Mindfulness-based Cognitive Therapy for Patients With Inflammatory Bowel Disease

Mindfulness-based Cognitive Therapy to Improve Stress and Sleep in Patients With Inflammatory Bowel Disease

Considering the limited availability of psychosocial interventions for IBD, this study aims to investigate MBCT as an adjunctive treatment to treatment as usual to reduce psychological stress and improve sleep quality/regularity in patients with IBD who report elevated stress levels. The study will have a follow-up duration of 12 months from baseline.

Study Overview

• Status: Completed
• Conditions: Inflammatory Bowel Diseases
• Intervention / Treatment: Behavioral: Mindfulness-based cognitive therapy + TAU; Other: Treatment as usual (TAU)

Detailed Description

Introduction:

Inflammatory bowel diseases (IBD) are chronic inflammatory diseases of the intestinal tract, consisting of crohn's disease (CD) and ulcerative colitis (UC). In The Netherlands, there are about 90,000 IBD patients, mainly young adults who are in a turbulent part of their life with starting a family and career. The prevalence of IBD seems to be rising. The peak incidence is between 15 and 30 years. The disease is characterized by periods of disease activity (flares) alternating with periods of (clinical) remission. Physical symptoms include abdominal pain, diarrhea, rectal bleeding and fatigue. Although the arsenal of drugs has increased in recent decades, there is no cure for the disease and patients are usually long-term treated with different (immunosuppressive) medications. Nevertheless, at this moment, we are only partially able to keep our IBD patients in remission.

Even in those in remission, IBD is associated with increased levels of psychological stress, with estimated prevalence rates of 21% for depressive symptoms and 35% for anxiety symptoms. In periods of disease activity, prevalence of elevated anxiety levels was even found to be as high as 75.6%. Besides psychological stress, IBD patients in remission report lower quality of life compared to the general population. This is due to the physical symptoms but also to fatigue, worries, anxiety, depression, impaired satisfaction with social role and sleep disturbances. More than 40 % of the IBD patients experience fatigue. This may contribute to the higher sick leave days and higher work impairment rates in quiescent IBD, causing high societal costs. In addition, poor sleep seems common in individuals with IBD and has been linked to disease activity and shown as a predictor for subclinical inflammation and a risk factor for relapse and poorer outcomes.

Mindfulness training, typically in the form of mindfulness-based stress reduction (MBSR) or mindfulness-based cognitive therapy (MBCT), is a psychosocial group-based intervention that has been shown to reduce psychological distress and improving quality of life, both in patients with mental health problems and those with chronic diseases such as diabetes, cancer, cardiovascular disease, rheumatoid arthritis and fibromyalgia. Mindfulness training focuses on the progressive acquisition of mindful awareness to better cope with negative repetitive thoughts and feelings, and for that reason may be a good option to reduce psychological stress and fatigue, and improve quality of life in patients with chronic conditions including IBD.

Although the available literature on the effectiveness of mindfulness-based interventions for IBD is still relatively scarce, a recent meta-analysis showed significant benefits in terms of stress, depression, and quality of life. However, the variety in types of interventions was rather high, and individual studies typically suffered from methodological limitations, including small sample size, poor blinding of the outcome assessors, incomplete data reporting and a relative lack of fidelity measures. Therefore, it seems warranted to conduct a high-quality, multicenter randomized controlled trial investigating the effectiveness of MBCT to improve stress, sleep quality, and quality of life.

Aims:

Considering the limited availability of psychosocial interventions for IBD, this study aims to investigate MBCT as an adjunctive treatment to TAU to reduce psychological stress in patients with IBD who report elevated stress levels. In addition, we aim to improve sleep quality/regularity and fatigue, IBD-related quality of life, perceived control over IBD, clinical indicators (fecal calprotectin, c-reactive protein levels, Harvey Brashaw Index for CD, Simple Clinical Colitis Activity Index for UC), IBD-related flare. We also aim to improve repetitive negative thinking, mindfulness skills, self-compassion skills, and positive mental health. We will investigate whether improving sleep quality may be one of the pathways through which mindfulness may help reduce psychological distress and improve quality of life in IBD (working mechanism).

