Haemodialysis Outcomes & Patient Empowerment Study 02
Conditions: End Stage Renal Disease, Dialysis; Complications, Volume Overload
Sponsor: Royal College of Surgeons, Ireland

 
 
Pilot-scale, single-arm, observational study to assess the 
utility and acceptability of a wearable hydration monitor in 
haemodialysis patients 
 
 
H​aemodialysis ​O​utcomes & ​P​atient ​E​mpowerment study 
02  
(HOPE-02) 
 
Protocol date: 26 February 2020 
 
Number of pages: 31 
 
Version 1.0 
 
Authors: 
 
Principal investigator:  
Dr. Conall O’Seaghdha, Beaumont Hospital, Dublin 9, Ireland. 
 
Co-investigators:  
Dr. Vicky Sandys, Beaumont Hospital, Dublin 9, Ireland. 
 
Dr. Colin Edwards, patientMpower Ltd., Digital Depot, Thomas St., Dublin D08 
TCV4, Ireland. 
 
Paul McAleese, Design to Value Ltd., Innishannon, Co. Cork, Ireland 
 
www.clinicaltrials.gov​ NCT 00000000 
 
 
 
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Table of Contents 
PROTOCOL SUMMARY
5 
FLOW CHARTS
6 
Flow chart 1 Assessments during observation period
7 
List of Figures and Tables
8 
List of Abbreviations and Terms
9 
1.  Introduction
10 
1.1  Medical background
11 
1.2  Product profile
12 
Figure 1.2: 1:  Photographs of prototype and expected final design of 
Sixty device
12 
2. Rationale, objectives and benefit-risk assessment
13 
2.1  Rationale for performing the trial
13 
2.2  Trial objectives
13 
2.3  Benefit-risk assessment
14 
3.  Description of design and trial population
14 
3.1  Overall design and plan
14 
Figure 3.1: 1  Diagram of trial design
15 
3.1.1  Administrative structure of trial
15 
3.2  Discussion of trial design, including choice of control group
16 
3.3  Selection of trial population
16 
3.3.1  Main diagnosis for study entry
16 
3.3.2  Inclusion criteria
16 
3.3.3  Exclusion criteria
17 
3.3.4  Removal of patients from therapy or assessments
17 
3.3.4.1  Removal of individual patients
17 
3.3.4.2  Discontinuation of the trial
17 
4.  Study observational intervention
17 
4.1  Observational intervention to be assessed
17 
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4.1.1  Identity of observational intervention and comparator(s)
17 
4.1.2  Method of assigning patients to observational groups
18 
4.1.3  Blinding and procedures for unblinding
18 
4.1.3.1  Blinding
18 
4.2  Concomitant therapy, restrictions and rescue treatment
18 
4.2.1  Rescue medication, emergency procedures and additional 
treatment
18 
4.2.1.1  Management of acute exacerbations
18 
4.2.1.2  Management of other adverse events
18 
4.2.2  Restrictions
18 
4.2.2.1  Restrictions on concomitant treatment
18 
4.2.2.2 Restrictions on diet and life-style
18 
4.3  Treatment compliance
19 
5  Variables and their assessment
19 
5.1  Efficacy
19 
5.1.1  Efficacy endpoints
19 
5.1.1.1  Primary endpoint
19 
5.1.1.2  Secondary endpoints
20 
5.1.2  Assessment of efficacy
21 
5.2  Safety
21 
5.3.  Other variables
21 
5.4  Appropriateness of measurements
21 
6 Investigational plan
22 
6.1  Visit schedule
22 
6.2. Patient recruitment process
22 
6.3  Details of trial procedures
22 
6.3.1  Baseline clinic visit (start of study)
22 
6.3.2  Haemodialysis visits during study observation period
24 
6.3.3  Week 1 and Week 2 clinic visits
24 
6.3.4 Week 3 visit (end of study observation period)
24 
7.  Statistical methods and determination of sample size
25 
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7.1  Statistical design and model
25 
7.2  Null and alternative hypotheses
25 
7.3  Planned analyses
25 
7.3.1  Primary analyses
26 
7.3.2  Secondary analyses
26 
7.3.3  Safety analyses
26 
7.3.4  Interim analyses
26 
7.3.5  Health economic analyses
26 
7.4  Handling of missing data
26 
7.5.  Randomisation
26 
7.6  Determination of sample size
26 
8.  Informed consent, data protection and trial records
27 
8.1  Study approval, patient information and informed consent
27 
8.2  Data quality assurance
27 
8.3  Records
27 
8.3.1  Source documents
27 
8.3.2  Direct access to source data and documents
27 
8.3.3  Storage of records
27 
8.4  Statement of confidentiality
28 
8.5  Completion of trial
28 
8.6  Protocol violations
28 
8.7  Compensation available to the patient in the event of study-related 
injury
28 
9 References
28 
10. Appendices
29 
Appendix 10.1 Cointerventions protocol
29 
Appendix 10.2 Recruitment of patients
29 
Appendix 10.3 Training of personnel
29 
Appendix 10.4 Trial registration on public registry
30 
Appendix 10.5 Funding
30 
Appendix 10.6 Incentives for participation:
30 
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Signatures
31 
 
