Mindfulness in Chronic Kidney Disease

Study Overview
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Brief Summary
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This study will test whether mindfulness meditation (MM) improves sympathetic function in chronic kidney disease (CKD) and whether transcutaneous vagus nerve stimulation (tVNS) optimizes the sympatho-inhibitory effects of mindfulness meditation (MM) and restores autonomic balance in CKD patients.

Detailed Description
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 30 million people in the US have chronic kidney disease (CKD) and are at 5-15 fold greater risk of cardiovascular (CV) disease and mortality. A major factor contributing to increased CV risk in these patients is chronic elevation of sympathetic nervous system (SNS) activity. New therapeutic strategies to safely and effectively ameliorate SNS over-activity are of paramount importance to improve clinical outcomes in this highly prevalent and high-risk patient population. This study will test whether mindfulness meditation (MM) improves sympathetic function in chronic kidney disease (CKD) and whether transcutaneous vagus nerve stimulation (tVNS) optimizes the sympatho-inhibitory effects of mindfulness meditation (MM) and restores autonomic balance in CKD patients.

Official Title
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Sympatho-inhibition With Mindfulness in Chronic Kidney Disease (MIND-CKD)

Conditions
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Chronic Kidney Diseases

Intervention / Treatment
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* Behavioral: Mindfulness-based stress reduction (MBSR)
* Behavioral: Health enhancement program (HEP)
* Device: Transcutaneous Vagus Nerve Stimulation (tVNS)
* Device: Sham-transcutaneous Vagus Nerve Stimulation (tVNS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: stages III and IV CKD as defined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation stable renal function (no greater than a decline of eGFR of 1 cc/min/1.73 m2 per month over the prior 3 months) Exclusion Criteria: severe CKD (eGFR<15 cc/min) diabetic neuropathy autonomic dysfunction any serious disease that might influence survival anemia with hemoglobin <10 g/dL treatment with central α-agonists or monoamine oxidase (MAO) inhibitors myocardial infarction or cerebrovascular accident within the past 6 months uncontrolled hypertension (BP≥170/100 mm Hg) low BP (BP<100/50 mm Hg) bradycardia (HR<55 beats/min) ongoing drug or alcohol abuse (defined as >2 drinks/day in men, and >1 drink/day in women) surgery within the past 3 months adjustment of antihypertensive medications within the past month pregnancy or plans to become pregnant psychosis suicidal ideation implanted electronic or metallic device such as a pacemaker implanted hearing aid, bone plate, carotid stent, bone screw at or near the neck carotid atherosclerosis concurrent use of another stimulating device such as a transcutaneous electrical nerve stimulation (TENS) unit.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Protocol 1 (R61): 50 CKD participants will be randomized to MBSR (N=25) versus an active control intervention (health enhancement program, HEP; N=25). Protocol 2 (R33): 75 CKD participants will be randomized to MBSR+tVNS (n=25), MBSR+sham-tVNS (n=25), HEP+tVNS (n=25), and HEP+sham-tVNS (n=25).
