Clinical Trial: Carbidopa for the Treatment of Excessive Blood Pressure Variability

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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

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 Summary:

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.

Current Primary Outcome:

• Adverse Events [ Time Frame: 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.
• Weight [ Time Frame: At each office visit, an expected average of 4-weeks ]
  Body mass measured in kg
• Number of patients with abnormal electrocardiographic interval patterns [ Time Frame: At each office visit, or at local an expected average of 4-weeks ]
  Clinically significant changes in the intervals of characteristic electrocardiographic patterns
• Standard deviation of systolic blood pressure variability (daytime) [ Time Frame: At each office visit, or at home measurements, via video conference,an expected average of 4-weeks ]
  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 [ Time Frame: At each office visit, or at home measurements, via video conference, an expected average of 4-weeks ]
  Maximum blood pressure captured on 24-h ambulatory monitoring
  
  
  

  Original Primary Outcome:

  • Adverse Events [ Time Frame: 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.
  • Weight [ Time Frame: At each office visit, an expected average of 4-weeks ]
    Body mass measured in kg
  • Number of patients with abnormal electrocardiographic interval patterns [ Time Frame: At each office visit, an expected average of 4-weeks ]
    Clinically significant changes in the intervals of characteristic electrocardiographic patterns
  • Standard deviation of systolic blood pressure variability (daytime) [ Time Frame: At each office visit, an expected average of 4-weeks ]
    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 [ Time Frame: At each office visit, an expected average of 4-weeks ]
    Maximum blood pressure captured on 24-h ambulatory monitoring
  • Vital signs [ Time Frame: At each office visit, an expe
    
    

    Current Secondary Outcome:

    • Number of subjects who discontinue the study [ Time Frame: Up to 90 days ]
      Patients that dropout of the study
    • Number of subjects who discontinue the study due to adverse events [ Time Frame: Up to 90 days ]
      Patients that dropout of the study due to an adverse event (a change in a patient's baseline condition including intercurrent illnesses irrespective of the relationship to carbidopa treatment)
    • Severity of hypotension during an active stand test [ Time Frame: At each office visit, an expected average of 4-weeks ]
      Lowest blood pressure captured during 3 minutes of standing
    • Lowest systolic BP (24-h) [ Time Frame: At each office visit, an expected average of 4-weeks ]
      Lowest blood pressure captured on 24-h ambulatory blood pressure monitoring
    • Worsening in orthostatic hypotension questionnaire scores [ Time Frame: At each office visit, an expected average of 4-weeks ]
      The orthostatic hypotension questionnaire was recently validated and consists of 10-items graded on an 11-point scale (0 to 10). Six items assess symptoms of neurogenic orthostatic hypotension and 4 address the impact they have on activities of daily living.
    • Frequency of symptoms noted in the patient's diary [ Time Frame: 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 [ Time Frame: At each office visit, an expected average of 4-weeks ]
      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) [ Time Frame: At each office visit, an expected average of 4-weeks ]
      The measurement of blood pressure variability based on the standard deviation that also takes into account the underlying level of BP.
    • Percent of systolic readings >140 mmHg in 24-h [ Time Frame: At each office visit, an expected average of 4-weeks ]
      Blood pressure excursions greater than 140 mmHg (systolic) captured on 24-h ambulatory blood pressure monitoring
    • Number of systolic readings >140 mmHg in 24-h [ Time Frame: At each office visit, an expected average of 4-weeks ]
      Blood pressure excursions greater than 140 mmHg (systolic) captured on 24-h ambulatory blood pressure monitoring
    • Maximum hypertensive peak produced by Stroop test (cognitive arousal) [ Time Frame: At each office visit, an expected average of 4-weeks ]
      Blood pressure responses to cognitive stress evaluated during the Stroop Word Color Test administered over 3 minutes.
    • Short-term beat-to-beat spontaneous standard deviation of BP (5-minutes) breathing spontaneous [ Time Frame: At each office visit, an expected average of 4-weeks ]
      Blood pressure will be measured using finger plethysmography and the arm supported at heart-level. Heart rate will be recorded from chest wall electrodes. Recordings will be made for 5-minutes while the patient is relaxed, calm and breathing spontaneously (pacing the breathing it impossible for most patients with FD to achieve). Baseline variability will be assessed using descriptive statistics (standard deviation, coefficient of variation).
    • Morning surge in systolic BP on awakening from sleep (24-h) [ Time Frame: At each office visit, an expected average of 4-weeks ]
      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
    
    
    

    Original Secondary Outcome: Same as current
    
    Information By: New York University School of Medicine
    

    Dates:
    Date Received: September 14, 2015
    Date Started: September 2015
    Date Completion: September 2018
    Last Updated: March 29, 2017
    Last Verified: March 2017