 
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PROTOCOL SUMMARY 
 
PRODUCT 
Sixty wearable hydration monitor 
CLINICALTRIALS.GOV IDENTIFIER NCT 00000000 
PROTOCOL TITLE 
Pilot-scale, single-arm, 
observational study to assess the 
utility and acceptability of a wearable 
hydration monitor in haemodialysis 
patients 
COORDINATING INVESTIGATOR 
Dr. C. O’Seaghdha, Beaumont 
Hospital, Beaumont Road, Dublin 9, 
Ireland 
NUMBER OF TRIAL SITES 
One: Beaumont Hospital dialysis 
centre. 
STUDY OBJECTIVES 
To determine the validity and 
reproducibility of the fluid status data 
captured by a wearable hydration 
monitor (Sixty device) compared 
with bioimpedance and 
haemodialysis machine data) in 
ambulatory haemodialysis patients. 
To assess the utility and patient 
acceptability of the Sixty device. 
METHODOLOGY 
Open, prospective, single-arm 
observation. 
Observation period: 3 weeks. 
NUMBER OF SUBJECTS 
Total randomised: 20 
DIAGNOSIS  
End Stage Kidney Disease requiring 
regular ongoing haemodialysis  
MAIN CRITERIA FOR INCLUSION 
Age ≥18 years, demonstrated 
understanding of use of the Sixty 
device and home blood pressure 
monitor, written informed consent 
TEST PRODUCT 
Sixty wearable hydration monitor 
COMPARATOR PRODUCT 
None 
END OF STUDY DEFINITION 
3 weeks 
PRIMARY ENDPOINT 
Volume status measured by Sixty 
device compared to haemodialysis 
machine and bioimpedance data  
SECONDARY ENDPOINTS 
Acceptability of Sixty device 
INTERIM ANALYSIS 
None planned 
STATISTICAL METHODS 
Descriptive tables or figures will be 
prepared. Within-patient comparison 
of fluid status data as determined by 
different methodologies. 
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FLOW CHARTS 
 
Flow chart 1
Assessments during observation period 
 
 
 
study observation period (3 weeks) 
 
Baseline 
clinic 
visit 
At each 
dialysis 
session 
Week 1 
Week 2 
Week 3 
(end) 
Informed consent 
X 
 
 
 
 
Demographic data 
(include dialysis & 
medicines history) 
X 
 
 
 
 
Vital signs, body 
weight, routine 
hemodialysis 
measurements 
in-clinic​A 
X 
X 
X 
X 
X 
Assess fluid status 
with bioimpedance​B 
X 
 
X 
X 
X 
Instruction/patient 
training on use of 
Sixty device 
X 
 
 
 
 
Wear Sixty device 
daily​C 
X 
X 
X 
X 
X 
Download data and 
recharge Sixty 
device​D 
 
X 
X 
X 
X 
Record symptoms 
related to fluid 
status​E 
X 
X 
X 
X 
X 
Record adverse 
events​F 
X 
X 
X 
X 
X 
Patient records blood 
pressure at home 
once/day​G 
once/day throughout study 
Stop using Sixty 
device​H 
 
 
 
 
X 
Acceptability of Sixty 
device questionnaire​I 
 
 
 
 
X 
End of study 
 
 
 
 
X 
 
A​ Routine measurements (at each hemodialysis session) include total fluid 
removal, interdialytic weight gain (IDWG), proportion of haemodialysis 
sessions in which IDWG is ≤ 4%, pre-dialysis and post-dialysis weight, 
pre-dialysis, intradialytic and post dialysis BP and pulse rate. 
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B ​Fluid status will be assessed by bioimpedance measurements immediately 
before start and immediately after end of haemodialysis.  
 
C ​Sixty is a wrist-worn hydration monitor. It uses optical spectroscopy and 
machine learning algorithms to determine hydration level. No data is 
displayed to the patient. The device should first be worn by the patient for five 
minutes before the haemodialysis session at the Baseline Visit and 
throughout that haemodialysis session. It should then be worn throughout the 
study observation period, including during all haemodialysis sessions.  
 
D ​The data in the Sixty device SD card should be downloaded before the start 
of each haemodialysis session. The device should then be recharged during 
the dialysis while the patient is wearing it. The Sixty device will continue to 
capture data while it is recharging.  
 
E​ Symptoms related to fluid status will be recorded before haemodialysis using 
the symptom score developed by Kraemer et al​8​.  
 
F ​For example, requirement for nursing intervention such as stopping dialysis 
or administering fluid bolus. Adverse events include, but are not limited to 
muscle cramps, symptomatic hypotension, access-related complications, 
hypertension-related symptoms, congestive heart failure, pulmonary edema, 
requirement for additional unscheduled dialysis, or need for hospitalisation 
and number and type(s) of BP medications.  
 
G​ The patient will be supplied with an A and D Medical Blood Pressure Monitor 
(model UA-651BLE)  at the baseline visit and will be asked to record their 
blood pressure at home once/day during the study observation period. The 
patient will be returned to the investigator at the end of the study. 
 
H​ The Sixty device should be worn until five minutes after the end of the 
haemodialysis session at the end-of-study visit. The data in the Sixty device 
SD card should be downloaded  after the end of this haemodialysis session. 
The Sixty device will then be returned to the investigator. 
 
I ​Patient opinions of the Sixty device sought by questionnaire. This is designed 
to understand the functionality and acceptability requirements. This will 
explore the experience of the current prototype as well as describe the 
industrial design, user interface and user experience that is proposed for the 
commercial product. 
 
