Clinical trial NCT04007406
Conditions: Primary Aldosteronism
Keywords: Hyperaldosteronism
Sponsor: Damian Pharma AG
Start date: 2019-11-21; Completion date: 2022-05-02
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the present phase II study is to determine whether DP13 displays the clinical safety and efficacy profile to support further development in patients with primary aldosteronism.

Detailed description:
A phase II, multi-centre, randomized, parallel group, baseline-and withdrawal-controlled study in patients with primary aldosteronism to determine the dose-dependent efficacy, safety and tolerability of DP13 after a 2-week single-blind placebo run-in period followed by a randomized 8-week double-blind treatment period. After an additional single-blind, 2-week DP13 placebo withdrawal period, patients are switched to standard of care.

Arms: arm 1: DP13 for 8 weeks arm 2: DP13 for 8 weeks arm 3: DP13 for 8 weeks
Interventions: intervention 1: dexfadrostat phosphate
Intervention descriptions: intervention 1: DP13 systemic administration

Protocol documents:
Prot_SAP_000.pdf: 
Study Protocol: DP13C201 
Page 1 
Version 5.0 
DP13 
DP13 – A Phase II Study in Patients with Primary 
Aldosteronism to Evaluate the Efficacy, Safety and 
Tolerability of the Aldosterone Synthase Inhibitor, DP13, 
over an 8-week Treatment Period 
Version 5.0 (amended protocol) 
12 December 2020 
DP13 
Aldosterone Synthase Inhibitor 
DAMIAN Pharma AG 
Haltli 6, 6318 Walchwil 
Switzerland 
2019-000919-85 
DP13C201 
OPIS s.r.l. 
Status: 
Date:  
Study Drug: 
Drug Class: 
Sponsor:  
EudraCT Number:  
Sponsor Reference: 
CRO:  
Central Reviewers: 
Paolo Mulatero, MD, 
Hans Brunner, MD 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor 


Study Protocol: DP13C201 
Confidential 
Page 2 
Version 5.0 
 
DP13 
Confidential 
IMPORTANT: This document contains proprietary and confidential information 
belonging to DAMIAN PHARMA. Its contents may not be disclosed or used without 
the express permission of DAMIAN. 
 
 
Confidenzialità 
IMPORTANTE: Questo documento contiene informazioni confidenziali di esclusiva 
proprietà de DAMIAN PHARMA. Il suo contenuto non deve essere né divulgato né 
utilizzato senza autorizzazione di DAMIAN. 
 
 
Vertraulichkeit 
WICHTIG: Dieses Dokument enthält Informationen, die vertraulich und Eigentum der 
DAMIAN PHARMA sind. Der Inhalt darf ohne ausdrückliche Genehmigung von 
DAMIAN weder weitergegeben noch für andere Zwecke verwendet werden. 
 
 
 


Study Protocol: DP13C201 
Confidential 
Page 3 
Version 5.0 
 
DP13 
 
TABLE OF CONTENT 
 
AMENDMENT 4............................................................................................................... 9 
AMENDMENT 3............................................................................................................... 9 
AMENDMENT 2............................................................................................................. 10 
AMENDMENT 1............................................................................................................. 10 
SYNOPSIS ....................................................................................................................... 11 
1 
INTRODUCTION .................................................................................................... 14 
1.1 
DP13 - Mechanism of Action ....................................................................... 14 
1.2 
DP13 – Treatment for Primary Aldosteronism ............................................. 14 
1.3 
DP13 – Risk / Benefit Assessment ............................................................... 15 
2 
STUDY OBJECTIVES ............................................................................................. 17 
2.1 
Primary Objectives ........................................................................................ 17 
2.2 
Secondary Objectives .................................................................................... 17 
2.3 
Exploratory Objectives ................................................................................. 17 
3 
STUDY OUTCOMES .............................................................................................. 18 
3.1 
Primary Outcomes......................................................................................... 18 
3.2 
Secondary Outcomes..................................................................................... 18 
3.3 
Exploratory Outcomes .................................................................................. 18 
4 
INVESTIGATIONAL PLAN ................................................................................... 19 
4.1 
Study Design and Study Doses ..................................................................... 19 
4.2 
Interim Analysis and Additional Patients ..................................................... 22 
4.3 
Justification for Study Design ....................................................................... 22 
4.4 
Justification for Study Doses ........................................................................ 23 
4.5 
Patient Withdrawal Criteria .......................................................................... 23 
4.6 
Management of Patient Safety ...................................................................... 24 
5 
INVESTIGATIONAL MEDICINAL PRODUCTS ................................................. 25 
5.1 
Description, Identification and Storage ........................................................ 25 
5.1.1 
Labelling of IMP and Unit Jars .................................................... 25 
5.1.2 
Drug Accountability ..................................................................... 25 
5.2 
Blinding ......................................................................................................... 26 
5.3 
Unblinding .................................................................................................... 26 
5.4 
Randomization .............................................................................................. 27 
5.5 
Treatment Compliance .................................................................................. 27 
5.6 
Concomitant Medication ............................................................................... 27 
5.6.1 
Rescue Medication ....................................................................... 28 
6 
STUDY POPULATION ........................................................................................... 29 
6.1 
Identification and Numbering of Patients ..................................................... 29 


Study Protocol: DP13C201 
Confidential 
Page 4 
Version 5.0 
 
DP13 
6.2 
Determination of Sample Size ...................................................................... 29 
6.3 
Inclusion Criteria........................................................................................... 29 
6.4 
Exclusion Criteria ......................................................................................... 30 
6.5 
Central Eligibility Verification ..................................................................... 31 
6.6 
Specific Restrictions/Requirements .............................................................. 32 
6.6.1 
Patient Diary ................................................................................. 32 
6.6.2 
Diet ............................................................................................... 32 
6.6.3 
Exercise ........................................................................................ 32 
6.6.4 
Blood Donation ............................................................................ 32 
6.6.5 
Contraception ............................................................................... 32 
6.7 
Patient Withdrawals/Replacements............................................................... 33 
6.8 
Patient Re-screening and Re-enrolment ........................................................ 33 
7 
STUDY PROCEDURES .......................................................................................... 34 
7.1 
Visits ............................................................................................................. 34 
7.1.1 
Home or Workplace Visits ........................................................... 35 
7.2 
Visit Procedures ............................................................................................ 35 
7.2.1 
Spot Urine Sample ........................................................................ 35 
7.2.2 
Body Weight Recording ............................................................... 36 
7.2.3 
Adverse Event Reporting ............................................................. 36 
7.2.4 
Lead Electrocardiogram ............................................................... 36 
7.2.5 
Blood Pressure Measurements ..................................................... 36 
7.2.6 
Blood Sampling ............................................................................ 36 
7.2.7 
Treatment Compliance Verification ............................................. 37 
7.2.8 
IMP/Hypertension Control Medication Supply............................ 37 
7.3 
Home Procedures .......................................................................................... 38 
7.3.1 
IMP/Hypertension Control Medication Intake ............................. 38 
7.3.2 
24-Hour Ambulatory Blood Pressure Monitoring ........................ 38 
7.3.3 
24-Hour Urine Sampling .............................................................. 38 
7.4 
Laboratory Procedures .................................................................................. 39 
7.4.1 
Sample Processing and Shipment ................................................. 39 
7.4.2 
Local Blood Analyses................................................................... 39 
7.4.3 
Central Blood Analyses ................................................................ 40 
7.4.4 
Local Urine Analyses ................................................................... 40 
7.4.5 
Central Urine Analyses................................................................. 40 
8 
SAFETY ................................................................................................................... 41 
8.1 
Adverse Event Reporting .............................................................................. 41 
8.1.1 
Adverse Event .............................................................................. 41 
8.1.2 
Adverse Drug Reactions ............................................................... 42 
8.1.3 
Serious Adverse Events ................................................................ 42 


Study Protocol: DP13C201 
Confidential 
Page 5 
Version 5.0 
 
DP13 
8.1.4 
Serious Adverse Event Reporting ................................................ 43 
8.1.5 
Special Situations ......................................................................... 44 
8.2 
Reporting of Pregnancy ................................................................................ 44 
9 
STUDY TERMINATION ........................................................................................ 45 
10 STATISTICAL METHODS ..................................................................................... 45 
10.1 
Hypothesis Testing and Sample Size Calculation ......................................... 45 
10.1.1 
Hierarchical Test Procedure ......................................................... 45 
10.1.2 
First Primary Objective ................................................................ 45 
10.1.3 
Second Primary Objective ............................................................ 46 
10.2 
Statistical Analysis Methods ......................................................................... 47 
10.2.1 
Analysis Set .................................................................................. 47 
10.2.2 
Baseline Characteristics................................................................ 48 
10.2.3 
Primary Analysis .......................................................................... 48 
10.2.4 
Secondary Analysis ...................................................................... 48 
10.2.5 
Missing Data ................................................................................. 49 
10.3 
Interim Analysis ............................................................................................ 49 
11 QUALITY ASSURANCE AND CONTROL .......................................................... 49 
11.1 
Data Quality Assurance ................................................................................ 49 
11.2 
Case Report Form ......................................................................................... 49 
11.3 
Monitoring .................................................................................................... 50 
11.4 
Data Storage and Archiving .......................................................................... 50 
12 REPORTS AND PUBLICATIONS ......................................................................... 51 
12.1 
Reports to the EC/IRB and HAs ................................................................... 51 
12.2 
Data Analysis ................................................................................................ 51 
12.3 
Clinical Study Report .................................................................................... 51 
12.4 
Publications ................................................................................................... 51 
13 REGULATORY CONSIDERATIONS .................................................................... 52 
13.1 
Clinical Trial Authorization .......................................................................... 52 
13.2 
Visits by Regulatory Authorities................................................................... 52 
14 ETHICAL CONSIDERATIONS .............................................................................. 52 
14.1 
Ethics Committee Approval .......................................................................... 52 
14.2 
Informed Consent .......................................................................................... 52 
14.3 
Declaration of Helsinki ................................................................................. 53 
15 REGULATIONS ...................................................................................................... 53 
15.1 
Good Clinical and Manufacturing Practice ................................................... 53 
15.2 
Protocol Adherence ....................................................................................... 53 
16 FINANCES AND INDEMNITY.............................................................................. 53 
17 INSURANCE ............................................................................................................ 53 
18 REFERENCES ......................................................................................................... 54 


Study Protocol: DP13C201 
Confidential 
Page 6 
Version 5.0 
 
DP13 
19 APPENDIX ............................................................................................................... 55 
19.1 
Study Plan ..................................................................................................... 55 
 
 
 


Study Protocol: DP13C201 
Confidential 
Page 7 
Version 5.0 
 
DP13 
LIST OF ABBREVIATIONS AND DEFINITION OF TERM 
 
ABPM 
ambulatory blood pressure monitoring 
ACTH 
adrenocorticotropic hormone 
aDBP 
ambulatory diastolic blood pressure 
AE 
adverse event 
APA 
aldosterone-producing adenoma 
ARR 
aldosterone-to-renin ratio 
aSBP 
ambulatory systolic blood pressure 
BAH 
bilateral adrenal hyperplasia 
BID 
bis in die / twice daily 
BMI 
body mass index 
BW 
body weight 
CLIA 
chemiluminescent immunoassay 
Cmin 
predose (trough level) DP13 blood concentrations 
CRO 
contract research organization 
CSR 
clinical study report 
CYP 
cytochrome P450 
CYP11B2 
aldosterone synthase 
DBP 
diastolic blood pressure 
Dx 
diagnosis 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EU 
European Union 
EV 
eligibility verification 
FAS 
full analysis set 
GC-MS 
gas chromatography-mass spectrometry 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HA 
Health Authority 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
I/E 
inclusion/exclusion criteria 
IMP 
investigational medicinal product 


Study Protocol: DP13C201 
Confidential 
Page 8 
Version 5.0 
 
DP13 
IRB 
Institutional Research Board 
ISE 
ion-selective electrodes 
ITT 
intention to treat 
IUD 
intrauterine device 
LC-MS 
liquid chromatography – mass spectrometry 
LC-MS/MS 
liquid chromatography – tandem mass spectrometry 
mmHg 
millimetre mercury 
oDBP 
office diastolic blood pressure 
oSBP 
office systolic blood pressure 
PA 
primary aldosteronism 
PAC 
plasma aldosterone concentration 
PP 
per protocol 
PRA 
plasma renin activity 
PRC 
plasma renin concentration 
QD 
quaque die / once daily 
QP 
qualified person 
QTc 
QT interval corrected for heart rate 
SOP 
standard operating procedure 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SoC 
standard of care 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TMF 
trial master file 
UPT 
urine pregnancy test 
 
 


Study Protocol: DP13C201 
Confidential 
Page 9 
Version 5.0 
 
DP13 
AMENDMENT 4 
The primary purpose of this amendment is to unify the protocol with the recommendations of 
the Committee on Research Involving Human Subjects for the Arnhem-Nijmegen Region of 
the Netherlands and Swissethics of the Canton of Bern in Switzerland and will include the 
following additional changes: 
• 
Section 6.8 – Patient Re-screening and Re-enrolment – has been added to address 
the occurrence of non-controllable events such as hospital closures due to the COVID-
19 emergency or other similar extraordinary circumstances. 
• 
Section 7.2.6 – Blood Sampling – has been further specified for consistency with urine 
analysis to include DP13 metabolites. 
• 
Section 7.4.3 – Central Blood Analyses – has been further specified for consistency 
with urine analysis to include DP13 metabolites.  
Furthermore, in order to alleviate the burden on patients related to the number of site visits 
and/or to implement EMA- or other local authority-mandated actions limiting patient access to 
sites to reduce COVID-19 related risks, some of the visits may now be performed at the 
patient’s home or workplace by medically-qualified personnel. Some of the assessments 
planned for these visits have been removed or rescheduled to ease the workload of the visiting 
medical personnel. The changes are summarized as follows: 
• 
Sections 4.1, 7.1, 7.3.2, 7.3.3 and 19.1 now state that the Day -1, 14, 42 and 55 visits 
may be performed at the patient's home or workplace by medically-qualified personnel.  
• 
Sections 4.1, 5.1.1, 7.2.8, 7.3.1 and 19.1 now state that on Day 1 and Day 28, two jars 
of IMP capsules are to be dispensed to ensure supply for one month in the event of a 
home/workplace visit. 
• 
Section 7.2.6 and Section 19.1 indicate that on Days 14 and 42, blood samples are 
collected by medically-qualified personnel at the patient’s home or workplace (if 
appropriate facilities are available) and that blood sampling for central analysis is 
limited to the evaluation of aldosterone/PRC, electrolytes and steroids.   
• 
Section 7.1.1 has been added to describe home/workplace visits. 
• 
Changes to (i) any other scheduled visit or (ii) scheduled assessment or (iii) 
assignment of the visit to the patient’s home or place of work due to unanticipated 
emergent local COVID-19 restrictions must be made by the local PI and under his/her 
responsibility and will be documented as per standard procedures. 
Additionally, the choice of calcium channel blockers for the hypertension control therapy is 
expanded to include diltiazem to reduce unnecessary within-class drug switching. 
• 
Synopsis and Sections 4.1, 4.3, 4.6, 5.5, 5.6, 6.3, 6.4, 7.2.6, and 19.1 now include the 
use of diltiazem (slow-release 90 - 360 mg daily) 
Finally, in order to allow BMI eligible patients with a greater height to participate in the study, 
the weight criterion has been expanded from 100 kg to 110 kg in Section 6.3 Inclusion Criteria. 
AMENDMENT 3 
The purpose of this amendment is to align the protocol with the recommendations of the 
Committee on Research Involving Human Subjects for the Arnhem-Nijmegen Region of the 
Netherlands. The main changes to the protocol are as follows: 
• 
Section 5.6 – Concomitant Medication – has been extended. 


Study Protocol: DP13C201 
Confidential 
Page 10 
Version 5.0 
 
DP13 
• 
Section 6.4 – Exclusion Criteria – has been further specified. 
AMENDMENT 2 
The purpose of this amendment is to correct the wording in Section 4.5 – Patient withdrawal 
criteria. The section now states that in case of withdrawal of consent, all personal data and 
biological samples will continue to be used in a coded form (and not anonymous form); no 
further data or samples will be collected. The same wording change has been applied to 
Section 11.4. 
AMENDMENT 1 
The purpose of this amendment is to align the protocol with the recommendations of the Ethics 
Commission of the Canton of Bern Switzerland. The main changes to the protocol and 
corresponding sections of the synopsis are as follows: 
• 
Section 3.2 – Secondary outcomes – has been corrected. 
• 
Section 4.3 – Justification of study design – has been updated with additional 
information. 
• 
Section 4.5 – Patient withdrawal criteria – now specifies that in case of withdrawal of 
consent, all personal data and biological samples will continue to be anonymized and 
that no further data or samples will be collected. 
• 
Section 6.2 – Determination of sample size – has been revised providing additional 
information. 
• 
Sexual abstinence as a means of contraception has been eliminated (see Section 6.4 
and Section 6.6.5). 
• 
Section 8.1.4.1 has been added describing the requirements for serious adverse event 
reporting at Swiss Centres. 
• 
Section 10.1.2 – First primary objective – has been modified to correct the effect size 
calculation for the first primary variable.  
• 
Section 11.1 – Data quality assurance – now specifies the database compliant with the 
Human Research Act. 
• 
Section 11.4 – Data storage and archiving – has been revised to clarify that biological 
samples may be retained exclusively for analyses stated in the protocol and until 
completion of the clinical study report, after which all samples will be destroyed. 
• 
Section 14.2 – Informed consent filing procedures have been corrected for clarity. 
Changes to the protocol are shown in the track changes version using strike through font for 
deletions and underlined font for insertions. 
 
