University of Wisconsin Meditation & Exercise Cold Study

Acute respiratory infection (ARI), including common cold and influenza, is a leading cause of
morbidity and mortality, and has a major economic impact. Both mental and physical health are
linked to ARI burden. For example, people who report more negative emotion and higher stress
are more likely to get ARI. Exercise affects the immune system, improves physical and mental
health, and may protect against ARI illness. Mindfulness meditation reduces perceived stress,
influences the immune system, and may protect against ARI. The investigators' own recent
NCCAM-funded trial randomized 154 people to 3 groups: 1) meditation, 2) moderate intensity
exercise, or 3) wait-list control. For the 149 people followed to study completion, there
were 40 ARI episodes and 453 days of illness in the control group, 27 episodes and 257 days
of ARI illness in the meditation group, and 26 episodes and 241 days of ARI illness in the
exercise group. Corresponding reductions in ARI-related work days lost to ARI illness were
observed. The proposed research will build upon these findings with refined methodology in a
larger sample to: A) determine whether these findings are replicable, and B) investigate
potential explanatory pathways.

This research will use state-of-the-art randomized controlled trial (RCT) methodology to
assess potential effects of meditation or exercise on ARI outcomes. This will be a 5-year
project, with 4 yearly cohorts of n=99 per cohort randomized into 3 groups of n=33 each.
Assuming 9% loss to follow-up, the final sample size will be n=360 study participants, with
n=120 in each comparison group. Participants will be randomized to 1 of 3 groups: 1) an
8-week training program in mindfulness meditation, 2) an attention, duration and
location-matched program in progressive exercise, or 3) a non-interventional wait-list
control group. Each cohort will be observed for 8 months comprising the annual cold and flu
season. Enrollment, randomization and study interventions will begin in September of each
year. Participants will be monitored by weekly self-report through May. Summers will be used
for data cleaning, preliminary analyses, and for recruiting the next year's cohort.

The primary goal of this project is to determine whether behavioral training in mindfulness
meditation or moderate intensity sustained exercise can lead to reductions in acute
respiratory infection (ARI) illness, such as common cold and influenza like illness. The
primary outcome will be severity-weighted total days of ARI illness (global severity),
calculated as trapezoidal approximation to area under the time severity curve during ARI
illness, with severity assessed once daily using self-reports on the validated Wisconsin
Upper Respiratory Symptom Survey (WURSS-24).

Computer-assisted weekly monitoring will assure that ARI illness episodes are detected, and
will serve to document secondary outcomes, including health care utilization and work or
school absenteeism. Visits to health care facilities and time lost from work and school will
be documented, then classified as ARI-related (or not) by personnel blinded to allocation.
Questionnaire measures assessing perceived stress, self-efficacy, sleep quality, depression,
and general mental and physical health will also be analyzed as secondary outcomes. Degree of
stress reduction, mindfulness, positive and negative emotion, social support, self-efficacy
and sleep quality will be analyzed as potential mediators of effects of interventions on
outcomes.

Laboratory assessed objective measures will primarily serve to corroborate self-reports of
disease severity, but will also be analyzed as potential mediators of effects of behavioral
interventions on ARI illness incidence, duration, and severity. As potential mediators,
pro-inflammatory cytokines (CRP, IL-6, IL-8, IP-10) will be assessed as change from baseline
to one month after the 8 week behavioral interventions finish. These will serve as indicators
of a pro-inflammatory state. Repeating these assays 3 months later will assess whether
pro-inflammatory changes from baseline will be sustained. Cytokines from samples taken during
ARI illness will be assessed as corroborating biomarkers of disease severity. Identification
of viral agents using multiplex PCR will also serve to corroborate ARI self-reports.

Self-report measures of perceived stress, positive and negative emotion, self-efficacy,
social support, sleep quality, mindfulness, and general mental and physical health will be
used to assess potential pathways through which interventions may exert influence on primary
outcomes. Potential mediating effects of psychological and physical health domains will be
assessed using appropriate mediation (process) analysis statistical models.

