Cutting back on low-value health care practices supports sustainable kidney care.

July 2023 marked the hottest month on record, underscoring the urgent need for action on climate change. The imperative to reduce carbon emissions extends to all sectors, including health care, with it being responsible for 5.5% of global emissions. In decarbonizing health care, although much attention has focused on greening health care infrastructure and procurement, less attention has focused on reducing emissions through demand-side management. An important key element of this is reducing low-value care, given that ≈20% of global health care expenditure is considered low value. "Value" in health care, however, is subjective and dependent on how health outcomes are regarded. This review, therefore, examines the 3 main value perspectives specific to health care. Clinical effectiveness defines low-value care as interventions that offer little to no benefit or have a risk of harm exceeding benefits. Cost-effectiveness compares health outcomes versus costs compared with an alternative treatment. In this case, low-value care is care greater than a societal willingness to pay for an additional unit of health (quality-adjusted life year). Last, community perspectives emphasize the value of shared decision-making and patient-centered care. These values sit within broader societal values of ethics and equity. Any reduction in low-value care should, therefore, also consider patient autonomy, societal value perspectives and opportunity costs, and equity. Deimplementing entrenched low-value care practices without unnecessarily compromising ethics and equity will require tailored strategies, education, and transparency.

Association between diabetic status and risk of all-cause and cause-specific mortality on dialysis following first kidney allograft loss.

Background: Diabetes mellitus (DM) is associated with a greater risk of mortality in kidney transplant patients, primarily driven by a greater risk of cardiovascular disease (CVD)-related mortality. However, the associations between diabetes status at time of first allograft loss and mortality on dialysis remain unknown. Methods: All patients with failed first kidney allografts transplanted in Australia and New Zealand between 2000 and 2020 were included. The associations between diabetes status at first allograft loss, all-cause and cause-specific mortality were examined using competing risk analyses, separating patients with diabetes into those with pre-transplant DM or post-transplant diabetes mellitus (PTDM). Results: Of 3782 patients with a median (IQR) follow-up duration of 2.7 (1.1-5.4) years, 539 (14%) and 390 (10%) patients had pre-transplant DM or developed PTDM, respectively. In the follow-up period, 1336 (35%) patients died, with 424 (32%), 264 (20%) and 199 (15%) deaths attributed to CVD, dialysis withdrawal and infection, respectively. Compared to patients without DM, the adjusted subdistribution HRs (95% CI) for pre-transplant DM and PTDM for all-cause mortality on dialysis were 1.47 (1.17-1.84) and 1.47 (1.23-1.76), respectively; for CVD-related mortality were 0.81 (0.51-1.29) and 1.02 (0.70-1.47), respectively; for infection-related mortality were 1.84 (1.02-3.35) and 2.70 (1.73-4.20), respectively; and for dialysis withdrawal-related mortality were 1.71 (1.05-2.77) and 1.51 (1.02-2.22), respectively. Conclusions: Patients with diabetes at the time of kidney allograft loss have a significant survival disadvantage, with the excess mortality risk attributed to infection and dialysis withdrawal.

Predicting Tacrolimus Concentrations in the Skin of Adult Kidney Transplant Recipients: A Feasibility Study.

Solid organ transplant recipients are at an increased risk of developing skin cancers due to chronic immunosuppression, particularly with calcineurin inhibitors. Tacrolimus is the most prescribed calcineurin inhibitor in this patient cohort, and understanding tacrolimus concentrations in the skin will facilitate the development of anti-cancer preventive and therapeutic strategies. Here, we show that in mice, tacrolimus blood levels peaked rapidly ∼1 h post last oral dose while skin levels rose more slowly and remained high for at least 6 h. Subsequently, tacrolimus skin and blood concentrations were assessed in 15 kidney transplant recipients. The mean age was 61 years, the average time post-transplant was 7 years (range 0-21 years) and 87% were male. The average skin sampling time post tacrolimus dosing was 6 h 32 min. Skin tacrolimus concentrations ranged from 7.1 ng/g to 71.2 ng/g and correlated with blood concentrations (r = 0.6). Mouse and human mean skin concentrations were in a similar range. Our data suggests that tacrolimus measurements in the blood may be used to approximate tacrolimus concentrations in the skin of kidney transplant recipients, and further exploited for the delivery of anti-cancer therapies designed to antagonize the immunosuppressive effects of tacrolimus in the skin.

