Neck-related function and its connection with disability in chronic whiplash-associated disorders: secondary analysis of a randomized controlled study.

BACKGROUND: More than 40% of individuals with whiplash injury experience persistent neck pain and disability years later, called whiplash-associated disorders (WAD). A randomized controlled trial evaluated three exercise interventions in WAD and found that neck-specific exercise (NSE) and NSE with a behavioral approach (NSEB) significantly improve disability compared to prescribed physical activity (PPA). However, the relationship between neck-related function and disability is inconclusive and needs to be further investigated. AIM: The present study compares the effect of NSE, NSEB, and PPA on neck muscle endurance (NME), active cervical range of motion (AROM), grip strength, and pain intensity immediately before and after the physical tests, and neck disability in individuals who are below or above the cut-off for normative reference values regarding NME, AROM, and grip strength. DESIGN: Follow-up to a multicenter randomized clinical trial. SETTING: Primary healthcare centers and hospital outpatient services. POPULATION: The selected population of this study included 216 patients with persistent WAD grades II and III. METHODS: This is a secondary analysis including 12 months' follow-up. NME, AROM, grip strength, pain, and self-reported disability were recorded at baseline, 3, 6, and 12 months. Linear mixed models were used, and sub-group analyses evaluated by non-parametric tests. RESULTS: NSE and NSEB resulted in greater improvements compared to PPA (P<0.01) in ventral (only males) and dorsal NME, AROM, and pain intensity during testing. We found no significant between-group differences in grip strength and no significant differences between the NSE and NSEB groups. Improvement in disability was seen at the 12-month follow-up of NSE and/or NSEB for individuals both below and above the cut-off reference values for NME and AROM. Individuals in the PPA group below the reference values for NME and AROM reported increasing disability at 12 months compared to baseline. CONCLUSIONS: The results suggest that neck-specific exercises (i.e., NSE, NSEB) improve clinical function and decrease disability in chronic WAD compared to PPA, but PPA can increase disability for patients with low neck-related function. CLINICAL REHABILITATION IMPACT: Higher neck-related function seems to be important for reduced disability in persistent WAD grades II and III. Neck-specific exercises could lead to higher neck-related function.

Adoption of a research-based program for neck disorders implemented in primary care physiotherapy: a short- and long-term follow-up survey study.

Neck disorders are common in primary health care (PHC) physiotherapy. A neck-specific exercise program based on research findings was implemented among physiotherapists in Swedish PHC. The aim of the study was to evaluate the adoption of the program. We invited PHC physiotherapists to an educational session including theoretical information and practical training. Before the educational session the participants (n = 261) completed a baseline questionnaire. After 3 and 12 months, we distributed surveys to identify changes in practice and in confidence regarding diagnosis and treatment. We compared data from 3-months and 12-months follow-up, respectively, with baseline data. Self-reported frequency of most of the included assessment methods was unchanged after 12 months. Frequency of assessment of neck proprioception had increased significantly. Specific neck muscle exercise for treatment of whiplash associated disorders was applied more frequently after 3 and after 12 months than at baseline. Frequency of other treatment methods remained unchanged. Confidence in diagnosis and treatment increased significantly, particularly among women. The program was not adopted as expected, but resulted in increased confidence regarding diagnosis and treatment. The provision of a short educational session seemed not to be sufficient to obtain a sustained change in practice.

Preparedness to Implement Physical Activity and Rehabilitation Guidelines in Routine Primary Care Cancer Rehabilitation: Focus Group Interviews Exploring Rehabilitation Professionals' Perceptions.

To explore primary care professionals' perceptions of physical activity and other cancer rehabilitation practice in cancer survivors, investigating the preparedness to implement guidelines regarding cancer rehabilitation. We collected qualitative data through seven semi-structured focus group interviews with 48 rehabilitation professionals, with mean 9 years of experience in primary care rehabilitation (32 physiotherapists, 15 occupational therapists, and 1 rehabilitation assistant) in a primary care setting. Data was analyzed using content analysis. Primary care rehabilitation professionals expressed limited experience of cancer survivors, experienced lack of knowledge of cancer-related disability, and had doubts concerning how to treat cancer survivors. They also experienced uncertainty about where to find collaboration and support in the healthcare system outside their own rehabilitation clinic. There is a need to combine different implementation strategies to tackle multiple barriers for effective cancer survivor rehabilitation in primary care, to boost individual rehabilitation professionals' knowledge and self-efficacy, to clarify roles and responsibilities for cancer rehabilitation across levels of care, and to develop and strengthen organizational bridges to provide adequate access to rehabilitation for cancer survivors.

