Effectiveness of two stress reduction interventions in patients with chronic diabetic foot ulcers (PSY-DFU): protocol for a longitudinal RCT with a nested qualitative study involving family caregivers

Citation: Pereira, M.G.; Vilaça, M.; Carvalho, E. Effectiveness of Two Stress Reduction Interventions in Patients with Chronic Diabetic Foot Ulcers (PSY-DFU): Protocol for a Longitudinal RCT with a Nested Qualitative Study Involving Family Caregivers. Int. J. Environ. Res. Public Health 2022,19, 8556. https:// doi.org/10.3390/ijerph19148556 Academic Editor: Paul B. Tchounwou Received: 1 June 2022 Accepted: 11 July 2022 Published: 13 July 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). International Journal of Environmental Research and Public Health Study Protocol Effectiveness of Two Stress Reduction Interventions in Patients with Chronic Diabetic Foot Ulcers (PSY-DFU): Protocol for a Longitudinal RCT with a Nested Qualitative Study Involving Family Caregivers M. Graça Pereira 1,* , Margarida Vilaça 1and Eugenia Carvalho 2,3 1Psychology Research Centre (CIPsi), School of Psychology, University of Minho, 4710-057 Braga, Portugal; [email protected] 2Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; [email protected] 3Institute for Interdisciplinary Research (IIIUC), University of Coimbra, 3030-789 Coimbra, Portugal *Correspondence: [email protected]; Tel.: +351-253-604228 Abstract: Diabetic foot ulcer (DFU) is the leading cause of lower-limb amputations, with a significant impact on patients, families, and society. Since DFU medical treatments represent a major socioeconomic burden, cost-effective interventions are needed. This trial aims to assess the effectiveness of a muscle relaxation intervention compared to a hypnosis intervention versus active and passive control groups on DFU healing, physiological indicators of healing prognosis, and quality of life (QoL) in clinically distressed patients with a chronic DFU. A multicenter, randomized controlled trial with three assessment moments (baseline, two months post-intervention, and four months follow-up) will be conducted. Approximately 170 patients will be randomized and allocated to either treatment or control groups. Primary outcomes will be DFU healing, physiological indicators of healing prognosis, and QoL. Secondary outcomes will include perceived stress, psychological morbidity, and DFU representations. The efficacy of sessions on DFU healing will be qualitatively assessed in 12 patients allocated to the treatment and active control groups, as well as their family caregivers. This study will provide evidence regarding the effectiveness of two psychological interventions for the DFU healing process and the QoL of patients, with direct clinical relevance regarding DFU treatment and recurrence. Keywords: diabetic foot ulcer; clinical distress; muscular relaxation; hypnosis; physiological indicators of healing prognosis; quality of life; RCT; protocol study 1. Background Diabetes represents a growing public health concern with a growing global incidence during the last three decades [ 1 ] due to lifestyle changes and aging. According to the International Diabetics Federation, in 2021, an estimated 6.7 million adults have died as a result of diabetes or its complications. Over time, patients with diabetes have an increased risk of developing serious comorbidities, such as cardiovascular disease, blindness, kidney failure, and foot ulcerations [2]. Diabetic foot disease is one of the most serious complications of diabetes, impacting nearly 15% of all patients [ 3 ]. Diabetic foot ulcer (DFU) is a full-thickness wound below the ankle, in most cases, caused by poor glycemic control, calluses, ill-fitting footwear, underlying neuropathy, peripheral vascular disease, or improper foot care. Around 11–14% of worldwide patients diagnosed with diabetes will develop DFUs [ 4 ], which is the leading cause of lower-limb amputations in approximately 80% of these patients [ 5 ]. According to Zhang et al., the current DFU prevalence worldwide was 6.7%, while in Europe was 5.1% [6]. Int. J. Environ. Res. Public Health 2022,19, 8556. https://doi.org/10.3390/ijerph19148556 https://www.mdpi.com/journal/ijerph Int. J. Environ. Res. Public Health 2022,19, 8556 2 of 14 In addition to the devastating consequences of DFU development to patients and their families, the socioeconomic cost involved has become a burden. From 2007 to 2021, the direct cost of DFU treatment worldwide has increased from USD 232 to 966 billion, which reflects a dramatic increase. In Europe alone, the total medical costs for the management