Pharmacy-based Interdisciplinary Program for Patients With Chronic Heart Failure (PHARM-CHF): A Randomized Controlled Trial
Phase: NA
Conditions: Chronic Heart Failure
Sponsor: Federal Union of German Associations of Pharmacists

 
 
Pharmacy-based Interdisciplinary Program for Patients with Chronic Heart Failure (PHARM-CHF):  
A Randomized Controlled Trial 
 
Apothekenbasiertes interdisziplinäres Programm für Patienten mit chronischer Herzinsuffizienz 
(PHARM-CHF):  
eine randomisierte kontrollierte Studie 
 
 
 
PROTOCOL 
 
 
Scientific Heads of the Study: 
 
Prof. Dr. med. Ulrich Laufs 
Department of Cardiology, University Hospital, University of Leipzig, Germany  
and 
Prof. Dr. rer. nat. Martin Schulz 
ABDA - Bundesvereinigung Deutscher Apothekerverbände e.V., Department of Medicine, Berlin, and 
Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, 
Germany 
 
 
Sponsor*: 
 
ABDA - Bundesvereinigung Deutscher Apothekerverbände, Berlin 
 
 
 
 
 
*) Investigator Initiated Study: The term “Sponsor” is used although this study is not a clinical trial 
according to German Drug Law or Medical Device Law. 

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II 
I. 
Table of Contents 
I. 
Table of Contents........................................................................................................................... II 
II. 
Glossary of Abbreviations ............................................................................................................. IV 
1 
Title ................................................................................................................................................ 1 
2 
Responsibilities and Contact Details ............................................................................................. 1 
3 
Synopsis ........................................................................................................................................ 2 
4 
Scientific Background .................................................................................................................... 4 
5 
Aim of the Study ............................................................................................................................. 5 
6 
Study Objectives ............................................................................................................................ 5 
6.1 
Primary Variables ..................................................................................................................... 5 
6.2 
Secondary Variables ................................................................................................................ 5 
7 
Study Design .................................................................................................................................. 6 
7.1 
Enrolment ................................................................................................................................. 6 
7.1.1 
Medical Practices and Pharmacies ................................................................................ 6 
7.1.2 
Patients ........................................................................................................................... 6 
7.2 
Inclusion and Exclusion Criteria ............................................................................................... 6 
7.2.1 
Inclusion Criteria ............................................................................................................. 6 
7.2.2 
Exclusion Criteria ............................................................................................................ 6 
8 
Study Procedures .......................................................................................................................... 7 
8.1 
Time Schedule Medical Practices ............................................................................................ 7 
8.2 
Visits / Data Collection in Medical Practices ............................................................................ 7 
8.2.1 
Screening / Visit 1 (V1) ................................................................................................... 7 
8.2.2 
Medical Practice Visits 3 and 5 (V3, V5) ........................................................................ 7 
8.2.3 
Medical Practice Visit 6 (V6) ........................................................................................... 7 
8.2.4 
Telephone Visits (V2, V4) ............................................................................................... 7 
8.2.5 
Continuous Data Collection of Events ............................................................................ 8 
8.3 
Data Collection at the end of the study .................................................................................... 8 
8.4 
Control and Intervention Group ................................................................................................ 9 
8.4.1 
Control Group ................................................................................................................. 9 
 
Medical Practice ..................................................................................................... 9 
 
Pharmacy ................................................................................................................ 9 
8.4.2 
Intervention Group .......................................................................................................... 9 
 
Medical Practice ..................................................................................................... 9 
 
Pharmacy ................................................................................................................ 9 
8.4.2.2.1 
Medication Review ................................................................................................. 9 
8.4.2.2.2 
Weekly Pharmacy Visit ........................................................................................ 10 
9 
Training and Monitoring ............................................................................................................... 11 
9.1 
Training and Information Material .......................................................................................... 11 
9.2 
Monitoring .............................................................................................................................. 11 

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III 
10 
Data Management ....................................................................................................................... 11 
10.1 
Responsibilities ................................................................................................................. 11 
10.2 
Data Collection ................................................................................................................. 11 
10.2.1 
Additional Sources for Data Collection ......................................................................... 12 
10.2.2 
Assessment of Safety ................................................................................................... 12 
10.3 
Data Handling ................................................................................................................... 12 
10.4 
Storage and Archiving of Data .......................................................................................... 12 
11 
Biometrics .................................................................................................................................... 13 
11.1 
Sample Size ...................................................................................................................... 13 
11.2 
Interim Analysis ................................................................................................................ 13 
11.3 
Analysis Populations ........................................................................................................ 13 
11.4 
Statistical Methods............................................................................................................ 14 
11.4.1 
Primary Efficacy Analysis ............................................................................................. 14 
11.4.2 
Primary Safety Analysis ................................................................................................ 15 
11.4.3 
Secondary Efficacy Analyses ....................................................................................... 15 
 
Adherence to medication ...................................................................................... 15 
 
Quality of life (Minnesota Living with Heart Failure Questionnaire, total score) ... 15 
 
Patient global assessment (PGA) ......................................................................... 15 
 
PHQ-9 ................................................................................................................... 15 
 
Self estimated adherence ..................................................................................... 15 
11.4.4 
Secondary Safety Analyses .......................................................................................... 15 
11.4.5 
Subgroup Analyses ...................................................................................................... 16 
11.4.6 
Randomization .............................................................................................................. 16 
11.4.7 
Blinding ......................................................................................................................... 16 
11.5 
Methods to Avoid Bias ...................................................................................................... 17 
11.5.1 
Selection Bias ............................................................................................................... 17 
11.5.2 
Performance Bias ......................................................................................................... 17 
11.5.3 
Exclusion Bias .............................................................................................................. 17 
12 
Adverse Events ............................................................................................................................ 17 
13 
Ethical and Legal Aspects ........................................................................................................... 17 
13.1 
Responsibilities of Scientific Heads .................................................................................. 18 
13.2 
Approval of Study Protocol and Amendments .................................................................. 18 
13.3 
Ongoing Information for Independent Ethics Committee ................................................. 18 
14 
Committees .................................................................................................................................. 18 
15 
Agreements .................................................................................................................................. 18 
15.1 
Financing of the Study ...................................................................................................... 18 
15.2 
Reports ............................................................................................................................. 18 
15.3 
Publication ........................................................................................................................ 18 
16 
Signatures .................................................................................................................................... 19 
17 
References ................................................................................................................................... 20 

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IV 
II. 
Glossary of Abbreviations 
ABDA 
ABDA – Bundesvereinigung 
Deutscher Apothekerverbände 
e.V.  
(Federal Union of German 
Associations of Pharmacists)  
ACEi 
Angiotensin-converting enzyme 
inhibitors 
AMK 
Arzneimittelkommission der 
Deutschen Apotheker  
 
