Fluid Restriction in Heart Failure Versus Liberal Fluid Uptake
Phase: NA
Conditions: Heart Failure
Sponsor: Radboud University Medical Center

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fluid REStriction in Heart failure versus liberal 
fluid UPtake: the FRESH-UP study 
 
 
 
 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
 
 
 
Fluid REStriction in Heart failure versus liberal fluid Uptake: the FRESH-UP study 
 
Protocol ID 
NL75112.091.20 / NCT04551729 
Short title 
FRESH-UP 
Version 
2.0 
Date 
30th November 2020 
Project leaders 
R.R.J van Kimmenade MD PhD (Radboudumc) 
D.H.F. Gommans MD PhD (Radboudumc) 
Coordinating investigators 
 
D.H.F. Gommans MD PhD (Radboudumc) 
Principal investigator per site:  
 
R.R.J van Kimmenade MD PhD (Radboudumc) 
H.P. Brunner-La Rocca MD PhD (MaastrichtUMC+) 
 
 
Steering committee 
R.R.J van Kimmenade MD PhD (Radboudumc) 
D.H.F. Gommans MD PhD (Radboudumc) 
H.P. Brunner-La Rocca MD PhD (MaastrichtUMC+) 
L. Bellersen MD (Radboudumc) 
F. Beckers-Wesche, Specialized HF nurse 
(MaastrichtUMC+) 
T. Jaarsma MD PhD (Linköping University, 
Linköping, Sweden) 
Data Safety Monitoring Board 
J. Januzzi MD (chair; Massachusetts General 
Hospital, Boston, USA) 
A. Bayes-Genis MD PhD (Germans Trias i Pujol 
University Hospital, Badalona (Barcelona), Spain)  
R. Nieuwlaat PhD (McMaster University, Hamilton, 
Canada) 
Independent event adjudication 
committee 
To be determined 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
 
 
 
Sponsor 
Department of Cardiology, Radboudumc, Nijmegen, 
the Netherlands 
 
 
Subsidising party 
Dutch Heart Foundation (grant: 2019T100) 
Independent expert 
M.F. Corsten MD PhD (department of Internal 
Medicine, Radboudumc) 
 
 
 
 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
 
 
 
PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
N. van Royen MD PhD 
Head of Department Cardiology 
 
 
 
Project leader: 
R.R.J. van Kimmenade MD PhD 
Cardiologist Radboudumc 
 
 
 
 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
 
 
 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .................................................................................. 9 
2. 
OBJECTIVES .................................................................................................................... 10 
3. 
STUDY DESIGN ............................................................................................................... 12 
4. 
STUDY POPULATION ...................................................................................................... 14 
4.1 
Population base ......................................................................................................... 14 
4.2 
Inclusion criteria ......................................................................................................... 14 
4.3 
Exclusion criteria........................................................................................................ 14 
4.4 
Sample size calculation ............................................................................................. 14 
5. 
TREATMENT OF SUBJECTS .......................................................................................... 16 
5.1 
Investigational treatment ........................................................................................... 16 
5.2 
Discontinuation of study treatment ............................................................................ 16 
6. 
METHODS......................................................................................................................... 17 
6.1 
Study parameters/endpoints ..................................................................................... 17 
6.1.1 
Main study parameter......................................................................................... 17 
6.1.2 
Secondary study parameters ............................................................................. 17 
6.1.3 
Other study parameters...................................................................................... 17 
6.2 
Independent event adjudication committee .............................................................. 17 
6.3 
Randomisation and treatment allocation................................................................... 18 
6.4 
Study procedures....................................................................................................... 18 
6.4.1 
Baseline visit....................................................................................................... 18 
6.4.2 
Week 6: Patient reported fluid intake ................................................................. 19 
6.4.3 
Follow-up visit at 3 months after randomization ................................................ 19 
6.5 
Withdrawal of individual subjects .............................................................................. 20 
6.6 
Replacement of individual subjects after withdrawal ................................................ 20 
6.7 
Premature termination of the study ........................................................................... 20 
7. 
SAFETY REPORTING ...................................................................................................... 21 
7.1 
Temporary halt for reasons of subject safety ............................................................ 21 
7.2 
AEs, SAEs and SUSARs ........................................................................................... 21 
7.2.1 
Adverse events (AEs)......................................................................................... 21 
7.2.2 
Serious adverse events (SAEs) ......................................................................... 21 
7.3 
Follow-up of adverse events ..................................................................................... 22 
7.4 
Data Safety Monitoring Board ................................................................................... 22 
8. 
STATISTICAL ANALYSIS................................................................................................. 24 
SPSS will be used to conduct all statistical analyses. ......................................................... 24 
8.1 
Descriptive statistics .................................................................................................. 24 
8.2 
Analysis populations .................................................................................................. 24 
8.3 
Primary study parameter ........................................................................................... 24 
8.4 
Secondary study parameters .................................................................................... 25 
8.5 
Other study parameters ............................................................................................. 25 
9. 
ETHICAL CONSIDERATIONS ......................................................................................... 26 
9.1 
Regulation statement................................................................................................. 26 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
 
 
 
9.2 
Recruitment and consent........................................................................................... 26 
9.3 
Benefits and risks assessment, group relatedness .................................................. 26 
9.4 
Compensation for injury............................................................................................. 27 
9.5 
Incentives ................................................................................................................... 27 
10. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .......................... 28 
10.1 
Handling and storage of data and documents .......................................................... 28 
10.2 
Monitoring and Quality Assurance ............................................................................ 28 
10.3 
Amendments .............................................................................................................. 28 
10.4 
Annual progress report .............................................................................................. 28 
10.5 
Temporary halt and (prematurely) end of study report ............................................. 29 
10.6 
Public disclosure and publication policy .................................................................... 29 
11. 
STRUCTURED RISK ANALYSIS ................................................................................. 30 
11.1 
Potential issues of concern........................................................................................ 30 
11.2 
Synthesis ................................................................................................................... 32 
12. 
REFERENCES .............................................................................................................. 34 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
7 of 35 
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
General Assessment and Registration form (ABR form), the application 
form that is required for submission to the accredited Ethics Committee; 
in Dutch: Algemeen Beoordelings- en Registratieformulier (ABR-
formulier) 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials  
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
(S)AE 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics; in Dutch: officiële 
productinformatie IB1-tekst 
Sponsor The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A 
party that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
UAVG 
Dutch Act on Implementation of the General Data Protection Regulation; 
in Dutch: Uitvoeringswet AVG 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
8 of 35 
 
SUMMARY 
Rationale: Chronic heart failure (HF) is an increasing global health concern with over 20 
million patients worldwide. Although it is common practice for clinicians to advice fluid 
restriction to prevent symptoms and hospitalisations due to fluid retention, there is no 
evidence to support this treatment strategy, as also stated in the most recent HF guidelines. 
Moreover, fluid restriction is associated with thirst distress and may adversely impact quality 
of life (QoL). 
Objective: To investigate the effect of liberal fluid intake versus fluid restriction on QoL in 
chronic HF. 
Study design: Multi-centre open-label 1:1 randomized clinical trial with 6 months follow-up.  
Study population: Adult clinically stable outpatient chronic HF patients (n=498). 
Intervention: On a background of standard guideline-directed medical therapy patients will 
be randomized to an advice by the treating physician and/or HF specialized nurse of either 
fluid restriction of 1500cc/24hours versus liberal fluid intake for a period of 3 months.  
Main study parameters/endpoints: Primary study parameters are QoL at 3 months after 
randomization, as assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ) 
Overall Summary Score; and thirst distress using a validated thirst distress scale. Secondary 
and other study parameters are QoL as assessed with the KCCQ Clinical Summary Score 
and each of the separate domains, QoL as assessed with a visual analogue scale (EQ-5D-
5L), serum biomarkers (NT-proBNP, sodium, osmolality); and the occurrence of adverse 
events such as death, hospitalisations and need for iv-loop diuretics during the 6-month 
follow-up. 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: Participants will be recruited and followed at the specialized HF 
outpatient clinic according to standard clinical practice with a 3-month interval including 
standard laboratory analyses (renal function, electrolytes, NT-proBNP). Subjects will be 
randomized for 3 months to an advice of either liberal fluid intake or fluid restriction of 
1500cc/24hours, of which the latter is current standard clinical practice. At baseline and after 
3 months, participants will be asked to fill out a QoL questionnaire. In addition, subjects will 
be asked to report their daily fluid intake at week 6.  
In terms of benefits and risks, fluid restriction in HF leads to an undesirable sensation of 
thirst. For patients with HF, thirst can be distressing and can decrease quality of life. There is 
no evidence that fluid restriction reduces symptom burden or adverse events such as HF 
hospitalizations due to fluid retention, whereas liberal fluid intake may result in increased 
quality of life due a decrease in thirst. Given the vast target population of chronic HF patients 
worldwide, and the simplicity of the intervention, potentially millions of HF patients may 
benefit from the results of this study.  

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
9 of 35 
1. INTRODUCTION AND RATIONALE 
 
Chronic heart failure (HF) is a huge global health problem, affecting approximately 1–2% 
of the adult population in developed countries, rising to ≥10% among people >70 years of 
age. HF has a large burden of disease with high morbidity adversely affecting overall quality 
of life (QoL). The goals of treatment in patients with chronic HF are to improve their clinical 
status, functional capacity and QoL, prevent hospital admission and reduce mortality (1, 2). 
Symptoms and signs of chronic HF, such as orthopnea and peripheral edema, may arise 
from fluid retention, which could lead to serious adverse events such as hospitalization. In 
light of this, it has been common clinical practice for many decades to advice chronic HF 
patients to limit their fluid intake to 1500cc/24 hours. Strikingly, this advice is not based on 
clinical evidence but mainly on intuition. Moreover, the limited data available demonstrate 
that fluid restriction in HF is not more beneficial than liberal fluid intake (3-6).  
In the absence of supportive evidence, the Northern American Guidelines give fluid 
restriction a Class IIa/ level of evidence C recommendation, and the European Guidelines 
provide only a general recommendation supporting fluid restriction for symptomatic HF, 
without providing a level of evidence (1, 2, 7). Despite the fact that the guidelines state that 
there is no supportive evidence for fluid restriction, it is in daily practice recommended by 
many cardiologists, specialized heart failure nurses and dieticians to virtually every chronic 
HF patient. 
While the beneficial effect of fluid restriction in chronic HF is uncertain, it has been 
suggested that it may even adversely impact these patients (3, 8, 9). Fluid restriction as a 
daily part of chronic HF care is from a patients’ perspective considered to be most 
challenging and cumbersome, because 1) patients have to monitor fluid intake, 2) fluid 
restriction leads to thirst distress and 3) it constantly confronts patients with their chronic 
disease. As a consequence, non-adherence is common, which may detrimentally impact 
doctor-patient relationship and/or patient’s self-esteem (8). All of these factors of fluid 
restriction may contribute to a reduced QoL for HF patients. 
In light of the above and the need for more data on the effect of fluid management in 
chronic HF, we designed a randomized clinical trial on the effect of liberal fluid intake versus 
standard fluid restriction on QoL of chronic HF patients.  
 
 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
10 of 35 
2. OBJECTIVES 
 
This study investigates the hypothesis that liberal fluid intake has significant beneficial effects 
on QoL as compared to standard fluid restriction on QoL in outpatient chronic HF patients, 
without signals of potential safety issues. Specifically, we will investigate the following. 
 
Primary Objective:  
To investigate the effect of liberal fluid intake versus standard fluid restriction 
(1500cc/24hours) on QoL in outpatient chronic HF patients at 3 months after randomization, 
as assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ) (10) and the 
validated Thirst Distress Scale (11).  
As recently described in a “state-of-the-art-paper” in JACC: Heart Failure, the KCCQ is a 
well-validated questionnaire specific to HF, is sensitive to change in clinical status, and 
moreover, a change in KCCQ is predictive of future adverse disease progression (12, 13).  
For example, whereas an improvement in general well-being in terms mental health is 
expected to positively affect the score, any deterioration of HF is expected to negatively 
affect the score. Therefore, the KCCQ is perfectly suited to address both aspects of the 
hypothesis of this study (i.e. beneficial effects on QoL as well as signals of potential safety 
issues).  
In addition, the Thirst Distress Scale is most likely a sensitive measure to subtle changes in 
QoL due to differences in lifestyle advice concerning fluid intake. 
 
Secondary Objectives: 
• 
To investigate the effect of standard fluid restriction (1500cc/24hours) versus liberal 
fluid intake on QoL at 3 months after randomization, as assessed with a visual 
analogue scale (EQ-5D-5L); 
• 
To investigate the effect of standard fluid restriction (1500cc/24hours) versus liberal 
fluid intake on patient reported fluid intake at week 6. 
• 
To investigate the effect of standard fluid restriction (1500cc/24hours) versus liberal 
fluid intake on patient reported thirst intensity (VAS) 
• 
To investigate the effect of liberal fluid intake versus standard fluid restriction 
(1500cc/24hours) on safety as assessed by the number of occurrence of the 
composite clinical endpoint death, all-cause hospitalisation and the requirement to 
apply iv-loop diuretics during the 6-month clinical follow-up duration. 
 
Exploratory objectives: 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
11 of 35 
• 
To investigate the effect of liberal fluid intake versus standard fluid restriction 
(1500cc/24hours) on safety as assessed by (time to the first) occurrence of each of 
the components of the composite clinical endpoint death, all-cause hospitalisation, 
the requirement of iv-loop diuretics and also unplanned HF hospitalisations during the 
6-month clinical follow-up duration; 
• 
To investigate the effect of standard fluid restriction (1500cc/24hours) versus liberal 
fluid intake on the (time to the first) occurrence of acute kidney injury defined as a 
50% decline in estimated glomerular filtration rate relative to baseline, or decrease of 
>30 ml/min/1.73m2 and to a value below 60 ml/min/1.73m2 during the 6-month clinical 
follow-up duration; 
• 
To investigate the effect of standard fluid restriction (1500cc/24hours) versus liberal 
fluid intake on in serum biomarkers (NT-proBNP, sodium, osmolality, haemoglobin, 
haematocrit) and weight at 3 months after randomization; 
• 
To investigate the effect of standard fluid restriction (1500cc/24hours) versus liberal 
fluid intake on the use of concomitant medication (diuretics in particular) 
 
Subgroup analyses: 
We aim to perform the following exploratory subgroup-analyses: 
• 
Gender (male/female) 
• 
Admission hospital (study site) 
• 
HF category (HFrEF/HFmrEF/HFpEF) 
• 
NYHA class (NYHA class II / III) 
• 
Age (above/below median) 
• 
Diuretic dose (above/below median) 
• 
Baseline sodium, urea, creatinine and NT-proBNP concentration (above/below 
median) 
 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
12 of 35 
3. STUDY DESIGN 
 
This study is a multi-center open-label 1:1 randomized clinical trial to investigate the effect of 
liberal fluid intake versus standard fluid restriction on QoL at 3 months after randomization in 
outpatient chronic HF patients.  
In addition to the assessment of QoL by the KCCQ, this study investigates any potential 
safety issues of liberal fluid intake versus standard fluid restriction during an extended 6-
month clinical follow-up duration for HF hospitalizations and mortality. 
 
Duration of the clinical trial 
Study flow chart is provided below. Adult chronic HF patients will be asked to participate in 
the study according to the informed consent procedure as described in detail in paragraph 
9.2. Upon providing written informed consent, patients will be asked to fill out questionnaires 
on QoL. Thereafter, patients will be randomized and receive advice on fluid management 
accordingly. After 3 months, patients will be invited to the outpatient clinic according to 
standard clinical practice including laboratory analysis At this outpatient clinic visit, patients 
will again be asked to complete the same questionnaires. After that, further fluid 
management can be performed according to the discretion of the treating physician and 
patient. For clinical follow-up, the patient will again be invited to the outpatient clinical at 
month 6 according to standard clinical practice for assessment of the safety endpoint 
regarding death, hospitalization and the need for iv-loop diuretics. This visit will end study 
participation.  

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
13 of 35 
 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
14 of 35 
4. STUDY POPULATION 
 
4.1 Population base 
The source population comprises all adult outpatient chronic HF patients at the participating 
centres (n>1500). 
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
• 
Diagnosis of chronic HF with NYHA class II/III according to the prevailing 
guidelines > 6 months prior to randomization (1) 
• 
Adult (age ≥ 18 years) 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
• 
Reversible cause of HF (thyroid disorders, severe anemia, vitamin deficiencies) 
• 
Hopital admission for HF within 3 months of randomization 
• 
Chronic HF with NYHA class IV  
• 
Hyponatremia at baseline (sodium <130mmol/l) 
• 
Estimated Glomerular Filtration Rate (eGFR) of < 30ml/min/1.73 m2 at baseline 
• 
Scheduled cardiac surgery within 3 months of randomization 
• 
Recent (within 3 months) coronary intervention (PCI or CABG) or implantation of 
pacemaker device 
• 
Comorbidity for which fluid restriction is advised by a different treating physician 
(e.g. nephrologist) 
• 
Life expectancy of less than 6 months 
• 
The treating clinician believes that participation in the study would not be in the 
best interests of the patient 
• 
Inability to provide informed consent  
 
4.4 Sample size calculation 
Sample size calculation was performed with the software package G*Power 3.1.7 and 
performed as previously described methods for repeated measures ANCOVA analysis, using 
baseline QoL as a covariate (14).  

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
15 of 35 
For our sample size calculation, we assume a correlation of 0.88 between baseline and 
follow-up KCCQ-OS score (15). Furthermore, we assume a follow-up KCCQ-OS score of 
66.25 with a standard deviation of 20 for liberal fluid intake group (16-20). Next, we assume a 
2.5-point difference in KCCQ-OS follow-up scores at 3 months between both randomization 
groups (16-20). To test this difference at a p-value of 0.05 and power of 80%, we need a total 
of 454 evaluable patients. Anticipating a drop-out rate of 10% we aim to enrol 498 patients. 
This sample size also allows adequate power to asses a 1.5-point difference in thirst distress 
at 3 months between both randomization groups (mean score of 16 with a standard deviation 
of 8 and intraclass correlation of 0.88; p-value: 0.05 and power: 80%). 
Both primary hypotheses on QoL by the KCCQ-OS score and thirst distress scale will be 
tested at a 2-sided 5% significance level. In the case of non-significant findings for the first 
primary end point (KCCQ), the second primary end point will be tested at the 2-sided 5% 
significance level but will be regarded as an exploratory end point, and a nominal P value will 
be produced. No adjustments for multiplicity will be made for secondary or exploratory end 
points. 
Currently, the outpatient HF population of the participating centres comprise >1,500 patients. 
Based on the excellent logistics of the participating centres and no strict limitations in terms 
of eligibility of potential subjects, we expect that the required number of inclusions is feasible. 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
16 of 35 
5. TREATMENT OF SUBJECTS 
 
5.1 Investigational treatment 
The investigational treatment concerns an advice by the treating physician and/or 
specialized HF nurse according to randomization at baseline of either a standard fluid 
restriction of 1500cc/24 hours or liberal fluid intake for the duration of the study period of 3 
months. Currently, fluid restriction of 1500cc per 24 hours is considered standard clinical 
practice for most HF patients worldwide. Consequently, liberal fluid intake is considered 
the investigational treatment. 
In case of contacts between the participant and the treating physician and/or specialized 
HF nurse during the study period, the advice according to randomization will be 
emphasized. 
Background medical treatment will be standard guideline-directed medical therapy and 
lifestyle advice according to standard practice, such as advice on sodium restriction, 
exercise and how to respond to clinical deterioration. 
Specifically, the use of diuretics can be adjusted freely and is not subject to protocol 
directives. Notably, any change in diuretics will be meticulously registered.  
 
5.2 Discontinuation of study treatment 
Participants will be instructed to follow the advice on fluid intake according to 
randomization. There are no formal stopping rules for discontinuation of study treatment. 
There are, however, multiple scenarios for which the treating physician at his/her 
discretion can judge that the advice according to randomization is no longer appropriate 
and fluid management should be adjusted accordingly. Patients will be instructed to 
contact their treating physician and/or specialized HF nurse in case of doubt whether to 
adhere to the randomized treatment regimen. 
Scenarios for which discontinuation of fluid restriction may be considered are dehydration, 
fever or any other scenario that may lead to a decreased circulatory volume with 
consequent end-organ injury such as prerenal acute kidney injury. 
A scenario for which discontinuation of liberal fluid intake may be considered is severe 
hyponatraemia (<125mmol/L) or progression of HF to NYHA class IV.  
Patients for whom study treatment is discontinued will be followed according to study 
protocol (intention-to-treat principle). 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
17 of 35 
6. METHODS 
6.1 Study parameters/endpoints 
6.1.1 Main study parameters 
- QoL at 3 months after randomization, as assessed with the KCCQ Overall 
Summary (OS) Score (10) 
- QoL at 3 months after randomization, as assessed with the Thirst Distress Scale 
(11) 
6.1.2 Secondary study parameters  
- QoL at 3 months after randomization, as assessed with the KCCQ Clinical 
Summary (CS) Score and each of the KCCQ domains (10); 
- Proportion of patients with clinically meaningful changes in KCCQ-OS and KCCQ-
CS scores (improved: ≥5 points increase; stable: <5 points increase or decrease; 
declined: ≥5 points decrease); 
- QoL at 3 months after randomization, as assessed with a visual analogue scale 
(EQ-5D-5L); 
- Thirst intensity at 3 months after randomization, as assessed with a visual 
analogue scale; 
- Patient reported fluid intake during week 6. 
- Events (death, hospitalisations, iv loop diuretic treatment) up to month 6. 
6.1.3 Other study parameters  
- Serum biomarkers (NT-proBNP, sodium, osmolality, haemoglobin, haematocrit), 
weight and measures of patient satisfaction on self-care at 3 months after 
randomization; 
- The occurrence of acute kidney injury defined as a 50% decline in estimated 
glomerular filtration rate relative to baseline, or decrease of >30 ml/min/1.73m2 and 
to a value below 60 ml/min/1.73m2, during the 6-months clinical follow-up duration; 
- The occurrence of (temporary) discontinuation of study treatment; 
- Baseline variables such as comorbidity, previous fluid restriction, vital parameters 
and concomitant medication will be acquired. 
 
6.2  Independent event adjudication committee 
An independent event adjudication committee will be formed to adjudicate any 
hospitalizations as either HF-related or not, and to adjudicate the cause of death. The 
committee comprises three clinical experts with experience in clinical trials and capable of 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
18 of 35 
event adjudication. One of the members is appointed as chair person. The events of 
interest will be adjudicated as according to a predefined scheme based on consensus by 
two committee members; in case of non-consensus the third committee member will 
provide final adjudication. The event adjudication committee members are not involved as 
investigators and are not part of the DSMB of the current protocol. 
 
6.3 Randomization, blinding and treatment allocation 
Randomization will take place after the participant has provided informed consent and is 
eligible according to the in- and exclusion criteria. The informed consent procedure is 
described in detail in paragraph 9.2.  
At the screening visit, patients will be assigned an incremental subject number according 
to chronological order after informed consent. The informed consent procedure is 
described in detail in paragraph 9.2. The subject number remains unchanged during the 
study and allows the patient to be identified during the whole study.  
Patients will be randomized using Castor. Subjects will be 1:1 randomized to either liberal 
fluid intake or standard fluid restriction. A patient is considered randomized as soon as the 
randomization is completed in the eCRF (Castor). A patient cannot be randomized more 
than once in the study. 
Inherent to the type of intervention both the investigator/treating physician as well as the 
subject are not blinded to randomization. However, the members of the event adjudication 
committee as well as the statistician, who will perform the primary analysis, will be blinded 
for randomization.  
 
6.4 Study procedures 
6.4.1 
Baseline visit 
For screening of eligibility no additional study procedures are required. In- and exclusion 
criteria can be derived from the patients’ medical record, including results from physical 
examination and laboratory analysis at baseline, which is performed in the setting of 
standard clinical practice. 
After providing written informed consent, all subjects will be asked to fill out 3 simple and 
validated questionnaires concerning quality of life: the Kansas City Cardiomyopathy 
Questionnaire (10), the Thirst Distress Score (11) and the EQ-5D-5L. These procedures 
will take about 20 minutes in total. Next, all subjects will be randomized by the investigator 
using the eCRF and will receive lifestyle advice accordingly. All subjects will receive 
lifestyle advice according to a standardized script. 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
19 of 35 
All subjects will be instructed at baseline on how to report fluid intake in week 6, using a 
fluid intake diary, which will be provided at baseline. 
6.4.2 
Week 6: Patient reported fluid intake 
All subjects will be notified a few days prior to week 6 by telephone contact by the 
investigator that they are asked to report fluid intake for 1 week in a fluid intake diary, as 
provided at baseline, and take the diary with them at the standard 3 months follow-up visit. 
Importantly, the patients’ diary on fluid intake will not be assessed by the treating 
physician or treating specialized HF nurse, but by an independent study investigator, who 
is not involved in the treatment of the subject. Patients will be informed about this explicitly 
at baseline. This is done to promote an honest assessment of daily fluid intake; by 
removing any pressure on the patient to fill in answers to please the treating 
professionals. 
6.4.3 
Follow-up visit at 3 months after randomization 
All subjects will undergo laboratory analysis, physical examination and clinical follow-up 
according to standard clinical practice, at the discretion of the treating physician. At this 
outpatient clinic visit, all subjects will be asked to again fill out 3 simple and validated 
questionnaires concerning quality of life: the Kansas City Cardiomyopathy Questionnaire 
(10). the Thirst Distress Score (11) and the EQ-5D-5L. These procedures will take about 
20 minutes in total. Moreover, information will be acquired on the occurrence of clinical 
events and (temporary) discontinuation of study treatment. 
After that, further fluid management will be determined according to the discretion of the 
treating physician and patient as part of shared-decision making. 
6.4.4 
Follow-up visit at 6 months after randomization 
All subjects will undergo laboratory analysis, physical examination and clinical follow-up 
according to standard clinical practice, at the discretion of the treating physician. At this 
outpatient clinic visit specifically, the occurrence of hospitalisations and the need for iv-loop 
diuretics will be assessed. In case an outpatient clinic visit is not feasible, clinical follow-up 
will be assessed through telephone contact. Clinical follow-up at 6 months after 
randomization will end study participation. Hereafter, subjects can participate in a long-term 
follow-up registry with telephone contact every 6 months on the occurrence of all-cause 
hospitalization and mortality. 
 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
20 of 35 
6.5 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. 
 
6.6 Replacement of individual subjects after withdrawal 
 
Subjects will not be replaced. Potential dropout is accounted for in the sample size. 
 
6.7  Premature termination of the study 
The study may be terminated if the study procedures are not being performed according 
to GCP and/or if subjects are placed at undue risk because of clinically relevant findings 
based on the planned interim-analyses as defined below. 
 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
21 of 35 
7. SAFETY REPORTING 
7.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 
health or safety. The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 
7.2 AEs, SAEs and SUSARs 
7.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to the investigational treatment. 
All adverse events reported spontaneously by the subject or observed by the 
investigator or his staff will be recorded. The investigator collects relevant AEs in the 
eCRF within five working days after obtaining knowledge of the event. 
 
7.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the sponsor without undue delay within 24 
hours after obtaining knowledge of the events via the Castor eCRF. In addition, the 
investigator will notify the sponsor by e-mail of the occurrence of an SAE. The 
sponsor will have a central e-mail address for SAE reporting. 
 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
22 of 35 
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening followed by a period of maximum of 8 
days to complete the initial preliminary report. All other SAEs will be reported within a 
period of maximum 15 days after the sponsor has first knowledge of the serious 
adverse events. 
 
7.3 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
protocol. 
 
7.4 Data Safety Monitoring Board 
Details on the DSMB are described in the attached DSMB Charter. 
A DSMB will be established to perform analyses according to the DSMB charter. The 
composition of the DSMB will comprise a chair clinical expert, a second clinical expert and 
a statistician with experience in RCTs, independent of the sponsor. 
 
The DSMB has two mandates: 
1) To perform two interim analyses at the enrolment of 33% and 66% of the subjects for 
safety on the occurrence of the composite clinical endpoint death, all-cause hospitalisation 
and the need for iv-loop diuretics; and for safety on the occurrence of acute kidney injury; 
2) To monitor the overall conduct of the trial, i.e. to monitor the enrolment rate. 
 
The above interim stage analyses will be performed for safety on two timepoints based on 
the number of enrolled subjects. First interim analysis will be performed at enrolment of 
33% of the subjects, second at enrolment of 66% of the subjects.  
In addition, the overall conduct in terms of enrollment rate will be monitored and in case of 
non-satisfactory enrollment advice may be given for improvement. Moreover, the DSMB is 
entitled to stop the study prematurely based on the above mandates. 
 
The advice and reports of the analyses of the DSMB will be sent to the sponsor of the 
study and to the accredited METC. Should the sponsor decide not to fully implement the 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
23 of 35 
advice of the DSMB, the sponsor will send the advice to the reviewing METC, including a 
note to substantiate why (part of) the advice of the DSMB will not be followed. 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
24 of 35 
8. STATISTICAL ANALYSIS 
SPSS will be used to conduct all statistical analyses. 
 
8.1 Descriptive statistics 
Descriptive statistics will be presented by treatment arm. Continuous variables will be 
summarized using mean ± standard deviation if normally distributed or median 
(interquartile interval) if not normally distributed. Differences between groups for 
continuous variables will be tested with Students’ t test or Mann-Whitney U test, 
whichever appropriate. Categorical determinants will be presented with numbers and 
percentages. Differences between groups for categorical variables will be tested with Chi-
square or Fisher exact test, whichever appropriate. A p-value of <0.05 will be considered 
significant. Measurements that were not performed or not recorded will be treated as 
missing data. For all analyses, missing data will not be imputed data unless otherwise 
described. 
 
8.2 Analysis populations 
The intention-to-treat principle will be used for the analysis, i.e. in the analysis participants 
will be included in the randomized assignment study group.  
In addition, we will perform an analyses according to the per-protocol principle, i.e. in this 
analysis participants will be included in case they adhered to the randomized fluid intake 
regimen. The patient reported fluid intake in week 6 will be used to assess whether the 
standard fluid restriction arm patients did adhere to the standard fluid restriction of 
1500/24 hours.  
 
8.3 Primary study parameters 
The difference between the two treatment arms in QoL after 3 months, as assessed with  
KCCQ OS Score and Thirst Distress Score, will be tested with the use of a repeated 
measures ANCOVA analysis, using baseline QoL as a covariate. A p-value of <0.05 will 
be considered significant.  
Primarily, we will analyze the data for those patients, of whom both baseline and follow-up 
are available, similar to previous studies (16, 21). We do not expect a difference in rate of 
lost-to-follow-up for the primary study parameters, and rates of lost-to-follow-up will be 
reported for both randomization groups. 
We will also perform an ancillary supportive analysis on KCCQ-OS score, in which we will 
give all “non-responders” at follow-up a score of 10 or 20 points below their baseline 
score, in case they are respectively alive or deceased. 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
25 of 35 
 
8.4 Secondary study parameters 
For the secondary parameters QoL at 3 months after randomization, as assessed with the 
KCCQ CS Score, each of the KCCQ domains and the EQ-5D-5L; and thirst intensity at 3 
months after randomization, a similar approach as for the primary study parameters will 
be adopted. The difference between groups in proportion of patients with clinically 
meaningful changes in KCCQ-OS, KCCQ-CS scores and the percentage of events 
(death, all-cause hospitalisations, the need for iv-loop diuretics and acute kidney injury) 
will be tested with Chi-square or Fisher exact test, whichever appropriate. The difference 
in between groups patient reported fluid intake will be analyzed with a Students’ t test or 
Mann-Whitney U test, whichever appropriate. 
 
8.5 Other study parameters 
Time-to-event outcomes will be analyzed using a Cox proportional hazards model, with, if 
necessary, baseline covariate adjustment in case of unexpected differences in baseline 
descriptive statistics. The estimated treatment effect will be presented in the form of 
hazard ratios with 95% confidence intervals. Kaplan-Meier plots will be used to present 
the pattern of events per treatment group over the follow-up period. The assumption of 
proportional hazards will be checked using statistical tests and graphical diagnostics 
based on the Schoenfeld residuals. 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
26 of 35 
ETHICAL CONSIDERATIONS 
8.6 Regulation statement 
The study will be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki and are consistent with ICH/GCP and in accordance with the 
Medical Research Involving Human Subjects Act (WMO) and other guidelines, 
regulations and Acts. 
 
8.7 Recruitment and consent 
All potential eligible patients will receive a letter (at least one week prior to their upcoming 
outpatient clinic visit) by their treating physician or heart failure nurse to inform them about 
the initiation of the study and to ask them to read the study patient information letter 
carefully prior to their upcoming outpatient clinic visit. The letter by the treating physician / 
heart failure nurse and the patient information letter specifically states that participation is 
voluntary and the decision to participate will not affect regular follow-up or the patient-
doctor relationship. 
During the outpatient clinic visit patients will be informed more into detail by the treating 
physician and/or specialized HF nurse about the study. In case the patient has no further 
questions and is willing to participate, written informed consent will be obtained. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. 
all of the procedures described in the protocol). The process of obtaining informed 
consent should be documented in the patient source documents. 
 
8.8 Benefits and risks assessment, group relatedness 
Below a justification of the proposed study is provided. For more detailed information and 
a structured risk analysis we refer to Chapter 11. 
There are only two small comparative, randomized studies performed on the effect of fluid 
restriction in less <70 patients (3, 4). In these 2 studies, fluid restriction showed no clinical 
benefit compared to unrestricted fluid intake, while liberal uptake resulted in an improved 
patient reported outcome, i.e. less thirst. These data underscore the need for more 
randomized data in larger studies. Subjects will be intensively monitored according to 
standard clinical practice by their experienced heart failure team. Patients are well 
instructed, stable at inclusion and familiar with logistics in case of unexpected 
deterioration. We are therefore convinced that our study is safe. In light of the presumed 
negative impact of fluid restriction on QoL and potential implications of this trial for 
millions of HF patients worldwide, we feel that the design of this trial is appropriate. 
 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
27 of 35 
8.9 Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of 
the WMO. 
  
The sponsor (also) has an insurance which is in accordance with the legal requirements 
in the Netherlands (Article 7 WMO). This insurance provides cover for damage to 
research subjects through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
 
8.10 Incentives  
Subjects will not receive any special incentives, compensation or treatment through 
participation in the study. 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
28 of 35 
9. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
9.1 Handling and storage of data and documents 
The data generated will be encoded and a separate patient identification log will be 
created. The key to the code will only be available to the principal investigator and 
delegated investigators. The acquired encoded data imputed in the eCRF will be 
accessible with passwords to the researchers involved; and the monitoring team. 
 
9.2 Monitoring and Quality Assurance  
A plan for will monitoring and Quality Assurance will be constructed by the Radboud 
Technology Centre of Clinical studies. According to the “Richtlijn Kwaliteitsborging 
Mensgebonden Onderzoek 2019” by the NFU the study is considered moderate risk (22). 
 
9.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favourable opinion. 
 
A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to 
affect to a significant degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
 
9.4 Annual progress report 
The sponsor will submit a summary of the progress of the trial to the accredited METC 
once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, 
serious adverse events/ serious adverse reactions, other problems, and amendments.  
 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
29 of 35 
9.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action.  
In case the study is ended prematurely, the sponsor will notify the accredited METC 
within 15 days, including the reasons for the premature termination. 
Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC.  
 
9.6 Public disclosure and publication policy 
It is expected that this study will lead to several abstracts and publications in international 
peer-reviewed journals. We agree with the CCMO-statement on publication policy and we 
will therefore act accordingly (23). 
 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
30 of 35 
10. STRUCTURED RISK ANALYSIS  
This chapter focusses into detail on how the study design addresses potential safety 
concerns. In addition, we underscore the importance of the role of our DSMB, which is 
described into detail in the DSMB Charter. 
 
10.1 Potential issues of concern 
Participants will be advised according to randomization to adhere to either a restricted fluid 
intake of 1500cc/24hours or a liberal fluid intake regimen. 
 
In general in chronic HF, symptoms and signs, such as orthopnea and peripheral edema, 
may arise from fluid retention, which could lead to serious adverse events such as 
hospitalization. In light of this, it has been common clinical practice for many decades to 
advice chronic HF patients to limit their fluid intake to 1500cc/24 hours. This advice is not 
based on clinical evidence but mainly on intuition. Moreover, the limited data available 
demonstrate that fluid restriction in HF may not be more beneficial than liberal fluid intake (3-
6).  
In the absence of supportive evidence, the Northern American Guidelines give fluid 
restriction a Class IIa/ level of evidence C recommendation, and the European Guidelines 
provide only a general recommendation supporting fluid restriction for symptomatic HF, 
without providing a level of evidence (1, 2, 7). Despite the fact that the guidelines state that 
there is no supportive evidence for fluid restriction, it is recommended in daily practice by 
many cardiologists, specialized heart failure nurses and dieticians to virtually every chronic 
HF patient. 
While fluid restriction may not have a beneficial effect in chronic HF, it has been 
demonstrated that it may even adversely impact these patients in terms of QoL (3, 8). Fluid 
restriction as a daily part of chronic HF care is from a patients’ perspective considered to be 
most challenging and cumbersome, because 1) patients have to monitor intake, 2) fluid 
restriction leads to thirst distress and 3) it confronts patients with their chronic disease. As a 
consequence, noncompliance is common, which may detrimentally impact doctor-patient 
relationship and/or patient’s self-esteem (8). All of these factors of fluid restriction may 
contribute to a reduced QoL for HF patients. 
Apart from the potential detrimental effect on QoL, the rationale of fluid restriction in HF 
management has been questioned by several other investigators previously (3, 5, 6, 24). The 
limitation of water supply in the diet can aggravate the status of reduced effective circulating 
volume, which is in itself already present in HF, due to the fall in cardiac output and 
slowdown in the circulating flow. This reduction in intravascular volume is especially present 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
31 of 35 
in the cases of HF with marked systemic venous hypertension, widespread edema, or 
ascites (25). In this scenario, the receptors of supraoptic and paraventricular nuclei of the 
hypothalamus, known to be involved in the secretion of antidiuretic hormone (ADH) in cases 
of reduced intravascular volume, may be activated as a consequence of the restricted water 
intake in the diet (26, 27). Thus, due to the non-osmotic stimulation of these receptors, a 
further release of ADH stimulates reabsorption of water at the level of the renal collecting 
ducts, and substantial maintenance of the state of widespread edema may occur despite the 
fluid restriction. Moreover, the limitation of fluid dietary intake may promote reduction in renal 
blood flow, with worsening of renal filtration (decrease of GFR) and risk of elevation of 
nitrogenous wastes in the blood (increase of blood urea nitrogen and creatinine). Finally, 
kidney dysfunction and cardiac ischemia caused by hypoperfusion may concur to provoke 
rather than prevent a condition of worsening HF. 
Although these concerns may seem quite plausible, from the limited data available there 
is no consistent adverse effect of fluid restriction demonstrated on symptoms of fluid 
retention, hospital admissions or renal function, as pointed out in systematic reviews and 
meta-analyses (5, 6).  
On the other hand, potential issues of concern may be that in case of randomization to 
liberal fluid intake an increase of HF signs and symptoms and serious adverse events such 
as HF hospitalizations and HF-related mortality may occur due to fluid retention more often 
compared to the fluid restriction arm. However, as previously stated, this is contradicted by 
the limited available data summarized in systematic reviews and meta-analyses (5, 6). There 
is, however, one study to suggest that fluid restriction of <1000c/24hours is superior to 
<2000cc/24hours for the prevention of adverse events such as HF re-admissions (28). It 
should be acknowledged that this concerns a highly selected population of HF patients. That 
particular population was recently discharged from the hospital, had a left ventricular ejection 
fraction <35%, had diuretic resistance with decreased urinary volume (<500 ml/day), and low 
natriuresis (<60 mEq/day), despite high dose diuretics. This highly vulnerable population with 
limited diuresis might benefit from strict fluid restriction compared to liberal fluid intake. In that 
regard, we have decided to exclude patients with poor kidney function and those who have 
comorbidity for which a different treating physician has prescribed fluid restriction (see 
exclusion criteria paragraph 4.3). Moreover, to be eligible the HF patients need to be stable 
for at least 3 months. Lastly, it may be that after the intervention period of 3 months, patients 
who have been randomized to liberal fluid intake may have an increase of HF signs and 
symptoms and serious adverse events such as HF hospitalizations and HF-related mortality 
due to fluid retention more often compared to the fluid restriction arm. Filling pressures may 
rise during the intervention period. While this may not lead to a change a clinical presentation 
within the first three months, it may have an effect on the patients’ vulnerability for adverse 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
32 of 35 
effects due to fluid retention in the following months. In that regard, we have lengthened 
clinical follow-up for 3 months after the intervention in order to address this potential safety 
issue. 
Another potential issue of concern may be patients who are hyponatremic. In a small 
study (n=46), it was suggested that fluid restriction in hyponatremic HF patients might results 
in higher QoL compared to liberal fluid intake (29). In light of this study, we decided to 
exclude HF patients with a sodium concentration <130mmol/l (see exclusion criteria 
paragraph 4.3). 
 
 
Appreciating the complex nature of chronic HF with potential unexpected 
deterioration, it is very important that chronic HF patients are well instructed on selfcare 
management according to professional recommendations (7). Subjects will be enrolled at the 
excellent specialized multidisciplinary HF outpatient clinics of the participating centers with 
vast experience in HF patient management. In order to be eligible patients will have to be 
diagnosed with HF for at least 6 months to ensure that all subjects are adequately instructed 
on what to do in case of potential deterioration. In case of signs and/or symptoms of either 
fluid retention or dehydration, the specialized multidisciplinary HF outpatient clinics are well 
equipped to address these adequately and prevent (further) deterioration. For example, in 
case of fluid retention, diuretics may be temporarily increased and/or fluid intake may be 
temporarily restricted. And for example, in case of dehydration, patients may be temporarily 
instructed to increase their fluid intake or temporarily decrease diuretic use.  
 
Acknowledging the above potential issues of concern and the tailored study design, we 
consider this study to be safe and appropriate to investigate the effect of fluid restriction 
versus liberal fluid intake, which may impact the current guidelines for millions of chronic HF 
patients worldwide. 
 
In addition to the above, a DSMB will be composed to perform 2 safety interim analyses 
on 1) the occurrence of death, all-cause hospitalisations and the need for iv-loop diuretics; 
and 2) the occurrence of acute kidney injury at two timepoints to ensure the safe and 
appropriate continuation of the study. 
 
10.2 Synthesis 
There are only two small comparative, randomized studies performed on the effect of fluid 
restriction in less <70 patients (3, 4). In these 2 studies, fluid restriction showed no clinical 
benefit compared to unrestricted fluid intake, while liberal uptake resulted in an improved 
patient reported outcome, i.e. less thirst. These data underscore the need for more 
randomized data. 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
33 of 35 
From a safety perspective, we will exclude patients with a sodium concentration <130mmol/l 
and poor kidney function (eGFR < 30ml/min/1.73 m2). Furthermore, patients will be 
intensively followed up and monitored as usual and in case of decompensation seen by their 
experienced HF team. Patients are well instructed, stable at inclusion and familiar with 
logistics in case of unexpected deterioration. Moreover, a DSMB will perform two additional 
safety analyses. In conclusion, our study design is appropriate in light of the need for 
randomized data regarding this controversial topic with implications for millions of HF 
patients worldwide. 
 
 
 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
34 of 35 
11. REFERENCES 
 
• 1. 
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 
2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The 
Task Force for the diagnosis and treatment of acute and chronic heart failure of the 
European Society of Cardiology (ESC). Developed with the special contribution of the Heart 
Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891-975. 
• 2. 
Writing Committee M, Yancy CW, Jessup M, Bozkurt B, Butler J, Casey 
DE, Jr., et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the 
American College of Cardiology Foundation/American Heart Association Task Force on 
practice guidelines. Circulation. 2013;128(16):e240-327. 
• 3. 
Holst M, Stromberg A, Lindholm M, Willenheimer R. Liberal versus 
restricted fluid prescription in stabilised patients with chronic heart failure: result of a 
randomised cross-over study of the effects on health-related quality of life, physical capacity, 
thirst and morbidity. Scand Cardiovasc J. 2008;42(5):316-22. 
• 4. 
Travers B, O'Loughlin C, Murphy NF, Ryder M, Conlon C, Ledwidge M, et 
al. Fluid restriction in the management of decompensated heart failure: no impact on time to 
clinical stability. J Card Fail. 2007;13(2):128-32. 
• 5. 
De Vecchis R, Baldi C, Cioppa C, Giasi A, Fusco A. Effects of limiting fluid 
intake on clinical and laboratory outcomes in patients with heart failure. Results of a meta-
analysis of randomized controlled trials. Herz. 2016;41(1):63-75. 
• 6. 
Li Y, Fu B, Qian X. Liberal versus restricted fluid administration in heart 
failure patients. A systematic review and meta-analysis of randomized trials. Int Heart J. 
2015;56(2):192-5. 
• 7. 
Lainscak M, Blue L, Clark AL, Dahlstrom U, Dickstein K, Ekman I, et al. 
Self-care management of heart failure: practical recommendations from the Patient Care 
Committee of the Heart Failure Association of the European Society of Cardiology. Eur J 
Heart Fail. 2011;13(2):115-26. 
• 8. 
Waldreus N, Hahn RG, Jaarsma T. Thirst in heart failure: a systematic 
literature review. Eur J Heart Fail. 2013;15(2):141-9. 
• 9. 
Eng SH, Jaarsma T, Lupon J, Gonzalez B, Ehrlin J, Diaz V, et al. Thirst and 
factors associated with frequent thirst in patients with heart failure in Spain. Heart Lung. 
2020. 
• 10. 
Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and 
evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure 
for heart failure. J Am Coll Cardiol. 2000;35(5):1245-55. 
• 11. 
Waldreus N, Jaarsma T, van der Wal MH, Kato NP. Development and 
psychometric evaluation of the Thirst Distress Scale for patients with heart failure. Eur J 
Cardiovasc Nurs. 2018;17(3):226-34. 
• 12. 
Spertus J, Peterson E, Conard MW, Heidenreich PA, Krumholz HM, Jones 
P, et al. Monitoring clinical changes in patients with heart failure: a comparison of methods. 
Am Heart J. 2005;150(4):707-15. 
• 13. 
Spertus JA, Jones PG, Sandhu AT, Arnold SV. Interpreting the Kansas City 
Cardiomyopathy Questionnaire in Clinical Trials and Clinical Care: JACC State-of-the-Art 
Review. J Am Coll Cardiol. 2020;76(20):2379-90. 
• 14. 
Borm GF, Fransen J, Lemmens WA. A simple sample size formula for 
analysis of covariance in randomized clinical trials. J Clin Epidemiol. 2007;60(12):1234-8. 
• 15. 
Medical Device Development Tool Qualification Decision Summary for 
Kansas City Cardiomyopathy Questionnaire. FDAgov. 2016. 
• 16. 
McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et 
al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 
2014;371(11):993-1004. 
• 17. 
Ekman I, Chassany O, Komajda M, Bohm M, Borer JS, Ford I, et al. Heart 
rate reduction with ivabradine and health related quality of life in patients with chronic heart 
failure: results from the SHIFT study. Eur Heart J. 2011;32(19):2395-404. 

NL75112.091.20 / NCT04551729 
 
FRESH-UP 
Version number: 2.0, 30th November 2020 
 
35 of 35 
• 18. 
Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, et al. 
Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 
2013;368(13):1210-9. 
• 19. 
Veazie PJ, Noyes K, Li Q, Hall WJ, Buttaccio A, Thevenet-Morrison K, et al. 
Cardiac resynchronization and quality of life in patients with minimally symptomatic heart 
failure. J Am Coll Cardiol. 2012;60(19):1940-4. 
• 20. 
Lewis EF, Claggett BL, McMurray JJV, Packer M, Lefkowitz MP, Rouleau 
JL, et al. Health-Related Quality of Life Outcomes in PARADIGM-HF. Circ Heart Fail. 
2017;10(8). 
• 21. 
Nassif ME, Windsor SL, Tang F, Khariton Y, Husain M, Inzucchi SE, et al. 
Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With 
Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial. Circulation. 
2019;140(18):1463-76. 
• 22. 
Richtlijn Kwaliteitsborging Mensgebonden Onderzoek 2019. 
• 23. 
www.ccmo-online.nl. 
• 24. 
Holst M, Stromberg A, Lindholm M, Willenheimer R. Description of self-
reported fluid intake and its effects on body weight, symptoms, quality of life and physical 
capacity in patients with stable chronic heart failure. J Clin Nurs. 2008;17(17):2318-26. 
• 25. 
Feigenbaum MS, Welsch MA, Mitchell M, Vincent K, Braith RW, Pepine CJ. 
Contracted plasma and blood volume in chronic heart failure. J Am Coll Cardiol. 
2000;35(1):51-5. 
• 26. 
Valania G, Singh M, Slawsky MT. Targeting hyponatremia and 
hemodynamics in acute decompensated heart failure: is there a role for vasopressin 
antagonists? Curr Heart Fail Rep. 2011;8(3):198-205. 
• 27. 
De Vecchis R, Ariano C, Esposito C, Giasi A, Cioppa C, Cantatrione S. In 
right or biventricular chronic heart failure addition of thiazides to loop diuretics to achieve a 
sequential blockade of the nephron is associated with increased risk of dilutional 
hyponatremia: results of a case-control study. Minerva Cardioangiol. 2012;60(5):517-29. 
• 28. 
Paterna S, Parrinello G, Cannizzaro S, Fasullo S, Torres D, Sarullo FM, et 
al. Medium term effects of different dosage of diuretic, sodium, and fluid administration on 
neurohormonal and clinical outcome in patients with recently compensated heart failure. Am 
J Cardiol. 2009;103(1):93-102. 
• 29. 
Albert NM, Nutter B, Forney J, Slifcak E, Tang WH. A randomized 
controlled pilot study of outcomes of strict allowance of fluid therapy in hyponatremic heart 
failure (SALT-HF). J Card Fail. 2013;19(1):1-9.