Frailty in patients on dialysis.

Frailty is a condition that is frequently observed among patients undergoing dialysis. Frailty is characterized by a decline in both physiological state and cognitive state, leading to a combination of symptoms, such as weight loss, exhaustion, low physical activity level, weakness, and slow walking speed. Frail patients not only experience a poor quality of life, but also are at higher risk of hospitalization, infection, cardiovascular events, dialysis-associated complications, and death. Frailty occurs as a result of a combination and interaction of various medical issues in patients who are on dialysis. Unfortunately, frailty has no cure. To address frailty, a multifaceted approach is necessary, involving coordinated efforts from nephrologists, geriatricians, nurses, allied health practitioners, and family members. Strategies such as optimizing nutrition and chronic kidney disease-related complications, reducing polypharmacy by deprescription, personalizing dialysis prescription, and considering home-based or assisted dialysis may help slow the decline of physical function over time in subjects with frailty. This review discusses the underlying causes of frailty in patients on dialysis and examines the methods and difficulties involved in managing frailty among this group.

The Prepare for Kidney Care Study: prepare for renal dialysis versus responsive management in advanced chronic kidney disease.

Shared decision making in advanced chronic kidney disease (CKD) requires unbiased information on survival and person-centred outcomes known to matter to patients: quality of life, symptom burden and support from family and healthcare professionals. To date, when deciding between dialysis and conservative care, patients have had to rely on evidence from small observational studies. Clinicians recognize that like is not being compared with like in these studies, and interpret the results differently. Furthermore, support differs considerably between renal units. What patients choose therefore depends on which renal unit they attend. To address this, a programme of work has been underway in the UK. After reports on survival and symptoms from a small number of renal units, a national, mixed-methods study-the Conservative Kidney Management Assessment of Practice Patterns Study-mapped out conservative care practices and attitudes in the UK. This led to the Prepare for Kidney Care study, a randomized controlled trial comparing preparation for dialysis versus preparation for conservative care. Although powered to detect a positivist 0.345 difference in quality-adjusted life years between the two treatments, this trial also takes a realist approach with a range of person-centred secondary outcomes and embedded qualitative research. To understand generalizability, it is nested in an observational cohort study, which is nested in a CKD registry. Challenges to recruitment and retention have been rapidly identified and addressed using an established embedded mixed methods approach-the QuinteT recruitment intervention. This review considers the background to and progress with recruitment to the trial.

Quality of life among caregivers of people with end-stage kidney disease managed with dialysis or comprehensive conservative care.

BACKGROUND: To measure health-related and care-related quality of life among informal caregivers of older people with end-stage kidney disease (ESKD), and to determine the association between caregiver quality of life and care recipient's treatment type. METHODS: A prospective cross-sectional study was conducted. Three renal units in the UK and Australia were included. Informal caregivers of people aged ≥75 years with ESKD managed with dialysis or comprehensive conservative non-dialytic care (estimated glomerular filtration (eGFR) ≤10 mL/min/1.73m2) participated. Health-related quality of life (HRQoL) was assessed using Short-Form six dimensions (SF-6D, 0-1 scale) and care-related quality of life was assessed using the Carer Experience Scale (CES, 0-100 scale). Linear regression assessed associations between care-recipient treatment type, caregiver characteristics and the SF-6D utility index and CES scores. RESULTS: Of 63 caregivers, 49 (78%) were from Australia, 26 (41%) cared for an older person managed with dialysis, and 37 (59%) cared for an older person managed with comprehensive conservative care. Overall, 73% were females, and the median age of the entire cohort was 76 years [IQR 68-81]. When adjusted for caregiver sociodemographic characteristics, caregivers reported significantly worse carer experience (CES score 15.73, 95% CI 5.78 to 25.68) for those managing an older person on dialysis compared with conservative care. However, no significant difference observed for carer HRQoL (SF-6D utility index - 0.08, 95% CI - 0.18 to 0.01) for those managing an older person on dialysis compared with conservative care. CONCLUSIONS: Our data suggest informal caregivers of older people on dialysis have significantly worse care-related quality of life (and therefore greater need for support) than those managed with comprehensive conservative care. It is important to consider the impact on caregivers' quality of life when considering treatment choices for their care recipients.

A novel glucocorticoid-free maintenance regimen for anti-neutrophil cytoplasm antibody-associated vasculitis.