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mindfulness-Based Stress Reduction (MBSR)<br>Mindfulness-Based Stress Reduction (MBSR) tis designed to provide education about mindfulness and stress; experiential mindfulness practice, and discussion of participants' experiences with mindfulness practice. MBSR is delivered in 8 weekly 2.5-hour group sessions and one day-long retreat that occurs after the 6th session. | Behavioral: Mindfulness-based stress reduction (MBSR)<br>* Mindfulness-based stress reduction (MBSR) is delivered in 8 weekly 2.5-hour group sessions and one day-long retreat that occurs after the 6th session. MBSR teaches to become more aware of thoughts, feelings, and sensations, and to skillfully respond to stressors. Each of the sessions includes education about mindfulness and stress; experiential mindfulness practice, and discussion of participants' experiences with mindfulness practice. Participants learn formal mindfulness practices (e.g., meditation, yoga, body scan, body scan) as well as informal such as awareness of breath, thoughts, or emotions, and mindfulness of daily activities. Participants will receive digital audio (MP3) downloads with guided MM practices, a home practice manual, and handouts with each week's assignments. Daily home practice will consist of 40-45 minutes of recorded practice. Participants will log their daily practice. If a participant misses a class, it is possible to make up the class on a different day.<br>|
| Active Comparator: Health enhancement program (HEP)<br>Health enhancement program (HEP) is designed to provide a structurally parallel, active control intervention to MBSR with health benefits in their own right, while omitting any components of mindfulness. HEP participants will meet with a health educator in a group setting for 8 weekly 2.5-hour sessions with a day-long retreat. | Behavioral: Health enhancement program (HEP)<br>* 8-week health enhancement program (HEP) is designed to provide a structurally parallel, active control intervention to MBSR with health benefits in their own right, while omitting any components of mindfulness. HEP matches MBSR in structure and content, and in parallel to MBSR, consists of music therapy, nutritional education, posture and balance movements, walking and stretching. Work with all practices with group discussion and exercises during an all-day spa day will match the all-day retreat in MBSR. HEP participants will meet with a health educator in a group setting for 8 weekly 2.5-hour sessions. Participants will receive MP3 downloads on an MP3 player with recordings of health education topics, a home listening manual, and weekly handouts with each week's listening assignments. Participants will listen to these MP3 recordings daily for 40-45 minutes and log their daily adherence.<br>|
| Experimental: MBSR+tVNS<br>Mindfulness-Based Stress Reduction (MBSR) tis designed to provide education about mindfulness and stress; experiential mindfulness practice, and discussion of participants' experiences with mindfulness practice. MBSR is delivered in 8 weekly 2.5-hour group sessions and one day-long retreat that occurs after the 6th session. Transcutaneous vagus nerve stimulation (tVNS) is a simple, noninvasive, self-administered adjunctive therapy, that may enhance the sympatho-inhibitory effects of mindfulness meditation (MM) in chronic kidney disease (CKD) . | Behavioral: Mindfulness-based stress reduction (MBSR)<br>* Mindfulness-based stress reduction (MBSR) is delivered in 8 weekly 2.5-hour group sessions and one day-long retreat that occurs after the 6th session. MBSR teaches to become more aware of thoughts, feelings, and sensations, and to skillfully respond to stressors. Each of the sessions includes education about mindfulness and stress; experiential mindfulness practice, and discussion of participants' experiences with mindfulness practice. Participants learn formal mindfulness practices (e.g., meditation, yoga, body scan, body scan) as well as informal such as awareness of breath, thoughts, or emotions, and mindfulness of daily activities. Participants will receive digital audio (MP3) downloads with guided MM practices, a home practice manual, and handouts with each week's assignments. Daily home practice will consist of 40-45 minutes of recorded practice. Participants will log their daily practice. If a participant misses a class, it is possible to make up the class on a different day.<br>Device: Transcutaneous Vagus Nerve Stimulation (tVNS)<br>* Transcutaneous Vagus Nerve Stimulation (tVNS) is delivered using gammaCore (Electrocore), a multi-use, hand-held, rechargeable portable device consisting of a rechargeable battery, signal generating and amplifying electronics, and a button for operator control of the stimulation intensity. Conductive gel is applied to the stainless steel round discs on the device and placed vertically on the skin overlying the vagus nerve under the angle of the mandible, between the trachea and sternocleidomastoid muscle. A low-voltage electrical signal is delivered consisting of 5-kilohertz (kHz) sine wave series for 1 ms and repeated every 40 ms, with a maximum delivery of 24 V and 60 milliampere (mA) output. Stimulation amplitude is adjusted by the user and is increased until there is a vibration and slight muscle contraction in the lower face or neck. Stimulation is delivered for 2 minutes on the left side of the neck, and 2 minutes on the right side of the neck, for a total 4 minutes per one dose.<br>|
