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Trial record 14 of 88 for:    "Neuromuscular Disease" | "Norepinephrine"

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

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ClinicalTrials.gov Identifier: NCT02553265
Recruitment Status : Completed
First Posted : September 17, 2015
Last Update Posted : September 12, 2019
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Dysautonomia, Familial Baroreflex Failure Syndrome Drug: Carbidopa Low Dose Other: Placebo Drug: Carbidopa High Dose Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Carbidopa in Familial Dysautonomia: Phase-II Study, Investigational New Drug (IND) 117435, Date: 01/07/13
Study Start Date : September 2015
Actual Primary Completion Date : May 10, 2019
Actual Study Completion Date : May 10, 2019


Arm Intervention/treatment
Active Comparator: Placebo, Low Dose Carbidopa, High Dose Carbidopa
This is a 14-week study. Patients will receive, in random order, high dose carbidopa (600mg/day), low dose carbidopa (300 mg/day) or placebo. Between each crossover, there will be a titration down over 2-days followed by a 2-day washout.
Drug: Carbidopa Low Dose
Other Name: Lodosyn ®, DL-α-methyl-α-hydrazino-3, 4-dihydroxyphenyl-propionic acid, HMD, MK-486

Other: Placebo
A placebo containing an inert substance, in capsule form that does not contain an active drug ingredient.
Other Name: Placebo control pill

Drug: Carbidopa High Dose
Other Name: Lodosyn ®, DL-α-methyl-α-hydrazino-3, 4-dihydroxyphenyl-propionic acid, HMD, MK-486

Active Comparator: High Dose Carbidopa, Placebo, High Dose Carbidopa
This is a 14-week study. Patients will receive, in random order, high dose carbidopa (600mg/day), low dose carbidopa (300 mg/day) or placebo. Between each crossover, there will be a titration down over 2-days followed by a 2-day washout.
Drug: Carbidopa Low Dose
Other Name: Lodosyn ®, DL-α-methyl-α-hydrazino-3, 4-dihydroxyphenyl-propionic acid, HMD, MK-486

Other: Placebo
A placebo containing an inert substance, in capsule form that does not contain an active drug ingredient.
Other Name: Placebo control pill

Drug: Carbidopa High Dose
Other Name: Lodosyn ®, DL-α-methyl-α-hydrazino-3, 4-dihydroxyphenyl-propionic acid, HMD, MK-486

Active Comparator: Low Dose Carbidopa, High Dose Carbidopa, Placebo
This is a 14-week study. Patients will receive, in random order, high dose carbidopa (600mg/day), low dose carbidopa (300 mg/day) or placebo. Between each crossover, there will be a titration down over 2-days followed by a 2-day washout.
Drug: Carbidopa Low Dose
Other Name: Lodosyn ®, DL-α-methyl-α-hydrazino-3, 4-dihydroxyphenyl-propionic acid, HMD, MK-486

Other: Placebo
A placebo containing an inert substance, in capsule form that does not contain an active drug ingredient.
Other Name: Placebo control pill

Drug: Carbidopa High Dose
Other Name: Lodosyn ®, DL-α-methyl-α-hydrazino-3, 4-dihydroxyphenyl-propionic acid, HMD, MK-486




Primary Outcome Measures :
  1. Adverse Events [ 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.

  2. Weight [ Time Frame: At each office visit, an expected average of 4-weeks ]
    Body mass measured in kg

  3. Number of patients with abnormal electrocardiographic interval patterns [ Time Frame: At each office visit, or at local an expected average of 4-weeks ]
    Clinically significant changes in the intervals of characteristic electrocardiographic patterns

  4. Standard deviation of systolic blood pressure variability (daytime) [ Time Frame: At each office visit, or at home measurements, via video conference,an expected average of 4-weeks ]
    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

  5. Highest systolic blood pressure [ Time Frame: At each office visit, or at home measurements, via video conference, an expected average of 4-weeks ]
    Maximum blood pressure captured on 24-h ambulatory monitoring

  6. Vital signs [ Time Frame: At each office visit, or at home via video conferences an expected average of 4-weeks ]
    Blood pressure in the seated position

  7. Vital signs [ Time Frame: At each office visit or at home via Fitbit an expected average of 4-weeks ]
    Heart rate in the seated position

  8. Laboratory safety values (blood) [ Time Frame: At each office visit, an expected average of 4-weeks ]
    Clinically significant laboratory values on complete blood count and metabolic panel

  9. Laboratory safety values (urine) [ Time Frame: At each office visit, an expected average of 4-weeks ]
    Clinically significant values on urinalysis