Objectives: Glucocorticoids (GCs) are a mainstay of treatment for patients with ANCA-associated vasculitis (AAV) but are associated with significant adverse effects. Effective remission induction in severe AAV using extremely limited GC exposure has not been attempted. We tested an early rapid GC withdrawal induction regimen for patients with severe AAV. Methods: Patients with active MPO- or PR3-ANCA vasculitis or ANCA-negative pauci-immune glomerulonephritis were included. Induction treatment consisted of two doses of rituximab, 3 months of low-dose CYC and a short course of oral GC (for between 1 and 2 weeks). Clinical, biochemical and immunological outcomes as well as adverse events were recorded. Results: A total of 49 patients were included, with at least 12 months of follow-up in 46. All patients achieved remission, with decreases observed in creatinine, proteinuria, CRP, ANCA level and BVAS. Three patients requiring dialysis at presentation became dialysis independent. Two patients required the introduction of maintenance GC for treatment of vasculitis. Overall outcomes were comparable to those of two matched cohorts (n = 172) from previous European Vasculitis Society (EUVAS) trials, but with lower total exposure to CYC and GCs (P < 0.001) and reduced rates of severe infections (P = 0.02) compared with the RITUXVAS (rituximab versus cyclophosphamide in AAV) trial. We found no new cases of diabetes in the first year compared with historic rates of 8.2% from the EUVAS trials (P = 0.04). Conclusion: Early GC withdrawal in severe AAV is as effective for remission induction as the standard of care and is associated with reduced GC-related adverse events.

Healthcare use, costs and quality of life in patients with end-stage kidney disease receiving conservative management: results from a multi-centre observational study (PACKS).

BACKGROUND: Previous research has explored the cost of providing renal replacement therapies in patients with end-stage kidney disease and their quality of life. This is the first study to examine the healthcare costs of patients receiving conservative care without dialysis for end-stage kidney disease. This alternative to dialysis is an option for patients who prefer a supportive and palliative care approach. AIM: Descriptive cost and quality of life analyses alongside a UK-based multi-centre observational study in patients receiving conservative management for end-stage kidney disease. DESIGN: Health service use was recorded up to 12 months after making the decision to receive conservative management. Mean costs were calculated for each 3-month time period. The annual cost was calculated in two ways: by using only patients with complete cost data and by using all available data weighted by the number of patients at each time point. SETTING: In total, 42 patients who opted for conservative management over dialysis were recruited. RESULTS: Mean costs were £1622 (0-3 months), £1008 (3-6 months), £554 (6-9 months) and £2626 (9-12 months). Mean annual cost based on complete data ( n = 8) was £5511, and the weighted mean annual cost was £5620. CONCLUSION: The importance of this study is twofold. First, it provides substantive new information for health and social care planning of conservative management by demonstrating where demand exists for services, in both the United Kingdom and other countries with a comparable health service structure. Second, methodologically, it indicates that it is feasible to collect service use data directly from this patient population.

Loss of appendicular muscle mass in haemodialysis patients is associated with increased self-reported depression, anxiety and lower general health scores.

BACKGROUND: Previous reports have suggested an association between depression and nutritional status. To investigate whether there is an association with loss of muscle mass (sarcopenia), we screened HD patients for depression. METHODS: We screened for depressive symptoms using the Beck Depression Inventory-II (BDI-II), Hospital Anxiety and Depression Scale (HADS), and general health using the short form 36 (SF36), and additionally measured appendicular lean mass post-dialysis with segmental bioimpedance. RESULTS: We studied 113 patients, 84 (74.3%) male, mean age 64.9 ± 14.9 years, median duration of haemodialysis 27.0 (15.7-61.0) months, body mass index post-dialysis 25.2 (22.8-28.6) kg/m2, appendicular lean mass (ALM) index 6.98 (6.22-8.10) kg/m2. BDI-II 11 (4-17), HADS 10 (5-16.5), and SF36 average 43.3(36.6-48.4). Lower ALM index was associated with greater BDI-II and HADS depression scores (r = 0.29, p = 0.008; r = 0.27, p = 0.012) respectively, whereas higher ALM index was associated with increased SF36 physical functioning and general health (r = 0.34, p = 0.001; r = 0.26, p = 0.019), respectively on univariate analysis. On logistic regression, lower ALM index was independently associated with high HADS cut off ≥8 (standardised ß-0.31, p = 0.007). There were no associations with weight, body mass index or fat index. Greater extracellular water both pre- and post-dialysis was associated with reduced SF36 physical functioning (r = -0.24, p = 0.011, r = -0.22, p = 0.26), respectively. CONCLUSION: We report an association between ALM index measured by segmental bioimpedance and increased self-reported depression, anxiety and decreased general health. Whether treatment programs designed to improve muscle mass, can lead to reduced levels of depression, and anxiety and improved perceived general health, remains to be determined.

