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Mechanisms for Individual Differences in Hypertension in Obstructive Sleep (PISA-BP)

This study is currently recruiting participants.
Verified June 2017 by University of Pennsylvania
Sponsor:
ClinicalTrials.gov Identifier:
NCT03176732
First Posted: June 5, 2017
Last Update Posted: June 8, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
University of Pennsylvania
  Purpose
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.

Condition Intervention
Sleep Apnea, Obstructive Hypertension Device: Positive Airway Pressure

Study Type: Observational
Study Design: Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Mechanisms for Individual Differences in Hypertension in Obstructive Sleep

Further study details as provided by University of Pennsylvania:

Primary Outcome Measures:
  • Nocturnal mean arterial blood pressure (nMAP) [ Time Frame: Measured for 24-hours at baseline and repeated after 4 months of PAP treatment. ]
    Measured using 24-hour ambulatory blood pressure monitoring


Secondary Outcome Measures:
  • Oxidative stress [ Time Frame: Collected overnight at baseline and repeated after 4 months of PAP treatment. ]
    Measured in urinary 8-isoprostane.

  • Sympathetic activity [ Time Frame: Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment. ]
    Measured in blood plasma


Other Outcome Measures:
  • Plasma renin [ Time Frame: Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment. ]
    Measured in blood plasma

  • Aldosterone [ Time Frame: Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment. ]
    Measured in blood plasma

  • Oxidized LDL [ Time Frame: Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment. ]
    Measured in blood plasma

  • Plasma endothelin-1 [ Time Frame: Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment. ]
    Measured in blood plasma

  • Inflammatory biomarkers [ Time Frame: Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment. ]
    Measured in blood plasma

  • Neutrophil NADPH oxidase activity [ Time Frame: Fasting blood draw collected at baseline and repeated after 4 months of PAP treatment. ]
    Measured in blood neutrophils


Biospecimen Retention:   Samples With DNA
As a part of the research protocol, we intend to draw from each participant at baseline and following 4 months of PAP therapy. All samples will be processed according to the recommended procedures for the different analyses we intend to measure and stored at -80°C until analysis.

Estimated Enrollment: 200
Actual Study Start Date: June 6, 2017
Estimated Study Completion Date: September 30, 2021
Estimated Primary Completion Date: September 30, 2021 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Group 1: Normotensive
Categorized by 24-hr systolic BP (SBP): normotensive (< 125 mm Hg) on no BP medications
Device: Positive Airway Pressure
Participants will use Positive Airway Pressure (PAP) treatment
Group 2: Controlled Hypertensive
Categorized by 24-hr systolic BP (SBP): controlled hypertensive (< 130 mm Hg) on BP medication(s) and/or lifestyle modification
Device: Positive Airway Pressure
Participants will use Positive Airway Pressure (PAP) treatment
Group 3: Uncontrolled Hypertensive
Categorized by 24-hr systolic BP (SBP): uncontrolled hypertensive (≥ 130 mm Hg) on 1-2 BP medications
Device: Positive Airway Pressure
Participants will use Positive Airway Pressure (PAP) treatment
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)
Device: Positive Airway Pressure
Participants will use Positive Airway Pressure (PAP) 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.
  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Adult subjects between the ages of 18 and 70 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.
Criteria

Inclusion Criteria:

  • Age between 18 and 70 years
  • Apnea-Hypopnea Index (AHI) ≥ 15 events/hr on diagnostic polysomnography(PSG)
  • No previous history of medical or surgical treatment of OSA
  • 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), tetrahydrocannabinol (THC), 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 ≥ 130 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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03176732


Contacts
Contact: Colleen M Walsh, MS 215-614-0047 coleen.walsh@uphs.upenn.edu
Contact: Samuel T Kuna, MD 215-823-4400 skuna@mail.med.upenn.edu

Locations
United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Colleen M Walsh, MS    215-614-0047    coleen.walsh@uphs.upenn.edu   
Contact: Samuel T Kuna, MD    215-823-4400    skuna@mail.med.upenn.edu   
Principal Investigator: Samuel T Kuna, MD         
Principal Investigator: Raymond R Townsend, MD         
Sub-Investigator: Julio A Chirinos, MD         
Sub-Investigator: Allan I Pack, MD         
Sub-Investigator: Thorarinn Gislason, MD         
Iceland
University of Iceland Recruiting
Reykjavík, Iceland
Contact: Erna Sif Arnardottir, PhD       ernasif@landspitali.is   
Principal Investigator: Thorarinn Gislason, MD         
Sponsors and Collaborators
University of Pennsylvania
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Samuel T Kuna, MD University of Pennsylvania
Principal Investigator: Raymond R Townsend, MD University of Pennsylvania
  More Information

Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03176732     History of Changes
Other Study ID Numbers: 823172
P01HL094307-06A1 ( U.S. NIH Grant/Contract )
First Submitted: June 1, 2017
First Posted: June 5, 2017
Last Update Posted: June 8, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Pennsylvania:
Sleep Apnea
Hypertension
Positive Airway Pressure
Blood Pressure

Additional relevant MeSH terms:
Hypertension
Sleep Apnea Syndromes
Sleep Apnea, Obstructive
Vascular Diseases
Cardiovascular Diseases
Apnea
Respiration Disorders
Respiratory Tract Diseases
Sleep Disorders, Intrinsic
Dyssomnias
Sleep Wake Disorders
Nervous System Diseases