Mindfulness-Based Stress-Reduction in Patients With Crohn's Disease
Condition: Crohn's Disease Colon
MeSH terms: Crohn Disease
Study type: Interventional

Summary: 
      A randomized controlled study which aims to improve the quality of life of Crohn's disease
      adult patients suffering from mild to moderate level of symptoms. Patients will be randomized
      to Intervention or Wait-List groups and will undergo eight Cognitive Behavioral and
      Mindfulness, one on one, sessions with a social worker via SkypeTM. The Intervention group
      will receive intervention upon recruitment while the Wait-List group will receive the same
      intervention after 3 months. Clinical, biological and psycho-social data will be collected at
      four time points over the 12-months of the study.
    

Detailed description: 
      1. Overall objectives:

             1. Primary outcome: To determine whether mindfulness-based stress reduction will lead
                to a better health-related quality-of-life by use of three questionnaires:

                • the Crohn's disease specific SIBDQ (Short Inflammatory Bowel Disease
                Questionnaire, with mean score and 4 subscales: bowel, systemic, social, emotional)

                  -  SF-12 (MOS Short-Form-12) which is derived from the generic SF-36 used in our
                     previous research (SF-36 measures a Physical Health Summary Score comprised of
                     physical functioning, role-physical, bodily pain and general health, and a
                     Mental Health Summary Score comprised of vitality, role-emotional, social
                     functioning and mental health).

                  -  EQ-5D (EuroQol questionnaire, for calculation of utility weights)

             2. Secondary outcomes: improvement in mindfulness (FMI, Freiburg Mindfulness
                Inventory); reduction of stress, anxiety and depression (BSI - Brief Symptom
                Inventory, GSI - General Severity Index stress measure, MSPSS- Multidimensional
                Scale of Perceived Social Support, PSS-4 Perceived Stress Scale, LEQ- life events
                questionnaire); better satisfaction with life (SWLS, Satisfaction with Life Scale);
                improved family function (FAD, Family Assessment Device); pain reduction (HBI,
                Harvey-Bradshaw Index of activity of Crohn's disease); less fatigue (FACIT Fatigue
                Scale); better coping with disease (COPE: Brief Cope Inventory - Brief Coping
                Operations Preference Enquiry); better performance at work (WPAI, Work Productivity
                and Activity Impairment) and cost estimation. Significant changes in the scores of
                these questionnaires, based on our current work comparing P-HBI remission versus
                active disease, are the following (all are given in points, except WPAI is
                percent): SIBDQ 6, SWLS 5, FAD 0.15, COPE dysfunctional 2.5, COPE emotion-focused
                0.7, COPE problem-focused 0.6, WPAI time missed 14, WPAI percent impairment 29,
                WPAI work impairment 28, WPAI activity impairment 30, GSI 0.6, BSI anxiety 0.6, BSI
                depression 0.6. We did not use the SF-12, EQ-5D, MSPSS, PSS-4 and the FACIT Fatigue
                Scale in our previous research and will look at reports in the literature and our
                newly acquired data to determine what are significant improvements.

             3. Before and at the end of each intervention session a short assessment of patient's
                subjective units of distress (SUDS) will be done, as per Wolpe, Joseph (1969), The
                Practice of Behavior Therapy, New York: Pergamon Press, and the 4 question
                Short-Form Perceived Stress Scale, as per Warttig et al, J Health Psychology
                2013;18:1617-28.

             4. Correlations of psychological measures with demography, economic status, HBI,
                immune regulation, telomere shortening, fMRI data, changes in composition of
                microbiota. Change in biophysical parameters as sleep physical activity & pulse
                rate.

             5. To determine whether the intervention is cost-saving or cost-effective, by
                prospective monitoring of resource use and indirect costs.

             6. To determine whether the intervention can be given effectively using telemedicine
                with Skype or alternative software.

