Pilates for neck pain: A systematic review and meta-analysis of randomised controlled trials

BackgroundAlthough widely used in clinical practice, evidence on the effectiveness of the Pilates method in people with neck pain has not been adequately summarised yet.ObjectiveTo systematically review the literature on the effectiveness of the Pilates method on improving pain and disability in patients with neck pain.MethodsWe performed searches in multiple databases from their inception to October 2021. We included randomised controlled trials comparing the effects of the Pilates method with other treatments on pain and disability in patients with neck pain. Two authors independently selected studies, rated risk of bias, extracted data, and judged the overall certainty of evidence using GRADE.ResultsWe included five RCTs (n = 224 participants). There is low certainty evidence that Pilates method did not significantly improve pain compared to other treatments at short-term (mean difference (MD): MD: 9.29 points, 95% CI -25.84 to 7.26; I2 = 93%). Low certainty evidence suggested that the Pilates method did not significantly improve disability compared to other treatments at short-term (MD: 3.20 points, 95% CI -7.70 to 1.30; I² = 75%).ConclusionBased on low certainty evidence, the Pilates method is not better than other treatments at 3 months to reduce pain and disability. High quality trials are required.     

普拉提运动联合肌内效贴对慢性非特异性颈痛的临床疗效观察

目的：探究普拉提运动联合肌内效贴（KT）对慢性非特异性颈痛（CNNP）的临床疗效。方法：选取60例符合纳入标准的CNNP患者,采用随机数字表法将其分为普拉提组、KT组及联合组,每组20例。3组患者均接受健康宣教和物理因子治疗;普拉提组在此基础上增加普拉提运动;KT组增加KT治疗;联合组先接受KT治疗,结束后立即进行普拉提运动,持续治疗4周。治疗前、治疗后及治疗后1个月,采用视觉模拟评分（VAS）、颈椎功能障碍指数（NDI）和颈椎各方向活动度对患者颈部疼痛程度、功能障碍及活动度进行评定并比较。结果：与治疗前相比,3组患者治疗后与治疗后1个月时VAS、NDI评分明显降低,颈椎活动度明显增加（均P<0.05）。与治疗后相比,治疗后1个月3组患者的VAS、NDI评分均降低,颈椎活动度均增加（均P<0.05）。治疗后及治疗后1个月,普拉提组上述评分优于KT组,联合组优于普拉提组（均P<0.05）。结论：普拉提运动联合KT治疗可有效缓解CNNP患者的疼痛症状及改善其颈部功能障碍。     

Program of therapeutic exercises associated with electrotherapy in patients with chronic neck pain: Protocol for a randomized controlled trial

Conservative treatment is the most common clinical management for the proper rehabilitation of patients with chronic neck pain, and there is a trend towards the use of therapeutic exercise. However, some uncertainty about the efficacy of therapeutic exercises remains, and it is necessary to conduct more studies with high methodological rigor, especially in regard to multimodal treatment, as in the combination of therapeutic exercises with electrotherapy. Thus, the objective of this study will be to evaluate the clinical effects of adding high- and low-frequency transcutaneous electrical nerve stimulation (TENS) in a program of specific therapeutic exercises for the treatment of patients with chronic neck pain. Sixty participants will be randomized into three groups: therapeutic exercise + placebo TENS group (n = 20), therapeutic exercise + high-frequency TENS group (n = 20), and therapeutic exercise + low-frequency TENS group (n = 20). Eight treatment sessions will be performed, and participants will be evaluated before and after the eight sessions and four weeks after the end of treatment. The Numerical Rating Pain Scale, Neck Disability Index, Pain-Related Catastrophizing Thoughts Scale, and Tampa Scale for Kinesiophobia will be used for participant evaluations. In the statistical analysis, a linear mixed model will be applied considering interaction between time and group factors. The addition of this electrotherapeutic modality to a therapeutic exercise program is expected to generate clinical improvements for patients with chronic neck pain, and if the results demonstrate benefits in the treatment group, this form of care could be used.     

The effects of neck mobilization in patients with chronic neck pain: A randomized controlled trial

Objective

To determine the effect of mobilization and routine physiotherapy on pain, disability, neck range of motion (ROM) and neck muscle endurance (NME) in patients having chronic mechanical neck pain (NP).