Method:

A two-armed randomized, multicenter, parallel group pragmatic trial comparing Mindfulness-Based Cognitive Therapy (MBCT) vs. Treatment As Usual (TAU) for reducing psychological distress in distressed patients with Inflammatory Bowel Disease (IBD). Assessments will be conducted at baseline, post treatment (3 months) and follow-ups at 6, 9, and 12 months. Objective sleep measures will be taken at baseline, post treatment and 12 months.

The control group will receive treatment as usual (TAU) according to Dutch and European IBD treatment guidelines. The intervention group will receive Mindfulness-Based Cognitive Therapy (MBCT) in addition to TAU. The MBCT protocol that will be used is based on the protocol published by Segal, Williams and Teasdale. MBCT consists of eight weekly 2.5h group sessions, a six-hour silent day and daily home practice assignments guided by audio files. Mindfulness is characterized by deliberate, non-judging and sustained moment-to-moment awareness. Health related benefits include enhanced emotional processing and coping regarding the effects of chronic illness and stress, improved self-efficacy and control, and a more accepting attitude towards difficult emotions, thought and bodily sensations. Psycho-education and interactive dialogue typically focus on stress management, balancing activities, lifestyle factors, and strategies to stay well in the future (relapse prevention). Each group will be comprising 8-12 participants. MBCT courses will be taught on site by qualified mindfulness teachers. Teacher competency will be assessed with the Mindfulness-Based Interventions - Teaching Assessment Criteria, using a random selection of videotaped sessions, assessed by expert teachers who have been trained to use these assessment criteria.

• Study Type: Interventional
• Enrollment (Actual): 142
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Arnhem, Netherlands
    • Rijnstate Ziekenhuis
  • Den Bosch, Netherlands
    • Jeroen Bosch ziekenhuis
  • Nijmegen, Netherlands
    • Canisius Wilhelmina Ziekenhuis
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GC
      • Radboud University Nijmegen Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Confirmed IBD diagnosis of Crohn's disease (CD), Ulcerative colitis (UC) or Indeterminate colitis (IC)
• Current IBD remission (Calprotectin < 250 mg/kg) since at least three months
• Hospital Anxiety and Depression Scale-score of >=11, indicating at least mild levels of psychological distress (Vodermaier 2011).
• Age of 16 or older
• Taking no IBD medication or on a stable dose of 5-ASA products, immunosuppressive medication, or biologics for at least three months prior to enrollment.

Exclusion Criteria:

• Severe psychiatric disorders (e.g. acute suicidality, psychosis)
• Current alcohol or drug dependency
• Untreated anemia
• Prior participation in an 8-week MBSR or MBCT-programme

