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

Primary Purpose

Dysautonomia, Familial, Baroreflex Failure Syndrome

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Carbidopa Low-Dose
Placebo
Carbidopa High-Dose
Sponsored by
NYU Langone Health
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Dysautonomia, Familial focused on measuring Familial dysautonomia (HSAN III), Norepinephrine, Sympathetic nervous system, Autonomic nervous system, Blood pressure variability, Hypertension, Carbidopa/Lodosyn, Afferent baroreflex failure, Clinical trial

Eligibility Criteria

10 Years - 60 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • NYU Langone Medical Center, Dyautonomia Center, Suite 9Q
  • NYU Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Experimental

Active Comparator

Arm Label

Placebo

Low-Dose Carbidopa

High-Dose Carbidopa

Arm Description

Matching placebo

Outcomes

Primary Outcome Measures

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.
Number of Participants With Significant Changes in Body Mass That Resulted in Discontinuation From the Study.
Body mass measured in kg
Number of Participants With Abnormal Electrocardiographic Interval Patterns
Clinically significant changes in the intervals of characteristic electrocardiographic patterns
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
Highest Systolic Blood Pressure
Maximum blood pressure captured on 24-h ambulatory monitoring
Systolic Blood Pressure
SBP measured in the seated position
Heart Rate
Heart rate in the seated position
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
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

Secondary Outcome Measures

Severity of Hypotension During an Active Stand Test
Lowest blood pressure captured during 3 minutes of standing
Number of Participants Who Reported Worsening of OH Symptoms or Dropped Out Because of Worsening OH While on Active Study Drug
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.
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.
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.
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

Full Information

First Posted
September 14, 2015
Last Updated
January 13, 2022
Sponsor
NYU Langone Health
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1. Study Identification

Unique Protocol Identification Number
NCT02553265
Brief Title
Carbidopa for the Treatment of Excessive Blood Pressure Variability
Acronym
CarbiFD
Official Title
Carbidopa in Familial Dysautonomia: Phase-II Study, Investigational New Drug (IND) 117435, Date: 01/07/13
Study Type
Interventional

2. Study Status

Record Verification Date
January 2022
Overall Recruitment Status
Completed
Study Start Date
September 2015 (undefined)
Primary Completion Date
May 10, 2019 (Actual)
Study Completion Date
May 10, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
NYU Langone Health

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
22 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Matching placebo
Arm Title
Low-Dose Carbidopa
Arm Type
Experimental
Arm Title
High-Dose Carbidopa
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Carbidopa Low-Dose
Other Intervention Name(s)
Lodosyn ®, DL-α-methyl-α-hydrazino-3, 4-dihydroxyphenyl-propionic acid, HMD, MK-486
Intervention Description
300 mg/day
Intervention Type
Other
Intervention Name(s)
Placebo
Other Intervention Name(s)
Placebo control pill
Intervention Description
A placebo containing an inert substance, in capsule form that does not contain an active drug ingredient.
Intervention Type
Drug
Intervention Name(s)
Carbidopa High-Dose
Other Intervention Name(s)
Lodosyn ®, DL-α-methyl-α-hydrazino-3, 4-dihydroxyphenyl-propionic acid, HMD, MK-486
Intervention Description
600 mg/day
Primary Outcome Measure Information:
Title
Number of Participants Who Reported Adverse Events Related to Study Drug
Description
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.
Time Frame
Up to 90 days
Title
Number of Participants With Significant Changes in Body Mass That Resulted in Discontinuation From the Study.
Description
Body mass measured in kg
Time Frame
Up to 90 days
Title
Number of Participants With Abnormal Electrocardiographic Interval Patterns
Description
Clinically significant changes in the intervals of characteristic electrocardiographic patterns
Time Frame
Up to 90 days
Title
Average Systolic Blood Pressure Variability (Daytime)
Description
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
Time Frame
up to Week 14
Title
Highest Systolic Blood Pressure
Description
Maximum blood pressure captured on 24-h ambulatory monitoring
Time Frame
Day 1 of treatment period
Title
Systolic Blood Pressure
Description
SBP measured in the seated position
Time Frame
up to Week 14
Title
Heart Rate
Description
Heart rate in the seated position
Time Frame
up to Week 14
Title
Number of Participants Who Displayed Clinical Significant Laboratory Values on CBC or Metabolic Panel
Description
Clinically significant laboratory values include complete blood count (CMC) and metabolic panel related to treatment with carbidopa
Time Frame
Up to 90 days
Title
Number of Participants Who Displayed Clinically Significant Values in Urine Safety Parameters
Description
Clinically significant values on urinalysis, urine safety parameters related to treatment with carbidopa
Time Frame
Up to 90 days
Secondary Outcome Measure Information:
Title
Severity of Hypotension During an Active Stand Test
Description
Lowest blood pressure captured during 3 minutes of standing
Time Frame
up to Week 14
Title
Number of Participants Who Reported Worsening of OH Symptoms or Dropped Out Because of Worsening OH While on Active Study Drug
Time Frame
Up to 90 days
Title
Frequency of Worsening Symptoms Noted in the Patient's Diary
Description
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.
Time Frame
Up to 90 Days
Title
24-h Urinary Norepinephrine Excretion
Description
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.
Time Frame
up to Week 14
Title
Coefficient of Systolic BP Variability (Daytime)
Description
The measurement of blood pressure variability based on the standard deviation that also takes into account the underlying level of BP.
Time Frame
up to Week 14
Title
Morning Surge in Systolic BP on Awakening From Sleep (24-h)
Description
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
Time Frame
up to Week 14

10. Eligibility

Sex
All
Minimum Age & Unit of Time
10 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Horacio C Kaufmann, MD
Organizational Affiliation
NYU School of Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Lucy J Norcliffe-Kaufmann, PhD
Organizational Affiliation
NYU School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
NYU Langone Medical Center, Dyautonomia Center, Suite 9Q
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
NYU Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
23553478
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.
Results Reference
background
PubMed Identifier
22739220
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.
Results Reference
background
PubMed Identifier
22129610
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.
Results Reference
background
PubMed Identifier
22045363
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.
Results Reference
background
PubMed Identifier
21098405
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.
Results Reference
background
PubMed Identifier
25323828
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.
Results Reference
background
Links:
URL
http://dysautonomiacenter.com
Description
Clinical Research Updates from the Dysautonomia Center
URL
http://med.nyu.edu/neurology/dysautonomia-center
Description
New York University (NYU) Dysautonomia Center Research Site
URL
http://nyulangone.org/conditions/familial-dysautonomia
Description
Familial dysautonomia medical information
URL
http://familialdysautonomia.org/
Description
Patient Advocacy Group

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Carbidopa for the Treatment of Excessive Blood Pressure Variability

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