Effect of adding stretching to standardized procedures on cervical range of motion,pain, and disability in patients with non-specific mechanical neck pain: A randomized clinical trial

Objectiveto investigate the benefit of adding stretching exercises to cervical joint mobilization and active rotation exercises for patients with non-specific mechanical neck pain.MethodsThirty-eight subjects with non-specific mechanical neck pain were randomly assigned to a standard procedure group (passive cervical mobilization and active cervical rotation range of motion exercise) or a combined procedure (passive cervical mobilization, active cervical rotation range of motion exercises, and stretching procedures). Mixed factorial analysis of variance was used to compare changes between groups over time in active cervical range of motion, Numeric Pain Rating Scale, Neck Disability Index, Global Rating of Change, and Pressure Pain Threshold.ResultsThere was a significant change in mean active range of motion in all directions, Pressure Pain Threshold, perceived pain, disability levels, and global rating of change over time (p < 0.001). There was a significant group by time interaction in mean active range of motion during extension (p = 0.01), right rotation (p = 0.004), right and left lateral flexion (p = 0.05, and p = 0.02 respectively). However, there was no significant group by time interaction in mean active range of motion during flexion, left rotation, pain intensity (p = 0.09), right and left pressure pain threshold (p = 0.30, 0.47, respectively), and disability (p = 0.07).ConclusionsBoth study groups improved significantly in all subjective and objective outcome measures. However, data from this study suggest that adding stretching to the standard procedures may be more effective than the standard procedure alone at improving cervical extension, right rotation, and lateral flexion active range of motion, but not pain and disability.     

Effects of scapular stabilization and upper limb proprioception as an adjunct to cervical stabilization in chronic neck pain patients: A randomized controlled trial

BackgroundChronic neck pain is a prevalent health condition and a leading cause of disability worldwide. Prompt therapeutic measures are required to overcome this condition.ObjectivesTo evaluate the efficacy of incorporation of scapular stabilization and upper limb proprioceptive exercises to cervical stabilization exercises in patients with chronic neck pain (CNP).DesignA single-blinded randomized controlled design.MethodsA sample of convenience was deployed to recruit twenty-eight patients having CNP (18–45 years) and was randomized into two groups: group A (cervical stabilization exercises group) and group B (scapular stabilization and upper limb proprioceptive exercises group + cervical stabilization exercises). Pain intensity, disability, sleep quality, quality of life, scapular muscles strength and proprioception were assessed at 4 weeks follow up to determine the efficacy of the intervention.ResultsA mixed model ANOVA was used. A statistically significant (p < 0.05) group by time interaction for pain intensity (p = 0.000), scapular muscles strength of all muscles (p = 0.000) was observed. Significant group interaction for absolute error (p = 0.00), for pain (p = 0.001), disability (p = 0.04) and scapular muscle's strength (p = 0.000) was also demonstrated.ConclusionThe results indicated that scapular stabilization and upper limb proprioceptive exercises when combined with cervical stabilization exercises are more beneficial in alleviating pain and disability and improving scapular muscle strength and proprioception in patients with CNP.     

Osteopathic manipulative treatment combined with exercise improves pain and disability in individuals with non-specific chronic neck pain: A pragmatic randomized controlled trial

PurposeTo determine effectiveness of osteopathic manipulative treatment combined with stretching and strengthening exercises in the cervical region on pain and disability in individuals with non-specific chronic neck pain.Methods90 adults with non-specific chronic neck pain were randomized to either exercises group (EG, n = 45) or osteopathic manipulative treatment associated with exercises group (OMT/EG, n = 45). The primary outcomes were obtained by the use of Numeric Pain-Rating Scale (NPRS), Pressure Pain Threshold (PPT) and Neck Disability Index (NDI). Secondary outcomes included range of motion (ROM) for cervical spine rotation, Fear-Avoidance Beliefs Questionnaire Work/Physical Activity (FABQ-W/PA) and Pain-self efficacy at two different moments: baseline and 4 weeks after the first treatment. Techniques and dosages of OMT were selected pragmatically by a registered osteopath. Generalized Estimating Equations model (GEE), complemented by the Least Significant Difference (LSD) and the intention-to-treat analysis, was used to assess the clinical outcomes.ResultsAnalysis with GEE indicated that OMT/EG reduced pain and disability more than the EG alone after 4 weeks of treatment with statistically significant difference (p < 0,05), as well as cervical active rotation was significantly improved (p = 0.03). There were no between-group differences observed in Pressure Pain Threshold (PPT) measure, Fear-Avoidance Beliefs Questionnaire and Pain-self efficacy.ConclusionThe association between OMT and exercises reduces pain and improves functional disability more than only exercise for individuals with non-specific chronic neck pain.     

