Clinical trial NCT02290613
Conditions: Systemic Sclerosis Pulmonary Hypertension
Keywords: pulmonary hypertension systemic sclerosis
Sponsor: Heidelberg University
Start date: 2014-07-01; Completion date: 2017-12-31
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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 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.

Detailed description:
Treatment naïve patients with SSc-APAH will be included in the investigator initiated trial (IIT) to assess efficacy and safety of ambrisentan. As patients life-expectancy after diagnosis of untreated patients is only one year we put forward a screening to identify borderline PAH patients and treat them before PH manifests. Therapy with ambrisentan reached a significant improvement in SSc-IPAH patients (Galiè et al. 2008). In PAH mPAP improved about 15% due to ambrisentan (Klinger et al. 2011).

Thus, especially patients with SSc-APAH have a high need for an early diagnosis and therapy. It is important to determine factors predictive of incident SSc-APAH and PH as well as the event rate of PAH and PH occurrence. Early identification and intervention with specific modern therapies as with ambrisentan may improve hemodynamic, symptoms, exercise capacity, quality of life and outcomes in this patient population, in particular in SSc-patients of borderline-PAH. It is considered reasonable that the development of manifest APAH might be preventable in this defined population with SSc and early pulmonary vascular changes. A reliable trial testing this latter hypothesis cannot be performed without critical evidence which defines the response to medical PAH-targeted therapy in borderline-PAH and the associated disease progression of manifest PAH.

Due to the positive results in the treatment of patients with SSc-APAH, the initiation of this proof-of-concept study is justified.

Previously identified patients with borderline PAH indicated by borderline mPAP values will be included in this single centre randomized, controlled, double-blind, parallel group, proof-of-concept (PoC) phase IIa IIT. If assessments necessary for screening have already been made under the screening for PH in Systemic sclerosis trial (non-drug trial, Ethics committee of Heidelberg # S360/2009), these examinations may be used for screening for this trial, as long as they have been performed within the given time frame of the screening period.

On their first visit the patients' 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 at rest and during exercise and right heart catheterization will be carried out. If patients fulfill the inclusion criteria and still suffer from borderline mPAP values they will be invited to join the study. Patients will be asked to sign the informed consent form (ICF) before the initial screening will be conducted. Randomization will be performed after a maximum of 28 days and medication or placebo will be provided. If patients have been identified within the last 6 months before baseline by right heart catheterization, the measurements are considered valid for the baseline visit to spare patients a repetition of this invasive procedure. Non-invasive measurements that are out of the time-frame have to be repeated for the study. An 1:1 oral ambrisentan: oral Placebo randomization will be performed.

Patients will be randomized into either:

* A treatment arm with ambrisentan treatment (19 patients)
* A placebo arm (19 patients will receive placebo). Safety and tolerability will be controlled at each study visit until the end of study (day 180 ± 2 weeks). If necessary, the dose will be adapted. As to common practice of the clinic, the patient will adapt the dose according to tolerability and after consultation (by phone or personally) with one of the investigators.

Arms: arm 1: Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/day). arm 2: Placebo tablet
Interventions: intervention 1: Ambrisentan intervention 2: Placebo
Intervention descriptions: intervention 1: Titration:

As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators.

Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented.

Maximum dose allowed: not to exceed 10 mg/day.

Administration:

Ambrisentan and placebo will be administered orally with or without food intake. intervention 2: Placebo tablet (one to two tablets corresponding to one to two verum tablets)

Protocol documents:
Prot_000.pdf: 
   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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1 
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 


EudraCT: 2014-001882-28 
 
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6 
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 
  

SAP_001.pdf: 
EDITA Statistical analysis plan 
V01 
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Statistical analysis plan 
EDITA 
 
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 
 
 
 
Authors of the statistical analysis plan: 
 
Dr. sc hum Christine Fischer 
MSc Nicola Benjamin 
 


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1 
Objectives 
 
1.1 Trial objectives 
Primary [Objectives/ Endpoints] 
Determine whether mPAP of SSc patients with borderline-PAH (mPAP 21-24 mmHg, 
TPG ≥11 mmHg) can be reduced by 3 mmHg (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 
1. Determine whether exercise induced elevated mPAP-values (>30 mmHg 
without left 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 
2. 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) 
3. Assessment of tolerability and safety 
 
1.2 Trial design 
This is a monocentric, randomized, controlled, double-blind study. Male or female 
SSc patients with borderline PAH will be randomized into two groups: Ambrisentan 
group and Placebo group. The primary endpoint will be the change of mean 
pulmonary arterial pressure between baseline and after 6 months compared to 
placebo. 
 
2 
Analysis of data quality 
This analysis will be performed before unblinding the therapy arms. 
1. For all variables at baseline, after 3-months and 6-months descriptive statistics 
mean standard deviation, median, IQR, min max, boxplot inspections of outliers for 
continuous variables and frequencies for categorical variables. Validation/correction 
will be performed by queries. 


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2. Calculation of differences for the parameters mPAP and all secondary endpoints. 
Descriptive statistics as in 1. for the differences to evaluate plausibility of the data. 
3. Control of inclusion and exclusion criteria and withdrawal criteria, definition of 
patients to be excluded if applicable. 
4. Control of laboratory values (and comparison to normal values) 
 
3 
Closure of the database and unblinding of treatment groups 
1. After all data quality and plausibility checks have been performed and queries 
haven been answered 
2. Database lock will be signed by data management, statisticians, principal 
investigator and trial coordinator 
3. Data Transfer from open clinica to SPSS 
4. Unique labeling of all major variables for the statistical Evaluation 
5. Data dictionary   
6. Merging of the data with the randomization list/group allocation 
 
4 
Analysis sets 
 
4.1 Definitions 
All patients randomized and treated will be valid for the intention-to-treat analysis 
population. A randomized patient is valid for the intention-to-treat, if at least one dose 
of study medication was administered. A patient is valid for per-protocol analysis, if 
the patient has an adequate hemodynamic measurement at baseline and after 12 
weeks or if withdrawn due to lack of efficacy, who has an adequate hemodynamic 
assessment at any time post-baseline up to 12 weeks, and shows no major protocol 
deviation. 
Major protocol deviations are: 
1. 
Patients who do not meet the inclusion criteria 
2. 
Administration of study medication not according to protocol (e.g. compliance 
less than 80% or greater 120%) 


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The above specifications of the analysis populations are in accordance with the 
recommendations given in the ICH-E9 Guideline “Note for guidance on statistical 
principles for clinical trials”.  
 
The safety set comprises all patients who have been included in the study.  
 
4.2 Application 
Efficacy analyses will be performed for the intention-to-treat analysis set. A sensitivity 
analysis for the primary endpoint will be performed with the per-protocol set. 
Safety analyses will be performed with the safety set. 
 
5 
Trial centres 
Zentrum für pulmonale Hypertonie, Thoraxklinik am Universitätsklinikum Heidelberg 
 
6 
Analysis variables 
  
6.1 Demography and baseline characteristics 
Age, height, weight, systemic sclerosis characteristics, duration of systemic sclerosis, 
concomitant disease, concomitant medication 
And all efficacy variables at baseline 
 
6.2 Primary variable 
Analyze if patients with SSc and borderline-PAP show an improvement by treatment 
with ambrisentan 10 mg/die over 6 months in mPAP 
 
6.3 Secondary variables 
 
6.3.1  Efficacy 
(1) 
Analyze if in patients with SSc and borderline-PAP an improvement by 
treatment with ambrisentan 10 mg/die over 6 months is show in: 
(2) 
6-Minute-walking test  
(3) 
Echocardiography: right atrial area (RA-area), right ventricular area (RV-
area), Tei, Tricuspid Annular Plane Systolic Excursion (TAPSE), systolic 
pulmonary arterial pressure (sPAP), right ventricular pump function, left 
ventricular pump function,  


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(4) 
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 
(5) 
Borg Dyspnea Index 
(6) 
WHO-functional class  
(7) 
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) at rest and 
during exercise 
(8) 
Raynaud-syndrome and skin involvement, assessed by the modified 
Rodnan-Skin score and Symptoms of Scleroderma (descriptive) 
(9) 
WHO functional class 
(10) Laboratory parameters (NT-proBNP) 
 
6.3.2  Safety/Tolerability 
Adverse events, Laboratory: hemoglobin, hematocrit, AST, ALT, bilirubin, CRP, 
sodium, urea, creatinine, clearance, NT-proBNP 
Vital signs, hospitalisations, time point from baseline and duration, Hemodynamics: 
Cardiac Output, venous oxygen saturation (during RHC) 
 
6.3.3  Quality of life 
Quality of life (QoL, SF-36); Two summation scores: Mental component score, 
Physical component score; 8 subscales: vitality, physical functioning, bodily pain, 
general health perceptions, physical role functioning, emotional role functioning, 
social role functioning, mental health. 
 
7 
Handling of missing values and outliers 
 
7.1 Missing values 
Variables with more than 20% missing values will be excluded. For all others, a 
complete case data analysis for each variable will be performed. No imputation 
method will be applied. 
 


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7.2 Outliers 
Definition: outliers and extreme values (according to boxplots) 
The primary and all secondary efficacy parameters and their difference between 
baseline and 6 month visit will be analysed whether there are outliers or extreme 
values in the respective medication group. Outliers are defined as values that are 
larger than Q75+1.5*IQR or lower than Q25-1.5*IQR; extreme Values are defined as 
values that are larger than Q75+3*IQR or lower than Q25-3*IQR. 
 
8 
Statistical analyses / methods 
8.1 Subject disposition 
Systemic sclerosis severity (modified Rodnan Skin score; disease duration; type of 
systemic sclerosis; systemic sclerosis characteristics including presence of digital 
ulcera, calcinosis, dysphagia, teleangiectasia, Raynaud phenomenon, joint pain), 
hemodynamics at baseline (mPAP at rest and during exercise, achieved workload, 
cardiac index and cardiac output) and WHO-FC will be analyzed descriptively within 
the therapy groups and compared. Changes during the study will be analysed 
descriptively. 
 
8.2 Demography and baseline characteristics 
All variables (demographic and other baseline characteristics, continuous data at 
each visit and their change to baseline) will be characterized by arithmetic mean, 
median, standard deviation, standard error, 95% confidence limits of mean, median, 
first and third quartiles, minimum, and maximum for quantitative variables. Frequency 
tables for qualitative data will be provided. 
 
8.3 Prior or concomitant medication and diseases 
Frequencies by organ system and duration, difference between therapy groups. 
 
8.4 Exposition to treatment/Compliance 
Frequencies and duration of intake or application, difference between treatment 
groups will be analysed. A compliance between 80-120% will be defined as target 
level. 
 


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8.5 Efficacy Analysis primary 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, if the assumptions for a 
covariance analysis are fulfilled. Otherwise the individual differences of baseline 
mPAP and 6 months mPAP will be compared between therapy groups by robust 
comparisons of means as implemented in JMP14. 
 
8.6 Analysis secondary parameters   
No subgroup analyses and interim analyses planned. 
 
8.6.1 Efficacy 
Secondary 
efficacy 
analysis 
comprises 
hemodynamics, 
vital 
signs, 
electrocardiogram, echocardiography, systemic sclerosis characteristics, laboratory 
parameters, pulmonary function, 6-minute walking distance, quality of life scales. For 
continuous variables the therapy groups will be compared with the same methods as 
for the primary parameter. 
WHO functional class is supposed to either remain the same, improve by one or two 
categories, or deteriorate by one category in most cases. A change score (baseline 
minus end of study) will be calculated, which could go from -3 (class 4 at baseline 
and class 1 at end of study) to +1 (class 3 at baseline and class 4 at end of study). 
This will be analyzed using the Wilcoxon test. 
For categorical variables Mc Nemar Tests will be applied. 
  
8.6.2 Safety/Tolerability 
The safety analysis will be performed in the population valid for safety. All tabulations 
will be descriptive only. Tables will be produced for drug-related treatment-emergent 
adverse events and serious adverse events. 
Mortality in the 6 month period of the study will be summarized descriptively. Any 
deaths in the study period will be listed, with day of death relative to start and stop of 
study drug and cause of death. Vital signs will be summarized by visit and treatment 
group. 
 


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8.6.2.1 Adverse events 
Frequency tables of adverse events with classification of system organ class 
according to MedDRA classification will be provided. Adverse events will be provided 
according to suspected and no suspected relation to the study medication. Serious 
adverse events will be listed separately.  
Hospitalisations due to worsening or adverse events will be listed. 
 
8.6.2.2 Laboratory parameters  
For the clinical parameters Laboratory: hemoglobin, hematocrit, AST, ALT, bilirubin, 
CRP, sodium, urea, creatinine, clearance, NT-proBNP arithmetic mean, median, 
standard deviation, standard error, median, first and third quartiles, minimum, and 
maximum for quantitative variables) for baseline and 6 month time points for each 
therapy group separately as well as frequency tables with number of values outside 
their limits of normal (or 3 x upper limit of normal for hepatic transaminases) will be 
displayed.  
 
8.6.2.3 Vital signs  
For diastolic and systolic blood pressure, heart rate and weight we will list arithmetic 
mean, median, standard deviation, standard error, first and third quartiles, minimum, 
and maximum for quantitative variables for baseline and 6 month time point for each 
therapy group. 
Furthermore, frequency tables of pathologic findings in the physical examination will 
be displayed. 
 
8.6.3 Quality of life 
Quality of life scales (QoL, SF-36) are secondary efficacy parameters. Their change 
from baseline to 6 months will be compared with the same methods as for the 
primary parameter. 
 
9 
Deviations from the protocol 
Description and explanation of deviations regarding withdrawal criteria, in- and 
exclusion criteria, adherence to time window and treatment compliance will be 
provided. 
Major protocol deviations are: 
1. 
Patients who do not meet the inclusion criteria 


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2. 
Administration of study medication not according to protocol (e.g. compliance 
less than 80% or greater 120%); Discrepancies of study medication intake are noted 
as comments in the CRF. 
 
10 Interpretation of results 
Effect size estimation and description 
Clinical worsening on the individual level is defined as 15% higher mPAP values at 6 
months compared to baseline. Clinically significant improvement is defined as 15% 
lower mPAP values at 6 months compared to baseline. 
Scatterplots of baseline versus 6-month measurements will be plotted with a linear fit 
for therapy. In case of outliers or extreme values robust fits will be used. Frequency 
tables with patients who have a clinically relevant worsening/improvement after 6 
months of therapy will be displayed.  
 
Descriptive analysis of differences of secondary parameters. 
Secondary efficacy parameters will be screened whether they support the results of 
the primary endpoint or not. 
 
 
11 Software 
SPSS V24, SAS JMP 14 
 
12 References 
https://www.jmp.com/en_us/support/online-help.html  
(last queried 17.7.2018) 
https://www-01.ibm.com/support/docview.wss?uid=swg27047033  
(last queried 17.7.2018) 
 
13 Appendices 
 
13.1 Reference ranges of laboratory parameters 
  
male 
female 
Hemoglobin 
♂ 0-3 Day(s) 14.5 - 22.5 g/dl 
♀ 0-3 Day(s) 14.5 - 22.5 g/dl 
♂ 4-7 Day(s) 13.5 - 21.5 g/dl 
♀ 4-7 Day(s) 13.5 - 21.5 g/dl 
♂ 8-14 Day(s) 14 - 20 g/dl 
♀ 8-14 Day(s) 14 - 20 g/dl 


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♂ 15-30 Day(s) 15 - 20 g/dl 
♀ 15-30 Day(s) 15 - 20 g/dl 
♂ 31-182 Day(s) 9.5 - 13.5 g/dl 
♀ 31-182 Day(s) 9.5 - 13.5 g/dl 
♂ 183-365 Day(s) 11 - 16 g/dl 
♀ 183-365 Day(s) 11.0 - 16 g/dl 
♂ 1-6 Year(s) 11 - 14.5 g/dl 
♀ 1-6 Year(s) 11 - 14.5 g/dl 
♂ 7-12 Year(s) 11.5 - 15 g/dl 
♀ 7-12 Year(s) 11.5 - 15 g/dl 
♂ 13-18 Year(s) 12 - 16 g/dl 
♀ 13-18 Year(s) 12 - 16 g/dl 
♂ 19-99 Year(s) 13 - 17 g/dl 
♀ 19-99 Year(s) 12 - 15 g/dl 
  
male 
female 
Hematocrite 
♂ 0-3 Day(s) 0.45 - 0.67 l/l 
♀ 0-3 Day(s) 0.45 - 0.67 l/l 
♂ 4-7 Day(s) 0.42 - 0.66 l/l 
♀ 4-7 Day(s) 0.42 - 0.66 l/l 
♂ 8-14 Day(s) 0.39 - 0.63 l/l 
♀ 8-14 Day(s) 0.39 - 0.63 l/l 
♂ 15-30 Day(s) 0.45 - 0.64 l/l 
♀ 15-30 Day(s) 0.45 - 0.64 l/l 
♂ 31-60 Day(s) 0.28 - 0.42 l/l 
♀ 31-60 Day(s) 0.28 - 0.42 l/l 
♂ 61-365 Day(s) 0.35 - 0.44 l/l 
♀ 61-365 Day(s) 0.35 - 0.44 l/l 
♂ 1-2 Year(s) 0.33 - 0.39 l/l 
♀ 1-2 Year(s) 0.33 - 0.39 l/l 
♂ 3-6 Year(s) 0.31 - 0.37 l/l 
♀ 3-6 Year(s) 0.31 - 0.37 l/l 
♂ 7-12 Year(s) 0.33 - 0.40 l/l 
♀ 7-12 Year(s) 0.33 - 0.40 l/l 
♂ 13-99 Year(s) 0.38 - 0.52 l/l 
♀ 13-99 Year(s) 0.36 - 0.47 l/l 
  
male 
female 
Thrombocytes 
♂ 0-10 Day(s) 140 - 320 /nl 
♀ 0-10 Day(s) 140 - 320 /nl 
♂ 11-30 Day(s) 150 - 380 /nl 
♀ 11-30 Day(s) 150 - 380 /nl 
♂ 31-365 Day(s) 200 - 480 /nl 
♀ 31-365 Day(s) 200 - 480 /nl 
♂ 1-10 Year(s) 180 - 530 /nl 
♀ 1-10 Year(s) 180 - 530 /nl 
♂ 11-199 Year(s) 150 - 440 /nl 
♀ 11-199 Year(s) 150 - 440 /nl 
  
male 
female 
Creatinine 
♂ 0-1 Day(s) 0.4 - 1.3 mg/dl 
♀ 0-1 Day(s) 0.4 - 1.3 mg/dl 
♂ 2-7 Day(s) 0.16 - 1.0 mg/dl 
♀ 2-7 Day(s) 0.16 - 1.0 mg/dl 
♂ 8-30 Day(s) 0.1 - 0.6 mg/dl 
♀ 8-30 Day(s) 0.1 - 0.6 mg/dl 
♂ 31-365 Day(s) 0.1 - 0.65 mg/dl 
♀ 31-365 Day(s) 0.1 - 0.65 mg/dl 
♂ 1-6 Year(s) 0.3 - 0.8 mg/dl 
♀ 1-6 Year(s) 0.3 - 0.8 mg/dl 
♂ 7-13 Year(s) 0.3 - 1.0 mg/dl 
♀ 7-13 Year(s) 0.3 - 1.0 mg/dl 
♂ 14-17 Year(s) 0.3 - 1.2 mg/dl 
♀ 14-17 Year(s) 0.3 - 1.2 mg/dl 
♂ 18-60 Year(s) 0.6 - 1.2 mg/dl 
♀ 18-60 Year(s) 0.5 - 0.9 mg/dl 
♂ 61-70 Year(s) 0.6 - 1.3 mg/dl 
♀ 61-70 Year(s) 0.5 - 1.0 mg/dl 
♂ 71-80 Year(s) 0.6 - 1.4 mg/dl 
♀ 71-80 Year(s) 0.5 - 1.1 mg/dl 
♂ 81-199 Year(s) 0.6 - 1.7 mg/dl 
♀ 81-199 Year(s) 0.5 - 1.4 mg/dl 
  
male 
female 
Potassium 
♂ 0-30 Day(s) 3.6 - 6.0 mmol/l 
♀ 0-30 Day(s) 3.6 - 6.0 mmol/l 
♂ 31-365 Day(s) 3.5 - 5.7 mmol/l 
♀ 31-365 Day(s) 3.5 - 5.7 mmol/l 
♂ 1-17 Year(s) 3.5 - 4.8 mmol/l 
♀ 1-17 Year(s) 3.5 - 4.8 mmol/l 
♂ 18-40 Year(s) 3.4 - 4.6 mmol/l 
♀ 18-40 Year(s) 3.4 - 4.6 mmol/l 
♂ 41-60 Year(s) 3.4 - 4.8 mmol/l 
♀ 41-60 Year(s) 3.4 - 4.8 mmol/l 
♂ 61-199 Year(s) 3.4 - 5.0 mmol/l ♀ 61-199 Year(s) 3.4 - 5.0 mmol/l 
  
male 
female 
SGOT/ASAT 
♂  0-180 Day(s) <74 U/l 
♀ 0-180 Day(s) <74 U/l 


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Serum-Glutamate-
Oxalacetate-
Transaminase  
♂ 181-365 Day(s) <52 U/l 
♀ 181-365 Day(s) <52 U/l 
♂ 1-5 Year(s) <43 U/l 
♀ 1-5 Year(s) <43 U/l 
♂ 6-14 Year(s) <39 U/l 
♀ 6-14 Year(s) <39 U/l 
♂ 15-17 Year(s) <50 U/l 
♀ 15-17 Year(s) <35 U/l 
♂ 18-199 Year(s) <46 U/l 
♀ 18-199 Year(s) <37 U/l 
  
male 
female 
SGPT/ALT 
Serum-Glutamate-
Pyruvate-Transaminase 
♂ 0-180 Day(s) <60 U/l 
♀ 0-180 Day(s) <60 U/l 
♂ 181-365 Day(s) <43 U/l 
♀ 181-365 Day(s) <43 U/l 
♂ 1-199 Year(s) <50 U/l 
♀ 1-199 Year(s) <35 U/l 
  
male 
female 
LDH 
Lactate dehydrogenase 
♂ 0-30 Day(s) <780 U/l 
♀ 0-30 Day(s) <780 U/l 
♂ 31-365 Day(s) <416 U/l 
♀ 31-365 Day(s) <416 U/l 
♂ 1-5 Year(s) <364 U/l 
♀ 1-5 Year(s) <364 U/l 
♂ 6-14 Year(s) <312 U/l 
♀ 6-14 Year(s) <312 U/l 
♂ 15-17 Year(s) <248 U/l 
♀ 15-17 Year(s) <248 U/l 
♂ 18-40 Year(s) <316 U/l 
♀ 18-40 Year(s) <264 U/l 
♂ 41-60 Year(s) <317 U/l 
♀ 41-60 Year(s) <308 U/l 
♂ 61-199 Year(s) <342 U/l 
♀ 61-199 Year(s) <301 U/l 
  
male 
female 
CK 
Creatinkinase 
♂ 0-3 Day(s) <777 U/l 
♀ 0-3 Day(s) <777 U/l 
♂ 4-10 Day(s) <420 U/l 
♀ 4-10 Day(s) <420 U/l 
♂ 11-365 Day(s) <286 U/l 
♀ 11-365 Day(s) <286 U/l 
♂ 1-199 Year(s) <190 U/l 
♀ 1-199 Year(s) <170 U/l 
  
male 
female 
CRP 
♂ 0-  Year(s) <5 mg/l 
♀ 0-  Year(s) <5 mg/l 
  
male 
female 
NTproBNP 
♂ 0-70 Year(s) <125 ng/l 
♀ 0-70 Year(s) <125 ng/l 
  
♂ 71- Year(s) <450 ng/l 
♀ 71- Year(s) <450 ng/l 
  
  
  
ß-HCG 
  
 negative