Carbidopa for the Treatment of Excessive Blood Pressure Variability (CarbiFD)

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

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.

Study Overview

• Status: Completed
• Conditions: Dysautonomia, Familial; Baroreflex Failure Syndrome
• Intervention / Treatment: Other: Placebo; Drug: Carbidopa Low-Dose; Drug: Carbidopa High-Dose

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10016
      • NYU Medical Center
    • New York, New York, United States, 10016
      • NYU Langone Medical Center, Dyautonomia Center, Suite 9Q

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 60 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Investigators: Principal Investigator: Horacio C Kaufmann, MD, NYU School of Medicine; Principal Investigator: Lucy J Norcliffe-Kaufmann, PhD, NYU School of Medicine

Publications and helpful links

General Publications

• 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, 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.
• 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.

Helpful Links

• Clinical Research Updates from the Dysautonomia Center
• New York University (NYU) Dysautonomia Center Research Site
• Familial dysautonomia medical information
• Patient Advocacy Group

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Actual): May 10, 2019
• Study Completion (Actual): May 10, 2019

Study Registration Dates

• First Submitted: September 14, 2015
• First Submitted That Met QC Criteria: September 15, 2015
• First Posted (Estimate): September 17, 2015

Study Record Updates

• Last Update Posted (Actual): February 9, 2022
• Last Update Submitted That Met QC Criteria: January 13, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Hypertension; Autonomic nervous system; Clinical trial; Norepinephrine; Blood pressure variability; Sympathetic nervous system; Familial dysautonomia (HSAN III); Carbidopa/Lodosyn; Afferent baroreflex failure
• Additional Relevant MeSH Terms: Nervous System Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Nervous System Malformations; Polyneuropathies; Hereditary Sensory and Autonomic Neuropathies; Primary Dysautonomias; Autonomic Nervous System Diseases; Dysautonomia, Familial; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Dopamine Agents; Antiparkinson Agents; Anti-Dyskinesia Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Carbidopa
• Other Study ID Numbers: 13-00065; FD-R-004772 (Other Grant/Funding Number: FDA)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No