 
 
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List of Figures and Tables 
 
Figure 1.2: 1: 
Photographs of prototype and expected final design of 
Sixty device 
 
Figure 3.1: 1: 
Diagram of trial design 
 
 
 
 
 
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List of Abbreviations and Terms 
 
BP
blood pressure 
BVM
blood volume monitoring 
CV
cardiovascular 
DTIF
Disruptive Technologies Innovation Fund 
ECW
extracellular water 
HOPE
Haemodialysis Outcomes & Patient Empowerment 
IDWG
interdialytic weight gain (i.e. fluid weight gain between dialysis 
sessions) 
L
litre 
OH
overhydration 
PND
paroxysmal nocturnal dyspnea 
 
 
 
 
 
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1. 
Introduction 
1.1 
Medical background 
 
End stage kidney disease is defined by kidney failure severe enough to 
require some form of renal replacement therapy. This replacement has three 
forms, kidney transplant, haemodialysis and peritoneal dialysis. 
Haemodialysis is the most common form of replacement therapy and usually 
entails three sessions of dialysis per week on alternate days starting either on 
Monday or Tuesday. The period between dialysis sessions is known as the 
interdialytic period and as dialysis is delivered on alternate days there is one 
interdialytic period per week that is longer than the other. In order to maintain 
extracellular fluid balance and to prevent high blood pressure, haemodialysis 
sessions focus on removing the fluid that was gained between dialysis 
sessions. 
 
Haemodialysis patients experience high rates of mortality, driven largely by an 
exceptionally high rate of cardiovascular (CV)-related mortality, which 
exceeds that of the general population by 10-to 20-fold​1, 2​. High levels of both 
interdialytic weight gain and rate of fluid removal during dialysis have been 
linked with increased mortality, particularly during the longer interdialytic 
period​1​. It is postulated that the haemodynamic effects of high fluid removal 
rates during dialysis may result in cardiovascular morbidity and mortality. 
Similarly, volume depletion induced by excessive ultrafiltration is associated 
with myocardial stunning, cerebrovascular events and mortality​3,4​.  
 
In one study​5​ up to 27% of prevalent dialysis patients were estimated to be 
volume overloaded. The prevalence increased to 66.2% when patients with 
mild fluid overload are included. 31.1% of patients met the criteria for 
normovolaemia and 2.7% were classified as fluid-depleted.  
 
Technology to evaluate the optimal volume status of haemodialysis exists. 
Use of validated measures of volume such as bioimpedance, however, are 
limited by time and cost constraints​6​.  Volume reduction as guided by 
alternative interventions, such as blood volume monitoring (BVM) have been 
associated with increased mortality​7​. 
  
Wearable technology which can record patient parameters such as vital signs, 
electrical rhythms, and serum potassium levels have allowed patients to 
monitor their conditions in real-time. A similar option for volume monitoring in 
haemodialysis patients would enable patients and care providers to optimise 
fluid status and reduce complications associated with under- and 
overhydration. To date, no specific wearable hydration monitor for 
haemodialysis patients is available and validated. The purpose of this trial is 
to compare a wearable hydration monitor against gold standard 
measurements of volume in haemodialysis patients.  
 
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To date, this approach has not been explored in haemodialysis patients. 
 
1.2 
Product profile 
 
The Sixty device is a wearable hydration monitor that is currently in 
development. Photographs of the current prototype and expected final 
designs are shown in Figure 1.2: 1. 
Figure 1.2: 1: 
Photographs of prototype and expected final design 
of Sixty device  
 
  
 
 
 
The prototype device (left-hand image) measures 66mm x 48mm x 10mm. 
The on/off button and charging port are visible on the top edge. The surface 
facing the camera will be in contact with the dorsal surface of the user’s wrist. 
The expected final design is shown in the right-hand image. This is expected 
to be approximately the size of a commercially available smart watch (e.g. 
Apple watch). 
 
The Sixty device uses diffuse reflectance spectroscopy to measure fluid levels 
subdermis. Optical sensors shine light of a specific wavelength onto the skin 
and the amount of light reflected back can be correlated to different body 
components (e.g. water). The machine learning algorithm is trained using a 
calibrated data set of known fluid states allowing the device to interpret the 
data and provide feedback on fluid status.  
 
The prototype device used in this study does not reflect the final aesthetic or 
“looks like” design, but provides the necessary functionality to establish proof 
of principle in fluid overloaded patients. It is designed to be very simple to 
operate, with only one button to turn it on and off. The simple user interface 
indicates that the device is on/off and is functioning correctly. The prototype 
device will only collect data and does not provide feedback to the user on their 
hydration status. Data is collected locally on a memory card (i.e. SD card) 
which will be removed periodically to recover the data.  
 
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The device and battery is designed to run for an extended period and can be 
charged via a USB cable. Charging the device and collection of data will be 
coordinated at the haemodialysis study centre to minimise data gaps and to 
reduce unnecessary complexity for the patient. 
 
Patent acceptability will be assessed. 
2.
Rationale, objectives and benefit-risk assessment 
2.1 
Rationale for performing the trial 
 
This trial will evaluate if a wearable hydration monitor (the Sixty device), has 
validity and reproducibility against gold standard measurements of fluid 
volume in haemodialysis patients. 
 
This is a pilot-scale study to assess if this approach has merit and could be 
tested and developed further. 
 
As no specific wearable hydration monitor for haemodialysis patients is 
available and validated, there is sufficient justification in testing the 
effectiveness and acceptability of the Sixty device in a controlled 
observational setting. 
 
2.2 
Trial objectives 
 
The objective of this pilot-scale study is to assess how the Sixty hydration 
monitoring device functions when used in a range of haemodialysis patients of 
varying age, gender, body habitus and volume status. Patients with a range of 
baseline fluid status (ranging from 15% above to 10% below their dry weight 
as determined by bioimpedance) will be considered for enrollment.  
 
