Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05000515 |
| Other study ID # |
AG071506 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 19, 2022 |
| Est. completion date |
August 1, 2025 |
Study information
| Verified date |
January 2024 |
| Source |
University of Colorado, Boulder |
| Contact |
Daniel H Craighead, PhD |
| Phone |
303-492-3010 |
| Email |
imststudy[@]colorado.edu |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
High blood pressure (BP) is the major modifiable risk factor for cardiovascular diseases
(CVD) and related health conditions, particularly among postmenopausal (PM) women. In adults
age ≥50 years this risk is primarily driven by above-normal systolic BP (SBP ≥120 mmHg), as
diastolic BP plateaus, then decreases in older adulthood. Although SBP is lower in
premenopausal women vs. age-matched men, SBP reaches, then surpasses men after age 60. As
such, >75% of PM women in the U.S. have above-normal SBP, which, in turn, is responsible for
a 2-fold increase in risk of hypertension and corresponding increases in risk of CVD, chronic
kidney disease and many other disorders. A key process linking high SBP to CVD and related
conditions is vascular endothelial dysfunction, mediated by excessive reactive oxygen species
(ROS)-induced oxidative stress and reductions in nitric oxide (NO) bioavailability. As the
number of PM women is rapidly growing, further increases in SBP-related CV disorders are
projected without effective intervention.
- Aerobic exercise (AE) is a first-line, standard-of-care therapy for lowering BP. In PM
women with baseline SBP ≥120 mmHg, AE reduces casual (resting) SBP by ~3 mmHg (back to
baseline ≤4 weeks post-training), whereas 24-hour SBP is typically unchanged. However,
only 25-30% of PM women meet guidelines for 150 min/week of moderate-intensity AE,
citing the extensive time requirement, facility access and travel disruptions as major
barriers. Another, far less recognized, limitation is that AE training consistently
improves endothelial function in midlife/older men, but not in estrogen-deficient PM
(PMe-) women, i.e., in >95% of the 60+million PM women in the U.S. Thus, establishing
new lifestyle therapies that induce and sustain reductions in SBP and increases in
endothelial function in PMe- women with above-normal SBP is an important public health
goal.
- High-resistance inspiratory muscle strength training (IMST) is a time-efficient (5
minutes per session) lifestyle intervention consisting of 30 inspiratory maneuvers
performed against a high resistance. Preliminary data suggest 6-weeks of IMST performed
6 days/week reduces SBP by 9 mmHg in adults with above-normal SBP (i.e., greater than
120 mmHg) at baseline. Importantly, this reduction in SBP is equal to or greater than
the reduction in blood pressure typically achieved with time- and effort-intensive
healthy lifestyle strategies like conventional aerobic exercise. In addition, IMST
improved endothelial function in the PMe- women in a small pilot study.
- To translate these promising preliminary results towards clinical practice, this
randomized clinical trial is being conducted to directly compare the efficacy of a
longer, clinically relevant treatment duration of IMST (3 months) against home-based,
moderate-intensity (standard-of-care) AE in PMe-women. The primary outcome will be the
change in casual SBP (IMST vs. AE). Changes in 24-hour SBP and endothelial function will
serve as secondary outcomes. Effects on NO bioavailability, ROS/oxidative stress, and
the role of "circulating factors" will provide insight into mechanisms of action. The
sustained effects on SBP and endothelial function also will be assessed.
- Accordingly, a randomized, blinded, sham-controlled, parallel group design clinical
trial will be conducted to assess the efficacy of 3-months of IMST (75 percent maximal
inspiratory pressure) vs. brisk walking (40-60% heart rate reserve; an established
healthy lifestyle strategy) for lowering SBP and improving endothelial function in PMe-
women age 50 years and older with above-normal SBP. It is hypothesized that IMST will
lower SBP and improve endothelial function by decreasing oxidative stress and increasing
nitric oxide bioavailability. It is also expect that adherence to the intervention will
be excellent (over 80 percent of all training sessions completed at the appropriate
intensity).
- To test this hypothesis, 90 PMe- women age 50 years and older who have SBP >/= 120 mmHg
will be recruited. Participants will undergo baseline testing for casual (resting) SBP,
24-hour ambulatory SBP and endothelial function. Innovative mechanistic probes including
pharmaco-dissection with vitamin C, analysis of biopsied endothelial cells, and
high-throughput metabolomics, will be performed to assess oxidative stress and nitric
oxide bioavailability at baseline.
- After baseline testing, subjects will be randomized to perform either 3-months of
high-resistance IMST or brisk walking. Subjects will train 6 days/week. Following 3
months of training, subjects will redo all the tests that were done during baseline
testing to assess training-induced changes in SBP, physiological functions, and
underlying mechanisms. Subjects will then cease training for 6 weeks before returning to
the lab for follow-up testing to determine the persistent effects of IMST.