(Drug Commission of German 
Pharmacists) 
AMTS  
Arzneimitteltherapiesicherheit  
(Drug Safety) 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ARB 
Angiotensin receptor blockers 
BAK 
Bundesapothekerkammer 
(Federal Chamber of 
Pharmacists) 
BB 
ß-blockers 
BMG 
Bundesministerium für 
Gesundheit 
(Federal Ministry of Health) 
BNP 
Brain Natriuretic Peptide  
(B-type natriuretic peptide) 
CEC 
Clinical Event Committee 
CHF 
Chronic Heart Failure 
CV 
Cardiovascular 
DMP 
Disease Management Program 
DRP 
Drug-related Problem 
DPC 
Committee for Data Protection 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EF 
Ejection Fraction  
HF 
Heart Failure 
HFmEF 
Heart Failure with Mid-range 
Ejection Fraction 
HFpEF 
Heart Failure with Preserved 
Ejection Fraction 
HFrEF 
Heart Failure with Reduced 
Ejection Fraction 
ITT 
Intention-to-Treat 
IZKS Mainz 
Interdisziplinäres Zentrum 
Klinische Studien Mainz 
(Interdisciplinary Center Clinical 
Trials Mainz) 
KV 
Kassenärztliche Vereinigung  
(Associations of Statutory 
Health Insurance Physicians 
LVEF 
Left Ventricular Ejection 
Fraction 
MLHFQ 
Minnesota Living with Heart 
Failure Questionnaire 
MRA 
Mineralocorticoid receptor 
antagonists 
NT-proBNP 
N-terminal fragment of BNP 
NYHA 
New York Heart Association 
Functional Classification 
OTC drug 
Over-the-Counter drug 
QoL 
Quality of Life 
PCNE 
Pharmaceutical Care Network 
Europe 
PDC 
Proportion of Days covered 
PGA 
Self-reported Patient Global 
Assessment 
PHQ-9 
Patient Health Questionnaire 
(depression module) 
PMV  
PMV forschungsgruppe an der 
Universität zu Köln 
PP 
Per Protocol 
RDE 
Remote Data Entry 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SOP 
Standard Operating Procedure 
UdS  
Universität des Saarlandes 
V 
Visit
 
 

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1 
1 Title 
Pharmacy-based Interdisciplinary Program for Patients with Chronic Heart Failure (PHARM-CHF): A 
Randomized Controlled Trial. 
 
Apothekenbasiertes interdisziplinäres Programm für Patienten mit chronischer Herzinsuffizienz 
(PHARM-CHF): eine randomisierte kontrollierte Studie. 
2 Responsibilities and Contact Details  
SCIENTIFIC HEADS  
OF THE STUDY 
Prof. Dr. med. Ulrich Laufs 
Universität Leipzig 
Direktor 
Klinik und Poliklinik für Kardiologie 
Universitätsklinikum Leipzig 
Liebigstrasse 20, 04103 Leipzig  
 
Prof. Dr. rer. nat. Martin Schulz 
ABDA - Bundesvereinigung Deutscher Apothekerverbände e.V., 
Bundesapothekerkammer und Deutscher Apothekerverband e.V. 
Geschäftsführer, Geschäftsbereich Arzneimittel und 
Vorsitzender der Arzneimittelkommission  
der Deutschen Apotheker (AMK) 
Unter den Linden 19 - 23, 10117 Berlin 
SPONSOR 
ABDA - Bundesvereinigung Deutscher Apothekerverbände e.V.  
Unter den Linden 19 - 23, 10117 Berlin 
STEERING 
COMMITTEE 
(EXECUTIVE BOARD): 
Prof. Dr. med. Ulrich Laufs (co-chair) 
Prof. Dr. rer. nat. Martin Schulz (co-chair) 
Prof. Dr. med. Stefan Anker, PhD 
Prof. Dr. med. Michael Böhm 
Dr. rer. nat. Nina Griese-Mammen 
Prof. Dr. rer. nat. Charlotte Kloft 
Prof. Dr. med. Friedrich Köhler 
Prof. Dr. rer. nat. Dietmar Trenk 
STUDY 
COORDINATION: 
Universität des Saarlandes 
Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische 
Intensivmedizin, 
Universitätsklinikum des Saarlandes  
Kirrberger Straße, 66421 Homburg/Saar 
 
ABDA - Bundesvereinigung Deutscher Apothekerverbände e.V. 
Geschäftsbereich Arzneimittel 
Unter den Linden 19 - 23, 10117 Berlin 
 
Interdisziplinäres Zentrum Klinische Studien Mainz (IZKS) 
Langenbeckstraße 1,55131 Mainz 
DATA MANAGEMENT/ 
BIOMETRY/ 
MONITORING 
Interdisziplinäres Zentrum Klinische Studien Mainz (IZKS) 
Langenbeckstraße 1, 55131 Mainz 
CLINICAL EVENT 
COMMITTEE 
A Clinical Event Committee (CEC) has been implemented. 

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2 
3 Synopsis  
AIM OF THE STUDY 
 
The aim of the study is to investigate, whether a continuous interdisciplinary 
intervention improves medication adherence (primary efficacy variable of 
interest) and leads to a reduction of hospitalizations and mortality (primary 
safety variable of interest) in elderly patients with chronic heart failure (CHF). 
The intervention, consisting of regular contacts with the local pharmacy and 
weekly dosing aids, aims to improve medication management. 
STUDY DESIGN 
PHARM-CHF is a prospective, multicentre, randomized controlled study. 
PRIMARY  
VARIABLES 
Primary efficacy variable: Medication adherence during the 365 days 
following randomization, pre-specified as a significant difference of the 
proportion of days covered (PDC) between the intervention and control 
group using pharmacy claims data for three CHF medications (angiotensin-
converting enzyme inhibitors or angiotensin receptor blockers [ACEi/ARB], 
ß-blockers [BB], and mineralocorticoid receptor antagonists [MRA]) 
prescribed at baseline 
Primary safety variable: All-cause mortality or unplanned cardiovascular 
hospitalizations 
as 
days 
lost 
due 
to 
unplanned 
cardiovascular 
hospitalizations or death of any cause 
SECONDARY 
VARIABLES 
Secondary efficacy variables 
- PDC for each drug class (ACEi/ARB, BB, MRA), percentage of patients 
with a mean PDC ≥80% (=adherent), and percentage of patients with 
a PDC ≥80% for each drug class (sensitivity analyses for a 
cutpoint ≥88%) 
- Quality of life (Minnesota Living with Heart Failure Questionnaire) after 
1 and 2 years 
- Self-reported patient global assessment (PGA) after 1 and 2 years 
(scale) 
- Patient Health Questionnaire (PHQ-9) after 1 year 
- Self-estimated medication adherence (Scale 0-100%) after 1 year 
 
