Prospective, Randomized, Controlled Trial of the Effect of Long-term Oxygen Therapy on 6-minute Walking Distance, Clinical Parameters and Hemodynamics in Patients With PAH and CTEPH
Phase: PHASE2
Conditions: Oxygen Deficiency, Pulmonary Arterial Hypertension, CTEPH
Sponsor: Heidelberg University

CONFIDENTIAL 
   CLINICAL STUDY PROTOCOL 
A prospective, randomized, controlled trial to assess the effect of long-term oxygen therapy 
on 6-minute walking distance, clinical parameters and hemodynamics in patients with 
pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary 
hypertension (CTEPH) 
 
SOPHA 
Local Project ID: 2018-11SO* 
 
 
Clinical Trial Code:  SOPHA 
EudraCT No.:  
2018-001387-39 
Clinical Phase:  
II 
Version:  
 
1.2, 14.01.2019 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
The recipient of this document agrees to keep it strictly confidential. The information 
contained in this document must not be communicated to a third party without prior 
written approval of Thoraxklinik at Heidelberg University Hospital. 
 
 
 

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PRINCIPAL INVESTIGATOR/ 
COORDINATING INVESTIGATOR 
(LEITER DER KLINISCHEN PRÜFUNG*) 
AND INVESTIGATOR 
SPONSOR 
 
Klinikdirektor  
 
Prof. Dr. med. Ekkehard Grünig 
Thoraxklinik am Universitätsklinikum 
Heidelberg 
Roland Fank  
Thoraxklinik am Universitätsklinikum 
Heidelberg 
Zentrum für pulmonale Hypertonie 
 
Röntgenstraße 1 
69126 Heidelberg 
Röntgenstraße 1 
69126 Heidelberg 
Phone: 06221 / 396 8053 
Phone: 06221 / 396 2100 
Fax: 06221 / 396 1209 
Fax: 06221 / 396 2102 
ekkehard.gruenig@med.uni-heidelberg.de 
roland.fank@med.uni-heidelberg.de 
* According to § 40 German Drug Law (AMG) 
 
 
 
DEPUTY INVESTIGATOR 
Dr. med. Benjamin Peter Egenlauf 
Zentrum für pulmonale Hypertonie 
Röntgenstraße 1 
69126 Heidelberg 
Phone: 06221 / 396 8078 
Fax: 06221 / 396 1209 
Benjamin.Egenlauf@med.uni-heidelberg.de 
INVESTIGATOR 
Dr. med. Satenik Harutyunova 
Dr. med. Panagiota Xanthouli 
Zentrum für pulmonale Hypertonie 
Röntgenstraße 1 
69126 Heidelberg 
Phone: 06221 / 396 8025 und 8270 
Fax: 06221 / 396 1209 
Satenik.harutyunova@med.uni-heidelberg.de    
Panagiota.xanthouli@med.uni-heidelberg.de 
BIOMETRICIAN 
TRIAL COORDINATOR 
Dr. Christine Fischer & MSc Nicola Benjamin 
Amina Salkić, LL.M. 
Institut für Humangenetik  
Administratives Projektmanagement 
INF 366, 69120 Heidelberg // 
Thoraxklinik Heidelberg, Röntgenstraße 1, 
69126 Heidelberg 
Thoraxklinik-Heidelberg gGmbh 
Röntgen Str. 1 
69126 Heidelberg 
Phone: 06221 56 5060 //06221 396 8076 
Tel.: +49 (0)6221 396 2761 
Fax: 06221 56 33691 // 06221 396 1209 
Fax: +49 (0)6221 396 2772 
christine.fischer@med.uni-heidelberg.de 
E-Mail: Amina.Salkic@med.uni-heidelberg.de 

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nicola.benjamin@med.uni-heidelberg.de 
 
 
CLINICAL MONITOR* 
DATA MANAGEMENT 
Anna-Lena Gamer 
Evelin Deeg  
 
Coordination Centre for Clinical Trials (KKS) 
Marsilius-Arkaden – Turm West 
Coordination Centre for Clinical Trials (KKS) 
Marsilius-Arkaden – Turm West 
Im Neuenheimer Feld 130.3  
69120 Heidelberg 
Im Neuenheimer Feld 130.3  
69120 Heidelberg 
Phone: +49-6221 / 56-34323 
Fax: +49-6221 / 56-33508 
E-Mail: 
Anna-Lena.Gamer@med.uni-
heidelberg.de 
Phone: +49-6221 / 56-36215 
Fax: +49-6221 / 56-33508 
E-Mail: Evelin.Deeg@med.uni-heidelberg.de 
 
 
 
 
 
 
 
 
 

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STEERING COMMITTEE (SC) 
 
Prof. Dr. med. Ekkehard Grünig 
 
Thoraxklinik Heidelberg gGmbH am Universitätsklinikum Heidelberg 
 
Zentrum für pulmonale Hypertonie  
Röntgenstraße 1 
69126 Heidelberg 
 
Phone: 06221 / 396-8053 
 
Fax: 06221 / 396-1209 
 
ekkehard.gruenig@med.uni-heidelberg.de 
 
PD Dr. Silvia Ulrich 
Prof. Dr. Konrad E. Bloch 
Pulmonary clinic 
University Hospital of Zurich 
Raemistrasse 
1008091 Zurich 
Phone: 0041-44 255-54362 
Fax:    0041-44 255-8519 
silvia.ulrich@usz.ch 
Konrad.bloch@usz.ch 
 
 
 
 
PARTICIPATING SITES  
Thoraxklinik Heidelberg gGmbH am Universitätsklinikum Heidelberg 
Zentrum für pulmonale Hypertonie 
Röntgenstraße 1 
69126 Heidelberg 
Tel.: 06221 / 396-8053 
Fax: 06221 / 396-1209 
 
 

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TABLE OF CONTENTS 
1 
CLINICAL STUDY PROTOCOL SYNOPSIS .............................................................................................. 8 
1.1 
OVERVIEW OF VISITS AND ASSESSMENTS (S. DIAGRAM) ............................................................................... 21 
ASSESSMENTS ........................................................................................................................................................ 21 
2 
INTRODUCTION ........................................................................................................................................... 27 
2.1 
SCIENTIFIC BACKGROUND ............................................................................................................................ 27 
2.2 
TRIAL RATIONALE/ JUSTIFICATION ............................................................................................................... 28 
2.3 
BENEFIT/ RISK ASSESSMENT ......................................................................................................................... 28 
2.4 
STEERING COMMITTEE .................................................................................................................................. 28 
3 
TRIAL OBJECTIVES AND ENDPOINTS .................................................................................................. 29 
3.1 
PRIMARY OBJECTIVE AND PRIMARY ENDPOINT ............................................................................................ 29 
3.2 
SECONDARY OBJECTIVES .............................................................................................................................. 29 
4 
TRIAL DESIGN .............................................................................................................................................. 29 
5 
TRIAL DURATION AND SCHEDULE ....................................................................................................... 30 
5.1 
STUDY PHASES .............................................................................................................................................. 30 
5.2 
TRIAL DURATION .......................................................................................................................................... 30 
6 
SELECTION OF SUBJECTS ........................................................................................................................ 30 
6.1 
NUMBER OF SUBJECTS .................................................................................................................................. 30 
6.2 
GENERAL CRITERIA FOR SUBJECTS’ SELECTION ........................................................................................... 31 
6.3 
INCLUSION CRITERIA .................................................................................................................................... 32 
6.4 
EXCLUSION CRITERIA ................................................................................................................................... 32 
6.5 
CRITERIA FOR REMOVAL OR WITHDRAWAL .................................................................................................. 33 
6.5.1 
Withdrawal of Subjects........................................................................................................................ 33 
6.5.2 
Replacement of Subjects ...................................................................................................................... 34 
6.5.3 
Premature Closure of the Clinical Trial ............................................................................................. 34 
6.6 
PRIOR AND CONCOMITANT ILLNESSES .......................................................................................................... 35 
6.7 
PRIOR AND CONCOMITANT TREATMENTS ..................................................................................................... 35 
7 
INVESTIGATIONAL MEDICINAL PRODUCT ........................................................................................ 35 
7.1 
GENERAL INFORMATION ABOUT THE INVESTIGATIONAL MEDICINAL PRODUCT ........................................... 35 
7.1.1 
Oxygen (O2) ......................................................................................................................................... 35 
7.2 
THERAPEUTIC EFFECTS ................................................................................................................................. 36 
7.3 
KNOWN SIDE EFFECTS .................................................................................................................................. 37 
7.4 
DOSAGE SCHEDULE, TITRATION AND ADMINISTRATION ............................................................................... 37 
7.5 
TREATMENT ASSIGNMENT ............................................................................................................................ 38 
7.6 
RANDOMIZATION .......................................................................................................................................... 38 
7.7 
LABELLING AND SUPPLY ............................................................................................................................... 38 
7.8 
SUPPLIES AND ACCOUNTABILITY .................................................................................................................. 38 
7.9 
COMPLIANCE ................................................................................................................................................ 39 
8 
TRIAL METHODS ......................................................................................................................................... 40 
8.1 
OVERVIEW OF VISITS AND ASSESSMENTS ...................................................................................................... 40 
ASSESSMENTS ........................................................................................................................................................ 40 
8.2 
ASSESSMENTS ............................................................................................................................................... 42 
8.2.1 
Physical examination and demographic data ..................................................................................... 42 
8.2.2 
Hemodynamic parameters ................................................................................................................... 42 
8.2.3 
Echocardiography and Stress Doppler Echocardiography with cardiopulmonary exercise testing .. 43 
8.2.4 
Determination of WHO functional class ............................................................................................. 43 
8.2.5 
Lung function tests and blood gas analysis ......................................................................................... 44 
8.2.6 
6-minute walking distance and Borg dyspnea Score (CR 10) ............................................................. 44 
8.2.7 
Quality of Life (QoL) ........................................................................................................................... 45 
8.2.8 
Vital signs ............................................................................................................................................ 45 
8.2.9 
Electrocardiography ........................................................................................................................... 45 

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8.2.10 
Clinical laboratory investigations .................................................................................................. 45 
8.3 
STUDY PHASES AND VISITS ........................................................................................................................... 45 
8.3.1 
Screening Phase .................................................................................................................................. 45 
8.3.2 
Visit 1 Baseline / Randomization [DAY 1] .......................................................................................... 46 
8.3.3 
DAY 1-90 (3 Months) .......................................................................................................................... 46 
8.3.4 
Month three / Day 90 visit 2 (± 7 days) ............................................................................................... 46 
8.3.5 
Month four / Day 120 (± 7 days) (30 days after close out) ................................................................. 46 
8.3.6 
Termination Visit ................................................................................................................................. 47 
8.3.7 
Pre-treatment period and duration of observation and follow-up ...................................................... 47 
8.4 
METHODS OF DATA COLLECTION ................................................................................................................. 47 
8.4.1 
Efficacy Parameters ............................................................................................................................ 47 
8.4.2 
Safety Parameters ............................................................................................................................... 47 
8.5 
PLAN FOR TREATMENT OF CARE AFTER THE TRIAL ...................................................................................... 48 
9 
ADVERSE EVENTS ....................................................................................................................................... 48 
9.1 
DEFINITIONS ................................................................................................................................................. 48 
9.1.1 
Adverse Event ...................................................................................................................................... 48 
9.1.2 
Serious Adverse Event ......................................................................................................................... 48 
9.1.3 
Expectedness ....................................................................................................................................... 49 
9.1.4 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ................................................................ 49 
9.1.5 
Grading of AEs .................................................................................................................................... 50 
9.1.6 
Relationship and outcome of AEs, action taken .................................................................................. 50 
9.2 
PERIOD OF OBSERVATION AND DOCUMENTATION ........................................................................................ 52 
9.3 
REPORTING OF SERIOUS ADVERSE EVENTS BY THE INVESTIGATOR .............................................................. 52 
9.4 
EXPEDITED REPORTING ................................................................................................................................. 53 
9.5 
EMERGENCY TREATMENT ............................................................................................................................. 53 
10 
STATISTICAL PROCEDURES .................................................................................................................... 54 
10.1 SAMPLE SIZE CALCULATION ......................................................................................................................... 54 
10.2 ANALYSIS VARIABLES .................................................................................................................................. 55 
10.3 DEFINITION OF TRIAL POPULATION TO BE ANALYSED ................................................................................... 57 
10.4 STATISTICAL METHODS ................................................................................................................................ 58 
10.4.1 
General ........................................................................................................................................... 58 
11 
DATA MANAGEMENT ................................................................................................................................. 59 
11.1 DATA COLLECTION ....................................................................................................................................... 59 
11.2 DATA HANDLING .......................................................................................................................................... 60 
11.3 STORAGE AND ARCHIVING OF DATA ............................................................................................................. 60 
12 
ETHICAL AND LEGAL ASPECTS ............................................................................................................. 60 
12.1 GOOD CLINICAL PRACTICE ........................................................................................................................... 60 
12.2 SUBJECT INFORMATION AND INFORMED CONSENT ....................................................................................... 60 
12.3 CONFIDENTIALITY ......................................................................................................................................... 61 
12.4 RESPONSIBILITIES OF THE INVESTIGATOR ..................................................................................................... 61 
12.5 APPROVAL OF TRIAL PROTOCOL AND AMENDMENTS ................................................................................... 61 
12.6 CONTINUOUS INFORMATION TO INDEPENDENT ETHICS COMMITTEE............................................................. 62 
12.7 NOTIFICATION OF REGULATORY AUTHORITIES ............................................................................................. 62 
12.8 REGISTRATION OF THE TRIAL ........................................................................................................................ 62 
12.9 INSURANCE ................................................................................................................................................... 62 
13 
QUALITY ASSURANCE ............................................................................................................................... 63 
13.1 MONITORING................................................................................................................................................. 63 
13.2 INSPECTIONS/ AUDITS ................................................................................................................................... 64 
14 
AGREEMENTS ............................................................................................................................................... 64 
14.1 FINANCING OF THE TRIAL ............................................................................................................................. 64 
14.2 FINANCIAL DISCLOSURE ............................................................................................................................... 64 
14.3 REPORTS ....................................................................................................................................................... 64 
14.4 PUBLICATION ................................................................................................................................................ 64 
15 
SIGNATURES ................................................................................................................................................. 65 