The primary objective is to determine the validity and reproducibility of the 
data captured by the Sixty device in haemodialysis patients. (The goal is to 
determine if the data captured by the Sixty device and the additional 
haemodialysis parameters described can be developed into algorithms that 
provide actionable insights to better manage fluid overload in the interdialytic 
period.)  
 
Haemodialysis parameters will be assessed as usual during the study and will 
include: 
●
total fluid removal (each haemodialysis session) 
●
interdialytic weight gain (IDWG) 
●
proportion of haemodialysis sessions in which IDWG is ≤ 4%. 
●
pre-dialysis weight 
●
post-dialysis weight 
●
pre-dialysis blood pressure (BP) 
●
intradialytic BP 
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●
post-dialysis BP 
●
number and type(s) of BP medications 
●
requirement for nursing interventions (e.g. stopping dialysis or 
administering fluid bolus) 
●
adverse events requiring or prolonging hospitalisation 
●
requirement for additional unscheduled dialysis 
 
Fluid volume data measured by the Sixty device will be compared to recorded 
extracted fluid and volume status as measured by haemodialysis machine 
data and bioimpedance findings.  
 
Patient-reported symptoms related to haemodialysis and the underlying 
medical condition will be recorded before haemodialysis. Symptoms data will 
be assessed and compared with fluid status data. 
 
Data on BP measured once/day at home during the interdialytic period will 
also be recorded. 
 
An additional objective of this observational study is to assess the 
acceptability and utility of the Sixty device (from the patient perspective). 
 
2.3 
Benefit-risk assessment 
 
This study is designed to contribute to the development  of a multivariate 
algorithm to help haemodialysis patients monitor and manage their fluid 
intake. The Sixty device will collect data during multiple haemodialysis 
sessions allowing the algorithm to be trained to recognise different fluid 
states, from dry weight to varying degrees of fluid overload. Furthermore, the 
continuous monitoring in the interdialytic period will capture the “real world” 
data, and will be used to verify the validity of the algorithm. 
 
The Sixty device prototype will not provide feedback to the patient so it is not 
expected that the study or the Sixty device will create any additional risks for 
haemodialysis patients. In the event of any technical problems with the 
device, the Sixty team will be available to provide technical support.  
 
All patients will receive optimal haemodialysis during the study. In addition, 
the on-call nephrology registrar at Beaumont hospital will be available to 
handle any medical enquiries from patients enrolled in the study. 
3. 
Description of design and trial population 
3.1 
Overall design and plan 
 
Prospective, open-label run-in observation period with Sixty device (3 weeks). 
 
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The study will not make any changes to the usual haemodialysis schedule for 
the patients. 
 
A diagram of the trial design is shown on Figure 3.1: 1 below. 
 
Figure 3.1: 1
Diagram of trial design 
 
 
 
3.1.1 Administrative structure of trial 
 
This is a single centre study at the Beaumont Hospital, a tertiary care centre 
for nephrology in Dublin, Ireland. 
 
The Sixty hydration monitor was developed and is owned by Design to Value 
Ltd, Innishannon, Cork, Ireland.  
 
The study is being conducted as part of the Haemodialysis Outcomes & 
Patient Empowerment (HOPE) project supported by the Disruptive 
Technology Innovation Fund of Ireland (DTIF). The HOPE project is a 
collaboration between the Royal College of Surgeons in Ireland, Beaumont 
Hospital, patientMpower Ltd., Digital Depot, Dublin and Sixty (registered as 
Design to Value Ltd.), Innishannon, Co. Cork. The objective of HOPE is to 
develop artificial intelligence-enabled software to improve determination and 
maintenance of fluid balance in haemodialysis patients with a long-term goal 
of increasing the proportion of patients receiving dialysis at home. This study 
is a collaboration between all partners in HOPE and the data and outcomes 
will be shared with all partners. The study is funded by the DTIF.  
 
The protocol was designed by Dr. Conall O’Seaghdha (Principal Investigator), 
Dr. Vicki Sandys (both of Beaumont Hospital, Dublin 9, Ireland), Design to 
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Value Ltd, Innishannon, Co. Cork, Ireland and patientMpower Ltd., Digital 
Depot, Dublin 8, Ireland. 
 
3.2 
Discussion of trial design, including choice of control group 
 
This is a pilot-scale, prospective, open-label, single-arm observational study.  
 
All patients will be allocated to the same observation sequence. 
 
Patients will follow their usual haemodialysis regimen throughout the study. 
Patients’ dry weight will be optimised using gold standard care (bioimpedance 
measurements) during the study. 
 
Clinical assessments (e.g. IDWG, BP, pulse rate, ultrafiltration volume, 
symptoms) will be assessed at each dialysis visit.  
 
The trial design will allow assessment of the validity and reproducibility of data 
collected by the Sixty device in haemodialysis patients. Data from the Sixty 
device will be compared against other validated methods of volume 
assessment (haemodialysis machine and bioimpedance data) and with 
observed symptoms in patients across a range of age, genders and volume 
status. 
 
The study will also allow evaluation of the utility and acceptability of the Sixty 
device in a haemodialysis patient population. This will be assessed from the 
patient perspective. 
 
3.3 
Selection of trial population 
 
3.3.1 Main diagnosis for study entry 
 
Require maintenance haemodialysis in an ambulatory care setting.  
 
Patients with a range of baseline fluid status (ranging from 15% above to 10% 
below their dry weight as determined by bioimpedance) will be considered for 
enrollment. 
3.3.2 Inclusion criteria 
 
Aged at least 18 years 
 
Demonstrates understanding of correct use of the Sixty device. 
 
Capable and willing to measure blood pressure at home on a daily basis.  
 
Willing to give written informed consent. 
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3.3.3 Exclusion criteria 
 
Conditions precluding accurate use of bioimpedance (e.g. limb amputations, 
severe malnourishment). 
 
Significant confusion or any concomitant medical condition, which would limit 
the ability of the patient to record symptoms or other parameters. 
 
3.3.4 Removal of patients from therapy or assessments 
 
3.3.4.1 
Removal of individual patients 
 
Patients are free to withdraw from the study at any time without any impact on 
their ongoing medical care. 
 
The investigator may withdraw a patient from the study at any time if they 
believe that further participation in the study is not in the best interests of the 
patients. 
3.3.4.2 
Discontinuation of the trial 
 
The study may be terminated early if recruitment is significantly behind 
schedule or if for any other reason, it is unlikely that the study can be 
completed. 
4. 
Study observational intervention 
 
All patients will continue to receive their usual haemodialysis regimen 
throughout the study as prescribed by their healthcare professionals. 
4.1 
Observational intervention to be assessed 
 
4.1.1 Identity of observational intervention and comparator(s) 
 
The Sixty device is a wearable hydration monitor that is currently in 
development. It uses diffuse reflectance spectroscopy to measure fluid levels 
subdermis. Optical sensors shine light of a specific wavelength onto the skin 
and the amount of light reflected back can be correlated to different body 
components (e.g. water). The prototype device used in this study provides the 
necessary functionality to establish proof of principle in fluid overloaded 
patients. This prototype device will only collect data and will not provide 
feedback to the user on their hydration status. 
 
There is no comparator intervention.  
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4.1.2 Method of assigning patients to observational groups 
 
All patients who give informed consent and enter the study will be allocated to 
the same observation sequence.  
 
4.1.3 Blinding and procedures for unblinding 
4.1.3.1 
Blinding 
 
The study is open-label. 
 
4.2 
Concomitant therapy, restrictions and rescue treatment 
4.2.1 Rescue medication, emergency procedures and additional 
treatment 
 
If any patient or their healthcare professional has a concern the renal registrar 
on call at Beaumont Hospital will respond to calls out of hours and at 
weekends.  
 
4.2.1.1 
Management of acute exacerbations 
 
Any exacerbations of the patient’s underlying medical condition(s) should be 
treated according to standard procedures. 
 
4.2.1.2 
Management of other adverse events 
 
Any other adverse events should be treated according to standard 
procedures. 
4.2.2 Restrictions 
4.2.2.1 
Restrictions on concomitant treatment 
 
There are no restrictions on concomitant treatment. All concomitant 
treatments as prescribed by the patients’ healthcare professionals are 
allowed. Patients will continue to take all medicines and other treatments as 
prescribed by their healthcare professionals. As per the co-interventions 
protocol (Appendix 10.1), all nephrologists working at Beaumont Hospital will 
be asked not to alter their usual fluid balance management during the study. 
4.2.2.2
Restrictions on diet and life-style 
 
The study does not mandate any additional restrictions on diet or life-style. 
Patients will continue to follow all instructions on diet, exercise and lifestyle as 
directed by their healthcare professionals. 
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4.3 
Treatment compliance 
 
Patients will be asked to wear the Sixty device throughout the study 
observation period (including during haemodialysis sessions). 
 
Patients will be asked to measure blood pressure once/day at home during 
the study observation period. 
5 
Variables and their assessment 
 
5.1 
Efficacy 
 
5.1.1 Efficacy endpoints 
 
5.1.1.1 
Primary endpoint 
 
The primary endpoint will be to evaluate the accuracy of the Sixty device data 
in assessing volume in haemodialysis patients compared to gold standard 
monitoring techniques. The volume status as measured by the Sixty device 
will be compared with volume status as measured by bioimpedance, patient 
symptoms, and traditional haemodialysis parameters.  
 
The primary endpoint variables include: 
 
Comparison of volume status as measured by Sixty device compared to 
bioimpedance pre- and post-dialysis:  
●
volume overload as defined by bioimpedance: overhydration 
(OH)/extracellular water (ECW) > 15% (corresponding to 2.5L)  
●
normohydration defined as: ECW -6 to + 6% (corresponding to -1.1L to 
+ 1L)  
 
Correlation of volume status with patients’ symptoms before haemodialysis 
based upon the symptom score developed by Kraemer et al​8​.  
 
Symptoms of hypovolaemia: 
●
thirst directly after haemodialysis 
●
symptomatic hypotension, on change of position  
●
symptomatic hypotension 
●
nausea and vomiting 
●
muscle cramps 
●
limpness/ tiredness between dialysis sessions 
●
dizziness between dialysis sessions 
 
Symptoms of hypervolaemia  
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●
chronic coughing (new)  
●
dyspnea on recumbency  
●
dyspnea at rest; 1 pillow  
●
dyspnea at rest: 2 pillow 
●
dyspnea at rest: 3 pillows 
●
pretibial oedema 
●
paroxysmal nocturnal dyspnea (PND) 
 
Correlates of volume status as measured by haemodialysis parameters 
including:  
●
total fluid removal (each haemodialysis session) 
●
IDWG 
●
proportion of haemodialysis sessions in which IDWG is ≤ 4%. 
●
pre-dialysis and post-dialysis weight  
●
pre-dialysis, intradialytic and post dialysis BP 
●
pulse rate  
●
requirement for nursing intervention such as stopping dialysis or 
administering fluid bolus 
●
adverse events including, but not limited, to muscle cramps, 
symptomatic hypotension, access-related complications, 
hypertension-related symptoms, congestive heart failure, pulmonary 
edema, requirement for additional unscheduled dialysis, or need for 
hospitalisation 
●
number and type(s) of BP medications 
●
home BP measured once/day during the interdialytic period 
  
5.1.1.2 
Secondary endpoints 
 
A secondary objective is a descriptive analysis of the data captured by the 
Sixty device and the additional haemodialysis parameters used to measure 
volume status in haemodialysis patients. The proportion of haemodialysis 
sessions in which normohydration was achieved will be recorded. 
 