| Active Comparator: MBSR+sham-tVNS<br>Mindfulness-Based Stress Reduction (MBSR) tis designed to provide education about mindfulness and stress; experiential mindfulness practice, and discussion of participants' experiences with mindfulness practice. MBSR is delivered in 8 weekly 2.5-hour group sessions and one day-long retreat that occurs after the 6th session. Sham stimulation will be delivered using a sham device that is identical in appearance and function to tVNS, but programmed to produce a lower frequency biphasic signal that can be felt by the participant without actually stimulating the vagus nerve. | Behavioral: Mindfulness-based stress reduction (MBSR)<br>* Mindfulness-based stress reduction (MBSR) is delivered in 8 weekly 2.5-hour group sessions and one day-long retreat that occurs after the 6th session. MBSR teaches to become more aware of thoughts, feelings, and sensations, and to skillfully respond to stressors. Each of the sessions includes education about mindfulness and stress; experiential mindfulness practice, and discussion of participants' experiences with mindfulness practice. Participants learn formal mindfulness practices (e.g., meditation, yoga, body scan, body scan) as well as informal such as awareness of breath, thoughts, or emotions, and mindfulness of daily activities. Participants will receive digital audio (MP3) downloads with guided MM practices, a home practice manual, and handouts with each week's assignments. Daily home practice will consist of 40-45 minutes of recorded practice. Participants will log their daily practice. If a participant misses a class, it is possible to make up the class on a different day.<br>Device: Sham-transcutaneous Vagus Nerve Stimulation (tVNS)<br>* Sham stimulation will be delivered using a sham device that is identical in appearance and function, but programmed to produce a lower frequency biphasic signal that can be felt by the participant without actually stimulating the vagus nerve.<br>|
| Experimental: HEP+tVNS<br>Health enhancement program (HEP) is designed to provide a structurally parallel, active control intervention to MBSR with health benefits in their own right, while omitting any components of mindfulness. HEP participants will meet with a health educator (a registered dietician) in a group setting for 8 weekly 2.5-hour sessions. Transcutaneous vagus nerve stimulation (tVNS) is a simple, noninvasive, self-administered adjunctive therapy, that may enhance the sympatho-inhibitory effects of mindfulness meditation (MM) in chronic kidney disease (CKD). | Behavioral: Health enhancement program (HEP)<br>* 8-week health enhancement program (HEP) is designed to provide a structurally parallel, active control intervention to MBSR with health benefits in their own right, while omitting any components of mindfulness. HEP matches MBSR in structure and content, and in parallel to MBSR, consists of music therapy, nutritional education, posture and balance movements, walking and stretching. Work with all practices with group discussion and exercises during an all-day spa day will match the all-day retreat in MBSR. HEP participants will meet with a health educator in a group setting for 8 weekly 2.5-hour sessions. Participants will receive MP3 downloads on an MP3 player with recordings of health education topics, a home listening manual, and weekly handouts with each week's listening assignments. Participants will listen to these MP3 recordings daily for 40-45 minutes and log their daily adherence.<br>Device: Transcutaneous Vagus Nerve Stimulation (tVNS)<br>* Transcutaneous Vagus Nerve Stimulation (tVNS) is delivered using gammaCore (Electrocore), a multi-use, hand-held, rechargeable portable device consisting of a rechargeable battery, signal generating and amplifying electronics, and a button for operator control of the stimulation intensity. Conductive gel is applied to the stainless steel round discs on the device and placed vertically on the skin overlying the vagus nerve under the angle of the mandible, between the trachea and sternocleidomastoid muscle. A low-voltage electrical signal is delivered consisting of 5-kilohertz (kHz) sine wave series for 1 ms and repeated every 40 ms, with a maximum delivery of 24 V and 60 milliampere (mA) output. Stimulation amplitude is adjusted by the user and is increased until there is a vibration and slight muscle contraction in the lower face or neck. Stimulation is delivered for 2 minutes on the left side of the neck, and 2 minutes on the right side of the neck, for a total 4 minutes per one dose.<br>|
