PURE-HF: Peripheral Ultrafiltration for the RElief From Congestion in Heart Failure
Phase: NA
Conditions: Heart Failure, Acute Heart Failure
Sponsor: Fresenius Medical Care Deutschland GmbH

Fresenius Medical Care Deutschland GmbH 
Clinical Research 
PURE-HF 
Version: 5.0  
Study code: UF-HF-02-INT 
 
 
CONFIDENTIAL 
Page: 1 of 10 
 
Study protocol - Synopsis 
PURE-HF: Peripheral Ultrafiltration for the RElief from 
Congestion in Heart Failure 
Study code: 
 
 
UF-HF-02-INT  
NCT No: 
 
 
NCT03161158 
Investigational device: 
Chiara, peripheral ultrafiltration 
device 
Control device: 
 
 
Not applicable 
Control therapy: 
 
Usual care including high-dose IV 
diuretics 
Study design: 
 
Multicenter, prospective, 
randomized, parallel-group 
controlled clinical trial   
Protocol status: 
 
 
Final version 5.0 
Date of current version: 
19. December 2018 
Confidential: 
The information of this documentation is provided to you as a 
principal investigator, potential investigator or consultant for review 
by you, your staff and institutional review board. The information 
contained in this document and the documentation itself is 
confidential and, except to the extent necessary to obtain informed 
consent, may not be disclosed unless such disclosure is required by 
federal regulations or state law. Persons to whom the information is 
disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 
 
 
Clinical Research  
Else-Kröner-Strasse 1 
D-61352 Bad Homburg 
Phone:  
+49 6172 609 93488 
Email: 
Jennifer.Braun@fmc-ag.de 
 
 

Fresenius Medical Care Deutschland GmbH 
Clinical Research 
PURE-HF 
Version: 5.0  
Study code: UF-HF-02-INT 
 
 
CONFIDENTIAL 
Page: 2 of 10 
 
 
STUDY SYNOPSIS 
Title: 
PURE-HF: Peripheral Ultrafiltration for the RElief from 
Congestion in Heart Failure 
Study code: 
UF-HF-02-INT 
Study design: 
Multicenter, prospective, randomized, parallel-group controlled 
clinical trial   
Investigational device: Chiara, peripheral ultrafiltration 
Control device: 
not applicable 
Control therapy:        
Usual care including high-dose intravenous (IV) diuretics 
Study objectives: 
Primary objective  
To 
evaluate 
whether 
tailored, 
peripheral 
ultrafiltration 
complementary to low-dose diuretics is associated with a 
reduction    in cardiovascular mortality in 90 days after 
randomization and heart failure events in 90 days after 
discharge 
compared 
to 
usual 
care 
including 
stepped 
intravenous diuretics, in acutely decompensated chronic heart 
failure with fluid overload (not fully responsive to diuretic 
therapy).  
 
Secondary objective  
 
The secondary aims will be to examine the effect of the above 
treatment assignments on: 
1. Heart failure rehospitalization analyzed as a recurrent event 
in 90 days after discharge   
2. Time until first HF rehospitalization in 90 days after 
discharge 
3. Time until first urgent HF visit in 90 days after discharge 
4. Quality of life (Patient Global Assessment at baseline, 
discharge, FU30, FU90; Short Kansas City Cardiomyopathy 
Questionnaire and EQ-5D-5L at discharge, FU30, FU90) 
5. Days alive and out of hospital up to 90 days after discharge 
6. Cardiovascular mortality in 90 days after randomization 
7. Resolution of congestion defined as resolution of at least 
two of the final eligibility criteria present at randomization 
(this does not include chest x-ray criterion, i.e. if x-ray 
criterion was one out of two final eligibility criteria, only 
resolution of the other criterion is necessary), thus:  
• Jugular venous pressure of <8cm H2O 
• No orthopnea 
• Trace or no peripheral edema  
• Respiratory rate no longer ≥20/minute 
8. In-hospital worsening heart failure until discharge 
9. Weight loss at 96h after randomization and at discharge 

Fresenius Medical Care Deutschland GmbH 
Clinical Research 
PURE-HF 
Version: 5.0  
Study code: UF-HF-02-INT 
 