Secondary safety variables 
- All-cause mortality or unplanned cardiovascular hospitalizations as 
recurrent event (number) 
- Unplanned cardiovascular hospitalizations (recurrent event, number) 
- Unplanned hospitalizations for heart failure (recurrent event, number) 
- Days lost due to hospitalizations of any cause or death 
- Unplanned all-cause hospitalizations 
- All-cause mortality 
STUDY POPULATION 
Inclusion Criteria 
- Age: 60 years and older 
- Diagnosis of chronic heart failure (CHF)  
- Stable CHF medication including a diuretic 
- Hospitalization for decompensated heart failure within past 12 months 
OR a value of ≥ 350 pg/mL for BNP or ≥ 1400 pg/mL for NT-proBNP 
- Written informed consent 
 
 

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3 
Exclusion Criteria 
- Regular/assisted use of a weekly dosing aid 
- Unwillingness or inability to visit a participating pharmacy once a week 
- Planned cardiac surgery 
- Life-expectancy < 6 months 
- Unwillingness or inability to comply with the study protocol (including 
drug abuse or alcohol dependency) 
- Participation in other studies (currently or in the last 4 weeks) 
DURATION OF THE 
STUDY  
The mean follow-up is expected to 24 months with a minimum of 12 
months. 
NUMBER OF 
SUBJECTS 
N = 248 
- Estimated effect of intervention: 10% (SD 22%) 
- α = 0.05, power: 85%  
- Calculated sample size: 176 + 30% drop out  
STUDY SITES 
Approximately 40 medical practices 
Approximately 80 pharmacies  
STUDY VISITS  
Intervention and control group: 
- Visits in the medical practice at baseline (V1), after 12 months (V3), and 
at the end of the study (V6), and, if applicable, after 24 months (V5) 
- Telephone visits by the medical practice after 6 months (V2) and, if 
applicable, after 18 months (V4) 
INTERVENTION 
 
Regular, pharmacy based intervention conducted in cooperation with the 
treating physician: 
- Medication review (Type 2a) at baseline: Recording of all medicines 
currently taken (prescribed medication and self-medication), check for 
drug-related problems, consolidation of a medication plan considering 
medication list of treating physician 
- Regularly (weekly or bi-weekly): Dose-dispensing of the medication 
(weekly dosing aid), discussion and counselling regarding medication, 
adherence, potential side effects, and signs and symptoms of cardiac 
decompensation, blood pressure and pulse measurement, updating 
medication plan if necessary 
- If required: Contact with patients’ physician  
FOCUS OF 
INTERVENTION  
- Improving medication adherence  
- Early detection of signs and symptoms of cardiac decompensation 
- Detection, solution, and prevention of drug-related problems  

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4 
4 Scientific Background  
Heart failure is one of the most prevalent diseases. In Germany, approximately 2.8 million patients 
suffer from heart failure [1]. The prevalence increases with age and amounts to 10% in elderly people 
aged 80 and older [2]. Heart failure is the most frequent cause for hospital admission in Germany and 
the third most frequent cause of death [3]. In 2008, the costs for treatment of patients with heart failure 
were estimated to 3.2 billion Euro [4]. The continuous intake of several medicines is an essential part 
of the therapy [5]. Several large clinical studies have reported that pharmacotherapy taken according 
to the guidelines, can increase quality of life, improve morbidity, and decrease mortality [5]. However, 
in daily practice this effect can often not be achieved. Reasons include non-adherence and other drug-
related problems.  
 
Non-adherence with pharmacotherapy affects 20-50% of all patients with chronic diseases [6–8]. 
Reasons for non-adherence include forgetfulness, high complexity of the drug regimen, wrong 
expectations, and experienced side effects [8–10]. Prospective studies and register studies showed 
that adherence with pharmacotherapy correlates with the morbidity and mortality in patients with chronic 
diseases [6, 11] such as chronic heart failure (CHF) [12]. For example, a subgroup analysis of the large 
heart failure study CHARM showed that the hazard ratio for mortality was 35% lower for patients with 
an adherence > 80% compared to patients with an adherence < 80% [13]. So far, only comprehensive 
interventions, which combined several different elements, were shown to improve adherence [14]. 
Effective interventions included elements such as education and counselling, motivation, intensive 
interaction between patient and health care professionals, reminder, and the dispensing of medicines 
in dosing aids. A pharmacist care program combining education and counselling with the preparation 
of medicines in a weekly dosing aid led to an increased adherence (61% to 97%). This improvement 
was associated with improved blood pressure and lipid values. Clinical endpoints, such as 
hospitalizations or mortality, have not been assessed [15]. The current literature shows that poor 
adherence cannot be “cured” and decreases after interventions to improve adherence end. Therefore, 
there is a need for a continuous strategy. 
 
Patients diagnosed with CHF in Germany received an average of 43.1 prescriptions per patient in 2008 
[1]. Older patients receiving several medicines are at a high risk to experience drug-related problems 
(DRP), e.g. problems with the application of the drug, double medication, interactions, adverse drug 
reactions. Gastelurrutia et al. found risks for drug-related negative outcomes in 78% of the patients with 
heart failure; 94% of those were considered preventable and 86% could have been resolved by an 
intervention of a pharmacist. Non-adherence was one of the most frequent drug-related problems 
detected [16].  
 
Rapid weight gain as well as deterioration of symptoms are early indicators of a cardiac 
decompensation in CHF. Adherence with weight monitoring was found to be associated with a lower 
mortality [17]. Guidelines recommend that patients with chronic heart failure should weigh themselves 
daily and record weight in a protocol [5]. Patients should contact a health care provider in case of a 
rapid weight gain or worsening of symptoms, such as dyspnoea. However, studies reported delays in 
contacting health care providers. CHF patients frequently either do not monitor weight and symptoms 
or do not recognize the signs [18,19]. Interventions, which have been found to improve medication 
adherence, might also be effective to improve adherence with symptom monitoring.  
 
A meta-analysis of pharmacist-led or pharmacy-based studies in patients with CHF found a significant 
reduction of hospitalizations and a non-significant reduction of mortality [20]. Patients with CHF who 
received a medication review (including clinical data) had a 37% lower risk of hospitalizations compared 
to patients receiving usual care [21]. Studies were most successful, when the pharmacist acted as part 
of a multidisciplinary team. The interventions consisted of education and counselling about 
pharmacotherapy, control of weight changes, recommendations for visiting physicians, and adherence 

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5 
assessment. However, reported data cannot directly be applied to the German setting, as studies have 
been conducted in different health care systems. In addition, the methodology of the included studies 
varied widely, e.g. some studies were not sufficiently powered. Furthermore, all interventions consisted 
of few intensive patient contacts. Based on literature [11], we hypothesize that regular and long term 
patient contacts will lead to an improved medication adherence and an early detection of signs of 
cardiac decompensation and drug-related problems, which may result in a decreased mortality and 
reduced hospitalizations eventually. 
 