Training healthcare professionals to administer Goal Attainment Scaling as an outcome measure.

BACKGROUND: Goals generated by Goal Attainment Scaling (GAS) can be used as an outcome measure to promote person-centred research and care. There are no training packages which support its use outside of the rehabilitation discipline. This paper describes the development and evaluation of a training package to support the implementation of GAS as an outcome measure in healthcare research. The training package consisted of classroom teaching, a training manual for self-directed learning, one-on-one simulation and hot reviews. It was developed for the GOAL Trial, a randomised controlled trial assessing a Comprehensive Geriatric Assessment's effectiveness in enabling frail older people living with chronic kidney disease to attain their goals. Training participants were invited to complete pre- and post-training online evaluation surveys. RESULTS: Forty-two healthcare professionals attended an initial online classroom teaching, with 27 proceeding to administer GAS to GOAL Trial patients. Response rates for the online pre- and post-training surveys were 95% and 72%, respectively. Prior to training, only 15% of participants reported being able to appropriately scale and troubleshoot GAS goals. Post-training this was 92%. There was 100% participant satisfaction for the training manual, one-on-one simulation, and hot reviews. CONCLUSIONS: This training package helps ensure healthcare professionals administering GAS have adequate knowledge and skills. It has the potential for adoption as a guide to support the implementation of GAS by other researchers seeking to embrace persont-centred principles in their work.

Validation of a Core Patient-Reported Outcome Measure for Life Participation in Kidney Transplant Recipients: the SONG Life Participation Instrument.

Introduction: Life participation has been established as a critically important core for trials in kidney transplantation. We aimed to validate a patient-reported outcome measure for life participation in kidney transplant recipients. Methods: A psychometric evaluation of the Standardized Outcomes in Nephrology life participation (SONG-LP) measure was conducted in adult kidney transplant recipients. The measure includes 4 items of life participation (leisure, family, work, and social) each with a 5-point Likert scale. Each item is scored from 0 (never) to 4 (always) and the summary measure score the average of each item. Results: A total of 249 adult kidney transplant recipients from 20 countries participated. The SONG-LP instrument demonstrated internal consistency (Cronbach's α = 0.87; 95% confidence intervals [CI]: 0.83-0.90, baseline) and test-retest reliability over 1 week (intraclass correlation coefficient of 0.62; 95% CI: 0.54-0.70). There was moderate to high correlation (0.65; 95% CI: 0.57-0.72) with the PROMIS Ability to Participate in Social Roles and Activities Short Form 8a that assessed a similar construct, and moderate correlation with measures that assessed related concepts (i.e., EQ5D 0.57; 95% CI: 0.49-0.65), PROMIS Cognitive Functional Abilities Subset Short Form 4a (0.40; 95% CI: 0.29-0.50). Conclusion: The SONG-LP instrument is a simple, internally consistent, reliable measure for kidney transplant recipients and correlates with similar measures. Routine incorporation in clinical trials will ensure consistent and appropriate assessment of life participation for informed patient-centered decision-making.

Outcomes for clinical trials involving adults with chronic kidney disease: a multinational Delphi survey involving patients, caregivers, and health professionals.

BACKGROUND: Many outcomes of high priority to patients and clinicians are infrequently and inconsistently reported across trials in CKD, which generates research waste and limits evidence-informed decision making. We aimed to generate consensus among patients/caregivers and health professionals on critically important outcomes for trials in CKD prior to kidney failure and the need for kidney replacement therapy, and to describe the reasons for their choices. METHODS: Online two-round international Delphi survey. Adult patients with CKD (all stages and diagnoses), caregivers and health professionals, who could read English, Spanish, or French were eligible. Participants rated the importance of outcomes using a Likert scale (7-9 indicating critical importance) and a best-worst scale. The scores for the two groups were assessed to determine absolute and relative importance. Comments were analysed thematically. RESULTS: In total, 1 399 participants from 73 countries completed Round 1 of the Delphi survey including 628 (45%) patients/caregivers and 771 (55%) health professionals. In Round 2, 790 participants (56% response rate) from 63 countries completed the survey including 383 (48%) patients/caregivers and 407 (52%) health professionals. The overall top five outcomes were: kidney function, need for dialysis/transplant, life participation, cardiovascular disease, and death. In the final round, patients/caregivers indicated higher scores for most outcomes (17/22 outcomes), and health professionals gave higher priority to mortality, hospitalization, and cardiovascular disease (mean difference > 0.3). Consensus was based upon the two groups yielding median scores of ≥ 7 and mean scores > 7, and the proportions of both groups rating the outcome as 'critically important' being greater than 50%. Four themes reflected the reasons for their priorities: imminent threat of a health catastrophe, signifying diminishing capacities, ability to self-manage and cope, and tangible and direct consequences. CONCLUSION: Across trials in CKD, the outcomes of highest priority to patients, caregivers, and health professionals were kidney function, need for dialysis/transplant, life participation, cardiovascular disease, and death.

