Contribution of Psychological Factors in the Healing of the Diabetic Foot Ulcer

Study Overview
=================
Brief Summary
-----------------
Diabetic foot ulcers (DFU) are one of the most serious complications of diabetes and can lead to amputations in 85% of cases, resulting in physical, psychological, family, social and economic consequences. Research suggests that psychological factors may play an important role in DFU healing. Relaxation and hypnosis seem to contribute to faster wound healing. More research is needed to assess the effectiveness of different types of intervention on different types of wounds, in particular chronic wounds such as DFU. This study will evaluate the efficacy of relaxation and hypnosis, both with guided imagery, in DFU healing, physiological indicators (inflammatory, metabolic, oxidative stress, angiogenic, and miRNA biomarkers) of wound healing prognosis, and QoL, in patients with diabetic foot and a chronic ulcer. This study is a Randomized Controlled Study of a Psychological Intervention that aims to evaluate the efficiency of a muscle relaxation intervention with guided imagery (experimental group - EG1) compare to a hypnosis intervention with guided imagery (experimental group - EG2) and a neutral guided imagery placebo (active control group - ACG) and a group that does not receive any psychological intervention (passive control group - PCG). This study will also examine, qualitatively, the perspectives of patients with DFU on the relaxation and hypnosis interventions, in order to check its effectiveness; as well as the perspectives of informal caregivers on this adjuvant therapys. Participants must have a diagnosis of Diabetes Mellitus and Diabetic Foot; one or two chronic active ulcers at the time of assessment; and clinical levels of stress or anxiety or depression. Participants will be randomized by the four conditions - EG1, EG2, ACG and PCG - and assessed on the day of the first consultation or nursing treatment for chronic DFU (T0), two months later (T1), and six months later (T2; follow-up). Two weeks after T1, an interview will be conducted independently with patients that completed the relaxation, hypnosis, and placebo sessions, and with the informal caregivers who provided them the DFU care. The results of the present study will contribute for a better understanding of DFU progression, healing, prevention of re-ulceration and future amputations and, consequently, for the improvement of patients' quality of life.

Detailed Description
-----------------
General Aim: This RCT aims to assess the effectiveness of a muscle relaxation intervention with guided imagery (EG1) compared to hypnosis with guided imagery intervention (EG2) and a neutral guided imagery placebo (ACG) and a group that does not receive any psychological intervention (PCG), in DFU healing, physiological indicators of healing prognosis, and quality of life (QoL), in patients with diabetic foot and a chronic ulcer. This study will also examine, qualitatively, the perspectives of patients and their respective family caregivers regarding the interventions (EG1 and EG2) and placebo sessions in order to check the treatments' effectiveness. Specific aim: To compare the impact of both experimental groups (EG1 and EG2) on psychological stress markers, in DFU healing, physiological indicators of healing prognosis, and QoL compared to the (PCG); between pre and post-intervention in the EG1 and EG2, controlling for clinical and sociodemographic variables, adherence to DFU care, and patients' literacy. Nested qualitative study specific aims: To understand the perspectives of patients and family caregivers on the efficacy of EG1 and EG2 interventions versus ACG sessions to the DFU healing, comparing cases with a positive evolution (healing of the DFU) with cases with a negative evolution (DFU non-healing). Sample size calculation: Using Sakpal formula (2010), and according to the descriptive results of the pilot study (Ferreira et al., 2022), considering the difference in the mean (1.93) and standard deviation (6) of the treatment versus passive control groups, with a statistical power of 80% and a statistical significance level of 5%, a definitive RCT will require 152 participants. Considering a dropout rate for intervention sessions of 11%, a definitive RCT with four groups will require a sample of 169 participants, with 42 patients per group (Ferreira et al., 2022). Procedure: The doctor or nurse, in the medical appointment, identifies patients that meet the medical inclusion criteria. Patients are invited to participate in the study by the Researcher at the end of the medical appointment and are informed about the aims of the study and the voluntary nature of participation through an informed and informative consent. If patients agree to participate, they will sign the consent form. Nurses will then complete RESVECH 2.0 at the end of the appointment and doctors will complete the clinical questionnaire. Afterward, the Researcher will accompany the patient to a room provided by the Hospital in order to administer the battery of questionnaires in the interview format. After answering the questionnaires, the researcher will score the PSS and HADS instruments to confirm the presence of significant clinical levels of stress, anxiety or depression, and if the patient is eligible, at the end of that week, the participant will be randomized into one of four possible groups. In the next diabetic foot appointment, the respective participant will be informed about the group to which he or she has been allocated and whether will benefit, if appropriate, from four sessions of relaxation (EG1), hypnosis (EG2), or neutral guided imagery (ACG). If allocated to the PCG, the patient will not receive any psychological or placebo session. If the participant is available, the first session will take place on the same day. The following