Secondary Outcome Measures :
  1. Number of subjects who discontinue the study [ Time Frame: Up to 90 days ]
    Patients that dropout of the study

  2. Number of subjects who discontinue the study due to adverse events [ Time Frame: Up to 90 days ]
    Patients that dropout of the study due to an adverse event (a change in a patient's baseline condition including intercurrent illnesses irrespective of the relationship to carbidopa treatment)

  3. Severity of hypotension during an active stand test [ Time Frame: At each office visit, an expected average of 4-weeks ]
    Lowest blood pressure captured during 3 minutes of standing

  4. Lowest systolic BP (24-h) [ Time Frame: At each office visit, an expected average of 4-weeks ]
    Lowest blood pressure captured on 24-h ambulatory blood pressure monitoring

  5. Worsening in orthostatic hypotension questionnaire scores [ Time Frame: At each office visit, an expected average of 4-weeks ]
    The orthostatic hypotension questionnaire was recently validated and consists of 10-items graded on an 11-point scale (0 to 10). Six items assess symptoms of neurogenic orthostatic hypotension and 4 address the impact they have on activities of daily living.

  6. Frequency of symptoms noted in the patient's diary [ Time Frame: 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.

  7. 24-h Urinary norepinephrine excretion [ Time Frame: At each office visit, an expected average of 4-weeks ]
    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.

  8. Coefficient of systolic BP variability (daytime) [ Time Frame: At each office visit, an expected average of 4-weeks ]
    The measurement of blood pressure variability based on the standard deviation that also takes into account the underlying level of BP.

  9. Percent of systolic readings >140 mmHg in 24-h [ Time Frame: At each office visit, an expected average of 4-weeks ]
    Blood pressure excursions greater than 140 mmHg (systolic) captured on 24-h ambulatory blood pressure monitoring

  10. Number of systolic readings >140 mmHg in 24-h [ Time Frame: At each office visit, an expected average of 4-weeks ]
    Blood pressure excursions greater than 140 mmHg (systolic) captured on 24-h ambulatory blood pressure monitoring

  11. Maximum hypertensive peak produced by Stroop test (cognitive arousal) [ Time Frame: At each office visit, an expected average of 4-weeks ]
    Blood pressure responses to cognitive stress evaluated during the Stroop Word Color Test administered over 3 minutes.

  12. Short-term beat-to-beat spontaneous standard deviation of BP (5-minutes) breathing spontaneous [ Time Frame: At each office visit, an expected average of 4-weeks ]
    Blood pressure will be measured using finger plethysmography and the arm supported at heart-level. Heart rate will be recorded from chest wall electrodes. Recordings will be made for 5-minutes while the patient is relaxed, calm and breathing spontaneously (pacing the breathing it impossible for most patients with FD to achieve). Baseline variability will be assessed using descriptive statistics (standard deviation, coefficient of variation).

  13. Morning surge in systolic BP on awakening from sleep (24-h) [ Time Frame: At each office visit, an expected average of 4-weeks ]
    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



Information from the National Library of Medicine

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Ages Eligible for Study:   10 Years to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02553265


Locations
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United States, New York
NYU Langone Medical Center, Dyautonomia Center, Suite 9Q
New York, New York, United States, 10016
NYU Medical Center
New York, New York, United States, 10016
Sponsors and Collaborators
NYU Langone Health
Investigators
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Principal Investigator: Horacio C Kaufmann, MD NYU School of Medicine
Principal Investigator: Lucy J Norcliffe-Kaufmann, PhD NYU School of Medicine

Additional Information:
Publications:
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Responsible Party: NYU Langone Health
ClinicalTrials.gov Identifier: NCT02553265     History of Changes
Other Study ID Numbers: 13-00065
FD-R-004772 ( Other Grant/Funding Number: FDA )
First Posted: September 17, 2015    Key Record Dates
Last Update Posted: September 12, 2019
Last Verified: September 2019
Keywords provided by NYU Langone Health:
Familial dysautonomia (HSAN III)
Norepinephrine
Sympathetic nervous system
Autonomic nervous system
Blood pressure variability
Hypertension
Carbidopa/Lodosyn
Afferent baroreflex failure
Clinical trial
Additional relevant MeSH terms:
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Neuromuscular Diseases
Primary Dysautonomias
Autonomic Nervous System Diseases
Dysautonomia, Familial
Nervous System Diseases
Hereditary Sensory and Autonomic Neuropathies
Nervous System Malformations
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Polyneuropathies
Peripheral Nervous System Diseases
Congenital Abnormalities
Genetic Diseases, Inborn
Carbidopa
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Aromatic Amino Acid Decarboxylase Inhibitors
Enzyme Inhibitors