 
CONFIDENTIAL 
Page: 3 of 10 
 
 
 
Study hypotheses: 
In acutely decompensated chronic heart failure patients who 
are admitted to the hospital due to symptoms and signs of 
congestion and who are not fully responsive to diuretic 
therapy, tailored, peripheral ultrafiltration complementary to 
low-dose diuretics provides better 90 day outcomes than usual 
care 
(guideline-directed 
medical 
therapy 
including 
IV 
diuretics).  
Patients: 
Acutely decompensated chronic heart failure patients who are 
admitted to the hospital due to symptoms and signs of 
congestion and who are not fully responsive to diuretic therapy 
Sample size: 
Sample size including 10% loss to follow-up and 13% 
treatment failure is 864 (432 in each group), minimum age of 
18 years, no maximum age, both sexes, regions (western, 
central and eastern Europe). 
 
Inclusion criteria: 
General:  
 
 
Informed consent signed and dated by study patient and investigator/authorized 
physician 
 
Minimum age of 18 years 
 
Ability to understand the nature and requirements of the study 
 
Study-specific: 
 
 
Heart failure (HF) patients with preserved, mid-range or reduced ejection fraction 
(confirmed according to the current definitions of heart failure with preserved 
(HFpEF), mid-range (HFmrEF) and reduced ejection fraction (HFrEF) requiring 
echocardiographic assessment within the prior 12 months) who are admitted to 
the hospital due to signs/symptoms of congestion (left- or right sided) 
 
On regularly scheduled oral loop diuretics prior to admission 
 
Patients who have received IV loop diuretics for decongestion within 24 hours 
after hospital admission and prior to screening. The dosages are administered 
according to clinical judgment.  
 
Symptoms of congestion and clinical evidence at the time of screening for 
eligibility: 
• 
Fluid overload manifested by at least 2 of the following:  
• 
Pitting edema ≥2+ of the lower extremities 
• 
Jugular venous pressure >8 cm H2O 
• 
Pulmonary congestion or pleural effusion on chest x-ray 
• 
Paroxysmal nocturnal dyspnea or ≥2− pillow orthopnea 
• 
Respiration rate ≥20 per minute 
 

Fresenius Medical Care Deutschland GmbH 
Clinical Research 
PURE-HF 
Version: 5.0  
Study code: UF-HF-02-INT 
 
 
CONFIDENTIAL 
Page: 4 of 10 
 
 
Additional objective documentation of congestion: Lung or inferior vena cava 
ultrasound, chest x-ray or elevated filling pressures, if available, at the time of 
randomization (optional) 
Exclusion criteria: 
Candidates will be excluded from the study if ANY of the following conditions apply: 
General: 
 
Any condition which could interfere with the patient’s ability to comply with the 
study 
 
In case of female patients: pregnancy or lactation period 
 
Participation in an interventional clinical study during the preceding 30 days 
 
Previous participation in the same study 
 
Unwillingness or inability to complete follow up 
 
Active drug or alcohol abuse (smoking allowed) 
 
Study-specific: 
 
Acute coronary syndrome requiring intervention during index hospitalization 
 
Severe renal dysfunction requiring renal replacement therapy 
 
Systolic blood pressure <90 mmHg at the time of randomization 
 
Pulmonary hypertension not secondary to left heart disease 
 
Pulmonary disease thought to be primarily responsible for symptoms 
 
Contraindication to systemic anticoagulation 
 
Severe concomitant disease expected to prolong hospitalization or to cause death 
in ≤90 days 
 
Sepsis  
 
Severe uncorrected valvular stenosis at the time of randomization 
 
Active myocarditis 
 
Hypertrophic obstructive cardiomyopathy 
 
Constrictive pericarditis or restrictive cardiomyopathy 
 
Liver cirrhosis due to primary liver disease 
 
Known infection with human immunodeficiency virus (HIV) or active hepatitis C 
 
Previous solid organ transplant 
 
Presence or requirement for mechanical respiratory support 
 
Presence or requirement of a mechanical circulatory support device 
 
Need for IV positive inotropic agents at the time of randomization 
 
Treatment: 
 
Ultrafiltration group:  
Patients in the intervention group will be treated with veno-venous ultrafiltration (UF) 
complementary to low-dose diuretic therapy according to the low-dose IV diuretic 
treatment algorithm and other medical therapy as judged indicated by the investigator. 
Patients will receive 1-7 UF sessions (6-10h/session, number of sessions depending on 
clinical assessment according to algorithm) during a maximum time period of 10 days.  