Clinician views of patient decisional conflict when deciding between dialysis and conservative management: Qualitative findings from the PAlliative Care in chronic Kidney diSease (PACKS) study.

BACKGROUND: Only a paucity of studies have addressed clinician perspectives on patient decisional conflict, in making complex decisions between dialysis and conservative management (renal supportive and palliative care). AIM: To explore clinician views on decisional conflict in patients with end-stage kidney disease. DESIGN: Interpretive, qualitative study. SETTING AND PARTICIPANTS: As part of the wider National Institute for Health Research, PAlliative Care in chronic Kidney diSease study, semi-structured interviews were conducted with clinicians (nephrologists n = 12; 7 female and clinical nurse specialists n = 15; 15 female) across 10 renal centres in the United Kingdom. Interviews took place between April 2015 and October 2016 and a thematic analysis of the interview data was undertaken. RESULTS: Three major themes with associated subthemes were identified. The first, 'Frequent changing of mind regarding treatment options', revealed how patients frequently altered their treatment decisions, some refusing to make a decision until deterioration occurred. The second theme, 'Obligatory beneficence', included clinicians helping patients to make informed decisions where outcomes were uncertain. In weighing up risks and benefits, and the impact on patients, clinicians sometimes withheld information they thought might cause concern. Finally, 'Intricacy of the decision' uncovered clinicians' views on the momentous and brave decision to be made. They also acknowledged the risks associated with this complex decision in giving prognostic information which might be inaccurate. LIMITATIONS: Relies on interpretative description which uncovers constructed truths and does not include interviews with patients. CONCLUSION: Findings identify decisional conflict in patient decision-making and a tension between the prerequisite for shared decision-making and current clinical practice. Clinicians also face conflict when discussing treatment options due to uncertainty in equipoise between treatments and how much information should be shared. The findings are likely to resonate across countries outside the United Kingdom.

Prolonged Duration of Renal Recovery Following ANCA-Associated Glomerulonephritis.

BACKGROUND: As renal biopsies are not routinely repeated to monitor treatment response in anti-neutrophil cytoplasm antibody (ANCA)-associated glomerulonephritis, serum creatinine (SC) and proteinuria assessed by urine protein:creatinine ratio (UPCR) measurements are relied upon to provide a non-invasive estimate of disease activity within the kidney. However, sparse information exists about the time to achieve maximal improvement in these parameters, which has important implications for treatment decisions and disease-scoring systems. METHODS: We analysed patients with ANCA-associated glomerulonephritis and renal impairment from cohorts in the United Kingdom and Ireland, with the primary objective of determining actuarial time to nadir SC and UPCR. Time to disappearance of haematuria was analysed as a secondary objective. RESULTS: Ninety-four patients fulfilled our selection criteria, with 94 (100%) and 66 (70%) having reached their nadir SC and UPCR respectively during the follow-up period. Nadir SC was achieved after a median of 88 days (95% CI 74-102), UPCR at 346 days (95% CI 205-487). Those of Indo-Asian ethnic origin reached their nadir SC faster (34 days) than other ethnicities (p < 0.01). There were no significant differences in time to nadir SC or UPCR on the basis of gender, clinical diagnosis, ANCA positivity or renal biopsy findings. CONCLUSION: In this retrospective study, nadir creatinine and proteinuria occur later than other signs of clinical remission, suggesting that ongoing renal recovery continues for a significant time after diagnosis. It may benefit disease-scoring systems to take into account SC levels beyond the initial assessment.

UK Scleroderma Study Group (UKSSG) guidelines on the diagnosis and management of scleroderma renal crisis.