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DECLARATION OF INVESTIGATOR ....................................................................................................... 66 
18 
REFERENCES ................................................................................................................................................ 67 
19 
APPENDICES ................................................................................................................................................. 68 
 
 
 

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1 
 Clinical study protocol synopsis 
Protocol title: 
A prospective, randomized, controlled trial to assess 
the effect of long-term oxygen therapy on 6-minute 
walking distance, clinical parameters and 
hemodynamics in patients with pulmonary arterial 
hypertension (PAH) and chronic thromboembolic 
pulmonary hypertension (CTEPH) 
Acronym 
SOPHA 
Phase: 
Phase II  
Regulatory 
obligations: 
[Pharmaceutical study under the Pharmaceutical 
DrugLaw (AMG); requires BfARM approval and 
institutional Ethical Review Board approval.] 
Study location: 
Heidelberg, Germany  
No. of study sites: 
1 
Principal 
investigator: 
 
Prof. Dr. Ekkehard Grünig 
Thoraxklinik at Heidelberg University Hospital 
Centre for pulmonary hypertension 
Röntgenstraße 1 
69126 Heidelberg 
Phone:0049-6221 396-8053 
Fax:  0049-6221 396-1209 
Mail: Ekkehard.Gruenig@med.uni-heidelberg.de 
 
Study type: 
Interventional 
Study design: 
 
Investigator-Initiated-Trial (IIT)  
This is a prospective, randomised, controlled, parallel-
group, open label monocenter (Heidelberg) study with 
a partial cross-over design, which investigates the 
effect of long term oxygen treatment in patients with 
pulmonary 
arterial 
hypertension 
or 
chronic 
thromboembolic pulmonary hypertension who present 
with mild or moderate hypoxemia at rest or during 
physical activity and therefore may require longterm 
oxygen therapy.  
Patients will be divided in a supplemental-oxygen 
group 
(primary 
intervention 
group) 
and 
no-
supplemental-oxygen group (control group). Patients of 
the control group will be offered to participate in the 
interventional treatment arm after they have terminated 
the control period (partial cross-over; secondary 
intervention group). 
Efficacy of long term oxygen therapy will be 
investigated by assessing invasive and non-invasive 
clinical parameters at baseline and after 3 months. 
Efficacy parameters will be compared intra-individual 

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(primary and secondary intervention group) and 
between the intervention and the control group.  
Randomization will be performed in a 1:1 ratio. 
Patients will be assessed at baseline and after 3 months. 
Clinical assessments will comprise of medical history, 
WHO functional class, electrocardiogram, blood gas 
analysis, lung function, 6-minute walking distance, 
echocardiography, laboratory including NT-proBNP, 
invasive 
hemodynamics 
using 
right 
heart 
catheterization, cardiopulmonary exercise testing with 
stress-Doppler echocardiography and quality of life 
questionnaire (SF-36) at baseline and after 3 months, 
worsening of saturation and clinical worsening events. 
 
Interventions 
 
Patients will be divided in a supplemental-oxygen group 
and no-supplemental-oxygen group (control group) 
- 
Patients in the supplemental-oxygen group will 
be prescribed >16-hour oxygen (liquid oxygen) 
for 12 weeks, aiming at O2 saturation values of 
>90% at rest and during exercise or physical 
activity. Oxygen flow will be determined by 
titration 
- 
Patients in the control group will not receive 
oxygen supply throughout the study (12 weeks), 
unless severe resting desaturation (SpO2 ≤80%) 
or severe exercise-induced desaturation (SpO2 
<80% for ≥10 minutes) developed. If either of 
these conditions develop, oxygen will be 
prescribed and the oxygen requirement will be 
reassessed after 30 days. 
- 
Patients of the control group will be offered to 
participate in the interventional treatment arm 
after they have terminated the control period 
(partial 
cross-over; 
secondary 
intervention 
group). Assessments of the secondary control 
group will be performed in analogy to the 
primary intervention group. 
 
Randomization will be performed in a 1:1 ratio. 
 
Study duration 
Q1 2019- Q4 2021 * 
Background 
Most patients with PAH, except those with congenital 
heart defects and pulmonary-to-systemic shunts, have 
minor degrees of hypoxemia at rest and during the 
night (Hildebrand et al. 2012).  
Current recommendations including the pneumological 

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guidelines for LTOT (Galiè et al. 2015) are based on 
evidence 
in 
patients 
with 
chronic 
obstructive 
pulmonary disease, as data for patients with PH are 
lacking:  
- 
When O2 partial pressure is repeatedly <8 kPa 
(<60 mmHg; alternatively, 90% of O2 saturation), 
patients are advised to use O2 to achieve a saturation of 
>8 kPa. (Galiè et al. 2015)  
- The use of ambulatory O2 can be considered when 
there is evidence of a symptomatic response or 
correction of exercise-induced desaturation. 
In patients with COPD it has already been shown that 
supplemental oxygen improves dyspnea and the 
distance walked during a five-minute walk test 
compared to supplemental air (Nonoyama et al. 2007). 
Data regarding survival benefits due to long-term 
oxygen therapy in COPD is inconsistent (Medical 
Research Council Working Party 1981, Nocturnal 
Oxygen Therapy Trial Group 1980, Chaouat et al. 
1999, Górecka 1997). 
There are only few studies investigating the effect of 
oxygen supply in pulmonary hypertension, most of 
which merely investigate acute effects of O2 
administration. Short-term oxygen administration has 
been shown to reduce mean pulmonary arterial 
pressure, pulmonary vascular resistance and to increase 
cardiac output in PAH patients (Leuchte et al. 2013, 
Roberts et al. 2001). In one study, oxygen supply also 
reversed the progression of PH in patients with chronic 
obstructive pulmonary disease (COPD) (Weitzenblum 
et al. 1985).  
One recent randomized-controlled trial indicates that 
O2 given during cardiopulmonary exercise significantly 
improves maximal work rate and endurance (Ulrich et 
al. 2017). Furthermore, nocturnal oxygen supply for 
one week significantly improved 6-minute walking 
distance in patients with PH (Ulrich et al. 2015), sleep-
associated breathing difficulties, exercise performance 
during the day as well as cardiac repolarisation 
(Schumacher et al. 2014). Patients with Eisenmenger’s 
syndrome gain little benefit from nocturnal O2 therapy 
(Sandoval et al. 2001). 
Whether these positive effects of O2 supplementation 
during exercise would translate into long-term 
improvements of exercise capacity, quality of life, 
hemodynamics and disease progression is not known to 
date. Up to now, there are no randomised studies 
suggesting that long-term O2 therapy is indicated or 
when it should be initiated.  

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This will be the first study to investigate the effect of 
long-term oxygen treatment for ≥16h/day for 3 months 
compared to no oxygen supply in patients with PAH or 
CTEPH on 6-minute walking distance, clinical 
parameters, quality of life and hemodynamics. Exercise 
capacity, clinical parameters, quality of life and 
invasive hemodynamics will be measured at baseline 
and after 3 months (12 weeks). 
 
References 
Chaouat A, Weitzenblum E, Kessler R, Charpentier C, Enrhart M, 
Schott R, Levi-Valensi P, Zielinski J, Delaunois L, Cornudella R, 
Moutinho dos Santos J. A randomized trial of nocturnal oxygen 
therapy in chronic obstructive pulmonary disease patients. Eur 
Respir J. 1999;14(5):1002. 
 
Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, 
Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, 
Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, 
Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, 
Zompatori M, Hoeper M. 2015 ESC/ERS Guidelines for the 
diagnosis and treatment of pulmonary hypertension: The Joint 
Task Force for the Diagnosis and Treatment of Pulmonary 
Hypertension of the European Society of Cardiology (ESC) and 
the European Respiratory Society (ERS): Endorsed by: 
Association for European Paediatric and Congenital Cardiology 
(AEPC), International Society for Heart and Lung Transplantation 
(ISHLT). Eur Respir J. 2015;46(4):903-75. 
 
Górecka D, Gorzelak K, Sliwiński P, Tobiasz M, Zieliński J. 
Effect of long-term oxygen therapy on survival in patients with 
chronic obstructive pulmonary disease with moderate hypoxaemia. 
Thorax. 1997;52(8):674. 
 
Hildenbrand FF, Bloch KE, Speich R, Ulrich S. Daytime 
measurements underestimate nocturnal oxygen desaturations in 
pulmonary arterial and chronic thromboembolic pulmonary 
hypertension. Respiration; international review of thoracic 
diseases. 2012;84(6):477-84. 
 
Leuchte HH, Baezner CJ, Baumgartner RA, Mernitz P, Neurohr C, 
Behr J. Acute hemodynamic responses to supplemental oxygen 
and their prognostic implications in pulmonary hypertension. 
Respiration. 2013;85(5):400-7. 
 
Medical Research Council Working Party. Long term domiciliary 
oxygen therapy in chronic hypoxic cor pulmonale complicating 
chronic bronchitis and emphysema. Report of the Medical 
Research Council Working Party. Lancet. 1981;1(8222):681.  
 
Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal 
oxygen therapy in hypoxemic chronic obstructive lung disease: a 
clinical trial. Ann Intern Med. 1980;93(3):391.  
 
Nonoyama ML, Brooks D, Guyatt GH, Goldstein RS  Effect of 
oxygen on health quality of life in patients with chronic 
obstructive pulmonary disease with transient exertional 
hypoxemia. Am J Respir Crit Care Med. 2007;176(4):343. 
 

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Roberts DH, Lepore JJ, Maroo A, Semigran MJ, Ginns LC. 
Oxygen therapy improves cardiac index and pulmonary vascular 
resistance in patients with pulmonary hypertension. Chest. 
2001;120(5):1547-55. 
 
Sandoval J, Aguirre JS, Pulido T, Martinez-Guerra ML, Santos E, 
Alvarado P, et al. Nocturnal oxygen therapy in patients with the 
Eisenmenger syndrome. Am J Respir Crit Care Med. 
2001;164(9):1682-7. 
 
Schumacher DS, Müller-Mottet S, Hasler ED, Hildenbrand FF, 
Keusch S, Speich R, Bloch KE, Ulrich S. Effect of oxygen and 
acetazolamide on nocturnal cardiac conduction, repolarization, and 
arrhythmias in precapillary pulmonary hypertension and sleep-
disturbed breathing. Chest. 2014;146(5):1226-1236. 
 
Ulrich S, Keusch S, Hildenbrand FF, Lo Cascio C, Huber LC, 
Tanner FC, Speich R, Bloch KE. Effect of nocturnal oxygen and 
acetazolamide on exercise performance in patients with pre-
capillary pulmonary hypertension and sleep-disturbed breathing: 
randomized, double-blind, cross-over trial. Eur Heart J. 
2015;36(10):615-23. 
 
Ulrich S, Hasler ED, Saxer S, Furian M, Bloch KE.et al. Effect of 
breathing oxygen-enriched air on exercise performance in patients 
with precapillary pulmonary hypertension: randomized, sham-
controlled cross-over trial; Eur Heart J. 2017;14;38(15):1159-
1168. 
 
Weitzenblum E, Sautegeau A, Ehrhart M, Mammosser M, 
Pelletier A. Long-term oxygen therapy can reverse the progression 
of pulmonary hypertension in patients with chronic obstructive 
pulmonary disease. The American review of respiratory disease. 
1985;131(4):493-8. 
 
 
 
 

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Materials & 
Supplies 
 
Investigator-Initiated-Trial (IIT) 
Indication of oxygen supply will be determined according to current 
recommendations of long term oxygen treatment in patients with 
pulmonary hypertension (see above). Oxygen treatment with liquid 
oxygen as applicable will be prescribed to patients of the intervention 
group. Oxygen flow will be determined by titration, aiming at O2 
saturation values of >90% at rest.  
Patients in the control group will be offered prescription of oxygen 
supply after the end of control period (control phase), serving as 
secondary intervention group. 
 
Indication 
PAH patients experiencing oxygen desaturations at rest and during 
physical activity, when O2 partial pressure is repeatedly <8 kPa 
(<60 mmHg; alternatively, 90% of O2 saturation). 
 
Aims and 
Objectives 
1) To determine patient benefits from a long-term oxygen therapy 
(LTOT) given continuously during ≥16h/day for 12 weeks, measured 
by improvement of exercise performance assessed by the 6 minute 
walking distance (6MWD)  
2) To investigate effects of oxygen treatment on QoL, measured with 
SF-36 questionnaire 
3) To determine the hemodynamic and functional  responses during 
long term oxygen treatment by echocardiography, stress-doppler 
echocardiography cardiopulmonary exercise testing and right heart 
catheterisation  
4) To investigate the change of clinical parameters such as blood gas 
analysis, laboratory (NT-proBNP), WHO functional class 
5) To assess time to worsening of oxygen saturation and time to clinical 
worsening  
 
Sample size 
N= 40 (with 20 patients randomized in each group) 
The minimally important difference of 6-minute walking distance in 
patients with pulmonary hypertension is considered to be 33 meters, 
according to the literature (Mathai et al. 2012). 
A recent study of Ulrich et al. has shown a 25 meter difference between 
nocturnal oxygen and sham-O2 for an intervention period of one week 
with a concentrator device in patients with pulmonary hypertension 
(Ulrich et al. 2015). We assume a standard deviation of the difference of 
50 meters (as seen in the data of Ulrich et al.) and a higher effect of 35 
meters due to a longer intervention period and the use of oxygen supply 
≥16h/day, which lies also above the threshold of minimally important 
difference for the 6-minute walking distance. 
The primary endpoint will be analysed in a hierarchical testing strategy 
with: 
1. Intra-individual analysis of 6MWD in the primary and secondary 
intervention group (difference from baseline to follow-up) 

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2. If (1) is significantly different, the treatment effect on 6MWD 
will be compared between the primary intervention group and 
the control group. 
Sample size assumptions: 
1) If the true treatment effect is at least an increase of 35meters in 
the 6-minute walking distance in the intervention group with a  
standard deviation of 50 meters, a sample size of 29 patients will 
provide a >95% power with a matched-pairs two-sided student’s 
t-test with a significance level of 0.05 (intra-individual 
comparison of difference baseline to follow-up of patients from 
primary and secondary intervention group). 
2) If the true treatment effect is at least a control group corrected 
increase of 50meters in the 6-minute walking distance with an 
equal standard deviation of 50 meters, a sample size of 17 
patients in each group (total sample size n=34) will provide an 
80% power with a two-sided student’s t-test with a significance 
level of 0.05 comparing two independent means (comparison of 
differences baseline to follow-up between the two groups).  
The sample size of 18 patients in each group with an anticipated 
dropout rate of 10% leads to a final sample size of 40 (20 in each 
group). 
The primary endpoint, 6-minute walking distance, will be compared by 
ANCOVA of the differences (baseline to follow-up) (1) intra-individual 
and (2) between the two groups with the baseline value as covariate, 
providing a power-advantage over the student’s t-test which leads to a 
power of >95% and 83% or more, respectively. 
 