The influence of home exercise programs for patients with non-specific or specific neck pain: a systematic review of the literature

Abstract

Study design: Systematic review of randomized controlled trials (RCT).

Objectives: To examine the effects of a therapeutic home exercise program (HEP) for patients with neck pain (associated with whiplash, non-specific, or specific neck pain, with or without radiculopathy, or cervicogenic headache) on pain, function, and disability. Our secondary aim was to describe the design, dosage, and adherence of the prescribed HEPs.

Background: Neck pain is a leading cause of disability that affects 22–70% of the population. Different techniques have been found effective for the treatment of neck pain. However, there is conflicting evidence to support the role of a therapeutic HEP to reduce pain, disability, and improve function and quality of life (QOL).

Methods: A systematic review in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement for reporting systematic reviews. The full-text review utilized the Maastricht–Amsterdam assessment tool to assess quality among RCTs.

Results: A total of 1927 subjects included within seven full-text articles met our specific search strategy. It was found that HEPs with a focus on strength and endurance-training exercises, as well as self- mobilization, have a positive effect when used in combination with other conservative treatments or alone.

Conclusions: Home exercise programs that utilize either self-mobilizations within an augmented HEP to address specific spinal levels, or strengthening, and/or endurance exercise are effective at reducing neck pain, function, and disability and improving QOL. The benefit of HEPs in combination with other conservative interventions yields some benefit with a range of effect sizes.     

Effects of the craniocervical flexion and isometric neck exercise compared in patients with chronic neck pain: A randomized controlled trial

ABSTRACT

Introduction: The present study compared the effects of neck isometric exercise (NIE) and craniocervical flexion exercise (CFE) on cervical lordosis, muscle endurance of cervical flexion, neck disability index (NDI), and active cervical range of motion (ACROM) in all three planes in patients with non-specific, chronic neck pain (CNP). Materials and Methods: Forty-one patients from a university hospital-based rehabilitation center were randomly assigned to an experimental (22 patients performing CFE) or control (19 patients performing NIE) group. All patients performed three 30-second repetitions of stretching exercises for the neck flexor, extensor, lateral flexor, and rotator as warm-up and cool-down exercises. The patients in the experimental group then underwent CFE 30 minutes/day, 3 times a week, for 8 weeks, while the control group underwent NIE. The main outcome measures were pain on visual analogue scale (VAS) and perceived disability based on the neck disability index (NDI). The secondary outcomes were cervical lordosis measured by an absolute rotation angle (ARA), muscle endurance of cervical flexion, and ACROM. Results: Both groups showed improved pain, NDI, endurance of the cervical flexor muscles, and ACROM in all three planes after 8 weeks (p < 0.001 for all). All these outcomes, except for the NDI, showed significantly greater improvements following CFE than following NIE (p < 0.05 for all). In particular, a significantly improved ARA of cervical lordosis was found following CFE but not following NIE (p < 0.05). Conclusions: CFE targeted at retraining the craniocervical flexor muscles was useful for improving or restoring the pain, cervical lordosis, and neck-related function disorders among patients with non-specific CNP.     

Short- and long-term effects of a six-week clinical Pilates program in addition to physical therapy on postmenopausal women with chronic low back pain: a randomized controlled trial

Purpose: To determine the short- and long-term effectiveness of the application of Clinical Pilates in addition to physical therapy versus a physical therapy treatment alone in a population of postmenopausal women with chronic low back pain (CLBP). Methods: A single-blind randomized controlled trial with repeated measures and a follow-up period. One hundred and one patients were randomly allocated to a Pilates?+?physical therapy (PPT) group or to a physical therapy (PT) only group for six weeks. Pain and disability were measured by visual analog scale (VAS) and the Oswestry disability index respectively preintervention, after 6 weeks of treatment and after 1-year follow-up. Results: There were significant differences between groups in pain and disability after 6 weeks of treatment, with better results in the PPT group with an effect size of d?=?3.14 and d?=?2.33 for pain and disability. After 1-year follow-up, only PPT group showed better results compared with baseline with an effect size of d?=?2.49 and d?=?4.98 for pain and disability. Conclusion: The results suggest that using Clinical Pilates in addition to physical therapy provides improved results on pain management and functional status for postmenopausal woman with CLBP and that its benefits still linger after one year.