Acceptability, Adherence, Safety and Experiences of Low Energy Diets in People With Obesity and Chronic Kidney Disease: A Mixed Methods Study.

OBJECTIVES: Obesity is a modifiable risk factor for chronic kidney disease (CKD) progression. Low energy diets (LEDs) have not been adequately studied in people with CKD. This study aimed to explore acceptability, adherence, safety, and experiences of two LED prescriptions in adults living with obesity and CKD. DESIGN AND METHODS: In a mixed-methods study, obese adults with CKD were prescribed two LEDs (∼800 to 1000 kcal/day each), in a randomised order for 2 weeks each. One diet consisted of four meal replacement products daily (Optifast®, Nestlé Health Science) and the other two pre-prepared frozen meals (Lite n' Easy®, Mitchell's Quality Foods). Participants received weekly dietitian support, completed daily adherence checklists (converted to % of provided meals/replacements consumed) and participated in post-intervention semi-structured interviews to capture their experience. RESULTS: Nine participants were included (mean age 46.5 ± 14.3 years, estimated glomerular filtration rate 64 ± 26 mL/min/1.73 m2, 4/9 male). Mean self-reported adherence was 88 ± 11% and mean 4-week weight change was -7.3 ± 5.6 kg. Two participants withdrew at week two. Most frequently reported side effects were hunger and headaches. Adverse events of interest included one episode each of hyperkalaemia and hypoglycaemia. No serious adverse events occurred. Four overarching themes of patient experiences were identified: strategies used to adapt, disruption to the norm, individual preferences, and influences on acceptability. CONCLUSIONS: LEDs were found to be acceptable and safe with high self-reported adherence rates. Future LED trials should include specialist diabetes management, close monitoring for hyperkalaemia and adequate support to assist with managing side effects and dietary and social adjustments.

Feasibility of Symptom monitoring WIth Feedback Trial (SWIFT) for adults on hemodialysis: a registry-based cluster randomized pilot trial.

BACKGROUND: Patients with kidney failure on hemodialysis (HD) experience considerable symptom burden and poor health-related quality of life (HRQoL). There is limited use of patient reported outcome measures (PROMs) in facility HD units to direct immediate care, with response rates in other studies between 36 to 70%. The aim of this pilot study was to evaluate feasibility of electronic PROMs (e-PROMs) in HD participants, with feedback 3-monthly to the participants' treating team, for severe or worsening symptoms as identified by the Integrated Palliative Outcome Scale (IPOS-Renal), with linkage to the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry, compared with usual care. METHODS: This is a registry-based cluster-randomized controlled pilot trial involving all adults receiving HD in 4 satellite units in Australia over a 6-month period. HD units were cluster randomized 1:1 to the control (HRQoL data collection only) or intervention arm (symptom monitoring with feedback to treating team every 3 months). Feasibility was assessed by participant response rate (percentage of eligible HD participants, including new incident participants, who completed the questionnaire at each time point); retention rate (percentage of participants who completed the baseline questionnaire and all subsequent measures); and completion time. HRQoL and symptom burden scores are described. RESULTS: There were 226 unique participants who completed the e-PROMs (mean age 62 years, 69% males, 78% White-European, median dialysis vintage 1.62 years). At 6 months, response rate and retention rate for the intervention arm were 54% and 68%, respectively, and 89% and 97% in the control arm. Median time to complete IPOS-Renal was 6.6 min (5.3, 10.1) at 3 months, and when combined with the outcome measure (EQ-5D-5L), the median time was 9.4 min (6.9, 13.6) at 6 months. CONCLUSIONS: Electronic symptom monitoring among HD participants with feedback to clinicians is feasible. Variations in response and retention rates could be potentially explained by the lengthier questionnaire, and higher frequency of data collection time points for participants in the intervention arm. A definitive national RCT is underway. TRIAL REGISTRATION: ACTRN12618001976279 (07/12/2018).