 


Study Protocol: DP13C201 
Confidential 
Page 11 
Version 5.0 
 
DP13 
SYNOPSIS 
 
Title of Study: 
DP13 – A Phase II Study in Patients with Primary Aldosteronism 
to Evaluate the Efficacy, Safety and Tolerability of the 
Aldosterone Synthase Inhibitor DP13 over an 8-week Treatment 
Period 
Objectives: 
Primary Objectives 
• 
To determine the efficacy of daily oral DP13 treatment to 
decrease the plasma aldosterone-to-renin ratio (ARR) 
from baseline in patients with primary aldosteronism 
(PA) 
• 
To determine the efficacy of daily oral DP13 treatment to 
reduce 24-hour ambulatory systolic blood pressure 
(aSBP) from baseline in patients with PA 
Secondary Objectives 
• 
To determine the safety and tolerability of DP13 
treatment in patients with PA 
• 
To determine the efficacy of daily oral DP13 (all dose 
arms combined) to reduce office systolic blood pressure 
(oSBP) from baseline in patients with PA 
• 
To determine the efficacy to decrease the plasma ARR 
from baseline in each individual dose arm 
• 
To determine the efficacy of daily oral DP13 to reduce 
oSPB and 24-hour aSBP from baseline in each individual 
dose arm 
• 
To determine the DP13 dose-dependent efficacy to 
decrease the plasma ARR from baseline in patients with 
PA 
• 
To determine the DP13 dose-dependent efficacy to 
reduce oSBP and 24-hour aSBP from baseline in 
patients with PA 
Exploratory Objectives: 
• 
To determine the recovery of the plasma ARR after 
discontinuation of DP13 treatment in patients with PA 
• 
To determine the recovery of oSBP after discontinuation 
of DP13 treatment in patients with PA 
• 
To determine the DP13 dose-dependent treatment 
effects on mean diurnal (day and night) ambulatory 
systolic and diastolic blood pressure (aSBP/aDBP) in 
patients with PA 
• 
To determine the DP13 dose-dependent efficacy to 
decrease urinary aldosterone excretion from baseline in 
patients with PA 
• 
To determine the dose-dependent efficacy of daily oral 
DP13 treatments to raise blood potassium levels from 
baseline in patients with PA 


Study Protocol: DP13C201 
Confidential 
Page 12 
Version 5.0 
 
DP13 
• 
To determine the steady-state pharmacokinetics of once 
daily DP13 administration in patients with PA 
Methodology / 
Study Design: 
A phase II, multi-centre, randomized, parallel group, baseline-
and withdrawal-controlled study in 36 patients with PA to 
determine the dose-dependent efficacy, safety and tolerability of 
once daily oral DP13 after a 2-week single-blind placebo run-in 
period followed by a randomized 8-week double-blind treatment 
period. After an additional single-blind, 2-week DP13 placebo 
withdrawal period, patients are switched to standard of care. 
Guideline-diagnosed patients with PA on fixed dose background 
hypertension control therapy are enrolled upon central eligibility 
verification. Baseline characteristics are determined by 24-hour 
ambulatory blood pressure monitoring and urine sampling 
starting on Day -1, by office blood pressure measurement and 
blood sample collections for central ARR and electrolyte 
determinations on Day 1. Patients are subsequently randomized 
into three parallel DP13 active treatment groups of 12 patients 
each and followed through biweekly visits. The end of treatment 
characteristics is determined by 24-hour ambulatory blood 
pressure monitoring and urine sampling starting on Day 55 and 
by office blood pressure measurement and blood sample 
collections for central ARR and electrolyte determinations on 
Day 56. Persistence of treatment effect and return of effects to 
baseline characteristics are determined on Day 70. The Day -1, 
14, 42 and 55 visits may be performed at the patient's home or 
workplace (if appropriate facilities are available) by medically-
qualified personnel. 
Number of Patients: 
36 patients with PA are randomized into three treatment groups 
of 12 patients each.  
Diagnosis and Main 
Criteria for Inclusion: 
Patients with a recent (<1 year) diagnosis of PA irrespective of 
any subtype determination (aldosterone-producing adenoma or 
bilateral adrenal hyperplasia). The diagnosis includes case 
detection and confirmation following the Endocrine Society 
Clinical Practice Guidelines 2016 and locally approved 
protocols.  
Specifically, patients are female or male and 18 to 65 years of 
age with: 
• 
ARR of ≥40 with plasma aldosterone concentration 
(PAC) ≥15 ng/dL and plasma renin activity (PRA) <1.0 
ng/mL/h. A pre-screening ARR of ≥3.7 results by using 
plasma renin concentration (PRC) <15 mU/L instead of 
PRA as denominator. 
• 
A IV saline loading test (2 litres of 0.9% saline infused 
over 4 hours) with resulting PAC >7.0 ng/dL after 
infusion. For patients at risk for volume expansion, a 
captopril test (50 mg captopril peroral) can be used 
instead with resulting ARR >30 and PAC >11 ng/dL 
(respectively ARR >2.4 using PRC in mU/L instead of 
PRA as denominator).  


Study Protocol: DP13C201 
Confidential 
Page 13 
Version 5.0 
 
DP13 
• 
Systolic blood pressure >145 mmHg by automatic office 
blood pressure measurement and in presence of 
hypertension control therapy (doxazosin 1 - 8 mg QD 
and, only if necessary, verapamil slow release 40 - 120 
mg BID or diltiazem slow-release 90 - 360 mg daily or 
amlodipine 2.5 - 10 mg QD). 
• 
Estimated glomerular filtration rate (eGFR) ≥45 
mL/min/1.73 m2 using the MDRD-4 GFR equation 
Formal eligibility verification after implementation of a dose-
adjusted blood pressure control therapy with a documented 
case review process led by the Central Review Board is 
mandatory prior to final enrolment. 
Test Product, Dose and 
Mode of Administration: 
Formulated white opaque capsules (VCaps® Plus) size I 
containing:  
• 
 0 mg DP13 (placebo)  
• 
 4 mg DP13  
• 
 8 mg DP13   
• 
12 mg DP13 
One capsule is taken per day (QD) orally in the morning 
between 06:30 and 08:30 before breakfast. 
Duration of Treatment: 
Patients start the study with a 2-week placebo run-in period that 
is followed by a 8-week DP13 treatment period and complete 
the study with a 2-week placebo withdrawal period. 
Date and version 
12 December 2020, v.5.0 
 
 
 
 
 


Study Protocol: DP13C201 
Confidential 
Page 14 
Version 5.0 
 
DP13 
1 
INTRODUCTION  
1.1 
DP13 - Mechanism of Action 
 
DP13 represents a first-in-class orally available, small molecular weight aldosterone synthase 
inhibitor compound. Aldosterone synthase or CYP11B2 is the rate-limiting enzyme for 
aldosterone synthesis in the adrenal glands. The enzyme mediates the conversion of 11-
deoxycorticosterone to aldosterone in the zona glomerulosa of the adrenal cortex. DP13, by 
inhibiting the enzymatic conversion, causes an increase in the substrate 11-
deoxycorticosterone and concomitant decrease in the product aldosterone. Steroid-binding 
proteins in plasma neutralize changes in 11-deoxycorticosterone levels in contrast to 
aldosterone, which is only weakly protein bound.  
The principal regulators of adrenal aldosterone biosynthesis are the renin-angiotensin system, 
extracellular potassium and adrenocorticotropic hormone (ACTH). Renin is synthesized and 
released by the juxtaglomerular cells in the afferent arteriole of the kidney in response to 
reduced intravascular volume and sodium concentration of the macula densa. Renin catalyses 
the hydrolysis of liver-produced angiotensinogen to angiotensin I, which is converted in the 
vascular endothelium to biologically active angiotensin II. Angiotensin II raises blood pressure 
by direct vasoconstriction, increased sympathetic nerve activity and by stimulating adrenal 
aldosterone production and enhancing renal salt and water retention. Acutely, angiotensin II 
stimulates aldosterone biosynthesis whereas chronically, it leads to zona glomerulosa 
hypertrophy and hyperplasia with increased CYP11B2 expression. The resulting increased 
aldosterone secretion promotes sodium and water retention, which in turn suppress renin 
release. Potassium regulates aldosterone production sensitively and acutely. Potassium 
stimulates CYP11B2 expression and aldosterone secretion synergistically with angiotensin II 
via membrane depolarization and calcium-mediated activation of gene transcription. 
Increased aldosterone secretion regulates potassium homeostasis by stimulating sodium 
reabsorption in the distal tubules and collecting duct of the kidneys in exchange for potassium. 
ACTH is the principal effector peptide of the hypothalamic / pituitary adrenal axis and is 
primarily involved in the regulation of glucocorticoids. However, it controls the diurnal rhythm 
of aldosterone production (Connell et al., Endocrine Rev 2008). 
In an extensive clinical phase I study (DP13C101) in healthy volunteers, DP13 demonstrated 
upon once daily dosing not only good safety and tolerability but also dose-dependent 
suppression of aldosterone production over time (DP13 – Investigator Brochure 2019). 
Pharmacological suppression of aldosterone triggered the expected physiological responses. 
Increased urinary sodium excretion was reflected in lower plasma sodium concentrations 
whereas concomitant reabsorption of potassium led to slightly higher plasma potassium 
concentrations. In addition, reduced plasma aldosterone concentrations (PAC) and inherent 
sodium loss were reflected in increased plasma renin activity (PRA). Therefore, in order to 
mediate sustained aldosterone suppression over time, DP13 had to overcome reactively 
increased angiotensin II and potassium levels, the physiological stimuli for aldosterone 
production. Plasma cortisol and ACTH levels were unaffected, as was the diurnal rhythm of 
adrenal steroid production. 
 
1.2 
DP13 – Treatment for Primary Aldosteronism  
Dysregulation of the mechanisms regulating aldosterone biosynthesis results in primary 
aldosteronism (PA); a disorder characterized by elevated plasma aldosterone concentrations 
(PAC) and low plasma renin activity (PRA) levels, hypertension, often hypokalaemia and 
vascular fibrosis. The two major causes of PA are unilateral aldosterone producing adenoma 
(APA) and bilateral adrenal hyperplasia (BAH), accounting for approximately 95% of all PA 


Study Protocol: DP13C201 
Confidential 
Page 15 
Version 5.0 
 
DP13 
cases. In both forms, aldosterone production is autonomous and not or hardly suppressible 
by physiologic stimuli. Potassium channel defects have been identified in APA leading to 
sustained calcium signalling and aldosterone production independent of angiotensin II or 
potassium regulation. Occurrence of aldosterone-producing cell clusters or micronodules and 
genetic defects are proposed to sustain CYP11B2 activity in bilateral adrenal hyperplasia.  
The Endocrine Society clinical practice guidelines for diagnosis of PA recommend the 
determination of the aldosterone-to-renin ratio (ARR) as the most reliable test because the 
ratio is less affected by diurnal and postural variations (Funder et al., J Clin Endocrinol Metab 
2016). The variability of the ARR as an initial detection system is reduced practically if 
guideline recommendations for patient preparation are followed and technically if common 
units for PAC (ng/dL) and PRA (ng/mL per h) and assay systems (specified immunoassay) 
are used. The ARR is hence very sensitive but not very specific for the diagnosis of PA without 
the subsequent demonstration of at least partly autonomous, i.e. angiotensin II-independent 
aldosterone production. Angiotensin II can be removed with the intravenous saline loading test 
that leads to volume expansion and renin suppression or with the captopril challenge test to 
inhibit acutely angiotensin-converting enzyme. Likewise, the variability of the confirmatory 
aldosterone suppression test is reduced with standardized preparatory and technical 
procedures. 
Autonomous aldosterone production, independent of renin activity, characterizes patients with 
PA and their higher risk for cardiovascular morbidity and mortality compared to patients with 
essential hypertension. Mineralocorticoid receptor (MR) antagonists are the recommended 
medical therapy for patients with PA. A retrospective cohort study analysed whether MR 
antagonist treatment effectively reduces events (stroke, heart failure, myocardial infarction) 
for patients with PA (Hundemer et al., Lancet Diabetes Endocrinol 2017). The incidence of 
cardiovascular events and mortality were higher in patients with PA treated with MR 
antagonists compared to age- and blood pressure-matched essential hypertensives. 
However, the excess risk was limited to patients whose PRA remained suppressed (<1 ng/mL 
per h). Patients who tolerated higher MR antagonist doses had unsuppressed PRA (>1 ng/mL 
per h) and no significant excess risk for events. The authors advocated that PA patients be 
medically adjusted not only to blood pressure control but also to raised renin levels. 
Once daily intake of DP13 capsules by healthy volunteers led to a dose-dependent decrease 
of PAC and concomitant increase of PRA, hence a reduction in the ARR compared to placebo 
treatment. In addition, DP13 selectively suppressed aldosterone production without affecting 
cortisol secretion upon ACTH-stimulation. Placebo-treated volunteers responded hereby with 
PAC levels that are typically seen in patients with PA (DP13 – Investigator Brochure 2019). 
Therefore, once daily administration of DP13 capsules to patients with PA is expected to lower 
the plasma ARR by both decreasing PAC and increasing PRA. In response, the lowering of 
the ARR is expected to translate into a lower ambulatory systolic blood pressure within an 8-
week treatment period.  
 
1.3 
DP13 – Risk / Benefit Assessment  
The anticipated risk/benefits of treating PA patients with DP13 are predominantly derived from 
its DP13C101 phase I study but also from the extensive clinical database of the DP13 parent 
compound assembled from various studies in female and male patients (DP13 – Investigator 
Brochure 2019). DP13C101 (EudraCT 2016-003648-36; clinicaltrials.gov NCT03046589) was 
a single centre, 2-part, randomized, double blind, placebo controlled, single and multiple 
ascending oral dose study in healthy male volunteers. Part A was an alternating-group, 3-
period study with 16 subjects and part B was a sequential group study with 32 subjects 
investigating 
the 
safety, 
tolerability, 
pharmacokinetics, 
renal 
metabolism 
and 


Study Protocol: DP13C201 
Confidential 
Page 16 
Version 5.0 
 
DP13 
pharmacodynamics of once daily DP13 doses of 4 mg, 8 mg and 16 mg administered over 8 
days. Dose-dependent linear drug exposure over 24 hours in blood led to selective 
pharmacological inhibition of aldosterone synthase in the adrenal glands as demonstrated by 
suppressed aldosterone levels, increased renin activity, increased potassium and decreased 
sodium levels.  
Therefore, the anticipated benefits of treating PA patients with DP13 may include: 
• 
Targeted suppression of uncontrolled and excessive aldosterone secretion at the rate-
limiting step in the adrenal glands addressing the principal etiologic basis of the 
disease 
• 
Correction of aldosterone-mediated hemodynamic changes leading to hypertension, 
volume retention, hypokalaemia and suppressed renin 
• 
Higher target selectivity and therefore better tolerability and improved compliance over 
the standard of care medical therapy, spironolactone 
• 
Suitable for mild to moderately renal impaired patients due to limited renal elimination 
of compound and metabolites   
• 
Dose-dependent linear pharmacokinetic and pharmacodynamic properties without 
indication for drug accumulation or drug tolerance over time 
• 
Convenient once daily oral administration of neutral tasting capsules without known 
susceptibility for metabolic drug-drug interactions    
Mean serum potassium levels increased in a dose-dependent manner to the final timepoint 
on day 8, 24 hours postdose, with mean changes from baseline of -0.11 mmol/L for placebo, 
+0.22 mmol/L for 4 mg DP13, +0.46 mmol/L for 8 mg DP13 and +0.78 mmol/L for 16 mg DP13.  
The multiple dosing part with 32 enrolled subjects recorded 13 treatment-emergent adverse 
events (TEAEs) in 10 subjects considered either possibly related or related to DP13. Two 
TEAEs (headache and pollakiuria) were reported following placebo treatment, 5 TEAEs (2 
events of dizziness, 2 of headache, 1 of abnormal gastrointestinal sound) were reported 
following 4 mg DP13 QD, 3 TEAEs (headache, change of bowel habit and diarrhoea) were 
reported following 8 mg DP13 QD and 3 TEAEs (headache, dizziness and postural dizziness) 
were reported following 16 mg DP13 QD. No trends in vital signs and 12-lead ECG parameters 
were noted over time. 
Therefore, the potential risks for PA patients on DP13 treatment may include: 
• 
Development of hyperkalaemia 
• 
Incidence of headaches, dizziness, orthostasis, hypotension 
• 
Abdominal discomforts 
Overall, the clinical phase I profile of DP13 supported by the safety history of the previously 
developed racemic parent compound suggests that the anticipated therapeutic benefits 
provided by DP13 outweigh the potential safety risks. 
 
