Baroreflex Failure Syndrome, Dysautonomia, Familial
Conditions
Keywords
Familial dysautonomia (HSAN III), Norepinephrine, Sympathetic nervous system, Autonomic nervous system, Blood pressure variability, Hypertension, Carbidopa/Lodosyn, Afferent baroreflex failure, Clinical trial
Brief summary
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.
Detailed description
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.
Interventions
DRUGCarbidopa Low-Dose
300 mg/day
OTHERPlacebo
A placebo containing an inert substance, in capsule form that does not contain an active drug ingredient.
DRUGCarbidopa High-Dose
600 mg/day
Sponsors
NYU Langone Health
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
10 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Male or female patients with familial dysautonomia (FD) age 10 or older * Unstable blood pressure, defined as: * Systolic BP standard deviation \>15 mmHg * Or coefficient of variation \>15% * Or documented episodic hypertensive peaks (\>140mmHg) * Confirmed diagnosis of FD (genetic testing) * Providing written informed consent (or ascent) to participate in the trial * Ability to comply with the requirements of the study procedures.
Exclusion criteria
* Patients taking monoamine oxidase (MAO)-inhibitors * Patients taking: metoclopramide, domperidone, risperidone or other dopamine blockers * Patients taking tricyclic antidepressants * Patients taking neuroleptic drugs (haloperidol and chlorpromazine) * Patients with a known hypersensitivity to any component of this drug. * Patients with atrial fibrillation, angina or significant ECG abnormality * Patients with significant pulmonary, cardiac, liver, renal (creatinine \>2.0 mg/ml) * Patients who have a significant abnormality on clinical examination that may, in the investigator's opinion might jeopardize their healthy participating in this trial. * Women who are pregnant or lactating.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Displayed Clinically Significant Values in Urine Safety Parameters | Up to 90 days | Clinically significant values on urinalysis, urine safety parameters related to treatment with carbidopa |
| Number of Participants With Abnormal Electrocardiographic Interval Patterns | Up to 90 days | Clinically significant changes in the intervals of characteristic electrocardiographic patterns |
| Average Systolic Blood Pressure Variability (Daytime) | up to Week 14 | 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 |
| Highest Systolic Blood Pressure | Day 1 of treatment period | Maximum blood pressure captured on 24-h ambulatory monitoring |
| Systolic Blood Pressure | up to Week 14 | SBP measured in the seated position |
| Heart Rate | up to Week 14 | Heart rate in the seated position |
| Number of Participants Who Displayed Clinical Significant Laboratory Values on CBC or Metabolic Panel | Up to 90 days | Clinically significant laboratory values include complete blood count (CMC) and metabolic panel related to treatment with carbidopa |
| Number of Participants Who Reported Adverse Events Related to Study Drug | Up to 90 days | 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. |
| Number of Participants With Significant Changes in Body Mass That Resulted in Discontinuation From the Study. | Up to 90 days | Body mass measured in kg |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Reported Worsening of OH Symptoms or Dropped Out Because of Worsening OH While on Active Study Drug | Up to 90 days | — |
| Frequency of Worsening Symptoms Noted in the Patient's Diary | Up to 90 Days | 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. |
| 24-h Urinary Norepinephrine Excretion | up to Week 14 | 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. |
| Coefficient of Systolic BP Variability (Daytime) | up to Week 14 | The measurement of blood pressure variability based on the standard deviation that also takes into account the underlying level of BP. |
| Morning Surge in Systolic BP on Awakening From Sleep (24-h) | up to Week 14 | 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 |
| Severity of Hypotension During an Active Stand Test | up to Week 14 | Lowest blood pressure captured during 3 minutes of standing |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low Dose Carbidopa, High Dose Carbidopa, Placebo This is a 14-week study. Patients will receive, in random order, high dose carbidopa (600mg/day), low dose carbidopa (300 mg/day) or placebo. Between each crossover, there will be a titration down over 2-days followed by a 2-day washout.
Carbidopa Low Dose
Placebo: A placebo containing an inert substance, in capsule form that does not contain an active drug ingredient.