Long-term Outcomes of Single and Dual En Bloc Kidney Transplants From Small Pediatric Donors: An ANZDATA Registry Study.

Kidney transplants from small pediatric donors are considered marginal and often transplanted as dual grafts. This study aimed to compare long-term outcomes between recipients of single kidney transplants (SKTs) and dual en bloc kidney transplants (EBKTs) from small pediatric donors. Methods: Data were obtained from the Australia and New Zealand Dialysis and Transplant Registry. All adult recipients of kidney transplants from donors aged ≤5 y were identified. The primary outcome of interest was death-censored graft survival by donor type. The secondary outcomes were early graft loss, delayed graft function, serum creatinine posttransplantation, acute rejection, and patient survival. Results: There were 183 adult recipients of kidney transplants from donors aged ≤5 y old. Of these, 60 patients had EBKT grafts, 79 patients had SKT grafts, and 44 patients had grafts of unknown type. Compared with SKT donors, EBKT donors had lower mean age (P < 0.001) and body weight (P < 0.001). There was no significant difference in death-censored graft survival between the groups, with median survival of 23.8 y (interquartile range 21.2-25) in the EBKT cohort and 21.8 y (11.6-26.8) in the SKT cohort (hazard ratio 1.3; 95% confidence interval, 0.59-2.64; P = 0.56). EBKT grafts had lower acute rejection rates than SKT grafts (P = 0.014). There was no significant difference observed between groups with respect to early graft loss, delayed graft function, posttransplantation serum creatinine posttransplantation, or patient survival. Conclusions: EBKT and SKTs from small pediatric donors are associated with excellent long-term graft survival rates.

Defining myocardial infarction in trials of people receiving hemodialysis: consensus report from the SONG-HD MI Expert Working group.

Cardiovascular disease is the leading cause of death in patients receiving hemodialysis. Currently, there is no standardized definition of myocardial infarction (MI) for patients receiving hemodialysis. Through an international consensus process MI was established as the core CVD measure for this population in clinical trials. The Standardised Outcomes in Nephrology Group-Hemodialysis (SONG-HD) initiative convened a multidisciplinary, international working group to address the definition of MI in this population. On the basis of current evidence, the working group recommends using the Fourth Universal Definition of Myocardial Infarction with specific caveats with regard to the interpretation of "ischemic symptoms" and performing a baseline 12-lead electrocardiogram to facilitate interpretation of acute changes on subsequent tracings. The working group does not recommend obtaining baseline cardiac troponin values, though does recommend obtaining serial cardiac biomarkers in settings where ischemia is suspected. The application of an evidence-based uniform definition should increase the reliability and accuracy of trial results.

Australian Workshops on Patients' Perspectives on Hemodialysis and Incremental Start.

Introduction: Most patients with kidney failure commence and continue hemodialysis (HD) thrice weekly. Incremental initiation (defined as HD less than thrice weekly) is increasingly considered to be safe and less burdensome, but little is known about patients' perspectives. We aimed to describe patients' priorities and concerns regarding incremental HD. Methods: Patients currently, previously, or soon to be receiving HD in Australia participated in two 90-minute online workshops to discuss views about HD focusing on incremental start and priorities for trial outcomes. Transcripts were analyzed using thematic analysis. Outcomes were ranked on the basis of the sum of participants' priority scores (i.e., single allocation of 3 points for most important, 2 for second, and 1 for third most important outcome). Results: All 26 participants (1 caregiver and 25 patients) preferred an incremental HD approach. The top prioritized outcomes were quality of life (QOL) (56 points), residual kidney function (RKF) (27 points), and mortality (16 points). The following 4 themes underpinning outcome priorities, experience, and safety concerns were identified: (i) unpreparedness and pressure to adapt, (ii) disruption to daily living, (iii) threats to safety, and (iv) hope and future planning. Conclusion: Patients with kidney failure preferred an incremental start to HD to minimize disruption to daily living and reduce the negative impacts on their education, ability to work, and family life. QOL was the most critically important outcome, followed by RKF and survival.