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mindfulness-based cognitive therapy (MBCT) added to treatment as usual; Patients in the MBCT arm will in addition to their treatment as usual be invited to participate in MBCT.	Behavioral: Mindfulness-based cognitive therapy + TAU; The proposed intervention is mindfulness-based cognitive therapy (MBCT), based on the protocol published by Segal, Williams and Teasdale. MBCT consists of eight weekly 2.5h group sessions, a six-hour silent day and daily home practice assignments guided by audio files. The program includes both formal and informal meditation exercises. Cognitive techniques include monitoring and scheduling of activities, identification of negative automatic thoughts and devising a relapse prevention plan. Psycho-education and interactive dialogue typically focus on stress management, balancing activities, and (lifestyle) strategies to stay well in the future (relapse prevention).
Active Comparator: Treatment as usual (TAU); Patients in this arm will receive treatment as usual.	Other: Treatment as usual (TAU); Treatment as usual (TAU) according Dutch and European IBD treatment guidelines. TAU focuses on pharmacological and surgical disease control, and prevention of complications.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Psychological distress	Measured by the Hospital Anxiety and Depression Scale (HADS). The HADS consists of 14 items, 7 related to depression and 7 related to anxiety. Scoring for each item ranges from zero to three. Three denotes highest anxiety or depression level meaning that a person can score between 0 and 21 for either anxiety or depression.	Change between baseline and 3 months
Psychological distress	Measured by the Hospital Anxiety and Depression Scale (HADS). The HADS consists of 14 items, 7 related to depression and 7 related to anxiety. Scoring for each item ranges from zero to three. Three denotes highest anxiety or depression level meaning that a person can score between 0 and 21 for either anxiety or depression.	Change between 3 and 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective sleep quality	operationalized as total sleep time, time spent in slow wave sleep, sleep continuity, all measured with wearable sleep EEG (iBand+/ Arenar and Fitbit activity tracker).	Change between baseline and 3 months
Objective sleep quality	operationalized as total sleep time, time spent in slow wave sleep, sleep continuity, all measured with wearable sleep EEG (iBand+/ Arenar and Fitbit activity tracker).	Change between 3 and 12 months
Subjective sleep quality	Measured by the Pittsburgh Sleep Quality Inventory (PSQI). The PSQI consist of 19 items offering 7 components scores and one composite score. Scoring for each component ranges from zero to three. The overall PSQI score is then calculated by totaling the seven component scores, providing an global score ranging from zero to twenty-one. Lower scores indicate a healthier sleep quality.	Change between baseline and 3 months
Subjective sleep quality	Measured by the Pittsburgh Sleep Quality Inventory (PSQI). The PSQI consist of 19 items offering 7 components scores and one composite score. Scoring for each component ranges from zero to three. The overall PSQI score is then calculated by totaling the seven component scores, providing an global score ranging from zero to twenty-one. Lower scores indicate a healthier sleep quality.	Change between 3 and 12 months
Fatigue	measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F).The FACIT-F is a 40-item self-reported measure that assesses fatigue and its impact on daily activities and function. Subdomains include: physical Well-Being, Social/Family Well-Being, Emotional Well-Being, Functional Well-Being and Fatigue. The subdomain fatigue consists of 13-items. Items are scored on a 0-4 response scale with anchors ranging from 'not at all' to 'very much so'. All items are summed to create a global fatigue score with a range from 0 to 52. Higher scores indicate increased fatigue.	Change between baseline and 3 months
Fatigue	measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F).	Change between 3 and 12 months
IBD-related quality of life	measured by the Inflammatory Bowel Disease Quality of Life Questionnaire (IBDQ). The IBDQ has 32 items scored on a 7-point Likert scale, ranging from 1 (worst health) to 7 (best health). Overall score range from 32 to 224, with higher scores reflecting better quality of life.	Change between baseline and 3 months
IBD-related quality of life	measured by the Inflammatory Bowel Disease Quality of Life Questionnaire (IBDQ). The IBDQ has 32 items scored on a 7-point Likert scale, ranging from 1 (worst health) to 7 (best health). Overall score range from 32 to 224, with higher scores reflecting better quality of life.	Change between 3 and 12 months
Perceived control over IBD	measured by the IBD-Control questionnaire. The IBD-Control Questionnaire consists of eight items, which generate an overall score ranging from 0 (worst control) to 16 (best control).	Change between baseline and 3 months
Perceived control over IBD	Measured by the IBD-Control questionnaire. The IBD-Control Questionnaire consists of eight items, which generate an overall score ranging from 0 (worst control) to 16 (best control).	Change between 3 and 12 months
Calprotectin	Assessed in accordance with regular medical procedures. Having higher levels of calprotectin generally means that there is active inflammation in the body or intestines. For a calprotectin test, a normal reading is less than 100 mcg/g.	Change between baseline and 3 months