 
 


Study Protocol: DP13C201 
Confidential 
Page 17 
Version 5.0 
 
DP13 
2 
STUDY OBJECTIVES  
2.1 
Primary Objectives 
• 
To determine the efficacy of daily oral DP13 treatment (all dose arms combined) to 
decrease the plasma aldosterone-to-renin ratio (ARR) from baseline in patients with 
primary aldosteronism (PA) 
• 
To determine the efficacy of daily oral DP13 treatment (all dose arms combined) to 
reduce 24-hour ambulatory systolic blood pressure (aSBP) from baseline in patients 
with PA 
 
2.2 
Secondary Objectives 
• 
To determine the safety and tolerability of DP13 treatment in patients with PA 
• 
To determine the efficacy of daily oral DP13 treatment (all dose arms combined) to 
reduce office systolic blood pressure (oSBP) from baseline in patients with PA 
• 
To determine the efficacy of daily oral DP13 treatment to decrease the plasma ARR 
from baseline in each individual dose arm 
• 
To determine the efficacy of daily oral DP13 treatment to reduce 24-hour aSBP from 
baseline in each individual dose arm 
• 
To determine the efficacy of daily oral DP13 treatment to reduce oSBP from baseline 
in each individual dose arm 
• 
To determine the dose-dependent efficacy of daily oral DP13 treatment to decrease 
the ARR from baseline in patients with PA 
• 
To determine the dose-dependent efficacy of daily oral DP13 treatment to reduce 24-
hour aSBP from baseline in patients with PA 
• 
To determine the dose-dependent efficacy of daily oral DP13 treatment to reduce 
oSBP from baseline in patients with PA 
 
2.3 
Exploratory Objectives 
• 
To determine the recovery of the plasma ARR after discontinuation of daily DP13 
treatment in patients with PA in all dosage arms combined and in each individual 
dosage arm 
• 
To determine the recovery of the oSBP after discontinuation of daily oral DP13 
treatment in patients with PA in all dosage arms combined and in each individual 
dosage arm 
• 
To determine the dose-dependent effects of daily oral DP13 treatment on mean diurnal 
(day and night) ambulatory systolic and diastolic ambulatory blood pressure 
(aSBP/aDBP) in patients with PA 
• 
To determine the dose-dependent efficacy of daily oral DP13 treatment to decrease 
urinary aldosterone excretion from baseline values in patients with PA 
• 
To determine the dose-dependent efficacy of daily oral DP13 treatment to raise blood 
potassium values from baseline in patients with PA 


Study Protocol: DP13C201 
Confidential 
Page 18 
Version 5.0 
 
DP13 
• 
To determine the steady-state pharmacokinetics of daily oral DP13 treatment in 
patients with PA 
 
3 
STUDY OUTCOMES 
3.1 
Primary Outcomes 
Change in the plasma ARR from baseline (Day 1) to the end of the 8-week daily oral DP13 
treatment period (Day 56) for all dose arms combined 
Change in mean 24-hour aSBP from baseline (Day 1) to the end of the 8-week daily oral DP13 
treatment period (Day 56) for all dose arms combined  
 
3.2 
Secondary Outcomes 
Occurrence of treatment-emergent adverse events (TEAE) and serious adverse events (SAE) 
over the entire study duration  
Change in oSBP from baseline (Day 1) to the end of the 8-week daily oral DP13 treatment 
period (Day 56) for all dose arms combined 
Change in the plasma ARR from baseline (Day 1) to biweekly visits (week 2, week 4, week 6) 
and to the end of the 8-week daily oral DP13 treatment period (Day 56) in each individual dose 
arm 
Change in 24-hour aSBP from baseline (Day 1) to the end of the 8-week daily oral DP13 
treatment period (Day 56) in each individual dose arm 
Change in oSBP from baseline (Day 1) to biweekly visits (week 2, week 4, week 6) and to the 
end of the 8-week daily oral DP13 treatment period (Day 56) in each individual dose arm 
 
3.3 
Exploratory Outcomes 
Change in the plasma ARR from end of daily oral DP13 treatment (Day 56) to end of the 2-
week withdrawal period (Day 70) in all dose arms combined and in each individual dose arm 
Change in oSBP from end of daily oral DP13 treatment (Day 56) to end of the 2-week 
withdrawal period (Day 70) in all dose arms combined and in each individual dose arm 
Change in mean diurnal (day and night) aSBP/aDBP from baseline (Day 1) to end of the 8-
week daily oral DP13 treatment period (Day 56) in all dose arms combined and in each 
individual dose arm 
Change in 24-hour urinary tetrahydroaldosterone excretion from baseline (Day 1) to end of 
the 8-week daily oral DP13 treatment period (Day 56) in all dose arms combined and in each 
individual dose arm 
Change in plasma potassium concentrations from baseline (Day 1) to biweekly visits (week 2, 
week 4, week 6) to the end of the 8-week daily oral DP13 treatment period (Day 56) and the 
end of the 2-week withdrawal period (Day 70) in all dose arms combined and in each individual 
dose arm 


Study Protocol: DP13C201 
Confidential 
Page 19 
Version 5.0 
 
DP13 
Change in predose plasma DP13 concentrations (Cmin) during biweekly visits (week 2, week 
4, week 6) to the end of the 8-week daily oral DP13 treatment period (Day 56) in each 
individual dose arm 
 
4 
INVESTIGATIONAL PLAN 
DP13C201 is a multi-centre, randomised, double-blind, baseline- and withdrawal-controlled 
study with single-blind placebo run-in and withdrawal periods. The start of the study is defined 
as the date the study-specific informed consent form (ICF) is signed by the first eligible study 
participant. The end of the study is defined as the date the last patient completes the study 
procedures including any follow-up visits, i.e. last patient last visit. 
 
4.1 
Study Design and Study Doses 
Study Design 
DP13C201 is a dose range-finding study with three parallel groups of 12 patients each treated 
with DP13. The treatment effects are baseline- and withdrawal-controlled at the study start 
and study end, respectively. 
 
Recruitment Strategies 
Patients with PA may enrol in the DP13C201 study as either de novo diagnosed patients not 
yet on disease specific treatment or recently diagnosed patients on standard of care (SoC) 
treatment for PA. Diagnosis in presence of hypertension control therapy and treatment 
recommendations for patients with PA are outlined in the Endocrine Society clinical practice 
guidelines (Funder et al., J Clin Endocrinol Metab 2016). The medications for hypertension 
control therapy are protocol-specified and selected from the guidelines. Doxazosin is used as 
first-line medication and verapamil or diltiazem or amlodipine as second-line medications. The 
medications are prescribed at the Investigator’s discretion (exceptionally, a calcium channel 
blocker can be used first-line if medically justified). 
De novo and per guideline diagnosed (Dx) PA patients who meet the inclusion/exclusion (I/E) 
criteria in the presence of protocol-specified hypertension control medications may sign an 
informed consent form (ICF) to maintain control therapy at fixed doses. Patient characteristics 
are entered into the eCRF system and undergo eligibility verification (EV) by the Central 
Review Board. The pre-screening diagnostic data collected as per local guideline can be used 
to address the I/E criteria if available as source document and performed within 10 weeks 
before study enrolment and include the local guideline-recommended plasma ARR and 
suppression test (ST), blood pressure (BP) and potassium concentrations K as well as a 
safety ECG recording.  
 


St u d y Pr ot o c ol: D P 1 3 C 2 0 1
C o nfi d e nti al
P a g e 2 0
V er si o n 5. 0
D P 1 3
D x, di a g n o si s; A R R, al d o st er o n e -t o-r e ni n r ati o; S T, s u p pr e s si o n t e st;  B P, bl o o d pr e s s ur e; K , bl o o d p ot a s si u m 
c o n c e ntr ati o n;  E C G,  el e ctr o c ar di o gr a m;  I/ E, i n cl u si o n/ e x cl u si o n;  I C F,  i nf or m e d  c o n s e nt  f or m;  E V,  eli gi bilit y 
v erifi c ati o n; S o C, st a n d ar d of c ar e ; * m e di c ati o n s ar e d o x a z o si n, v er a p a mil, dilti a z e m or a ml o di pi n e
P ati e nt s wit h a r e c e nt di a g n o si s of P A n e e d t o w a s h o ut t h eir S o C or ot h er di a g n o si s i nt er f eri n g 
m e di c ati o n s  f oll o wi n g  i nf or m e d  c o n s e nt  t o  d et er mi n e  t h e  a p pli c a bilit y  of  t h e  I/ E  crit eri a i n 
pr e s e n c e of pr ot o c ol- s p e cifi e d h y p ert e n si o n c o ntr ol m e di c ati o n s . T h e w a s h o ut p eri o d m a y l a st 
u p  t o 8  w e e k s,  a s  i n t h e  c a s e  of  p ati e nt s  b ei n g tr e at e d  wit h  s pir o n ol a ct o n e. T h e  s cr e e ni n g 
di a g n o sti c pr o c e d ur e s n e c e s s ar y t o a d dr e s s t h e a p pli c a bilit y of t h e I/ E crit eri a ar e p erf or m e d 
wit hi n 1 0 w e e k s b ef or e st u d y e nr ol m e nt a n d  i n cl u d e t h e pl a s m a A R R, bl o o d pr e s s ur e ( B P) 
a n d p ot a s si u m c o n c e ntr ati o n s K a s w e ll a s a s af et y E C G r e c or di n g ( a r e p e at of t h e ori gi n al 
di a g n o sti c s u p pr e s si o n t e st i s n ot n e c e s s ar y if a v ail a bl e a s s o ur c e d o c u m e nt a n d p erf or m e d 
wit hi n 1 y e ar of st u d y e nr ol m e nt u nl e s s t h e ori gi n al di a g n o si s di d n ot i n cl u d e a s u p pr e s si o n 
t e st). Eli gi bl e p ati e nt s m ai nt ai n t h e c o ntr ol t h er a p y at fi x e d d o s e s a n d h a v e t h eir c h ar a ct eri sti c s 
e nt er e d i nt o t h e e C R F s y st e m f or c e ntr al E V. 
D P 1 3 C 2 0 1
E V
S o C
I C F
d e n o v o
P ati e nt
D x
I/ E
Pr e s cr e e ni n g
A R R
S T
B P
[K ]
E C G
H y p ert e n si o n c o ntr ol 
t h er a p y f or di a g n o si s*
M ai nt ai n c o ntr ol t h er a p y at fi x e d d o s e s 
u ntil e n d of st u d y
P er G ui d eli n e
I n pr e s e n c e of st a bl e 
c o ntr ol t h er a p y
P A
P ati e nt
I C F
I/ E
( D x)
S cr e e ni n g
A R R
B P
[K ]
E C G
D P 1 3 C 2 0 1
E V
S o C
M ai nt ai n c o ntr ol t h er a p y at fi x e d d o s e s 
u ntil e n d of st u d y
W a s h o ut & s wit c h t o st a bl e 
h y p ert e n si o n c o ntr ol t h er a p y*


Study Protocol: DP13C201
Confidential
Page 21
Version 5.0
DP13
The formal eCRF-based eligibility case review process led by the Central Review Board
verifies the patient’s fulfilment of pre-screening/screening I/E criteria for study consistency.
Importantly, the systolic blood pressure inclusion criterion is validated in the context of a
recommended 2-week stable hypertension control therapy. Upon central approval the patient 
enrols into the study.
Study Duration and Visits
Patients start the study with a single-blind placebo run-in period of 2 weeks to stabilize their 
baseline characteristics. On the last run-in day, Day -1, blood pressure is measured by a 24-
hour ambulatory blood pressure monitoring (ABPM) device to define baseline values. A 24-
hour urine sample is collected in parallel to the ABPM recording.
On the Day 1 office visit and after recording of all baseline characteristics, patients are 
randomized into three parallel groups and treated for 8 weeks with DP13. During the double-
blind DP13 treatment period, patients are consulted on week 2, week 4 and week 6 visits. At 
the end of the 8-week DP13 treatment period, blood pressure is re-measured by a 24-hour 
ABPM device starting on Day 55. A 24-hour urine sample is collected in parallel to the ABPM 
recording. 
After a single-blind, placebo withdrawal period of 2 weeks, patients return for an end of study 
(EoS) visit on Day 70 to assess the persistence of treatment effect and recovery to baseline 
values. Subsequently, patients are switched to standard of care.
The Day -1, 14, 42 and 55 visits may be performed at the patient's home or workplace (if
appropriate facilities are available) by medically-qualified personnel.
*The Day -1, 14, 42 and 55 visits may be performed at the patient's home or workplace (if appropriate facilities are available) 
by medically-qualified personnel.
Day
-14
Day
28
Day
55/56
Day
42
Day
-1/1
Day
70
Day
14
Office*
Office
Office
DP13 – 4 mg QD  (N=12)
Placebo
Placebo
Office*
DP13 – 8 mg QD  (N=12)
DP13 – 12 mg QD  (N=12)
Office
24h ABPM 
24h Urine*
24h ABPM 
24h Urine*
> office blood pressure / sampling / safety laboratory / AE / compliance monitoring <        
single-blind
run-in period
- 2 weeks -
double-blind
treatment period
- 8 weeks -
single-blind
withdrawal period
- 2 weeks -
Enrolment
∨
EoS
∨
Fixed Dose Hypertension Control Therapy
Randomization
∨


Study Protocol: DP13C201 
Confidential 
Page 22 
Version 5.0 
 
DP13 
Dose Regimen 
Upon enrolment in the study, patients will receive an anonymised jar with 14(+4) placebo 
capsules to complete the run-in period. The capsules are taken daily (QD) with a glass of 
water on an empty stomach (prior to breakfast) in the morning between 06:30 and 08:30. Upon 
randomization, patients receive at each office visit an anonymised jar (or, in the case of a 
home/workplace visit, patients receive 2 jars in order to ensure supply for 1 month) with 14(+4) 
DP13 capsules of the same strength to be taken daily (QD) in the morning with a glass of 
water on an empty stomach (prior to breakfast) to complete the active treatment period. The 
DP13 capsule strength for the respective three study arms is 4 mg, 8 mg and 12 mg. During 
the treatment period patient and Investigator are blinded to actual capsule strength. On the 
last treatment day, Day 56, patients will receive an anonymised jar with 14(+4) placebo 
capsules to complete the 2-week withdrawal period. Throughout the entire study, patients are 
blinded to jar content (placebo versus DP13 capsules). 
 
Safety and Safety Review 
Patients will maintain their hypertension control therapy throughout the study until the end of 
study visit. An internal safety review group consisting of a Sponsor representative, the 
Investigator of the Inselspital in Bern and the Central Review Board will receive blinded data 
for safety (safety laboratory, treatment-emergent adverse event recordings, blood pressure 
values) after each visit to determine any study adaptations. 
 
4.2 
Interim Analysis and Additional Patients 
Following a blinded interim analysis for sample size adjustment after 24 patients have 
completed the protocol to verify the statistical standard deviations of baseline and change from 
baseline values, additional patients may be added to the study after a protocol amendment. 
Up to 6 patients per dose group or up to 18 patients for the three dose groups combined may 
be added. The recommendation for additional patients will be agreed with the Sponsor and 
Investigators, documented in the Trial Master File (TMF) and the respective ethics committee 
(EC) will be notified of the changes. 
 
4.3 
Justification for Study Design 
The design of the DP13C201 phase II study in recently diagnosed patients with PA intends to 
compare DP13 efficacy and safety in parallel arms over an 8-week treatment period. The 
dose-range finding for a future phase III study is provided by comparing absolute efficacy to 
baseline and after treatment discontinuation, as well as relative efficacy between study arms 
at the end of the 8-week treatment period. 
Efficacy and safety will be evaluated in the presence of a blood pressure control therapy to 
protect patients. Control therapy with the drugs doxazosin and amlodipine or diltiazem or 
verapamil must therefore be administered compliantly and at fixed doses over the entire study 
period in order to provide solid conclusions. Because stable blood pressure adjustment may 
take several weeks, it is recommended that the control therapy be dose-fixed 2 weeks prior to 
enrollment. Stabilization of hypertension control therapy followed by a placebo run-in period 
of 2 weeks allows standardization of patient disposition for biochemical and hemodynamic 
baseline assessment prior to randomization. Patients are randomized into three active but 
dose-blinded treatment arms in order to offer all patients disease control with DP13 over the 
8-week treatment period. The opportunity for active treatment will also increase patient interest 


Study Protocol: DP13C201 
Confidential 
Page 23 
Version 5.0 
 
DP13 
to enrol in the study and assure patient compliance during the study. Based on reported 
interventional studies with aldosterone-targeted therapies in patients with PA or essential 
hypertension, an 8-week treatment period is considered a minimal but adequate duration for 
blood pressure to adapt to ARR suppression in a majority of patients (Amar et al., 
Hypertension 2010; Parthasarathy et al., J Hypertens 2011; Calhoun et al., Circulation 2011). 
This timeline is also substantiated by observed blood pressure changes after adrenalectomies 
(Williams et al., Lancet Diabetes Endocrinol 2017). For the same reason, a biweekly or 
monthly dose-titration regimen as used previously in open-label interventional studies is 
considered not informative. Biweekly visits assure safety, compliance and blood pressure 
control during the 8-week treatment period as well as the 2-week run-in and treatment 
withdrawal periods. A DP13 withdrawal period of 2 weeks after eight weeks of treatment 
provides an opportunity to assess the persistence and reversibility of the treatment effect and 
to ensure the safety of investigational drug discontinuation. 
 