Range and Consistency of Cardiovascular Outcomes Reported by Clinical Trials in Kidney Transplant Recipients: A Systematic Review.

Cardiovascular disease is a major cause of morbidity and mortality in kidney transplant recipients. Trial evidence to improve cardiovascular outcomes is limited by inconsistent reporting of outcomes, which may also lack patient-relevance. This study aimed to assess the range and consistency of cardiovascular outcomes reported by contemporary trials in kidney transplant recipients. Methods: A systematic review of all randomized controlled trials involving adult kidney transplant recipients that reported at least 1 cardiovascular outcome from January 2012 to December 2019 was performed, including Embase, MEDLINE, Cochrane, and ClinicalTrials.gov electronic databases. Trial characteristics were extracted and all levels of specification of the cardiovascular outcome measures reported were analyzed (the measure definition, metric' and method of aggregation). Measures assessing a similar aspect of cardiovascular disease were categorized into outcomes. Results: From 93 eligible trials involving 27 609 participants, 490 outcome measures were identified. The outcome measures were grouped into 38 outcomes. A cardiovascular composite was the most common outcome reported (40 trials, 43%) followed by cardiovascular mortality (42%) and acute coronary syndrome (31%). Cardiovascular composite was also the most heterogeneous outcome with 77 measures reported followed by cardiovascular mortality (n = 58) and inflammatory biomarkers (n = 51). The most common cardiovascular composite outcome components reported were major cardiovascular events (18 trials), stroke unspecified (11 trials), and myocardial infarction unspecified (10 trials). Conclusions: There is substantial heterogeneity in cardiovascular outcome reporting in kidney transplant trials.

Sex Disparity in Cause-Specific and All-Cause Mortality Among Incident Dialysis Patients.

RATIONALE & OBJECTIVE: Early mortality rates of female patients receiving dialysis have been, at times, observed to be higher than rates among male patients. The differences in cause-specific mortality between male and female incident dialysis patients with kidney failure are not well understood and were the focus of this study. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Incident patients who had initiated dialysis in Australia and New Zealand in 1998-2018. EXPOSURE: Sex. OUTCOMES: Cause-specific and all-cause mortality while receiving dialysis, censored for kidney transplant. ANALYTICAL APPROACH: Adjusted cause-specific proportional hazards models, focusing on the first 5 years following initiation of dialysis. RESULTS: Among 53,414 patients (20,876 [39%] female) followed for a median period of 2.8 (IQR, 1.3-5.2) years, 27,137 (51%) died, with the predominant cause of death attributed to cardiovascular disease (18%), followed by dialysis withdrawal (16%). Compared with male patients, female patients were more likely to die in the first 5 years after dialysis initiation (adjusted hazard ratio [AHR], 1.08 [95% CI, 1.05-1.11]). Even though female patients experienced a lower risk of cardiovascular disease-related mortality (AHR, 0.93 [95% CI, 0.89-0.98]) than male patients, they experienced a greater risk of infection-related (AHR, 1.20 [95% CI, 1.10-1.32]) and dialysis withdrawal-related (AHR, 1.19 [95% CI, 1.13-1.26]) mortality. LIMITATIONS: Possibility of residual and unmeasured confounders. CONCLUSIONS: Compared with male patients, female patients had a higher risk of all-cause mortality in the first 5 years after dialysis initiation, a difference driven by higher rates of mortality from infections and dialysis withdrawals. These findings may inform the study of sex differences in mortality in other geographic settings.

Range and consistency of gastrointestinal outcomes reported in peritoneal dialysis trials: A systematic review.

