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; Summary of changes V1.0 05-06-2024 
 
 
 
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Fluid REStriction in Heart failure versus liberal fluid Uptake: the FRESH-UP study 
 
Summary of changes 
Protocol ID 
NL75112.091.20 / NCT04551729 
Short title 
FRESH-UP 
First approved version 
2.0 
Date of first approved 
version 
30th November 2020 
Protocol version 
3.0 
Date of change 
21st July 2021 
Section of change 
Protocol information page 
Description of change 
The following was added: 
J.J. Herrmann MD (Radboudumc) 
R. Pisters MD PhD (Rijnstate) 
Rationale for change 
New coordinating investigator was added (J.J. Herrmann MD, 
Radboudumc, Nijmegen, The Netherlands).  
New including site was added (Rijnstate Hospital, Arnhem, 
the Netherlands). 
Section of change 
4.3 Exclusion criteria 
Description of change 
The following criterion was added: 
• Changes in HF medical therapy in last 14 days prior to 
randomization. 
Rationale for change 
To ensure within the protocol that recent pharmacological 
changes of the study participants could not influence baseline 
measurements (including Kansas City Cardiomyopathy 
Questionnaire (KCCQ)). 
Section of change 
7.4 Data Safety Monitoring Board 
Description of change 
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 

NL75112.091.20 / NCT04551729                         FRESH-UP; Summary of changes V1.0 05-06-2024 
 
 
 
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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.  
 
Was changed to: 
The DSMB has two mandates: 
1) To perform two interim analyses when data is available 
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 when data is 
available at the enrolment of 33% of the subjects, second 
when data is available at the enrolment of 66% of the 
subjects. 
Rationale for change 
To elucidate that the interim analyses will be performed when 
data from the first 33% and 66% of the study population are 
available. 
Protocol version 
3.1 
Date of change 
21st February 2022 
Section of change 
Protocol information page 
Description of change 
The following was added: 
S. van Wijk MD PhD (Zuyderland Medisch Centrum) 

NL75112.091.20 / NCT04551729                         FRESH-UP; Summary of changes V1.0 05-06-2024 
 
 
 
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Rationale for change 
New including site was added (Zuyderland Medisch Centrum, 
Heerlen, the Netherlands). 
Protocol version 
4.0 
Date of change 
1st June 2022 
Section of change 
Protocol information page 
Description of change 
To be determined 
 
Was changed to: 
P. Van Der Meer MD PhD (chair; UMCG) 
Remaining members Tto be determined 
Rationale for change 
New chair of the event adjudication committee (EAC) was 
added (P. Van Der Meer MD PhD (UMC Groningen, 
Groningen, the Netherlands). 
Section of change 
2. Objectives 
Description of change 
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 (11, 12).  
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).  

NL75112.091.20 / NCT04551729                         FRESH-UP; Summary of changes V1.0 05-06-2024 
 
 
 
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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); 
 
Was changed to: 
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) Overall Summary Score (OSS) (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 (11, 12).  
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. 
 

NL75112.091.20 / NCT04551729                         FRESH-UP; Summary of changes V1.0 05-06-2024 
 
 
 
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Secondary Objectives: 
• 
To investigate the effect of standard fluid 
restriction (1500cc/24hours) versus liberal fluid intake on 
thirst distress at 3 months after randomization, as 
assessed with TDS-HF (13); 
• 
To investigate the effect of standard fluid restriction 
(1500cc/24hours) versus liberal fluid intake on QoL at 3 
months after randomization, as assessed with by KCCQ 
Clinical Summary Score (CSS), each of the KCCQ 
domains and the proportion of patients with clinically 
meaningful changes in these scores and a visual 
analogue scale (EQ-5D-5L); 
Section of change 
4.4 Sample size calculation 
Description of change 
The following was deleted: 
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. 
Section of change 
6.1 Study parameters/endpoints 
Description of change 
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  
 
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); 
 

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Was changed to: 
6.1.1 Main study parameters 
- QoL at 3 months after randomization, as assessed with the 
KCCQ Overall Summary (OSS) Score (10) 
- QoL at 3 months after randomization, as assessed with the 
Thirst Distress Scale  
 
6.1.2 Secondary study parameters  
- Thirst distress at 3 months after randomization, as 
assessed with the TDS-HF (13) 
- QoL at 3 months after randomization, as assessed with the 
KCCQ Clinical Summary Score (CSS) Score and each of the 
KCCQ domains (10); 
Rationale for the three 
changes above 
Based on external peer and editorial review by the Journal of 
Cardiac Failure of our “rationale-and-design-paper” and 
second internal statistical review, we improved the quality of 
our protocol accordingly. The comments and rebuttal letter 
are included in Appendix A. At the time of submission, and 
during the review process, only 140 patients were included 
and therefore no DSMB analysis was performed yet.  
Because of these changes, the primary research question 
how quality of life is affected by liberal fluid intake compared 
to fluid restriction will be answered more unambiguously.  
The results of the study will be easier to interpret by using 
one primary endpoint 
Section of change 
4.4 Sample size calculation 
Description of change 
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. 
 
Was changed to: 
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 498 506 patients. 

NL75112.091.20 / NCT04551729                         FRESH-UP; Summary of changes V1.0 05-06-2024 
 
 
 
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Rationale for change 
To correct the inaccurate way of processing the anticipated 
10% dropout rate in the sample size calculation using the 
standard LTF adjustment. 
Section of change 
8. Statistical analysis 
Description of change 
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 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.  
 
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. 
 
Was changed to: 
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 

NL75112.091.20 / NCT04551729                         FRESH-UP; Summary of changes V1.0 05-06-2024 
 
 
 
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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 studiesaccording to the intention-to-treat 
principle (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. 
In the unlikely case that any baseline scores on the 
KCCQ-OSS are missing, these will first be multiply 
imputed using imputations drawn from the distribution 
of the full study population. Following this, the 
imputation model will be specified separately by 
treatment arm and will include baseline and 3-month 
KCCQ-OSS as well as any auxiliary variables that are 
considered to be associated with the outcome or with 
the probability of missing the 3-month KCCQ scores.  
We will also perform an ancillary sensitivitysupportive 
analysis to examine the sensitivity of the results to 
missing data assumptionson 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. For this sensitivity 
analysis, a delta-adjustment approach will be applied, 
with a fixed constant (to be elicited from a panel of 
experts) added to the values imputed under the standard 
MAR procedure (22). 
 
8.4 
Secondary study parameters 
For the secondary parameters thirst distress, as assessed 
with the TDS-HF, and 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 

NL75112.091.20 / NCT04551729                         FRESH-UP; Summary of changes V1.0 05-06-2024 
 
 
 
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after randomization, a similar approach as for the primary 
study parameters will be adopted. 
Rationale for change 
To emphasize that the intention-to-treat method will be used 
for the primary analysis as described in paragraph 8.2. 
To increase the generalizability of the possible imputed 
missing baseline scores, the single imputation method was 
changed to a multiple imputation method. However, since 
quality of life measurements are known to be missing not at 
random, a sensitivity analysis was included. 
Section of change 
DSMB Charter; Annex 3: interim analysis 
Description of change 
The following will be the main parameters of interest for the 
DSMB: 
• 
KCCQ scores 
• 
The occurrence of HF hospitalizations 
• 
The occurrence of death 
• 
The occurrence of acute kidney injury 
These data will be made available to the DSMB before to the 
interim analyses, should be explicitly discussed and reported 
by the DSMB in their reports.  
 
This trial aims to include 498 patients. The first interim 
analysis by the DSMB will be performed when data is 
available on 33% of patients and the second when data is 
available on 66% of patients. Possible recommendations 
after the interim analysis could include, but are not exclusive 
to: 
• 
No action needed, trial continues as planned  
• 
Early stopping due to harm of a treatment or clear 
superiority 
• 
Sanctioning and/or proposing protocol changes, such 
as a change in sample size in case of large discrepancies 
between expected and observed event rates in the control 
arm. 
 
Was changed to: 

NL75112.091.20 / NCT04551729                         FRESH-UP; Summary of changes V1.0 05-06-2024 
 
 
 
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The following will be the main parameters of interest for the 
DSMB: 
• 
KCCQ scores 
• 
The occurrence of HF hospitalizations 
• 
The occurrence of death 
• 
The occurrence of acute kidney injury 
These data will be made available to the DSMB before to the 
interim analyses, should be explicitly discussed and reported 
by the DSMB in their reports.  
 
This trial aims to include 498506 patients. The first interim 
analysis by the DSMB will be performed when data is 
available on 33% of patients and the second when data is 
available on 66% of patients. Possible recommendations 
after the interim analysis could include, but are not exclusive 
to: 
• 
No action needed, trial continues as planned  
• 
Early stopping due to harm of a treatment or clear 
superiority 
• 
Sanctioning and/or proposing protocol changes, such 
as a change in sample size in case of large discrepancies 
between expected and observed event rates in the control 
arm. 
Rationale for change 
To clarify that the DSMB only can make recommendations to 
the investigators concerning continuation, termination, or 
other modifications of the study based on safety and not 
efficacy. 
Protocol version 
4.1 
Date of change 
29th September 2022 
Section of change 
Protocol information page 
Description of change 
The following was added: 
J.W.M. Van Eck MD PhD MSc (Jeroen Bosch Ziekenhuis) 

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Rationale for change 
New including site was added (Jeroen Bosch Hospital, Den 
Bosch, the Netherlands). 
Section of change 
Protocol information page 
Description of change 
The following was added: 
F.H. Verbrugge MD PhD (UZ Brussel, België) 
M.L. Handoko MD PhD (Amsterdam UMC) 
Rationale for change 
New members of the EAC were added (F.H. Verbrugge MD 
PhD (UZ Brussel, Belgium) and M.L. Handoko MD PhD 
(Amsterdam UMC, Amsterdam, The Netherlands)). 
Protocol version 
4.2 
Date of change 
2nd December 2022 
Section of change 
Protocol information page 
Description of change 
The following was added: 
G.C.M. Linssen MD PhD (Ziekenhuisgroep Twente) 
Rationale for change 
New including site was added (Ziekenhuisgroep Twente, 
Almelo, the Netherlands). 
Protocol version 
4.3 
Date of change 
5th December 2023 
Section of change 
Protocol information page 
Description of change 
The following was added: 
S.C.A.M. Bekkers MD PhD (Bernhoven Ziekenhuis) 
Rationale for change 
New including site was added (Bernhoven Hospital, Uden, 
the Netherlands). 
Protocol version 
4.4 
Date of change 
15th May 2024 
Section of change 
Protocol information page  
Description of change 
The following was added: 
E. Wierda MD LLM PhD (Dijklander Ziekenhuis) 

NL75112.091.20 / NCT04551729                         FRESH-UP; Summary of changes V1.0 05-06-2024 
 
 
 
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Rationale for change 
New including site was added (Dijklander Hospital, Hoorn, 
the Netherlands).