References 
Mathai SC, Puhan MA, Lam D, Wise RA. The minimal important difference in the 6-
minute walk test for patients with pulmonary arterial hypertension. Am J Respir Crit 
Care Med. 2012 Sep 1;186(5):428-33. 
 
Ulrich S, Keusch S, Hildenbrand FF, Lo Cascio C, Huber LC, Tanner FC, Speich R, 
Bloch KE. Effect of nocturnal oxygen and acetazolamide on exercise performance in 
patients with pre-capillary pulmonary hypertension and sleep-disturbed breathing: 
randomized, double-blind, cross-over trial. Eur Heart J. 2015;36(10):615-23. 
 
Statistical methods 
Data will be pseudonymized and checked for plausibility. After database 
closure, data will be analysed. All data will be listed and trial summary 
tables will be provided with means, medians, variances and respective 
confidence intervals and with frequency tables. 
Baseline Parameters will be described and compared between study 
arms and study centres. 
The primary endpoint, 6-minute walking distance, will be compared by 
(1) matched-pairs two-sided student’s t-test of primary and secondary 
intervention group and (2) ANCOVA of the differences (baseline to 
three months) between the two groups with the baseline value as 
covariate.  

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Secondary parameters at baseline and during follow-up will be 
compared intra-individually and between groups comparing the 
difference between baseline and follow-up visits. Data will be displayed 
by means and standard deviations, medians and variances with 
respective 95% confidence intervals. 
p-values <0.05 will be considered as statistically significant. 
Patients who withdraw from the study will be asked to complete a final 
examination which will be included in the data analysis.  
 
Inclusion Criteria 
Patients in both groups (n = 40) with precapillary PH, WHO class I -IV 
(mPAP ≥ 25 mm Hg, pulmonary arterial occlusion pressure ≤15 mm 
Hg), who are stable on optimized pharmacological treatment for at least 
six weeks and who do not suffer from other cardio-pulmonary disease 
will be recruited if arterial or capillary O2 partial pressure is repeatedly 
(<60 mmHg; alternatively, 90% of O2 saturation) at rest and during 
physical activity hypoxemia still persist (O2 partial pressure <60 mmHg 
pO2 90 % ). 
 
men and women 18 years of age or older 
 
patient is diagnosed with Pulmonary Arterial Hypertension 
(World Health Organization (WHO) Category Group 1-3 (by the 
WHO Clinical classification system)), including Idiopathic 
(IPAH), Heritable PAH (HPAH, Familial PAH), and CTEPH, 
with exceptions as noted in exclusion criteria  
 
patient is willing and able to provide written informed consent  
 
patient is willing and able to comply with the protocol, including 
required follow-up visits  
 
Patient experiences oxygen desaturations below 90% (or pO2 
below 60 mmHg) at rest with oxygen desaturations below 90% 
(or pO2 below 60 mmHg)  during physical activity 
 
patient has a stable functional class of PAH with no changes of 
medication during the last six weeks before inclusion  
 
Exclusion Criteria 
 
Patient is a female who is pregnant, nursing, or of child bearing 
potential and is not on a reliable form of birth control  
 
patient has already been treated with long-term oxygen therapy 
within the last 3 weeks. 
 
patient with pulmonary venous hypertension 
 
significant 
functional 
limitation 
in 
lung 
function 
tests 
(FEV1>60%,TLC <60%) and  CT morphological signs of  
pulmonary disease 
 
significant left heart disease, requires acute pharmacological or 
interventional treatment  
 
unstable 
conditions 
requiring 
pharmacological 
or 
other 
treatment, intensive care or relevant severe concomitant disease  
 
patient is enrolled, has participated within the last thirty days, or 
is planning to participate, in a concurrent drug and/or device 
study during the course of this clinical trial. Co-enrolment in 

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concurrent trials is only allowed with documented pre-approval 
from the study manager that there is not a concern that co-
enrolment could confound the results of this trial.  
 
patient has been initiated on a new oral or parenteral PAH 
therapy in the last two months  
 
patient has had a recent (within three months) or otherwise 
unresolved infection requiring antibiotic treatment  
 
patient with a cardiac index (CI)  <1.8L/min/m2 
 
patient is Functional Class IV (New York Heart Association 
(NYHA)) 
 
active smoking status  
 
patient with severe resting desaturation (repeatedly SpO2 ≤85%) 
or severe exercise-induced desaturation (SpO2 <80% for ≥10 
minutes) 
Individual drop out 
criteria 
 
new events such as lung embolisms 
 
severe left heart insufficiency as well as chronic left heart disease 
with signs of decompensation 
 
radiological signs of severe disease, interstitial lung disease 
(pneumonia) 
 
patient with severe resting desaturation (repeatedly SpO2 ≤85%) 
or severe exercise-induced desaturation (SpO2 <80% for ≥10 
minutes) 
 
noncompliance, defined as oxygen treatment <12 hours per day 
for >7 days within 6 weeks (equals ~80%), assessed by patient 
interviews 
Efficacy and safety 
variables 
 
Efficacy Variables 
The primary efficacy variable is the distance walked in 6 minutes in 
meters. 
The following study procedures will be performed in every patient 
according to the visits schedule and analyzed as secondary efficacy 
variables. 
- 
quality of life assessed by the SF-36 questionnaire  
 
- 
Feasibility of oxygen treatment, assessed by patient consent to 
participate in the study (recruitment rate) and by patient 
compliance 
 
- 
History, questionnaire evaluation, and clinical examination:  
Complete medical history will be obtained. Physical examination 
will include weight, height, blood pressure, heart rate, cardiac 
and pulmonary auscultation, assessments of jugular distension 
and peripheral oedema. WHO functional class will be assessed 
by specific questionnaire. Quality of life will be assessed by the 
short form of the medical outcome questionnaire (SF-36). 
Assessment of compliance via questionnaire. 
 

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- 
Echocardiography:  
Following parameters will be assessed: systolic pulmonary 
arterial pressure (sPAP, mmHg), right ventricular area (RV-area, 
cm2), and right atrial area (RA-area,cm2), tricuspid annular plane 
systolic excursion (TAPSE), left ventricular eccentricity index 
(LV-EI), RV-pump function and LV-pump function (EF).   
 
- 
Stress-Doppler-echocardiography and cardiopulmonary exercise 
testing (spiroergometry): 
WHO protocol for incremental increase of workload (25 Watt 
every 2 minutes) will be used to assess cardiopulmonary 
response during exercise, including the following parameters: 
 sPAP,  
 RV-pump function,  
 heart rate,  
 systemic blood pressure,  
 oxygen consumption,  
 oxygen consumption/kg body weight,  
 oxygen saturation,  
 minute ventilation, 
 carbon dioxide and oxygen equivalents,  
 O2 pulse,  
 ventilatory threshold,  
 respiratory reserve.  
 
- 
Analyses of blood samples: 
Venous blood will be analysed to determine:  
 N-terminal natriuretic peptide (NT-pro BNP)  
 And additional laboratory tests that include inflammation 
factors, kidney, liver, blood cell count parameters   
- 
Blood for blood gas analyses: 
 oxygen partial pressure 
 carbon dioxide partial pressure  
 oxygen saturation of the blood (SaO2) 
 pH values  
 Bicarbonates  
 Base Excess  
 
- 
Pulmonary hemodynamics by right heart catheterization: 
 cardiac index in liters per minute per square meter (of 
body surface area) (CI) 
 systolic pulmonary artery pressure (sPAP) 
 mean pulmonary artery pressure (mPAP) 
 diastolic pulmonary artery pressure (dPAP) 
 pulmonary artery wedge pressure (PAWP) 
 right atrial pressure (RAP) 
 pulmonary vascular resistance (PVR)   
 cardiac output and ejection fraction (CO, HZV), cardiac 
index (CI) 

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 central venous saturation, via blood gas analysis from 
pulmonary artery  
Worsening of saturation will be determined as: 
- 
repeated oxygen desaturation ≤85% at rest or  
- 
severe exercise-induced desaturation (SpO2 <80% for ≥10 
minutes) 
Clinical worsening will be determined as  
- 
worsening of WHO functional class and deterioration of walking 
distance >15% compared to baseline 
- 
need of iv pulmonary hypertension targeted treatment 
- 
hospitalization due to worsening of PH 
 
Safety variables 
Patients with a serious adverse event occurring during the study 
treatment will be followed by the study team until the serious adverse 
event will have resolved to the pre-study level and/or will have been 
addressed according to best clinical practice. Patients withdrawing from 
the study prematurely will have a final physical examination.  
If a patient withdraws from treatment (intervention group) or is in need 
of oxygen therapy (control group) and agrees to stay in the study, study 
related examinations will be performed and data will be obtained 
according to protocol. 
 

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Course of the study Screening phase: Eligible patients will be asked to participate upon 
written informed consent. In case of agreement medical history will be 
taken and they will undergo screening examinations.  
The right heart catheterisation should not be older than 6 months before 
baseline and should be performed after the patient was on stable 
treatment for at least six weeks. In patients who have not performed a 
right heart catheter within the preceding 6 months, invasive 
hemodynamics will be measured before the beginning of the 
intervention. Oxygen will be prescribed and the oxygen system will be 
delivered to the patient. Baseline will be within 28 days after screening. 
Baseline / Day 1 visit: clinical evaluation, laboratory, blood gas 
analysis, SF-36 questionnaire, 6MWD, echocardiography, Stress-
Doppler-echocardiography and cardiopulmonary exercise testing. 
Day 1-90: LTOT with oxygen system for 16h/day vs. no oxygen supply. 
Interim phone calls each month (month 1 and 2). 
Month three / Day 90 visit (± 14 days): clinical evaluation, laboratory, 
blood gas analysis, SF-36 questionnaire, 6MWD, echocardiography, 
Stress-Doppler-Echocardiography 
and 
Cardiopulmonary 
Exercise 
Testing and right heart catheterisation. Patients of the control group will 
be offered to participate in secondary intervention group to receive long-
term oxygen treatment. (Week 12 visit will be performed again after 12 
weeks, in total 24 weeks of study with control and secondary 
intervention phase). 
Month four / Day 120 (± 14 days) (30 days after close out): follow-up 
visit to assess adverse events; outpatient visit or phone call.  
Excluded 
medication: 
None 
Pre-treatment 
period: 
N/A 
Duration of 
observation 
90 days (up to 180 days in the control group with switch to secondary 
intervention group) + follow-up period. 
 
Follow-up period 
30 days after close out visit each patient performs a follow-up Visit 
Clinical follow-up of all SAEs until they have been resolved. 
Clinic visits 
Screening visit, baseline visit, month three and month four (follow-up); 
month six according to month three assessment in secondary 
intervention group and respective follow-up. 
Secondary intervention group will have an additional visit after 180 days 
(in analogy to month three visit). 

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Dosing regimen 
Oxygen flow adaptation (titration): 
Until a SpO2 >90% or pO2 >60mmHg is achieved 
 
Route of 
administration 
Inhaled (nasal) Oxygen Therapy 
 
Timelines 
01/2019 – 12/2021 
Data collection 
Data management/analysis 
Study report/manuscript 
 
Q1 2019-Q4 2020 
Q1 2021-Q3 2021 
Q4 2021 
 
 
Endpoints 
Primary 
 
6-MWD, difference from baseline 
Secondary 
 
 
 
 
 
 
Change from baseline in hemodynamic parameters assessed by 
echocardiography, right-heart catheter, cardiopulmonary exercise testing 
and laboratory parameter as NT-proBNP at month three. Change from 
baseline in quality of life as assessed by SF-36. 
Parameters are listed under the section “efficacy variables”. 
 
 
 
 
 
 

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1.1 
Overview of visits and assessments (s. Diagram)  
Primary intervention group 
Assessments 
Screening  
Visit 1 
Baseline 
Phone visit 1 Phone visit 2 
Visit 2 
Follow up 
(Treatment 
group) 
  
Day 1 
Day 30 
Day 60 
Day 90 
Day 120 
 -28 days 
 
± 14 days 
± 14 days 
± 14 days 
± 14 days 
1 
1 
1 
1 
1 
1 
Informed Consent 
1 
- 
- 
- 
- 
- 
Inclusion / exclusion 
criteria 
1 
 
- 
- 
 
 
Evaluation of prior and 
concomitant medication 
1 
1 
- 
- 
1 
- 
PAH classification, 
etiology, diagnosis date  
1 
- 
- 
- 
- 
- 
WHO-FC 
1 
1 
- 
- 
1 
- 
Vital Sign 
Measurements incl. 
Heart Rate and SpO2 
1 
1 
- 
- 
1 
- 
6MWD, Borg Dyspnea 
Score, 
1 
1 
- 
- 
1 
- 
Height / Weight 
1 
1 
- 
- 
1 
- 
Lung function testing 
(TLC; DLCO) 
1 
1 
- 
- 
1 
- 
Blood gas analysis 
1 
1 
- 
- 
1 
- 
RHC hemodynamics: 
mPAP, mRAP, PAWP, 
PVR, cardiac index (for 
initiation of trial-
specific therapy: within 
6 months prior or at) 
1* 
- 
- 
- 
1 
- 
Physical examination 
1 
1 
- 
- 
1 
- 
Hematology, Chemistry 
1 
1 
- 
- 
1 
- 
NT-proBNP 
1 
1 
- 
- 
1 
- 
For females only: 
Pregnancy test 
- child bearing potential 
- currently pregnant 
(Yes***/No/Unknown) 
1 
1 
- 
- 
1 
- 
Echocardiogram , stress-
doppler-
echocardiography and 
Cardiopulmonary 
Exercise Testing 
1 
1 
- 
- 
1 
- 
Quality of life (SF-36) 
1 
1 
- 
- 
1 
- 
Adverse Events 
- 
- 
1 
1 
1 
1 
Phone visits 
- 
- 
1 
1 
- 
1 
* RHC at baseline will only be performed in patients who have not performed a RHC within the preceding 6 months 
 
