Menkes Disease, Occipital Horn Syndrome
Conditions
Keywords
Dysautonomia
Brief summary
The purpose of this study is to evaluate whether Northera (Droxidopa) is safe and effective in young adults with Menkes disease who survived the most severe complications of their illness or adults with occipital horn syndrome (OHS), who have trouble with intermittent low blood pressure and other symptoms of dysautonomia. The outcomes and information from this study may help adult survivors of Menkes disease and individuals with OHS lead more normal day-to-day lives.
Detailed description
This pilot clinical trial will evaluate the safety, tolerability, dosing, and preliminary efficacy of Northera (Droxidopa) treatment in young adults who survived the major neurodegenerative and neurocognitive effects of Menkes disease through early Copper Histidinate treatment. We hypothesize that Northera (Droxidopa) in Menkes disease survivors with symptoms of dysautonomia (e.g., syncope, dizziness, orthostatic hypotension, abnormal sinoatrial conduction, nocturnal bradycardia, and bowel or bladder dysfunction) from persistent deficiency of the copper-dependent enzyme, dopamine-β-hydroxylase, will be safe, and correct or improve blood neurochemical levels, raise systolic blood pressure, and produce symptomatic improvement and better overall quality of life. We will test this hypothesis in six to ten Menkes disease survivors or OHS patients in a double-blind placebo-controlled randomized crossover clinical trial.
Interventions
DRUGDroxidopa
Subjects will self-administer capsules of Droxidopa by mouth twice daily for six weeks.
OTHERPlacebo
Subjects will self-administer capsules of placebo by mouth twice daily for six weeks.
Sponsors
Stephen G. Kaler, MD
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Double-blind Placebo-controlled Randomized Crossover Clinical Trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Related Adverse Events as Assessed by CTCAE v4.0 | TEAEs in 6 week periods of either active drug (droxidopa) or placebo | Treatment related adverse events as assessed by CTCAE v 4.0 by study arm |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Systolic Blood Pressure in Tilt Position | Change in systolic BP in tilt position during each 6 week treatment arm (droxidopa and placebo) compared to baseline. | Change in systolic BP in tilt position during each treatment arm (droxidopa and placebo) compared to baseline. |
| Mean Change in Diastolic Blood Pressure in Tilt Position | The change in diastolic BP in tilt position during each 6 week treatment arm (droxidopa and placebo) compared to baseline. | The change in diastolic BP in tilt position during each treatment arm (droxidopa and placebo) compared to baseline. |
| Plasma Catechol Levels | Change in plasma catechols between each 6 week treatment arm (droxidopa and placebo) | Change in plasma catechols between placebo and droxidopa treatment arms |
| Change From Baseline in Daily Bowel Movements | Change from baseline in daily bowel movements per day during each 6 week treatment arm (droxidopa and placebo). | Change from baseline in daily bowel movements |
| Change From Baseline in Time Standing Duration | Change from baseline in standing time duration during each 6 week treatment arm (droxidopa and placebo). | Change from baseline in Time standing duration |
| Change From Baseline in Timed Up and Go (TUG) Test Performance | Change from baseline in TUG test performance during each 6 week treatment arm (droxidopa and placebo) | Change from baseline in Timed Up and Go (TUG) test performance |
| Change From Baseline in 6 Minute Walk Test Performance | Change from baseline in the 6MW distance during each 6 week treatment arm (droxidopa and placebo) | Change from baseline in 6 minute walk test performance |
| Change From Baseline in Scores on the Orthostatic Hypotension Symptom Assessment (OHSA) Questionnaire | Change from baseline in OHSA score during each 6 week treatment arm (droxidopa and placebo) | Change from baseline in scores on the Orthostatic Hypotension Symptom Assessment questionnaire. The scale rates the severity of OH symptoms from 0 to 10 ; with 10 defined as the worst possible. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORStephen G Kaler, MD
Vagelos College of Physicians & Surgeons, Columbia University, New York, NY
Participant flow
Recruitment details
Three adult participants were consented and screened for eligibility between July 2021 and October 2023.
Pre-assignment details
Three Adult participants were assigned randomly to receive either Northera (droxidopa) then placebo placebo (Arm 1) or Placebo then Northera (droxidopa) (Arm 2). An open label dose titration was utilized in advance to determine each participant's maximally tolerated dose (100, 200, or 300mg) of droxidopa. Participants then underwent a 7 to 10 day washout period prior to beginning the treatment arms. There was also a washout period of 7 to 10 days between each of the two treatment arms.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Height | 174.85 cm |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 3 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 2 Participants |
| Weight | 57.73 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 1 / 3 | 3 / 3 | 1 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 |
Outcome results
None listed