4.4 
Justification for Study Doses 
The DP13C101 phase I study in healthy volunteers (EudraCT N° 2016-003648-36) 
demonstrated compelling safety and tolerability, as well as a clear pharmacokinetic and 
pharmacodynamic efficacy response profile for DP13. DP13C101 supported a once daily (QD) 
in the morning oral administration of DP13 capsules. Furthermore, three suitable dose levels 
for the treatment of PA were derived.  
• 
The 4 mg DP13 QD dose is considered a low dose potentially benefiting milder disease 
phenotypes.  
• 
The 8 mg DP13 QD dose is considered a target dose for patients with PA.  
• 
The 12 mg DP13 QD dose is considered a higher dose that could be necessary to treat 
florid disease types.    
The 12 mg QD dose is lower than the 16 mg QD dose tested in the DP13C101 phase I study. 
There were no dose-dependent safety or tolerability trends observed in healthy volunteers. 
The dose levels are kept constant over the 8-week treatment period as aldosterone-dependent 
blood pressure effects are expected to occur with large individual time-response variance.  
 
4.5 
Patient Withdrawal Criteria 
Patients will be withdrawn after a scheduled or unscheduled visit by the Investigator if any of 
the following criteria are met during the DP13 treatment period: 
• 
Any verified clinically relevant signs or symptoms that, in the opinion of the Investigator 
after consultation with the Central Review Board warrant subject withdrawal. 
• 
A subject's absolute QTc value >500 msec (confirmed by repeat testing). If this criterion is 
met, QTcB will be calculated; if QTcB readings meet the same criterion, the ECGs will then 
be manually over-read to confirm the QTc increase. 
• 
Evidence of tachycardia (>150 beats/min) is seen in the resting sitting position (confirmed 
by 2 repeat measurements) on at least 2 occasions within a 1-hour interval. 
• 
Evidence of uncontrolled hypertension (systolic blood pressure >190 mmHg and/or 
diastolic blood pressure >110 mmHg) is seen in the resting sitting position (confirmed by 
2 repeat measurements) on at least 2 occasions within a 2-week interval, i.e., two visits. 


Study Protocol: DP13C201 
Confidential 
Page 24 
Version 5.0 
 
DP13 
• 
Evidence of moderate hypotension (systolic blood pressure <90 mmHg and/or diastolic 
blood pressure <50 mmHg) is seen in the resting sitting position (confirmed by 2 repeat 
measurements) on at least 2 occasions within a 2-week interval, i.e. two visits. 
• 
Evidence of unexplained clinically significant increases in liver function tests (AST, ALT, 
ALP, bilirubin and/or GGT), defined as >3 times the upper limit of the reference range 
(confirmed with repeat testing within 48 hours). 
• 
Evidence of clinically significant increases in serum creatinine, defined as >2.0-fold above 
the upper limit of the reference range. 
• 
Evidence of clinically significant hyperkalaemia (serum potassium >6 mmol/L) confirmed 
with repeat testing (that is not caused by technical or laboratory issues, e.g. haemolysis). 
• 
Evidence of persistent hypokalaemia (serum potassium <2.5 mmol/L) in presence of oral 
potassium supplements on a least 2 occasions within a 2-week interval, i.e., two visits. 
• 
Evidence of clinically significant hyponatraemia (serum sodium <130 mmol/L) confirmed 
with repeat testing. 
• 
Non-compliance with the study procedures/restrictions, as considered applicable by the 
Investigator. 
• 
Patient self-withdrawal. 
In case of withdrawal of consent, all personal data and biological samples will continue to be 
used encoded; no further data or samples will be collected. 
 
4.6 
Management of Patient Safety 
Patients remain on a personalized background hypertension control therapy throughout the 
study, if required, consisting of a fixed-dose regimen with the first-line alpha receptor blocker 
doxazosin, 1 – 8 mg QD and, if necessary, only one calcium channel blocker: verapamil slow 
release, maximum 40 – 120 mg BID or diltiazem slow-release 90 - 360 mg daily or amlodipine 
2.5 – 10 mg QD according to the  Investigator’s judgement to assure office systolic and 
diastolic blood pressure (oSBP) do not exceed 190 mmHg and/or 110 mmHg, respectively 
during the study. Biweekly compliance checks during visits will not only focus on the proper 
IMP intake but also on the prescribed intake of the blood pressure control medications. 
Upon enrolment, each patient is given a card to carry at all times in case of an emergency 
outside the Investigator’s supervision. The card gives details of the study number, start and 
end date of the patient’s involvement in the study, patient details, name of the study 
Investigator, and the address and telephone number of the clinical site. Patients may destroy 
the card 4 weeks after they have completed the study. 
 


Study Protocol: DP13C201 
Confidential 
Page 25 
Version 5.0 
 
DP13 
5 
INVESTIGATIONAL MEDICINAL PRODUCTS 
5.1 
Description, Identification and Storage 
DP13 active pharmaceutical ingredient (API) along with the batch numbers and Certificates of 
Analysis (CoA) is supplied by the Sponsor’s contract manufacturing organization Alcami 
Corporation (Vliesenweg 1, 6002 NM Weert, the Netherlands). DP13 formulated capsules are 
supplied by the Sponsor’s contract manufacturing organization Ardena Corporation (Kleimoer 
4, 9030 Mariakerke, Belgium). The DP13 capsules contain a filling and glidant excipient and 
either 4 mg, 8 mg or 12 mg drug substance. A Certificate of Release authorized by a Qualified 
Person (QP) in the European Union (EU) and Switzerland is issued for each IMP batch prior 
to administration to patients. 
Placebo capsules are only composed of filling and glidant excipients. The formulated placebo 
capsules are sourced and supplied by the Sponsor’s contract manufacturing organization 
Ardena Corporation in Belgium. A Certificate of Release authorized by a Qualified Person 
(QP) in the European Union (EU) and Switzerland will be issued for each batch of IMP prior 
to administration to patients. 
The VCaps® Plus capsules are of size (I) and white opaque in appearance. The IMP is stored 
at room temperature at the respective clinical site pharmacy, which is locked with restricted 
access. No special procedures are required for the safe handling of the IMP by the patient.  
 
5.1.1 
Labelling of IMP and Unit Jars 
Ardena will prepare jars with 14(+4) capsules for a biweekly (or monthly in the case of a 
home/workplace visit) supply. Further information on the manufacture and assembly of unit 
doses will be maintained in the pharmacy documentation, which will be generated by Ardena 
and approved by the Sponsor prior to the first manufacture. The sequence of jars and capsules 
for study DP13C201 is provided as follows: 
 
2-Week Run-in Period 
8-Week Treatment Period 
2-Week Withdrawal Period 
Study 
Cohort 
DP13 
Dose 
Caps 
per 
Patient 
Jar per 
Patient 
Study 
Group 
DP13 
Dose  
Caps 
per 
Patient 
Jar per 
Patient 
Study 
Cohort 
DP13 
Dose 
Caps 
per 
Patient 
Jars 
per 
Patient 
N=36 
0 mg 
14 
1 
N=12 
4 mg 
56 
4 
N=36 
0 mg 
14 
1 
N=12 
8 mg 
56 
4 
N=12 
12 mg 
56 
4 
Actual numbers of jars dependent on interim analysis and any size adaptation 
Bulk medication labels will be in the local language, will comply with the legal requirements of 
each country and will include use instructions and storage conditions. The labels will not 
contain any personal information on the patient. 
 
5.1.2 
Drug Accountability 
Records will be maintained showing the receipt and disposition of the study supplies. The 
Sponsor will be permitted at intervals and upon request during the study to check the supplies 
storage and records. 
Enrolled patients will be asked to return the IMP containing jar and any unused capsule(s) at 
every office visit. The Investigator records the reconciled IMP intake over the visit period. The 


Study Protocol: DP13C201 
Confidential 
Page 26 
Version 5.0 
 
DP13 
Investigator will witness directly the IMP intake on the day of study enrolment (Day -14) and 
randomization (Day 1) and on the days starting the 24-hour ambulatory blood pressure 
monitoring (Day -1 and Day 55).  
Upon satisfactory completion of all accountability procedures, each patient jar and any unused 
capsule(s) as well as any unused IMP jars from the block supply will be retained until 
completion of the study and returned to the Sponsor. The Sponsor will perform a final study 
drug reconciliation and issue a Certificate of Destruction. 
 
5.2 
Blinding 
Staff at Ardena in Belgium not involved in patient recruitment or other study activities will label 
and pack the IMP-containing jars according to a standard operating procedure (SOP) and 
based on the randomization list provided by OPIS s.r.l. The following controls will be employed 
to maintain the double-blind status of the study: 
• 
The placebo capsules will be identical in appearance to the DP13 capsules. 
• 
The IMP supply jar covers biweekly (or monthly in the case of a home/workplace visit) 
visits irrespective of the study period. 
• 
The Investigator and other members of staff involved in the study will remain blinded to 
the treatment randomisation code. 
• 
Interim bioanalytical/hemodynamic data will be provided to the Inselspital in a blinded 
manner. 
 
5.3 
Unblinding 
Emergency unblinding should only be undertaken when it is essential for patient care. If 
unblinding becomes necessary to manage patient safety (in the event of possibly treatment-
related severe adverse events, SAEs), the decision to unblind resides solely with the 
Investigator. Whenever possible and provided it does not interfere with or delay any decision 
in the best interest of the patient, the Investigator will discuss the intended code-break with 
the Central Review Board and Sponsor.  
Emergency unblinding is performed using the web-based electronic data capture system. As 
a backup to the eCRF, individual sealed envelopes containing the treatment codes for each 
patient are kept at Ardena’s clinical supply department and at the biopharmaceutical analyst 
at the Bern Inselspital. These individual sealed envelopes should be used only in case it is not 
possible to use the eCRF for unblinding and can only be requested by the Investigator when 
knowledge of the actual dose received is deemed essential for the patient’s care.  
If it becomes necessary to break the patient code during the study, the date, time, and reason 
will be recorded in the subject's source data and eCRF.   
Also, in case of Serious Adverse Event (SAE) considered to be a Suspected Unexpected 
Serious Adverse Reaction (SUSAR), the Pharmacovigilance Unit delegated in agreement with 
the Sponsor will be able to break the code in order to permit the notification of the case to the 
Regulatory Authorities in unblind version (see 8.1.4 section). 
 


Study Protocol: DP13C201 
Confidential 
Page 27 
Version 5.0 
 
DP13 
5.4 
Randomization 
Upon central patient eligibility verification and registration in the web-based electronic data 
capture system, the system will randomize enrolled patients in a 1:1:1 ratio to one of the three 
interventional dosage arms. An independent statistician using a computer-generated pseudo-
random permutation procedure will produce the randomization code and allocation sequence. 
Randomization is stratified by center and gender. An interactive web response system (IWRS) 
will manage the randomization and the shipment of clinical supply kits to a clinic. Prior to the 
start of the study, a copy of the master randomization code will be supplied to Ardena’s clinical 
supply services and to the biopharmaceutical analyst at the Bern Inselspital in sealed 
envelopes. The statistician responsible for the final analysis will have no access to the code 
until the primary analysis of the trial is completed. 
 
5.5 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance.  
• The first placebo dose on enrolment day (Day -14) will be administered under supervision 
of a suitably qualified clinical staff after completion of the office procedures. 
• The first DP13 dose of the treatment (Day 1) will be administered under the supervision 
of a suitably qualified clinical staff after completion of the recording of the patient’s 
baseline characteristics.  
• The IMP intake upon starting the 24-hour ambulatory blood pressure monitoring on Day -
1 and on Day 55 is supervised by a suitable qualified clinical staff.  
• Blood samples collected during the biweekly (or monthly in the case of a home/workplace 
visit) visits will be assessed for steady-state DP13 drug concentrations. In addition, blood 
samples for testing of the hypertension control therapy (doxazosin, verapamil or diltiazem 
or amlodipine) are collected and can be verified for proper medication intake. Patients will 
be reminded that drug concentration levels in the blood will be used as compliance 
checks. 
• At each office visit, a clinical supply inventory will be performed on the returned IMP 
containers counting the unused capsules. The capsule counts are compared with the 
patient’s diary records. 
 
5.6 
Concomitant Medication 
After de novo diagnosis or confirmed diagnosis of PA, patients should not take diagnosis-
interfering medications as listed in the Endocrine Society clinical practice guidelines for the 
duration of the study (Funder et al., J Clin Endocrinol Metab 2016). The guidelines list beta-
adrenergic blockers, central alpha agonists, non-steroidal anti-inflammatory drugs (NSAIDs), 
potassium-wasting as well as potassium-sparing diuretics, angiotensin-converting enzyme 
inhibitors (ACEi), angiotensin receptor blockers (ARBs), renin inhibitors. In order to prevent 
uncontrolled hypertension during the study, a fixed-dose regimen of the alpha-receptor blocker 
doxazosin (1 - 8 mg QD) as first-line medication and, only if necessary, the calcium channel 
blocker verapamil slow release (40 – 120 mg BID) or diltiazem (slow-release 90 - 360 mg 
daily) or amlodipine (2.5 – 10 mg QD) is implemented if clinically applicable 2 weeks prior to 
eligibility verification and the placebo run-in period. The medications are prescribed by the 


Study Protocol: DP13C201 
Confidential 
Page 28 
Version 5.0 
 
DP13 
Investigator and supplied by local practice. The pharmacology of the two drugs have minimal 
effects on the renin-angiotensin-aldosterone system and drug-metabolizing enzymes and are 
therefore recommended for use during the diagnosis of PA. At the Investigator’s discretion, 
the doses of doxazosin, verapamil or diltiazem or amlodipine are adjusted up to the run-in 
period should office systolic blood pressure exceed 190 mmHg or fall below 145 mmHg. The 
Investigator may adapt the background hypertension control therapy if in his opinion 
medication-related severe clinical sign or symptoms can be alleviated. If the medications are 
required and the doses adapted, the brand name, strength, frequency of dosing and reason 
for use is documented in the patient’s source data. The dosage and regimen of the 
hypertension control therapy is fixed 2 weeks prior to study enrolment until study end. 
In men, approximately 5% of an oral DP13 dose is excreted into the urine in both unchanged 
form or as hydroxylated and glucuronidated metabolites. Therefore, no interaction with renally 
cleared co-medications is expected. In vitro, no metabolism-relevant cytochrome P450 (CYP) 
enzyme revealed to be significantly responsible for DP13 metabolism or was significantly 
inhibited by DP13. Therefore, no specific drug-drug interactions can be anticipated. Doxazosin 
is primarily metabolized in the liver by CYP3A4 and excreted into the faeces (SmPC). 
Verapamil is subject of a significant first pass effect in the liver involving CYP3A4, 1A2, 2C8, 
2C9, 2C18 and primarily cleared by the kidneys (SmPC). Diltiazem is primarily metabolized in 
the liver by CYP3A4 and excreted into the urine (SmPC). Amlodipine is primarily metabolized 
in the liver by CYP3A4 and excreted into the urine (SmPC). 
Patients will not take any new prescription or over-the-counter (OTC) medication, or have 
medication changes within 14 days prior to study start through completion of the post-study 
assessments (the duration of the study) without consent from the Central Review Board and 
Sponsor. Initiation of a new medication, OTC medication or medication change more than 14 
days prior to starting the study should be already captured in the electronic database under 
concomitant medications and reviewed by the Central Review Board as per protocol prior to 
study enrolment. Paracetamol (up to 2 g/day for up to 5 days) is an acceptable concomitant 
medication to treat minor discomforts, illnesses, headaches or colds. 
Patients are allowed to continue other medications that are not excluded by the Endocrine 
Society Guidelines for the diagnosis of PA and by the Central Review Board if the patient is 
taking the medications consistently as prescribed for a specified condition. Generally, if any 
medication is required, the name, brand, strength, dosing frequency and reason for use is 
documented in the patient’s source data. Patients will be asked to contact the Investigator 
should they desire any new concomitant medication. 
 
5.6.1 
Rescue Medication 
At the Investigator’s discretion, the following rescue treatments are proposed: 
Patients with serum/plasma potassium levels <2.5 mmoL/L should be given oral potassium 
supplements up to 3 grams per day.  
Patients with serum/plasma potassium levels ≥6.0 mmol/L during study treatment should 
undergo repeat blood sampling to verify the value in absence of any haemolysis. If the repeat 
sample indicates potassium levels ≥6.0 mmol/L, an ECG will be performed. In the absence of 
ECG changes, furosemide can be given to produce renal potassium excretion. In the presence 
of ECG changes, calcium gluconate can be given to decrease membrane excitability or insulin 
together with glucose can be given to shift potassium out of the blood system. 
Patients with an adverse event of symptomatic hypoadrenalism can be given substitutive 
therapy such as cortisol and if necessary, fludrocortisone to replace glucocorticoid and 
mineralocorticoid hormones. 


Study Protocol: DP13C201 
Confidential 
Page 29 
Version 5.0 
 
DP13 
Patients with symptomatic hypotension should be put in the supine position and saline infusion 
can be given to restore blood pressure. 
 