 
 
 

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Secondary intervention group (control group with crossover) 
Assessments 
Screening 
Visit 1: 
Baseline 
Phone 
visit 1 
Phone 
visit 2 
Visit 2 
Phone 
visit 3 
Phone 
visit 4 
Visit 3 
Follow 
up 
(Contro
l group) 
  
Day 1  
Day 30 
Day 60 
Day 90 
Day 120 Day 150 
Day 
180 
Day 210 
-28 days 
 
± 14 days 
± 14 days 
± 14 
days 
± 14 
days 
± 14 
days 
± 14 
days 
± 14 
days 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Informed Consent 
1 
- 
- 
- 
- 
- 
- 
- 
- 
Inclusion / exclusion 
criteria 
1 
- 
- 
- 
- 
- 
- 
- 
- 
Evaluation of prior and 
concomitant medication 
1 
1 
- 
- 
1 
- 
- 
1 
- 
PAH classification, 
etiology, diagnosis date 
1 
- 
- 
- 
- 
- 
- 
- 
- 
WHO-FC 
1 
1 
- 
- 
1 
- 
- 
1 
- 
Vital Sign Measurements 
incl. Borg Dyspnea Score, 
Heart Rate and SpO2 
1 
1 
- 
- 
1 
- 
- 
1 
- 
6MWD  
1 
1 
- 
- 
1 
- 
- 
1 
- 
Height / Weight 
1 
1 
- 
- 
1 
- 
- 
1 
- 
Lung function testing 
(TLC; DLCO) 
1 
1 
- 
- 
1 
- 
- 
1 
- 
Blood gas analysis 
1 
1 
- 
- 
1 
- 
- 
1 
- 
Stress-Doppler-
Echocardiography and 
Cardiopulmonary 
Exercise Testing 
- 
1 
- 
- 
1 
- 
- 
1 
- 
RHC hemodynamics: 
mPAP, mRAP, PAWP, 
PVR, cardiac index (for 
initiation of trial-specific 
therapy: within 6 months 
prior or at) 
1* 
- 
- 
- 
1 
- 
- 
1 
- 
Physical examination 
1 
1 
- 
- 
1 
- 
- 
1 
- 
Hematology, Chemistry 
1 
1 
- 
- 
1 
- 
- 
1 
- 
NT-proBNP 
1 
1 
- 
- 
1 
- 
- 
1 
- 
For females only: 
Pregnancy test 
- child bearing potential 
- currently pregnant 
(Yes***/No/Unknown) 
1 
1 
- 
- 
1 
- 
- 
1 
- 
Echocardiogram 
1 
1 
- 
- 
1 
- 
- 
1 
- 
Quality of life (SF-36) 
1 
1 
- 
- 
1 
- 
- 
1 
- 
Adverse Events 
- 
- 
1 
1 
1 
1 
1 
1 
1 
Phone visit 
- 
- 
1 
1 
- 
1 
1 
- 
1 
* RHC at baseline will only be performed in patients who have not performed a RHC within the preceding 6 months 
 
 

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Diagram: 

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Abbreviations 
6MWD 
 
6-Minute Walking Distance 
AE 
 
 
Adverse Event 
ANCOVA 
 
Analyses of Covariance 
APAH  
 
Associated Pulmonary Arterial Hypertension 
AMG  
 
German Drug Law (Deutsches Arzneimittelgesetz) 
ATS 
 
 
American Thoracic Society 
BDSG  
 
Bundesdatenschutzgesetz 
BfArM  
 
Bundesinstitut für Arzneimittel und Medizinprodukte 
BP 
 
 
Blood Pressure 
CI 
 
 
Cardiac Index 
CO 
 
 
Cardiac Output 
COPD  
 
Chronic Obstructive Pulmonary Disease 
CRF 
 
 
Case Report Form 
CT 
 
 
Computed Tomography 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CTEPH 
 
Chronic thromboembolic pulmonary hypertension 
CV 
 
 
Curriculum Vitae 
DBL 
 
 
Data Base Lock 
DLCO  
 
Diffusion limited carbon monoxide 
dPAP  
 
Diastolic Pulmonary Artery Pressure 
DSUR  
 
Development Safety Update Report 
EC 
 
 
Ethics Committee 
ECG  
 
Electrocardiogram 
ERS 
 
 
European Respiratory Society 
ESC 
 
 
European Society of Cardiology 
FEV1  
 
Forced expiratory volume in the first second 
FPI 
 
 
First Patient In 
FSI 
 
 
First Subject In 
FVC 
 
 
Forced Vital Capacity 
GCP  
 
Good Clinical Practice 
GCP-V 
 
Good Clinical Practice Ordinance (GCP-Verordnung) 
GLDH  
 
Glutamate Dehydrogenase 
HDL  
 
High Density Lipoprotein 
HIV   
 
Human Immunodeficiency Virus 
HPAH  
 
Heritable PAH (Familial PAH) 
HR 
 
 
Heart Rate 
HZV 
 
 
Herzzeitvolumen 
ICF 
 
 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical Requirements  
for Registration of Pharmaceuticals for Human Use 
IIT 
 
 
Investigator Initiated Trial 

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IMP 
 
 
Investigational Medicinal Product 
INN 
 
 
International Nonproprietary Name 
IPAH  
 
Idiopathic Pulmonary Arterial Hypertension 
ISF 
 
 
Investigator Site File 
ISRCTN 
 
International Standard Randomized Controlled Trial Number 
ITT 
 
 
Intention To Treat 
LKP 
 
 
Coordinating Investigator according to AMG (Leiter der Klinischen  
 
 
 
Prüfung) 
LSI 
 
 
Last Subject In 
LSO 
 
 
Last Subject Out 
LTOT  
 
Long-Term Oxygen Therapy 
LV-EI  
 
Left Ventricular Eccentricity Index 
mPAP  
 
Mean Pulmonary Artery Pressure 
mRAP  
 
Mean Right Arterial Pressure 
NCI 
 
 
National Cancer Institute 
NT-proBNP 
 
N-terminal prohormone of brain natriuretic peptide 
NYHA  
 
New York Heart Association 
O2 
 
 
Oxygen 
PAH  
 
Pulmonary Arterial Hypertension 
PAP 
 
 
Pulmonary Arterial Pressure 
PAWP  
 
Pulmonary Artery Wedge Pressure 
PH 
 
 
Pulmonary Hypertension 
PHAROS 
 
Population based Hematological Registry for Observational Studies 
pO2 
 
 
Partial Pressure of Oxygen 
PVR 
 
 
Pulmonary Vascular Resistance 
QoL 
 
 
Quality of Life 
RA(-area) 
 
Right Atrial (Area) 
RAP 
 
 
Right Atrial Pressure 
RHC  
 
Right Heart Catheterization 
RV 
 
 
Residual Volume 
RV(-area) 
 
Right Ventricular (Area) 
SAE 
 
 
Serious Adverse Event 
SaO2  
 
Arterial Oxygen Saturation 
SpO2  
 
Peripheral Oxygen Saturation 
SC 
 
 
Steering Committee 
SF-36  
 
36-Item Short Form Survey as part of the Medical Outcome Study 
SGPT  
 
Serum Glutamic-Pyruvate Transaminase, also known as ALAT 
SGOT  
 
Serum Glutamic-Oxaloacetic Transaminase, also known as ASAT 
sPAP  
 
Systolic Pulmonary Artery Pressure 
SmPC/SPC 
 
Summary of Product Characteristics 
SUSAR 
 
Suspected Unexpected Serious Adverse Reaction 
SvO2  
 
Venous Oxygen Saturation 

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TAPSE 
 
Tricuspid Annular Plane Systolic Excursion 
TLC 
 
 
Total Lung Capacity 
USA 
 
 
United States of America 
WHO  
 
World Health Organization 
WHO-FC 
 
World Health Organization Functional Class 
 
 
 

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2 
Introduction 
2.1 
Scientific Background 
Most patients with PAH, except those with congenital heart defects and pulmonary-to-systemic 
shunts, have minor degrees of arterial hypoxemia at rest and during the night (Hildebrand et al. 
2012).  
Current recommendations including the pneumological guidelines for LTOT (Galiè et al. 2015) 
are based on evidence in patients with chronic obstructive pulmonary disease, as data for patients 
with PH are lacking:  
- When O2 partial pressure is repeatedly <8 kPa (<60 mmHg; alternatively, 90% of O2 
saturation), patients are advised to use O2 to achieve a saturation of >8 kPa. (Galiè et al. 2015)  
- The use of ambulatory O2 can be considered when there is evidence of a symptomatic response 
or correction of exercise-induced desaturation. 
In patients with COPD it has already been shown that supplemental oxygen improves dyspnea 
and the distance walked during a five-minute walk test compared to supplemental air (Nonoyama 
et al. 2007). Data regarding survival benefits due to long-term oxygen therapy in COPD is 
inconsistent (Medical Research Council Working Party 1981, Nocturnal Oxygen Therapy Trial 
Group 1980, Chaouat et al. 1999, Górecka 1997). 
There are only few studies investigating the effect of oxygen supply in pulmonary hypertension, 
most of which merely investigate acute effects of O2 administration. Short-term oxygen 
administration has been shown to reduce mean pulmonary arterial pressure, pulmonary vascular 
resistance and to increase cardiac output in PAH patients (Leuchte et al. 2013, Roberts et al. 
2001). In one study, oxygen supply also reversed the progression of PH in patients with chronic 
obstructive pulmonary disease (COPD) (Weitzenblum et al. 1985).  
One recent randomized-controlled trial indicates that O2 given during cardiopulmonary exercise 
significantly improves maximal work rate and endurance (Ulrich et al. 2017). Furthermore, 
nocturnal oxygen supply for one week significantly improved 6-minute walking distance in 
patients with PH (Ulrich et al. 2015), sleep-associated breathing difficulties, exercise 
performance during the day as well as cardiac repolarisation (Schumacher et al. 2014). Patients 
with Eisenmenger’s syndrome gain little benefit from nocturnal O2 therapy (Sandoval et al. 
2001). 
 

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Whether these positive effects of O2 supplementation during exercise would translate into long-
term improvements of exercise capacity, quality of life, hemodynamics and disease progression 
is not known to date. Up to now, there are no randomised studies suggesting that long-term O2 
therapy is indicated or when it should be initiated.  
This will be the first study to investigate the effect of long-term oxygen treatment for ≥16h/day 
for 3 months compared to no oxygen supply in patients with PAH or CTEPH on 6-minute 
walking distance, clinical parameters, quality of life and hemodynamics. Exercise capacity, 
clinical parameters, quality of life and invasive hemodynamics will be measured at baseline and 
after 3 months (12 weeks). 
2.2 
Trial Rationale/ Justification 
Treatment of O2 naïve patients with PAH will be included in this investigator-initiated trial (IIT) 
to assess efficacy and safety of oxygen substitution. Nocturnal oxygen substitution improved the 
6MWD compared to placebo in one clinical trial in PAH patients (Ulrich et al. 2015). Due to the 
positive results in the treatment of patients with PAH, the initiation of this proof-of-concept 
study is justified. 
2.3 
Benefit/ Risk Assessment 
One recent randomized-controlled trial indicates that O2 given during cardiopulmonary exercise 
significantly improves maximal work rate and endurance (Ulrich et al. 2017). Furthermore, 
nocturnal oxygen supply for one week significantly improved 6-minute walking distance in 
patients with PH (Ulrich et al. 2015), sleep-associated breathing difficulties, exercise 
performance during the day as well as cardiac repolarisation (Schumacher et al. 2014). Patients 
with Eisenmenger’s syndrome gain little benefit from nocturnal O2 therapy (Sandoval et al. 
2001). 
Whether these positive effects of O2 supplementation during exercise would translate into long-
term improvements of exercise capacity, quality of life, hemodynamics and disease progression 
is not known to date. Up to now, there are no randomised studies suggesting that long-term O2 
therapy is indicated or when it should be initiated.  
2.4 
Steering Committee 
In order to monitor specific aspects of the current trial the following Reference Committees will 
be established: The clinical study will be an investigator initiated trial in the Thoraxclinic in 
Heidelberg specialized in the treatment of patients with PH. The Steering Committee will be 
responsible for coordinating the conduct of this trial. The Steering Committee will also protect 
the safety interests of patients in this trial by monitoring the progress and safety data of the trial. 

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3 
Trial Objectives and Endpoints 
3.1 
Primary Objective and Primary Endpoint 
1) To determine the benefits for PH patients from a long-term oxygen therapy (LTOT) given 
continuously during ≥16h/day for 12 weeks, measured by improvement of exercise performance 
assessed by the 6 minute walking distance (6MWD). 
3.2 
Secondary Objectives 
1) To investigate effects of oxygen treatment on QoL, measured with SF-36 questionnaire 
2) To determine the hemodynamic and functional responses during long term oxygen treatment 
by echocardiography, stress-doppler echocardiography cardiopulmonary exercise testing and 
right heart catheterisation  
3) To investigate the change of clinical parameters such as blood gas analysis, laboratory (NT-
proBNP), WHO functional class (WHO-FC) 
4) To assess time to worsening of oxygen saturation and time to clinical worsening  
4 
Trial Design 
Investigator-Initiated-Trial (IIT)  
This is a prospective, randomised, controlled, parallel-group, open label monocenter 
(Heidelberg) study with a partial cross-over design, which investigates the effect of long term 
oxygen treatment in patients with pulmonary arterial hypertension or chronic thromboembolic 
pulmonary hypertension (CTEPH) who present with mild or moderate hypoxemia at rest and/or 
during physical activity and therefore may require longterm oxygen therapy.  
Patients will be divided in a supplemental-oxygen group (primary intervention group) and no-
supplemental-oxygen group (control group). Patients of the control group will be offered to 
participate in the interventional treatment arm after they have terminated the control period 
(partial cross-over; secondary intervention group). 
Efficacy of long term oxygen therapy will be investigated by assessing invasive and non-
invasive clinical parameters at baseline and after 3 months. Efficacy parameters will be 
compared intra-individually (primary and secondary intervention group) and between the 
intervention and the control group.  
Randomization will be performed in a 1:1 ratio. 