Fresenius Medical Care Deutschland GmbH 
Clinical Research 
PURE-HF 
Version: 5.0  
Study code: UF-HF-02-INT 
 
 
CONFIDENTIAL 
Page: 5 of 10 
 
Control group: 
Patients in the control group will be treated with high-dose diuretic therapy according to 
the high-dose diuretic treatment algorithm and other medical therapy as judged indicated 
by the investigator.  
 
Target variables: 
 
 
Primary endpoint:  
Composite endpoint of cardiovascular mortality in 90 days after randomization and heart 
failure events in 90 days after discharge. HF events are defined as HF rehospitalization or 
an urgent HF visit. 
 
Secondary endpoints: 
1. Heart failure rehospitalization analyzed as a recurrent event in 90 days after 
discharge   
2. Time until first HF rehospitalization in 90 days after discharge 
3. Time until first urgent HF visit in 90 days after discharge 
4. Quality of life (Patient Global Assessment at baseline, discharge, FU30, FU90; 
Short Kansas City Cardiomyopathy Questionnaire and EQ-5D-5L at discharge, 
FU30, FU90) 
5. Days alive and out of hospital up to 90 days after discharge 
6. Cardiovascular mortality in 90 days after randomization 
7. Resolution of congestion defined as at least two of the final eligibility criteria 
present at randomization have resolved (this does not include chest x-ray 
criterion, i.e. if x-ray criterion was one out of two final eligibility criteria, only 
resolution of the other criterion necessary), thus:  
 Jugular venous pressure of <8cm H2O 
 No orthopnea 
 Trace or no peripheral edema  
 Respiratory rate no longer ≥20/minute 
8. In-hospital worsening heart failure until discharge 
9. Weight loss at 96h after randomization and at discharge 
 
Safety endpoints: 
1. Increase in serum creatinine by 26.5 µmol/L  
(0.3 mg/dL) or more and/or a ≥25% increase in serum creatinine OR a ≥20% 
drop in GFR) at discharge 
2. Access-related complications (bleeding, infection) 
 
Exploratory variables: 
1. Length of stay during initial hospitalization 
2. Change in furosemide-equivalent dose from preadmission to discharge (in 
mg/day)  
3. All-cause mortality rates up to 90 days after randomization  
 

Fresenius Medical Care Deutschland GmbH 
Clinical Research 
PURE-HF 
Version: 5.0  
Study code: UF-HF-02-INT 
 
 
CONFIDENTIAL 
Page: 6 of 10 
 
Planned start and end of study:  
 
Start of Study Preparations  
 
 
Q 3 2016 
Start of Trial / First patient in  
 
 
Q 3 2017 
End of Trial / Last patient out  
 
 
Q 3 2021 
Data Base Lock   
 
 
 
Q 3 2021 
Statistical Analysis and Report  
 
 
Q 4 2021 
 
 
 
 
Intervention scheme and trial flow: 
 
 
Of note, patients must be randomized within 24 hours after admission to designated 
hospital floor. 
 
 
 
 

Fresenius Medical Care Deutschland GmbH 
Clinical Research 
PURE-HF 
Version: 5.0  
Study code: UF-HF-02-INT 
 
 
CONFIDENTIAL 
Page: 7 of 10 
 
1. STATISTICS 
1.1. PRIMARY ANALYSIS 
The primary endpoint of the trial is the composite of cardiovascular mortality in 90 days 
after randomization or a heart failure event in the 90 days after discharge. 
 
The primary analysis of the effectiveness of the UF treatment will be conducted in the ITT 
population (see section 1.5). The occurrence of cardiovascular deaths or heart failure event 
after discharge from hospital will be summarized using event proportions, i.e. number of 
patients with an event divided by the number of patients randomized to the respective 
treatment group. 
 