• Implications for Rehabilitation

• Chronic Low Back Pain could benefit from the Pilates practice in postmenopausal women.

• Improvement in pain and disability derived from CLBP seem to be maintained over time due to Pilates practice.

• Pilates constitutes a safe tool to be applied in older population with CLBP due to its ability to be adapted to every performance and physical level.

     

悬吊式核心稳定训练对慢性非特异性下背痛的疗效

目的:探讨悬吊式核心稳定训练对比垫上核心稳定训练对慢性非特异性下背痛患者的疗效.方法:30例慢性非特异性下背痛患者,随机分为悬吊式核心稳定训练组(悬吊组)和垫上核心稳定训练组(垫上组)两组,每组15例.通过视觉模拟疼痛评分法(VAS)、Oswestry功能障碍指数问卷(ODI)和背伸肌肌肉力量测定,分别于治疗前、治疗结束时和治疗结束6个月时,对患者疼痛、腰部功能和背伸肌肌力进行评价.结果:治疗结束6个月时,悬吊组VAS得分改变值高于垫上组,差异有显著性意义(P＜0.05);与治疗前相比,悬吊组在治疗结束时和治疗结束6个月时,VAS评分均有降低,差异有显著性意义(P＜0.01);垫上组在治疗结束时VAS评分下降,差异有显著性意义(P＜0.01).治疗结束时和治疗结束6个月时,悬吊组得分改变值均大于垫上组,差异有显著性意义(P＜0.05).与治疗前相比,治疗结束时两组患者ODI评分均有下降(P＜0.05),治疗结束6个月时悬吊组ODI评分下降(P＜0.05).治疗结束时和治疗结束6个月时,悬吊组患者背伸肌肌力测定改变值均高于垫上组(P＜0.05);与治疗前相比,治疗结束时和治疗结束6个月时悬吊组背伸肌肌力均提高(P＜0.05),而垫上组患者背伸肌肌力仅在治疗结束时有显著提高(P＜0.01).结论:悬吊式核心稳定训练与垫上训练均可以减轻下腰疼痛,改善腰部功能,提高日常生活活动能力;而悬吊组改善下背痛疼痛的长期效果可能优于垫上组.     

Comparative short-term effects of two thoracic spinal manipulation techniques in subjects with chronic mechanical neck pain: A randomized controlled trial

Spinal Manipulation (SM) has been purported to decrease pain and improve function in subjects with non-specific neck pain. Previous research has investigated which individuals with non-specific neck pain will be more likely to benefit from SM. It has not yet been proven whether or not the effectiveness of thoracic SM depends on the specific technique being used. This double-blind randomized trial has compared the short-term effects of two thoracic SM maneuvers in subjects with chronic non-specific neck pain. Sixty participants were distributed randomly into two groups. One group received the Dog technique (n = 30), with the subject in supine position, and the other group underwent the Toggle-Recoil technique (n = 30), with the participant lying prone, T4 being the targeted area in both cases. Evaluations were made of self-reported neck pain (Visual Analogue Scale); neck mobility (Cervical Range of Motion); and pressure pain threshold at the cervical and thoracic levels (C4 and T4 spinous process) and over the site described for location of tense bands of the upper trapezius muscle. Measurements were taken before intervention, immediately afterward, and 20 min later. Both maneuvers improved neck mobility and mechanosensitivity and reduced pain in the short term. No major or clinical differences were found between the groups. In the between-groups comparison slightly better results were observed in the Toggle-Recoil group only for cervical extension (p = 0.009), right lateral flexion (p = 0.004) and left rotation (p < 0.05).     