6 
STUDY POPULATION 
6.1 
Identification and Numbering of Patients 
Each patient is identified in the study by a unique number that is automatically assigned by 
the system when the patient is first enrolled for screening and is retained as the primary 
identifier for the patient throughout the study. Once assigned, the patient identifier must not 
be changed or reused for any other patient. A list identifying the patients by their number will 
be kept in the trial master file. 
 
6.2 
Determination of Sample Size 
The sample size is set to N=36 patients with PA randomized into three treatment arms of 
approximately N=12 each. The sample size calculation was based on representative individual 
patient data derived from the PATO study (Monticone et al., J Am Coll Cardiol 2017) and on 
reported interventional studies with the aldosterone synthase inhibitor LCI699 (Amar et al., 
Hypertension 2010) and mineralocorticoid receptor antagonists in patients with PA 
(Parthasarathy et al., J Hypertens 2011). A potential dropout of up to 6 patients is considered 
in the sample calculation. 
The power calculation is based on both primary endpoints, i.e. the change in ARR and the 
change in blood pressure. The calculation yields a total of 30 patients for ARR and 26 patients 
for blood pressure. Therefore, a minimum of 30 patients are required to answer the two 
primary study questions. In order to consider possible dropouts, a total of 36 patients are to 
be enrolled. Since we are testing the two endpoints hierarchically in the primary analysis, the 
overall type I error is preserved at the 5% level. 
For the first primary study objective, a change in the ARR of 40% in the combined treatment 
groups is expected. This corresponds to an effect size of 0.69 on the log scale based on a 
standard deviation of 0.74 of log-transformed ARR as calculated from the data of the PATO 
study. Assuming a correlation of 0.5 between values at start and end of the 8-week treatment 
period, 30 patients are required to detect an ARR decrease of 40% with a power of 95% at 
two-sided alpha levels of 0.05 based on a paired means test.  
For the second primary study objective, a change in ambulatory systolic blood pressure 
(aSBP) of 6 mmHg in the combined treatment groups can be significantly detected in 26 
patients at a two-sided alpha level of 0.05 with a power of 95% based on a standard deviation 
of 8 mmHg.   
Furthermore, a 60% ARR decrease and a 10-mmHg aSBP reduction can be significantly 
measured in 11 patients. Therefore, these assumptions may allow the detection of treatment 
effects in the individual dose arms and allow the assessment of a dose-response relationship. 
 
6.3 
Inclusion Criteria 
Patients will be required to satisfy all of the following eligibility criteria: 
1. Patients with a guideline-recommended diagnosis of PA consisting of: 


Study Protocol: DP13C201 
Confidential 
Page 30 
Version 5.0 
 
DP13 
1.1. ARR ≥40 derived from a PAC ≥15 ng/dL and a PRA <1.0 ng/mL/h; an ARR ≥3.7 is 
derived with PRC <15 mU/L instead of PRA as denominator 
 and 
1.2. PAC >7.0 ng/dL after a 4-hour infusion of 2 litres 0.9% saline (saline load suppression 
test) or instead if clinically justified for risk of volume expansion ARR>30 and PAC 
>11 ng/dL (respectively ARR>2.4 with PRC in mU/L instead of PRA as denominator) 
after 2 hours of an oral intake of 50 mg captopril 
 and 
1.3. determined within <1 year of study enrolment  
2. Patients with PA per above criteria and 
2.1. sitting office systolic blood pressure (oSBP) >145 mmHg 
and if applicable 
2.2. in presence of non-interfering hypertension control therapy consisting of doxazosin (1 
– 8 mg QD) as first-line medication and, if necessary, only verapamil slow release (40 
– 120 mg BID) or diltiazem (slow-release 90 - 360 mg daily) or amlodipine (2.5 – 10 
mg QD) at adjusted and fixed doses 
3. Patients with PA per above criteria will have a: 
3.1. estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 using the MDRD-4 
GFR equation: GFR = 175 x [serum creatinine (mg/dL)]-1.154 x (age)-0.203 x f* 
*f=1.000 for men; f=0.742 for women; the formula is further multiplied by factor 1.210 for 
black skinned patients 
3.2. body mass index (BMI) between 18 and 34 kg/m2, inclusive 
3.3. body weight between 40 and 110 kg, inclusive 
4. Patients with PA per above criteria will be: 
4.1. female or male patients between 18 and 65 years of age, inclusive 
4.2. able to provide voluntary informed written consent to study enrolment 
 
6.4 
Exclusion Criteria 
Patients will be excluded from the study if they satisfy any of the following criteria: 
1. Patients with PA and: 
1.1. treated with spironolactone within 2 months of enrolment 
1.2. hyperkalaemia of >5.0 mmol/L 
1.3. prolonged QT intervals with QTc of >500 msec using Bazett’s formula 
2. Patients with PA and: 
2.1. Sitting office systolic office blood pressure (oSBP) >190 mmHg 
and/or 
2.2. sitting office diastolic office blood pressure (oDBP) >110 mmHg 


Study Protocol: DP13C201 
Confidential 
Page 31 
Version 5.0 
 
DP13 
and if applicable 
2.3. in presence of non-interfering hypertension control therapy consisting of doxazosin (1 
– 8 mg QD) as first-line medication and, if necessary, only verapamil slow release (40 
– 120 mg BID) or diltiazem (slow-release 90 - 360 mg daily) or amlodipine (2.5 – 10 
mg QD) at adjusted and fixed doses 
3. Patients with PA who will not consent to special contraception measures during the entire 
study period, specifically 
3.1. female patients not withdrawing oral contraceptives >2 weeks prior to enrolment 
3.2. female patients not using intrauterine devices (IUD), diaphragm or sponge with 
spermicide 
3.3. male patients not using condoms and not refraining from sperm donation 
4. Patients with PA and a medical history of: 
4.1. cerebro- and cardiovascular events (stroke, myocardial infarction, percutaneous 
transluminal coronary angioplasty, long QT syndrome, Brugada syndrome, acute 
heart failure) within 6 months of study enrolment 
4.2. gastrointestinal tract surgeries or malabsorption syndromes 
4.3. chronic use of oral or parenteral corticosteroids 
4.4. use of drugs prolonging the QT interval (e.g., digoxin, sotalol) 
5. Patients with PA who: 
5.1. participated in any clinical study within 6 weeks 
5.2. suffered a significant blood loss within <2 months 
5.3. had a significant illness within <2 weeks 
5.4. are pregnant or breastfeeding  
5.5. are unable to follow all study procedures 
 
6.5 
Central Eligibility Verification 
In order to assure the enrolment of a homogenous patient population without any selection 
bias, central and formal eligibility verification with a documented eCRF-based case review 
process led by the Central Review Board is mandatory prior to enrolment by Day - 14. The 
Investigator presents via eCRF the case and the Central Review Board leads the case review 
through a structured assessment of patient diagnosis, meeting the inclusion and exclusion 
criteria and any clinical precautions. Eligibility confirmation must be completed by study Day -
14. 
 
Parameter 
Verification 
Gender 
Supportive information 
Age 
I/E criterion 
PAC 
I/E criterion 
PRA and/or PRC 
I/E criterion 
Blood potassium concentration 
I/E criterion 
Hypertension control therapy 
Medication/dose/duration 


Study Protocol: DP13C201 
Confidential 
Page 32 
Version 5.0 
 
DP13 
Office SBP 
I/E criterion 
Office DBP 
Supportive information 
PAC after saline load 
I/E criterion 
PAC and PRA/PRC after captopril 
I/E criterion 
ECG 
I/E criterion 
Blood Creatinine 
I/E criterion 
Comorbidities 
Supportive information 
Co-medications 
Supportive information 
Adrenal CT Scan (if available) 
Supportive information 
Adrenal vein sampling (AVS) (if available) 
Supportive information 
 
The Central Review Board has the final decision on enrolment. The criteria for enrolment or 
rejection are documented in the patient’s source data and eCRF. 
 
6.6 
Specific Restrictions/Requirements 
6.6.1 
Patient Diary  
Patients are requested to record their daily drug intake in a provided diary. The diary will list 
the time of the intake of the investigational drug as well as the control blood pressure 
medications. In addition, on the days of ambulatory blood pressure monitoring (Day -1/1 and 
Day 55/56), patients will record their physical activities, meals and sleep hours.  
 
6.6.2 
Diet  
Patients are not requested to follow any specific dietary restrictions such as a salt-controlled 
diet or alcohol restrictions before or during the study. Alcohol consumption is however limited 
to 25 grams of ethanol per day (e.g. 2 ordinary beers, 2 glasses of wine). Patients have blood 
sampling (Day -14, Day 1, Day 14, Day 28, Day 42, Day 56 and Day 70) in an overnight fasted 
state. 
 
6.6.3 
Exercise 
Patients will be requested not to undertake physical exercise on the days of visits prior to 8:00 
am and on the days of 24-hour ABPM (Day -1/1 and Day 55/56). 
 
6.6.4 
Blood Donation 
Patients are requested not to donate blood 2 weeks prior to study start, during the study and 
1 month after the final visit. 
 
6.6.5 
Contraception 
Female patients and male patients with partners of childbearing potential must use one barrier 
method of contraception and another method of proven efficacy. Acceptable methods of 
contraception include: 
• 
Male condoms 


Study Protocol: DP13C201 
Confidential 
Page 33 
Version 5.0 
 
DP13 
• 
Female condoms 
• 
Intrauterine device (IUD) 
• 
Male sterilization or vasectomy 
• 
Female sterilization 
• 
Diaphragm, cap, or sponge in conjunction with spermicide 
Hormonal contraceptives are not permitted during the study as they interfere with the renin-
angiotensin-aldosterone system. Patients are required to refrain from donation of sperm from 
enrolment until 3 months after the last dose of study drug. For patients who are exclusively in 
same sex relationships, contraceptive requirements do not apply. 
 
6.7 
Patient Withdrawals/Replacements 
A patient is free to withdraw from the study at any time. In addition, the Investigator together 
with the Central Review Board may decide for justified reasons of medical prudence to 
discontinue a patient (see section 4.5 on Patient Withdrawal Criteria). The Sponsor will be 
notified and date and reason(s) for the withdrawal documented in the patient’s source data 
and eCRF. Should the randomization code be broken for a patient, the date, time and reason 
will be recorded in the patient’s source data.  
According to the intention-to-treat (ITT) principle, no replacement of randomized patients if 
they are withdrawn or choose to withdraw is foreseen. Investigators will make every 
reasonable effort to keep each patient on the study until all planned treatments and 
assessments have been performed. If a patient is withdrawn or chooses to withdraw, all 
relevant end-of-treatment procedures such as physical and clinical laboratory evaluations and 
office blood pressure measurements will be performed prior to discharge from the study. If the 
patient has been on DP13 treatment for >1 week, a 24-hour ambulatory blood pressure 
monitoring is performed prior to discharge from the study if possible. The Investigator may 
also request that the patient return for an additional follow-up visit.  
 
6.8 
Patient Re-screening and Re-enrolment 
Re-screening 
Patients are eligible for re-screening after a >3-month time lapse from initial screening if non-
controllable events such as the COVID-19 pandemic and/or hospital closures for ambulatory 
procedures or other extraordinary circumstances prevent study enrolment according to 
protocol. Patients may also be re-screened after a >6-month time lapse if disease progression 
as assessed by the Investigator justifies the re-assessment of study eligibility.  
 
Re-enrolment 
Patients are eligible for re-enrolment after a >3-month time lapse from initial enrolment prior 
to randomization if non-controllable events such as the COVID-19 pandemic and/or hospital 
closures for ambulatory procedures or other extraordinary circumstances prevent study 
continuation according to protocol. 
 


Study Protocol: DP13C201 
Confidential 
Page 34 
Version 5.0 
 
DP13 
7 
STUDY PROCEDURES 
The schedule and timing of study procedures is outlined in the appended Study Plan (section 
19.1). All protocol-defined procedures including repeat evaluations must be reported in the 
patient’s source documentation. Any other procedures are entered in the “Unscheduled Visit” 
eCRF page. Every effort will be made to schedule and perform office procedures in 
accordance with the nominal time, giving considerations to appropriate posture conditions, 
practical restrictions and the other procedures to be performed at the same time. The order of 
priority for scheduling procedures around is (in descending order of priority): 
1) Collection of 24-hour urine bottle and ABPM devices (Day 1 and Day 56 only) 
2) Spot urine, body weight recording, AE recording and ECG monitoring after rest and in 
a sitting position  
3) Blood pressure measurements (after a >15-minute rest) 
4) Blood sampling 
5) Verification of treatment compliance 
6) IMP supply 
7) Supervised IMP intake (Day -14, Day -1, Day 1 and Day 55 only) 
8) Any other procedures 
 
7.1 
Visits 
Patients will schedule biweekly visits with a flexibility of +/- 3 days except for the Day 55/56 
visits, where +/- 2 days flexibility is acceptable (note, like Day -1 and Day 1 visits, Day 55 and 
56 visits must occur on subsequent days to accommodate 24-hour recordings). Patients will 
report to the clinical research unit for their visits in the morning and undergo all procedures as 
summarized below by 10:00 am. The Day -1, 14, 42 and 55 visits may be performed at the 
patient's home or workplace (if appropriate facilities are available) by medically-qualified 
personnel. 
The study starts with the Day -14 visit to record the run-in baseline characteristics and a 
supervised first IMP intake. For the assessment of the baseline (Day 1 visit) and end of DP13 
treatment characteristics (Day 56 visit), patients will be provided with the ambulatory blood 
pressure monitoring devices and 24-hour urine sample bottles 24 hours ahead (Day -1 and 
Day 55 visits). On these days and on Day 1, clinically qualified staff properly supervises IMP 
intake and activates the ABPM device. The visits will last up to 1 hour. 
During the patient’s sitting rest period of ≥15 minutes, the Investigator will monitor body weight, 
adverse events, ECG, available safety and tolerability data i.e. laboratory safety data, urine 
pregnancy tests (UPT) and vital signs to confirm the patient’s wellbeing and subsequently 
proceed with blood pressure recordings and blood sampling procedures. In addition, the 
Investigator will check on the patient’s treatment adherence and clinical supply inventory and 
remind him/her of the importance of study compliance. If necessary, the patient will remain in 
the clinic until any adverse events or safety assessments of concern have been resolved. 
Additional non-residential visits may be required based on ongoing review of study data.  


Study Protocol: DP13C201 
Confidential 
Page 35 
Version 5.0 
 
DP13 
7.1.1 
Home or Workplace Visits 
The Investigator, according to the patient’s needs and clinical condition and/or to implement 
EMA- or other local authority-mandated actions limiting patient access to sites to reduce 
COVID-19 related risks, may consider having the Day-1, Day 14, Day 42 and Day 55 visits at 
the patient’s home or workplace. Home/workplace visits must be performed by medically 
qualified personnel if appropriate facilities are available. 
The home/workplace visits will be managed by medically-qualified personnel approved, 
properly trained and delegated by the local PI. The home/workplace visits will be conducted 
according to a home/workplace visit-specific manual approved by the Sponsor. 
 
  
*Note: The Day -1, 14, 42 and 55 visits may be performed at the patient's home or workplace by medically-qualified 
personnel (if appropriate facilities are available). 
7.2 
Visit Procedures 
7.2.1 
Spot Urine Sample 
The Investigator will collect a spot urine sample for a safety analysis. The sample will be 
analyzed at the local laboratory for routine measures. The results are reviewed and interpreted 
by the Investigator.  
A pregnancy test by means of urine dipstick is performed on women of childbearing potential. 
 
Visit
Day -14
Day -1*
Day 1
Day 14*
Day 28
Day 42*
Day 55*
Day 56
Day 70
Patient Home 
Procedures
Overnight 
Fast
Overnight 
Fast
Overnight 
Fast
Overnight 
Fast
Overnight 
Fast
Overnight 
Fast
Overnight 
Fast
IMP 
Intake
IMP 
Intake
IMP 
Intake
IMP 
Intake
IMP 
Intake
Diary
Diary
Diary
Diary
Diary
Diary
Diary
Diary
Diary
Investigator Office 
Procedures
Urine
Bottle 
Pickup
ABPM 
Setup
Urine 
Bottle 
Delivery
ABPM 
Collection
Urine
Bottle 
Pickup
ABPM 
Setup
Urine 
Bottle 
Delivery
ABPM 
Collection
Urinalysis
UPT
Urinalysis
Urinalysis
UPT
Urinalysis
Urinalysis
UPT
Urinalysis
Urinalysis
UPT
Rest with 
recording 
of BW
AE
ECG
Rest with 
recording 
of BW
AE
ECG
Rest with 
recording 
of BW
AE
Rest with 
recording 
of BW
AE
ECG
Rest with 
recording 
of BW
AE
Rest with 
recording 
of BW
AE
ECG
Rest with 
recording 
of BW
AE
ECG
Pressure 
Recording
Pressure 
Recording
Pressure 
Recording
Pressure 
Recording
Pressure 
Recording
Pressure 
Recording
Pressure 
Recording
Blood 
Sampling
Blood 
Sampling
Blood 
Sampling
Blood 
Sampling
Blood 
Sampling
Blood 
Sampling
Blood 
Sampling
Complian-
ce Check
Complian-
ce Check
Complian-
ce Check
Complian-
ce Check
Complian-
ce Check
Complian-
ce Check
Complian-
ce Check
Complian-
ce Check
Complian-
ce Check
IMP (1) 
Handout
IMP (2) 
Handout
IMP (3) 
Handout
IMP (4) 
Handout
IMP (5) 
Handout
IMP (6) 
Handout
Super-
vised IMP 
Intake
Super-
vised IMP 
Intake
Super-
vised IMP 
Intake
Super-
vised IMP 
Intake


Study Protocol: DP13C201 
Confidential 
Page 36 
Version 5.0 
 
DP13 
7.2.2 
Body Weight Recording 
The Investigator will record the patient’s body weight (in underclothes and without shoes) upon 
arrival to the scheduled office visits. Subsequently, the patient is seated for resting and for 
AE/ECG recordings.  
 