To the best of our knowledge, PHARM-CHF is worldwide the first prospective randomized study to 
investigate the effects of a continuous interdisciplinary intervention using regular contacts with the local 
pharmacy and weekly dosing aids in patients with CHF. PHARM-CHF is the first prospective 
randomized study in patients with CHF with clinical endpoints performed in cooperation of physicians 
and pharmacists in Germany. Pharmacists and physicians will cooperate to improve adherence, 
prevent and solve drug-related problems and improve the monitoring of symptoms. 
5 Aim of the Study 
The aim of the study is to investigate, whether a continuous interdisciplinary intervention improves 
medication adherence, and leads to a reduction of hospitalizations and mortality in elderly patients with 
chronic heart failure (CHF). The intervention, consisting of regular contacts with the local pharmacy and 
weekly dosing aids, aims to improve medication management. 
6 Study Objectives 
6.1 Primary Variables 
Primary efficacy variable: Medication adherence to cardiovascular medication, pre-specified as a 
significant difference between the intervention and control group using pharmacy claims data for three 
CHF medications (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers 
[ACEi/ARB], ß-blockers [BB], and mineralocorticoid receptor antagonists [MRA]) prescribed at baseline. 
Medication adherence will be calculated based on the proportion of days covered (PDC) during the 
365-days following randomization, adjusted for inpatient days, medication switches, medication fills 
prior to randomization, and death. 
 
Primary safety variable: All-cause mortality or unplanned cardiovascular hospitalizations as days lost 
due to unplanned cardiovascular hospitalizations or death of any cause. 
6.2 Secondary Variables 
Secondary efficacy variables 
- 
PDC for each drug class (ACEi/ARB, BB, MRA), percentage of patients with a mean 
PDC ≥80% (=adherent), and percentage of patients with a PDC ≥80% for each drug class 
(sensitivity analyses for a cutpoint ≥88%). 
- 
Quality of life (Minnesota Living with Heart Failure Questionnaire) after one year and after two 
years 
- 
Self-reported patient global assessment (PGA) after one year and after two years (scale) 
- 
Patient Health Questionnaire (PHQ-9) after one year and after two years 
- 
Self-estimated medication adherence (Scale 0-100%) after 1 year 
 
 

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6 
Secondary safety variables 
- 
All-cause mortality or unplanned cardiovascular hospitalizations as recurrent event (number) 
- 
Unplanned cardiovascular hospitalizations (recurrent event, number) 
- 
Unplanned hospitalizations for heart failure (recurrent event, number) 
- 
Days lost due to hospitalizations of any cause or death 
- 
Unplanned all-cause hospitalizations 
- 
All-cause mortality 
7 Study Design 
PHARM-CHF is a prospective multicentre, randomized controlled study. 
 
7.1 Enrolment 
7.1.1 Medical Practices and Pharmacies 
Approximately 40 medical practices and 80 pharmacies from different regions in Germany will be 
enrolled. 
7.1.2 Patients 
Recruitment of patients takes place in participating medical practices. At least, 248 patients shall be 
recruited and randomized in the control and the intervention group. 
 
7.2 Inclusion and Exclusion Criteria 
7.2.1 Inclusion Criteria 
- 
Age: 60 years and older 
- 
Diagnosis of chronic heart failure (CHF) 
- 
Stable CHF medication including a diuretic 
- 
Hospitalization for decompensated heart failure within past 12 months OR a value of ≥ 350 pg/mL 
for BNP or ≥ 1400 pg/mL for NT-proBNP [22,23] 
- 
Written informed consent  
7.2.2 Exclusion Criteria 
- 
Use of a weekly dosing aid  
- 
Unwillingness or inability to visit the participating pharmacy once a week 
- 
Planned cardiac surgery 
- 
Life-expectancy < 6 months  
- 
Unwillingness or inability to comply with the study protocol (including drug abuse or alcohol 
dependency) 
- 
Participation in other studies (currently or in the last 4 weeks)  
 
No subject will be allowed to be enrolled in this study more than once. 

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8 Study Procedures  
8.1 Time Schedule Medical Practices 
 
Figure 1 Time Schedule Medical Practices 
 
8.2 Visits / Data Collection in Medical Practices 
8.2.1 Screening / Visit 1 (V1) 
Eligible patients are informed about the study and participating pharmacies in the medical practice. The 
patient receives the patient's information and signs and dates the informed consent after his approval. 
The physician signs and dates the informed consent and archives it. The patient receives an original of 
the informed consent. The physician documents the contact data of the patient and e.g. family members 
or other caregivers, who could be contacted. 
The patient is allocated into the intervention or control group by the medical practice using the Online 
Randomization tool "RandomiXer" (see 11.4.6). 
Furthermore, the physician records patient characteristics (e.g. vital signs, medical history, medication) 
and patients are asked to fill in questionnaires (e.g. PHQ-9, MLHFQ) (table 1). 
Screening visit, randomization and visit 1 can be conducted in one single visit. 
8.2.2 Medical Practice Visits 3 and 5 (V3, V5) 
The medical practice records patient characteristics (e.g. vital signs, medical history, and medication) 
after 12 months (V3) and, if applicable, after 24 months (V5). Furthermore, the patients are asked to fill 
in questionnaires (table 1). 
8.2.3 Medical Practice Visit 6 (V6) 
The IZKS Mainz informs the medical practice and the pharmacy about the end of the study, the medical 
practice performs visit 6 (table 1). 
8.2.4 Telephone Visits (V2, V4) 
The medical practice calls the patient after 6 months (V2) and, if applicable, after 18 months (V4) to 
inquire about hospitalizations. If a consultation takes place at this time, the medical practice can ask 
the patient face-to-face (table 1). 

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8.2.5 Continuous Data Collection of Events  
Additionally to the visits, events are recorded continuously in the medical practices. When death or an 
unplanned hospitalization occurs, the date and, in case of an unplanned hospitalization, the referral 
letter and the duration of the event are sent to IZKS Mainz as soon as possible.  
 
