University of Wisconsin Meditation & Exercise Cold Study
Condition: Acute Respiratory Infection
MeSH terms: Infections; Respiratory Tract Infections
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Mindfulness Meditation; Exercise
Intervention type(s): Other; Other
Intervention description(s): Training will consist of a standardized 8-week Mindfulness Based Stress Reduction (MBSR) program, including 2½ hour weekly sessions and regular at-home daily practice. Didactic sessions center on awareness of physical, emotional, cognitive, and interpersonal responses to stress. A half day meditation "retreat" on a weekend day at the end of week 6 will allow participants to practice their skills.; Exercise training will primarily focus on walking or jogging, activities that are convenient, easy to teach and do not require special equipment. Individualized programs will be developed for those who have access to specific equipment, are unable to do walking/jogging, or prefer different types of exercise. Each weekly exercise session will include 1½ hours of didactic and 1 hour of group exercise. A half day exercise retreat designed to match the meditation retreat will occur the weekend of week 6. The retreat will include didactics, group discussion and activities, and individualized exercise practice.
Other intervention name(s): MBSR; physical activity
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: respiratory tract infections; common cold; exercise; influenza; meditation