Effect of muscle energy technique and static stretching on pain and functional disability in patients with mechanical neck pain: A randomized controlled trial

BackgroundMechanical neck pain is one of the common musculoskeletal disorders. Muscle energy technique (MET) may be a useful intervention for treating such disorder.ObjectiveThe aim of this study was to compare the effect of MET with passive stretching on pain and functional disability in people with mechanical neck pain.MethodsA randomized controlled trial was undertaken. Sixty patients with mechanical neck pain were randomly allocated to either the MET group or control group. The former group received MET, and the latter group received static stretching. Both groups received conventional therapy. Treatment was given once a day for 6 days. A visual analogue scale (VAS) was used to measure the intensity of pain, and functional disability was assessed using the neck disability index (NDI) was immediately before treatment and again on the 6^th day.ResultsVAS and NDI scores showed a significant improvement in both MET and stretching groups on the 6^th day postintervention (p < 0.05). However, both VAS and NDI scores showed better improvement in the MET group as compared to the stretching group (p < 0.025).ConclusionMuscle energy technique was better than stretching technique in improving pain and functional disability in people with mechanical neck pain.     

Comparative effects of 12 weeks of equipment based and mat Pilates in patients with Chronic Low Back Pain on pain,function and transversus abdominis activation. A randomized controlled trial

BackgroundPilates method has been recommended for patients with chronic low back pain (CLBP) and the activation of transversus abdominis has been deemed to play an important role in the improvement of these patients. Nevertheless, the evidence of the activation of TrA in Pilates practitioners remains unclear.ObjectiveTo assess the effectiveness of 12 weeks of Pilates practice in disability, pain, kinesiophobia and transversus abdominis activation in patients with chronic nonspecific Low Back Pain.DesignA randomized controlled trial was carried out.MethodsA single-blind randomized controlled trial with repeated measures at 6 and 12 weeks was carried out. A total of ninety eight patients with low back pain were included and randomly allocated to a Pilates Mat group (PMG) equipment based with apparatus Pilates (PAG) or control group (CG). Roland Morris Disability Questionnaire (RMDQ), visual analog scale (VAS) Tampa Scale of Kinesiophobia (TSK), and transversus abdominis (TrA) activation assessed by real time ultrasound measurement (US) were assessed as outcome measures.ResultsImprovement were observed in both intervention groups in all the included variables at 6 and 12 weeks (p < 0.001). Faster enhancement was observed in the equipment based Pilates group (p = 0.007).ConclusionsEquipment based and mat Pilates modalities are both effective in the improvement of TaA activation in patients with CLBP with associate improvement on pain, function and kinesiophobia. Significant differences were observed after 12 weeks of intervention in PMG and PAG with faster improvement in PAG suggesting that, feedback provided by equipment could help in the interiorization of Pilates principles.     

Comparative effectiveness of proprioceptive neuromuscular facilitation and passive vertebral mobilization for neck disability in patients with mechanical neck pain: A randomized controlled trial

ObjectiveTo compare the effectiveness of Proprioceptive Neuromuscular Facilitation (PNF) and Passive Vertebral Mobilization (PVM), both when given in adjunct to routine physical therapy (RPT), on neck disability in patients with mechanical neck pain (MNP).MethodsA single-blinded randomized controlled trial was conducted on 90 patients with MNP at the National Institute of Rehabilitation Medicine, Islamabad, Pakistan, from September 2015 to March 2018. The participants aged between 18 and 65 years were recruited through a simple random sampling technique and randomly divided into three groups i.e. PNF + RPT, PVM + RPT, and RPT. Each participant was evaluated pre and post-intervention (after four weeks) through neck disability index (NDI). The data were analyzed by using SPSS version 21.ResultsThe MANOVA was run on the pre-post mean differences of the variables to determine the changes within the groups which showed that the participants improved significantly in all the groups in terms of the NDI components and overall NDI score (p < 0.05). Univariate analysis with the post-hoc comparison and Tuckey HSD correction was used to determine the differences between the groups which showed that there was a significant difference between the interventional groups in the overall pain intensity, as well as pain experienced while performing personal care activities, reading, doing work, driving, sleeping, recreation and in the total NDI score (p < 0.05).ConclusionPVM (in adjunct to RPT) was more effective than PNF (in adjunct to RPT) for the patients with MNP to manage themselves in daily activities.Clinical trial registrationNCT03813680 (at clinicaltrials.gov) (https://clinicaltrials.gov/ct2/show/NCT03813680)     

Efficacy of the Pilates versus general exercises versus educational workshops on neuromuscular parameters: A randomized controlled trial