of DFUs in 2010 were estimated to be USD 105.5 billion, while in 2030, it is expected to reach USD 124.6 billion [ 2 ]. Thus, planning cost-effective interventions focused on DFU recovery becomes essential. This is also true regarding the impact on the environment, fewer trips to DFU clinics, fewer hospitalizations, and less clinical waste produced. It is known that adherence to self-care behaviors and treatment is essential to wound healing. However, psychological factors, such as depression or anxiety, may also negatively influence DFU healing via psycho immunological effects [ 7 , 8 ]. Furthermore, DFU is associated with distress [ 9 ], and negative emotions contribute to prolonged infections, delayed wound healing, and poor quality of life (QoL), which is associated with low treatment responses and low remission rates, a major health concern [7,10,11]. Previous literature has emphasized the impact of stress on wound healing, almost exclusively in acute wounds, e.g., [ 12 ]. In fact, stress raises the level of cortisol, which has a negative impact on the immune system, particularly on wound repair due to immunity suppression [ 13 , 14 ]. By increasing the release of proinflammatory cytokines during tissue repair and driving tissue oxygen levels lower, psychological stress delays wound healing [15,16] . Stress may also impact the expression and function of microRNAs (miRNAs), important regulatory molecules that can be used as biomarkers for diagnosis or progression of complications from diabetes due to their ability to fine-tune cellular responses [ 17 ]. Thus, by modulating miRNA biogenesis, expression, and complex activity, stress can cause important changes in metabolism that may hamper DFU healing [18]. Glycemic control is one of the main strategies to monitor diabetes, reducing the complication of diabetes and the risk of hypoglycemia. Hemoglobin A1c (HbA1c) testing represents the best method to monitor glycemia in patients with diabetes, as it reflects levels of blood glucose over several weeks. Although distress has been associated with poor glycemic outcomes [ 19 ], the role of HbA1c in wound healing is not consensual. In fact, if some studies show direct associations between HbA1c levels and wound-healing rate, e.g., [ 20 ], other studies found no association between this biomarker and wound outcomes, e.g., [21]. Since there is evidence that psychological distress affects negatively wound healing [ 11 ], it is expected that reducing-stress interventions have positive implications on DFU recovery. Adjuvant interventions as relaxation training techniques have shown promising results in patients with diabetes [ 22 , 23 ] and patients with chronic DFUs [ 24 , 25 ]. Previous research also indicated hypnosis as an effective adjunct treatment in the management of diabetes, contributing to reduced blood glucose levels, better metabolic control, and increased blood flow to extremities, decreasing the risk of diabetic foot problems [26–29]. Although there is evidence suggesting the benefits of psychological interventions to patients with DFUs, the effectiveness of stress reduction interventions in DFU recovery, physiological indicators of wound healing, and patients’ QoL improvement has not been established. This is mainly because there are limited data evaluating the efficacy of psychological treatments in this area of research [ 30 ]. Thus, randomized controlled trials of low-cost psychological interventions to focus on the promotion of QoL and DFU healing are required. This paper describes the development of the PSY-DFU study protocol, which focuses on two interventions to reduce and manage stress and summarizes the advantages and limitations of this fully scripted treatment approach. 2. Methods 2.1. Objectives The present study aims to: 1. Assess the effectiveness of a muscle relaxation intervention with guided imagery (TG1) compared to hypnosis with guided imagery (TG2) versus a neutral guided imagery placebo (ACG) and a group that does not receive any psychological intervention Int. J. Environ. Res. Public Health 2022,19, 8556 3 of 14 (PCG) regarding DFU healing, physiological indicators of healing prognosis, and QoL in patients with clinical distress and a chronic DFU. 2. Understand the perspectives of patients and family caregivers on the efficacy of TG1 and TG2 interventions versus ACG sessions for DFU healing. Primary Specific Aims The primary specific aims of this RCT are: (i) to compare the impact of both treatment groups (TG1 and TG2) in regard to DFU healing, physiological indicators of healing prognosis (biochemical parameters, inflammatory and angiogenic markers, miRNAs, and immune cells), and QoL, compared to control groups; (ii) to compare patients pre and post-intervention in the TG1 and TG2, controlling for patients’ health literacy, clinical characteristics (e.g., duration of diabetes and DFU, type of diabetic foot), and sociodemographic variables (e.g., gender, age, education, socioeconomic level); and (iii) to compare the efficacy of TG1 and TG2 versus ACG to DFU healing, according to participants and their respective family caregiver’s perceptions. 