Carbidopa for the Treatment of Excessive Blood Pressure Variability

Study Overview
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Brief Summary
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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
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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.

Official Title
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Carbidopa in Familial Dysautonomia: Phase-II Study, Investigational New Drug (IND) 117435, Date: 01/07/13

Conditions
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Dysautonomia, Familial, Baroreflex Failure Syndrome

Intervention / Treatment
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* Drug: Carbidopa Low-Dose
* Other: Placebo
* Drug: Carbidopa High-Dose


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Matching placebo | Other: Placebo<br>* A placebo containing an inert substance, in capsule form that does not contain an active drug ingredient.<br>* Other names: Placebo control pill;|
| Experimental: Low-Dose Carbidopa<br> | Drug: Carbidopa Low-Dose<br>* 300 mg/day<br>* Other names: Lodosyn ®, DL-α-methyl-α-hydrazino-3, 4-dihydroxyphenyl-propionic acid, HMD, MK-486;|
| Active Comparator: High-Dose Carbidopa<br> | Drug: Carbidopa High-Dose<br>* 600 mg/day<br>* Other names: Lodosyn ®, DL-α-methyl-α-hydrazino-3, 4-dihydroxyphenyl-propionic acid, HMD, MK-486;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | Up to 90 days | 
| Number of Participants With Abnormal Electrocardiographic Interval Patterns | Clinically significant changes in the intervals of characteristic electrocardiographic patterns | 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 | up to Week 14 | 
| Highest Systolic Blood Pressure | Maximum blood pressure captured on 24-h ambulatory monitoring | Day 1 of treatment period | 
| Systolic Blood Pressure | SBP measured in the seated position | up to Week 14 | 
| Heart Rate | Heart rate in the seated position | up to Week 14 | 
| 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 | 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 | Up to 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of Hypotension During an Active Stand Test | Lowest blood pressure captured during 3 minutes of standing | 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 |  | 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. | 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. | 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. | 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 | up to Week 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertension, Carbidopa/Lodosyn, Afferent baroreflex failure, Clinical trial, Familial dysautonomia (HSAN III), Norepinephrine, Sympathetic nervous system, Autonomic nervous system, Blood pressure variability