Screening 
/ V1 
(month 0) 
V2  
(after 6 
months 
V3  
(after 12 
months) 
V4  
(after 18 
months) 
V5  
(after 24 
months) 
V6  
(end of 
the study) 
In- and exclusion criteria 
X 
 
 
 
 
 
Heart 
failure 
(leading 
cause, duration) 
X 
 
 
 
 
 
CV-risk factors 
X 
 
 
 
 
 
Sociodemographic data 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
LVEF (if available) 
X 
 
 
 
 
 
DMP participation 
X 
 
X 
 
X 
 
Medical history 
X 
 
X 
 
X 
 
Device treatment 
X 
 
X 
 
X 
 
Medication plan 
X 
 
X 
 
X 
 
NYHA class 
X 
 
X 
 
X 
 
Care level (Pflegestufe) 
X 
 
X 
 
X 
 
Blood pressure 
X 
 
X 
 
X 
 
Pulse 
X 
 
X 
 
X 
 
Weight 
X 
 
X 
 
X 
 
Documentation of 
laboratory values  
X 
 
X 
 
X 
 
Hospitalization  
 
X 
X 
X 
X 
X 
Quality of life 
questionnaire (MLHFQ) 
X 
 
X 
 
X 
 
Patient health 
questionnaire (depression 
module, PHQ-9) 
X 
 
X 
 
X 
 
Self-estimated medication 
adherence 
(Scale 
0-
100%) 
X 
 
X 
 
X 
 
Self-reported patient 
global assessment (PGA) 
 
 
X 
 
X 
 
Table 1. Data collection at visits V1, V2, V3, V4, V5, and V6 
Abbreviations: BNP/NT-proBNP, (N-terminal fragment) brain natriuretic peptide; CV, cardiovascular; 
EF, ejection fraction; DMP, disease management program; NYHA, New York Heart Association; 
MLHFQ, Minnesota Living with Heart Failure Questionnaire; PHQ, patient health questionnaire; PGA, 
patient global assessment 
8.3 Data Collection at the end of the study 
Health insurance funds as well as data processing centres are asked for information on prescribed 
medicinal products dispensed at community pharmacies, and health insurance funds about 
hospitalizations at the end of the study.  

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9 
8.4 Control and Intervention Group 
8.4.1 Control Group 
 Medical Practice  
Patients receive usual medical care. Usual medical care is defined as the treatment of chronic heart 
failure at the discretion of the treating physician. 
 Pharmacy 
Patients visit their usual pharmacy/pharmacies to receive their medication and usual care. Participating 
pharmacies are not informed about the enrolment of patients in the control group. 
8.4.2 Intervention Group 
 Medical Practice  
Patients receive the usual medical care. Additionally, the medical practice interacts closely with the 
pharmacy, e.g. for consolidation of the medication plan or discussion of DRP. 
 
Patients in the intervention group can choose one of the participating pharmacies. They are advised in 
the medical practice to contact the selected pharmacy within 7 days after inclusion. The medical practice 
informs the pharmacy about the inclusion of the patient and provides the patient’s medication plan. 
 Pharmacy 
Patients receive the following interventions: At baseline, the pharmacist performs a medication review 
(Type 2a according to the Pharmaceutical Care Network Europe (PCNE) classification) in the 
community pharmacy with the aim of generating a medication plan, consolidated between the patient, 
his physician(s) and the pharmacist. Thereafter, the patient visits the pharmacy regularly to collect his 
medication in weekly dosing aids prepared in the pharmacy. Consultation between the pharmacist and 
the physician takes place in case of the necessity to update the medication plan, when new DRP appear 
or signs/symptoms of cardiac decompensation are reported by the patient to the pharmacist. 
 
The committee action plan drug safety (AMTS) of the Federal Ministry of Health (BMG) has developed 
a template for a medication plan [24]. This template will be used in this study. 
8.4.2.2.1 Medication Review 
Patient interview 
Patients in the intervention group are advised by the physician to visit or to arrange an appointment at 
the selected pharmacy within the next week. This appointment should take place within two weeks after 
randomization. The pharmacist asks the patients to bring their entire medication currently taken, 
including non-prescription (OTC) drugs, to this appointment. Patients, who do not contact the pharmacy 
within 7 days after inclusion, will be contacted by the pharmacy.  
To prepare the interview, the pharmacist performs a preliminary risk check based on the medication 
plan provided by the medical practice and the medication history recorded in the pharmacy (if available). 
 
The patient brings all medicines currently taken including non-prescription (OTC) drugs to the 
appointment. The pharmacist documents all medicines currently taken by the patient, the dosage and 
the application time according to the information given by the patient. In addition, potential side effects 
and (potential) problems administering the medication are documented.  
 
Medication plan 
After the interview, the pharmacist checks for drug-related problems (DRP) based on the patient 
interview, the medication dispensing history available in the pharmacy, and the medication plan 

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10 
provided by the medical practice and pays special attention to potential discrepancies. To ensure a 
standardized approach, the pharmacists uses a checklist summarizing DRP such as double medication 
or drug-drug-interactions. If necessary, the pharmacist contacts the physician to discuss detected 
(potential) DRP. The physician decides about medical interventions. The pharmacist documents 
(potential) DRP discussed with the physician as well as DRP, which are resolved directly by the 
pharmacist. 
 
Based on the consolidated medication plan the patient receives his first weekly dosing aid together with 
a printout of the medication plan, at the latest two weeks after the appointment.  
8.4.2.2.2 Weekly Pharmacy Visit 
Preparing the weekly dosing aids 
The pharmacy chooses the type of weekly dosing aid together with the patient. The dosing aid contains 
all medications in a day- and time-specific manner for one week and is clearly labelled with information 
regarding the patient, contents and contact information of the pharmacy. The pharmacy prepares the 
weekly dosing aid of the patient based on an up-to-date medication plan. The preparation follows the 
recommendations of the Federal Chamber of Pharmacists (BAK). 
 
Newly prescribed medication that is indicated for immediate treatment (e.g. antibiotics) is taken by the 
patient in addition to the dosing aid. In general, changes in the medication are included in the weekly 
dosing aid whenever the next aid is due. Therefore, it is important that the physician’s office or the 
patient inform the pharmacy about a change in medication. Furthermore, the pharmacist asks at every 
visit about potential changes. With every change, the pharmacist checks for DRPs, contacts the 
physician if necessary and updates the medication plan. The physician decides about medical 
interventions. The pharmacist documents (potential) DRP discussed with the physician as well as DRP, 
which are solved directly by the pharmacist. 
 
Pharmacy visit 
The patient visits the pharmacy once a week to collect the medication in a weekly dosing aid. The 
pharmacist provides the patient with information about the medication (especially at the beginning of 
the intervention and if a new medication is prescribed) and motivates the patient to take the medication, 
to self-manage symptoms and weight changes (e.g. daily weighing, weight diary). 
 