Exercise, headache, and factors associated with headache in chronic whiplash: Analysis of a randomized clinical trial.

BACKGROUND: Almost 40% of individuals with chronic whiplash-associated disorders (WAD) report headache after 5 years, making it one of the most common persistent symptoms besides neck pain, but randomized treatment studies are lacking. This study aimed to evaluate the effect of 3 different exercise approaches on headache in chronic WAD grades 2 and 3, and to identify potential factors associated with such headache, and whether they differ depending on 3 different aspects of such headache (current headache, maximum headache, or headache bothersomeness). METHODS: This was an analysis of a randomized clinical trial of people with chronic WAD and headache (n = 188), who were randomized to either 12 weeks of neck-specific exercise without (NSE) or with a behavioral approach (NSEB) or physical activity prescription (PPA). Data were collected at baseline and at 3, 6, and 12 months. Physical and psychosocial factors were tested for association with headache. Multivariate regression models and linear mixed models were used. RESULTS: The NSE/NSEB groups reported reduced headache both over time and compared to PPA. Up to 51% (NSE) and 61% (NSEB) reported at least 50% reduction in their headache at 12 months. The PPA group was not improved over time. Neck pain and dizziness were associated with headache regardless of aspect of headache. The only associated psychosocial factor was anxiety, which was associated with headache bothersomeness. Other factors were mainly physical, and up to 51% of the variance was explained. CONCLUSION: Headache in chronic WAD, may be reduced with neck-specific exercise with or without a behavioral approach. Chronic headache was associated with neck pain and dizziness regardless of aspect tested. Other factors associated with headache in chronic WAD were mainly physical rather than psychosocial. TRIAL REGISTRATION NUMBER: Clinical Trials.gov, no: NCT015285.

The effect of three exercise approaches on health-related quality of life, and factors associated with its improvement in chronic whiplash-associated disorders: analysis of a randomized controlled trial.

PURPOSE: The aim was to evaluate whether neck-specific exercise, with (NSEB) or without (NSE) a behavioural approach, improves health-related quality of life (HRQoL) compared to physical activity prescription (PPA) in chronic whiplash-associated disorders (WAD) grades 2 and 3. A secondary aim was to identify factors associated with HRQoL and HRQoL improvement following exercise interventions. METHODS: This is a secondary analysis of a multicentre randomized clinical trial. Participants (n = 216) with chronic WAD grades 2 and 3 were randomized to 12 weeks of PPA or physiotherapist-led NSE or NSEB. The EQ-5D 3L/EQ-VAS and SF-36v2 physical (PCS) and mental (MCS) component summaries were collected together with several neck-related and psychosocial outcomes at baseline, after 3, 6 and 12 months, and were analysed with linear mixed models (all time points) and multivariate linear regressions (baseline, 6 months). RESULTS: NSE/NSEB resulted in better outcomes than PPA (EQ-VAS and SF-36 PCS, both groups, p < 0.01) but not in a higher EQ-5D score. Improvement over time was seen in EQ-5D/EQ-VAS for the NSEB group (p < 0.01), and for NSE/NSEB as measured with the PCS (p < 0.01). Factors associated with baseline HRQoL and change to 6 months in HRQoL (R2 = 0.38-0.59) were both neck-related and psychosocial (e.g. depression, work ability). CONCLUSION: Neck-specific exercise, particularly with a behavioural approach, may have a more positive impact on HRQoL than physical activity prescription in chronic WAD grades 2 and 3. HRQoL is however complex, and other factors also need to be considered. Factors associated with HRQL and improvements in HRQoL following exercise are multidimensional. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, No. NCT01528579.

Neck-specific exercise may reduce radiating pain and signs of neurological deficits in chronic whiplash - Analyses of a randomized clinical trial.

