Clinical trial NCT03270332
Conditions: Pulmonary Hypertension
Sponsor: University of Miami
Start date: 2017-10-05; Completion date: 2020-07-02
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of the present pilot study is to test the hypothesis that in patients with group 1 pulmonary arterial hypertension (PAH) who are on regular oral pulmonary vasodilator therapy, inhaled albuterol causes transient pulmonary vasodilation.

Detailed description:

Arms: arm 1: Participants in this group will receive albuterol first followed by Placebo on the next visit arm 2: Participants in this group will receive placebo first followed by albuterol on the next visit
Interventions: intervention 1: Albuterol intervention 2: Placebo
Intervention descriptions: intervention 1: inhalation of 270μg albuterol through a spacer intervention 2: inhalation of placebo through a spacer

Protocol documents:
Prot_SAP_000.pdf: 
 
Eprost ID: 20170552 
NCT Number: NCT03270332 
Version Date: 04 August 2021 
 
 
Effect of inhaled albuterol on pulmonary hemodynamics in patients 
with group 1 pulmonary arterial hypertension on oral pulmonary 
vasodilator therapy: A proof of concept study 
Adam Wanner1, Barry Hurwitz2, David De la Zerda1, Eliana S Mendes1 
1Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University 
of Miami Miller School of Medicine 
2 Department of Psychology & Department of Biomedical Engineering, 
University of Miami 
 
Abstract 
Inhaled J32-adrenergic agonists have been shown to reduce pulmonary 
vascular resistance (PVR) in hypoxic COPD patients, and right ventricular 
systolic pressure in normoxic COPD patients with mild pulmonary 
hypertension (PH). Furthermore, we have recently found that inhaled 
albuterol lowers PVR as assessed by echocardiography in healthy smokers 
and non-smokers (Chest 2017; 151: 650-657). While the pulmonary 
vascular effects of J32-adrenergic agonists could be indirectly related to the 
drug's bronchodilator action in patients with COPD, the demonstrated J32- 
adrenergic agonist induced pulmonary vasodilation in healthy subjects 
strongly suggests a direct pulmonary vasodilatory effect. This raises the 
possibility that inhaled J32-adrenergic agonists could cause pulmonary 
vasodilation in patients with pulmonary hypertension not associated with 
heart disease, chronic lung disease or thromboembolic disease (WHO 
group 1 PAH). In the present proof of concept proposal, we will use 
echocardiography to assess the acute pulmonary hemodynamic effect of 
albuterol in 6 patients with group 1 PAH documented by right heart 
catheterization (mean pulmonary arterial pressure >25mmHg, PVR > 3 
wood/u and pulmonary wedge pressure <15). The patients 
will be on regular oral pulmonary vasodilator therapy. Mean pulmonary 
arterial pressure (MPAP) and cardiac output will be measured before and 
serially for 2 hours after the administration of either 270µg albuterol or 
placebo by inhalation using a spacer. PVR will be calculated by using an 


 
estimate of left atrial pressure. This pilot study, if showing that albuterol 
lowers MPAP and PVR significantly, could form the basis for a phase 2 trial 
in a larger cohort of patients with group 1 PAH in whom a long acting J32- 
adrenergic agonist is administered as add-on to commonly used oral 
pulmonary vasodilators. 


 
 
 
Background 
 
While the treatment strategies for PAH are undergoing a paradigm shift 
away from vasoactive drugs towards tackling the structural remodeling of 
the pulmonary vasculature, vasodilators still maintain a central position in 
the currently available treatment modalities. Often, drugs that target 
different pathways leading to pulmonary vasodilation are administered 
concomitantly for better effect, especially in patients with group 1 PAH. 
These drugs include orally administered calcium channel blockers, 
endothelin receptor blockers and phosphodiesterase-5 inhibitors. J32- 
adrenergic agonists are potent vasodilators and could be administered by 
inhalation as add-ons to currently used oral vasodilators in patients with 
group 1 PAH. Thus far, this possibility has not been explored in this 
population. 
 
We have previously reported that the short acting J32-adrenergic agonist 
albuterol, administered by inhalation, markedly and significantly reduced 
PVR in lung-and heart healthy current smokers and never smokers (1). 
Other studies involving inhaled J32- adrenergic agonists were carried out in 
patients with COPD without or with PAH (group 3). Early studies have 
shown that short-acting J32-adrenergic agonists can reduce PVR in hypoxic 
COPD patients with PAH (2,3). More recently, Cazzola et al (4) assessed 
two long-acting J32-adrenergic agents (formoterol and salmeterol) in COPD 
patients, with or without mild pulmonary hypertension. Following 
administration of these agents, they observed a reduction in 
echocardiographic systolic pulmonary arterial pressure that lasted less than 
180 min, with a trough minimizing between 15 min and 60 min. It is difficult 
to separate direct from indirect vasodilation in these studies, i.e. did the J32- 
adrenergic agonists have a direct effect on the pulmonary circulation or an 
indirect effect by improving airway function. This caveat also applies to 
another investigation of albuterol's action in patients with PAH in whom the 
drug caused both bronchodilation and pulmonary vasodilation at the time of 
right heart catheterization to assess responses to vasodilators, with the 
possibility that a change in ventilation/perfusion relationship reversed 
hypoxic vasoconstriction thereby lowering pulmonary arterial pressure (5). 
 
The purpose of the present pilot study is to test the hypothesis that in 
patients with group 1 PAH who are on regular oral pulmonary vasodilator 


 
therapy, inhaled albuterol causes transient pulmonary vasodilation. If the 
results support this premise, they could serve as the basis for a phase 2 
trial investigating the potential for using inhaled long-acting 2-adrenergic 
agonists as add-on therapy in group 1 PAH. 
 
 
'Research Plan 
 
Test subjects 
 
 Ten patients (males and females) over the age of 18 years with group 1 PAH 
will be enrolled on the study. Participants will be recruited from the 
University of Miami Pulmonary Hypertension Clinic under the direction of 
Dr. David De la Zerda, a co-investigator. 
 
Inclusion criteria 
 
- A MPAP >25mmHg, PVR>3 wood/units and pulmonary arterial 
wedge pressure 15mmHg, as documented by right heart 
catheterization within the last 3 years 
- Regular use of oral pulmonary vasodilators 
 
 
Exclusion criteria 
 
- Presence of chronic respiratory disease (as documented by prior lung 
imaging and pulmonary function tests), cardiovascular disease (as 
documented by prior echocardiography and/or left heart 
catheterization), thromboembolic PAH (as documented by pulmonary 
angiography) 
- women of childbearing potential who do not use accepted birth- 
control measures 
- pregnant and breast-feeding women (vide infra) 
- respiratory infection within 4 weeks of testing 
- A systemic systolic arterial BP> 150 and/or diastolic arterial BP>100 
on the experiment day 
- A resting 02 saturation of< 90% 
- Current smoking 
- BMI >35 kg/m2 and/or a diagnosis of obstructive sleep apnea 
- Use of inhaled or intravenous pulmonary vasodilators 


 
 
 
 
Targeted outcomes 
 
Change in MPAP, PVR after inhalation of 270µg albuterol administered 
with a spacer. These parameters, measured/calculated by 
echocardiography, will be obtained before and at 15, 30, 60 and 120 after 
albuterol or placebo inhalation. At each measurement point, systemic blood 
pressure, 02 saturation by pulse oximetry and spirometry will also be 
measured (the latter to rule out drug induced changes in airway function 
that could indirectly influence pulmonary hemodynamics). We previously 
have observed that the albuterol response wanes by 60 min in healthy 
subjects (1). Each participant will serve as his/her own control and the two 
treatments will be administered on different experiment days in random 
order. Participants and investigators will be blinded (HFA albuterol and 
matching placebo are available to the investigators). 
 
Measurements 
 
Echocardiography and calculation of PVR: 
 
Studies will be performed using the SONOS 5500 ultrasound system 
(Philips Medical Systems) as previously used in our laboratory (1). 
Measurements will start following 15 min of supine rest. The imaging will 
proceed according to the following sequence at each time point (baseline 
and 15, 30, 60, and 120min post-drug administration). Images will be 
acquired for 1-2 breaths or at least 10 cardiac cycles in order to obtain 3 
cycles for quantification. All measurements are made offline. Blood 
pressure and heart rate will be measured on the final image of each time 
point measurement using an automated monitor (Dinamap, model 
1846XT). Traditionally, the maximum velocity of the tricuspid regurgitation 
(TRvmax; cm/sec) has been used to calculate pulmonary vascular resistance 
(PVR). However, this method is not feasible when TR is absent or trivial. 
Therefore, we will also obtain the pulmonary artery acceleration time 
(PAAT), which has been shown to correlate highly with invasively 
measurement of mean pulmonary artery pressure (6). The PAAT will be 
used as an alternative to the TR method because it does not rely on the 
presence of an anatomic defect or valvular regurgitation and is highly 
correlated (r = -.96) with TRvmax (7). TRvmax will be defined as the maximal 


 
velocity of the TR jet measured using continuous-wave Doppler in the 4- 
chamber view. Estimated peak systolic pulmonary artery pressure (PSPAP) 
will be calculated using the modified Bernoulli equation: 4 x TRvmax2 + 
10mmHg (to account for right atrial pressure) (8). The use of 10mmHg as 
an estimate of right atrial pressure has been shown to yield similar 
correlates with catheter-based estimates of right ventricular systolic 
pressure (RVSP) (9). The PAATwill be measured using the pulse-wave 
Doppler profile in the parasternal short axis view. PAAT (msec) will be 
defined as the interval between the onset of systolic pulmonary arterial flow 
and peak flow velocity. The MPAPPAAT (mm Hg) will be computed by: 
79 - (PAAT x 0.45) (9). The right ventricular ejection time (RVET) will also 
be obtained and defined as the interval between the onset of RV ejection to 
the point of systolic pulmonary arterial flow cessation. Using pulse-wave 
Doppler in the 5-chamber view, measures of cardiac function will include 
stroke volume (SV), wherein SV = 3.14 x (LVOT diameter/2)2 x VTI. The 
inter-beat interval is used to derive heart rate (HR) and cardiac output (CO) 
is the product of SV and HR. Left atrial pressure (LAP) is estimated using 
Doppler echocardiography (1O); thus, LAP (mm Hg) is computed from the 
ratio of the E and e' waves of Doppler trans-mitral flow and mitral annulus 
tissue Doppler imaging as follows: LAP = 1.24 x E/e' +2. 
 
Pulmonary vascular resistance (PVR) will be estimated in two ways based 
on the estimation of pulmonary artery pressure and LAP: a) as derived from 
the TR method, PSPAP will be used to estimate mean pulmonary artery 
pressure (MPAPrR) as follows: MPAPrR = 0.6 x PSPAP +2 (11). Then, the 
PVRrR is the ratio of (MPAPrR - LAP) and CO; and b) as derived from the - 
PAAT method, the PVRPAAT is the ratio of (MPAPPAAT - LAP) and CO. All 
values used for analysis will be computed from the average of three cardiac 
cycles per time point. 
 
Pulmonary function 
 
Spirometry will be done to rule out airflow obstruction (FEV1/FVC <0.7). In 
the tracing with the highest FVC of three forced vital capacity, FEV1, FVC, 
FEV1/FVC, IC, MMEF and peak flow will be analyzed. Predicted normal 
values will be taken from Harkinson NHANES Ill. The results will be 
expressed in absolute values and percent of predicted. 


 
 
Statistical analysis 
 
The study is a repeated-measures design with medication treatment vs. 
placebo and time post-treatment (pre-inhalation baseline, 15, 30, 60, 
120min) as fixed within subject effects. The resulting factorial combinations 
will permit ANCOVA estimation of the main effects of treatment and time, 
as well as the 2-way interaction (treatment by time). In addition, ANCOVA 
analyses will be performed to examine treatment effects on the different 
outcomes. Significance will be accepted at p<0.05. 
 
Procedures 
 
There will be 3 study assessment visits per participant, including the 
screening visit to confirm study eligibility. Visits 2 and 3 will commence about 
9am. The subjects will be asked to keep taking their usual oral pulmonary 
vasodilator on the experiment days. 
 