During these weekly visits, the pharmacist inquires after potential side effects, medication adherence, 
as well as signs and symptoms of a potential cardiac decompensation (e.g. shortness of breath). The 
pharmacist measures blood pressure and pulse (SOP BAK, see 9.1). If significant changes in vital signs 
are detected or if the patient reports relevant symptoms or signs (e.g. a significant weight increase), the 
pharmacist contacts the physician or recommends the patient to contact his physician.  
If the patient does not collect his medication, the pharmacy contacts first the patient or his caregiver(s). 
Additionally, in case of difficulties, the pharmacy contacts the medical practice. 
 
Adoption of the intervention 
a) Once the patient has attended the weekly visits in the pharmacy for a minimum of four continuous 
weeks and if needed, the patient and his pharmacist can agree on bi-weekly visits to the pharmacy. 
 
b) When a patient cannot visit the pharmacy, e.g. the patient is ill/home-bound, the pharmacy can either 
deliver the weekly dosing aid to the patient’s home or it can be dispensed to a caregiver. If the patient 
is absent for longer than a week, e.g. on holiday, the pharmacy can supply the patient with more than 
one weekly dosing aid. As the pharmacy visit is an essential part of the intervention, it is important, that 
the patient attends the interview at the pharmacy regularly. Hence, the supply of weekly dosing aids for 
more than two weeks should be strictly limited to these exceptions. 

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11 
9 Training and Monitoring 
9.1 Training and Information Material 
Training will be performed by ABDA, UdS and IZKS Mainz. Participating pharmacists and physicians 
are trained either by telephone, on site or during a workshop about study-specific aspects and will 
receive information material. They receive standardized material including study guidelines, checklists 
and forms, the study protocol, study material, information about the electronic case report form (eCRF), 
and a contact list. 
A telephone hotline to UdS as well as a website (www.pharm-chf.de) is available as information source 
and for requests of participating pharmacists and physicians. When necessary, questions will be 
forwarded to ABDA or IZKS Mainz. 
Medication is dose-dispensed based on the recommendations of the BAK, i.e. by dual control. A SOP 
of the BAK for the measurement of blood pressure and pulse is available in the intervention pharmacies.  
9.2 Monitoring 
Monitoring visits are conducted by the IZKS in the medical practices. As described in the study specific 
monitoring manual, monitoring will be done either by personal visits of a clinical monitor or by telephone 
contacts according to SOP of the IZKS Mainz (if applicable). The monitor checks the informed consent 
forms and reviews the entries into the eCRF based on source documents. The physician allows the 
monitor access to all essential documents and provides support to the monitor. 
The IZKS Mainz assists the physician to conduct the study according to the protocol as well as 
regulatory and ethical requirements. 
Moreover, pharmacists are assisted to conduct the study according to the protocol by employees 
(research associates) of ABDA. 
10 Data Management 
10.1 Responsibilities 
On behalf of the sponsor, IZKS Mainz conducts the data management of the PHARM-CHF study. A 
detailed methodology for the data management in this study will be documented in a data management 
plan. The document may modify the procedures outlined in this protocol. However, any major 
modifications of the data handling will also lead to a protocol amendment. 
10.2 Data Collection 
Obtained data is documented in an electronic case report form (eCRF), with an exception of the patient 
questionnaires. Patients answer questionnaires using a paper form. All protocol-required information 
collected during the study is entered by the investigator, or a designated representative in the eCRF. 
The paper-based data is entered by the IZKS Mainz into the study database. The investigator and the 
study site staff will receive system documentation, training and support for the use of the eCRF. In case 
of new study site staff, the training can be performed by personnel at the study site. IZKS Mainz can be 
contacted to support the data entry.  
All data changes (entry, modification and deletion) are recorded automatically in an electronic audit trail 
by storing the individual subject, the original value, the new value and time and date of the change. 
Previous data can be viewed or restored by the audit trail. All electronic data is entered by the site in 
compliance with applicable record retention regulations. 
The system is secured to prevent unauthorized access to the data or the system. Only people provided 
with a user ID and a password are able to enter or change data. The investigator maintains a list of 
individuals who are authorized to enter data. 

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12 
Computer hardware and software (for accessing the eCRF data) will be maintained at the site. The 
remote data entry (RDE) system is capable to make exact copies of data in legible paper form for audits. 
The architecture of the computer system of the IZKS Mainz will be described in the data management 
plan.  
10.2.1 Additional Sources for Data Collection 
To complete the data obtained from pharmacies and medical practices, there are also other sources to 
obtain information e.g., about events. Health insurance funds (Statutory Health insurance (SHI) and 
private) 
are 
asked 
for 
information, 
as 
well 
as 
German 
data 
processing 
centres 
(Apothekenrechenzentren) and comparable resources, e.g. registration offices (Einwohnermeldeämter) 
or health offices. All data will be kept in safe and confidential custody at IZKS Mainz.  
10.2.2 Assessment of Safety  
In case of hospitalizations, the blinded documents are sent to the clinical event committee (CEC) for 
adjudication according to pre-specified criteria in the CEC charter. Adjudicated events will be 
categorized by their cause and assigned into cardiovascular and non-cardiovascular events. 
10.3 Data Handling 
During data entry, integrity checks help to minimize entry failures. These data entry checks are defined 
in the data validation plan. The data entry system allows the study monitors to control the entry process 
with the help of the system-own review functions. Comments and requests can be processed by the 
study site just in time.  
During the study, data is exported into the statistical analysis system (SAS) and checked additionally 
for plausibility, consistency and completeness. Based on these checks, queries are produced. Any 
missing data or inconsistencies are reported back to the respective site and clarified by the responsible 
investigator. If all corrections are done, the database is closed and used for statistical analyses. 
All collected data will be processed according to the German Data Protection Law and handled in 
strictest confidence. To cover all relevant aspects of data protection a data protection commissioner is 
involved. A Data-Safety concept will be implemented and specified in a separate document. The latter 
will be prepared in cooperation with and handed in for approval to the data protection commissioner. 
Personal data will be strictly separated from the study database. 
10.4 Storage and Archiving of Data 
The investigator archives all study data (e.g. subject identification list, informed consent) and relevant 
correspondence in a standardized project folder. This folder, all source data and all documents are 
archived after finalization of the study according to the legal regulations. 
IZKS Mainz assures storage and archiving of the electronic data during the study. After completion of 
the study all electronic data is handed over to the sponsor. 
 
 

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13 
11 Biometrics 
11.1 Sample Size 
 
 
Figure 2: Sample Size Calculation 
The primary efficacy variable is adherence to CHF medication. We conservatively assume an 
improvement of the summary PDC ≥10% in the intervention group compared to usual care as clinically 
relevant. 
 
