University of Wisconsin Meditation & Exercise Cold Study
University of Wisconsin Meditation & Exercise Cold Study
The primary goal of this project is to determine whether behavioral training in mindfulness
 meditation or moderate intensity sustained exercise will lead to reductions in acute
 respiratory infection (ARI) illness, such as common cold and influenza like illness.
 Specifically, this project aims to:

 1. Determine whether an 8-week training program in mindfulness meditation, as compared to
 the control group, will lead to significant reductions in incidence, duration, and
 severity of ARI illness.

 2. Determine whether an 8-week training program in moderate intensity sustained exercise,
 as compared to the control group, will lead to reductions in incidence, duration, and
 severity of ARI illness.

 3. Assess whether any observed reductions in ARI illness are accompanied by fewer
 ARI-related health care visits and less time lost to productive work (reduced
 absenteeism).

 4. Compare the potential benefits of mindfulness meditation to those from moderate
 intensity sustained exercise.

 5. Discern potential mediating factors and causal pathways that might help explain how
 these interventions lead to improved ARI illness-related outcomes.

 The investigators' preliminary findings suggest substantial benefit of these interventions in
 terms of reduced incidence, duration and severity of ARI illness, with corresponding
 reductions in days of work lost to illness. If the proposed research confirms these findings,
 there will be major implications for public and private health-related policy and practice,
 as well as for scientific knowledge regarding health maintenance and disease prevention.
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.