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Patients will be assessed at baseline and after 3 months. Clinical assessments will comprise of 
medical history, WHO functional class, electrocardiogram, blood gas analysis, lung function, 6-
minute walking distance, echocardiography cardiopulmonary exercise testing with stress-
Doppler echocardiography, laboratory tests including NT-proBNP, invasive hemodynamics 
using right heart catheterization, and quality of life (questionnaire SF-36) at baseline and after 3 
months, worsening of saturation and clinical worsening events. 
5 
Trial Duration and Schedule 
5.1 
Study Phases 
 
Screening Phase: up to 28 days before treatment start 
 
Treatment phase: 6 months (180 ± 7 days) 
 
Safety Follow-up: patient’s well-being will be monitored by phone after 30 ± 7 days after 
last intake of study drug. 
5.2 
Trial Duration 
The overall duration of the trial is expected to be approximately 3 years. Recruitment of subjects 
will start in January 2019 till December 2020.* The actual overall duration or recruitment may 
vary.  
Total trial duration: 
[3 years] 
Duration of the clinical Phase: 
[180 ± 7 + 30 ± 7 follow-up phase]   
Beginning of the preparation Phase: 
[Q1 2019] 
 
FSI (First Subject In): 
[Q1 2019] 
 
LSI (Last Subject In): 
[Q4 2020] 
 
LSO (Last Subject Out): 
[Q2 2021] 
 
DBL (Data Base Lock): 
[Q3 2021] 
 
Statistical Analyses Completed: 
[Q3 2021] 
 
Trial Report Completed: 
[Q4 2021] 
 
6 
Selection of Subjects 
6.1 
Number of Subjects 
As calculated in section 10.1, 40 subjects should be enrolled in the clinical trial, 20 subjects per 
treatment group. 
The minimally important difference of 6-minute walking distance in patients with pulmonary 
hypertension is considered to be 33 meters, according to the literature (Mathai et al. 2012). 

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A recent study of Ulrich et al. has shown a 25 meter difference between nocturnal oxygen and 
sham-O2 for an intervention period of one week with a concentrator device in patients with 
pulmonary hypertension (Ulrich et al. 2015). We assume a standard deviation of the difference 
of 50 meters (as seen in the data of Ulrich et al.) and a higher effect of 35 meters due to a longer 
intervention period and the use of oxygen supply ≥16h/day, which lies also above the threshold 
of minimally important difference for the 6-minute walking distance. 
The primary endpoint will be analysed in a hierarchical testing strategy with Intra-individual 
analysis of 6MWD in the primary and secondary intervention group (difference from baseline to 
follow-up). 
If (1) is significantly different, the treatment effect on 6MWD will be compared between the 
primary intervention group and the control group. 
Sample size assumptions 
If the true treatment effect is at least an increase of 35 meters in the 6-minute walking distance 
with an equal standard deviation of 50 meters, a sample size of 29 patients will provide a >95% 
power with a matched-pairs two-sided student’s t-test with a significance level of 0.05 (intra-
individual comparison of difference baseline to follow-up in primary and secondary intervention 
group). 
If the true treatment effect is at least a control group corrected increase of 50 meters in the 6-
minute walking distance with an equal standard deviation of 50 meters, a sample size of 18 
patients in each group will provide an 83% power with a two-sided student’s t-test with a 
significance level of 0.05 comparing two independent means (comparison of differences baseline 
to follow-up between the two groups).  
The sample size of 18 patients in each group with an anticipated dropout rate of 10% leads to a 
final sample size of 40 (20 in each group). 
The primary endpoint, 6-minute walking distance, will be compared by ANCOVA of the 
differences (baseline to follow-up) (1) intra-individual and (2) between the two groups with the 
baseline value as covariate, providing a power-advantage over the student’s t-test which leads to 
a power of >95% and 83% or more, respectively. 
6.2 
General Criteria for Subjects’ Selection 
It is assumed that for any patient, considered for inclusion, a regular diagnostic work up in 
accordance with PH guidelines (ESC/ERS Guidelines) was performed in advance. 

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Oxygen saturation will be validated at rest and during exercise at the screening visit. For 
statistical considerations see section 10. 
6.3 
Inclusion Criteria 
Patients in both groups (n=40) with precapillary PH, WHO class I -IV (mPAP ≥ 25 mm Hg, 
pulmonary capillary occlusion pressure ≤15 mm Hg), who are stable on optimized 
pharmacological treatment for at least six weeks and who do not suffer from other cardio-
pulmonary disease will be recruited if O2 partial pressure is repeatedly (<60 mmHg; 
alternatively, 90% of O2 saturation) at rest and during physical activity hypoxemia still persist 
(O2 partial pressure <60 mmHg SpO2 90 % ). 
 men and women 18 years of age or older 
 patient is diagnosed with Pulmonary Arterial Hypertension (World Health Organization 
(WHO) Category Group 1-3 (by the WHO Clinical classification system)), including 
Idiopathic (IPAH), Heritable PAH (HPAH, Familial PAH), and CTEPH, with exceptions 
as noted in exclusion criteria  
 patient is willing and able to provide written informed consent  
 patient is willing and able to comply with the protocol, including required follow-up 
visits  
 patient experiences oxygen desaturations below 90% (or pO2 below 60 mmHg) at rest 
with oxygen desaturations below 90% (or pO2 below 60 mmHg)  during physical activity 
 patient has a stable functional class of PAH with no changes of medication during the last 
six weeks before inclusion. 
 
6.4 
Exclusion Criteria 
 
Female patient who is pregnant, nursing, or of child bearing potential and is not on a 
reliable form of birth control  
 
patient has already been treated with oxygen therapy within the last 3 weeks 
 
patient with pulmonary venous hypertension 
 
significant functional limitation in lung function tests (FEV1>60%, TLC <60%) and  CT 
morphological signs of  pulmonary disease 
 
significant left heart disease, requires acute pharmacological or interventional treatment  
 
unstable conditions requiring pharmacological or other treatment, intensive care or 
relevant severe concomitant disease  

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 
patient is enrolled, has participated within the last thirty days, or is planning to 
participate, in a concurrent drug and/or device study during the course of this clinical 
trial. Co-enrolment in concurrent trials is only allowed with documented pre-approval 
from the study manager that there is not a concern that co-enrolment could confound the 
results of this trial.  
 
patient has been initiated on a new oral or parenteral PAH therapy in the last two months  
 
patient has had a recent (within three months) or otherwise unresolved infection requiring 
antibiotic treatment  
 
patient with a cardiac index (CI)  <1.8L/min/m2 
 
patient is Functional Class IV (New York Heart Association (NYHA))  
 
active smoking status  
 
patient with severe resting desaturation (repeatedly SpO2 ≤85%) or severe exercise-
induced desaturation before enrolment (SpO2 <80% for ≥10 minutes) 
6.5 
Criteria for Removal or Withdrawal 
6.5.1 Withdrawal of Subjects 
A subject will be withdrawn from the trial treatment for the following reasons: 
 
at their own request or at request of the legal representative  
 
if, in the investigator's opinion, continuation of the trial would be detrimental to the 
subject's well-being 
 
occurrence of a severe serious adverse event (SAE) caused by the IMP 
 
occurrence of an adverse event (AE) which makes the continuation of the study 
undesirable 
 
new events such as lung embolisms 
 
severe left heart insufficiency as well as chronic left heart disease with signs of 
decompensation 
 
radiological signs of severe interstitial lung disease (pneumonia) 
 
patient with severe resting desaturation (repeatedly SpO2 ≤85%) and/or severe exercise-
induced desaturation (SpO2 <80% for ≥10 minutes) 
 
noncompliance, defined as oxygen treatment <12 hours per day for >7 days within 6 
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The Coordinating investigator decides about withdrawal of subjects from trial treatment in case 
of occurrence of criteria mentioned above. Any decision to continue with the study treatment 
despite occurrence of any of the withdrawal criteria has to be justified in written form in the Case 
Record Form (CRF) and in the subject’s medical records. 
Any patient removed from the study due to an AE or SAE will be monitored up until no more 
signs and symptoms are verifiable or the subject is on stable condition. The patient, either 
willingly withdrawn from the study or due to premature termination, will be asked thoroughly to 
complete all examinations scheduled for the final trial day, and these will be performed as far as 
possible and documented.  
In all cases, the reason for withdrawal must be recorded in the CRF and in the subject’s medical 
records. 
In case of withdrawal of a subject at his/ her own request, the reason should be asked for as 
extensively as possible and documented. 
All efforts will be made to follow up the subject.  
A subject may/ will be withdrawn from all trial related procedures (including follow-up visits) 
for the following reasons: 
- at his/her own request or at request of his/her legal representative 
- non-adherence to the trial-related requirements, which may (have) influence(d) the 
validity of the trial data 
In case of clinical worsening / deterioration of patients in the control group, an early termination 
visit may be performed and patients may be offered to take part in the interventional treatment 
arm in order to receive long-term oxygen treatment ahead of schedule. 
6.5.2 Replacement of Subjects 
Per treatment arm, 20 subjects will be enrolled and included into the intention to treat (ITT) and 
safety analysis (SA). Subjects who terminate the study prematurely will not be replaced as a 20% 
drop-out rate is included in this sample size calculation.  
6.5.3 Premature Closure of the Clinical Trial 
The trial can be prematurely closed or suspended by the Coordinating Investigator in case if new 
serious risks for subjects become known. The Ethics Committee (EC) and the competent 
regulatory authorities must then be informed. Furthermore, the Ethics Committee(s) and 
competent regulatory authorities themselves may decide to stop or suspend the trial.  

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Should the trial be closed prematurely, all trial material (completed, partially completed, and 
blank CRF, randomization envelopes, IMP, etc.) must be returned to and/or kept within the files 
of the Coordinating Investigator.  
All involved investigators have to be informed immediately about a cessation/ suspension of the 
trial. The decision is binding to all trial centres and investigators.  
6.6 
Prior and Concomitant Illnesses 
Relevant additional illnesses present at the time of informed consent are regarded as concomitant 
illnesses and will be documented on the appropriate pages of the CRF as medical history. 
Included are conditions that are seasonal, cyclic, or intermittent (e.g. seasonal allergies; 
intermittent headache). 
Abnormalities which appear for the first time or worsen (intensity, frequency) during the trial are 
adverse events (AEs) and must be documented on the appropriate pages of the CRF. 
6.7 
Prior and Concomitant Treatments 
Relevant additional treatments administered to the subjects on entry to the trial or at any time 
during the trial are regarded as concomitant treatments and must be documented on the 
appropriate pages of the CRF. 
In case of clinical worsening and if clinically indicated additional PAH-targeted rescue 
medication will be initiated at the discretion of the investigators. Participants will not be included 
if scheduled to receive another investigational drug during the course of this study. 
7 
Investigational Medicinal Product 
7.1 
General Information about the Investigational Medicinal Product 
7.1.1 Oxygen (O2) 
Investigational medicinal product: Oxygen medicAL 
International Nonproprietary Name (INN): Oxygen 
ATC code: V03AN01 
Pharmaceutical formulation: O2 ≥ 99.5 Vol. %; other components H2O ≤ 67 parts per 
million by volume (ppmv), CO2 ≤ 300 ppmv, CO ≤ 5 ppmv 
Route of administration: nasal 
Time and frequency of administration: long-term oxygen therapy (LTOT) given 
continuously during ≥16h/day for 12 weeks 
Dosage: titration 

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Storage conditions: no special storage conditions required  
Marketing authorization holder: different marketing authorization holders will be available, 
as oxygen will be prescribed according to marketing approval in Germany /(e.g. VitalAire, 
Linde, Vivisol, …).  
Devices: liquid oxygen may be applied via different devices, such as Freelox, Liberator, 
Stroller, Spirit, Helios, Inogen One 
 
7.2 
Therapeutic Effects 
Most patients with PAH, except those with congenital heart defects and pulmonary-to-systemic 
shunts, have minor degrees of hypoxemia at rest and during the night (Hildebrand et al. 2012).  
Current recommendations including the pneumological guidelines for LTOT (Galiè et al. 2015) 
are based on evidence in patients with chronic obstructive pulmonary disease, as data for patients 
with PH are lacking:  
 When O2 partial pressure is repeatedly <8 kPa (<60 mmHg; alternatively, 90% of O2 
saturation), patients are advised to use O2 to achieve a saturation of >8 kPa. (Galiè et al. 
2015)  
 The use of ambulatory O2 can be considered when there is evidence of a symptomatic 
response or correction of exercise-induced desaturation. 
In patients with COPD it has already been shown that supplemental oxygen improves dyspnea 
and the distance walked during a five-minute walk test compared to supplemental air (Nonoyama 
et al. 2007). Data regarding survival benefits due to long-term oxygen therapy in COPD is 
inconsistent (Medical Research Council Working Party 1981, Nocturnal Oxygen Therapy Trial 
Group 1980, Chaouat et al. 1999, Górecka 1997). 
There are only few studies investigating the effect of oxygen supply in pulmonary hypertension, 
most of which merely investigate acute effects of O2 administration. Short-term oxygen 
administration has been shown to reduce mean pulmonary arterial pressure, pulmonary vascular 
resistance and to increase cardiac output in PAH patients (Leuchte et al. 2013, Roberts et al. 
2001). In one study, oxygen supply also reversed the progression of PH in patients with chronic 
obstructive pulmonary disease (COPD) (Weitzenblum et al. 1985).  
One recent randomized-controlled trial indicates that O2 given during cardiopulmonary exercise 
significantly improves maximal work rate and endurance (Ulrich et al. 2017). Furthermore, 
nocturnal oxygen supply for one week significantly improved 6-minute walking distance in 