Assuming a mean PDC in the year before randomization of approximately 0.7 a sample size of N=176 
patients (88/group) is needed to detect a 10% (SD 22%) improvement between the intervention group 
and the usual care group with a power of 85% and an alpha of 5%. Assuming a dropout and lost to 
follow up of 30% N=248 patients have to be enrolled in the study.  
The study is powered for the primary efficacy variable only.  
11.2 Interim Analysis 
No interim analysis will be performed. 
11.3 Analysis Populations 
Intention to treat 
The intention to treat (ITT) population consists of all patients who have post-baseline data available and 
who did not fail to satisfy major entry criteria. Patients in the intervention arm (with or without withdrawal 
of consent), for whom no consolidated medication plan is available i.e., subjects failed to comply with 

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14 
the study protocol at entry (i.e. did not undertake the medication review at the pharmacy - which is 
comparable of not taken any trial medication), have no post-baseline data available. 
 
Per Protocol 
The per protocol (PP) population consists of all subjects of the ITT population who completed the study 
without major protocol violations. These are violation of inclusion criteria, meeting exclusion criteria, 
post-baseline data not available, consolidated medication plan not available (intervention group patients 
only) and premature termination (except death). As data for patients withdrawn (with withdrawal of 
consent) from the study will be anonymized immediately, pseudonymized data acquisition from other 
sources e.g., health insurance funds is impossible. 
11.4 Statistical Methods 
The main analysis comprises the eCRF data and pharmacy claims data of prescribed medicinal 
products dispensed at community pharmacies from data processing centres (Apothekenrechenzentren) 
and health insurance funds (statutory and private) and hospitalization data from health insurance funds. 
On behalf of the sponsor, IZKS Mainz conducts the main analysis of the PHARM-CHF study. The PDC 
will be determined at the PMV (Universitiy Cologne) and will be submitted to the IZKS Mainz for further 
analysis. Analyses regarding the intervention in participating pharmacies like analyses of drug-related 
problems (DRPs) and medication discrepancies are based on the eCRF and data documented during 
the intervention from pharmacists. These analyses will be performed by the Department of Medicine, 
ABDA, Berlin. The detailed methodology for the statistical analysis of this study will be documented in 
a statistical analysis plan (SAP). The SAP has to be signed by the scientific heads of the study, the 
statistician at IZKS and the study coordinator at ABDA. 
11.4.1 Primary Efficacy Analysis 
The primary efficacy analysis is the analysis of the PDC for three CHF medications (ACEi/ARB, BB and 
MRA). The pharmacy claims data are provided by data processing centres and health insurance funds. 
If health insurance data are not available for all patients, an analysis will be performed comparing the 
data from health insurance funds and data processing centres. The analysis will be adjusted for data 
from health insurance funds (yes/no). 
The PDC will be analysed by a two-sided stratified Wilcoxon signed-rank test (van Elteren test) on a 
two-sided level of significance of 5%. 
The following hypothesis will be tested: 
H0: mi=mc vs. H1: mi≠mc, 
Where mi denotes the median value of the intervention group and mc denotes the median value of the 
control group.  
Although statistical guidelines (“Points to consider on adjustment for baseline covariates”) suggest 
adjusting the analysis for all stratification variables of the randomization process, this is omitted. It is 
desired to get a robust result, if one treatment regimen is favourable to the other across all stratification 
factors. Nevertheless, supportive analyses adjusting for the stratification factors will be conducted as 
sensitivity analyses. 
 
 

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11.4.2 Primary Safety Analysis 
The primary safety variable is all-cause mortality or unplanned cardiovascular hospitalizations as days 
lost due to unplanned cardiovascular hospitalizations or death. 
The number of days lost due to death of any cause or unplanned cardiovascular hospitalizations will be 
analysed by a Wilcoxon signed-rank test comparing both treatment groups. Additionally, the number of 
days lost due to death of any cause or unplanned cardiovascular hospitalizations will be analysed 
descriptively by treatment group and in total. 
11.4.3 Secondary Efficacy Analyses 
 
Adherence to medication 
The primary efficacy analyses will also be repeated for each drug class (ACEi/ARB, BB, MRA). The  
percentage of patients with a mean PDC ≥80% (=adherent), and percentage of patients with a 
PDC ≥80% for each drug class (sensitivity analyses for a cutpoint ≥88%) will be calculated. 
 
Quality of life (Minnesota Living with Heart Failure Questionnaire, total 
score) 
The changes to baseline of the total score of the Minnesota Living with Heart Failure Questionnaire 
after 1 year and, if sufficient data are available, after 2 years will be analysed by an ANCOVA, including 
treatment as fixed effect and total score at baseline as covariate. Parameter estimates and adjusted 
mean differences will be shown together with their corresponding p-values and 95% confidence 
intervals.  
Additionally, the total score as well as the corresponding change to baseline will be analysed 
descriptively by visit, treatment group and in total. 
 
Patient global assessment (PGA) 
The self-reported patient global assessment (PGA) will be displayed by numbers and percentages by 
visit (after 1 year and, if sufficient data are available, after 2 years), treatment group and in total. A Chi-
Square test for treatment comparison will be used. 
 
PHQ-9 
The PHQ-9 total score and the changes to baseline will be analysed descriptively by visit (after 1 year 
and, if sufficient data are available, after 2 years) for each treatment group and in total. t-tests for 
comparing treatment groups will be performed. 
 
Self estimated adherence 
Self-estimated adherence will be analysed descriptively by visit (after 1 year and, if sufficient data are 
available, after 2 years), for each treatment group and in total. T-tests for comparing treatment groups 
will be performed. 
11.4.4 Secondary Safety Analyses 
The following secondary safety variables will be analysed by descriptive methods and exploratory p-
values: 
 
- 
All-cause mortality or unplanned cardiovascular hospitalizations as recurrent event (number) 
- 
Unplanned cardiovascular hospitalizations (recurrent event, number) 
- 
Unplanned hospitalizations for heart failure (recurrent event, number) 
- 
Days lost due to hospitalizations of any cause or death 
- 
Unplanned all-cause hospitalizations 
- 
All-cause mortality 
 
All primary and secondary variables are also analysed for the PP Population. These analyses are only 
considered as exploratory. 

