The overall study objectives are to determine whether carbidopa (Lodosyn®) is safe and well tolerated and to assess whether it can inhibit catecholamine-induced paroxysmal hypertension and normalize or reduce the exaggerated blood pressure variability in patients with familial dysautonomia (FD, also called hereditary sensory and autonomic neuropathy type III or Riley-Day syndrome). Funding Source- FDA OOPD.
The investigators propose to perform a double-blind randomized trial with a cross over design to compare high dose (600 mg/day) and low dose (300 mg per day) carbidopa blockade with placebo. Patients will be randomly assigned to a high-dose/low-dose/placebo sequence, lowdose/placebo/high-dose sequence or placebo/high-dose/low-dose sequence. Participants will remain on each treatment period for 28-days. Aim 1: To evaluate the safety and tolerability of carbidopa in FD patients with particular emphasis on the orthostatic fall in blood pressure. Aim 2: As proof of concept, examine the hemodynamic effects of carbidopa and determine its effects on norepinephrine production, BP variability and paroxysmal hypertension. Aim 3: In a dose finding study, compare the effects of low (300 mg/day) and high (600 mg/day) dose carbidopa blockade vs. placebo on BP variability and paroxysmal hypertension.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
22
300 mg/day
A placebo containing an inert substance, in capsule form that does not contain an active drug ingredient.
600 mg/day
NYU Langone Medical Center, Dyautonomia Center, Suite 9Q
New York, New York, United States
NYU Medical Center
New York, New York, United States
Number of Participants Who Reported Adverse Events Related to Study Drug
Adverse events defined as: a change in a patient's baseline condition including intercurrent illnesses irrespective of the relationship to carbidopa treatment. This will be monitored primarily with phone calls at weekly intervals. In addition, patients will be asked about adverse events while at the office. Patients will also fill a daily diary with a specific prompts to note any adverse events.
Time frame: Up to 90 days
Number of Participants With Significant Changes in Body Mass That Resulted in Discontinuation From the Study.
Body mass measured in kg
Time frame: Up to 90 days
Number of Participants With Abnormal Electrocardiographic Interval Patterns
Clinically significant changes in the intervals of characteristic electrocardiographic patterns
Time frame: Up to 90 days
Average Systolic Blood Pressure Variability (Daytime)
Patients with FD undergo ambulatory BP monitoring while keeping a detailed log of their activities (sleep/meal-times/medications/posture/symptoms). Variability in blood pressure overtime will be measured by the standard deviation during awake hours
Time frame: up to Week 14
Highest Systolic Blood Pressure
Maximum blood pressure captured on 24-h ambulatory monitoring
Time frame: Day 1 of treatment period
Systolic Blood Pressure
SBP measured in the seated position
Time frame: up to Week 14
Heart Rate
Heart rate in the seated position
Time frame: up to Week 14
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Number of Participants Who Displayed Clinical Significant Laboratory Values on CBC or Metabolic Panel
Clinically significant laboratory values include complete blood count (CMC) and metabolic panel related to treatment with carbidopa
Time frame: Up to 90 days
Number of Participants Who Displayed Clinically Significant Values in Urine Safety Parameters
Clinically significant values on urinalysis, urine safety parameters related to treatment with carbidopa
Time frame: Up to 90 days
Severity of Hypotension During an Active Stand Test
Lowest blood pressure captured during 3 minutes of standing
Time frame: up to Week 14
Number of Participants Who Reported Worsening of OH Symptoms or Dropped Out Because of Worsening OH While on Active Study Drug
Time frame: Up to 90 days
Frequency of Worsening Symptoms Noted in the Patient's Diary
A tailored questionnaire to examine symptoms over the treatment period and the used of as needed medications. Each day will have a designated page. Since nausea/vomiting and hypertension occur together in FD we will use a diary consisting of a simplified version of the Rhodes Index 44 symptoms of nausea/retching, with items addressing vomiting/throwing up omitted, as most participants will have had anti-reflux surgery to prevent vomiting (fundoplication), graded on a 5-point scale (appendix 2). The diary will also include space to write down any adverse events on a daily basis.
Time frame: Up to 90 Days
24-h Urinary Norepinephrine Excretion
Norepinephrine concentration determined from a 24-hour urine sample in a bottle shielded from light containing preservative. Patients will be instructed to refrigerate their sample and bring it on the morning of their visit in a cool bag.
Time frame: up to Week 14
Coefficient of Systolic BP Variability (Daytime)
The measurement of blood pressure variability based on the standard deviation that also takes into account the underlying level of BP.
Time frame: up to Week 14
Morning Surge in Systolic BP on Awakening From Sleep (24-h)
The morning surge will be calculated as the difference between the mean systolic blood pressure during the hour that included the lowest blood pressure during sleep and maximum value detected within 2-h of awakening from sleep
Time frame: up to Week 14