Carbidopa in Familial Dysautonomia: Phase-II Study, Investigational New Drug (IND) 117435, Date: 01/07/13
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- NYU Langone Health
- Enrollment
- 22
- Locations
- 2
- Primary Endpoint
- Number of Participants Who Reported Adverse Events Related to Study Drug
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 10 Years to 60 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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.
Arms & Interventions
Placebo
Matching placebo
Intervention: Placebo (Other)
Low-Dose Carbidopa
Intervention: Carbidopa Low-Dose (Drug)
High-Dose Carbidopa
Intervention: Carbidopa High-Dose (Drug)
Outcomes
Primary Outcomes
Number of Participants Who Reported Adverse Events Related to Study Drug
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.
Average Systolic Blood Pressure Variability (Daytime)
Time Frame: 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
Time Frame: Day 1 of treatment period
Maximum blood pressure captured on 24-h ambulatory monitoring
Systolic Blood Pressure
Time Frame: up to Week 14
SBP measured in the seated position
Heart Rate
Time Frame: up to Week 14
Heart rate in the seated position
Number of Participants Who Displayed Clinical Significant Laboratory Values on CBC or Metabolic Panel
Time Frame: 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.
Time Frame: Up to 90 days
Body mass measured in kg
Number of Participants With Abnormal Electrocardiographic Interval Patterns
Time Frame: 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
Time Frame: Up to 90 days
Clinically significant values on urinalysis, urine safety parameters related to treatment with carbidopa
Secondary Outcomes
- Severity of Hypotension During an Active Stand Test(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(Up to 90 Days)
- 24-h Urinary Norepinephrine Excretion(up to Week 14)
- Coefficient of Systolic BP Variability (Daytime)(up to Week 14)
- Morning Surge in Systolic BP on Awakening From Sleep (24-h)(up to Week 14)