Carbidopa for the Treatment of Excessive Blood Pressure Variability

NCT02553265 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 13-00065FD-R-004772
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 2

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.

Conditions

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

Outcome Measures

Primary Outcomes (9)

• 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 Outcomes (6)

• 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

Study Arms (3)

Placebo

PLACEBO COMPARATOR

Matching placebo

Other: Placebo

Low-Dose Carbidopa

EXPERIMENTAL

Drug: Carbidopa Low-Dose

High-Dose Carbidopa

ACTIVE COMPARATOR

Drug: Carbidopa High-Dose

Interventions

Carbidopa Low-Dose DRUG

300 mg/day

Also known as: Lodosyn ®, DL-α-methyl-α-hydrazino-3, 4-dihydroxyphenyl-propionic acid, HMD, MK-486

Low-Dose Carbidopa

Placebo OTHER

A placebo containing an inert substance, in capsule form that does not contain an active drug ingredient.

Also known as: Placebo control pill

Placebo

Carbidopa High-Dose DRUG

600 mg/day

Also known as: Lodosyn ®, DL-α-methyl-α-hydrazino-3, 4-dihydroxyphenyl-propionic acid, HMD, MK-486

High-Dose Carbidopa

Eligibility Criteria

• Age: 10 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• NYU Langone Health: lead

Study Sites (2)

NYU Langone Medical Center, Dyautonomia Center, Suite 9Q

New York, New York, 10016, United States

Location

NYU Medical Center

New York, New York, 10016, United States

Location

Related Publications (6)

• 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.

  PMID: 23553478 BACKGROUND

• 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.

  PMID: 22739220 BACKGROUND

• 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.

  PMID: 22129610 BACKGROUND

• 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.

  PMID: 22045363 BACKGROUND

• 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.

  PMID: 21098405 BACKGROUND

• 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.

  PMID: 25323828 BACKGROUND

Related Links

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

MeSH Terms

Conditions

Dysautonomia, Familial; Hypertension

Interventions

Carbidopa; Oxymetholone

Condition Hierarchy (Ancestors)

Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Hereditary Sensory and Autonomic Neuropathies; Nervous System Malformations; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Methyldopa; Dihydroxyphenylalanine; Catecholamines; Amines; Organic Chemicals; Hydrazines; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Androstanols; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Horacio C Kaufmann, MD
• Organization: NYU Langone Health

Horacio.Kaufmann@nyulangone.org

212-263-7225

Study Officials

• Horacio C Kaufmann, MD

  NYU School of Medicine

  PRINCIPAL INVESTIGATOR

• Lucy J Norcliffe-Kaufmann, PhD

  NYU School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 14, 2015
• First Posted: September 17, 2015
• Study Start: September 1, 2015
• Primary Completion: May 10, 2019
• Study Completion: May 10, 2019
• Last Updated: February 9, 2022
• Results First Posted: February 9, 2022

Record last verified: 2022-01

Locations

US (2)