Description:
Study Overview: This is a randomized, single-blind, parallel-design, clinical trial assessing
the efficacy of high-resistance inspiratory muscle strength training (IMST) to lower systolic
blood pressure (SBP), improve vascular endothelial function and investigate associated
mechanisms in estrogen-deficient postmenopausal (PMe-) women with above-normal SBP (i.e., >/=
120 mmHg) at baseline. IMST will be compared to moderate-intensity aerobic exercise (AE; 150
min/week brisk walking) training, a standard-of-care lifestyle intervention for lowering SBP
and improving vascular endothelial function. AE lowers casual SBP by approximately 3 mmHg in
PMe- women; however, data from our laboratory has shown that AE does not consistently improve
vascular endothelial function in this subject group. In addition, only 25-30% of PM women
adhere to AE guidelines. Data from the PMe- women who participated in our 6-week IMST pilot
trial suggest that IMST lowers casual SBP by 8 mmHg and improves vascular endothelial
function, measured as brachial artery flow-mediated dilation (FMDba), by more than 40% in
these women. In addition, IMST is a time-efficient intervention (5 min/day) that promotes
adherence due to the minimal time burden (95% adherence in our pilot study). Therefore, IMST
is a promising lifestyle intervention to improve cardiovascular health in PMe- women.
However, these data from a small number of PMe- women need to be confirmed in an
appropriately-powered clinical trial with a guideline-based treatment duration.
- Subject Enrollment and Screening: Potential participants will be made aware of the
proposed study through described recruitment efforts (see Recruitment and Retention Plan
section). Interested participants will contact a staff research assistant via phone or
email (contact information supplied with recruitment materials) and will be administered
a general screening form online through the Research Electronic Data Capture (REDCap)
system to determine eligibility. REDCap is a secure web-based application designed to
support data capture for research studies.
- After hearing a study description and having questions answered by the staff research
assistant, those eligible and interested in participating in the study will provide
written and verbal informed consent, and undergo in-person screening at the University
of Colorado (CU) Boulder Clinical Translational Research Center (CTRC). Informed consent
will only be obtained by members of the research team who have been observed and
approved by the CTRC Research Subject Advocate (see Protection of Human Subjects). We
plan to consent and screen 120 subjects in order to meet our enrollment targets (to
account for an approximately 33% rate of exclusion based on inclusion/exclusion
criteria).
- In-person screening will include: review of medical history; physical exam; resting
heart rate; resting blood pressure; blood draw for metabolic profile, lipid profile,
complete blood count, and thyroid stimulating hormone; measurement of ankle-brachial
index; and 12-lead ECG at rest and during graded exercise testing (see Eligibility
Criteria section for detailed inclusion/exclusion criteria).
- Resting blood pressure will be measured on a second occasion within one week of the
initial screening to establish baseline blood pressure status. SBP measured on the two
separate days will be averaged and must be >/= 120 mmHg for enrollment into the study.
- Assessment of Study Outcomes: All subjects will undergo testing for all primary,
secondary, and other outcome measures, as well as assessment of subject characteristics
known to effect SBP and vascular endothelial function, before and after 3 months of
IMST/AE training. Additionally, casual SBP, 24-hour SBP and FMDba will be measured again
6 weeks after the cessation of training to establish the long-lasting effects of IMST.
All testing will take place in the CU Boulder CTRC.
- Testing day 1: All day 1 measurements will be made after a 12-hour fast from food and
caffeine (water allowed) and 24 hours after abstaining from alcohol and exercise.
- Casual BP;
- I.V. placement and blood sampling;
- Venous endothelial cell collection;
- FMDba (vascular endothelial function);
- FMDba after supra-therapeutic vitamin C infusion (ROS-mediated suppression of vascular
endothelial function);
- Brachial artery dilation to sublingual nitroglycerin (endothelium-independent dilation;
control measure).
- Following day 1 testing, subjects will be outfitted with an ambulatory BP monitor
pre-programmed to automatically measure BP once every 20 minutes. Subjects will be
provided with written and verbal instructions for proper monitor operation and will wear
the monitor for 24 hours before returning it to the investigators. A study team member
will evaluate ambulatory BP data for completeness immediately upon return of the
monitor; if an unsatisfactory number of BP measurements (<67% of expected) were made to
properly characterize 24-hour SBP, the subject will be re-outfitted with the ambulatory
monitor, re-instructed on its use, and wear it for an additional 24-hour period.
- Testing day 2: All day 2 measurements will be made approximately 2 hours after eating a
small meal or snack and 24 hours after abstaining from alcohol and exercise.
- Three-day diet records to ensure that daily fluid and caloric intake remain stable;
- The Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire will
be completed and physical activity assessed by accelerometer (Actigraph, three-day
records) to document stability of physical activity level outside of the physical
activity prescribed in the intervention;
- Sleep stability assessed with the Epworth Sleepiness Scale;
- Maximal oxygen consumption using indirect calorimetry during incremental treadmill
exercise (Balke protocol) will be measured to document aerobic fitness; and
- Body composition assessed by dual energy x-ray absorptiometry (DEXA) and anthropometry
to measure body composition; body mass also will be determined during check-in visits.
- The Research Strategy and Outcome Measures sections provide more detailed descriptions
of these procedures. Similar protocols and procedures are well established in the
Integrative Physiology of Aging Laboratory and the CU Boulder CTRC.
- Participant Randomization: After completing baseline testing, subjects will be
randomized to either IMST or AE. A randomized block design will be used to balance
groups for age (midlife:
