Early Treatment of Borderline Pulmonary Arterial Hypertension Associated With Systemic Sclerosis (SSc-APAH) A Randomized, Controlled, Double-blind, Parallel Group, Proof-of-concept Trial EDITA
Phase: PHASE2
Conditions: Systemic Sclerosis, Pulmonary Hypertension
Sponsor: Heidelberg University

   CLINICAL TRIAL PROTOCOL 
SYNOPSIS 
Early Treatment of Borderline Pulmonary Arterial Hypertension Associated with Systemic 
Sclerosis (SSc-APAH) 
A randomized, controlled, double-blind, parallel group, proof-of-concept trial  
EDITA 
Local Project ID: 2014-05ED 
 
 
Clinical Trial Code:  EDITA 
EudraCT No.:  
2014-001882-28 
Clinical Phase:  
IIA (proof of concept) 
Version:  
 
3.1 Version, Amendment 2 29.04.2016 
 
 
 
 
 
 
 

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Protocol Outline 
Title 
Early Treatment of Borderline Pulmonary Arterial Hypertension Associated with Systemic 
Sclerosis (SSc-APAH) 
Short title: EDITA 
Local Project ID: 2014-05ED 
Phase 
IIA (proof of concept) 
Sponsor 
Thoraxclinic at the University Hospital Heidelberg represented by its commercial director 
Roland Fank 
Principal Investigator/ Coordinating Investigator  
Prof. Dr. med. Ekkehard Grünig 
Thoraxclinic at the University of Heidelberg 
Centre for pulmonary hypertension 
Röntgenstraße 1 
69126 Heidelberg 
Financing/ Status of the Sponsor  
Co-financing by pharmaceutical industry GlaxoSmithKline GmbH 
 
Indication 
Clinical phenotype systemic sclerosis-patients with borderline-PAH: mean pulmonary arterial 
pressure (mPAP) values at rest (between 21-24 mmHg) and/or elevated mPAP during exercise 
(>30 mmHg, with transpulmonary gradient (TPG) >11 mmHg and pulmonary artery wedge 
pressure (PAWP) < 15 mmHg at rest and <18 mmHg at exercise).  
I27.0 Primary pulmonary hypertension 
M34.9 Systemic sclerosis, unspecified, or 
M35.8 Other specified systemic involvement of connective tissue 
MedDRA (V. 12.0) 
Systemic Sclerosis ID 10042953, Level 4 
Pulmonary Hypertension 10037400, Level 4 
 
 

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Trial Population 
Inclusion Criteria 
Male or female SSc patients with borderline - PAH and 
1. mPAP 21-24 mmHg, TPG > 11 mmHg, PAWP <15 mmHg and/or 
2. Exercise induced elevated mPAP-values >30 mmHg, PAWP <18 mmHg; TPG >15 
mmHg, as defined in Saggar et al. (2012) without left heart or severe lung disease or 
systemic arterial hypertension 
3. Adult patients having completed his/her 18th birthday 
4. Patients with definite diagnosis of Systemic Sclerosis using the scleroderma criteria 
of the American Rheumatism Association  
5. SSc-disease duration >3 years  
6. Able to understand and willing to sign the Informed Consent Form 
7. Negative pregnancy test at the start of the trial and appropriate contraception 
throughout the study for women with child-bearing potential. 
Exclusion Criteria 
1. Any connective tissue diseases (CTD) other than SSc 
2. Pulmonary hypertension (PH) confirmed by right heart catheter (RHC) before 
enrolment, i.e. mPAP ≥25 mmHg at rest  
3. Patients presenting normal mPAP values, i.e. mPAP<21 mmHg at rest, and ≤30 mmHg 
during exercise, and/or PAWP 15 mmHg at rest or 18 mmHg during exercise 
4. Ongoing or a history of >2 weeks of continued use of therapies that are considered 
definitive PH treatment: endothelin receptor antagonists (ERA; e.g. bosentan, 
ambrisentan), phosphodiesterase type 5 inhibitors (PDE5; e.g. sildenafil, tadalafil, 
vardenafil), prostanoids (e.g. epoprostenol, treprostinil, iloprost, beraprost) and soluble 
guanylate cyclase stimulator (e.g. Riociguat). Intermittent use of PDE5 inhibitors for 
male erectile dysfunction is permitted. 
5. Except for diuretics and corticosteroids medical treatment should not be expected to 
change 4 weeks prior inclusion into the study and during the entire 12-week study 
period. 
6. Known intolerance to ambrisentan or one of its excipients 
7. Clinically significant anemia (hemoglobin concentration of less than 75% of the lower 
limit of normal, LLN) 
8. Forced vital capacity (FVC) <60%, forced expiratory volume in first second (FEV1) 

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<65% 
9. Severe interstitial lung disease, idiopathic pulmonary fibrosis 
10. Renal insufficiency (glomerular filtration rate [GFR] <60 mL/min/1.73m2 at least for the 
last 3 months before inclusion) 
11. Baseline values of hepatic aminotransferases (ALT and/or AST) >3 x upper limit of 
normal (ULN) 
12. Systolic blood pressure <85 mmHg;  
13. evidence of inadequately treated blood pressure >160/90 mmHg and/or blood pressure 
during exercise >220/120 mmHg 
14. Patients referred with clinically significant overt heart failure 
15. Clinically significant fluid retention 
16. Previous evidence or diagnosis of clinically relevant left heart disease, i.e. at least one of 
the following: Previous echocardiography with estimated left ventricular (LV) ejection 
fraction <50%, previous history of cardiogenic pulmonary edema, increased size of left 
atrium (>50 mm) 
17. Known significant diastolic dysfunction associated with clinical heart failure 
18. Known coronary disease or significant valvular heart disease 
19. Known congenital heart defects such as single ventricle, transposition, Eisenmenger 
20. Known hypertrophic cardiomyopathy or left ventricular hypertrophy (interventricular 
septum thickness (IVS) or posterior wall thickness (PWD) >1.2 cm) 
21. Participation in any clinical drug trial within 4 weeks prior to screening of this study 
and/or who is scheduled to receive another investigational medicinal product (IMP) 
during the course of this study 
22. Pregnancy or lactation 
 
Objectives 
Primary [Objectives/ Endpoints] 
1. Determine whether mPAP of SSc patients with borderline-PAH (mPAP 21-24 mmHg, 
TPG ≥11 mmHg) can be reduced by 3 mm Hg (absolute change baseline vs. 6 months; 
equals 15%) by treatment with ambrisentan 10 mg/die (may be initiated with 5 mg/die 
and escalated to 10 mg/die) over 6 months (primary endpoint) compared to baseline and 
placebo. 
Secondary Objectives 
2. Determine whether exercise induced elevated mPAP-values (>30 mmHg without left 

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heart or severe lung disease or systemic arterial hypertension) and further measures of 
exercise capacity, symptoms and quality of life can be reduced by ambrisentan 
10 mg/die over 6 months 
3. Analyze if the progression (adverse events, hospitalization, initiation of pulmonary 
hypertension treatment) of borderline-PAH to manifest PH can be avoided by 
ambrisentan-treatment (descriptive, observational) 
4. Assessment of tolerability and safety 
Secondary Endpoints 
Analyze if in patients with SSc and borderline-PAP show an improvement by treatment with 
ambrisentan 10 mg/die over 6 months in: 
- 
6-Minute-walking test  
- 
Quality of life (QoL, SF-36)  
- 
Echocardiography: right atrial area (RA-area), right ventricular area (RV-area), Tei, 
Tricuspid Annular Plane Systolic Excursion (TAPSE), systolic pulmonary arterial 
pressure (sPAP) 
- 
Lung function tests: forced expiratory flow (FEV1), total lung capacity (TLC), diffusion-
limited carbon monoxide (DLCo), DLCo/alveolar volume (VA), forced vital capacity 
(FVC), forced expiratory volume in one second (FEV1), residual volume 
- 
Borg Dyspnea Index 
- 
WHO-functional class  
- 
further invasively measured hemodynamic parameters evaluated by RHC: right atrial 
pressure, pulmonary vascular resistance, cardiac output (CO), cardiac index (CI), 
PAWP, venous oxygen saturation (SvO2) 
- 
Raynaud-syndrome and skin involvement, assessed by the modified Rodnan-Skin score 
and Symptoms of Scleroderma (descriptive) 
 
Trial Design 
Patients with borderline PAH indicated by borderline mPAP values will be included in this 
single centre study. This clinical investigation is performed as a Proof-of-Concept (PoC) 
investigator initiated trial (IIT) using a prospective, randomized, double-blind, parallel group, 
placebo-controlled, phase IIA clinical study design. On their first visit their medical history will 
be obtained and physical examination will be conducted. Moreover, an electrocardiogram 
(ECG), laboratory testing (NT-proBNP, uric acid and other laboratory tests), echocardiography 

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at rest and right heart catheterization will be carried out. If patients have been identified within 
the last 6 months before screening investigations by right heart catheterization, the 
measurements are considered valid as baseline investigations and will not be repeated. If 
patients fulfill the inclusion criteria and still suffer from borderline mPAP values they will be 
invited to join the study. The clinical investigations will begin within 28 days. The prospective 
study will comprise a 6 months study period (180 ±2 weeks) plus the screening phase up to 28 
days and a follow-up phase of 30 ±7 days. 
 
Investigational Medicinal Product(s) (IMPs) 
IMP: Test treatment  
 
Ambrisentan [Volibris®] once daily starting at 5 mg/die in the beginning of the study. 
Dosage will be up-titrated to 10 mg/die after 1-4 weeks according to the physician’s and 
the patient’s estimation.  
 
Study medication will be provided orally with or without food. Treatment effect will be 
controlled at each study visit and the dose will be adapted. The patient will take one or 
two tablets of ambrisentan 5 mg once daily. 
IMP: Placebo 
  
Placebo tablets with the same treatment regimen (once daily) as the verum therapy will 
be provided. One pill a day will be given. Treatment effect will be controlled at each 
study visit and the sham dose will be adapted. The patient will take one or two tablets 
once daily. 
 
Sample Size  
In this randomized, controlled, double-blind study patients with borderline PAH will be 
randomized into two groups: one group receiving ambrisentan and one Placebo. The main 
comparison will be the difference in treatment effect between ambrisentan arm and placebo. The 
primary endpoint will be the change of mean pulmonary arterial pressure between baseline and 
after 6 months compared to placebo.  
Based on previous data and the inclusion criteria we expect a baseline mPAP of 20 mmHg, a 
mean reduction of 3 mmHg (equals 15%) with standard deviation of the difference of 
2.5 mmHg. To reject the null hypothesis with 90 percent probability if the means of the mPAP 
differ by at least 3 mmHg (17 vs. 20 mmHg, 15%) a sample of 15 patients in each group is 
required, according to the two-tailed Student’s t-test, with a type I error of 0.05 (two-sided) and 
equal standard deviations of 2.5 mmHg in both patient groups.  

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Due to the fact that the borderline–PAP-group is defined by an mPAP of 21-24 mmHg the 
sample will have a small standard-deviation. The effect of lowering the mPAP in SSc-APAH-
patients by 15% has been reached in several studies as in Klinger et al. (2011). In order to cover 
a possible 20% drop-out rate, we will include 19 patients in each group = 38 patients in total. 
The sample size was calculated by means of a two-sided two-sample t-test. Primary efficacy 
analysis will be performed by an analysis of covariance (ANCOVA) model including baseline 
scores as covariate, thereby yielding a power advantage over the standard t-test used for sample 
size calculation. The calculated sample size will thus provide 90% power or more. 
Statistical Analysis 
General 
Descriptive statistics: 
           All data (demographic and other baseline characteristics, continuous data at each visit 
and their change to baseline) will be listed and trial summary tables will be provided. 
Descriptive statistics will be displayed by treatment and placebo corrected for the active 
treatment group (arithmetic mean, median, standard deviation, standard error, 95% 
confidence limits of mean and median, first and third quartiles, minimum, and maximum 
for quantitative variables). Frequency tables for qualitative data will be provided. 
Primary efficacy parameter: 
           The main parameter is the mPAP after 6 months compared to baseline. The differences 
will be compared between treatment and placebo group along with baseline mPAP as 
covariate using a covariance analysis. 
Secondary efficacy parameters: 
           Secondary efficacy analysis comprises hemodynamics, vital signs, electrocardiogram, 
echocardiography, systemic sclerosis characteristics, laboratory parameters, pulmonary 
function, 6-minute walking distance, quality of life questionnaire, safety parameters 
adverse events and concomitant medication. 
 
 

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1.1 
Flow Chart/ Trial Schedule  
 
Randomized; double-blind controlled study including 38 patients 
with “borderline-PAH” 
Assessment 
Screening 
“borderline-
PAH” 
day –28/-1 
Visit 1* 
Baseline° 
day 1* 
 
 
Visit 2 
After 3 
months/ 90 
days 
± 2weeks  
Visit 3 
After 6 
months/  
180 days 
 ± 2weeks 
 Visit 4* 
30±7 days 
Follow-up by 
phone 
Written Informed Consent, 
obtained before any study 
procedure 
X 
 
 
 
 
Check of eligibility criteria 
X 
X 
 
 
 
Demographics (height) 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
Physical Examination 
X 
X 
X 
X 
 
SSc characteristics 
 
X 
 
X 
 
Modified Rodnan Skin Score 
and Symptoms of Scleroderma 
 
X 
 
X 
 
Vital Signs (blood pressure, 
heart rate, oxygen saturation, 
body weight) 
X 
X 
X 
X 
 
WHO functional class  
X 
X 
X 
X 
 
Electrocardiogram 
 
X 
X 
X 
 
Pulmonary function tests: 
DLCo, DLCo/VA, FVC, 
FEV1, TLC, residual volume; 
blood gas analysis 
 
X 
 
X 
 
Local lab assessment # 
X 
X 
X 
X 
 
Pregnancy test (serum or urine) 
X 
X 
X 
X 
 
Echocardiography 
X 
X 
 
X 
 
Right heart catheterization** 
(RHC), at rest, during exercise 
X 
 
 
X 
 
Quality of life Questionnaire 
SF-36 
 
X 
 
X 
 
6MWD, Borg Dyspnea Index  
 
X 
X 
X 
 
Adverse events (AE) 
 
X 
X 
X 
X 
Concomitant medication  
X 
X 
X 
X 
 
Concomitant disease  
X 
X 
X 
X 
X 
Study medication and Diary  
hand out or check 
 
X 
X 
X 
 
° In borderline-PH-patients the screening assessment of PH screening (screening study, accepted by the Ethics 
committee University of Heidelberg) may be used as baseline examination for the randomized, double-blind part of 
the study when the screening assessment is not older than 28 days.  
* according to hospital practice possible in-hospital stay 
** Baseline-RHC may be up to 6 months old at inclusion, continuous ECG, CO and SvO2 recording during 
haemodynamic investigations 
# additional lab assessments for hepatic aminotransferases and haemoglobin will be performed at the patient’s 
general physician for safety reasons, reports will be faxed to the clinical site on a monthly basis