2.2. Study Design The current study is designed as a longitudinal, participant-blinded, sham-controlled, cluster randomized controlled trial (RCT) with a nested qualitative evaluation. The RCT study includes three-assessment periods over the course of six months, while the nested qualitative study involves an additional semi-structured interview two weeks after completing the treatment or placebo sessions. The protocol for this RCT is based on the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Checklist [ 31 ] (Table 1). The study design and flowchart of the protocol, following the CONSORT 2010 standards [ 32 ], are summarized in Figure 1. The study will be conducted in three major hospitals in the North of Portugal with multidisciplinary diabetic foot consultations, and was approved by the Ethics Committee of the three hospitals. The study is also registered on the ClinicalTrials.gov platform since the 7th of January 2021 (Registration number: NCT04698720). Table 1. Schedule of enrollment, interventions, and assessments of the PSY-DFU study, following the Standard Protocol Items Recommendations for Interventional Trials (SPIRIT) guidelines. TIMEPOINTS Enrollment Allocation Pos-Allocation Follow-Up T0 T0 T1 2 Weeks after T1 T2 Eligibility X Informed consent X Allocation X INTERVENTIONS Int. J. Environ. Res. Public Health 2022, 19, x FOR PEER REVIEW 4 of 15 Table 1. Schedule of enrollment, interventions, and assessments of the PSY-DFU study, following the Standard Protocol Items Recommendations for Interventional Trials (SPIRIT) guidelines. TIMEPOINTS Enrollment Allocation Pos-Allocation Follow-Up T0 T0 T1 2 Weeks after T1 T2 Eligibility X Informed consent X Allocation X INTERVENTIONS PMR + GI (TG1) H + GI (TG2) Control groups Active (ACG) Passive (PCG) ASSESSMENTS Sociodemographic data X Health literacy X Clinical data (PEDIS) X X X DFU evolution/healing a X X X Impact of DFU on QoL X X X Mental and physical QoL X X X Perceived stress X X X Psychological morbidity X X X DFU representations a X X X Blood pressure b X X X Heart rate b X X X Biochemical parameter X X X Inflammatory markers X X X Angiogenic markers X X X miRNAs X X X Immune cells X X X Semi-structured interviews X QoL—quality of life; PMR + GI—progressive muscular relaxation with guided imagery; H + GI—hypnosis with guided imagery; ACG—active control group; PCG—passive control group; PEDIS—Perfusion, Extent, Depth, Infection, and Sensation; DFU—diabetic foot ulcer. a In T1 and T2, when the DFU is healed, the DFU progression and DFU representations are not assessed. b Blood pressure and heart rate are assessed before and after each intervention (PMR + GI and H + GI) and placebo (ACG) session. PMR + GI (TG1) H + GI (TG2) Control groups Int. J. Environ. Res. Public Health 2022, 19, x FOR PEER REVIEW 4 of 15 Table 1. Schedule of enrollment, interventions, and assessments of the PSY-DFU study, following the Standard Protocol Items Recommendations for Interventional Trials (SPIRIT) guidelines. TIMEPOINTS Enrollment Allocation Pos-Allocation Follow-Up T0 T0 T1 2 Weeks after T1 T2 Eligibility X Informed consent X Allocation X INTERVENTIONS PMR + GI (TG1) H + GI (TG2) Control groups Active (ACG) Passive (PCG) ASSESSMENTS Sociodemographic data X Health literacy X Clinical data (PEDIS) X X X DFU evolution/healing a X X X Impact of DFU on QoL X X X Mental and physical QoL X X X Perceived stress X X X Psychological morbidity X X X DFU representations a X X X Blood pressure b X X X Heart rate b X X X Biochemical parameter X X X Inflammatory markers X X X Angiogenic markers X X X miRNAs X X X Immune cells X X X Semi-structured interviews X QoL—quality of life; PMR + GI—progressive muscular relaxation with guided imagery; H + GI—hypnosis with guided imagery; ACG—active control group; PCG—passive control group; PEDIS—Perfusion, Extent, Depth, Infection, and Sensation; DFU—diabetic foot ulcer. a In T1 and T2, when the DFU is healed, the DFU progression and DFU representations are not assessed. b Blood pressure and heart rate are assessed before and after each intervention (PMR + GI and H + GI) and placebo (ACG) session. Active (ACG) Passive (PCG) ASSESSMENTS Sociodemographic data X Health literacy X Int. J. Environ. Res. Public Health 2022,19, 8556 4 of 14 Table 1. Cont. TIMEPOINTS Enrollment Allocation Pos-Allocation Follow-Up T0 T0 T1 2 Weeks after T1 T2 Clinical data (PEDIS) X X X DFU evolution/healing aX X X Impact of DFU on QoL X X X Mental and physical QoL X X X Perceived stress X X X Psychological morbidity X X X DFU representations aX X X Blood pressure bX X X Heart rate bX X X Biochemical parameter X X X Inflammatory markers X X X Angiogenic markers X X X miRNAs X X X Immune cells X X X Semi-structured interviews X QoL—quality of life; PMR + GI—progressive muscular relaxation with guided imagery; H + GI—hypnosis with guided imagery; ACG—active control group; PCG—passive control group; PEDIS—Perfusion, Extent, Depth, Infection, and Sensation; DFU—diabetic foot ulcer. a In T1 and T2, when the DFU is healed, the DFU progression and DFU representations are not assessed. b Blood pressure and heart rate are assessed before and after each intervention (PMR + GI and H + GI) and placebo (ACG) session. 2.3. Participant Recruitment and Selection Criteria Patients with chronic DFU attending the first consultation of the multidisciplinary outpatient clinical of diabetic foot ulcer from three major hospitals in Northern Portugal will be recruited. In the first consultation, researchers (Researchers 1, 2, and 3) will collect the clinical information of each patient to signalize those that meet eligibility criteria. Patients will be consecutively enrolled in the study. The inclusion criteria are: (i) being 18 years old or more, (ii) having one or two diabetic chronic ulcers (a non-healing ulcer for six or more weeks and less than 12 weeks; in case of patients with two active chronic DFUs, the ulcer with the largest area will be selected as the index ulcer) at the time of baseline assessment, (iii) reporting clinical levels of psychological distress, and iv) providing written informed consent. Clinical distress is assessed according to the Hospital Anxiety and Depression Scale (HADS) [ 33 ] and the Perceived Stress Scale (PSS) [ 34 ], with patients scoring ≥ 11 on the HADS subscales or ≥ 13 (male patients) and ≥17 (female patients) on the PSS evaluated as being clinically distressed. Exclusion criteria include: (i) the DFU, at the time of baseline assessment, being a relapse; (ii) having three or more DFUs at the time of baseline assessment; (iii) having undergone a transplant; (iv) being on hemodialysis treatment; (v) having a cancer disease; (vi) having degenerative dementia or severe psychiatric illness (e.g., schizophrenia), (vii) receiving psychological counseling, or (viii) taking psychiatric medication during the study period. For the qualitative study, participants that completed at least 75% of the intervention sessions or placebo sessions (active control group) will be invited to participate, together with their family caregiver. Participants will be purposively selected according to the type of diabetic foot (neuropathic versus neuroischemic) and DFU progression (positive versus negative). The sample will also be selected according to participants’ capacity to provide in-depth and rich-textures information regarding the intervention’s effectiveness since qualitative purposive sampling is considered to be more efficient than random sampling [ 35 ]. Thus, the quantitative study sample will include four single-per-participant interviews per group (4 conditions × 3 groups), in a total of 12 patients’ interviews and 12 caregivers’ interviews. Int. J. Environ. Res. Public Health 2022,19, 8556 5 of 14 Figure 1. Study design and CONSORT flow chart. 2.4. Randomization All eligible patients will be randomly assigned to one of the four groups—TG1, TG2, ACG, or PCG—in varying size blocks so that, over time, all groups can have a similar number of participants [ 36 , 37 ]. An independent researcher (Researcher 4), unaware of the numeric coding for each group, will create the randomization sequence using an online random number generator (https://www.graphpad.com/quickcalcs/randomize1/, Int. J. Environ. Res. Public Health 2022,19, 8556 6 of 14 accessed on 15 December 2021) with a 1:1 allocation, using random block sizes of 12. Researchers 2, 3, and 4 are blind to the block size used in the randomization procedure. A priori stratification was defined considering the three hospitals where data collection will take place, as well as two common comorbid conditions deemed as factors of poor prognostic outcomes in patients with DFUs, specifically