             7. To study patient acceptability of the intervention, including recruitment and
                drop-out rate, and the adherence rate to home practice of the stress reduction
                measure taught.

        2. Expected outcomes

             1. Reduced HBI, improvement of all the psychological measures including both
                quality-of-life and satisfaction with life, less stress, less fatigue, more use of
                adaptive coping strategies, with no clear improvements in the control group.
                Improvement in biophysical parameters as sleep physical activity & pulse rate.

             2. The research will identify the best form of delivering the interventional therapy
                and if it is cost-saving or cost-effective.

             3. Confirmation of the reliability of measurements of modification of immune
                regulation mechanisms and telomere length, grey matter thickness and composition of
                the microbiota.

             4. Glucocorticoid resistance and related laboratory determinations on patients'
                leukocytes will add to understanding the biological mechanisms associated with
                stress-induced pathogenic autoimmunity in the patients in a sex-dependent manner.
                This will add to our understanding the biological mechanisms associated with stress
                in Crohn's disease.

        3. Work plan and methodology

           a. Patient recruitment i. Patients: 200 patients being treated at all the participating
           hospitals (Soroka Medical Center, Rambam Health Campus, Sheba Medical Center, Rabin
           Medical Center, Shaare Zedek Medical Center), which all have electronic records of large
           cohorts of patients with Crohn's disease and by advertising through patient support
           groups and institutions upon approval. The recruitment of patients will be offered in
           all the hospitals. Preference will be given to patients who have participated in the
           previous IIRN study and are now participating in the new IIRN studies proposed by the
           other hospitals, and those patients in higher risk groups (poorer men, female gender,
           etc.).

      iv. Patients on a fixed dose of corticosteroids and those who received corticosteroid therapy
      in last 6 months will present a special sub-group on whom the laboratory studies of cortisol
      and glucocorticoid resistance may differ significantly from patients not on this treatment,
      but this will have to be verified by measurements in a small sample to determine the
      magnitude of the effect before a decision to include or exclude these individuals.

      v. Patients with change of diagnosis in the course of the study period will be excluded from
      the final analysis.

      vi. Ethical considerations: This protocol will need approval of the Ethics Committee at all
      hospitals prior to commencement of patient recruitment and access of patient data at these
      hospitals. A signed informed consent form will be obtained from each participant.

      b. Assessment of patient status i. Medical status (HBI) and phenotype. No attempt will be
      made to modify the patients' treatments.

      ii. Psycho-social self-report questionnaires: demography, economic status, SIBDQ, EQ-5D,
      SF-12, WPAI, SWLS, FACIT, COPE, FAD, BSI, GSI, FMI, MSPSS, PSS-4, LEQ.

      iii. Objective outcomes:

        1. HBI, CRP, calprotectin, relevant imaging studies (radiology, endoscopy) biophysical
           parameters as sleep physical activity & pulse rate.

        2. Special tests on all or selected sub-sets of patients: immune regulation, telomeres,
           fMRI, and microbiota.

        3. Biophysical parameters as sleep physical activity & pulse rate will be monitored in 30
           patients by using commercially available smart watches.

           c. Psycho-social interventions i. The sample size calculation is based on α = 0.05,
           power = 0.8, SD = 14 (data from our current research) in order to achieve a 6-point
           change in the SIBDQ (the primary endpoint). Thus, the cohort will consist of 172
           patients computer-randomized to two groups; 86 patients with mindfulness-based stress
           reduction, and 86 wait-list controls that will enter the intervention phase after 3
           months. In order to allow for a 15% expected drop-out rate, these recruitment numbers
           may need to be increased to 200 patients. An equal number of women and men will be
           recruited at each hospital.

           ii. The group that receives mindfulness-based stress reduction at their entry into the
           study will have 7 sequential sessions during 3 months, and later have a booster session
           in month 5. This group will have 4 time points for assessment (see Table, below).