IntroductionMuscle strength, flexibility and changes in muscle recruitment patterns are usually associated to low back pain (LBP). Physical exercises can reverse the adverse changes associated to LBP.ObjectivesCompare Pilates, general exercises and educational workshop on muscle flexibility, strength and recruitment of the trunk extensor muscles in women with LBP.MethodsForty-six women were randomly divided into Pilates group (PG, n = 16), general exercise group (GEG, n = 15), and educational group (EG, n = 15). This study sought to determine flexibility, muscle strength, and muscle recruitment of right (RIL), left (LIL) iliocostalis lumbar; right (RMU) and left (LMU) lumbar multifidus muscles. Both PG and GEG performed 16 exercise sessions, while EG attended 4 workshops. Statistical analysis used data sample from Shapiro-Wilk test, Pearson's correlation, multivariate analysis, mixed variance analysis, and Cohen's index.ResultsFlexibility showed no differences (p > 0.05). Muscle strength increased in the intragroup analysis for PG (p = 0.003) and GEG (p = 0.002); however, the intergroup analysis presented no difference. Intergroup showed statistically significant differences for the recruitment of RMU in PG (p < 0.001). Intragroup analysis presented differences after interventions in PG for RIL (p = 0.001); in GEG for LIL (p = 0.005); and in EG for RIL (p = 0.007), LIL (p = 0.002) and RMU (p < 0.001).ConclusionsNone of the groups showed flexibility improvements. PG and GEG increased muscle strength through intragroup analysis. Intergroup analysis showed an increase in recruitment of the RMU muscle in PG and all groups demonstrated significant improvements in the intragroup analysis.     

腰椎稳定性训练结合肌内效贴治疗慢性非特异性腰背痛的临床疗效观察

目的:观察腰椎稳定性训练结合肌内效贴治疗慢性非特异性腰背痛的临床疗效。方法:将38例慢性非特异性腰背痛患者随机分为对照组和观察组各19例。对照组患者接受常规康复治疗,观察组患者在常规康复治疗的同时接受家庭腰椎稳定性训练和肌内效贴治疗。在康复治疗前、后用目测类比评分法(VAS),腰痛障碍指数(ODI)对患者进行评定。结果:经过4周的治疗,2组VAS及ODI评分均较治疗前明显下降(均P0.05);且观察组患者VAS及ODI评分均明显低于对照组(均P0.05)。结论:慢性非特异性腰背痛患者在接受常规康复治疗的同时,进行家庭腰椎稳定性训练联合肌内效贴治疗能有效地缓解腰痛,改善功能,值得临床上应用、推广。     

Effectiveness of standard cervical physiotherapy plus diaphragm manual therapy on pain in patients with chronic neck pain: A randomized controlled trial

BackgroundLiterature concerning the effect of diaphragm treatment to reduce neck pain symptoms is scarce. Aim of this trial was to investigate the effects of diaphragm manual therapy associated with standard physiotherapy treatment on pain in patients with Chronic Neck Pain (CNP).MethodsIn a private practice clinic, subjects with CNP were randomly assigned to receive three 30-min treatment sessions of standard cervical physiotherapy and Diaphragm Manual Therapy (DMT) or Sham Diaphragm Technique (SDT). Participants and assessors were blinded to the assignment. Primary outcome was pain, secondary outcomes were cervical active range of motion, pain pressure threshold, disability and quality of life measured at baseline, before and after each session, at 3 and 6-months. Adverse events were monitored. A non-parametric multivariate approach (combined permutation test) was applied to assess the effect of the treatment on all the outcomes. An intention to treat analysis was performed.ResultsForty patients were randomly allocated to DMT and SDT groups. Combined permutation test showed a significant higher improvement in DMT group compared to SDT group (p-value = 0.0002). The between-group comparisons on single outcomes showed a statistically significant improvement only for pain pressure threshold on upper trapezius (adjusted p-value = 0.029). No adverse events related to the intervention were registered.ConclusionsIn patients with CNP, addition of diaphragm manual techniques to standard cervical treatment seems to give a better global outcome, but this improvement is of unclear clinical relevance; the primary outcome seems not to have a role. Further studies are needed to confirm and clarify these results.Trial registrationRelease Date: July 18, 2017 Registered in ClinicalTrial.gov database ID: NCT03223285A.