chronic kidney disease (CKD) and peripheral arterial disease (PAD) [ 38 , 39 ], to ensure that distribution of patients between groups is balanced in terms of confounders. Thus, randomization is stratified according to (i) hospitals; (ii) CKD and its disease stages (without CKD/CKD stage 1 and 2/CKD stage 3 and 4); and (iii) PAD (without PAD/with PAD), in a total of 12 possible strata. Participants’ blinding will be maintained throughout the conduct of the trial, whereas Researchers 1, 2, and 3 will be aware of the allocation since they are responsible and will conduct the TG1 and ACG sessions. Quantitative data analysts will be blinded to participant allocation. The randomization process will be conducted at the end of each week to reduce the time interval between the randomization and the beginning of interventions. 3. Outcomes and Measures 3.1. Participant Timeline Participants in the intervention and control groups will be assessed at the pre-intervention baseline (T0), at the end of the intervention/two months later at post-test (T1), and six months after T1 at the follow-up (T2). Data will be collected through face-to-face interviews conducted by health psychologists (Researchers 1, 2, and 3). Regarding the biochemical sample collection (biochemical parameter, inflammatory and angiogenic markers, miRNAs, and immune cells), a blood sample will be collected during the consultation at the T0, T1, and T2 assessment moments (Table 1). 3.2. Characteristics of Patients Sociodemographic and clinical characteristics of all participants will be assessed. 3.2.1. Sociodemographic Characteristics Sociodemographic data will be collected prior to intervention through the Sociodemographic Questionnaire, a questionnaire developed for the purposes of this study that includes variables such as gender, age, education, residence, marital and professional status, having (or not) an informal caregiver, socioeconomic level, smoking history, and alcohol intake, among others. 3.2.2. Clinical Information Clinical data will be collected through the Clinical Questionnaire, developed specifically for this study, to be completed by the patients’ physician or nurse in the three assessment moments. This questionnaire asks about the type and duration of diabetes, complications associated with diabetes, diabetic foot type, DFU location and duration, concomitant treatment, ulcer healing time, and new DFUs. The clinical questionnaire also includes the Perfusion, Extent, Depth, Infection, and Sensation (PEDIS) classification system, proposed by the International Working Group of the Diabetic Foot, thus gathering information regarding the five most important categories to evaluate the DFU stage and progression [40]. 3.3. Measures of Primary Outcomes Primary outcomes are DFU healing, physiological indicators of healing prognosis, DFU impact on QoL, and physical and mental QoL. 3.3.1. Degree of DFU Healing Wound healing is defined as the complete epithelization of the wound and is assessed through the RESVECH 2.0-PT [41], a useful and validated tool to monitor the progression of chronic wounds of any etiology through six main parameters: wound area, depth and Int. J. Environ. Res. Public Health 2022,19, 8556 7 of 14 involved tissues, wound margins, type of tissue in the wound bed, levels of exudates, and presence of signs of infection/inflammations. This questionnaire will be filled out by the participant’s physician or nurse at the end of consultations to monitor DFU progression. Scores range from 0 to 35, where zero indicates complete healing and 35 corresponds to the worse possible wound. 3.3.2. Physiological Indicators of Healing Prognosis Physiological indicators include a biochemical parameter (HbA1c), inflammatory (IL-6, TNFα , lymphocyte populations) and angiogenic (VEGF) markers, miRNAs (miRNA-21, miRNA-155), and immune cells (lymphocytes T effective and naïve). The quantification of HbA1c in the plasma will be performed using the competitive inhibition enzyme immunoassay Cloud Clone Corp. The quantification of the plasma inflammatory cytokines levels (IL-6) and tumor necrosis factor (TNFα ) will be performed using a LEGENDplex ™ Human Angiogenesis Panel 1 Mix and Match (9-plex). Blood lymphocyte populations will be assessed in the whole blood by flow cytometry and an automated hematological cell counter. Levels of VEGF will be assessed through the serum by ELISA from Cell Signaling Technology. miRNA-21 and miRNA-155 will be assessed through blood collected in a tube from Qiagen (PAXgene Blood RNA Tubes, Qiagen, Hombrechtikon, Switzerland), and subsequently, the RNA will be converted into cDNA by “miScript Reverse Transcription Kit” (Qiagen). Amplification of miR-21 will be done through the light Cycler system with SYBR Green PCR Kit. The control gene will be the RNU6B. Immune cells will be calculated through the ratio of lymphocyte effectors CD4/CD8 to lymphocyte naïve CD4/CD8 cells. Blood samples will be collected and processed in the clinical laboratory of two of the three hospitals where data collection will take place. 