Carbidopa High Dose | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Enrollment | Death | 0 | 0 | 1 |
| First Intervention (28 Days) | Adverse Event | 1 | 0 | 0 |
| First Intervention (28 Days) | Withdrawal by Subject | 0 | 0 | 1 |
| Second Intervention (28 Days) | Adverse Event | 1 | 0 | 0 |
| Third Intervention (28 Days) | Adverse Event | 1 | 0 | 0 |
| Third Intervention (28 Days) | Lost to Follow-up | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Low Dose Carbidopa, High Dose Carbidopa, Placebo |
|---|---|
| Age, Continuous | 28 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 22 Participants |
| Region of Enrollment United States | 22 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 16 | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 4 / 16 | 3 / 16 | 0 / 16 |
| serious Total, serious adverse events | 1 / 16 | 0 / 16 | 0 / 16 |
Outcome results
Primary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Average Systolic Blood Pressure Variability (Daytime) | 22.92 mmHg | Standard Deviation 6.13 |
| Low-Dose Carbidopa | Average Systolic Blood Pressure Variability (Daytime) | 18.71 mmHg | Standard Deviation 4.83 |
| High-Dose Carbidopa | Average Systolic Blood Pressure Variability (Daytime) | 16.92 mmHg | Standard Deviation 4.14 |
Primary
Heart Rate
Heart rate in the seated position
Time frame: up to Week 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Heart Rate | 76 beats per minute (BPM) | Standard Deviation 11 |
| Low-Dose Carbidopa | Heart Rate | 72 beats per minute (BPM) | Standard Deviation 13 |
| High-Dose Carbidopa | Heart Rate | 78 beats per minute (BPM) | Standard Deviation 13 |
Primary
Highest Systolic Blood Pressure
Maximum blood pressure captured on 24-h ambulatory monitoring
Time frame: Day 1 of treatment period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Highest Systolic Blood Pressure | 175 mmHg | Standard Deviation 27 |
| Low-Dose Carbidopa | Highest Systolic Blood Pressure | 157 mmHg | Standard Deviation 20 |
| High-Dose Carbidopa | Highest Systolic Blood Pressure | 150 mmHg | Standard Deviation 17 |
Primary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Who Displayed Clinically Significant Values in Urine Safety Parameters | 0 Participants |
| Low-Dose Carbidopa | Number of Participants Who Displayed Clinically Significant Values in Urine Safety Parameters | 0 Participants |
| High-Dose Carbidopa | Number of Participants Who Displayed Clinically Significant Values in Urine Safety Parameters | 0 Participants |
Primary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Who Displayed Clinical Significant Laboratory Values on CBC or Metabolic Panel | 0 Participants |
| Low-Dose Carbidopa | Number of Participants Who Displayed Clinical Significant Laboratory Values on CBC or Metabolic Panel | 0 Participants |
| High-Dose Carbidopa | Number of Participants Who Displayed Clinical Significant Laboratory Values on CBC or Metabolic Panel | 0 Participants |
Primary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Who Reported Adverse Events Related to Study Drug | 0 Participants |
| Low-Dose Carbidopa | Number of Participants Who Reported Adverse Events Related to Study Drug | 0 Participants |
| High-Dose Carbidopa | Number of Participants Who Reported Adverse Events Related to Study Drug | 0 Participants |
Primary
Number of Participants With Abnormal Electrocardiographic Interval Patterns
Clinically significant changes in the intervals of characteristic electrocardiographic patterns
Time frame: Up to 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Abnormal Electrocardiographic Interval Patterns | 0 Participants |
| Low-Dose Carbidopa | Number of Participants With Abnormal Electrocardiographic Interval Patterns | 0 Participants |
| High-Dose Carbidopa | Number of Participants With Abnormal Electrocardiographic Interval Patterns | 0 Participants |
Primary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Significant Changes in Body Mass That Resulted in Discontinuation From the Study. | 0 Participants |
| Low-Dose Carbidopa | Number of Participants With Significant Changes in Body Mass That Resulted in Discontinuation From the Study. | 0 Participants |
| High-Dose Carbidopa | Number of Participants With Significant Changes in Body Mass That Resulted in Discontinuation From the Study. | 0 Participants |
Primary
Systolic Blood Pressure
SBP measured in the seated position
Time frame: up to Week 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Systolic Blood Pressure | 126 mmHg | Standard Deviation 27 |
| Low-Dose Carbidopa | Systolic Blood Pressure | 126 mmHg | Standard Deviation 18 |
| High-Dose Carbidopa | Systolic Blood Pressure | 126 mmHg | Standard Deviation 21 |
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 24-h Urinary Norepinephrine Excretion | 16 pg/mL | Standard Deviation 11 |
| Low-Dose Carbidopa | 24-h Urinary Norepinephrine Excretion | 6 pg/mL | Standard Deviation 3 |
| High-Dose Carbidopa | 24-h Urinary Norepinephrine Excretion | 8 pg/mL | Standard Deviation 6 |
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Coefficient of Systolic BP Variability (Daytime) | 19 mmHg | Standard Deviation 4 |
| Low-Dose Carbidopa | Coefficient of Systolic BP Variability (Daytime) | 16 mmHg | Standard Deviation 4 |
| High-Dose Carbidopa | Coefficient of Systolic BP Variability (Daytime) | 15 mmHg | Standard Deviation 3 |
Secondary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Frequency of Worsening Symptoms Noted in the Patient's Diary | 0 symptoms |
| Low-Dose Carbidopa | Frequency of Worsening Symptoms Noted in the Patient's Diary | 0 symptoms |
| High-Dose Carbidopa | Frequency of Worsening Symptoms Noted in the Patient's Diary | 0 symptoms |
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Morning Surge in Systolic BP on Awakening From Sleep (24-h) | 44 mmHg | Standard Deviation 24 |
| Low-Dose Carbidopa | Morning Surge in Systolic BP on Awakening From Sleep (24-h) | 19 mmHg | Standard Deviation 11 |
| High-Dose Carbidopa | Morning Surge in Systolic BP on Awakening From Sleep (24-h) | 20 mmHg | Standard Deviation 9 |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Who Reported Worsening of OH Symptoms or Dropped Out Because of Worsening OH While on Active Study Drug | 0 Participants |
| Low-Dose Carbidopa | Number of Participants Who Reported Worsening of OH Symptoms or Dropped Out Because of Worsening OH While on Active Study Drug | 0 Participants |
| High-Dose Carbidopa | Number of Participants Who Reported Worsening of OH Symptoms or Dropped Out Because of Worsening OH While on Active Study Drug | 0 Participants |
Secondary
Severity of Hypotension During an Active Stand Test
Lowest blood pressure captured during 3 minutes of standing
Time frame: up to Week 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Severity of Hypotension During an Active Stand Test | 96 mmHg | Standard Deviation 27 |
| Low-Dose Carbidopa | Severity of Hypotension During an Active Stand Test | 91 mmHg | Standard Deviation 28 |
| High-Dose Carbidopa | Severity of Hypotension During an Active Stand Test | 96 mmHg | Standard Deviation 24 |