The null hypothesis of no difference in event proportions between the randomized groups 
will be tested in a two sided test using logistic regression analysis adjusting for 
stratification variables (other than study site). Odds ratios including 95% confidence 
intervals (CI) will be presented as well as p-values (Wald methodology). In addition, 
descriptive analyses of the components of the primary outcome will be reported in the form 
of Kaplan-Meier (KM) curves for the time-to-event for each of cardiovascular mortality in 
90 days after randomization and heart failure event within 90 days after discharge 
(Kaplan and Meier, 1958).  Follow-up times will be censored at date of death, loss to 
follow-up or at the 90 day cut-off period. 
Hazard ratios comparing the two treatment groups under study will be determined within 
the Cox proportional hazard model and provided along with the 95% HR confidence limits 
(Wald-CI). 
 
1.2. SECONDARY ANALYSES 
The analysis of secondary endpoints and exploratory variables (see section Fehler! 
Verweisquelle konnte nicht gefunden werden.) including the total number of 
recurrent HF hospitalizations, weight loss during index hospitalization, duration of index 
hospitalization (in days), changes in laboratory measurements (e.g. resolution of 
congestion) as well as “Quality of Life” (short form of KCCQ with EQ-5D as standardized 
measure of health status) and Patient Global Assessment (PGA) will included in formal 
analyses. There will be no structured analysis taking into account multiple testing. 
Summary statistics such as mean, standard deviation [SD], median, 25th [Q1] and 75th 
[Q3] percentiles, minimum [Min] and maximum [Max]) will be calculated for continuous 
variables. Frequencies and percentages will be presented for categorical variables. 
 
The comparison between treatment groups will be evaluated using logistic regression 
analysis adjusting for stratification variables (other than study site) or Fisher’s exact test 
(in case of a rare outcome) for categorical variables, using joint modeling of death and 
recurrent events in the case of heart failure hospital admissions and linear regression 
analysis for continuous variables adjusting for stratification variables (other than study 
site)  and, where appropriate for baseline levels of the variable. Non-parametic methods 
will be used where appropriate.  
 
As described in section 1.1, patients who die or lost to follow-up after discharge are 
included in all secondary analyses with all available data up to the date of last contact. 
 
Descriptive summaries of KM curves will be presented for all-cause mortality. Patients alive 
at the end of the study will be censored at the last date known to be alive.  

Fresenius Medical Care Deutschland GmbH 
Clinical Research 
PURE-HF 
Version: 5.0  
Study code: UF-HF-02-INT 
 
 
CONFIDENTIAL 
Page: 8 of 10 
 
More detailed descriptions of statistical methods and assumptions including calculated 
variables and the proposed format and content of tables and figures in the final report will 
be detailed in the Statistical Analysis Plan (SAP). Wherever reasonable, evaluation will be 
stratified by subgroups (i.e. age, other baseline characteristics) and pre-defined in the 
SAP. All statistical analyses will be performed using the software package SAS® [SAS 
Institute Inc., The SAS system for Windows, Cary, NC: SAS Institute Inc., 2013]. 
 
1.3. SAFETY ANALYSES 
Standard procedures for reporting of adverse events will be used. Adverse events will be 
summarized as frequencies and percentages by treatment group. 
 
1.4. FURTHER STATISTICAL CONSIDERATIONS 
Sensitivity analysis 
For sensitivity and robustness, the analyses of the primary and secondary endpoints will 
be repeated for the Per-Protocol-Population. 
Handling of missing data 
We will perform multiple imputation for subjects with missing data on the primary and 
secondary outcomes at 90 days, if applicable (details will be specified in the SAP). 
 
1.5. ANALYSIS SETS 
For this study, the following analysis populations will be defined: 
Per-protocol-population (PP) 
Includes all subjects who entered the study in accordance with both the inclusion / 
exclusion criteria without major protocol deviations and who finished the study in 
accordance with the study protocol. 
 
(Modified) Intention-to-treat population (ITT=FAS) 
Includes all subjects who were randomized and for whom complete efficacy data are 
available. We will analyze subjects lost to follow up based on subjects´ status at time of 
withdrawal of consent and add a sensitivity analysis using multiple imputation for those 
with missing outcomes at 90 days. 
 