7.2.3 
Adverse Event Reporting 
The condition of each patient will be monitored from the time of signing the ICF to final 
discharge from the study including the follow-up period. Any signs or symptoms will be 
observed and elicited by the Investigator or medically-qualified personnel during the visit by 
open questioning such as: “How have you been feeling since you were last asked?” Patients 
will also be encouraged to spontaneously report adverse events occurring at any other time 
during the study and to list them in their diary.  
Any adverse events and remedial action required will be recorded in the patient’s source data. 
The nature, time of onset, duration and severity will be documented, together with the 
Investigator’s opinion of the relationship to study drug administration. Any clinically significant 
abnormalities identified during the course of the study will be followed up until they return to 
normal or can be clinically explained.  
Adverse event definitions, assignment of severity and causalities and procedures for reporting 
SAEs are detailed in section 8.  
 
7.2.4 
Lead Electrocardiogram 
A single 12-lead resting ECG with a 10-second rhythm strip will be recorded after the patient 
has been sitting for at least 5 minutes on Day -14, Day 1, Day 28, Day 56 and Day 70 visits 
according to Study Plan. The ECG recording will be repeated if the QTc is >500 msec. If 
repeated, the repeat values will be used for data analysis. 
Additional 12-lead ECGs will be performed at other times if judged to be clinically appropriate 
or if the ongoing review of data suggests a more detailed analysis. Clinical reference ranges 
will be applied to all ECG parameters throughout the study. The ECG machine will compute 
the PR and QT intervals, QTc, QRS duration and heart rate. The QT interval will be corrected 
for heart rate using Bazett’s formula (QTcB). 
 
7.2.5 
Blood Pressure Measurements 
Blood pressure and pulse rate will be measured at each visit after a >15-minute rest in sitting 
position as indicated in the Study Plan. Blood pressure and pulse rate will be measured using 
a locally calibrated and validated automated oscillometric device (e.g. Omron Healthcare). An 
adapted wrap cuff is placed on the dominant arm. Three repeat measurements with a 10-
minute interval are recorded; the average of the 2nd and 3rd measurements are study relevant. 
Each single patient will be assessed throughout the study with the same equipment and 
procedure. 
 
7.2.6 
Blood Sampling 
Blood samples from overnight fasted patients are collected for clinical laboratory evaluations 
at the visits indicated in the study plan. On Day 14 and Day 42, blood samples may be 


Study Protocol: DP13C201 
Confidential 
Page 37 
Version 5.0 
 
DP13 
collected by medically-qualified personnel at the patient’s home or workplace (if appropriate 
facilities are available). Because of the diurnal rhythm of the renin-angiotensin-aldosterone 
system, blood is drawn as early as possible in the morning hours of the visits, i.e. prior to 10:00 
am. Additional and/or more detailed clinical laboratory evaluations are performed at other 
times if judged to be clinically necessary by the Investigator. The maximum volume of blood 
drawn from each patient during one visit is 60 mL and over the entire study will not exceed the 
limit of 400 mL. Any changes to the scheduled times will be agreed with the Sponsor and 
documented in the TMF. Safety laboratory samples are analysed locally. The results are 
reviewed 
and 
interpreted 
by 
the 
Investigator. 
Samples 
for 
pharmacokinetics, 
pharmacodynamics and therapeutic drug monitoring are locally processed, stored frozen and 
at the end of the study shipped for central analysis. Detailed procedures for collecting and 
processing blood samples will be detailed in a separate Laboratory Manual.  
 
 
Volume per 
blood sample 
(mL) 
Maximum 
number of 
samples 
Total 
amount of 
blood (mL) 
Safety Laboratory 
 
 
 
   Clinical panel analysis 
7.5 
8 
60 
Pharmacokinetics: 
 
 
 
   DP13 & metabolite analysis 
6.0 
5 
30 
Pharmacodynamics:    
 
 
 
   Aldosterone/PRC analysis 
7.5 
7 
53 
   PRA analysis 
7.5 
5 
38 
   Electrolyte analysis 
4.7 
7 
33 
   ACTH analysis 
2.6 
5 
13 
   Steroid hormone panel analysis 
7.5 
7 
53 
Therapeutic Drug Monitoring 
 
 
 
   Doxazosin, verapamil, diltiazem, amlodipine 
7.5 
5 
38 
Total: 
51 
 
318 
 
7.2.7 
Treatment Compliance Verification 
The Investigator will verify treatment compliance on visit days by checking the patient’s 
adherence to the daily drug intake reported in the patient’s drug intake diary, by asking specific 
questions such as “When and how have you taken the capsule in the last days?” and by 
performing a clinical supply inventory by counting the content of the previous supply jar. In 
addition, the Investigator verifies adherence to the blood pressure control therapy and any 
other concomitant medication. The patient will also be reminded that treatment adherence will 
be demonstrated by the analysis of the blood samples for DP13 content along with any 
therapeutic drug monitoring of the hypertension control medications. Reasons for non-
compliance have to be identified and documented in the patient’s source data. 
 
7.2.8 
IMP/Hypertension Control Medication Supply 
After verification of treatment compliance, the Investigator will handout an IMP jar(s), each 
containing 14(+4) capsules for a bi-weekly or monthly visit supply to the patient. The handout 


Study Protocol: DP13C201 
Confidential 
Page 38 
Version 5.0 
 
DP13 
of a new supply jar at occurs only upon collection and inventory assessment of a previously 
used and returned jar.  
The required blood pressure control medications are prescribed by the Investigator after 
patients have signed their ICF for study enrolment. The content of the supply is eCRF recorded 
in order to verify treatment compliance at subsequent office visits.   
 
7.3 
Home Procedures 
7.3.1 
IMP/Hypertension Control Medication Intake  
Patients receive an IMP jar from the Investigator for a biweekly supply containing 14(+4) 
capsules. In the event of a home/workplace visit on Day 1 and Day 28, a monthly supply of 
capsules can be provided in order to ensure supply for 1 month. Patients are instructed to take 
one capsule with water in the morning between 06:30 and 08:30 prior to breakfast. The 
capsule should be swallowed whole and not chewed, dissolved or opened. Patients will record 
the daily capsule intake in their diary along with any time or intake deviation. A supervised 
capsule intake occurs only on Day -14, Day -1, Day 1 and Day 55 during the visit. 
The hypertension control medication is administered as prescribed by the Investigator. 
Patients will record the daily intake of the control medication in their diary. 
 
7.3.2 
24-Hour Ambulatory Blood Pressure Monitoring  
Twenty-four hour ambulatory blood pressure monitoring (ABPM) will include mean daytime 
systolic and diastolic blood pressure values (measured every 20 minutes from 8 am to 10 pm) 
and night-time values (measured every 20 minutes from 10 pm till 8 am) along with heart rate 
measurements on Day -1 prior to administration of the first DP13 dose and on Day 55 after 
the administration of the second-to-last DP13 dose. A locally calibrated and validated device 
(e.g. Spacelab Healthcare) will be used; the device is fitted at the hospital outpatient 
department or at the patient’s home or workplace by medically-qualified staff on Day -1 and 
Day 55 prior supervised IMP intake by the patient. The particular device used for a patient 
cannot be switched during treatment.  
The light digital monitor with convenient carry pouches takes the blood pressure reading at 
regular intervals by inflating and subsequently deflating customized cuffs placed around the 
non-dominant upper arm for 24-hour recording of about 70 readings. The patient may follow 
his/her regular routine yet refrain from exercising or taking a bath or shower. In addition, in 
order to assure proper measurements, the patient should sit down prior to reading, keep the 
cuff at the same level as the heart and rest the arm steady. The patient will also be asked to 
keep a diary on activities, meals and sleep to document what he/she was doing just before 
the reading was taken. At the end of the 24-hour period, the patient may remove the monitor 
and cuff, shower or bathe and return the device to the Investigator at the clinic. The machine 
will have stored all readings as source data that are uploaded in the eCRF. 
 
7.3.3 
24-Hour Urine Sampling  
Urine will be collected into standard weight polyethylene containers over 24 hours on Day -1 
(prior to the first treatment dose) and on Day 55 (prior to the last treatment dose). The 
Investigator or qualified staff will hand out the containers during the outpatient visit or 
home/workplace visit. Procedures for collecting and processing of the urine samples will be 
detailed in a separate document. The patient will return the urine containers to the Investigator 


Study Protocol: DP13C201 
Confidential 
Page 39 
Version 5.0 
 
DP13 
on the subsequent office visit (Day 1 and Day 56). After measuring the total 24-hour urine 
volume, volume-adjusted aliquots are generated following the Laboratory Manual procedures 
and shipped to the Central Laboratory at the Inselspital in Bern. 
 
7.4 
Laboratory Procedures 
7.4.1 
Sample Processing and Shipment 
Spot urine samples and blood samples for safety laboratory analyses are processed according 
to local routine practice. The other collected blood and 24-hour urine samples are processed 
according to the Laboratory Manual. Frozen plasma and urine aliquots for pharmacokinetic, 
pharmacodynamics and therapeutic drug monitoring will be shipped at the end of the study to 
the Central Laboratory at the Inselspital in Bern, Switzerland. Procedures for shipping will be 
detailed in a separate document. 
 
7.4.2 
Local Blood Analyses 
The safety laboratory sample is analysed at the local clinic laboratory for routine electrolyte, 
metabolic and lipid panels that may include the following measurements: 
 
Routine Biochemistry 
Units 
 
 
Units 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (ALP) 
Amylase 
Gamma-glutamyl transferase (GGT) 
Sodium 
Potassium 
Chloride 
Calcium 
Magnesium 
Inorganic phosphate 
Glucose 
IU/L 
IU/L 
IU/L 
IU/L 
IU/L 
mmol/L 
mmol/L 
mmol/L 
mmol/L 
mmol/L 
mmol/L 
mmol/L 
 
Urea 
Uric acid 
Total bilirubin 
Direct bilirubin 
Creatinine 
Total protein 
Albumin 
Total cholesterol 
Triglycerides 
Lactate dehydrogenase 
Creatine phosphokinase  
mmol/L 
μmol/L 
μmol/L 
μmol/L 
μmol/L 
g/L 
g/L 
mmol/L 
mmol/L 
IU/L 
IU 
Routine Haematology 
Units 
 
 
Units 
White blood cell (WBC) count 
Red blood cell (RBC) count 
Hemoglobin 
Hematocrit (packed cell volume) 
Mean cell volume (MCV) 
109/L 
1012/L 
g/dL 
% 
fL 
 
Mean cell hemoglobin (MCH) 
MCH concentration (MCHC) 
Platelet count 
Differential WBC 
pg 
g/dL 
109/L 
109/L or 
% 
Serum Pregnancy Test  
(only to confirm any initial positive results with the urine dipstick test) 
Unit 
Human chorionic gonadotropin (hCG) 
mIU/mL 
 
The screening blood samples are analysed at the local clinical laboratory for verification of 
applicability of I/E criteria with the following measurements: 
 


Study Protocol: DP13C201 
Confidential 
Page 40 
Version 5.0 
 
DP13 
Blood 
Assay 
Units 
Aldosterone concentration 
Local routine 
ng/mL 
Renin concentration or renin activity 
Local routine 
mU/L or ng/mL/h 
 
7.4.3 
Central Blood Analyses 
The pharmacokinetic and pharmacodynamic blood samples are processed locally to plasma 
samples and analysed at the Central Laboratory at the Bern Inselspital as outlined below: 
 
 
Sample 
Processing 
Assay 
(Manufacturer) 
Units 
Pharmacokinetics: 
 
 
 
   DP13 & metabolite analysis 
   (placebo samples are not analysed) 
EDTA/Plasma 
LC-MS/MS 
ng/mL 
Pharmacodynamics:    
 
 
 
   Aldosterone/PRC analysis 
EDTA-Plasma 
CLIA (DiaSorin) 
ng/dL / mU/L 
   PRA analysis 
EDTA-Plasma 
LC-MS/MS 
ng/mL/h 
   Electrolyte analysis 
   (e.g. sodium, potassium, chloride) 
Heparin-Plasma 
IES 900 (Roche) 
mmol/L 
   ACTH analysis 
EDTA-Plasma 
ECLIA (Roche) 
pg/mL  
   Steroid hormone panel analysis 
   (multiplexing of up to 17 steroids) 
EDTA-Plasma 
LC-MS/MS 
ng/mL 
 
7.4.4 
Local Urine Analyses 
The spot safety urine sample is analyzed at the local clinic laboratory for routine measures. 
Women of childbearing potential provide a pregnancy test. Any unclear results are clarified 
with a blood-based pregnancy test. 
 
Routine Urinalysis 
Units 
 
 
Units 
Microscopic examination 
Specific gravity 
pH 
Protein 
Glucose 
+ 
NA 
NA 
+ 
+ 
 
Ketones 
Leukocytes 
Blood 
Urobilinogen 
+ 
+ 
+ 
+ 
Urine Dipstick Pregnancy Test (UPT) 
Unit 
 
 
 
Human chorionic gonadotropin (hCG) 
NA 
 
 
 
 
7.4.5 
Central Urine Analyses 
The aliquots generated from quantitative 24-hour urine samples are analyzed at the Central 
Laboratory at the Bern Inselspital for:  
 
 


Study Protocol: DP13C201 
Confidential 
Page 41 
Version 5.0 
 
DP13 
 
Sample Processing 
Assay 
(Manufacturer) 
Units 
Pharmacokinetics: 
 
 
 
   DP13 & metabolite analysis 
Volume-adjusted aliquot 
LC-MS 
μg/24 hrs 
Pharmacodynamics:    
 
 
 
   Electrolytes & creatinine 
Volume-adjusted aliquot 
ISE 900 (Roche) 
mmol/24 hrs 
   Steroid hormone panel 
   (incl. Tetrahydroaldosterone) 
Volume-adjusted aliquot 
GC-MS 
μg/24 hrs 
 
8 
SAFETY 
8.1 
Adverse Event Reporting 
8.1.1 
Adverse Event 
An adverse event is any untoward medical occurrence in a patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the 
treatment. An adverse event can therefore be any unfavourable and/or unintended sign, 
symptom, or disease temporally associated with the use of a pharmaceutical product, whether 
or not related to the pharmaceutical product. Abnormal laboratory values constitute adverse 
events only if they induce clinical sign or symptoms that are considered clinically significant or 
require intervention.  
 
The causal relationship between an adverse event and the study drug is defined as follows: 
Not Related 
The adverse event is definitely caused by the patient's clinical state or 
the study procedure/conditions. 
Unlikely Related 
The temporal association between the adverse event and the drug is 
such that the drug is not likely to have any reasonable association with 
the adverse event. 
Possibly Related 
The adverse event follows a reasonable temporal sequence from the 
time of drug administration but could have been produced by the 
patient's clinical state or the study procedures/conditions. 
Related 
The adverse event follows a reasonable temporal sequence from the 
time of drug administration, abates upon discontinuation of the drug, 
and reappears when the drug is reintroduced. 
 
The severity of an adverse event will be recorded as one of the following: 
Mild 
Easily tolerated; does not interfere with normal daily activities; does 
not require intervention 
Moderate 
Causes some interference with daily activities; minimal, local, or 
non-invasive intervention indicated 
Severe 
Medically significant event; daily activities limited or completely halted; 
hospitalisation or prolongation of hospitalisation indicated 


Study Protocol: DP13C201 
Confidential 
Page 42 
Version 5.0 
 
DP13 
Every reasonable effort will be made to follow-up patients who have an adverse event at the 
post-study visit, if possible, until resolution.  
 
8.1.2 
Adverse Drug Reactions 
All noxious and unintended responses to an IMP (i.e. where a causal relationship between an 
IMP and an adverse event is at least a reasonable possibility) related to any dose should be 
considered adverse drug reactions. 
For marketed medicinal products, a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease 
or for modification of physiological function is to be considered an adverse drug reaction. 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (e.g. Investigator’s Brochure 
for an unapproved IMP). 
As Reference Safety Information (RSI), the Investigator Brochure will be used in order to 
evaluate the expectedness of each event. 
 
8.1.3 
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose either: 
• 
results in death 
• 
is life threatening 
• 
requires inpatient hospitalisation or prolongation of existing hospitalisation 
• 
results in persistent or significant disability/incapacity (disability is defined as a substantial 
disruption of a person’s ability to conduct normal life functions) 
• 
is a congenital anomaly/birth defect 
An important medical event that may not result in death, be life threatening or require 
hospitalisation may be considered a serious adverse drug experience when, based upon 
appropriate medical judgement, it may jeopardise the patient or may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in patient hospitalisation, 
or the development of drug dependency or drug abuse. 
Instances of death or congenital abnormality, if brought to the attention of the Investigator at 
any time after cessation of the study treatment and considered by the Investigator to be 
possibly related to the study treatment, will be reported to the Sponsor. 
 
