Carbidopa for the Treatment of Excessive Blood Pressure Variability

Overview

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.

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

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: May 10, 2019

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

  • Drug: Carbidopa Low Dose
  • Other: Placebo
    • A placebo containing an inert substance, in capsule form that does not contain an active drug ingredient.
  • Drug: Carbidopa High Dose

Arms, Groups and Cohorts

  • Active Comparator: Placebo, Low Dose Carbidopa, High Dose Carbidopa
    • 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.
  • Active Comparator: High Dose Carbidopa, Placebo, High Dose Carbidopa
    • 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.
  • Active Comparator: 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.

Clinical Trial Outcome Measures

Primary Measures

  • 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
  • Vital signs
    • Time Frame: At each office visit, or at home via video conferences an expected average of 4-weeks
    • Blood pressure in the seated position
  • Vital signs
    • Time Frame: At each office visit or at home via Fitbit an expected average of 4-weeks
    • Heart rate in the seated position
  • Laboratory safety values (blood)
    • Time Frame: At each office visit, an expected average of 4-weeks
    • Clinically significant laboratory values on complete blood count and metabolic panel
  • Laboratory safety values (urine)
    • Time Frame: At each office visit, an expected average of 4-weeks
    • Clinically significant values on urinalysis

Secondary Measures

  • 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

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 10 Years

Maximum Age: 60 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • NYU Langone Health
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Horacio C Kaufmann, MD, Principal Investigator, NYU School of Medicine
    • Lucy J Norcliffe-Kaufmann, PhD, Principal Investigator, NYU School of Medicine

References

Norcliffe-Kaufmann L, Martinez J, Axelrod F, Kaufmann H. Hyperdopaminergic crises in familial dysautonomia: a randomized trial of carbidopa. Neurology. 2013 Apr 23;80(17):1611-7. doi: 10.1212/WNL.0b013e31828f18f0. Epub 2013 Apr 3.

Norcliffe-Kaufmann LJ, Axelrod FB, Kaufmann H. Cyclic vomiting associated with excessive dopamine in Riley-day syndrome. J Clin Gastroenterol. 2013 Feb;47(2):136-8. doi: 10.1097/MCG.0b013e3182582cbf.

Norcliffe-Kaufmann L, Axelrod FB, Kaufmann H. Developmental abnormalities, blood pressure variability and renal disease in Riley Day syndrome. J Hum Hypertens. 2013 Jan;27(1):51-5. doi: 10.1038/jhh.2011.107. Epub 2011 Dec 1.

Kaufmann H, Malamut R, Norcliffe-Kaufmann L, Rosa K, Freeman R. The Orthostatic Hypotension Questionnaire (OHQ): validation of a novel symptom assessment scale. Clin Auton Res. 2012 Apr;22(2):79-90. doi: 10.1007/s10286-011-0146-2. Epub 2011 Nov 2.

Norcliffe-Kaufmann L, Axelrod F, Kaufmann H. Afferent baroreflex failure in familial dysautonomia. Neurology. 2010 Nov 23;75(21):1904-11. doi: 10.1212/WNL.0b013e3181feb283.

Palma JA, Norcliffe-Kaufmann L, Fuente-Mora C, Percival L, Mendoza-Santiesteban C, Kaufmann H. Current treatments in familial dysautonomia. Expert Opin Pharmacother. 2014 Dec;15(18):2653-71. doi: 10.1517/14656566.2014.970530. Epub 2014 Oct 17. Review.

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