Calprotectin	Assessed in accordance with regular medical procedures. Having higher levels of calprotectin generally means that there is active inflammation in the body or intestines. For a calprotectin test, a normal reading is less than 100 mcg/g.	Change between 3 and 12 months
C-reactive protein levels	Assessed in accordance with regular medical procedures. Also having higher levels of c-reactive protein generally means that there is active inflammation in the body or intestines. For a CRP test, a normal reading is less than 10 milligram per liter (mg/L).	Change between baseline and 3 months
C-reactive protein levels	Assessed in accordance with regular medical procedures. Also having higher levels of c-reactive protein generally means that there is active inflammation in the body or intestines. For a CRP test, a normal reading is less than 10 milligram per liter (mg/L).	Change between 3 and 12 months
Clinical disease activity	Assessed by a clinician with the Harvey Brashaw Index (HBI) for Crohn's disease and the Simple Clinical Colitis Activity Index	change between baseline and 3 months
Clinical disease activity	Assessed by a clinician with the Harvey Brashaw Index (HBI) for Crohn's disease and the Simple Clinical Colitis Activity Index	change between 3 and 12 months
Repetitive negative thinking	measured by the 15-item Perseverative Thinking Questionnaire (PTQ). The PTQ is a 15-item self-report questionnaire. Respondents are asked to describe how they typically think about negative experiences or problems. They rate each item on a 5-point Likert scale from 0 (never) to 4 (almost always) the extent to which each statement applies to them when they think about negative experiences or problems. All items are summed to create a global repetitive negative thinking score ranging from 0 to 60. Higher scores indicate increased repetitive negative thinking.	Change between baseline and 3 months
Repetitive negative thinking	measured by the 15-item Perseverative Thinking Questionnaire (PTQ). The PTQ is a 15-item self-report questionnaire. Respondents are asked to describe how they typically think about negative experiences or problems. They rate each item on a 5-point Likert scale from 0 (never) to 4 (almost always) the extent to which each statement applies to them when they think about negative experiences or problems. All items are summed to create a global repetitive negative thinking score ranging from 0 to 60. Higher scores indicate increased repetitive negative thinking.	Change between 3 and 12 months
Mindfulness skills	24-item Five Facet Mindfulness Questionnaire Short Form (FFMQ-SF). This questionnaire is divided into the subscales observing, describing, acting with awareness, non-judging and non-reactivity.	Change between baseline and 3 months
Mindfulness skills	24-item Five Facet Mindfulness Questionnaire Short Form (FFMQ-SF). This questionnaire is divided into the subscales observing, describing, acting with awareness, non-judging and non-reactivity.	Change between 3 and 12 months
Positive mental health	Measured by the Mental Health Continuum-Short Form (MHC-SF). MHC-SF consists of 14-items and assesses emotional, psychological and social well-being. All items are summed and then a mean score is calculated, which represents a global positive mental health score ranging from 0 to 5. Higher scores indicate a better positive mental health.	Change between baseline and 3 months
Positive mental health	Measured by the Mental Health Continuum-Short Form (MHC-SF). MHC-SF consists of 14-items and assesses emotional, psychological and social well-being. All items are summed and then a mean score is calculated, which represents a global positive mental health score ranging from 0 to 5. Higher scores indicate a better positive mental health.	Change between 3 and 12 months
Self-compassion	We will use the 12-item Dutch short-form version of the SCS-SF to measure self-compassion. The scale consists of six components, including self-kindness, self-judgment, common humanity, isolation, mindfulness and over-identification. In the short form, each scale consists of 2 items scored between 1 ((almost) never) to 7 ((almost) always) and subscale score ranges between 2 and 14. A higher score indicates a higher level of self-kindness, common humanity, and mindfulness, and lower scores of self-judgment, isolation, and over-identification. Total scores range from 12 to 84 (summed subscale scores), a higher score indicates a higher level of self-compassion.	Change between baseline and 3 months
Self-compassion	We will use the 12-item Dutch short-form version of the SCS-SF to measure self-compassion. The scale consists of six components, including self-kindness, self-judgment, common humanity, isolation, mindfulness and over-identification. In the short form, each scale consists of 2 items scored between 1 ((almost) never) to 7 ((almost) always) and subscale score ranges between 2 and 14. A higher score indicates a higher level of self-kindness, common humanity, and mindfulness, and lower scores of self-judgment, isolation, and over-identification. Total scores range from 12 to 84 (summed subscale scores), a higher score indicates a higher level of self-compassion.	Change between 3 and 12 months
Costs	This will be investigated by using the Trimbos iMTA Questionnaire for Costs associated with Psychiatric Illness (TiC-P) as a measure of healthcare utilization. Unit cost estimates are derived from the national manual for cost prices in the healthcare sector.	12 months
Health-related quality of life	This will be assessed by using the EuroQol-5D (EQ-5D-5L). The EQ-5D-5L consist of five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. This short self-report instrument is used to assess quality adjusted life years.	12 months