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patients with PH (Ulrich et al. 2015), sleep-associated breathing difficulties, exercise 
performance during the day as well as cardiac repolarisation (Schumacher et al. 2014). Patients 
with Eisenmenger’s syndrome gain little benefit from nocturnal O2 therapy (Sandoval et al. 
2001). 
Whether these positive effects of O2 supplementation during exercise would translate into long-
term improvements of exercise capacity, quality of life, hemodynamics and disease progression 
is not known to date. Up to now, there are no randomised studies suggesting that long-term O2 
therapy is indicated or when it should be initiated.  
7.3 
Known Side Effects 
People exposed to high concentrations of oxygen for long periods of time are at risk for oxygen 
toxicity. These include ventilator patients, premature infants and people receiving hyperbaric 
oxygen treatment (Collopy et al. 2012). For this reason, it is recommended that when oxygen 
therapy is warranted, the lowest effective dose be given (Jenkinson et al. 1993). 
Possible side effects of oxygen treatment are drying out of the mucous membranes in case of 
inappropriate application, coughing and increased dyspnea in case of oversupply. Patients with a 
serious adverse event occurring during the study treatment will be followed by the study team 
until the serious adverse event will have resolved to the pre-study level and/or will have been 
addressed according to best clinical practice. Patients withdrawing from the study prematurely 
will have a final physical examination.  
7.4 
Dosage Schedule, Titration and Administration 
Study medication will be oxygen (O2) in diverse concentrations, titrated until a SaO2>90% or 
pO2 >60 mmHg is achieved, for 20 patients vs. no supplemental O2 for 20 patients over 90 ± 7 
days. Patients of the control group will be offered to participate in the interventional treatment 
arm after they have terminated the control period (partial cross-over; secondary intervention 
group). After the end of the study it is up to the judgment of the investigator to prescribe oxygen 
to all patients who might benefit from the treatment. This decision will be based on the 
physician’s and the patient’s estimation taking into account the observed individual treatment 
effect, progression of disease, patient view and any comments from the Ethics Committee, if 
applicable. Patient care and monitoring will be performed in the patients’ specialized centers. 
Titration 
Oxygen flow adaptation (titration): Until a SpO2 >90% or pO2 >60mmHg is achieved 
Administration 

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Oxygen therapy will be administered inhaled (nasal). 
7.5 
Treatment Assignment 
Patients who have signed the consent form will be given a unique screening number including 
centre number (e.g. 01, 02…) and patient ID (001, 002, …). Screening number will ascend, 
starting with 001, 002, etc. If the patient is eligible for the prospective drug trial, a 1:1 
randomization will be performed into oxygen and no-supplemental oxygen group and a 
consecutive randomization number will be allocated to the patient. The oxygen supplier will 
provide the oxygen to the patients in the intervention group in a concentration based on the 
initial titration performed during baseline. The trial medication will be administered to subjects 
only after confirming their eligibility after the initial screening. Subjects withdrawn from the trial 
retain their identification codes (e.g. randomization number, if already given). New subjects 
must always be allotted a new identification code. 
7.6 
Randomization  
PAH patients experiencing oxygen desaturations at rest and during physical activity, when O2 
partial pressure is repeatedly <8 kPa (<60 mmHg; alternatively, 90% of O2 saturation). Patients 
will be divided in a supplemental-oxygen group (primary intervention group) and no-
supplemental-oxygen group (control group). Patients of the control group will be offered to 
participate in the interventional treatment arm after they have terminated the control period 
(partial cross-over; secondary intervention group). Randomization will be performed in a 1:1 
ratio. Randomization to one of the groups will be performed by block randomization. 
Randomization lists will be created by the data management using a computer to generate 
random numbers. 
7.7 
Labelling and Supply 
Indication of oxygen supply will be determined according to current recommendations of long 
term oxygen treatment in patients with pulmonary hypertension. Oxygen treatment with liquid 
oxygen as applicable will be prescribed to patients of the intervention group. Oxygen flow will 
be determined by titration, aiming at O2 saturation values of >90% at rest.  
Patients in the control group will be offered prescription of oxygen supply after the end of the 
control period (control phase), serving as secondary intervention group. 
7.8 
Supplies and Accountability 
Oxygen treatment with liquid oxygen as applicable will be prescribed to patients of the 
intervention group. 

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7.9 
Compliance 
Oxygen will be prescirbed to the subjects by the investigator. Compliance will be assessed by 
daily measurements of oxygen saturation at home. Furthermore, the patients will receive a 
patient diary recording oxygen saturation and time points. The patient diary will be checked for 
compliance at each study visit. Noncompliance will be defined as oxygen treatment <12 hours 
per day for >7 days within 6 weeks (equals ~80%), assessed by patient interviews. 
 
 
 

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8 
Trial Methods 
8.1 
Overview of visits and assessments 
Primary intervention group 
Assessments 
Screening  
Visit 1 
Baseline 
Phone visit 1 Phone visit 2 
Visit 2 
Follow up 
(Treatment 
group) 
  
Day 1 
Day 30 
Day 60 
Day 90 
Day 120 
 -28 days 
 
± 14 days 
± 14 days 
± 14 days 
± 14 days 
1 
1 
1 
1 
1 
1 
Informed Consent 
1 
- 
- 
- 
- 
- 
Inclusion / exclusion 
criteria 
1 
 
- 
- 
 
 
Evaluation of prior and 
concomitant medication 
1 
1 
- 
- 
1 
- 
PAH classification, 
etiology, diagnosis date,  
1 
- 
- 
- 
- 
- 
WHO FC  
1 
1 
- 
- 
1 
- 
Vital Sign 
Measurements incl. 
Borg Dyspnea Score, 
Heart Rate and SpO2 
1 
1 
- 
- 
1 
- 
6MWD (for initiation of 
a new PAH-specific 
therapy: within 3 
months prior or at) 
1 
1 
- 
- 
1 
- 
Height / Weight 
1 
1 
- 
- 
1 
- 
Lung function testing 
(TLC; DLCO) 
1 
1 
- 
- 
1 
- 
Blood gas analysis 
1 
1 
- 
- 
1 
- 
RHC hemodynamics: 
mPAP, mRAP, PAWP, 
PVR, cardiac index (for 
initiation of trial-
specific therapy: within 
6 months prior or at) 
1* 
- 
- 
- 
1 
- 
Physical examination 
1 
1 
- 
- 
1 
- 
Hematology, Chemistry 
1 
1 
- 
- 
1 
- 
NT-proBNP 
1 
1 
- 
- 
1 
- 
For females only: 
Pregnancy test 
- child bearing potential 
- currently pregnant 
(Yes***/No/Unknown) 
1 
1 
- 
- 
1 
- 
Echocardiogram, Stress-
Echo, Cardiopulmonary 
exercise test 
1 
1 
- 
- 
1 
- 
Quality of life (SF-36) 
1 
1 
- 
- 
1 
- 
Adverse Events 
- 
1 
1 
1 
1 
1 
Phone visits 
- 
- 
1 
1 
- 
1 
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Secondary intervention group (control group with crossover) 
Assessments 
Screening 
Visit 1: 
Baseline 
Phone 
visit 1 
Phone 
visit 2 
Visit 2 
Phone 
visit 3 
Phone 
visit 4 
Visit 3 
Follo
w up 
(Cont
rol 
group
) 
  
Day 1  
Day 30 
Day 60 
Day 90 
Day 120 Day 150 
Day 
180 
Day 
210 
-28 days 
 
± 14 days 
± 14 days 
± 14 
days 
± 14 
days 
± 14 
days 
± 14 
days 
± 14 
days 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Informed Consent 
1 
- 
- 
- 
- 
- 
- 
- 
- 
Inclusion / exclusion 
criteria 
1 
- 
- 
- 
- 
- 
- 
- 
- 
Evaluation of prior and 
concomitant medication 
1 
1 
- 
- 
1 
- 
- 
1 
- 
PAH classification, 
etiology, diagnosis date,  
1 
- 
- 
- 
- 
- 
- 
- 
- 
WHO FC  
1 
1 
- 
- 
1 
- 
- 
1 
- 
Vital Sign Measurements 
incl. Borg Dyspnea Score, 
Heart Rate and SpO2 
1 
1 
- 
- 
1 
- 
- 
1 
- 
6MWD (for initiation of a 
new PAH-specific 
therapy: within 3 months 
prior or at) 
1 
1 
- 
- 
1 
- 
- 
1 
- 
Height / Weight 
1 
1 
- 
- 
1 
- 
- 
1 
- 
Lung function testing 
(TLC; DLCO) 
1 
1 
- 
- 
1 
- 
- 
1 
- 
Blood gas analysis 
1 
1 
- 
- 
1 
- 
- 
1 
- 
RHC hemodynamics: 
mPAP, mRAP, PAWP, 
PVR, cardiac index (for 
initiation of trial-specific 
therapy: within 6 months 
prior or at) 
1* 
- 
- 
- 
1 
- 
- 
1 
- 
Physical examination 
1 
1 
- 
- 
1 
- 
- 
1 
- 
Hematology, Chemistry 
1 
1 
- 
- 
1 
- 
- 
1 
- 
NT-proBNP 
1 
1 
- 
- 
1 
- 
- 
1 
- 
For females only: 
Pregnancy test 
- child bearing potential 
- currently pregnant 
(Yes***/No/Unknown) 
1 
1 
- 
- 
1 
- 
- 
1 
- 
Echocardiogram, stress-
echocardiography, cardio-
pulmonary exercise test 
1 
1 
- 
- 
1 
- 
- 
1 
- 
Quality of life (SF-36) 
1 
1 
- 
- 
1 
- 
- 
1 
- 
Adverse Events 
- 
1 
1 
1 
1 
1 
1 
1 
1 
Phone visit 
- 
- 
1 
1 
- 
1 
1 
- 
1 
* RHC at baseline will only be performed in patients who have not performed a RHC within the preceding 6 months 
 
 

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8.2 
Assessments 
8.2.1 Physical examination and demographic data 
The physical examination comprises measurement of body weight and height (height will be 
measured only once) and a routine internal medical examination. Physical examinations will be 
performed to ensure suitability according to the inclusion and exclusion criteria and to document 
the health status before and following treatment with the IMPs. 
8.2.2 Hemodynamic parameters 
Hemodynamic parameters will be determined by right heart catheterization according to current 
guidelines (Opitz et al. 2011). The right heart catheterization (RHC) will be performed at 
baseline only in patients who have not performed a RHC within the preceeding 6 months during 
Visit 2  and end of the study only to the control group.  
Directly, invasive measured parameters are: right atrial pressure, mean pulmonary arterial 
pressure (mPAP), pulmonary capillary wedge pressure (PAWP), cardiac output (CO), cardiac 
index (CI), and venous oxygen saturation (SvO2). During the right heart catheterization, a 
continuous ECG will be performed. The values will be based on two to three measurements at 
one time point. Hemodynamics will be measured at rest and during exercise with a supine 
bicycle ergometer (all parameters except right atrial pressure, which will be measured at rest and 
optionally during exercise).  
Directly non-invasive measured parameters: heart rate, blood pressure 
Methodology: Swan-Ganz catheterization and thermodilution methodology 
Pulmonary hemodynamics by right heart catheterization: 
 cardiac index in liters per minute per square meter (of body surface area) /(CI) 
 systolic pulmonary artery pressure (sPAP) 
 mean pulmonary artery pressure (mPAP) 
 diastolic pulmonary artery pressure (dPAP) 
 pulmonary artery wedge pressure (PAWP) 
 right atrial pressure (RAP) 
 pulmonary vascular resistance (PVR)   
 cardiac output and ejection fraction (CO, HZV), cardiac index (CI) 
 central venous saturation via blood gas analysis from pulmonary artery  

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8.2.3 Echocardiography and Stress Doppler Echocardiography with cardiopulmonary 
exercise testing 
Echocardiography will be performed according to current guidelines (Rudski et al. 2010). 
Following parameters will be assessed: systolic pulmonary arterial pressure (sPAP, mmHg), 
right ventricular area (RV-area, cm2), and right atrial area (RA-area,cm2), tricuspid annular plane 
systolic excursion (TAPSE), left ventricular eccentricity index (LV-EI), RV-pump function and 
LV- pump fuction (EF). 
WHO protocol for incremental increase of workload (25 Watt every 2 minutes) will be used to 
assess cardiopulmonary response during exercise, including the following parameters: 
 sPAP,  
 RV-pump function,  
 heart rate,  
 systemic blood pressure,  
 oxygen consumption,  
 oxygen consumption/kg body weight,  
 oxygen saturation,  
 minute ventilation, 
 carbon dioxide and oxygen equivalents,  
 O2 pulse,  
 ventilatory threshold,  
 respiratory reserve.   
8.2.4 Determination of WHO functional class  
Functional assessment of pulmonary hypertension will be performed according to the WHO-
Functional Class, i.e. the Evian Symposium, 1998, modified New York Heart Association 
(NYHA) Classification: 
Class I: Patients with PH but without resulting limitation of physical activity. Ordinary physical 
activity does not cause undue dyspnoea of fatigue, chest pain or near syncope. 
Class II: Patients with PH resulting in slight limitation of physical activity. They are comfortable 
at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain or near syncope. 
Class III: Patients with PH resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes undue dyspnoea or fatigue, chest pain or 
near syncope. 

