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

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ClinicalTrials.gov Identifier: NCT01987219
Recruitment Status : Completed
First Posted : November 19, 2013
Results First Posted : June 2, 2016
Last Update Posted : June 2, 2016
Sponsor:
Information provided by (Responsible Party):
NYU Langone Health

Tracking Information
First Submitted Date  ICMJE November 5, 2013
First Posted Date  ICMJE November 19, 2013
Results First Submitted Date  ICMJE March 14, 2016
Results First Posted Date  ICMJE June 2, 2016
Last Update Posted Date June 2, 2016
Study Start Date  ICMJE March 2013
Actual Primary Completion Date December 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 26, 2016)
  • Change From Baseline of Forced Vital Capacity [ Time Frame: Pre and 30 minutes post study drug administration ]
    FVC is a measure of the amount of air exhaled, and is measured in liters of air per second. The percentage in the change in the amount of air exhaled from baseline, measured in liters of air per second. Increase in the percentage of air exhaled from baseline indicates improvement in respiratory function.
  • Change in Respiratory Function (Airway Resistance at 5 Hz) From Baseline [ Time Frame: Pre and 30 minutes post study drug administration ]
    The percentage change in respiratory function from baseline is measured in percentage change in Resistance, kPa/(L/s).
Original Primary Outcome Measures  ICMJE
 (submitted: November 12, 2013)
  • respiratory Function (airway resistance, R5HZ) [ Time Frame: Pre and 30 minutes post study drug administration ]
    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 ]
    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.
Change History Complete list of historical versions of study NCT01987219 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 26, 2016)
  • Change in Forced Expiratory Volume (FEV) From Baseline [ Time Frame: Pre and 30 post study drug admistration ]
    Forced expiratory volume is measured in liters of air per second. FEV was measured during the first second of exhalation.
  • Change in Forced Expiratory Flow Between 25-75% (FEF25-75) [ Time Frame: pre and 30 minutes post intervention ]
    FEF25-75 is measured in liters of air per second at 25-75%
Original Secondary Outcome Measures  ICMJE
 (submitted: November 12, 2013)
  • Cardiac function (blood pressure) [ Time Frame: Pre and 30 post study drug admistration ]
    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 ]
    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 ]
    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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Effects Of Bronchodilator Therapy On Respiratory And Autonomic Function In Patients With Familial Dysautonomia
Official Title  ICMJE The Effects of Bronchodilator Therapy On Respiratory and Autonomic Function in Patients With Familial Dysautonomia
Brief Summary 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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Familial Dysautonomia
Intervention  ICMJE
  • 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 ®)
  • Drug: Ipratropium-bromide
    Anti-cholinergic 500 mcg 3 cc inhalation Peak effect 30 - 90 mins. Duration of effect 2 - 4 hours.
    Other Name: (Atrovent ®)
  • Other: placebo
    Saline solution 3 cc NA
Study Arms  ICMJE
  • 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
    Intervention: Drug: Albuterol-sulphate
  • 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
    Intervention: Drug: Ipratropium-bromide
  • Placebo Comparator: Placebo
    Placebo Saline solution 3 cc NA
    Intervention: Other: placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 26, 2016)
15
Original Estimated Enrollment  ICMJE
 (submitted: November 12, 2013)
12
Actual Study Completion Date  ICMJE December 2014
Actual Primary Completion Date December 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years to 80 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01987219
Other Study ID Numbers  ICMJE 13-00004
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party NYU Langone Health
Study Sponsor  ICMJE NYU Langone Health
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account NYU Langone Health
Verification Date April 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP