- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03176732
Mechanisms for Individual Differences in Hypertension in Obstructive Sleep (PISA-BP)
April 24, 2023 updated by: University of Pennsylvania
Hypertension is a common consequence of obstructive sleep apnea (OSA).
However, not all individuals with OSA have hypertension and there are major individual differences in blood pressure response to positive airway pressure treatment of OSA.
This project is focused on determining the basis of these individual differences in blood pressure response to OSA and will evaluate the possible underlying reasons for these differences.
The results will help clinicians to know whether or not to expect a reduction in blood pressure (BP) to OSA treatment in a given patient and thereby personalize patient management.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Detailed Description
We seek to assess the clinical determinants and molecular/genetic mechanisms underlying known individual differences in BP response to obstructive sleep apnea (OSA).
This will result in a more personalized approach to BP management of OSA patients.
Hypertension is a common consequence of OSA.
Animal studies with cyclical intermittent hypoxia indicate that oxidative stress is likely the major mechanism, but cardiovascular response to arousals may also play a role.
However, not all individuals with OSA have hypertension.
Moreover, recent meta-analyses of treatment trials of OSA show major individual differences in BP response.
The largest drop in BP with positive airway pressure (PAP) therapy for OSA is in patients with resistant hypertension taking three or more BP medications.
This project is focused on determining the basis of these individual differences in BP response to OSA and PAP treatment.
For Aim 1, we will assemble four groups of OSA subjects with: 1) no hypertension; 2) controlled hypertension on medications and/or lifestyle modifications; 3) uncontrolled hyper-tension despite one or two anti-hypertensive medications; and 4) resistant hypertension.
We will assess reductions in BP with PAP therapy with mean nocturnal (sleep) arterial BP being the primary end-point.
The prediction is that group 4 will show the largest fall in BP, even after controlling for relevant covariates, group 3 the next biggest fall, while groups 1 and 2 will show minimal BP changes.
Both intent to treat and per protocol analyses, i.e., analyzing only those subjects who had PAP adherence of ≥ 4 hours/day and are adherent to medication, will be conducted.
All subjects will have the following measured before and after 4 months of therapy: urinary isoprostanes and plasma levels of norepinephrine, renin activity, aldosterone, oxidized LDL, endothelin-1, and inflammatory biomarkers.
In Aim 2, we hypothesize that those individuals with higher BP at baseline and the greatest BP response to PAP therapy will have higher levels of urinary isoprostanes and plasma norepinephrine at baseline and greater falls with therapy.
Animal studies show that the key enzyme mediating oxidative stress in OSA is nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) oxidase (NOX), in particular NOX2.
Thus, NADPH oxidase activity will also be assessed.
Individuals with the largest falls in BP on PAP therapy are hypothesized to have the highest activity of this enzyme at baseline.
There are known genetic variants of this enzyme that affect its structure/activity.
Thus, individual differences could be the result of genetic variants.
To address this, we will employ in-depth sequencing and evaluate variants in 7 key genes regulating NOX2 structure/activity.
Gene variants identified will be related to BP responses and to NADPH oxidase activity.
In Aim 3, the role of arousals in the BP response to OSA will be assessed using a novel measurement of heart rate response to arousal.
We hypothesize that the heart rate response to arousal will be related to the BP and molecular outcomes of Aims 1 and 2. Finally, given the complex relationship between OSA and BP, Aim 4 will utilize structural equation modeling to assess the relative impact of the various biological pathways.
Study Type
Observational
Enrollment (Actual)
155
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Reykjavík, Iceland
- University of Iceland
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19104
- University of Pennsylvania
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 75 years (Adult, Older Adult)
Accepts Healthy Volunteers
Yes
Sampling Method
Non-Probability Sample
Study Population
Adult subjects between the ages of 18 and 75 years of age with a diagnosis of untreated moderate to severe OSA as evidenced by an apnea/hypopnea index ≥ 15 events/hour who are about to be initiated on PAP treatment.
We will make a conscious effort to recruit from all ethnic and social economic backgrounds.
Description
Inclusion Criteria:
- Age between 18 and 75 years
- Apnea-Hypopnea Index (AHI) ≥ 15 events/hr on diagnostic polysomnography(PSG)
- No previous history of surgical treatment of OSA, and no medical treatment of OSA within the past 6 months
- Adherence to prescribed anti-hypertensive medications as assessed by an average adherence between Visits 1-2 of at least 0.85
- Arm circumference less than 50 cm
Exclusion Criteria:
- Unable or unwilling to provide informed consent
- No telephone access or inability to return for follow-up
- Diagnosis of another sleep disorder in addition to OSA (e.g., periodic limb movement disorder [greater than 5 limb movements associated with arousal/hr of sleep], central sleep apnea [greater than 50% of apneas are central apneas], obesity hypoventilation syndrome, narcolepsy)
- Positive urine drug screen for any of the following: amphetamines, cocaine, opiates, barbiturates, benzodiazepines, phencyclidine (PCP), alcohol (ETOH), methadone (Visit 1)
- Requiring oxygen, bi-level positive airway pressure, or adaptive servo-ventilation for treatment of OSA
- Oxygen saturation < 87% for a period of 2 minutes during resting wakefulness during home sleep testing (HST) or PSG (Visit 2)
- Severe and inadequately controlled arterial hypertension (SBP greater than 180 mm Hg; diastolic BP greater than 110 mm Hg on 2 of 3 spot measurements on Visit 1)
- Participants with 24-hr SBP ≥ 140 mm Hg who are not on BP medications and participants on 4 or more BP medications with a 24-hr SBP < 135 mm Hg (Visit 2)
- A clinically unstable medical condition as defined by a change in medications in the previous month, including anti-hypertensive medications, or a new medical diagnosis in the previous 2 months (e.g., myocardial infarction, chronic heart failure, unstable angina, active infection, thyroid disease, depression or psychosis, cirrhosis, surgery, or cancer)
- Shift workers, individuals who regularly experience jet lag, or have irregular work schedules by history over the last 3 months
- Women who are pregnant or sexually active and of child-bearing age not using a form of contraceptive
- Routine consumption of > 2 alcoholic beverages/day Excessive use of caffeine (greater than 10 cups/day)
- Inability to communicate verbally or less than a 5th grade reading level
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
---|---|
Group 1: Normotensive
Categorized by 24-hr systolic BP (SBP): normotensive (< 125 mm Hg) on no BP medications
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Participants will use Positive Airway Pressure (PAP) treatment
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Group 2: Controlled Hypertensive
Categorized by 24-hr systolic BP (SBP): controlled hypertensive (< 130 mm Hg) on BP medication(s) and/or lifestyle modification
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Participants will use Positive Airway Pressure (PAP) treatment
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Group 3: Uncontrolled Hypertensive
Categorized by 24-hr systolic BP (SBP): uncontrolled hypertensive (≥ 130 mm Hg) on 0-2 BP medications
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Participants will use Positive Airway Pressure (PAP) treatment
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Group 4: Hypertensive
Categorized by 24-hr systolic BP (SBP): hypertensive (≥ 135 mm Hg) resistant to 3 or more BP medications ideally including a diuretic (resistant hypertension)
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Participants will use Positive Airway Pressure (PAP) treatment
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Nocturnal mean arterial blood pressure (nMAP)
Time Frame: Measured for 24-hours at baseline and repeated after 4 months of PAP treatment.
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Measured using 24-hour ambulatory blood pressure monitoring
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Measured for 24-hours at baseline and repeated after 4 months of PAP treatment.
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Oxidative stress
Time Frame: Collected overnight at baseline and repeated after 4 months of PAP treatment.
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Measured in urinary 8-isoprostane.
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Collected overnight at baseline and repeated after 4 months of PAP treatment.
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Sympathetic activity
Time Frame: Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment.
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Measured in blood plasma
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Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment.
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Plasma renin
Time Frame: Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment.
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Measured in blood plasma
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Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment.
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Aldosterone
Time Frame: Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment.
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Measured in blood plasma
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Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment.
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Oxidized LDL
Time Frame: Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment.
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Measured in blood plasma
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Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment.
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Plasma endothelin-1
Time Frame: Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment.
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Measured in blood plasma
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Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment.
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Inflammatory biomarkers
Time Frame: Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment.
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Measured in blood plasma
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Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment.
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Neutrophil NADPH oxidase activity
Time Frame: Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment.
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Measured in blood neutrophils
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Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment.
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Investigators
- Principal Investigator: Samuel T Kuna, MD, University of Pennsylvania
- Principal Investigator: Raymond R Townsend, MD, University of Pennsylvania
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
June 6, 2017
Primary Completion (Actual)
April 30, 2022
Study Completion (Actual)
June 30, 2022
Study Registration Dates
First Submitted
June 1, 2017
First Submitted That Met QC Criteria
June 1, 2017
First Posted (Actual)
June 5, 2017
Study Record Updates
Last Update Posted (Actual)
April 26, 2023
Last Update Submitted That Met QC Criteria
April 24, 2023
Last Verified
April 1, 2023
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 823172
- P01HL094307-06A1 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
NO
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
No
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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