Visit 1 
On this screening visit, after the subjects have signed an informed consent 
and HIPAA forms, a medical history will be obtained and then a physical 
examination will be administered. If they meet screening entr-y c riteria, they 
will undergo spirometry and the determination of 02 saturation, blood 
pressure and heart rate. If the subjects still meet entry criteria, they will be 
invited to return for visit 2. 
 
Visit 2 and Visit 3 
Echocardiographic measurements will be made before and at 15, 30, 60, 
and 120 min after active drug or placebo inhalation. The choice of drug vs. 
placebo on each visit will be random, and a double blind procedure will be 
implemented such that the participants and investigators will not be 
informed which study agent will be used on these visits. The inhaler used 
for visit 3 will be the alternate of the one that the subject is randomized to 
for visit 2. 


 
 
 
 
 
Safety 
 
There is minimal risk: 
 
Echocardiography 
No side effects have been reported. 
 
Pulmonary function tests 
There is little risk from spirometry. Some people may have some chest 
soreness or lightheadedness from the hard blowing. The chest soreness 
usually is short-lived, but can be treated with non-prescription pain relievers. 
 
Inhaled Albuterol 
This drug is approved for clinical use in obstructive lung disease in the US, 
and will be administered at a clinically recommended dose. Possible 
serious side effects include chest and muscular pain, tremor, headache, 
tachycardia, throat irritation, nauseas and vomiting. Although a possible 
interaction between inhaled albuterol and oral pulmonary vasodilators has 
not been systematically evaluated to our knowledge, we believe that it is 
safe to add a f32-adrenergic agonist to oral vasodilators based on clinical 
experience in patients with co-existing PAH and obstructive lung disease. 
 
Study duration 
 
The total duration of the study will be 6 months from the time of IRS 
approval. We estimate a total of 30 participant visits (3 visits each for 
1Qe enrolled participants plus 4 visits for screen failures) or approximately 
one visit per week. Screen failures should be rare given the selection 
criteria and the extensive clinical data available prior to considering a 
patient for screening. 
 
Recruitment Process 
 
Potential candidates will be identified by the Pl and Co-Pl in the Pulmonary 
Hypertension(PH) clinic at the UHealth. If a patient with PH is eligible for 
the study and agrees to participate in the study, the Pl or the Sub-Pl will 


 
notify the study coordinator. The Research Team and the Pl will present 
the study to the patient. Eligible patients will be asked to read, 
comprehend, and sign an informed consent form. This procedure will be 
performed according to the local regulatory authorities. Potential 
participants will be given the choice to take a copy of Consent Form to 
review at home and or discuss with his/her PCP. 
 
No study procedures will be conducted until the informed consent form is 
previously signed. Participants will have to sign a HIPAA Form as well. A 
copy of the signed consent and HIPAA Form will be provided to the patient. 
A review of the subject's medical record will be conducted to confirm that 
the subject meets inclusion/exclusion criteria as per protocol. 
 
 
Pregnancy 
Taking the study drug may involve unknown risks to a pregnant woman, an 
embryo, fetus (unborn baby) or nursing infant. Therefore, if female 
participant is pregnant, planning to become pregnant or are breastfeeding a 
child, participant cannot participate in this study. In order to reduce the risk 
of pregnancy, participant must use an effective method of birth control 
while participating in this study (and for 1 month) after participant complete 
the study treatment. If participant is already using a method of birth control, 
the study doctor or study staff will discuss with her whether her current 
method of birth control is acceptable for use during this study. If, during this 
study and 3_0 days after completion of the study, participant becomes 
pregnant, she should notify the study doctor as soon as possible. The study 
drug will be stopped and her participation in this study will be ended. Data 
during pregnancy and pregnancy outcome will be collected. For those 
females who become pregnant because their male partner is in the study, 
pregnancy outcome data will not be collected. 
 
 
 
Data collection and storage: 
 
Case Report Forms (CRFs) will be provided for each subject. Participants 
will not be identified by name on any study documents collected by sponsor 
or its representative but may be identified by an SIN and initials. 
The paper records will be kept in a secure location (Pulmonary Research 
Office) in a locked office with limited access. 