The patient’s opinion of the acceptability of the Sixty device as assessed by 
their response to a questionnaire. Examples of questions in the acceptability 
questionnaire include: 
●
how do you currently manage your fluid intake in between dialysis 
sessions? 
●
on a scale of 1 to 5, how well do you feel in control of fluid status during 
this interdialytic period? (1 meaning "no control"... with 5 meaning "fully 
in control with good understanding what triggers fluid overload") 
●
would you wear a device similar in looks to a FitBit/Apple watch, if it 
could continuously monitor your fluid status and prompt you when and 
how much to drink to stay hydrated yet limit fluid overload? 
●
what are the minimum acceptable functionality that this device would 
need to have in order for you to wear it (check box list of features such 
as): 
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○
tells me my hydration level and prompts me on how to manage 
fluid intake. 
○
tells the time 
○
measures heart rate 
○
measures steps / activity 
○
measures sleep quality  
 
5.1.2 Assessment of efficacy 
 
The primary and secondary endpoint data will be listed and tabulated or 
displayed graphically.  
 
The primary endpoint will be assessed by comparison of the fluid status 
variables observed via the Sixty device with those observed via bioimpedance 
and haemodialysis machine data and with symptoms.  
 
The acceptability and utility of the Sixty device will be assessed by analysis of 
the responses to a patient questionnaire. 
 
5.2 
Safety 
 
It is not anticipated that any safety issues will arise from use of the Sixty 
device or bioimpedance assessment. Issues regarding abnormal BP readings 
will be addressed by the nephrology department at Beaumont Hospital. 
 
Any adverse events observed with medical treatments should be reported to 
the manufacturers or suppliers of those treatments. 
 
5.3. 
Other variables 
 
Demographic data [e.g. date of birth, gender, medical cause of haemodialysis, 
time since first ever dialysis, vascular access route for haemodialysis, 
medication(s) prescribed for hypertension]. 
 
5.4 
Appropriateness of measurements 
 
The primary efficacy endpoint variables are measurements which are 
important and accepted measures of fluid status and renal function in 
haemodialysis patients. 
 
 
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6
Investigational plan 
 
Patients who participate in the study will follow their usual haemodialysis 
regimen and will be asked to wear a wrist-worn hydration monitor (the Sixty 
device) for approximately three weeks. Patients will also be asked to record 
BP at home once/day for approximately three weeks. In addition to usual 
care, participating patients will have fluid status measured by bioimpedance 
on four occasions. 
 
6.1 
Visit schedule 
 
The total observation period will be approximately three weeks. It is 
anticipated that patients will attend the clinic for haemodialysis three times per 
week on average. No additional patient visits are required for this study. 
 
6.2.
Patient recruitment process 
 
Approximately 300 patients attend for dialysis under the governance of 
Beaumont Hospital. Eligible individuals will be invited to participate. It is 
estimated that twenty (20) people will be enrolled in this study. 
 
The study centre will publicise the study to their potential patient population. 
When potential patients who are interested in the study attend for a usual care 
haemodialysis visit, the research staff will discuss the study (face-to-face) with 
the patient. If the person wishes to participate, they will give written informed 
consent. The patient will receive a paper and electronic copy of the patient 
information document. 
 
The  study observation period can start after written informed consent.  
 
6.3 
Details of trial procedures  
 
The trial procedures at each visit are summarized in the flow chart on page 7. 
 
6.3.1 Baseline clinic visit (start of study) 
 
At a planned usual care haemodialysis visit, the study centre research team 
will discuss the study with the patient and confirm the patient's understanding 
of the study processes and their willingness to participate. The patient 
information document will be given to the patient. The patient will have the 
opportunity to ask questions on the study processes and will be asked to give 
their written informed consent before any study-specific procedures. 
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Demographic data, vital signs, medical history and concomitant therapy for 
renal and other relevant conditions will be recorded. 
 
At the baseline visit and at each haemodialysis visit during the study the 
following usual care parameters will be assessed and recorded: 
●
total fluid removal (each haemodialysis session) 
●
IDWG 
●
proportion of haemodialysis sessions in which IDWG is ≤ 4%. 
●
pre-dialysis and post-dialysis weight  
●
pre-dialysis, intradialytic and post-dialysis BP 
●
pulse rate  
●
requirement for additional nursing intervention (e.g.stopping dialysis, 
administering fluid bolus) 
●
adverse events related to the patient’s underlying condition (e.g. 
access-related complications, hypertension-related symptoms, 
congestive heart failure, pulmonary edema) 
●
requirement for additional unscheduled dialysis, or need for 
hospitalisation 
●
number and type(s) of BP medications  
 
In addition, fluid status will be assessed by bioimpedance immediately before 
and immediately after the start and end of haemodialysis. 
 
Patient symptoms related to volume status (questions described above in 
section 5.1.1.1) will be recorded before haemodialysis.  
 