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development; Rijnstate Hospital; Jeroen Bosch Ziekenhuis; Canisius-Wilhelmina Hospital; Donders Institute for Brain, Cognition and Behaviour
• Investigators: Principal Investigator: Anne Speckens, Dr., Radboud University Medical Center; Study Chair: Loes Nissen, Dr., Jeroen Bosch ziekenhuis; Study Chair: Marloes Huijbers, Dr., Radboud University Medical Center

Publications and helpful links

General Publications

• Scott-Sheldon LAJ, Gathright EC, Donahue ML, Balletto B, Feulner MM, DeCosta J, Cruess DG, Wing RR, Carey MP, Salmoirago-Blotcher E. Mindfulness-Based Interventions for Adults with Cardiovascular Disease: A Systematic Review and Meta-Analysis. Ann Behav Med. 2020 Jan 1;54(1):67-73. doi: 10.1093/abm/kaz020.
• Ewais T, Begun J, Kenny M, Rickett K, Hay K, Ajilchi B, Kisely S. A systematic review and meta-analysis of mindfulness based interventions and yoga in inflammatory bowel disease. J Psychosom Res. 2019 Jan;116:44-53. doi: 10.1016/j.jpsychores.2018.11.010. Epub 2018 Nov 14.
• Neuendorf R, Harding A, Stello N, Hanes D, Wahbeh H. Depression and anxiety in patients with Inflammatory Bowel Disease: A systematic review. J Psychosom Res. 2016 Aug;87:70-80. doi: 10.1016/j.jpsychores.2016.06.001. Epub 2016 Jun 6.
• Knowles SR, Graff LA, Wilding H, Hewitt C, Keefer L, Mikocka-Walus A. Quality of Life in Inflammatory Bowel Disease: A Systematic Review and Meta-analyses-Part I. Inflamm Bowel Dis. 2018 Mar 19;24(4):742-751. doi: 10.1093/ibd/izx100.
• IsHak WW, Pan D, Steiner AJ, Feldman E, Mann A, Mirocha J, Danovitch I, Melmed GY. Patient-Reported Outcomes of Quality of Life, Functioning, and GI/Psychiatric Symptom Severity in Patients with Inflammatory Bowel Disease (IBD). Inflamm Bowel Dis. 2017 May;23(5):798-803. doi: 10.1097/MIB.0000000000001060.
• Chavarria C, Casanova MJ, Chaparro M, Barreiro-de Acosta M, Ezquiaga E, Bujanda L, Rivero M, Arguelles-Arias F, Martin-Arranz MD, Martinez-Montiel MP, Valls M, Ferreiro-Iglesias R, Llao J, Moraleja-Yudego I, Casellas F, Antolin-Melero B, Cortes X, Plaza R, Pineda JR, Navarro-Llavat M, Garcia-Lopez S, Robledo-Andres P, Marin-Jimenez I, Garcia-Sanchez V, Merino O, Algaba A, Arribas-Lopez MR, Banales JM, Castro B, Castro-Laria L, Honrubia R, Almela P, Gisbert JP. Prevalence and Factors Associated With Fatigue in Patients With Inflammatory Bowel Disease: A Multicentre Study. J Crohns Colitis. 2019 Aug 14;13(8):996-1002. doi: 10.1093/ecco-jcc/jjz024.
• van der Valk ME, Mangen MJ, Leenders M, Dijkstra G, van Bodegraven AA, Fidder HH, de Jong DJ, Pierik M, van der Woude CJ, Romberg-Camps MJ, Clemens CH, Jansen JM, Mahmmod N, van de Meeberg PC, van der Meulen-de Jong AE, Ponsioen CY, Bolwerk CJ, Vermeijden JR, Siersema PD, van Oijen MG, Oldenburg B; COIN study group and the Dutch Initiative on Crohn and Colitis. Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFalpha therapy: results from the COIN study. Gut. 2014 Jan;63(1):72-9. doi: 10.1136/gutjnl-2012-303376. Epub 2012 Nov 7.
• Burisch J, Jess T, Martinato M, Lakatos PL; ECCO -EpiCom. The burden of inflammatory bowel disease in Europe. J Crohns Colitis. 2013 May;7(4):322-37. doi: 10.1016/j.crohns.2013.01.010. Epub 2013 Feb 8.