Up to 90% of people with neurological deficits following a whiplash injury do not recover and cervical muscle dysfunction is common. The aim of this multicentre, randomized controlled trial was to examine whether two versions of neck-specific exercise or prescription of physical activity (PPA) can improve radiating arm pain and clinical signs that can be associated with neurological deficits in people with chronic whiplash associated disorders (WAD). Participants with chronic WAD, arm symptoms and signs associated with neurological deficits (n = 171) were randomized to: 12 weeks of neck-specific exercise without (NSE) or with a behavioural approach (NSEB), or PPA. Pain/bothersomeness frequency, six measures of arm pain/paraesthesia (VAS scales), and four clinical neurological tests were evaluated after 3 months. The NSE group reported the lowest frequency and lowest levels of arm pain, the highest proportion of participants with at least 50% pain reduction and the highest proportion of normal arm muscle force. The NSEB group reported increased normal tendon reflexes. No improvements were recorded for the PPA group. Neck-specific exercise may improve arm pain and decrease signs of neurological deficits, but the addition of a behavioural approach does not seem to be of additional benefit.

Factors associated with work ability following exercise interventions for people with chronic whiplash-associated disorders: Secondary analysis of a randomized controlled trial.

OBJECTIVE: To investigate the efficacy of exercise interventions and factors associated with changes in work ability for people with chronic whiplash-associated disorders. DESIGN: Secondary analysis of a single-blind, randomized multi-centre controlled trial. SETTING: Interventions were conducted in Swedish primary care settings. PATIENTS: A total of 165 individuals with chronic whiplash-associated disorders grade II-III. METHODS: Participants were randomly allocated to neck-specific exercise, neck-specific exercise with a behavioural approach, or prescribed physical activity interventions. Work ability was evaluated with the Work Ability Index at baseline, 3, 6 and 12 months. RESULTS: The neck-specific exercise with a behavioural approach intervention significantly improved work ability compared with the prescribed physical activity intervention (3 months, p = 0.03; 6 months, p = 0.01; 12 months, p = 0.01), and neck-specific exercise at 12 months (p = 0.01). Neck-specific exercise was better than the prescribed physical activity intervention at 6 months (p = 0.05). An increase in work ability from baseline to one year for the neck-specific exercise with a behavioural approach group (p< 0.01) was the only significant within-group difference. Higher self-rated physical demands at work, greater disability, greater depression and poorer financial situation were associated with poorer work ability (p<0.01). CONCLUSION: This study found that neck-specific exercise with a behavioural approach intervention was better at improving self-reported work ability than neck-specific exercise or prescribed physical activity. Improvement in work ability is associated with a variety of factors.

Neck-specific exercises with internet-based support compared to neck-specific exercises at a physiotherapy clinic for chronic whiplash-associated disorders: study protocol of a randomized controlled multicentre trial.

BACKGROUND: Globally, neck pain is the fourth most common condition associated with longer periods of living with disability. Annually, approximately 0.3% of the population of Western countries undergo whiplash trauma, and half of those individuals will develop chronic problems with high costs for the individual and society. Evidence for chronic whiplash-associated disorders (WAD) treatment is scarce, though neck-specific training at a physiotherapy clinic twice a week for 12 weeks has demonstrated good results. More efficient, flexible rehabilitation with reduced waiting times and lower costs is needed, ideally replacing lengthy on-site treatment series by healthcare providers. Internet-based care has been shown to be a viable alternative for a variety of diseases and interventions, but studies are lacking on Internet-based interventions for individuals with chronic neck problems. The aim of the trial described here is to compare the effects of an Internet-based neck-specific exercise programme to the same exercises performed at a physiotherapy clinic in regards to self-reported and clinical measures, as well as cost-effectiveness. METHODS: This prospective, randomized controlled trial will involve 140 participants. Measurements will be made at baseline, 3 months (end of treatment), and 15 months (12 months after end of intervention) and will include ratings of pain, disability, satisfaction with care, work ability, quality of life, and cost-effectiveness. DISCUSSION: The study results may contribute to the development of a more effective rehabilitation, flexible and equal care, shorter waiting times, increased availability, and lower costs for healthcare and society. TRIAL REGISTRATION: ClinicalTrials.gov Protocol ID: NCT03022812 , initial release 12/20/2016.

Cost-effectiveness of neck-specific exercise with or without a behavioral approach versus physical activity prescription in the treatment of chronic whiplash-associated disorders: Analyses of a randomized clinical trial.