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Class IV: Patients with pulmonary hypertension with inability to carry out any physical activity 
without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/or fatigue 
may even be present at rest. Discomfort is increased by any physical activity. 
8.2.5 Lung function tests and blood gas analysis 
Lung function test: Body plethysmography (preferred method) including forced vital capacity 
(FVC), forced expiratory volume in one second (FEV1), total lung capacity (TLC), diffusion-
limited carbon monoxide (DLCO), residual volume), normally accounting for about 25% of 
TLC.  
Blood gas analysis: capillary or arterial blood gas analysis; partial pressure of oxygen and carbon 
dioxide, oxygen saturation (SpO2), pH values, bicarbonates, base excess. 
If the patient receives oxygen the amount will be recorded in the CRF in liters/minute. 
8.2.6 6-minute walking distance and Borg dyspnea Score (CR 10)  
Both tests will be performed according to ATS guidelines (ATS 2002). The patient is asked to 
walk along a prescribed path as far as possible during a 6 minute interval of time. The patient 
may walk at whatever pace he/she feels comfortable with the goal of walking the most distance 
he/she feels possible. If the patient feels the need to rest, he/she may do this. Blood pressure, 
heart rate and oxygen saturation will be measured before and after the test. The test will be 
performed two times at each time point: one test will be performed without oxygen; one test will 
be performed with oxygen supply (for all tests with the same amount of oxygen for each patient, 
which will be determined at baseline by titration). In between tests, the patient should rest for at 
least 30 minutes to prevent from interacting effects of oxygen and/or exhaustion. 
The Borg Scale (Breathlessness Scale) is commonly used to measure shortness of breath of 
patients or in sports medicine. In this study, the Borg Scale will be applied to record dyspnea 
immediately following the 6-minute walk test. 
The Borg Scale comprises the following parameters according to the ATS guidelines (ATS 
2002): 
0  
Nothing at All 
0.5 
Very very slight (just noticeable) 
1 
Very slight 
2 
Slight 
3 
Moderate 
4 
Somewhat Moderate 
5 
Severe 
6 
 
7 
Very Severe 
8 
 
9 
Very very severe (almost maximal) 
10 
Maximal 
 

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8.2.7 Quality of Life (QoL) 
QoL will be assessed using the SF 36-questionnaire (see Appendix) that will be handed out to 
the patients. Scoring will be carried out according to the test manual. 
The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their 
section. Each scale is directly transformed into a 0-100 scale, i.e. a score of zero is equivalent to 
maximum disability and a score of 100 is equivalent to no disability. The eight sections are: 
vitality; physical functioning; bodily pain; general health perceptions; physical role functioning; 
emotional role functioning; social role functioning; mental health. 
8.2.8 Vital signs 
Blood pressure, heart rate and oxygen saturation will be measured after the patient has been at 
rest for at least 5 minutes.  
Blood pressure (BP; systolic and diastolic) will be measured by means of a standard manual or 
an automatic blood pressure measuring device (cuff method). Nevertheless, the same method 
should be used during the entire study period (the type of device has to be recorded into the 
CRF). The same upper arm will be used for each measurement of blood pressure, preferably the 
left arm.  
Heart rate (HR) and oxygen saturation (SaO2) will be measured by pulse oximetry. 
8.2.9 Electrocardiography 
A 12-lead electrocardiogram (ECG) will be performed. For deriving the 12-lead ECGs the 
patients should always be in supine position. The 12-lead ECGs should be derived after a resting 
period of at least 10 minutes. The investigator will review the ECGs for potential AEs. 
A continuous 3-lead ECG monitoring will be applied during right heart catheterization. 
8.2.10 Clinical laboratory investigations  
Clinical laboratory investigations will comprise: 
Biomarkers 
NT-proBNP 
Additional 
laboratory tests that usually include inflammation factors, kidney, liver, 
blood cell count parameters   
All laboratory assessments will be determined locally on-site. 
8.3 
Study Phases and Visits 
8.3.1 Screening Phase 
Eligible patients will be asked to participate upon written informed consent. In case of agreement 
medical history will be taken and they will undergo screening examinations.  

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The right heart catheterisation should not be older than 6 months before baseline and should be 
performed after the patient was on stable treatment for at least six weeks. In patients who have 
not performed a right heart catheter within the preceding 6 months, invasive hemodynamics will 
be measured before the beginning of the intervention. Oxygen will be prescribed and the oxygen 
system will be delivered to the patient. Baseline will be within 28 days after screening. 
Screening visit, baseline visit, month three and month four (follow-up); month six according to 
month three assessment in secondary intervention group and respective follow-up. 
Secondary intervention group will have an additional visit after 180 days (in analogy to month 
three visit). 
8.3.2 Visit 1 Baseline / Randomization [DAY 1] 
Baseline visit may be performed according to the hospital’s routine practice as in-hospital stay. 
Baseline / Day 1 visit 1: During the visit clinical evaluation, laboratory, blood gas analysis, SF-
36 questionnaire, 6MWD, echocardiography, Stress-Doppler-echocardiography and cardio-
pulmonary exercise testing will be assessed and concomitant medications and diseases/clinical 
symptoms recorded. After the explanation of intake and titration, oxygen or no supplemental 
oxygen will be handed out. The treatment diary will be handed to the patients. Patient’s 
eligibility to participate in the IIT will be confirmed. Subsequently, patients will be randomized 
to either treatment arm with oxygen or the no supplemental O2 arm. 
8.3.3 DAY 1-90 (3 Months) 
Oxygen vs. no oxygen supply for at least 16 hours a day will be performed.  Interim phone calls 
each month (month 1 and 2) and assessment of adverse events. 
8.3.4 Month three / Day 90 visit 2 (± 7 days) 
Clinical 
evaluation, 
laboratory, 
blood 
gas 
analysis, 
SF-36 
questionnaire, 
6MWD, 
echocardiography, stress-echocardiography, cardiopulmonary exercise test, right heart 
catheterization and adverse events will be assessed. Patients of the control group will be offered 
to participate in secondary intervention group to receive long-term oxygen treatment. (week 12 
visit will be performed again after 12 weeks, in total 24 weeks of study with control and 
secondary intervention phase). 
8.3.5 Month four / Day 120 (± 7 days) (30 days after close out)  
The follow-up visit to assess adverse events will then take place in terms of an outpatient visit or 
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8.3.6 Termination Visit 
In case the decision has been made to stop the study prematurely, a termination visit should be 
performed at the respective point in time or as soon as possible after stop of medication. In 
general, the same safety and efficacy relevant measurements should be performed as at the last 
Visit, especially the hemodynamic measurements. In case of clinical worsening / deterioration of 
patients in the control group, an early termination visit may be performed and patients may be 
offered to take part in the interventional treatment arm in order to receive long-term oxygen 
treatment ahead of schedule. 
8.3.7 Pre-treatment period and duration of observation and follow-up 
There will be non-pre-treatment period. The duration of the observation will be 90 days (up to 
180 days in the control group with switch to secondary intervention group) + follow-up period. 
The follow-up period will be 30 days after close out visit each patient performs a follow-up Visit 
Clinical follow-up of all SAEs until they have been resolved. 
 
8.4 
Methods of Data Collection 
Data will be entered on a paper-based CRF by the center’s study nurses. The CRFs will be 
collected by the clinical monitor and forwarded to data management. All data will be entered 
into one database by the data management followed by data cleaning (e.g. range checks), queries 
and preparation for data analysis.  
8.4.1 Efficacy Parameters 
The primary efficacy variable is the distance walked in 6 minutes in meters. 
8.4.2 Safety Parameters 
Safety variables include and will be determined: 
1. Electrocardiogram (ECG) 
2. Vital signs: Blood pressure (BP), heart rate/pulse (HR) 
3. Hemodynamics: Cardiac Output, venous oxygen saturation (during RHC) 
4. Echocardiography 
5. Clinical laboratory investigations 
6. Concomitant medication 
7. Concomitant diseases 
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8.5 
Plan for Treatment of Care after the Trial 
After 6 months of supplementation, oxygen therapy may be prescribed to all patients who might 
benefit from the treatment. This decision will be based on the physician’s and the patient’s 
estimation. Patient care and monitoring will be performed in the patients’ specialized centers.  
9 
Adverse Events 
9.1 
Definitions 
9.1.1 Adverse Event 
According to Good Clinical Practice GCP, an adverse event (AE) is defined as follows: Any 
untoward medical occurrence in a subject administered a pharmaceutical product and which does 
not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the IMP. 
An AE may be: 
- New symptoms/ medical conditions 
- New diagnosis 
- Significant changes of laboratory parameters 
- Intercurrent diseases and accidents 
- Worsening (change in nature, severity or frequency) of medical conditions/ diseases 
existing before clinical trial start 
- Recurrence of disease 
- Increase of frequency or intensity of episodical diseases. 
- Events related or possibly related to concomitant medications 
A pre-existing disease or symptom will not be considered an adverse event unless there will be 
an untoward change in its intensity, frequency or quality. This change will be documented by an 
investigator. 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an AE. Planned surgical 
measures permitted by the clinical trial protocol and the condition(s) leading to these measures 
are not AEs, if the condition leading to the measure was present prior to inclusion into the trial. 
AEs are classified as "non-serious" or "serious". 
9.1.2 Serious Adverse Event 
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- Results in death 
- Is life-threatening (the term life-threatening refers to an event in which the subject was at 
risk of death at the time of event and not to an event which hypothetically might have 
caused death if it was more severe)  
- Requires subject hospitalization or prolongation of existing hospitalization (unless the 
admission results in a stay of less than 12 hours or the admission is pre-planned or the 
admission is not associated with an adverse event) 
- Results in persistent or significant disability/ incapacity or 
- Is a congenital anomaly/ birth defect. 
- Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious (e.g. treatment at home 
for allergic bronchospasm). 
 
The following events don’t need to be reported as an SAE: 
- 
Planned hospitalization due to scheduled elective catheterization (e.g. reevaluation for 
Eurotranplant listing), scheduled hospitalization for further diagnostics or therapeutic measures. 
 
9.1.3 Expectedness 
An ‘unexpected’ adverse event is one the nature or severity of which is not consistent with the 
applicable “Summary of Product Characteristics” (SmPC) or scientific literature. Furthermore, 
reports which add significant information on specificity or severity of a known adverse reaction 
constitute ‘unexpected’ events. 
9.1.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
SAEs that are both suspected, i.e. possibly related to IMP and ‘unexpected’, i.e. the nature and/ 
or severity of which is not consistent with the applicable product information are to be classified 
as Suspected Unexpected Serious Adverse Reactions (SUSARs). The definition covers also 
medication errors and uses outside what is foreseen in the protocol, including misuse and abuse 
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In case, either the investigator who primarily reported the SAE or the second assessor classify 
the SAE as ‘suspected’ (i.e. either related or probably or possibly related to the IMP or not 
assessable) and the SAE is unexpected it will be categorized as a SUSAR.  
All SUSARs are subject to an expedited reporting to the responsible ethics committee, the 
competent higher federal authority, i.e. Bundesinstitut für Arzneimittel und Medizinprodukte 
(BfArM), and to all participating investigators.  
9.1.5 Grading of AEs 
The grading of an AE should be assessed by the investigator according to the 5-grade scale 
defined in the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 established by 
the National Cancer Institute (NCI) of the United States of America (USA) as follows: 
Grade 1: 
mild AE, temporary event which is tolerated well by the subject 
Grade 2:  
moderate AE; event which results in discomfort for the subject and impairs his/ 
her normal activity 
Grade 3:  
severe AE; event which results in substantial impairment of normal activities of 
subject 
Grade 4: 
life-threatening AE or AE causing disablement 
Grade 5:  
death related to AE 
9.1.6 Relationship and outcome of AEs, action taken 
The investigator will evaluate each AE that occurred after administration of the IMP regarding 
the coherency with the administration of the investigational medicinal product possibly: 
related: 
There is a reasonable possibility that the event may have been caused by 
IMP. A certain event has a strong temporal relationship and an 
alternative cause is unlikely. 
probable: 
An AE that has a reasonable possibility that the event is likely to have been 
caused by IMP. The AE has a timely relationship and follows a known 
pattern of response, but a potential alternative cause may be present. 
possible: 
An AE that has a reasonable possibility that the event may have been 
caused by IMP. The AE has a timely relationship to the IMP; however, 
the pattern of response is untypical, and an alternative cause seems more 
likely, or there is significant uncertainty about the cause of the event. 
unlikely: 
Only a remote connection exists between the IMP and the reported adverse 
event. Other conditions including concurrent illness, progression or 
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appear to explain the reported adverse event. 
not related: 
An AE that does not follow a reasonable temporal sequence related to IMP 
and is likely to have been produced by the subject’s clinical state, other 
modes of therapy or other known etiology. 
not assessable: 
There is insufficient or incomplete evidence to make a clinical judgement 
of the causal relationship. 
 
The outcome of an AE at the time of the last observation will be classified as: 
Recovered/ resolved 
all signs and symptoms of an AE disappeared without any sequels at 
the time of the last interrogation 
Recovering/ resolving the intensity of signs and symptoms has been diminishing and/ or their 
clinical pattern has been changing up to the time of the last 
interrogation in a way typical for its resolution 
Not recovered/ 
not resolved 
signs and symptoms of an AE are mostly unchanged at the time of the 
last interrogation 
Recovered/ 
resolved with sequel 
actual signs and symptoms of an AE disappeared but there are sequels 
related to the AE 
Fatal 
resulting in death. If there is more than one adverse event only the 
adverse event leading to death (possibly related) will be characterized 
as ‘fatal‘ 
Unknown 
the outcome is unknown or implausible and the information cannot be 
supplemented or verified 
 
The action taken with the IMP will be assigned to one of the following categories: 
‘Dose not changed’:  no change in the dose of IMP. 
‘Dose reduced’:  
reduction in the dose of IMP. 
‘Dose increased’:  
increase in the dose of IMP. 
‘Drug withdrawn’: 
discontinuation of IMP. 
‘Unknown’:  
the information is unknown or implausible and it cannot be supplemented 
or verified. 
‘Not applicable’:  
the question is implausible (e.g. the subject is dead). 
The term ‘Countermeasures’ refers to the specific actions taken to treat or alleviate adverse 
events or to avoid their sequels. The following categories will be used to categorize the 
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None: 
no action taken 
Drug treatment: 
newly-prescribed medication or change in dose of a medication 
 
Others: 
other countermeasures, e.g. an operative procedure 
9.2 
Period of Observation and Documentation 
All AEs reported by the subject or detected by the investigator, will be collected during the trial 
and must be documented on the appropriate pages of the CRF. AEs must also be documented in 
the subject’s medical records. 
In this trial, all AEs that occur after first administration of the IMP up to the last visit (i.e. 
follow-up visit) will be documented on the pages provided in the CRF. AEs will be assessed by 
the investigator using no-leading questions or observed during any visit during the whole study. 
The patient should be motivated to report any AEs by phone to the investigator occurring in 
between study visits. All subjects who have AEs, whether considered associated with the use of 
the trial medication or not, must be monitored to determine the outcome. The clinical course of 
the AE will be followed up until resolution or normalization of changed laboratory parameters or 
until it has changed to a stable condition. 
Each event should be described in detail along with start and stop dates, severity, relationship to 
investigational product, action taken and outcome. 
9.3 
 Reporting of Serious Adverse Events by the Investigator 
All SAEs must be reported by the investigator to the responsible Safety Officer within 24 hours 
after the SAE becomes known using the "Serious Adverse Event" form. The initial report must 
be as complete as possible, including details of the current illness and (serious) adverse event, 
information regarding onset, end date, severity, outcome and action taken with the IMP, an 
assessment of the causal relationship between the event and the trial medication. 
The reporting will be performed by faxing a completed ‘SAE Form’ to the KKS Heidelberg,  
Fax number: 06221-56-33725 
 
At the time of the initial report, the investigator will fill in a SAE form comprising the following 
information: 
- 
Patient/subject demographics 
- 
Start and end date of treatment with the IMP 
- 
Nature of the AE including date of onset, severity and treatment (including 
hospitalization) 
- 
Action taken with respect to the IMP 

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- 
Relationship to the IMP in the opinion of the investigator 
- 
Relevant concomitant drug therapy,  relevant medical history, relevant test and diagnostic 
procedures  
- 
Outcome (clinical state at time of current observation) 
- 
Recovery date (if available) 
- 
In the case of death, the cause and post-mortem findings (if available). 
 