The research team will allocate a Sixty device to the patient and instruct them 
on correct use of the device. The Sixty device is designed to be simple to 
operate, with only one button to turn it on and off. The user interface indicates 
that the device is on/off and is functioning correctly. The device will only 
collect data and will not provide feedback to the user on their hydration status. 
Data is collected locally on a memory card (i.e. SD card). 
 
The patient will start to wear the Sixty device and switch it on at least five 
minutes before the start of haemodialysis at this clinic visit. The patient will 
wear the Sixty device throughout the haemodialysis session at this and all 
subsequent haemodialysis sessions during the study observation period. The 
patient will be asked to wear the Sixty device throughout the study 
observation period (approximately three weeks), except when bathing, 
swimming, showering or any other activity which would expose the device to 
large amounts of water. 
 
The patient will be given a home BP monitor and instructed on its correct use. 
The patient will be asked to measure BP at home once/day (at any time of 
day they wish) during the study observation period. 
 
 
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6.3.2
Haemodialysis visits during study observation period 
 
The patient will attend for haemodialysis as required for an observation 
period of approximately three weeks. 
 
The patient will be asked to wear the Sixty device throughout the study 
observation period (approximately three weeks), except when bathing, 
swimming, showering or any other activity which would expose the device to 
large amounts of water. 
 
At each clinic visit, before the patient starts haemodialysis the research team 
will remove the SD card from the patient’s Sixty device and download the data 
collected in the previous 2-3 days. The SD card will be re-inserted into the 
Sixty device and the patient will put on the Sixty device at least five minutes 
before starting haemodialysis. The patient will wear the Sixty device during 
the haemodialysis procedure and the Sixty device will be recharged during 
haemodialysis. (The Sixty device will continue to collect data while 
recharging.) The patient will continue to wear the Sixty device until the next 
planned haemodialysis session.  
 
The measurements related to haemodialysis and described in section 6.3.1 
(usual care haemodialysis parameters and symptoms) will be recorded at 
each haemodialysis visit during the study observation period. 
 
The patient will be asked to confirm that they have measured BP at home 
once/day during the study observation period. 
 
6.3.3 Week 1 and Week 2 clinic visits 
 
The measurements related to haemodialysis and described in section 6.3.1 
(usual care haemodialysis parameters and symptoms) will be recorded at this 
visit. 
 
In addition, fluid status will be assessed by bioimpedance immediately before 
and immediately after the start and end of haemodialysis. 
 
As described in section 6.3.2 above, the research team will download the data 
collected by the Sixty device during the previous 2-3 days and recharge the 
device while the patient is wearing it during haemodialysis. 
 
6.3.4 Week 3 visit (end of study observation period) 
 
Before the patient starts haemodialysis the research team will remove the SD 
card from the patient’s Sixty device and download the data collected in the 
previous 2-3 days. The Sixty device will be recharged and after recharging, 
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the patient will wear the Sixty device for at least five minutes before starting 
haemodialysis and during the haemodialysis procedure. 
 
The measurements related to haemodialysis and described in section 6.3.1 
(usual care haemodialysis parameters and symptoms) will be recorded at this 
visit. 
 
In addition, fluid status will be assessed by bioimpedance immediately before 
and immediately after the start and end of haemodialysis. 
 
The patient will wear the Sixty device during haemodialysis until at least five 
minutes after the end of the haemodialysis procedure. At this time, the 
research team will remove the SD card from the patient’s Sixty device and 
download the data collected during this haemodialysis session. 
 
The patient will return the Sixty device and the home BP monitor to the 
research team. 
 
The patient will complete a questionnaire to give their opinion on the 
acceptability of the Sixty device be assessed and recorded. 
 
The study procedures are concluded at this visit. 
 
7. 
Statistical methods and determination of sample 
size 
 
This a pilot-scale study to determine the validity and reproducibility of the data 
captured by the Sixty device in haemodialysis patients. 
 
7.1 
Statistical design and model 
 
This is a prospective, open-label, single-arm observational study.  
 
All patients will attend for haemodialysis according to their usual regimen 
during the study.  
 
7.2 
Null and alternative hypotheses 
 
Not relevant. 
 
7.3 
Planned analyses 
 
Results will be collected and summarized for descriptive statistical display. 
 
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7.3.1 Primary analyses 
 
The objective of this pilot-scale study is to assess how the Sixty hydration 
monitoring device functions when used in a range of haemodialysis patients of 
varying age, gender, body habitus and volume status. 
 
The primary endpoint will be assessed by comparison of the endpoint 
variables observed via the Sixty device with those observed via bioimpedance 
and haemodialysis machine data and symptoms.  
7.3.2 Secondary analyses 
 
The acceptability and utility of the Sixty device will be assessed by analysis of 
the responses to a patient questionnaire. 
 
7.3.3 Safety analyses 
 
Patient-reported symptoms and adverse events will be tabulated and 
displayed. 
 
7.3.4 Interim analyses 
 
None planned. 
7.3.5 Health economic analyses 
 
Any additional healthcare resource utilisation (e.g. additional unplanned 
haemodialysis sessions, hospitalisation) will be tabulated and displayed. 
 
7.4 
Handling of missing data 
 
No imputations of missing data will be made. 
 
7.5. 
Randomisation 
 
Not relevant. 
 
7.6 
Determination of sample size 
 
This is a pilot-scale study. The sample size (n = 20) was chosen arbitrarily. It 
is estimated that 10 Sixty devices will be available for testing at the planned 
date of the study. 
 
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8. 
Informed consent, data protection and trial 
records 
 
8.1 
Study approval, patient information and informed consent 
 
The study will be approved by the relevant ethics committee(s) for the 
participating centre. 
 