Safety-population (SP) 
Includes all subjects who were randomized. 
 
Assignment of patients to analysis populations will be done during the data review 
meeting. Primary analysis will be based on the ITT population; an additional analysis on PP 
will be performed to assess validity of results. Safety analyses will be performed on the SP. 
The primary endpoint measured at 90 days will be analyzed on an intention to treat basis. 
It is anticipated that there may be some “crossover” from the intervention group to the 
control group or from the control group to the intervention group. The number of 
crossovers will be documented to provide context for interpreting the primary results; 
however, treatment crossovers will be analyzed according to the intention to treat principle 
and thus will be included in the arm to which they were randomized. 
 

Fresenius Medical Care Deutschland GmbH 
Clinical Research 
PURE-HF 
Version: 5.0  
Study code: UF-HF-02-INT 
 
 
CONFIDENTIAL 
Page: 9 of 10 
 
1.6. SAMPLE SIZE JUSTIFICATION 
Previously published results from clinical trials comparing intravenous loop diuretics to 
mechanical fluid removal by isolated veno-venous ultrafiltration have yielded conflicting 
results regarding heart failure–related rehospitalization. The present PURE-HF study is 
similar to the AVOID-HF (Costanzo et al., 2015) in terms of study design and targets. The 
primary objective of the AVOID-HF study was to determine whether UF prolonged the time 
to first HF event within 90 days of hospital discharge. Regarding sample size 
considerations, the AVOID-HF trial refers to different publications in order to provide an 
estimate of the combined HF event rate for the control group and the assumed reduction of 
the HF event rate in the UF group (Felker et al., 2011, O'Connor et al., 2011, Costanzo et 
al., 2007, Konstam et al., 2007, Hernandez et al., 2010, Ross et al., 2010).   
 
Taking into account the assumptions and observations actually made in the prematurely 
terminated AVOID-HF study published by Costanzo et al. (Costanzo et al., 2016) we 
estimated that 864 patients (432 in each arm) should be sufficient to test whether there is 
a difference between the event proportions of the test and the control treatment. The 
proposed sample size calculations based on the two-sided Z test with unpooled variance 
and include the following assumptions: 1) α of 0.05 (α/2=0.025); 2) power (1-β) of 0.90; 
3) an HF event rate for the loop diuretics group of 25% plus 2% cardiovascular death and 
4) a reduction of the event proportion for the UF group of 37,5 % (this leads to an event 
proportion for the UF group of 16,88%). The estimated total sample size is displayed with 
additional patients included to account for 10% of subjects lost to follow-up and 13% 
treatment failures due to crossover during the treatment period  
 
Table 1: Sample size calculations according to assumptions of AVOID-HF trial. 
Event 
proportion   
  
Sample 
size N 
  
  
control 
group 
UF group
Reduction
Crude 
Incl. 10% 
loss to FU
Incl. 10% loss to FU and 
13% treatment failure 
27.00%
16.88%
37.50%
694
764
864
 
1) Test for two proportions, 
2) two-sided α of 0.05, 
3) power of 0.90, 
4) HF event rate of control group of 25% + 2% in-hospital death 
5) an event proportion for the loop diuretics group (control group) of 27%,  
6) an event proportion for the UF group (treatment group) of 16.88%  (37.50% 
reduction),  
7) including 10% loss to follow up and 13% crossover (i.e. treatment failure), 
 
 
The sample size calculation was carried out using PASS 14 [PASS 13. NCSS, LLC. 
Kaysville, Utah, USA. www.ncss.com.] 
 
1.7. INTERIM ANALYSIS  
No formal interim analysis will be performed. The requirements for safety are further 
defined in the context of the DMC and detailed in the DMC charter. Decisions will be 

Fresenius Medical Care Deutschland GmbH 
Clinical Research 
PURE-HF 
Version: 5.0  
Study code: UF-HF-02-INT 
 
 
CONFIDENTIAL 
Page: 10 of 10 
 
based on e.g. inspection of study-database, AE listings, event rates, etc. Thus, a 
statistical interim analysis is not applicable.