sessions will be scheduled according to the medical diabetic foot consultations. In each session, two assessments of blood pressure and heart rate will be performed, before starting the session and at the end of the session. At the end of the fourth session, the T1 assessment will be performed, with a new administration of the questionnaires. Six months after T0, the T2 (follow-up) evaluation will take place, with the last administration of the questionnaires. At T0, T1 and T2 a blood and DFU swab sample will be collected for the evaluation of the physiological variables. Plasma and peripheral blood mononuclear cells (PBMC)s will be separated from the blood samples and frozen at -80ºC for analysis by the biochemical team member. Blood lymphocyte populations will be analyzed by flow cytometry and the quantification of blood cell populations will be performed by an automated hematological cell counter on fresh blood samples. The medical and nurse team member, as well as the lab technicians will not be aware of which group participants belong to. The interviews with patients who completed the four sessions of EG1, EG2, and ACG, as well as their informal caregivers, will be conducted separately, two weeks after T1, by a different researcher than the one involved in the sessions conduction, to reduce the bias of social desirability. Data analysis: All standard statistical analyses will be done using the Rstudio, R version 3.6.2 (R Core Team, 2019) and the SPSS statistics, v. 24.0 (IBM SPSS Statistics for Windows, IBM Corp, Armonk, New York). The baseline data of the treatments and control groups will be compared, using chi-squared test for binary variables and the t-test for continuous variables. The comparison between experimental groups (EG1 and EG2) and control groups (ACG and PCG) will be analyzed through Generalized Mixed Models. A semi-structured interview guide consisting of open-ended questions will be administered to approximately 12 patients that benefited from interventions (EG1, EG2) and placebo (ACG) sessions), and 12 informal caregivers indicated by those patients. This script will remain unchanged throughout the interviews. The audio recording of the interviews will be done using a tablet, transcribed verbatim, and anonymized in order to safeguard participants and data confidentiality. The transcripts of the interviews will be analyzed in the same order as conducted, using the thematic content analysis technique, and the NVivo software (QSR International PtyLtd, 2018).

Official Title
-----------------
Contribution of Psychological Factors in the Healing of the Diabetic Foot Ulcer, in Physiological Indicators of Healing Prognosis and Quality of Life: a Randomized Longitudinal Trial With a Nested Qualitative Study of Effectiveness Assessment

Conditions
-----------------
Diabetes Mellitus, Diabetic Foot Ulcer

Intervention / Treatment
-----------------
* Behavioral: Muscle Relaxation with Guided Imagery
* Behavioral: Hypnosis with Guided Imagery
* Behavioral: Neutral Guided Imagery


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 18 years old or older; Diabetes Mellitus diagnosis; Diagnosis of Diabetic Foot; Having one or two active chronic ulcers (> 6 weeks and < 14 weeks) at the time of baseline assessment; Being followed at the Multidisciplinary Consultation of the Diabetic Foot from the Centro Hospitalar Universitário do Porto (CHUP), at the Diabetic Foot Clinic from the Centro Hospitalar do Tâmega e Sousa (CHTS) and from the Multidisciplinary Consultation of the Diabetic Foot of the Hospital de Braga (HB); Presenting clinical levels of stress (scores > 13 for males and > 17 for females on the Perceived Stress Scale) or anxiety or depression (scores > 11 on Hospital Anxiety and Depression Scale); Providing written informed consent. Exclusion Criteria: The active DFU at the time of the assessment being a relapse; Having more than two DFUs at the time of baseline assessment; Being on hemodialysis treatment; Presence of psychosis or dementia described in the patient's medical record; Having cancer disease; Having undergone a transplant; Receiving psychological counselling at the time of the assessment. For the RCT qualitative nested study, twelve participants that completed at least 75% of the treatment or placebo sessions, and that report having a informal/ family caregiver will be invite the participate. Participants will be selected according to the following criteria: Two typical cases of successful and unsuccessful patients with neuropathic foot, defined by the presence of neuropathic pain (e.g., heat, tingling, electrical shock), presence of distal pulses by palpation, and loss of protective sensitivity; Two typical cases of successful and unsuccessful patients with neuroischemic foot, defined by the presence of peripheral artery disease, intense-variable pain, absence of distal pulses by palpation, and variable protective sensitivity.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel Assignment This is a Randomized Controlled Study of a Psychological Intervention (Grant et al., 2018). This study will use a mixed-methods approach nested in a 4-arm randomized control design. Qualitative and quantitative data will be collected in order to provide better understanding about the effectiveness of the hypnosis intervention in patients with DFU. Participants will be randomised at a ratio of 1:1 for the four conditions - EG1, EG2, ACG and PCG; and will be evaluated on the day of the first chronic DFU appointment or nursing treatment (T0), two months later (at the end of the intervention in EG, EG2, and ACG; T1), as well as six months later (T2) in a follow-up evaluation. Participants from all four groups will undergo standard treatment for the DFU, according to the guidelines of the Portuguese General Health Direction (DGS, 2010) and the International Working Group on the Diabetic Foot (IWGDF, 2015).
