Clinical trial NCT02553265: Carbidopa for the Treatment of Excessive Blood Pressure Variability
Official title: Carbidopa in Familial Dysautonomia: Phase-II Study, Investigational New Drug (IND) 117435, Date: 01/07/13
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Dysautonomia, Familial
Baroreflex Failure Syndrome
Keywords: Familial dysautonomia (HSAN III)
Norepinephrine
Sympathetic nervous system
Autonomic nervous system
Blood pressure variability
Hypertension
Carbidopa/Lodosyn
Afferent baroreflex failure
Clinical trial
Lead sponsor: NYU Langone Health
Sponsor class: OTHER
First posted: 2015-09-17
Enrollment: 22
Sex: ALL
Minimum age (years): 10
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants Who Reported Adverse Events Related to Study Drug
timeFrame: Up to 90 days
measure: Number of Participants With Significant Changes in Body Mass That Resulted in Discontinuation From the Study.
timeFrame: Up to 90 days
measure: Number of Participants With Abnormal Electrocardiographic Interval Patterns
timeFrame: Up to 90 days
measure: Average Systolic Blood Pressure Variability (Daytime)
timeFrame: up to Week 14
measure: Highest Systolic Blood Pressure
timeFrame: Day 1 of treatment period
measure: Systolic Blood Pressure
timeFrame: up to Week 14
measure: Heart Rate
timeFrame: up to Week 14
measure: Number of Participants Who Displayed Clinical Significant Laboratory Values on CBC or Metabolic Panel
timeFrame: Up to 90 days
measure: Number of Participants Who Displayed Clinically Significant Values in Urine Safety Parameters
timeFrame: Up to 90 days
Secondary outcomes:
measure: Severity of Hypotension During an Active Stand Test
timeFrame: up to Week 14
measure: Number of Participants Who Reported Worsening of OH Symptoms or Dropped Out Because of Worsening OH While on Active Study Drug
timeFrame: Up to 90 days
measure: Frequency of Worsening Symptoms Noted in the Patient's Diary
timeFrame: Up to 90 Days
measure: 24-h Urinary Norepinephrine Excretion
timeFrame: up to Week 14
measure: Coefficient of Systolic BP Variability (Daytime)
timeFrame: up to Week 14
measure: Morning Surge in Systolic BP on Awakening From Sleep (24-h)
timeFrame: up to Week 14
Other outcomes:
Locations:
city: New York
country: United States
facility: NYU Langone Medical Center, Dyautonomia Center, Suite 9Q
state: New York
city: New York
country: United States
facility: NYU Medical Center
state: New York
Study officials:
affiliation: NYU School of Medicine
name: Horacio C Kaufmann, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NYU School of Medicine
name: Lucy J Norcliffe-Kaufmann, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.