| Active Comparator: HEP+sham-tVNS<br>Health enhancement program (HEP) is designed to provide a structurally parallel, active control intervention to MBSR with health benefits in their own right, while omitting any components of mindfulness. HEP participants will meet with a health educator in a group setting for 8 weekly 2.5-hour sessions. Sham stimulation is be delivered using a sham device that is identical in appearance and function to tVNS, but programmed to produce a lower frequency (0.1 Hz) biphasic signal that can be felt by the participant without actually stimulating the vagus nerve. | Behavioral: Health enhancement program (HEP)<br>* 8-week health enhancement program (HEP) is designed to provide a structurally parallel, active control intervention to MBSR with health benefits in their own right, while omitting any components of mindfulness. HEP matches MBSR in structure and content, and in parallel to MBSR, consists of music therapy, nutritional education, posture and balance movements, walking and stretching. Work with all practices with group discussion and exercises during an all-day spa day will match the all-day retreat in MBSR. HEP participants will meet with a health educator in a group setting for 8 weekly 2.5-hour sessions. Participants will receive MP3 downloads on an MP3 player with recordings of health education topics, a home listening manual, and weekly handouts with each week's listening assignments. Participants will listen to these MP3 recordings daily for 40-45 minutes and log their daily adherence.<br>Device: Sham-transcutaneous Vagus Nerve Stimulation (tVNS)<br>* Sham stimulation will be delivered using a sham device that is identical in appearance and function, but programmed to produce a lower frequency biphasic signal that can be felt by the participant without actually stimulating the vagus nerve.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mean Muscle Sympathetic Nerve Activity (MSNA) burst frequency (BF) | Multiunit postganglionic sympathetic nerve activity is recorded from a tungsten microelectrode inserted into the peroneal nerve with a reference microelectrode inserted in close proximity. Efferent nerve signals are amplified, filtered, rectified and integrated (time constant 0.1 s) to obtain a mean voltage display of MSNA. MSNA bursts are automatically detected using the following criteria: burst-to-noise ratio of 3:1 within a 0.5-s search window, with an average latency of 1.2-1.3 s in burst occurrence from the previous R-wave. MSNA is expressed as burst frequency (BF, bursts/min). | Baseline, 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in daytime burst frequency (BF) | Multiunit postganglionic sympathetic nerve activity is recorded from a tungsten microelectrode inserted into the peroneal nerve with a reference microelectrode inserted in close proximity. Efferent nerve signals are amplified, filtered, rectified and integrated (time constant 0.1 s) to obtain a mean voltage display of MSNA. MSNA bursts are automatically detected using the following criteria: burst-to-noise ratio of 3:1 within a 0.5-s search window, with an average latency of 1.2-1.3 s in burst occurrence from the previous R-wave. MSNA is expressed as burst frequency (BF, bursts/min). | Baseline, 8 weeks | 
| Change in nocturnal dipping of burst frequency (BF) | Multiunit postganglionic sympathetic nerve activity is recorded from a tungsten microelectrode inserted into the peroneal nerve with a reference microelectrode inserted in close proximity. Efferent nerve signals are amplified, filtered, rectified and integrated (time constant 0.1 s) to obtain a mean voltage display of MSNA. MSNA bursts are automatically detected using the following criteria: burst-to-noise ratio of 3:1 within a 0.5-s search window, with an average latency of 1.2-1.3 s in burst occurrence from the previous R-wave. MSNA is expressed as burst frequency (BF, bursts/min). | Baseline, 8 weeks | 
| Change in baroreflex sensitivity (BRS) | Afferent sympathetic baroreflex input travels to the brainstem via the glossopharyngeal and vagus nerves and integrate with brainstem centers that regulate efferent SNS (sympathetic BRS) and parasympathetic (cardiovagal BRS) outflow. BRS is defined as the change in interbeat interval (IBI) in milliseconds per unit change in BP. For example, when the BP rises by 10 mmHg and IBI increases by 100 ms, BRS would be 100/10 = 10 ms/mmHg. | Baseline, 8 weeks | 
| Change in Tumor necrosis factor (TNF) level | Tumor necrosis factor (TNF) is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. It will be measured by blood test. | Baseline, 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mindfulness, Transcutaneous Vagus Nerve Stimulation, tVNS, Sympatho-inhibitory effects