The Effects Of Bronchodilator Therapy On Respiratory And Autonomic Function In Patients With Familial Dysautonomia

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by New York University School of Medicine
Sponsor:
Information provided by (Responsible Party):
Horacio Kaufmann, New York University School of Medicine
ClinicalTrials.gov Identifier:
NCT01987219
First received: November 5, 2013
Last updated: November 12, 2013
Last verified: November 2013
  Purpose

Evaluate the effects of bronchodilator therapy on respiratory function. Our overall goal is to determine whether, in patients with familial dysautonomia (FD), there is a component of airway obstruction that is reversible. To this end, we will evaluate airway resistance before and after receiving the anti-cholinergic ipratropium (Atrovent ®) and the beta-2-agonist albuterol (ProVentil®/Ventolin®). We predict that the response to either drug will depend on the underlying level of sympathetic and parasympathetic activity and airway tone. We will then determine the cardiovascular effects of inhaled ipratropium and albuterol in patients with FD. Because patients with FD have fewer sympathetic neurons and denervation supersenstivity, we predict that following albuterol inhalation, there will be non-selective activation of alpha-1-adrenergic receptors. Furthermore, because of a congenital defect in the afferent baroreceptor neurons that sense blood pressure, we suspect that the resulting vasoconstriction will be unopposed leading to a pressor effect. We hypothesize that inhalation of the anti-cholinergic ipratopium will produce little rise in heart rate, due to the extent of parasympathetic denervation to the heart.


Condition Intervention Phase
Respiratory Disease in Familial Dysautonomia
Drug: Albuterol-sulphate
Drug: Ipratropium-bromide
Other: placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: THE EFFECTS OF BRONCHODILATOR THERAPY ON RESPIRATORY AND AUTONOMIC FUNCTION IN PATIENTS WITH FAMILIAL DYSAUTONOMIA

Resource links provided by NLM:


Further study details as provided by New York University School of Medicine:

Primary Outcome Measures:
  • respiratory Function (airway resistance, R5HZ) [ Time Frame: Pre and 30 minutes post study drug administration ] [ Designated as safety issue: No ]
    Our overall goal is to evaluate whether there is a component of airway obstruction that is reversible. To address this goal, we will compare the effects of a short acting, inhaled beta-2-adrenergic receptor agonist (albuterol) and an antagonist of acetylcholine (ipratropium) on airway resistance. Using pulse oscillometry, we will compare airway resistance before and after the brochodilators are administered. The variables that measure airway resistance are R5HZ and R20HZ.

  • respiratory function (airway resistance, R20HZ) [ Time Frame: Pre and 30 minutes post study drug administration ] [ Designated as safety issue: No ]
    Our overall goal is to evaluate whether there is a component of airway obstruction that is reversible. To address this goal, we will compare the effects of a short acting, inhaled beta-2-adrenergic receptor agonist (albuterol) and an antagonist of acetylcholine (ipratropium) on airway resistance. Using pulse oscillometry, we will compare airway resistance before and after the brochodilators are administered. The variables that measure airway resistance are R5HZ and R20HZ.


Secondary Outcome Measures:
  • Cardiac function (blood pressure) [ Time Frame: Pre and 30 post study drug admistration ] [ Designated as safety issue: No ]
    Our second aim is to evaluate the effects of both bronchodilators on cardiovascular function. Relative change in BP ,RR intervals and CO from baseline after receiving albuterol or ipratropium will be calculated.

  • RR interval [ Time Frame: pre and 30 minutes post intervention ] [ Designated as safety issue: No ]
    Our second aim is to evaluate the effects of both bronchodilators on cardiovascular function. Relative change in BP ,RR intervals and CO from baseline after receiving albuterol or ipratropium will be calculated.

  • Cardiac Output (CO) [ Time Frame: pre and post 30 minutes intervention ] [ Designated as safety issue: No ]
    Our second aim is to evaluate the effects of both bronchodilators on cardiovascular function. Relative change in BP ,RR intervals and CO from baseline after receiving albuterol or ipratropium will be calculated.


Estimated Enrollment: 12
Study Start Date: March 2013
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Albuterol-sulphate
Albuterol-sulphate (Proventil ®) Beta-2-adrenergic agonist 2.5 mg 3 cc inhalation Peak effect 15 - 30 mins. Mean duration of effect 3 hours
Drug: Albuterol-sulphate
Beta-2-adrenergic agonist 2.5 mg 3 cc inhalation Peak effect 15 - 30 mins. Mean duration of effect 3 hours
Other Name: (Proventil ®)
Active Comparator: Ipratropium-bromide (Atrovent ®)
IpratroAnti-cholinergic(Atrovent ®) 500 mcg 3 cc inhalation Peak effect 30 - 90 mins. Duration of effect 2 - 4 hours.pium-bromide
Drug: Ipratropium-bromide
Anti-cholinergic 500 mcg 3 cc inhalation Peak effect 30 - 90 mins. Duration of effect 2 - 4 hours.
Other Name: (Atrovent ®)
Placebo Comparator: Placebo
Placebo Saline solution 3 cc NA
Other: placebo
Saline solution 3 cc NA

Detailed Description:

