Familial DysautonomiaPhase 3NCT01987219
The Effects Of Bronchodilator Therapy On Respiratory And Autonomic Function In Patients With Familial Dysautonomia
A Phase 3 study testing Albuterol-sulphate and Ipratropium-bromide in people with Familial Dysautonomia, run by NYU Langone Health at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 12 to 80 years
- Conditions the study is for
- Familial Dysautonomia
- What is being tested?
- Albuterol-sulphate and Ipratropium-bromide
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 15 participants
- Where
- 1 siteUnited States
- Study dates
- Mar 2013to Dec 2014
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 to 80 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: The Effects of Bronchodilator Therapy On Respiratory and Autonomic Function in Patients With Familial Dysautonomia
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.
Read the 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.
- Conditions
- Familial Dysautonomia
- Being tested
- Albuterol-sulphate, Ipratropium-bromide, placebo
- Keywords
- familial dysautonomia
- Medical subject headings
- Dysautonomia, Familial
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Albuterol-sulphateDrug
Also called (Proventil ®)
Beta-2-adrenergic agonist 2.5 mg 3 cc inhalation Peak effect 15 - 30 mins. Mean duration of effect 3 hours
Ipratropium-bromideDrug
Also called (Atrovent ®)
Anti-cholinergic 500 mcg 3 cc inhalation Peak effect 30 - 90 mins. Duration of effect 2 - 4 hours.
placeboOther
Saline solution 3 cc NA
| Study group | Role | What they receive |
|---|---|---|
| Albuterol-sulphate | Active comparator | Albuterol-sulphate (Proventil ®) Beta-2-adrenergic agonist 2.5 mg 3 cc inhalation Peak effect 15 - 30 mins. Mean duration of effect 3 hours Receives: Drug: Albuterol-sulphate |
| Ipratropium-bromide (Atrovent ®) | Active comparator | IpratroAnti-cholinergic(Atrovent ®) 500 mcg 3 cc inhalation Peak effect 30 - 90 mins. Duration of effect 2 - 4 hours.pium-bromide Receives: Drug: Ipratropium-bromide |
| Placebo | Placebo comparator | Placebo Saline solution 3 cc NA Receives: Other: placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change From Baseline of Forced Vital Capacity
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.
Measured: Pre and 30 minutes post study drug administration
Change in Respiratory Function (Airway Resistance at 5 Hz) From Baseline
The percentage change in respiratory function from baseline is measured in percentage change in Resistance, kPa/(L/s).
Measured: Pre and 30 minutes post study drug administration
Secondary outcomes (2)
Change in Forced Expiratory Volume (FEV) From Baseline
Forced expiratory volume is measured in liters of air per second. FEV was measured during the first second of exhalation.
Measured: Pre and 30 post study drug admistration
Change in Forced Expiratory Flow Between 25-75% (FEF25-75)
FEF25-75 is measured in liters of air per second at 25-75%
Measured: pre and 30 minutes post intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Nov 2013 (estimated)
- Study startMar 2013
- Primary completionDec 2014
- Study completionDec 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Familial DysautonomiaStudies of the same condition, open and under way.
- More trials run by NYU Langone HealthThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- NYU Langone Health
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01987219
- Sponsor's protocol ID
- 13-00004
- Status last verified
- Apr 2016
- First submitted
- 5 Nov 2013
- Last updated
- 2 Jun 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 2 Jun 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects of Bronchodilator Therapy On Respiratory and Autonomic Function in Patients With Familial Dysautonomia
- ClinicalTrials.gov ID
- NCT01987219
- Acronym / sponsor ID
- 13-00004
- Conditions
- Familial Dysautonomia
- Keywords
- familial dysautonomia
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 15 participants (actual)
- Lead sponsor
- NYU Langone HealthUniversity, hospital or other
- Study start
- Mar 2013
- Primary completion
- Dec 2014 (actual)
- Study completion
- Dec 2014 (actual)
- First posted
- 19 Nov 2013 (estimated)
- Results
- Posted 2 Jun 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Albuterol-sulphate | Active comparator | Drug: Albuterol-sulphateAlbuterol-sulphate (Proventil ®) Beta-2-adrenergic agonist 2.5 mg 3 cc inhalation Peak effect 15 - 30 mins. Mean duration of effect 3 hours |
| Ipratropium-bromide (Atrovent ®) | Active comparator | Drug: Ipratropium-bromideIpratroAnti-cholinergic(Atrovent ®) 500 mcg 3 cc inhalation Peak effect 30 - 90 mins. Duration of effect 2 - 4 hours.pium-bromide |
| Placebo | Placebo comparator | Other: placeboPlacebo Saline solution 3 cc NA |
Who may qualify
- Ages
- 12 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (2 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Albuterol-sulphateAlso: (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 |
| Ipratropium-bromideAlso: (Atrovent ®)Anti-cholinergic 500 mcg 3 cc inhalation Peak effect 30 - 90 mins. Duration of effect 2 - 4 hours. | Drug | Ipratropium-bromide (Atrovent ®) |
| placeboSaline solution 3 cc NA | Other | Placebo |
Primary outcome
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).
2 secondary outcomes
Change in Forced Expiratory Volume (FEV) From Baseline
Time frame: Pre and 30 post study drug admistration
Change in Forced Expiratory Flow Between 25-75% (FEF25-75)
Time frame: pre and 30 minutes post intervention
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jun 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Related trials for Familial Dysautonomia
RecruitingObservational study
The Natural History of Familial Dysautonomia
Familial Dysautonomia (Riley-Day Syndrome), Hereditary Sensory and Autonomic Neuropathies
RecruitingObservational study
Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
Rare Disorders, Undiagnosed Disorders
Active, not recruitingObservational study
Exploring the Olfactory Mucosa, Blood and Urine for the Identification of Early Biomarkers of Parkinson's Disease, Atypical Parkinsonisms and Neurocognitive Disorders Due to Lewy Body Disease
Parkinson Disease, MSA - Multiple System Atrophy
Not yet recruiting
Empowered Relief for Caregivers
Chronic Pain, Musculoskeletal Pain
Active, not recruitingObservational study
Gait Analysis in Neurological Disease
Parkinson's Disease, Parkinsonian Disorders
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Albuterol-sulphate and Ipratropium-bromide in people with Familial Dysautonomia, run by NYU Langone Health at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Jun 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Jun 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change From Baseline of Forced Vital Capacity (time frame: Pre and 30 minutes post study drug administration). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jun 2016.