The study will be discussed with each patient and they will be provided with a 
written document describing the study conditions and procedures. 
 
All patients will give written informed consent before enrollment and any 
study-specific procedures. 
 
8.2 
Data quality assurance 
 
All endpoint data will be stored on a central database for analysis. The data 
as reported by the patients will not be queried before descriptive statistical 
analysis tables are prepared. 
 
8.3 
Records 
 
8.3.1 Source documents 
 
The original electronic data and relevant medical records will be the source 
documents. 
 
8.3.2 Direct access to source data and documents 
 
The research team will ensure that all data entered to the central database is 
a true record of events. Source data verification will not be performed. 
 
8.3.3 Storage of records  
 
Medical data relating to patient care will be stored in the medical records 
according to the usual procedures of the treatment site(s).  
 
The endpoint data recorded on the Sixty device, haemodialysis parameters 
(including bioimpedance data) and symptoms data will be stored on a central 
database managed by patientMpower Ltd. These data will be pseudonymised 
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and will be shared with Beaumont Hospital research team, Design to Value 
Ltd. (developer and owner of the Sixty device) and patientMpower Ltd. 
 
8.4 
Statement of confidentiality 
 
Patients will only be identified by a unique identification number on the study 
database (i.e. data will be pseudonymised). All data will be treated as 
confidential. Each patient’s data will be linked to their unique identification 
number.  
 
8.5 
Completion of trial 
 
The trial will be complete when 20 patients have completed the 3-week 
observation period. 
 
If it appears to be unlikely that the target number of patients can be achieved 
(e.g. because of slow recruitment) a lower target will be set (after discussion 
and agreement with the investigator). 
 
8.6 
Protocol violations 
 
All data will be analysed on an intention-to-treat basis without regard to 
protocol violations. 
 
8.7 
Compensation available to the patient in the event of 
study-related injury 
 
It is not anticipated that any study-related injury will occur. 
 
9
References 
 
 
1.
Foley RN, Gilbertson DT, Murray T​, et al.​ Long interdialytic interval and 
mortality among patients receiving hemodialysis. ​N Engl J Med​ 2011; 
365: ​1099-1107. 
 
2.
Collins AJ, Foley RN, Herzog C​, et al.​ Excerpts from the US Renal 
Data System 2009 Annual Data Report. ​Am J Kidney Dis​ 2010; ​55: 
S1-420, A426-427. 
 
3.
Burton J, Jefferies H, Selby N, McIntyre C. Hemodialysis-induced 
cardiac injury: determinants and associated outcomes. Clin J Am Soc 
Nephrol 2009; ​4​: 914-20 
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4.
Shoji T, Tsubakihara Y, Fujii M, Imai E. Hemodialysis-associated 
hypotension as an independent risk factor for two-year mortality in 
hemodialysis patients. Kidney International 2004; ​66​: 1212-20.  
 
5.
Dekker M. Marcelli D, Canaud B, Carioni P, Wang Y, Grassmann A et 
al. Impact of fluid status and inflammation and their impact on survival: 
a study in an international hemodialysis patient cohort. Kidney 
International 2017; 91: 1214-23. 
 
6.
Stenberg J, Henriksson C, Lindberg M, Furuland H. Perspectives on 
clinical use of bioimpedance in hemodialysis: focus group interviews 
with renal care professionals. BMC Nephrology 2018; ​19​: 121. 
 
7.
Reddan D, Szczech L, Hasselblad V, Lowrie R, Himmelfarb J, Toto R 
et al. Intradialytic blood volume monitoring in ambulatory hemodialysis 
patients: a randomized trial. J Am Soc Nephrol 2005; ​16​: 2162-9. 
 
8.
Kraemer, M., Rode, C. and Wizemann, V. (2006). Detection limit of 
methods to assess fluid status changes in dialysis patients. Kidney 
International 1006; ​69: ​1609-20. 
 
10.
Appendices 
 
Appendix 10.1
Cointerventions protocol 
 
All nephrologists working at Beaumont Hospital will be asked not to alter their 
usual fluid balance management during the study 
Appendix 10.2
Recruitment of patients 
 
The study team will undertake recruitment of participants. These individuals 
will be independent and will not be physicians or nurses who are responsible 
for the daily medical care of the potential patients. This is to ensure that 
dialysis patients do not feel obliged to participate.  
Appendix 10.3
Training of personnel 
 
Sixty have skilled personnel capable of demonstrating the use of the devices 
to study patients.  
 
 
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Appendix 10.4
Trial registration on public registry 
 
After research ethics approval, the study will be registered on the international 
clinical trials registry at www.clinicaltrials.gov. 
Appendix 10.5
Funding 
 
The study is being conducted as part of the Haemodialysis Outcomes & 
Patient Empowerment (HOPE) project supported by the Disruptive 
Technology Innovation Fund of Ireland (DTIF). HOPE is a collaboration 
between the Royal College of Surgeons in Ireland, Beaumont Hospital, 
patientMpower Ltd., Dublin and Sixty (registered as Design to Value Ltd.), 
Innishannon, Co. Cork. The study is funded by the DTIF.  
 
Appendix 10.6
Incentives for participation:  
 
There are no incentives for patients to take part in the study.  
 
 
 
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Signatures 
 
 
Signed: 
Date: 
Dr Conall O’Seaghdha 
On behalf of Beaumont Hospital 
 
 
Signed:
Date: 
Mr. Paul McAleese 
On behalf of Design to Value Ltd. 
 
Signed:
Date: 
Dr. Colin Edwards 
On behalf of patientMpower Ltd. 
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