The UK Scleroderma Study Group developed guidelines on the diagnosis and management of scleroderma renal crisis (SRC) based on best available evidence and clinical experience. SRC is characterised by the acute onset of severe hypertension and acute kidney injury. Current strategies to reduce the associated morbidity and mortality include identifying at risk patients to aid early diagnosis. ACE inhibitor therapy should be lifelong in all patients, regardless of whether they require renal replacement therapy. Patients with SRC may recover renal function up to 3 years after the crisis, most often within 12 to 18 months.

Successful outcome of pregnancy in patients with anti-neutrophil cytoplasm antibody-associated small vessel vasculitis.

Pregnancy in patients with anti-neutrophil cytoplasm antibody-associated vasculitis is reportedly associated with a high risk of fetal and maternal complications. Here we describe the outcome of pregnancies in patients with granulomatosis with polyangiitis and microscopic polyangiitis at five centers in the United Kingdom using a retrospective case review of all women who became pregnant following diagnosis. We report 15 pregnancies in 13 women resulting in 15 live births including one twin pregnancy and 13 singleton pregnancies. One patient had an unplanned pregnancy and a first trimester miscarriage while taking methotrexate. All other pregnancies were planned following a minimum of 6 months clinical remission. Eleven successful pregnancies were delivered vaginally at full term, whereas three were delivered by cesarean section. All infants were healthy with no neonatal complications on their initial health check within the first 24 h of delivery and no evidence of neonatal vasculitis. One relapse occurred during pregnancy and was successfully treated with an increased dose of azathioprine and corticosteroids, intravenous immunoglobulin, and plasma exchange therapy. One patient developed tracheal crusting and subglottic stenosis of infective etiology in the third trimester requiring tracheal debridement post delivery. No patient had a relapse in the first 12 months postpartum. Thus, successful pregnancy outcomes can occur following planned pregnancy in women in sustained remission on non-teratogenic therapies.

PAlliative Care in chronic Kidney diSease: the PACKS study--quality of life, decision making, costs and impact on carers in people managed without dialysis.

BACKGROUND: The number of patients with advanced chronic kidney disease opting for conservative management rather than dialysis is unknown but likely to be growing as increasingly frail patients with advanced renal disease present to renal services. Conservative kidney management includes ongoing medical input and support from a multidisciplinary team. There is limited evidence concerning patient and carer experience of this choice. This study will explore quality of life, symptoms, cognition, frailty, performance decision making, costs and impact on carers in people with advanced chronic kidney disease managed without dialysis and is funded by the National Institute of Health Research in the UK. METHODS: In this prospective, multicentre, longitudinal study, patients will be recruited in the UK, by renal research nurses, once they have made the decision not to embark on dialysis. Carers will be asked to 'opt-in' with consent from patients. The approach includes longitudinal quantitative surveys of quality of life, symptoms, decision making and costs for patients and quality of life and costs for carers, with questionnaires administered quarterly over 12 months. Additionally, the decision making process will be explored via qualitative interviews with renal physicians/clinical nurse specialists. DISCUSSION: The study is designed to capture patient and carer profiles when conservative kidney management is implemented, and understand trajectories of care-receiving and care-giving with the aim of optimising palliative care for this population. It will explore the interactions that lead to clinical care decisions and the impact of these decisions on informal carers with the intention of improving clinical outcomes for patients and the experiences of care givers.

Induction treatment of ANCA-associated vasculitis with a single dose of rituximab.

OBJECTIVES: Rituximab is effective in inducing remission in ANCA-associated vasculitis (AAV), with randomized evidence to support its use as four infusions of 375 mg/m(2) (the conventional lymphoma dosing schedule). As B cell depletion (BCD) appears to occur very rapidly after the first dose, we questioned the need for repeat dosing and adopted a standard single-dose protocol of 375 mg/m(2) to treat active AAV. METHODS: All consecutive cases with newly diagnosed or relapsing AAV for whom conventional immunosuppression was contraindicated or ineffective were enrolled. All were rituximab naive. Circulating CD19(+) B cells and clinical and serological markers of disease activity were recorded at regular intervals. Complete remission (CR) was defined as the absence of clinical features of AAV with a prednisolone dose <10 mg/day. RESULTS: Nineteen patients were included, 17 (89%) with generalized disease and 2 (11%) with severe disease (creatinine level >500 µM). Eight (42%) were on additional immunosuppression at the time of rituximab treatment. Satisfactory BCD (<0.005 cells/µl) was achieved in 89% of patients after a median of 13 days. Three-month BCD probability was 89%. Median time to CR following a single dose of rituximab was 38 days and the 3-month probability of CR was 80%. Median time to B cell repopulation was 9.2 months and to disease relapse/redose was 27 months. Use of this single-dose protocol saved an estimated £4533/patient (US$7103; €5276) compared with a 4 × 375 mg/m(2) dosing schedule. CONCLUSION: Our single-centre experience suggests that a single dose of rituximab of 375 mg/m(2) is a reasonable and more cost-effective therapy for inducing remission in patients with AAV.