• Qazi T, Farraye FA. Sleep and Inflammatory Bowel Disease: An Important Bi-Directional Relationship. Inflamm Bowel Dis. 2019 Apr 11;25(5):843-852. doi: 10.1093/ibd/izy334.
• Segal, Z. V., Williams, J. M. G., & Teasdale, J. D. (2013). Mindfulness-based cognitive therapy for depression (second).
• Guo J, Wang H, Luo J, Guo Y, Xie Y, Lei B, Wiley J, Whittemore R. Factors influencing the effect of mindfulness-based interventions on diabetes distress: a meta-analysis. BMJ Open Diabetes Res Care. 2019 Dec 11;7(1):e000757. doi: 10.1136/bmjdrc-2019-000757. eCollection 2019.
• Cillessen L, Johannsen M, Speckens AEM, Zachariae R. Mindfulness-based interventions for psychological and physical health outcomes in cancer patients and survivors: A systematic review and meta-analysis of randomized controlled trials. Psychooncology. 2019 Dec;28(12):2257-2269. doi: 10.1002/pon.5214. Epub 2019 Sep 11.
• Zhou B, Wang G, Hong Y, Xu S, Wang J, Yu H, Liu Y, Yu L. Mindfulness interventions for rheumatoid arthritis: A systematic review and meta-analysis. Complement Ther Clin Pract. 2020 May;39:101088. doi: 10.1016/j.ctcp.2020.101088. Epub 2020 Jan 11.
• Haugmark T, Hagen KB, Smedslund G, Zangi HA. Mindfulness- and acceptance-based interventions for patients with fibromyalgia - A systematic review and meta-analyses. PLoS One. 2019 Sep 3;14(9):e0221897. doi: 10.1371/journal.pone.0221897. eCollection 2019.
• Crane RS, Eames C, Kuyken W, Hastings RP, Williams JM, Bartley T, Evans A, Silverton S, Soulsby JG, Surawy C. Development and validation of the mindfulness-based interventions - teaching assessment criteria (MBI:TAC). Assessment. 2013 Dec;20(6):681-8. doi: 10.1177/1073191113490790. Epub 2013 Jun 21.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2021
• Primary Completion (Actual): October 3, 2023
• Study Completion (Actual): October 3, 2023

Study Registration Dates

• First Submitted: November 16, 2020
• First Submitted That Met QC Criteria: November 23, 2020
• First Posted (Actual): November 30, 2020

Study Record Updates

• Last Update Posted (Estimated): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 23, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: randomized controlled trial; fatigue; sleep; effectiveness; psychological distress; mindfulness-based cognitive therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Inflammatory Bowel Diseases; Intestinal Diseases
• Other Study ID Numbers: MBCT-IBD-2020-2024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The authors intend to make the data available to other researchers after completion of the study and will comply with open access procedures, including open access publishing, as much as possible.
• IPD Sharing Time Frame: we expect the final report of the primary endpoint of the study December 2024, and we will have an embargo period of 6 months after publication.
• IPD Sharing Access Criteria: We will use restricted access, such that interested researchers are welcome to contact us with requests for data. The project team will review the quality of the request and grant permission if the request is in accordance with the terms of use drafted by the Radboudumc.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No