3.3.3. Impact of the DFU on QoL The impact of the DFU on patients’ QoL will be assessed through the Diabetic Foot Ulcer Scale-Short Form (DFS-SF) [ 42 ], a self-report questionnaire to be fulfilled by participants to evaluate the effect of the DFU on patients’ general QoL. 3.3.4. Physical and Mental QoL Patients’ physical and mental health-related QoL will be assessed through the ShortForm Health Survey (SF-36) [43], a self-report questionnaire administered to participants. 3.4. Measures of Secondary Outcomes Data will also be used to assess the following secondary outcomes: perceived stress, psychological morbidity, and DFU representations. 3.4.1. Perceived Stress The overall stress perceived by patients will be assessed through the Perceived Stress Scale (PSS) [34], a self-reported measure to be answered by participants. 3.4.2. Psychological Morbidity Psychological morbidity or emotional distress will be assessed through the total score of the Hospital Anxiety and Depression Scale (HADS) [ 33 ], comprising both anxiety and depression subscales. HADS is also answered by participants. 3.4.3. DFU Representations Patient representations regarding the DFU will be evaluated through the Illness Perception Questionnaire—Brief (IPQ-B) [44], a self-report scale administered to participants. 3.5. Other Outcome Measures Health literacy, blood pressure, heart rate, time to complete wound healing, and time to favorable healing prognosis will also be assessed. Int. J. Environ. Res. Public Health 2022,19, 8556 8 of 14 3.5.1. Health Literacy Personal health literacy is evaluated through the Medical Term Recognition Test (METER) [ 45 ], a widely used health literacy self-assessment measure administered to participants . 3.5.2. Blood Pressure Systolic and diastolic pressure, in millimeters of mercury (mmHg), will be assessed through a validated and certified blood pressure measuring device. 3.5.3. Heart Rate Heart rate, in beats per minute (bpm), will be assessed through a validated and certified blood pressure measuring device. 3.5.4. Time to Complete Wound Healing This variable corresponds to the time interval (days) between the baseline assessment and the complete DFU healing. 3.5.5. Time to Favorable Healing Prognosis Based on the wound area, the time to a favorable prognosis will be assessed through the DFU area evolution (reduced versus increased, at the end of the participation in the study, i.e., T1 or T2 assessment moments). 3.6. Qualitative Assessment Approximately 12 patient participants allocated to the TGs and ACG, together with their respective family caregivers, will be invited to take part in semi-structured interviews to share their perceptions on the efficacy of sessions for DFU healing. The interview guide consists of open-ended questions to be administered individually to patients and the family caregiver indicated by the patient. The script will be unchanged throughout the interviews. All interviews will be audio-recorded in digital audio and transcribed verbatim. The transcribed interviews will be anonymized to safeguard the confidentiality of data and participants. Qualitative analysis of the interviews will be performed shortly after the transcription of the interviews. Interview contents will be inductively coded and theoretically analyzed through the thematic content analysis technique and later compared to the existing literature. To process, organize, code, and thematically analyze data, the NVivo software (QSR International PtyLtd, Melbourne, Australia) will be used. Researchers 1, 2, and 3 will be responsible for the interview implementation and the data analysis. 4. Interventions 4.1. Trial Arms All participants will receive standard of care medical/nursing treatment for DFU, according to the guidelines of the Portuguese General Health Direction [ 46 ] and the International Working Group on the Diabetic Foot [47]. 