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Muscle Relaxation with Guided Imagery<br>Participants in the Experimental Group 1 will receive four individual 45-minute sessions, every two weeks, of progressive muscle relaxation intervention with guided imagery focused on ulcer healing, carried out by the Psychologist responsible for implementing the project, on the day of the Diabetic Foot appointments. | Behavioral: Muscle Relaxation with Guided Imagery<br>* Relaxation intervention session begins with diaphragmatic breathing, followed by Jacobson's progressive muscle relaxation, which involves the contraction and subsequent relaxation of the 16 muscle groups of the body (forearm, arm, upper forehead, eye, mouth, jaw and throat, neck, shoulder, chest, stomach, thigh, leg and foot).The contraction is performed for 7 seconds while the relaxation lasts for about 40 to 50 seconds.The relaxation of the foot muscle group is only performed on the healthy foot, because dressing and bandages may bandage the foot with the DFU, which together with the typical joint stiffness of the diabetic foot, make it difficult to perform. After muscle relaxation, begins the guided imagery focused on DFU healing. The patient is instructed to think about his/her current state of health and to imagine the DFU as a dark area and the healing relaxation as a light associated to pleasant sensations, which will focus on the foot with DFU to heal it.<br>|
| Experimental: Hypnosis with Guided imagery<br>Participants in the Experimental Group 2 will receive a four individual 45-minute sessions, every two weeks, of hypnosis intervention with guided imagery focused on ulcer healing, carried out by the qualified Hypnotherapists external to the research study, on the day of the Diabetic Foot appointments. | Behavioral: Hypnosis with Guided Imagery<br>* In the beginning of the first session we apply the Eye-Roll Test for Hypnotizability of Herbert Spiegel. Each session follows the Hypnotic Protocol with the following steps:Pre-talk/Absortion/Ratification/Aliciation/Dissociation/Awakening. The four sessions train the participants in visual, auditory and kinesthetic perception on ulcer healing. The protocol also promotes medical treatment acceptance.<br>|
| Placebo Comparator: Active Control Group<br>Participants in the ACG will receive four individual 45-minute sessions of neutral guided imagery placebo focused on the patient's life before the foot ulcer, carried out by the Psychologist responsible for implementing the project, on the day of the Diabetic Foot appointments. | Behavioral: Neutral Guided Imagery<br>* This placebo consists of neutral guided imagery focused on themes of the patient's daily life before having DFU. Each session has a theme associated with the patient's life - family, work, friends, and leisure. Initially, the patient is asked to think about an event related to the theme of the session of his/her choice, positive or negative, which occurred before patient has the current DFU. Then, the patient is asked about a number of questions regarding the chosen episode in order to promote a more detailed reconstruction of the event. The patient is asked to imagine according to the instructions given by the Psychologist. When the whole episode is remembered, the patient is asked to tell what he or she imagined/remembered regarding each of the questions.<br>|
| No Intervention: Passive Control Group<br>Participants in the PCG will not receive any intervention or placebo session. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of the DFU on patients' quality of life | The Diabetic Foot Ulcer Scale-Short Form (DFS-SF; Bann, Fehnel, & Gagnon, 2003; Research version by Pereira et al., 2022) will be used to assess patients´ DFU-related quality of life. Raw scores are transformed into a scale from 0 to 100. Higher results correspond to better DFU-related quality of life. | Changes from baseline (T0) to the end of intervention/ 2 months later at post-test (T1), and after 6 months follow-up (T2) | 
| Degree of DFU healing | The degree of DFU healing will be assessed with the Portuguese version of Resultados esperados de la valoración y evolución de la cicatrización de las heridas crónicas Scale [Expected results of the evaluation and evolution of the healing of chronic wounds Scale - RESVECH 2.0] (Marques, 2015). The scores range from 0 to 35, where zero indicates complete healing. | Changes from baseline (T0) to the end of intervention/ 2 months later at post-test (T1), and after 6 months follow-up (T2) | 