BACKGROUND: Gastrointestinal (GI) health is considered vital to the success of peritoneal dialysis (PD) and is critically important to patients, caregivers and clinicians. However, the multiplicity of GI outcome measures in trials undermines the ability to evaluate the frequency, impact and treatment of GI symptoms in patients receiving PD. Therefore, this study aimed to assess the range and consistency of GI outcomes reported in contemporary PD trials. STUDY DESIGN: Systematic review. SETTING AND POPULATION: Individuals with kidney failure requiring PD. SELECTION CRITERIA: All randomised controlled trials involving patients on PD, identified from the PUBMED, EMBASE and COCHRANE Central Registry of controlled Trials (CENTRAL) database, from January 2010 to July 2022. INTERVENTIONS: Any PD-related intervention. OUTCOMES: The frequency and characteristics of GI outcome measures were analysed and classified. RESULTS: Of the 324 eligible PD trials, GI outcomes were only reported in 61 (19%) trials, mostly as patient-reported outcomes (45 trials; 74%). The most frequently reported outcomes were nausea in 27 (43%), diarrhoea in 26 (43%), vomiting in 22 (36%), constipation in 21 (34%) and abdominal pain in 19 (31%) of trials. PD peritonitis was the primary non-GI outcome reported in 24 (40%) trials, followed by death in 13 (21%) trials) and exit-site infection in 9 (15%) trials). Across all trials, 172 GI outcome measures were extracted and grouped into 29 different outcomes. Nausea and diarrhoea contributed to 16% and 15% of GI outcomes, respectively, while vomiting, constipation and abdominal pain contributed to 13%, 12% and 12%, respectively. Most (90%) GI outcomes were patient-reported adverse effects with no defined metrics. Faecal microbiome was reported as the primary study outcome in 3 (100%) trials using the subjective global assessment score, GI symptom rating scale and faecal microbiological and biochemical analysis. Two trials reported nausea as a primary study outcome using symptom assessment score (SAS) and kidney disease quality of life-short-form-36. One trial each reported anorexia and abdominal pain as the primary study outcome using SAS. Bowel habits, constipation and stool type were also reported as the primary study outcome in one trial each using the Bristol stool form scale. GI bleeding was reported as the secondary outcome in three (37%) out of eight trials reporting it. LIMITATIONS: Restricted sampling frame to focus on contemporary trials. CONCLUSIONS: Despite the clinical importance of GI outcomes among patients on PD, they are reported in only 19% of PD trials, using inconsistent metrics, often as patient-reported adverse events. Efforts to standardise GI outcome reporting are critical to optimising comparability, reliability and value of trial evidence to improve outcomes for patients receiving PD.

Study protocol for Vascular Access outcome measure for function: a vaLidation study In hemoDialysis (VALID) : A multi-center, multinational validation study to assess the accuracy and feasibility of measuring vascular access function in clinical practice.

BACKGROUND: A functioning vascular access (VA) is crucial to providing adequate hemodialysis (HD) and considered a critically important outcome by patients and healthcare professionals. A validated, patient-important outcome measure for VA function that can be easily measured in research and practice to harvest reliable and relevant evidence for informing patient-centered HD care is lacking. Vascular Access outcome measure for function: a vaLidation study In hemoDialysis (VALID) aims to assess the accuracy and feasibility of measuring a core outcome for VA function established by the international Standardized Outcomes in Nephrology (SONG) initiative. METHODS: VALID is a prospective, multi-center, multinational validation study that will assess the accuracy and feasibility of measuring VA function, defined as the need for interventions to enable and maintain the use of a VA for HD. The primary objective is to determine whether VA function can be measured accurately by clinical staff as part of routine clinical practice (Assessor 1) compared to the reference standard of documented VA procedures collected by a VA expert (Assessor 2) during a 6-month follow-up period. Secondary outcomes include feasibility and acceptability of measuring VA function and the time to, rate of, and type of VA interventions. An estimated 612 participants will be recruited from approximately 10 dialysis units of different size, type (home-, in-center and satellite), governance (private versus public), and location (rural versus urban) across Australia, Canada, Europe, and Malaysia. Validity will be measured by the sensitivity and specificity of the data acquisition process. The sensitivity corresponds to the proportion of correctly identified interventions by Assessor 1, among the interventions identified by Assessor 2 (reference standard). The feasibility of measuring VA function will be assessed by the average data collection time, data completeness, feasibility questionnaires and semi-structured interviews on key feasibility aspects with the assessors. DISCUSSION: Accuracy, acceptability, and feasibility of measuring VA function as part of routine clinical practice are required to facilitate global implementation of this core outcome across all HD trials. Global use of a standardized, patient-centered outcome measure for VA function in HD research will enhance the consistency and relevance of trial evidence to guide patient-centered care. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03969225. Registered on 31st May 2019.