Definition of Life Threatening 
An adverse event is life threatening if the patient was at immediate risk of death from the time 
of the event as it occurred; i.e. it does not refer to an event that might have caused death if it 
had occurred in a more serious form. For instance, drug-induced hepatitis that resolved 
without evidence of hepatic failure would not be considered life threatening even though 
drug-induced hepatitis can be fatal. 
 


Study Protocol: DP13C201 
Confidential 
Page 43 
Version 5.0 
 
DP13 
Definition of Hospitalisation 
Adverse events requiring hospitalisation should be considered serious. In general, 
hospitalisation signifies that the patient has been detained (usually involving an overnight stay) 
at the hospital or emergency ward for observation and/or treatment that would not have been 
appropriate at home. When in doubt as to whether hospitalisation occurred or was necessary, 
the adverse event should be considered serious. 
Hospitalisation for elective surgery or routine clinical procedures, which are not the result of 
an adverse event, need not be considered adverse events and should be recorded on a clinical 
assessment form and added to the eCRF. If anything untoward is reported during the 
procedure, this must be reported as an adverse event and either ‘serious’ or ‘non-serious’ 
attributed according to the usual criteria. 
 
8.1.4 
Serious Adverse Event Reporting 
Every Serious Adverse Event (SAE), regardless of suspected causality, occurring after the 
subject has provided informed consent and until at least 30 days after the subject has stopped 
study treatment must be reported to the Sponsor within 24 hours of site awareness. Any SAE 
experienced after this 30-day period should only be reported to the Sponsor if the Investigator 
suspects a causal relationship to the study treatment. Recurrent episodes, complications, or 
progression of the initial SAE must be reported as follow-up to the original episode within 24 
hours of the Investigator receiving the follow-up information. The follow-up information of an 
SAE should describe whether the event has resolved or continues, if and how it was treated, 
and whether the patient continued or withdrew from study participation. 
Information about all SAEs will be recorded using the safety tool integrated into the eCRF. In 
case of technical difficulties, SAE notification can be carried out by using a paper form 
contacting the Contract Research Organization (CRO) in charge of Pharmacovigilance via 
email at all_phv@opis.it or by fax using the following number: Fax: +39 0362 633622; Tel: +39 
0362 633311, +39 349 3925306. The event is nevertheless to be reported on the eCRF once 
technical difficulties have been resolved. 
If unblinding of an individual patient treatment code is deemed necessary, such as in case of 
patient emergencies or medically important adverse events (i.e. SUSAR), the code break will 
be performed using the tool integrated in eCRF by the Pharmacovigilance unit in charge, after 
agreement with the Sponsor. The documentation in an unblinded version will permit the 
notification of the case to the Regulatory Authorities. The treatment information will remain 
internally at the Pharmacovigilance Department and will be notified to the Sponsor only at the 
end of the study. 
8.1.4.1 
Serious adverse event reporting requirements for Swiss Centers 
Serious adverse events (SAE) and suspected unexpected serious adverse reactions (SUSAR) 
are to be reported in accordance with the Swiss Ordinance on Clinical Trials in Human 
Research as follows: 
Art. 40 - Serious adverse events (SAE) in clinical trials of medicinal products  
1. If, in the course of a clinical trial, serious adverse events occur in participants, the 
Investigator must document these in a standardised manner and notify the sponsor 
within 24 hours after they become known. 
2. The Investigator shall notify the responsible ethics committee of a fatal serious adverse 
event occurring at a trial site in Switzerland within 7 days.  


Study Protocol: DP13C201 
Confidential 
Page 44 
Version 5.0 
 
DP13 
3. The coordinating Investigator shall also report events as specified in paragraph 2 to 
the responsible ethics committees concerned within the same period. 
Art.41 -Suspected unexpected serious adverse reactions (SUSAR) in clinical trials of 
medicinal products 
1. If, in the course of a clinical trial, a suspected unexpected serious adverse reaction 
occurs in participants, the Investigator must document this in a standardised manner 
and notify the sponsor within 24 hours after it becomes known. 
2. The Investigator shall notify the responsible ethics committee of a fatal suspected 
unexpected serious adverse reaction occurring in Switzerland within 7 days, and of 
any other suspected unexpected serious adverse reaction within 15 days. 
3. If a suspected unexpected serious adverse reaction occurs at one of the trial sites, the 
coordinating Investigator shall also notify the responsible ethics committees concerned 
in accordance with paragraph 2, within the same period. 
4. The notifications specified in paragraph 2 shall also be made to the Agency. This 
obligation rests on the sponsor.  
 
8.1.5 
Special Situations 
Safety events of special situation include: 
1. 
Medication error 
2. 
Abuse/Misuse/Overdose 
All events of special situation, with or without associated adverse event, should be monitored 
and recorded in the eCRF, as described in 8.1.4 section. 
 
8.2 
Reporting of Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the treatment under 
study may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and handled 
as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented 
even if the patient was discontinued from the study. If a female patient becomes pregnant 
during the course of the study, the treatment should be discontinued immediately.  
Also, paternal exposure should be reported. Pregnancy of the patient’s partner is not 
considered to be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, 
elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be 
followed up and documented even if the patient was discontinued from the study. Where a 
report of pregnancy is received, prior to obtaining information about the pregnancy, the 
Investigator must obtain the consent of the patient’s partner. 
The Investigator shall report all pregnancy exposure occurring in a female patient or in a male 
patient’s partner within 24 hours to the Sponsor using the safety tool integrated into the eCRF. 
In case of technical difficulties, pregnancy notification can be carried out using a paper form 
by contacting the Contract Research Organization (CRO) OPIS in charge of 
Pharmacovigilance via email at all_phv@opis.it or by fax using the following number: Fax: +39 
0362 633622; Tel: +39 0362 633311, +39 349 3925306. 


Study Protocol: DP13C201 
Confidential 
Page 45 
Version 5.0 
 
DP13 
The Investigator should counsel the subject; discuss the risks of continuing with the pregnancy 
and the possible effects on the fetus. Monitoring of the subject should continue until conclusion 
of the pregnancy 
 
9 
STUDY TERMINATION 
If, in the opinion of the Investigator, the clinical observations in the study suggest that it may 
be unwise to continue, the Investigator may terminate part of or the entire study after 
consultation with the Sponsor. In addition, the Sponsor may terminate part of or the entire 
study for safety or administrative reasons. A written statement fully documenting the reasons 
for study termination will be provided to the EC/IRB and national Health Authorities.  
Patients completing per protocol the entire study are switched at the end of the study to their 
Investigator-prescribed standard of care. Any subsequent information on patient disease 
subtyping i.e. diagnostic work-up to identify the presence of an underlying aldosterone-
producing adenoma (APA), the lateralization of an APA or the detection of bilateral adrenal 
hyperplasia (BAH) are requested by the Central Review Board and Sponsor for potential 
additional retrospective analyses. This information will be obtained through contacts with the 
patients’ treating physician. 
 
10 
STATISTICAL METHODS 
10.1 
Hypothesis Testing and Sample Size Calculation 
10.1.1 
Hierarchical Test Procedure 
To maintain the overall type I error rate at 5%, a sequential test procedure for the two primary 
objectives is adopted. The first test determines the effect on ARR, the first primary objective 
at the nominal two-sided alpha level of 5%. If the null hypothesis can be rejected, the second 
test determines the effect on ambulatory systolic blood pressure, the second primary objective 
at the nominal two-sided alpha level of 5%. In order to have enough power for both primary 
comparisons as well as for secondary comparisons within single groups, the power for the 
individual tests is set at 95%.  
 
10.1.2 
First Primary Objective 
Hypothesis: 
The working hypothesis is that there is a difference in ARR 
between baseline and week 8 in all three groups combined. 
Null-hypothesis H0: 
m1 = m2 
Alternative hypothesis H1: 
m1 ≠ m2  
Primary outcome: 
Change in ARR from baseline to week 8 
Test: 
Paired means test 
Power: 
95% 
Significance level: 
5% (two-sided) 
Standard deviation: 
The standard deviation of ARR determined as PAC/PRA was 
derived from a representative sample of 27 patients with PA. 
Due to the skewed data distribution, ARR was first log-
transformed. The standard deviation of log-transformed ARR 
was 0.74, the back-transformed geometric mean was 1117 


Study Protocol: DP13C201 
Confidential 
Page 46 
Version 5.0 
 
DP13 
ng/L/ng/mL/h. Neither the correlation of log-transformed ARR 
between two time points nor the standard deviation of the 
change are known. 
Sample size: 
The sample size was calculated based on log-transformed 
values. The expected percent (%) decrease in ARR was log-
transformed and expressed as effect size. 
Total sample size: 
See table (the number for the whole study is given, i.e. all three 
groups combined) 
 
The total number of patients with PA varies depending on the expected ARR decrease and 
expected correlation between baseline and week 8 values: 
 
 
Decrease (%) 
Correlation Effect size 
Number of patients 
40 
0.4 
0.63 
35 
40 
0.5 
0.69 
30 
40 
0.6 
0.77 
24 
50 
0.4 
0.86 
20 
50 
0.5 
0.94 
17 
50 
0.6 
1.05 
14 
60 
0.4 
1.13 
13 
60 
0.5 
1.24 
11 
60 
0.6 
1.39 
9 
70 
0.4 
1.49 
9 
70 
0.5 
1.63 
8 
70 
0.6 
1.82 
7 
 
10.1.3 
Second Primary Objective 
Hypothesis: 
The working hypothesis is that there is a difference in ambulatory 
systolic blood pressure (aSBP) between baseline and week 8 in 
all three groups combined. 
Null-hypothesis H0: 
m1 = m2 
Alternative hypothesis H1: 
m1 ≠ m2  
Primary outcome: 
Change in aSBP from baseline to week 8 
Test: 
Paired means test 
Power: 
95% 
Significance level: 
5% (two-sided) 
Standard deviation: 
The standard deviation of the change in aSBP was derived from 
two publications and data from the DP13C101 phase I study. 
Amar et al. reported that treatment with LCI699 over 4 weeks 
reduced the 24-hour ambulatory SBP by -4.1 mmHg (95% CI: -
8.1 to -0.1), which yields a standard deviation of 7.4 mmHg for 
the difference. Parthasarathy et al. reported that reductions from 
baseline in office SBP at the final visit were -9.9 mmHg (SE 2.3) 
for eplerenone and -27.0 mmHg (SE 2.3) for spironolactone, 
which yields a standard deviation of 19.1. In the DP13 phase I 
study, standard deviations ranging from 6 to 10 mmHg were 


Study Protocol: DP13C201 
Confidential 
Page 47 
Version 5.0 
 
DP13 
observed for changes in supine SBP from baseline to day 2 to 8 
in the group receiving 8 mg DP13 QD. 
Total sample size: 
See table (the number for the entire study is given, i.e. all three 
groups together) 
 
The total number of patients with PA varies depending on the expected difference and the 
expected standard deviation of the difference between baseline and week 8 values: 
 
Difference 
[mmHg] 
SD of 
difference 
Number of patients 
-5.0 
6.0 
21 
-5.0 
7.4 
31 
-5.0 
8.0 
36 
-5.0 
10.0 
54 
-5.0 
19.1 
192 
-6.0 
6.0 
16 
-6.0 
7.4 
22 
-6.0 
8.0 
26 
-6.0 
10.0 
39 
-6.0 
19.1 
134 
-8.0 
6.0 
10 
-8.0 
7.4 
14 
-8.0 
8.0 
16 
-8.0 
10.0 
23 
-8.0 
19.1 
77 
-10.0 
6.0 
7 
-10.0 
7.4 
10 
-10.0 
8.0 
11 
-10.0 
10.0 
16 
-10.0 
19.1 
50 
 
The final sample size was set at 36 patients in total with 12 patients in each dose arm (see 
section 6.2). 
 
10.2 
Statistical Analysis Methods 
The detailed statistical analyses will be described in the statistical analysis plan (SAP) as a 
separate document.   
 
10.2.1 
Analysis Set 
The full analysis set (FAS) is defined as all randomized patients who received at least one 
dose of study drug. Following the intention-to-treat (ITT) principle, patients in this population 
will be analysed according to the treatment dose they were randomized to.  
The per-protocol (PP) set is based on the FAS excluding patients with major protocol violations 
and patients who did not receive the randomized treatment. Major protocol violation will be 


Study Protocol: DP13C201 
Confidential 
Page 48 
Version 5.0 
 
DP13 
defined as follows: 1) patients who did not receive the assigned treatment dose; 2) patients 
with significant protocol violation that affect efficacy evaluations. 
The safety population is defined as all randomized patients who received at least one dose of 
study drug. Patients will be analysed according to the actual dose they received. 
 
10.2.2 
Baseline Characteristics 
Baseline characteristics will be presented using descriptive statistics based on the FAS. 
Continuous variables will be summarized as mean and standard deviation as well as median 
and interquartile range. Categorical variables will be summarized as frequency and 
percentage. 
 
10.2.3 
Primary Analysis 
The primary analysis will be an ITT analysis, i.e. all patients will be analysed in the dose arms 
they were allocated to. The first primary outcome, change in ARR from baseline (Day 1) to 
end of the 8-week DP13 treatment period (Day 56), will be calculated from a linear model. 
Before analysis, ARR will be log-transformed due to its log-normal distribution. The log-
transformed ARR value at Day 56 will be used as dependent variable, the log-transformed 
baseline value, dosage group, and the stratification factors used for randomization as 
independent variables in the model. The overall change from baseline, the change in individual 
dosage groups, and the dose-dependence will be assessed using contrasts. All effect 
measures will be back-transformed to the original scale (i.e. exponentiated) and accompanied 
by a 95%-confidence interval and associated p-value. The second primary outcome, change 
in aSBP, will be analysed likewise. Since SBP values are normally distributed, no 
transformation is needed. 
 
10.2.4 
Secondary Analysis 
Changes in secondary and exploratory outcomes from baseline (Day 1) to end of the 8-week 
DP13 treatment period (Day 56) and end of the 2-week withdrawal period (Day 70) will be 
analysed as described above using linear models. If necessary, values will be transformed in 
an adequate way in order to obtain normally distributed model residuals. 
Office blood pressure will be repeatedly measured at baseline (Day 1) and at biweekly office 
visits (week 2, week 4, week 6, week 8 and week 10), and therefore be analysed in a mixed-
effects repeated-measure model, with dosage group, time point, and stratification factors as 
fixed effects and a random intercept for the patients. 
Adverse and serious adverse events will be presented descriptively, showing the total number 
of events as well as the absolute and relative frequency of patients with events in each dosage 
group. 
In a per-protocol analysis, all primary, secondary, and exploratory outcomes are analysed 
using the PP analysis set. Further secondary analyses such as subgroup analyses will be 
specified in the SAP 
 


Study Protocol: DP13C201 
Confidential 
Page 49 
Version 5.0 
 
DP13 
10.2.5 
Missing Data 
In main analyses according to the ITT principle, patients with missing outcome values will not 
be disregarded from the analysis. In a sensitivity analysis, multiple imputations will be applied. 
The procedure will be described in the SAP. 
 
10.3 
Interim Analysis 
There are currently no reliable data on the correlation between baseline and follow-up ARR 
and SBP values or on the standard deviation of the change of these values from baseline. 
Therefore, the sample size will be reassessed during the study to assure sufficient power. One 
blinded interim analysis is therefore planned after completion of two thirds of the patients 
(N=24) to reassess the sample size assumptions. The reassessment of the sample size will 
only be based on the standard deviation of the baseline and follow-up values, the standard 
deviation of changes from baseline and correlations between baseline and follow-up values 
observed in the study data. Observed changes will not be displayed, nor will expected changes 
used for power analysis be modified. No formal testing of changes will take place; therefore 
the alpha-level does not require adjustment. 
 
11 
QUALITY ASSURANCE AND CONTROL 
11.1 
Data Quality Assurance 
OPIS, the CRO working on behalf of the Sponsor, developed Clinical.net, a proprietary study 
web portal and database that is GCP and FDA 21 CFR Part 11 compliant. OPIS will review 
the data entered in the eCRF by investigational staff for completeness and accuracy and 
instruct site personnel to make any necessary corrections or additions. The Data Manager will 
perform the cleaning session by reviewing the warning messages raised by on-line checks 
and by running post-entry checks by means of validation programs and data listings specific 
for the study. The occurrence of any protocol deviations will also be checked. 
If clarifications are needed, the Data Manager will raise queries through the web application. 
Designated Investigator site staff will be required to respond to queries and the Data Manager 
will make the correction to the database according to the responses. 
Data collection and query flows, as well as the on-line and off-line checks, are detailed in the 
Data Management Plan and Data Validation documents. 
Concomitant medications and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the ATC classification system. Medical 
history/current medical conditions and AEs will be coded using MedDRA. 
The database will be locked after all the above actions have been completed and the database 
has been declared complete and accurate. 
 