 
All clinical information requested will be recorded in the CRFs . 
CRFs must be reviewed and verified for accuracy by the Principal 
Investigator and signed off before the data is entered on a safety password 
protected electronic system. A copy of the CRF will remain at the 
Investigator's site at the completion of the study. 
 
Data Recording 
 
All data will be entered into an electronic database (RedCap). Patients will 
be provided with a unique study number and only the study team will have 
access to the database. 
 
Maintenance of data confidentiality 
The investigator/delegate will ensure that data confidentiality is maintained. 
On CRFs or other documents, subjects will be identified only by number, 
and never by name or initials, hospital numbers, SSN or any other 
identifier. The investigator/delegate will keep a subject identification code 
list, at the site, showing the randomization number, the subject's name, 
date of birth and address or any other locally accepted identifiers. CRFs will 
be kept at the Pulmonary Research Center located at 1321 NW 14th Street 
suite 607, Miami Florida 33136 where only study personnel has access to 
this location. 
 
Database management and quality control 
 
Electronic CRFs will be used for all subjects through RedCap. The 
investigator will have access to the site CRF data until the database is 
locked. Thereafter, they will have read-only access. The CRF will be kept 
current to reflect subject status at any time point during the course of the 
study. 
 
While entering the data, the investigator/delegate will be instantly alerted to 
data queries by validated programmed checks. Additional data review will 
be performed on an ongoing basis to look for unexpected patterns in data 
and study monitoring by the Principal Investigator. If discrepant data are 
detected, a query specifying the problem and requesting clarification will be 
issued and visible to the investigator/delegate via the CRF. All electronic 
queries visible in the system either require a data correction (when 
applicable) and/or a response from the investigator/delegate to clarify the 
queried data directly in the CRF, or simply a data correction in the CRF. 


 
 
 
 
Confidentiality 
 
All information relating to this research protocol will be kept confidential to 
the extent permitted by law. However, records will be available to the 
University of Miami IRB, sponsor, appropriate governmental agencies, and 
by authorized University of Miami employees or other agents authorized by 
the University. Study staff is HIPAA trained and complied with our 
Institution requirements. 
 
A file for each subject will be maintained that includes the signed ICF and 
subject information sheet and the Investigator's copies of all source 
documentation related to that subject. The Investigator will ensure the 
reliability and availability of source documents from which the information in 
the CRF was derived. 
 
Data Security 
 
Access is limited to personnel involved in the study (Pl, sub-Pl, and the 
research team). 
 
Settings 
 
Site name and address: 
Pulmonary Research Office at the University of Miami Hospital West 
building, 1321 NW 14th Street Room 607 Miami, Florida 33125. 
 
Informed Consent 
 
Potential participants attending to the PH clinics at the University of Miami 
will be invited to participate on this registry by the Pl or Co-Pl. The purpose 
of the study and procedures will be extensively discussed with the patients. 
If he/she is willing to participate1   the Informed Consent process will take 
place. Patients will have enough time to decide about participation and. if 
requested taking the ICF to be discussed with family members or PCP. If 
Hispanic subjects who do not speak English will be enrolled, a translated 
approved version of the ICF will be provided to the subject. The study staff 
is bilingual. 


 
 
Patient reimbursement 
 
Patients will receive $200 for each visit attended with total amount of 
$600.00. This is to defray costs of time and travel for each visit. 
 
Removal of Subjects from Study 
 
A subject withdrawal is defined as a discontinuation from the study for any 
reason. Subjects may withdraw or be withdrawn from this study for the 
following reasons: 
 
• at their own request or at the request of their authorized representative at 
any time for any reason 
 
• if continuation in the study would be detrimental to the subject's well- 
being, in the investigator's opinion. 
 
Study Drug 
 
Albuterol will be administered as Ventolin HFA, purchased by the 
investigator. Ventolin placebo HFA has been provided to the investigators 
by Glaxo Smith Kline as samples for patient education. The two inhalers 
will be matched in appearance (label with blinded identifier, covering the 
entire cartridge, which is the same for active drug and placebo). 
 
 
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