Carbidopa for the Treatment of Excessive Blood Pressure Variability

Phase 2

Completed

• Conditions: Dysautonomia, Familial; Baroreflex Failure Syndrome
• Interventions: Drug: Carbidopa High-Dose; Other: Placebo; Drug: Carbidopa Low-Dose

• Registration Number: NCT02553265
• Lead Sponsor: NYU Langone Health

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.

Basic Information
|
Recruitment & Eligibility
|
Study & Design
|
Trial Locations

Study Timeline

• Study Start: 2015-09
• Study First Submitted: 2015-09-14
• Study First Submitted QC: 2015-09-15
• Study First Posted: 2015-09-17
• Primary Completion: 2019-05-10
• Study Completion: 2019-05-10
• Results First Submitted: 2021-06-08
• Status Verified: 2022-01
• Results First Submitted QC: 2022-01-13
• Last Update Submitted: 2022-01-13
• Results First Posted: 2022-02-09
• Last Update Posted: 2022-02-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 22

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.

Read More

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.

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
High-Dose Carbidopa	Carbidopa High-Dose	-
Placebo	Placebo	Matching placebo
Low-Dose Carbidopa	Carbidopa Low-Dose	-

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Reported Adverse Events Related to Study Drug	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.
Average Systolic Blood Pressure Variability (Daytime)	up to Week 14	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	Day 1 of treatment period	Maximum blood pressure captured on 24-h ambulatory monitoring
Systolic Blood Pressure	up to Week 14	SBP measured in the seated position
Heart Rate	up to Week 14	Heart rate in the seated position
Number of Participants Who Displayed Clinical Significant Laboratory Values on CBC or Metabolic Panel	Up to 90 days	Clinically significant laboratory values include complete blood count (CMC) and metabolic panel related to treatment with carbidopa
Number of Participants With Significant Changes in Body Mass That Resulted in Discontinuation From the Study.	Up to 90 days	Body mass measured in kg
Number of Participants With Abnormal Electrocardiographic Interval Patterns	Up to 90 days	Clinically significant changes in the intervals of characteristic electrocardiographic patterns
Number of Participants Who Displayed Clinically Significant Values in Urine Safety Parameters	Up to 90 days	Clinically significant values on urinalysis, urine safety parameters related to treatment with carbidopa

Secondary Outcome Measures

Name	Time	Method
Severity of Hypotension During an Active Stand Test	up to Week 14	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	Up to 90 days
Frequency of Worsening Symptoms Noted in the Patient's Diary	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	up to Week 14	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)	up to Week 14	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)	up to Week 14	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

Trial Locations

Locations (2)

NYU Langone Medical Center, Dyautonomia Center, Suite 9Q; 🇺🇸 New York, New York, United States

NYU Medical Center; 🇺🇸 New York, New York, United States