Effect of ethnicity and socioeconomic deprivation on uptake of renal supportive care and dialysis decision-making in older adults.

Background: Renal supportive care has become an increasingly relevant treatment option as the renal patient population ages. Despite the prevalence of kidney disease amongst ethnic minority and socioeconomically deprived patients, evidence focused on supportive care and dialysis decision-making in these groups is limited. Methods: This retrospective study selected older patients referred to a low clearance or supportive care service between 1 January 2015 and 31 December 2019. A descriptive analysis of clinical and socioeconomic characteristics according to treatment choice was produced and multivariate logistic regression models used to identify predictive factors for choosing supportive care. Surrogate markers for the success of decision-making processes were evaluated, including time taken to reach a supportive care decision and risk of death without making a treatment decision or within 3 months of starting kidney replacement therapy (KRT). Finally, the association between ethnicity and socioeconomic status and hospital admission rates was compared between treatment groups. Results: Amongst 1768 patients, 515 chose supportive care and 309 chose KRT. Predictive factors for choosing supportive care included age, frailty and a diagnosis of cognitive impairment. However, there was no association with ethnicity or deprivation. Similarly, these factors were not associated with time taken to make a supportive care decision or the mortality outcome. Amongst those on KRT, more socially advantaged patients had decreased rates of hospital admissions compared with those less advantaged (incident rate ratio 0.96, 95% confidence interval 0.92-0.99). Conclusion: Predictive factors for choosing supportive care were clinical, rather than socioeconomic. Lower socioeconomic status was associated with increased rates of hospitalization in the KRT group. This is a possible signal that these groups experienced greater morbidity on KRT versus supportive care, an association not demonstrated amongst higher socioeconomic groups.

Medical students as health workers during the COVID-19 pandemic.

BACKGROUND: We describe efforts at one tertiary university teaching hospital to rapidly recruit, train and deploy medical students into paid clinical support worker roles during the COVID-19 pandemic. METHODS: Recruitment was conducted by means of a single email outlining the emergent clinical situation and specifying role descriptions, terms and conditions, and temporary staff enrolment paperwork. Applicants could begin work provided they were in good standing and received departmental orientation. Student representatives liaised with teaching faculty and participating departments. Roles were modified in response to student and departmental feedback. RESULTS: Between 25 December 2020 and 9 March 2021, 189 students contributed 1335 shifts, providing 10 651 hours of clinical care in total. The median number of shifts worked per student was 6 (mean: 7; range: 1-35). Departmental leaders attested that the student workers eased the burden on hospital nursing teams. CONCLUSION: Medical students contributed usefully and safely to the provision of healthcare within well-defined and supervised clinical support worker roles. We propose a model of working which could be adapted in the event of future pandemics or major incidents. The pedagogical value to medical students of working in clinical support roles warrants closer evaluation.

Cocaine-induced granulomatosis with polyangiitis-an under-recognized condition.