Familial dysautonomia (FD) is a rare fatal autosomal recessive disease caused by a deficiency of the protein IKAP.1 This results in a selective developmental defect that affects mostly afferent (sensory) neurons including those in the dorsal root ganglia and cranial nerves.2, 3 We have shown recently that the protein deficiency impairs the development of afferent baroreceptor pathways, leaving the sympathetic efferent neurons reduced in number but functionally active. This results in the complete failure to detect and buffer fluctuations in blood pressure leading to volatile hypertension. In addition to the afferent baroreflex pathways, the deficiency of IKAP during embroyogenesis also affects the function of the chemoreflex pathways. As a result, patients fail to increase ventilation adequately in response to hypoxia and hypercapnia.4 As well as the impairment of the neurological mechanisms that regulate breathing, patients with FD also have a combination of obstructive, restrictive and probably also neuromuscular lung disease. Failure to coordinate swallowing results in recurrent bouts of aspiration pneumonia occurring from birth.5, 6 Imaging studies show that almost all patients with FD have bronchial wall thickening, atelectasis and almost 30% have bronchiectasis7. Pulmonary function tests show air flow limitation and associated lung restriction with reduction in diffusion capacity12. Sudden attacks of asthma like wheezing are common 8 and frequently associated with emotional upset,5 a time when sympathetic outflow to the vasculature is increased heightened.3 There is also a component of restrictive lung disease, with a very high incidence of scoliosis, which frequently begins at an early age. Complicating matters further, many patients opt to undergo spine fusion surgery, 9 which could potentially worsen further chest wall compliance.10 Patients with FD also lack muscle spindles, 2 making it likely that they have neuromuscular abnormalities arising from the absence of proprioceptive feedback from the respiratory muscles involved in the coordination of breathing.

Severe respiratory disease is a leading cause of death in patients with FD and many are treated empirically with inhaled bronchodilators. It is not known, however, whether these drugs are effective at reversing increased airway resistance. Hence, there is an urgent need to understand if the short acting beta-2-adrenergic agonist albuterol and the anticholinergic ipratropium, are effective bronchodilators. Furthermore, because treatment with these agents has potential cardiovascular side effects, we will also analyze their effects on blood pressure, heart rate and cardiac output.

  Eligibility

Ages Eligible for Study:   12 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 1. Diagnosis of familial dysautonomia (Riley-Day syndrome, hereditary sensory and autonomic neuropathy type III) 2. Ages 12 and older: Bronchodilators are routinely used in young children with FD therefore they should be included in this study. The spirometry maneuver is highly dependent on patient cooperation and effort, and FD patients already have limitations that make the spirometry maneuver more problematic to perform such as difficulty with mouth closure and drooling. Therefore, we believe age 12 is a suitable age for FD patients to be included in this study, though in the general population reliable results can be obtained from the age of 6 and sometimes even younger.

    3. Patients using Albuterol or Ipratroprium will be included in the study but will be instructed not to take the 24 hours prior to the testing. It is a common practice in clinical medicine to withhold the inhalation drugs prior to performing pulmonary function tests in order to evaluate the response to bronchodilators, an integral part of the test. Patients with an acute respiratory exacerbation will not be enrolled, as withholding bronchodilators would not be advisable.

    4. Patients who are taking medications that might affect autonomic function such as anti-hypertensives, beta-blockers, midodrine and florinef will be included in the study and we will record current medication regimen and the time the medication was taken.

Exclusion Criteria:

- 1. Patients who last used inhaled anti-cholinergics or beta-2-agonists within 4-half lives of the drug.

2. Patients with an acute respiratory illness 3. Patients who have had lobectomies. 4. Patients using oxygen therapy throughout the day. 5. Patients who are unable to comply with the study requirements.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01987219

Locations
United States, New York
NYU Medical Center Recruiting
New York, New York, United States, 10016
Contact: Jose Martinez, MA    212-263-7225    jose.martinez@nyumc.org   
Principal Investigator: Horacio Kaufmann, MD         
Sponsors and Collaborators
New York University School of Medicine
  More Information

No publications provided

Responsible Party: Horacio Kaufmann, Professor of Neurology, New York University School of Medicine
ClinicalTrials.gov Identifier: NCT01987219     History of Changes
Other Study ID Numbers: S13-00004
Study First Received: November 5, 2013
Last Updated: November 12, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by New York University School of Medicine:
familial dysautonomia

Additional relevant MeSH terms:
Dysautonomia, Familial
Autonomic Nervous System Diseases
Primary Dysautonomias
Respiration Disorders
Respiratory Tract Diseases
Autoimmune Diseases
Autoimmune Diseases of the Nervous System
Congenital Abnormalities
Demyelinating Diseases
Genetic Diseases, Inborn
Hereditary Sensory and Autonomic Neuropathies
Heredodegenerative Disorders, Nervous System
Immune System Diseases
Nervous System Diseases
Nervous System Malformations
Neurodegenerative Diseases
Neuromuscular Diseases
Peripheral Nervous System Diseases
Polyneuropathies
Polyradiculoneuropathy
Adrenergic Agonists
Albuterol
Bromides
Bronchodilator Agents
Ipratropium
Adrenergic Agents
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Anti-Asthmatic Agents
Anticonvulsants

ClinicalTrials.gov processed this record on October 29, 2014