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16 
11.4.5 Subgroup Analyses 
Several pre-specified subgroups will be explored. 
The following subgroups are planned:  
- 
Minimization-criteria: 
• Sex (male/female) 
• Age (<75, ≥75 years) 
• NYHA functional class (I and II, III and IV) 
• PHQ-9 (depression score <10, ≥10) 
• Diabetes mellitus (yes/no) 
• The study region will be omitted since this may lead to an over determination of the analysis 
model. 
- 
Time between last heart failure hospitalization and randomization (≤ 3 months vs. > 3 months 
before study) 
- 
Number of different drug substances (median at randomization), as an indicator of the level of 
illness burden 
- 
Number of different co-morbidities (median at randomization), as a further indicator of the level of 
illness burden 
- 
Heart failure medication at baseline (BB versus BB plus ACEi/ARB, BB plus ACEi/ARB versus BB 
plus ACEi/ARB/MRA) (subpopulations) 
- 
Heart rate at baseline (≤ 75 vs. > 75 min-1) 
- 
QoL score (MLHFQ Median)  
- 
HFrEF vs. HFmrEF/HFpEF (LVEF <40% vs. ≥ 40%) 
 
Each subgroup and the corresponding interaction with treatment group will be included into the analysis 
model (the PDC of each drug class will be analysed by an ANOVA, for the mean PDC ≥80% a logistic 
regression model will be used). 
11.4.6 Randomization  
Eligible patients are assigned in a 1:1 ratio to the intervention or control group. Minimization with 20% 
residual randomness is used to ensure balance of the following characteristics: Gender (male/female), 
age (<75, ≥75), NYHA functional class (I and II, III and IV), PHQ-9 (score <10, ≥10), diabetes mellitus 
(yes/no), study region (according to regional Associations of Statutory Health Insurance Physicians 
(KV-Region)). 
A web-based randomization tool developed by IZKS Mainz is used within this study allowing 
investigators to randomize patients via a secure web interface.  
Subjects withdrawn from the study retain their identification codes (i.e. patient number). New subjects 
must always be allotted a new identification code. 
11.4.7 Blinding 
PHARM-CHF is a prospective multicentre, randomized controlled study. Patients are randomized by 
the recruiting physician on an individual level. Pharmacists are unaware of the control patients. All other 
investigators, committees, and staff remain fully blinded throughout the study to the randomization 
status of the patients. 
 
 
 

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11.5 Methods to Avoid Bias 
11.5.1 Selection Bias 
See randomization. 
11.5.2 Performance Bias 
Potential bias: 
 
Physicians (unblinded) treat patients of the intervention group differently than patients of the control 
group to reach the aim of the study. 
 Difficult to avoid, the design of the study seems necessary for a realistic study setting. However, the 
interdisciplinary approach to improve medication adherence is part of the study design. In addition, the 
CHF medication in both groups will be analysed at V1 and V5. 
 
Contamination at medical practices: physicians intensively engage with the topic (i.e. heart failure, 
medication adherence and drug-related problems) and apply this additional knowledge to the control 
patients. 
 Difficult to avoid, the design seems necessary for a realistic study setting. Pharmacists are unaware 
of the control patients.  
 
Higher detection rate of potential events: Patients in the intervention group receive a more intensive 
care and have a more intensive contact with health care professionals. The intensified contact could 
lead to a higher detection rate of events. There is a risk that the recording rate of events differs between 
control and intervention group. 
 Involvement of e.g. health insurance companies to collect events recorded in the health insurance 
files.  
11.5.3 Exclusion Bias 
Potential bias: 
 
Patients of the intervention group may stop following the study protocol because they do not want to 
visit the pharmacy as frequent as required or because they do not like the weekly dosing aids.  
 Intention-to-treat-analysis 
12 Adverse Events  
Due to the fact that no investigational medical drug or device is tested, the standard of care is not 
altered during the study and hard endpoints for this study are chosen (mortality or unplanned 
hospitalization). Therefore, only hospitalizations and mortality will be documented. 
13 Ethical and Legal Aspects 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that all persons involved in the study abide by Good Clinical 
Practice (GCP) so far applicable and the ethical principles described in the current revision of the 
Declaration of Helsinki. The study is carried out according to the legal and ethical requirements (e.g. 
data protections laws). Written informed consent is obtained from all patients. 
 
 

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18 
13.1 Responsibilities of Scientific Heads 
The scientific heads ensure that all persons assisting with the study are adequately informed about the 
protocol, any amendments to the protocol, the study procedures, and their study-related duties and 
functions. They maintain a list of all qualified persons to whom they have delegated significant study-
related duties. 
13.2 Approval of Study Protocol and Amendments 
Before the start of the study, the study protocol, informed consent document, and any other appropriate 
document are submitted to the independent Ethics Committees (EC). Before the first subject is enrolled 
in the study, all ethical and legal requirements must be met. 
13.3 Ongoing Information for Independent Ethics Committee 
The EC will be informed of all subsequent protocol amendments, which might require formally approval. 
14 Committees 
Three different committees are involved in this study: 
A Steering Committee (Executive Board) is in charge of strategic advice. Furthermore, a blinded clinical 
event committee (CEC) for adjudication of hospitalizations and a Committee for Data Protection (DPC) 
have been implemented. These committees follow a specified charter, which describes the working 
procedures. 
15 Agreements 
15.1 Financing of the Study 
The study is financed by ABDA, and the pharmacists’ state chambers or foundations of Bavaria 
(Lesmueller-Foundation), North Rhine, and Westphalia-Lippe as well as the Foundation 
Pharmaceutical Care (FI). 
15.2 Reports 
ABDA prepares reports in collaboration with Leipzig University, PMV and IZKS Mainz. 
15.3 Publication 
All information concerning the study is confidential before publication. However, the study protocol will 
be accessible on the homepage developed for the study (www.pharm-chf.de) for authorized users. The 
study has been appropriately registered with Clinical Trials.gov Identifier: NCT01692119, before the 
first patient has been enrolled. 
 

 
 
16 Signatures 
The present study protocol (Version 3.0) was subject to critical review and has been approved in the 
present version by the persons undersigned. The information contained is consistent with 
- 
the current risk-benefit assessment of the study treatment(s) and 
- 
the moral, ethical, and scientific principles governing clinical research as set out in 
the Declaration of Helsinki and the principles of GCP so far applicable. 
 
 
Date: 
___________  
Signature: 
 
 
______________________________ 
 
 
 
 
Name (block letters): 
 
Prof. Dr. Ulrich Laufs  
Function: 
 
 
Scientific Head of Study 
 
Date: 
___________  
Signature: 
 
 
______________________________ 
 
 
 
 
Name (block letters): 
 
Prof. Dr. Martin Schulz 
Function: 
 
 
Scientific Head of Study 
 
Date: 
___________  
Signature: 
 
 
______________________________ 
 
 
 
 
Name (block letters): 
 
Dipl.Math. Christian Ruckes  
Function: 
 
 
Biometrician IZKS Mainz 
 
Date: 
___________  
Signature: 
 
 
______________________________ 
 
 
 
 
Name (block letters): 
 
Dr. Nina Griese-Mammen  
 
 
 
 
Function: 
 
 
Study Coordinator at ABDA 
 
Date: 
___________  
Signature: 
 
 
______________________________ 
 
 
 
 
Name (block letters): 
 
Dr. Lukas Schollenberger 
 
 
 
 
Function: 
 
 
Study Coordinator at IZKS Mainz  
 
 
 

 
 
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