Objectives: Cocaine and cocaine mixed with levamisole are increasingly used in the UK and result in significant direct nasal damage in addition to promoting vasculitis. Our aims were as follows: (1) to identify the main symptoms and presentation of cocaine-induced vasculitis; (2) to provide evidence regarding the best practice for the investigation and diagnosis of cocaine-induced vasculitis; and (3) to analyse the clinical outcomes of patients in order to understand the optimal management for the condition. Methods: We performed a retrospective case series analysis of patients presenting with cocaine-induced midline destructive lesions or vasculitis compatible with granulomatosis with polyangiitis (GPA) from two large tertiary vasculitis clinics between 2016 and 2021. Results: Forty-two patients (29 Birmingham, 13 London) with cocaine-induced midline lesions or systemic disease were identified. The median age was 41 years (range 23-66 years). Current cocaine use was common, and 20 of 23 samples provided were positive when routine urine toxicology was performed; 9 patients who denied ever using cocaine were identified as using cocaine based on urine toxicology analysis, and 11 who stated they were ex-users still tested positive. There was a high incidence of septal perforation (75%) and oronasal fistula (15%). Systemic manifestations were less common (27%), and only one patient had acute kidney injury. Fifty-six per cent of our patients were PR3-ANCA positive, with none testing positive for MPO-ANCA. Symptom remission required cocaine discontinuation even when immunosuppression was administered. Conclusion: Patients with destructive nasal lesions, especially young patients, should have urine toxicology performed for cocaine before diagnosing GPA and considering immunosuppressive therapy. The ANCA pattern is not specific for cocaine-induced midline destructive lesions. Treatment should be focused on cocaine cessation and conservative management in the first instance in the absence of organ-threatening disease.

Is dialysis a viable option for the older patient? Outcomes for patients starting dialysis aged 80 years or older.

BACKGROUND: Maximum conservative management (MCM) has been proposed as an alternative care pathway for the increasing number of elderly patients with progressive chronic kidney disease. METHODS: Retrospective analysis of patients aged ≥80 years of age, starting dialysis between 2000 and 2009 in a centre with an established MCM programme. Demographic data, baseline biochemical markers and survival were collected. RESULTS: 93 consecutive patients were studied; median age 83 years (IQR 81-86). 67 male, 32% diabetic. Median survival 46.5 months (range 0-107), with 1- and 5-year survival 78.5 and 38.3%, respectively. Factors predicting poorer survival were Caucasoid ethnicity (p = 0.04) and serum albumin ≤30 g/l (p = 0.01) at dialysis initiation. Duration of nephrology care prior to dialysis initiation did not effect survival. CONCLUSION: The very elderly electing dialysis were found to have good survival. Further patient characterisation is required to improve decision-making between dialysis and MCM for elderly patients with progressive chronic kidney disease.

Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial.

BACKGROUND: We report results from a phase II randomised placebo-controlled trial assessing zibotentan, a highly selective endothelin receptor antagonist (ERA), in chronic kidney disease (CKD) secondary to systemic sclerosis (SSc). METHODS: This trial included three sub-studies: ZEBRA 1-a randomised placebo-controlled, double-blind trial of zibotentan in SSc patients with CKD2 or CKD3 (and glomerular filtration rate (GFR) >45 ml/min) over 26 weeks; ZEBRA 2A-a 26-week placebo-controlled, single-blind trial of zibotentan in scleroderma renal crisis patients not requiring dialysis; and ZEBRA 2B-an open label pharmacokinetic study of zibotentan in patients on haemodialysis. RESULTS: Sixteen patients were screened for ZEBRA 1. Of these, 6 patients were randomised to zibotentan and 7 to placebo. In ZEBRA 1, there were 47 non-serious adverse events (AE) during the trial. Twenty-seven occurred in the placebo group and 20 in the zibotentan group. One serious adverse event (SAE) occurred during ZEBRA1, in the placebo arm. Descriptive statistics did not suggest an effect of study drug on serum sVCAM1. Estimated GFR numerically declined in patients treated with placebo at 26 weeks and 52 weeks. In contrast, average eGFR increased in zibotentan-treated cases. The 4 patients in ZEBRA 2A experienced 8 non-serious AEs, distributed equally between placebo and zibotentan. There was one SAE each in placebo and zibotentan groups, both unrelated to study medication. ZEBRA 2B recruited 8 patients, 6 completed first dosing, and 2 completed a second dosing visit. Pharmacokinetic analysis confirmed zibotentan levels within the therapeutic range. Three patients experienced 3 non-serious AEs. One SAE occurred and was unrelated to study drug. CONCLUSIONS: Zibotentan was generally well-tolerated. ZEBRA 1 did not show any effect of zibotentan on serum sVCAM-1 but was associated with numerical improvement in eGFR at 26 weeks that was more marked at 52 weeks. ZEBRA 2B suggested a feasible dose regimen for haemodialysis patients. TRIAL REGISTRATION: EudraCT no: 2013-003200-39 (first posted January 28, 2014) ClinicalTrials.gov Identifier: NCT02047708 Sponsor protocol number: 13/0077.