applicable, subject's consent to continue participation will again be obtained. Re-consent may 
occur at the next study visit or by telephone in the presence of a witness. Prior to a phone consent, 
the subject will be sent a blank copy of the revised consent document to review and instructed not to 
sign it until the informed consent process has been completed. After all changes have been explained 
and all questions answered, and if the subject agrees to give their consent for the changes, the subject 
will sign and return the consent form to the study team. The witness to the subject’s signature and 
the person obtaining consent will also sign the document. A copy of this fully executed version will 
be sent to the subject once available. 
8.4.1. 
Data Management  
All data and observations will be documented and securely stored on REDCap (Research Electronic 
Data Capture), supported by Research IT R&D (RISI) at Nationwide Children’s Hospital. The PI 
will be responsible for review and evaluation of information relevant to the safety of the drug.  
 
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