BACKGROUND: Fifty percent of people injured by whiplash still report neck pain after 1 year and costs associated with whiplash associated disorders (WAD) are mostly attributed to health service and sick-leave costs in chronic conditions. With increasing health care expenditures the economic impact of interventions needs to be considered. OBJECTIVE: To analyze the cost-effectiveness of physiotherapist-led neck-specific exercise without (NSE) or with a behavioral approach (NSEB), or prescription of physical activity (PPA) in chronic WAD, grade 2 to 3. METHODS: This is a secondary cost-effectiveness analysis of a multicenter randomized clinical trial of 216 participants with chronic WAD grade 2 to 3. The interventions were physiotherapist-led neck-specific exercise without or with a behavioral approach, or prescription of physical activity for 12 weeks. Incremental cost-effectiveness ratios (ICERs) were determined after 1 year and bootstrapped cost-effectiveness planes and sensitivity analyses of physiotherapy visits were performed. Health care and production loss costs were included and quality-adjusted life years (QALYs) were estimated, using the Euroqol-5D questionnaire. Comparisons with the Short Form-6D, and neck disability index (NDI) were also made. RESULTS: The 1-year follow-up was completed by 170 participants (79%). Both physiotherapist-led groups improved in health related quality of life. The intervention cost alone, per quality-adjusted life year (QALY) gain in the NSE group was US$ 12,067. A trend for higher QALY gains were observed in the NSEB group but the costs were also higher. The ICERs varied depending on questionnaire used, but the addition of a behavioral approach to neck-specific exercise alone was not cost-effective from a societal perspective (ICER primary outcome $127,800 [95% confidence interval [CI], 37,816-711,302]). The sensitivity analyses confirmed the results. The prescription of physical activity did not result in any QALY gain and the societal costs were not lower. CONCLUSION: Neck-specific exercise was cost-effective from a societal perspective in the treatment of chronic WAD compared with the other exercise interventions. ICERS varied depending on health-related quality of life questionnaires used, but the addition of a behavioral approach was not cost-effective from a societal perspective. The prescription of physical activity did not result in any QALY gain and was thus not considered a relevant option.

The effect of neck-specific exercise with or without a behavioral approach on psychological factors in chronic whiplash-associated disorders: A randomized controlled trial with a 2-year follow-up.

BACKGROUND: To investigate the effect of neck-specific exercise with (NSEB) or without (NSE) a behavioural approach and prescribed physical activity (PPA) on general pain disability and psychological factors in chronic whiplash-associated disorders (WAD), grade 2 and 3, with a 2-year follow-up. METHODS: A randomized controlled multi-centre study of 3 exercise interventions (NSE, NSEB or PPA) including a 2-year follow-up. A total of 216 volunteers with chronic WAD were recruited and 194 were analyzed, mean age 40.4 (Standard Deviation [SD] 11.4). Measures of general pain disability, pain catastrophizing, anxiety and depression, and kinesiophobia were evaluated at baseline, and 3, 6, 12 and 24 months with linear mixed models. RESULTS: General pain disability decreased by 28% in the NSEB group from baseline to 3 months (P < 0.001) and the improvements in disability were maintained over time (6, 12 and 24 months P < 0.01) compared to the NSE (P > 0.42) and PPA groups (P > 0.43). Pain catastrophizing decreased in the NSE group from baseline to 6 and 12 months (P < 0.01) and in the NSEB group from baseline to 3 and 24 months (P < 0.01) compared to the PPA group (P > 0.82) that showed no change over time. The NSE group improved in kinesiophobia over time from baseline to12 months (P < 0.01) compared to the NSEB (P = 0.052) and the PPA groups (P > 0.74). Anxiety decreased over time from baseline to 12 and 24 months in the NSE group (P > 0.02), but not in the NSEB (P > 0.25) or the PPA (P > 0.50) groups. The PPA had no effect on general disability or any of the measured psychological factors. CONCLUSION: This randomised controlled trial with a 2-year follow-up shows that physiotherapist-led neck-specific exercise with or without the addition of a behavioural approach had superior outcome on general disability and most psychological factors compared to the mere prescription of physical activity.

The pain drawing as an instrument for identifying cervical spine nerve involvement in chronic whiplash-associated disorders.