4.1.1. Intervention Groups Participants in the intervention groups are allocated in TG1 or TG2. Participants allocated to TG1 will receive four individual sessions of muscle relaxation with guided imagery (MR + GI), a technique of alternately tensing and relaxing muscle groups individually throughout the body. Relaxation intervention 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 (hand, forearm, biceps, upper forehead, eye, nose, mouth, jaw and throat, neck, shoulder, chest, stomach, thigh, leg, and foot). The contraction will be performed for seven seconds while the relaxation lasts for about 40–50 s. The relaxation of the foot muscle group will not be performed on the foot with the wound because dressing and bandages may restrict the foot movements Int. J. Environ. Res. Public Health 2022,19, 8556 9 of 14 and, together with the typical joint stiffness of the diabetic foot, will render difficult the performance of exercise. After the muscle relaxation exercises, the guided imagery focused on the DFU healing process will initiate. The participant will be instructed to think about his/her current state of health and to imagine the DFU as a decreasing dark area and the healing process as a light associated with pleasant sensations. After being trained by the Lead Researcher, Researcher 1, 2, or 3 will be responsible for conducting the TG1 sessions in the respective hospitals. In the TG2, participants will benefit from four individual sessions of hypnosis with guided imagery (H + GI), conducted by three qualified hypnotherapists external to the research study. The first session begins with the Eye-Roll Test for Hypnotizability [ 48 ]. Each session follows the Hypnotic Protocol with the following steps: pre-talk/absorption/ratification/ alitiation/dissociation/awakening. All hypnotic sessions will train participants in the visual, auditory, and kinesthetic perception of ulcer healing, and will also promote medical treatment adherence. The protocol for both treatment groups includes four scripted sessions, each one with duration of approximately 45 min, delivered once every two weeks, resulting in approximately a 2-month treatment course. Sessions will be conducted in a consulting room reserved by the hospital for the study, where patients will lie on a specialist couch. 4.1.2. Control Groups Participants in the ACG will receive neutral guided imagery sessions, i.e., sessions focused on the patient’s daily life before the DFU. Neutral sessions are conducted by Researchers 1, 2, and 3 following a scripted protocol that includes four biweekly sessions of approximately 45 min, each one dedicated to a different topic (family, work, friends, and leisure). Initially, the participant will be asked to choose a specific event related to the topic of the session, positive or negative, without telling the researcher which event he/she thought about. Then, the participant will answer several questions regarding the episode to promote a more detailed reconstruction of the event, being instructed to only think about the answers and not to reply orally. When the whole episode is remembered, the participant will be asked to tell what he/she imagined/remembered regarding each of the questions. The goal of the placebo sessions is to control for the effect of the received attention, from psychologists and hypnotherapists, on patients in the treatment groups. It is possible that the privileged contact may positively influence the patient’s healing process. Therefore, the attention control condition will allow us to differentiate between the impact of interventions versus the attention given to the ACG. Participants in the PCG will not receive any intervention besides the standard of care medical/nurse treatment. Both passive and active control patients will complete the same outcome questionnaires as the participants allocated to the interventions, at the same time intervals. 4.2. Adherence to the Treatment Plan Patients will be fully informed about the study goals, procedures, and potential benefits that may arise from the results of the DFU treatment. Assessment moments, intervention, and placebo sessions will be scheduled for diabetic foot appointment days so that patients will not have to go to the hospital on purpose to participate in the study. Before the appointment day, Researchers 1, 2, and 3 will call patients to remind them of their appointment with the research team for the purpose of the study. Participants will be asked to complete the last assessment (T2) even if they miss the mid-term assessment (T1). To engage the health professional staff (e.g., physicians, nurses, podologists), meetings will be held with the physicians responsible for the multidisciplinary consultation of diabetic foot and head nurses (in the three hospitals involved in the study), in order to introduce the study and clarify any questions that may arise.