Primary efficacy analysis will contrast total days of illness and area-under-curve global
severity in each intervention group with corresponding values in the control group.
Unadjusted contrasts will be done by t-test, using variable transformation if skewness
requires. Adjusted analyses will be based on zero-inflated regression models taking into
account the episodic and variable nature of ARI illness. Zero-inflated regression models
incorporate a logistic sub-model to account for people without ARI illness, and a linear
sub-model to account for the variability in continuous measures of severity and duration.
These will employ conservative estimates with standard error inflated using Huber/White
maximum likelihood estimation. Co-variates to be controlled for in this model will include:
age, sex, body mass index, smoking status, comorbidity, highest level of education achieved,
neuroticism, conscientiousness, general physical health and general mental health. The null
hypotheses of "no effect on primary outcome" will be rejected in favor of alternative
hypothesis of "some effect" if p-values are ≤0.025. Confidence intervals will be constructed
for all outcome variables, allowing estimation of effect size. Zero-inflated regression
models for primary efficacy analyses will be done using M-Plus version 6.1or similar
software.

Influence of interventions on secondary outcomes will be assessed using ANOVA-based
multivariate regression models using SAS software. Adjustment for multiple comparisons will
be incorporated, and interpretation will be cautious. In general, the investigators' will
want to see relationships with p<0.01 in order to justify tentative null hypothesis
rejection. Pre-planned secondary efficacy analyses will include effects of interventions on:
1) absenteeism, 2) health care utilization, 3) general physical health (SF-12), 4) general
mental health (SF-12); 5) perceived stress (PSS-10), 6) self-efficacy (MSES, ESE), 7) sleep
quality (PSQI), 8) body weight (BMI), 9) blood pressure and 10) pro-inflammatory cytokines.
One-sided testing will be based on the underlying hypotheses that the behavioral trainings
lead to improved physical and mental health, sleep quality and self-efficacy, and to
reductions in absenteeism, health care utilization, stress, body weight, blood pressure and
proinflammatory cytokines.

Apart from flu shots, hand-washing, smoke avoidance, and maintenance of general health, there
are no known safe and effective prevention strategies for acute viral respiratory infection.
Interventions to be tested are low risk, and more likely to confer benefit than harm.
Influenza vaccination (flu shots) will be provided free of charge to all participants, and
could be considered a benefit. Participants will not be required to forego any proven or
accepted preventions or treatments, and in fact will be encouraged to seek appropriate
medical attention for any condition, including respiratory infection, and to continue their
regular health care practices. Antibiotics, anti-influenza antivirals, and other ARI
treatments will not be disallowed, but instead will be tracked as secondary outcomes. In
general, participants will be asked to continue the study interventions they are assigned,
and to forego the study interventions they are not assigned. However, they will be informed
that they remain free to make their own health care, behavioral and life style decisions. In
particular, exercise will not be discouraged for participants in the meditation or wait-list
control group, as exercise is known to confer some health benefit. However, the
investigators' will ask participants in the exercise and control group to refrain from
starting a meditation program, and that all participants refrain from starting any
purportedly immune-modifying supplements (eg, echinacea, ginseng, zinc, elderberry, etc.),
unless advised to do so by their physicians. If any participants do choose to actively begin
an intervention they were not assigned (i.e. a person randomized to exercise chooses to take
the mindfulness meditation course instead), the investigators' will ask them to continue in
the study, and will use that "cross-over" information in secondary analyses using the
principles outlined in Section 4.3 of the protocol.

This proposed study was submitted to and approved by the Human Subjects Committee of the
Health Sciences Institutional Review Board of the University of Wisconsin - Madison (UW
HS-IRB), and will be in compliance with HIPAA and all other federally mandated human subjects
regulations. All members of the research team will complete the protection of human subjects'
tutorial required by the UW HS-IRB's Human Subjects Committee prior to the study's
initiation. All named UW Co-Investigators, Consultants, and current Project Personnel have in
fact already completed this tutorial. All study personnel, including research assistants,
will be trained in confidentiality, informed consent procedures, and other aspects of human
subject protection.

A Data and Safety Monitoring Committee (DSMC) will oversee human subjects recruitment and
monitoring, and will function independently of the principal investigator and
co-investigators. The investigators' expect that this committee will function similarly to
that established for the first MEPARI trial, and will choose to meet once or twice yearly to
monitor recruitment and retention, and to provide oversight and guidance in relation to
safety, bioethics, and other human subjects concerns that may arise.