           iii. Wait-list control patients will get no intervention at the start of the study and
           instead will be contacted by study personal 7 times to care for the patient in order to
           control for the 7 sessions performed in the intervention group. After three months they
           will be offered mindfulness-based stress reduction as 8 sequential sessions. The reason
           for wait-listing is to ensure that there will be a control group to parallel the first 3
           months of intervention therapy in the patients getting the therapy from the start. The
           control group will have the same time points for data assessment as the intervention
           group.

           iv. All interventions will be individual sessions. v. Patients will be accessed via
           internet apps such as Skype. vi. Mindfulness-based stress reduction is to be given by
           specially trained therapists: These are social workers (PhD or Masters candidate level),
           who have undergone a training session program provided by relevant researchers of this
           protocol (including clinicians) as well as invited outside psychologists and
           psychiatrists with specialization in this field.

           vii. Psycho-social, medical and biological data will be collected at the measurement
           points T1, T2, T3 and T4 (see Table) in all patients. fMRI (to be performed at Soroka
           Medical Center, without use of contrast) and microbiota studies (stool samples) will be
           performed on a subset of patients.

           d. Health-care cost i. Direct costs: admissions to hospital, surgery, consultations
           (primary care physicians, specialists, dieticians, social services) investigations and
           medications, travel costs to medical facilities.

           ii. Indirect costs: lost workdays, lost productivity, disability payments, travel costs
           and expenses of escorts.

           e. Immune regulation studies, glucocorticoid resistance in lymphocytes, telomeres i.
           Blood collections (see Table of events, below) will be performed on consenting patients
           with Crohn's disease before and after Mindfulness-based stress reduction at 3 time
           points, as well as in age- and gender-matched consenting healthy volunteer controls
           (consenting patients without inflammatory diseases attending at the Gastroenterology
           Department at Soroka Medical Center for screening endoscopies) at one time points.

           ii. Blood will be drawn immunological and telomere studies.

      1. Immunology: Blood is sampled twice from 60 Crohn's disease and from 60 controls for
      isolation of serum and peripheral blood mononuclear cell aliquots at enrollment and after
      Mindfulness-based stress reduction (provided these patients enter a phase of remission).
      Serum measures will include plasma C-reactive protein (CRP), ACTH, CBG and sex hormones.
      Similarly, peripheral blood mononuclear cell will undergo functional immune phenotyping of
      disease-implicated T cell and B cell subsets and assessments of their glucocorticoid
      resistance. Glucocorticoid signaling experiments will be performed in purified
      pro-inflammatory lymphocyte subsets found to exhibit glucocorticoid resistance. Results will
      be correlated with all other measures in this proposal. Controls for these tests will be
      matched healthy volunteers. The same tests will be carried out in the controls.

      2. Telomere studies in 30 patients with Crohn's disease and 30 controls: by TeloTAGGG™
      Telomere Length Assay (Merck). Two blood samples will be needed (see Table of events, below)
      f. Stool testing - stool samples will be collected at T1 and T2 i. Calprotectin will be
      measured in the stool at T1 and T2. ii. Microbiota study will be performed on 30 intervention
      patients and 30 control patients.

      g. fMRI - A non-contrast brain MRI will be performed on 30 intervention and 30 control
      patients at T1 and T2
    

Intervention name(s): Cognitive behavioral mindfulness intervention; Cognitive behavioral mindfulness intervention after 3-month wait list
Intervention type(s): Behavioral; Behavioral
Intervention description(s): The group that receives mindfulness-based stress reduction at their entry into the study will have 7 sequential sessions during 3 months, and later have a booster session in month 5; Wait-list control patients will get no intervention at the start of the study and instead will be contacted by study personal 7 times to care for the patient in order to control for the 7 sessions performed in the intervention group. After three months they will be offered mindfulness-based stress reduction as 8 sequential sessions.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Crohn's Disease; Health-related quality of life; Cognitive behavioral therapy; Mindfulness; Healthcare cost; Immune regulation