OBJECTIVE: The aim of the study was to investigate the psychometric properties of a standardized assessment of pain drawing with regard to clinical signs of cervical spine nerve root involvement. DESIGN: This cross-sectional study included data collected in a randomized controlled study. PATIENTS: Two hundred and sixteen patients with chronic (≥6 months) whiplash-associated disorders, grade 2 or 3, were included in this study. METHODS: The validity, sensitivity, and specificity of a standardized pain drawing assessment for determining nerve root involvement were analyzed, compared to the clinical assessment. In addition, we analyzed the interrater reliability with 50 pain drawings. RESULTS: Agreement was poor between the standardized pain drawing assessment and the clinical assessment (kappa =0.11, 95% CI: -0.03 to 0.20). Sensitivity was high (93%), but specificity was low (19%). Interrater reliability was good (kappa =0.64, 95% CI: 0.53 to 0.76). CONCLUSION: The standardized pain drawing assessment of nerve root involvement in chronic whiplash-associated disorders was not in agreement with the clinical assessment. Further research is warranted to optimize the utilization of a pain/discomfort drawing as a supportive instrument for identifying nerve involvement in cervical spinal injuries.

Effects of Neck-Specific Exercises Compared to Waiting List for Individuals With Chronic Whiplash-Associated Disorders: A Prospective, Randomized Controlled Study.

OBJECTIVE: To determine whether 3 months of neck-specific exercises (NSEs) could benefit individuals with chronic whiplash-associated disorder (WAD) who were on a waiting list (WL) for treatment. DESIGN: A prospective, randomized controlled study. SETTING: Primary health care. PARTICIPANTS: Individuals (N=41; 31 women, 10 men; mean age ± SD, 38±11.2y) with chronic (6-36mo) WAD, grades 2 and 3, were analyzed. INTERVENTIONS: Patients were randomly assigned to NSEs or no treatment for 3 months. MAIN OUTCOME MEASURES: Neck-specific disability (Neck Disability Index [NDI]), neck pain (visual analog scale), general pain-related disability (Pain Disability Index [PDI]), self-perceived performance ability (Self-Efficacy Scale [SES]), and health-related quality of life (EuroQol 5 dimensions [EQ-5D]) were measured. RESULTS: NSEs significantly improved the NDI, SES, and EQ-5D compared with WL (P<.01). There was significant improvement (P<.0001) over time in all outcomes for NSEs, and apart from the PDI, significant worsening (P=.002-.0002) over time for the untreated group. CONCLUSIONS: NSEs were more beneficial than no intervention while on a WL for individuals with chronic WAD.

Mechanical properties of the trapezius during scapular elevation in people with chronic whiplash associated disorders--A case-control ultrasound speckle tracking analysis.

BACKGROUND: Approximately 50% of people with Whiplash Associated Disorders (WAD) report longstanding symptoms. The upper trapezius is commonly painful yet its mechanical properties are not fully understood. OBJECTIVES: This study examined the deformation of different depths of the upper trapezius muscle during a scapular elevation task (shoulder shrugging) before and following loaded arm abduction. DESIGN AND METHODS: A cross-sectional case-control study of 36 people (26 female and 10 male, mean age 38 (SD 11)) with chronic WAD and 36 controls, matched for age and gender. Real-time ultrasound recordings of upper trapezius were taken during both scapular elevation tasks. Post-process speckle tracking analysis was undertaken of three different sections of the upper trapezius muscle (superficial, middle, deep). RESULTS: The WAD group had lower deformation of the superficial section of the upper trapezius compared to the control group in both concentric and eccentric phases of scapular elevation (p < 0.05) especially before the loaded arm abduction. After arm abduction, the deformation of the trapezius was reduced in both groups but only significantly in the WAD-group (p = 0.03). Within-group analysis revealed that the control group least engaged the deep section of upper trapezius during the task (p < 0.01). CONCLUSION: This study, measuring mechanical deformation of the upper trapezius during a scapular elevation task indicates that persons with WAD may display different patterns in engagement of the muscle sections than those in the control group. Further research is needed to replicate and understand the reasons for and implications of this possible change in motor strategy within upper trapezius. Clinical Trials.gov, Number: NCT01547624.

The effect of 3 different exercise approaches on neck muscle endurance, kinesiophobia, exercise compliance, and patient satisfaction in chronic whiplash.