| Physical quality of life | The Short-Form Health Survey (SF-36; Ferreira, 1998; Ferreira, Ferreira, & Pereira, 2012) will be administered to assess patients' physical health-related quality of life. Raw scores are transformed into a scale from 0 to 100. Higher results correspond to better physical quality of life. | Changes from baseline (T0) to the end of intervention/ 2 months later at post-test (T1), and after 6 months follow-up (T2) | 
| Mental quality of life | The Short-Form Health Survey (SF-36; Ferreira, 1998; Ferreira, Ferreira, & Pereira, 2012) will be administered to assess patients' mental health-related quality of life. Raw scores are transformed into a scale from 0 to 100. Higher results correspond to better mental quality of life. | Changes from baseline (T0) to the end of intervention/ 2 months later at post-test (T1), and after 6 months follow-up (T2) | 
| Metabolic marker | The quantification of HbA1c in the plasma will be performed using the competitive inhibition enzyme immunoassay Cloud Clone Corp | Changes from baseline (T0) to the end of intervention/ 2 months later at post-test (T1), and after 6 months follow-up (T2) | 
| Inflammatory markers | IL-6, IL-8, and TNF-a levels will be evaluated in the plasma using a LEGENDplexTM Human Angiogenesis Panel 1 Mix and Match (9-plex). Blood lymphocyte populations will be assessed in the whole blood by flow cytometry and automated hematological cell counter. | Changes from baseline (T0) to the end of intervention/ 2 months later at post-test (T1), and after 6 months follow-up (T2) | 
| Angiogenic markers | Angiopoietin-2, EGF, FGF-basic, PECAM-1, PIGF, and VEGF levels will be assessed in the plasma using a LEGENDplexTM Human Angiogenesis Panel 1 Mix and Match (9-plex). | Changes from baseline (T0) to the end of intervention/ 2 months later at post-test (T1), and after 6 months follow-up (T2) | 
| miRNA markers | miRNA-21 and miRNA-155 will be assessed with SYBR Green technology, using the RNU6B gene as control. | Changes from baseline (T0) to the end of intervention/ 2 months later at post-test (T1), and after 6 months follow-up (T2) | 
| Immune cells | Blood leukocyte and B and T-cell populations will be assessed in the whole blood by flow cytometry and automated hematological cell counter. | Changes from baseline (T0) to the end of intervention/ 2 months later at post-test (T1), and after 6 months follow-up (T2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Perceived Stress | The overall stress perceived by the patient will be assessed through the Perceived Stress Scale (PSS; Trigo, Canudo, Branco, & Silva, 2010). Scores range between 0 and 40, with higher results indicating higher levels of perceived stress. | Changes from baseline (T0) to the end of intervention/ 2 months later at post-test (T1), and after 6 months follow-up (T2) | 
| Emotional Distress | The emotional distress will be assessed through the total score of the Hospital Anxiety and Depression Scale, comprising both anxiety and depression scales (HADS; Pais-Ribeiro et al., 2007). Scores range between 0 and 42, with higher results indicating higher levels of distress. | Changes from baseline (T0) to the end of intervention/ 2 months later at post-test (T1), and after 6 months follow-up (T2) | 
| Anxiety symptoms | The anxious symptomatology will be assessed through the Hospital Anxiety and Depression Scale (HADS; Pais-Ribeiro et al., 2007). Scores range between 0 and 21, with higher results indicating higher levels of anxiety symptoms. | Changes from baseline (T0) to the end of intervention/ 2 months later at post-test (T1), and after 6 months follow-up (T2) | 
| Depression symptoms | The depressive symptomatology will be assessed through the Hospital Anxiety and Depression Scale (HADS; Pais-Ribeiro et al., 2007). Scores range between 0 and 21, with higher results indicating higher levels of depression symptoms. | Changes from baseline (T0) to the end of intervention/ 2 months later at post-test (T1), and after 6 months follow-up (T2) | 
| Representations regarding the DFU | Patient representations regarding the DFU will be evaluated through the Illness Perception Questionnaire - Brief (IPQ-B; Figueiras et al., 2010). The response scale ranges from 0 to 10. Higher scores indicate more threatening representations regarding DFU. | Changes from baseline (T0) to the end of intervention/ 2 months later at post-test (T1), and after 6 months follow-up (T2) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetic Foot Ulcer, Ulcer Healing, Quality of Life, Hypnosis, Relaxation