Acute infection from influenza and other respiratory viruses leads to much human suffering
and loss of economic productivity. The investigators' own evidence suggests that training in
either meditation or exercise may lead to substantial reductions in ARI disease burden and
work absenteeism. In addition to testing whether the investigators' findings are replicable
in a larger sample with refined methodology, this proposed comparative effectiveness
translational research will investigate mechanisms of action and provide initial estimates of
cost-effectiveness. If positive findings are confirmed, this line of research could have
direct and immediate impact on public and private health-related policies and clinical
practice, as well as on scientific understanding of respiratory infection.

A copy of the full protocol (including references) is available upon request.

Inclusion Criteria:

- Aged 30-69 years at study entry.

- Must answer "Yes" to either "Have you had at least 2 colds in the last 12 months?"
and/or "On average do you get at least 1 cold per year?"

- Prospective participants must meet the American Heart Association guidelines for
suitability for an exercise program. Prospective participants will be advised (but not
required) to seek their physicians' advice before enrollment.

- Self-reported ability and willingness to follow through with either exercise or
meditation training, or neither, according to randomized allocation, and to
participate in blood draws, nasal wash, self-report questionnaires, and weekly
monitoring for 9 months.

- A score of 14 or lower on the PHQ-9 depression screen, self-reported both at entrance
to run-in trial and again just prior to enrollment in the main study.

- Fluency and literacy in English language sufficient for understanding the study
protocol and completing questionnaires.

- Successful completion of tasks during run-in period, including 2 in-person
appointments, 1 phone contact, 1 set of homework questionnaires, and baseline nasal
wash and blood draw.

Exclusion Criteria:

- Current or recent use of meditative practice, or previous meditation training.
Assessed by answering "Yes" to any of the following questions: Do you meditate on a
regular basis? In the last year, have you meditated at least weekly for 2 or more
months in a row? Have you ever been trained in meditation? Have you ever been involved
in a mindfulness class or mindfulness practice?

- Potential participants must not engage in moderate exercise more than twice per week
or vigorous exercise more than once per week, as assessed by the following questions
adapted from the Behavioral Risk Factor Surveillance System (BRFSS) classification
system: On average, how many times per week do you engage in moderate recreational
activities such as walking, tennis doubles, ballroom dancing, weight training, or
similar activities that last at least 20 minutes per occasion? A) Less than 1 time per
week; B) 1 time per week; C) 2 times per week; D) 3 times per week; E) >4 times per
week. How many times per week do you engage in vigorous sport and recreational
activities such as jogging, swimming, cycling, singles tennis, aerobic dance or other
similar activities lasting at least 20 minutes per occasion? A) Less than 1 time per
week; B) 1 time per week; C) 2 times per week; D) 3 or more times per week.

- Women who are pregnant at screening or plan to become pregnant during the course of
the study (determined by self-report) will be excluded. Women who become pregnant any
time during the course of the trial will not be dropped and will continue to be
followed throughout the duration of the study.

- Physical, medical or mental condition(s) precluding adherence to study protocol.
Conditions include: malignant disease (prospective participants' physicians to advise
and Dr. Barrett, and/or designee Dr. Rakel or Dr. Muller, to make final decision); and
function-impairing psychopathology (prospective participants' psychiatrist or
psychologist to advise). Questionable cases will be reviewed by the study physicians.

- True contraindication for influenza vaccine (flu shots) or refusal to accept influenza
vaccine. Subjects will be asked to verify they have a) no known egg allergy, b) no
prior reaction to influenza vaccine, and c) never been told they have Guillain-Barre
Syndrome.

- Current use or forecasted need for immunoactive drugs (eg. steroids,
immunosuppressants, chemotherapy); nonsteroidal antiinflammatories will be allowed.

- Immune deficiency or auto-immune disease (eg. HIV/AIDS, lupus, rheumatoid arthritis,
multiple sclerosis, inflammatory bowel disease). Questionable cases will be reviewed
by study physicians.