OBJECTIVE: The purpose of this study was to compare the effects of 3 different exercise approaches on neck muscle endurance (NME), kinesiophobia, exercise compliance, and patient satisfaction in patients with chronic whiplash. METHODS: This prospective randomized clinical trial included 216 individuals with chronic whiplash. Participants were randomized to 1 of 3 exercise interventions: neck-specific exercise (NSE), NSE combined with a behavioral approach (NSEB), or prescribed physical activity (PPA). Measures of ventral and dorsal NME (endurance time in seconds), perceived pain after NME testing, kinesiophobia, exercise compliance, and patient satisfaction were recorded at baseline and at the 3- and 6-month follow-ups. RESULTS: Compared with individuals in the prescribed physical activity group, participants in the NSE and NSEB groups exhibited greater gains in dorsal NME (P = .003), greater reductions in pain after NME testing (P = .03), and more satisfaction with treatment (P < .001). Kinesiophobia and exercise compliance did not significantly differ between groups (P > .07). CONCLUSION: Among patients with chronic whiplash, a neck-specific exercise intervention (with or without a behavioral approach) appears to improve NME. Participants were more satisfied with intervention including neck-specific exercises than with the prescription of general exercise.

Factors associated with work ability in patients with chronic whiplash-associated disorder grade II-III: A cross-sectional analysis.

OBJECTIVE: To investigate the factors related to self-perceived work ability in patients with chronic whiplash-associated disorder grades II-III. DESIGN: Cross-sectional analysis. PATIENTS: A total of 166 working age patients with chronic whiplash-associated disorder. METHODS: A comprehensive survey collected data on work ability (using the Work Ability Index); demographic, psychosocial, personal, work- and condition-related factors. Forward, stepwise regression modelling was used to assess the factors related to work ability. RESULTS: The proportion of patients in each work ability category were as follows: poor (12.7%); moderate (39.8%); good (38.5%); excellent (9%). Seven factors explained 65% (adjusted R2 = 0.65, p < 0.01) of the variance in work ability. In descending order of strength of association, these factors are: greater neck disability due to pain; reduced self-rated health status and health-related quality of life; increased frequency of concentration problems; poor workplace satisfaction; lower self-efficacy for performing daily tasks; and greater work-related stress. CONCLUSION: Condition-specific and psychosocial factors are associated with self-perceived work ability of individuals with chronic whiplash-associated disorder.

Effects of neck-specific exercise with or without a behavioural approach in addition to prescribed physical activity for individuals with chronic whiplash-associated disorders: a prospective randomised study.

BACKGROUND: Up to 50% of chronic whiplash associated disorders (WAD) patients experience considerable pain and disability and remain on sick-leave. No evidence supports the use of physiotherapy treatment of chronic WAD, although exercise is recommended. Previous randomised controlled studies did not evaluate the value of adding a behavioural therapy intervention to neck-specific exercises, nor did they compare these treatments to prescription of general physical activity. Few exercise studies focus on patients with chronic WAD, and few have looked at patients' ability to return to work and the cost-effectiveness of treatments. Thus, there is a great need to develop successful evidence-based rehabilitation models. The study aim is to investigate whether neck-specific exercise with or without a behavioural approach (facilitated by a single caregiver per patient) improves functioning compared to prescription of general physical activity for individuals with chronic WAD. METHODS/DESIGN: The study is a prospective, randomised, controlled, multi-centre study with a 2-year follow-up that includes 216 patients with chronic WAD (> 6 months and < 3 years). The patients (aged 18 to 63) must be classified as WAD grade 2 or 3. Eligibility will be determined with a questionnaire, telephone interview and clinical examination. The participants will be randomised into one of three treatments: (A) neck-specific exercise followed by prescription of physical activity; (B) neck-specific exercise with a behavioural approach followed by prescription of physical activity; or (C) prescription of physical activity alone without neck-specific exercises. Treatments will be performed for 3 months. We will examine physical and psychological function, pain intensity, health care consumption, the ability to resume work and economic health benefits. An independent, blinded investigator will perform the measurements at baseline and 3, 6, 12 and 24 months after inclusion. The main study outcome will be improvement in neck-specific disability as measured with the Neck Disability Index. All treatments will be recorded in treatment diaries and medical records. DISCUSSION: The study findings will help improve the treatment of patients with chronic WAD. TRIALS REGISTRATION: ClinicalTrials.gov identifier: NCT01528579.