11.2 
Case Report Form 
Designated Investigator staff will enter the data required by the protocol into the eCRF using 
fully validated software that conforms to 21 CFR Part 11 requirements. Designated 
Investigator site staff will not be given access to the Electronic Data Capture system until they 
are trained.  


Study Protocol: DP13C201 
Confidential 
Page 50 
Version 5.0 
 
DP13 
Web-based software will be used, and no installation procedure is needed. Each site will be 
authorized by the administrator to access the eCRF. Each site-qualified personnel will be 
allowed to access the eCRF by means of a ‘login mask’ requiring user ID and password and 
may read, modify, and update only the information entered at his or her site and according to 
their profile. Each page lists a site code and a subject code. 
On-line validation programs will check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected before transfer to the CRO 
working on behalf of the Sponsor. The Investigator will certify that the data entered in the 
eCRF are complete and accurate.  
After database lock, the Investigator will receive a CD-ROM of subject data for archiving at 
the investigational site. 
 
11.3 
Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is compliant with the currently approved protocol/amendment(s), with 
International Conference on Harmonization Good Clinical Practice (ICH GCP), and with 
applicable regulatory requirement(s).  
The field monitor will visit the site to check the completeness of patient records, the accuracy 
of entries on the eCRFs, the adherence to the protocol and to GCP, the progress of enrolment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits.  
The Investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information. All information on CRFs must be traceable to these source documents in the 
patient's file. The Investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient). 
Monitoring standards require full verification for the presence of informed consent, adherence 
to the inclusion/exclusion criteria, documentation of SAEs, and of data that will be used for all 
primary variables. Additional checks of the consistency of the source data with the eCRFs are 
performed according to the study-specific Monitoring Plan (MP). No information in source 
documents about the identity of the patients/subjects will be disclosed. 
 
11.4 
Data Storage and Archiving 
All primary data generated in the clinical study or copies thereof (e.g. laboratory records, data 
sheets, correspondence, photographs, computer records), which are a result of the original 
observations and activities of the clinical study and are necessary for the reconstruction and 
evaluation of the study report, will be retained in the archive of the clinic for a period of 25 
years in coded form after issue of the final clinical study report (CSR). At this time the Sponsor 
will be contacted to determine whether the data should be returned, retained, or destroyed on 
their behalf. Regardless, all data shall remain encoded. The Sponsor will be notified of the 
financial implications of each of these options at the time. It is the Sponsor’s responsibility to 
consider any regulatory implications of these options. No data will be destroyed without the 
agreement of the Sponsor. 


Study Protocol: DP13C201 
Confidential 
Page 51 
Version 5.0 
 
DP13 
Biological samples may be retained exclusively for analyses stated in the protocol and until 
completion of the clinical study report, after which all samples will be destroyed. The samples 
will not be used for any other purposes. The Sponsor will be notified of the intent to destroy 
samples and any financial implications before specimens are destroyed on their behalf. 
 
12 
REPORTS AND PUBLICATIONS 
12.1 
Reports to the EC/IRB and HAs 
Upon completion of the study, the Investigator will provide the Ethics Committee (EC) or 
Institutional Research Board (IRB) with a summary of the study outcome. The national Health 
Authority (HA) will be provided with a Declaration of the End of a Clinical Trial form and safety 
report (within 90 days of completion or within 15 days of a premature termination).  
 
12.2 
Data Analysis 
The CRO will perform the data analysis. The study results will be reported in one clinical study 
report (CSR). A detailed statistical analysis plan (SAP) describing the methodology to be used 
will be issued by the CRO and finalized upon Sponsor approval prior to database lock.  
 
12.3 
Clinical Study Report 
The CRO will prepare an integrated clinical efficacy and safety report that requires Sponsor 
approval. The report will be in structure and content accordance with the International Council 
for Harmonisation (ICH). The draft report may be submitted for quality assurance audit, the 
findings of which will be incorporated into the final version. An electronic copy of the final report 
will be provided to the Sponsor. The study report will be provided in PDF format unless 
otherwise agreed with the CRO.  
 
12.4 
Publications 
The sponsor assures that all results of this study are published in a peer-reviewed journal in 
line with the Declaration of Helsinki (World Medical Association, 2008 #2). All results relate to 
all outcomes as defined in this protocol regardless of the direction or statistical significance. It 
will be assured that the manuscript follows the principle of the CONSORT guidelines or any 
other applicable reporting guideline (www.equator.org). Co-authorship on any of the 
publications will be based on contribution to the study and manuscript according to the criteria 
of the International Committee of Medical Journal Editors (International Committee of Medical 
Journal Editors, 2009; www.icmje.org). Before any data from the study are published on the 
initiative of the Central Review Board, a manuscript will be sent to the Sponsor for review and 
approval at least 30 days prior to submission to the publisher. 
 


Study Protocol: DP13C201 
Confidential 
Page 52 
Version 5.0 
 
DP13 
13 
REGULATORY CONSIDERATIONS 
13.1 
Clinical Trial Authorization 
This investigation will only be performed after the national Health Authorities have issued a 
Clinical Trial Authorisation for this study. Health Authority approval will be sought in parallel 
with EC approval. The Health Authorities must also give their written approval of any 
substantial amendments to the approved protocol or IMP Dossier likely to affect the safety of 
the subjects or the conduct of the study (with the exception of emergency modifications 
required for subject safety). The body responsible for making the submission of the clinical 
trial application will maintain records of all correspondence with the Health Authorities. 
 
13.2 
Visits by Regulatory Authorities 
With the exception of statutory regulatory authority inspections, the Sponsor will be consulted 
in the event of inspection of the clinical site by an outside authority before the Inspectors are 
permitted access to any of the study records or study areas. 
 
14 
ETHICAL CONSIDERATIONS 
14.1 
Ethics Committee Approval 
An Ethics Committee (EC) or Institutional Review Board (IRB) will consider this study. The 
study will not start until the EC have given their written approval of the protocol and informed 
consent form. If there are any changes to the approved protocol (with the exception of 
emergency modifications required for subject safety), a protocol amendment will be issued by 
the Sponsor. The EC must give their written approval of any substantial amendments likely to 
affect the safety of the subjects or the conduct of the study. The EC must be notified of all 
other changes. The CRO will maintain records of all correspondence with the EC. 
 
14.2 
Informed Consent 
Prior to the commencement of the study, each patient will be provided with a study-specific 
informed consent form (ICF) giving details of the investigational medicinal product (IMP), 
procedures, and potential risks involved. Patients will be asked to provide consent for their 
study samples to be used for further analysis, which will be reported separately from this study. 
Patients will also be instructed that they are free to obtain further information from the 
Investigator and that they are free to withdraw their consent and to discontinue their 
participation in the study at any time.  
The approved Informed Consent Form must be filed in the study files (clinical Trial Master File 
[TMF] and Investigator File [IF]). All signed ICFs will be filed in the Investigator’s file at site 
only. Patients will be identified in documentation and throughout evaluation by the number 
assigned to them during the study. Patients will be informed that all study findings will be 
stored electronically and handled in the strictest confidence. Following discussion of the study 
with the Investigator, patients will sign the ICF in the presence of a suitably trained member of 
staff to indicate that they are freely giving their informed consent. 
 


Study Protocol: DP13C201 
Confidential 
Page 53 
Version 5.0 
 
DP13 
14.3 
Declaration of Helsinki 
This study will be conducted in accordance with consensus ethics principles derived from the 
Declaration of Helsinki on medical research involving human subjects. 
 
15 
REGULATIONS 
15.1 
Good Clinical and Manufacturing Practice 
This study will be conducted in accordance with the following guidelines and directives: 
• 
ICH E6 (R2): Good Clinical Practice (GCP): Consolidated guideline CPMP/ICH/135/95 
(effective 14 June 2017), adopted in the EU by CPMP, the committee for proprietary 
medicinal products at the EMA 
• 
European Commission Directive 2001/20/EC (April 2001) 
• 
European Commission Directive 2003/94/EC (October 2003) 
• 
European Commission Directive 2005/28/EC (April 2005) 
• 
Manufacture of Investigational Medicinal Products: Volume 4, Annex 13 of the EU 
Guidelines to Good Manufacturing Practice (GMP) (February 2010) 
 
15.2 
Protocol Adherence 
The clinical site will adopt all reasonable measures to record data in accordance with the 
protocol. Under practical working conditions, however, some minor variations may occur due 
to circumstances beyond the control of the Investigator. All such deviations will be documented 
in the study records, together with the reason for their occurrence; where appropriate, 
deviations will be detailed in the clinical study report. 
The CRO Quality Assurance Unit may conduct an audit of the study procedures at the site. 
The findings will be reported to the Project Manager and site management. 
 
16 
FINANCES AND INDEMNITY 
The finances and indemnity for this study will be subject of separate agreements between the 
Sponsor and the Investigator-affiliated institutions as well as the Sponsor and the CRO. 
 
17 
INSURANCE 
The Sponsor will provide insurance for the clinical study. A copy of the certificate is filed in 
each Investigator site file and the trial master file. 


Study Protocol: DP13C201 
Confidential 
Page 54 
Version 5.0 
 
DP13 
18 
REFERENCES 
DP13 – Investigator’s Brochure (Edition 1, 12 December 2018) 
 
Amar L, Azizi M, Ménard J, Peyrard S, Watson C, Plouin PF. Aldosterone synthase inhibition 
with LCI699: a proof-of-concept study in patients with primary aldosteronism. 
Hypertension 2010;56:831-8 
 
Calhoun DA, White WB, Krum H, Guo W, Bermann G, Trapani A, Lefkowitz MP, Ménard J. 
Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: 
Results of a randomized, double-blind, placebo- and active-controlled phase 2 trial. 
Circulation 2011;124:1945-55 
 
Connell JM, MacKenzie SM, Freel EM, Fraser R, Davies E. A lifetime of aldosterone excess: 
long-term consequences of altered regulation of aldosterone production for 
cardiovascular function. Endocr Rev. 2008;29:133-54 
 
Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young 
WF Jr. The management of Primary Aldosteronism: Case detection, diagnosis, and 
treatment: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 
2016;101:1889-916 
 
Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A. Cardiometabolic outcomes 
and mortality in medically treated primary aldosteronism: a retrospective cohort 
study. Lancet Diabetes Endocrinol. 2018;6:51-59 
 
Monticone S, Burrello J, Tizzani D, Bertello C, Viola A, Buffolo F, Gabetti L, Mengozzi G, 
Williams TA, Rabbia F, Veglio F, Mulatero P. Prevalence and clinical manifestations 
of primary aldosteronism encountered in primary care practice. J Am Coll Cardiol 
2017;69:1811-20 
 
Parthasarathy HK, Ménard J, White WB, Young WF, Williams GH, Williams B, Ruilope LM, 
McInnes GT, Connell JM, MacDonald TM. A double-blind, randomized study 
comparing the antihypertensive effect of eplerenone and spironolactone in patients 
with hypertension and evidence of primary aldosteronism. J Hypertens 2011;29:980-
90 
 
Williams TA, Lenders JWM, Mulatero P, Burrello J, Rottenkolber M, Adolf C, Satoh F, Amar 
L, Quinkler M, Deinum J, Beuschlein F, Kitamoto KK, Pham U, Morimoto R, Umakoshi 
H, Prejbisz A, Kocjan T, Naruse M, Stowasser M, Nishikawa T, Young WF, Gomez-
Sanchez CE, Funder JW, Reincke M, Primary Aldosterone Surgery Outcome (PASO) 
investigators. Outcomes after adrenalectomy for unilateral primary aldosteronism: an 
international consensus on outcome measures and analysis of remission rates in an 
international cohort. Lancet Diabetes Endocrinol 2017;5:689-99 
 
 
 


Study Protocol: DP13C201 
 
Page 55 
Version 5.0 
 
DP13 
19 
APPENDIX 
19.1 
Study Plan 
 
Pre-screening 1 
Screening 2 
2-Week  
Run-in 
8-Week  
DP13 Treatment Period 
2-Week 
Withdrawal 
-12 Weeks to Day -15±3 
Day -14±3 
Day -13 
Day 1 
Day 14±33 
Day 28±3 
Day 42±33 
Day 55±23 
Day 56±2 
Day 70±3 
Enrollment / Safety and 
Tolerability 
 
 
 
 
 
 
 
 
Obtain Informed Consent 
X1/2 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X1/2 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
X 
Local Safety Laboratory Blood 
Sample 
X 
X 
 
X 
X 
 
X 
X 
Blood Pressure Control 
Medication Prescription4 
(dose adjustment up to 2 
weeks prior study enrolment; 
thereafter fixed dose 
throughout the study) 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test5 
 
X 
X 
 
 
Day 14±3 
Day 42±3 
 
 
X 
Pick-up/Installation: 
Urine Bottle / ABPM Device 
 
 
X 
 
 
X 
 
 
Return/Collection: 
Urine Bottle / ABPM Device   
 
 
 
X 
 
 
X 
 
Patient Diary dispensation 
X 
X 
X 
X 
X 
X 
X 
 


Study Protocol: DP13C201 
Confidential 
Page 56 
Version 5.0 
   DP13  
 
Pre-screening 1 
Screening 2 
2-Week  
Run-in 
8-Week  
DP13 Treatment Period 
2-Week 
Withdrawal 
-12 Weeks to Day -15±3 
Day -14±3 
Day -13 
Day 1 
Day 14±33 
Day 28±3 
Day 42±33 
Day 55±23 
Day 56±2 
Day 70±3 
Local Spot Urinalysis 
X 
X 
 
X 
X 
 
X 
X 
Body Weight Recording 
X 
X 
 
X 
X 
 
X 
X 
AE Recordings 
X 
X 
 
X 
X 
 
X 
X 
Resting ECG 
X 
X 
 
X 
Day 28±3 
 
X 
X 
Concomitant Medication 
Recording 
X 
X 
 
X 
X 
 
X 
X 
Study Drug Administration 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
Home IMP Intake 
 
 
 
 
X 
 
X 
X 
Compliance verification 
 
X 
X 
X 
X 
X 
X 
X 
IMP Supply Jar Handout 
 
X 
 
X6 
X6 
 
X 
 
Supervised IMP Intake 
 
X 
X 
X 
 
X 
 
 
Efficacy 
 
 
 
 
 
 
 
 
Blood Pressure, Heart Rate 
(automatic electronic device) 
X 
X 
 
X 
X 
 
X 
X 
Blood Sampling (central 
analysis): Aldosterone/PRC, 
PRA, Electrolytes, ACTH, 
Steroids, TDM (therapeutic 
drug monitoring) 
 
X 
 
X 
X7 
 
X 
X 
Urine Sample Aliquot (central 
analyses):  Electrolytes & 
Creatinine, Steroid Hormone 
Panel  
 
 
 
X 
 
 
X 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 


Study Protocol: DP13C201 
Confidential 
Page 57 
Version 5.0 
   DP13  
 
Pre-screening 1 
Screening 2 
2-Week  
Run-in 
8-Week  
DP13 Treatment Period 
2-Week 
Withdrawal 
-12 Weeks to Day -15±3 
Day -14±3 
Day -13 
Day 1 
Day 14±33 
Day 28±3 
Day 42±33 
Day 55±23 
Day 56±2 
Day 70±3 
Blood Sampling (central 
analyses): 
 DP13 & DP13-Metabolites 
 
X 
 
X 
Day 28 
 
X 
X 
Urine Sample Aliquot (central 
analyses):  
DP13 & DP13-Metabolites 
 
 
 
X 
 
 
X 
 
 
1 The pre-screening diagnostic data for de novo diagnosed PA patients (guideline-recommended plasma ARR, suppression test, blood pressure and potassium concentration as 
well as a safety ECG recording) can be used to confirm the inclusion/exclusion criteria if available as source documents. The pre-screening diagnostic tests are therefore 
performed before signing an informed consent form but within 10 weeks prior to study enrolment (Day -14) in order to maintain a hypertension control therapy. 
 
2 The screening assessment data for recently diagnosed PA patients on standard of care (guideline-recommended plasma ARR, blood pressure and potassium concentration 
as well as a safety ECG recording) are supplemented with suppression test data performed within 1 year of study enrolment if available as source document to confirm the 
inclusion/exclusion criteria. The screening data are collected after signing an informed consent form and within 10 weeks prior study enrolment (Day -14) to accommodate 
washout of standard of care, particularly a specified 8-week washout period for spironolactone, in presence of a hypertension control therapy.  
 
3 The Day -1, 14, 42 and 55 visits may be performed at the patient's home or workplace by medically-qualified personnel (if appropriate facilities are available). 
 
4 At the Investigator’s discretion, the doses of doxazosin, verapamil or diltiazem or amlodipine are adjusted up to 2 weeks before study enrolment should office systolic blood 
pressure exceed 190 mmHg or fall below 145 mmHg. The dosage and regimen of the hypertension control therapy is fixed 2 weeks prior to study enrolment until study end.     
 
5 Pregnancy test for women of childbearing potential by means of urine dipstick and, if positive, to be confirmed by a serum test. 
 
6 Two jars are to be dispensed on Day 1 and Day 28 to ensure IMP supply for one month in the event of a home/workplace visit. 
 
7 On Days 14 and 42, blood sampling for central analysis is limited to aldosterone/PRC, electrolytes and steroids.