Any requested supporting documentation (e.g. ECG, laboratory results, autopsy report) should be 
sent to the same address stated above. The original SAE-reports and all other reports will be kept 
by the investigator. 
 
9.4 
 Expedited Reporting 
SUSARs are to be reported to the ethics committee, competent higher federal authority (BfArM), 
and to all participating investigators within regulative defined timelines, i.e. they are subject to 
an expedited reporting. 
All SAE will be subject to a second assessment by a designated person, who will be independent 
from the reporting investigator and the trial sponsor. The designated person for the present trial, 
referred to as second assessor is: Dr. Christian Nagel. 
The assessor will fill out a ‘Narrative Second Assessment Form’ for each SAE containing at least 
the following information: i) Assessment of relationship between SAE and IMP; ii) Assessment 
of expectedness of SAE (derived from SmPC); iii) Assessment of relationship between SAE and 
underlying disease iv) Statement if the benefit/ risk assessment for the trial did change as a result 
of the SAE. 
The expedited reporting (to competent authority, responsible ethics committee and investigators) 
will be carried out by the responsible Safety Officer at KKS Heidelberg.  
Details concerning the SAE management including the reporting of SUSARs will be described in 
the separate document “Safety Manual”. 
9.5 
 Emergency Treatment 
During and following a subject’s participation in the trial, the investigator should ensure that 
adequate medical care is provided to a subject for any AE including clinically significant 
laboratory values. The investigator should inform a subject when medical care is needed for 
intercurrent illness(es) of which the investigator becomes aware. 

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In case of clinical worsening and if clinically indicated additional PAH-targeted rescue 
medication will be initiated. 
10 Statistical Procedures 
10.1 Sample Size Calculation 
In this randomized study patients with confirmed PAH will be randomized into two groups: one 
group receiving oxygen and without oxygen supplementation.  
The minimally important difference of 6-minute walking distance in patients with pulmonary 
hypertension is considered to be 33 meters, according to the literature (Mathai et al. 2012). 
A recent study of Ulrich et al. has shown a 25 meter difference between nocturnal oxygen and 
sham-O2 for an intervention period of one week with a concentrator device in patients with 
pulmonary hypertension (Ulrich et al. 2015). We assume a standard deviation of the difference 
of 50 meters (as seen in the data of Ulrich et al.) and a higher effect of 35 meters due to a longer 
intervention period and the use of oxygen supply ≥16h/day, which lies also above the threshold 
of minimally important difference for the 6-minute walking distance. 
The primary endpoint will be analysed in a hierarchical testing strategy. The main comparison 
will be the difference in a) intra-individual treatment effect and b) between oxygen arm and no 
oxygen. The primary endpoint will be the intra-individual analysis of 6MWD in the primary and 
secondary intervention group (difference from baseline to follow-up). If the primary endpoint is 
significantly different, the treatment effect on 6MWD will be compared between the primary 
intervention group and the control group. In order to cover a possible 20% drop-out rate, we will 
include 20 patients in each group N= 40 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 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. 
Sample size assumptions 
1. If the true treatment effect is at least an increase of 35 meters in the 6-minute walking 
distance with an equal standard deviation of 50 meters, a sample size of 29 patients will 
provide a >95% power with a matched-pairs two-sided student’s t-test with a significance 
level of 0.05 (intra-individual comparison of difference baseline to follow-up in primary 
and secondary intervention group). 

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2. If the true treatment effect is at least a control group corrected increase of 50 meters in 
the 6-minute walking distance with an equal standard deviation of 50 meters, a sample 
size of 18 patients in each group will provide a 83% power with a two-sided student’s t-
test with a significance level of 0.05 comparing two independent means (comparison of 
differences baseline to follow-up between the two groups).  
The sample size of 18 patients in each group with an anticipated dropout rate of 10% 
leads to a final sample size of 40 (20 in each group). 
The sample size was calculated by means of a two-sided two-sample t-test. Primary efficacy 
analysis will be performed by an 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. The primary endpoint, 6-minute 
walking distance, will be compared by ANCOVA of the differences (baseline to follow-up) (1) 
intra-individual and (2) between the two groups with the baseline value as covariate, providing a 
power-advantage over the student’s t-test which leads to a power of >95% and 83% or more, 
respectively. 
10.2 Analysis Variables 
Primary Outcome: 
The primary endpoint will be analysed in a hierarchical testing strategy with 
1. Intra-individual analysis of 6MWD in the primary and secondary intervention group 
(difference from baseline to follow-up) 
2. If (1) is significantly different, the treatment effect on 6MWD will be compared 
between the primary intervention group and the control group. 
 
Secondary Outcome Variables: 
The following study procedures will be performed in every patient according to the visits 
schedule and analyzed as secondary efficacy variables. The methods for analysis will be the 
same as for the primary endpoint. Parameters/assessments comprise 
- 
quality of life assessed by the SF-36 questionnaire (two main summation scores, eight 
subscales) 
 
- 
Feasibility of oxygen treatment, assessed by patient consent to participate in the study 
(recruitment rate) and by patient compliance 
 

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- 
History, questionnaire evaluation, and clinical examination:  
Complete medical history will be obtained. Physical examination will include weight, 
height, blood pressure, heart rate, cardiac and pulmonary auscultation, assessments of 
jugular distension and peripheral oedema. WHO functional class will be assessed by 
specific questionnaire. Quality of life will be assessed by the short form of the medical 
outcome questionnaire (SF-36). Assessment of compliance via questionnaire. 
 
- 
Echocardiography:  
Following parameters will be assessed: systolic pulmonary arterial pressure (sPAP, 
mmHg), right ventricular area (RV-area, cm2), and right atrial area (RA-area,cm2), 
tricuspid annular plane systolic excursion (TAPSE), left ventricular eccentricity index 
(LV-EI), RV-pump function   
 
- 
Stress-Doppler-echocardiography and cardiopulmonary exercise testing 
(spiroergometry): 
WHO protocol for incremental increase of workload (25 Watt every 2 minutes) will be 
used to assess cardiopulmonary response during exercise, including the following 
parameters: 
 sPAP,  
 RV-pump function,  
 heart rate,  
 systemic blood pressure,  
 oxygen consumption,  
 oxygen consumption/kg body weight,  
 oxygen saturation,  
 minute ventilation, 
 carbon dioxide and oxygen equivalents,  
 O2 pulse,  
 ventilatory threshold,  
 respiratory reserve.  
 
- 
Analyses of blood samples: 
Venous blood will be analysed to determine:  
 N-terminal natriuretic peptide (NT-pro BNP)  

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 And additional laboratory tests that usually include inflammation factors, kidney, 
liver, blood cell count parameters   
- 
Capillary blood for blood gas analyses: 
 oxygen partial pressure 
 carbon dioxide partial pressure  
 oxygen saturation of the blood(SaO2) 
 pH values  
 Bicarbonates  
 Base Excess  
 
- 
Pulmonary hemodynamics by right heart catheterization: 
 cardiac index in liters per minute per square meter (of body surface area) /(CI) 
 systolic pulmonary artery pressure (sPAP) 
 mean pulmonary artery pressure (mPAP) 
 diastolic pulmonary artery pressure (dPAP) 
 pulmonary artery wedge pressure (PAWP) 
 right atrial pressure (RAP) 
 pulmonary vascular resistance (PVR)   
 cardiac output and ejection fraction (CO, HZV), cardiac index (CI) 
 central venous saturation, via blood gas analysis from pulmonary artery  
10.3 Definition of Trial Population to be analysed 
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 he/she had at least one day  of oxygen 
administration.  
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 than 120%) 
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”.  

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10.4 Statistical Methods 
10.4.1 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 with and without oxygen supplementation 
corrected for the active treatment group, including the usual location and scale statistics (mean, 
median, standard deviation, standard error, first and third quartiles, minimum and maximum) and 
95% confidence limits of mean and median. 
Frequency tables for qualitative data will be provided. 
Hypotheses and statistical interference 
Hypothesis 1 
Null-Hypothesis (H0):  
The mean of the primary endpoint of the treatment group is the 
same at baseline and after 3 months. 
Alternative hypothesis (H1): The mean of the primary endpoint after 3 months differs from the 
distribution at baseline in the active group. 
 
If not mentioned otherwise, all statistical tests will be performed with a type I two-sided error 
rate of α= 0.05  
Efficacy analysis 
The primary efficacy analysis will be performed in patients valid for intention-to-treat analysis. 
The per-protocol analysis will be supportive. 
Primary endpoint  
The evaluation of the primary efficacy endpoint will be the change from baseline to 6 months in 
the 6-minutes walking distance in meters. The primary analysis set will be intention to treat set. 
Cases of missing values, where the patient withdraws or dies will be described and compared to 
the per-protocol set.  
The main comparison will be the difference in treatment effect between O2 arm and no O2 supply 
arm. 95% confidence intervals of treatment difference will also be calculated. The primary 
comparison will be an ANCOVA model including baseline scores as covariate.  
The above approach assumes 6-minute walking distance will be approximately normally 
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Secondary efficacy variables will be formally tested for statistical significance of a difference 
between the oxygen supplementation and no oxygen supplementation arm.  
Secondary efficacy analysis comprises quality of life (SF-36 questionnaire), feasibility of oxygen 
treatment assessed by patient consent to participate in the study, history, questionnaire 
evaluation, and clinical examination, echocardiography, stress-doppler-echocardiography and 
cardiopulmonary exercise testing, laboratory parameters, capillary blood for blood gas analyses, 
pulmonary hemodynamics by RHC. WHO functional class is supposed either to remain the 
same, to improve by one or two categories, or to 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 +3 (class 1 at baseline and class 4 at end of study). This 
will be analyzed using the Wilcoxon test. 
 
Safety analysis 
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. 
Biometric analysis will be defined in the statistical analysis plan which has to be authorized 
before data base lock by the biometrician and the Coordinating Investigator. 
11 Data Management 
11.1 Data Collection 
A paper-based case report form (CRF) will be used in this study. All entries made in the CRF 
must be verifiable against source documents. The source data parameter to be verified and the 
identification of the source document must be documented. 
All findings including clinical and laboratory data will be documented in the subject's medical 
record and in the CRF. The investigator is responsible for ensuring that all sections of the CRF 
are completed correctly and that entries can be verified against source data. Any errors should 
have a single line drawn through them so that the original entry remains legible. The correct data 
should be entered at the site with the investigator's signature, date and reason for change to 
confirm the correctness of entries in the CRF. Self-explanatory corrections need not to be 
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The correctness of entries in CRF will be confirmed by dated signature of the responsible 
investigator. The original CRF will be transferred to the data management; one copy will be kept 
by the investigator. 
11.2 Data Handling 
After first check for plausibility by eye, all data will be entered in a database as recorded in the 
CRF. After completion of data entry, checks for plausibility, consistency, and completeness of 
the data will be performed. Based on these checks, queries will be produced combined with the 
queries generated by visual control.  
All missing data or inconsistencies will be reported back to the center and clarified by the 
responsible investigator. If no further corrections are to be made in the database it will be 
declared closed and used for statistical analysis. 
11.3 Storage and Archiving of Data 
According to the §13 (10) of the German GCP-Ordinance all important trial documents (e.g. 
CRF) will be archived for at least 10 years after the trial termination.  
The investigator(s) will archive all trial data (source data and Investigator Site File (ISF) 
including subject identification list and relevant correspondence) according to the section 4.9 of 
the ICH Consolidated Guideline on GCP E6(R2) and to local law or regulations. 
12 Ethical and Legal Aspects 
12.1 Good Clinical Practice 
The procedures set out in this trial protocol, pertaining to the conduct, evaluation, and 
documentation of this trial, are designed to ensure that all persons involved in the trial abide by 
Good Clinical Practice (GCP) and the ethical principles described in the applicable version of the 
Declaration of Helsinki. The trial will be carried out in keeping with local legal and regulatory 
requirements. 
12.2 Subject Information and Informed Consent 
Before being admitted to the clinical trial, the subject must consent to participate after the nature, 
scope, and possible consequences of the clinical trial have been explained in a form 
understandable to him or her. The subject must give consent in writing. The signed Informed 
Consent Form will be filed by the investigator. 
A copy of the signed informed consent document must be given to the subject. The documents 
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The subjects will be informed as soon as possible if new information may influence his/her 
decision to participate in the trial. The communication of this information should be documented. 
12.3 Confidentiality 
The data obtained in the course of the trial will be treated pursuant to the General Data 
Protection Regulation (GDPR) (EU) 2016/679 and relevant national. 
During the clinical trial, subjects will be identified solely by means of their initials, year of birth, 
and an individual identification code (subject number, randomization number). Trial findings 
stored on a computer will be stored in accordance with local data protection law and will be 
handled in strictest confidence. For protection of these data, organizational procedures are 
implemented to prevent distribution of data to unauthorized persons. The appropriate regulations 
of EU and national data legislation will be fulfilled in its entirety. 
The subject consents in writing to release the investigator from his/her professional discretion in 
so far as to allow inspection of original data for monitoring purposes by health authorities and 
authorized persons (inspectors, monitors, auditors).  
According to relevant European and national provisions authorized persons (clinical monitors, 
auditors, inspectors) may inspect the subject-related data collected during the trial . 
The investigator will maintain a subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 
Subjects who did not consent to circulate their pseudonymized data will not be included into the 
trial. 
12.4 Responsibilities of the Investigator 
The investigator should ensure that all persons assisting with the trial are adequately informed 
about the protocol, any amendments to the protocol, the trial treatments, and their trial-related 
duties and functions. 
The investigator should maintain a list of sub-investigators and other appropriately qualified 
persons to whom he or she has delegated significant trial-related duties. 
12.5 Approval of Trial Protocol and Amendments 
Before the start of the trial, the trial protocol, informed consent document, and any other 
appropriate documents will be submitted to the independent Ethics Committee (EC) as well as to 
the competent higher federal authority (BfArM). A written favorable vote of the EC and an 
(implicit) approval by the competent higher federal authority are a prerequisite for initiation of 
this clinical trial. The statement of EC should contain the title of the trial, the trial code, the trial 
site, and a list of reviewed documents. It must mention the date on which the decision was made 

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and must be officially signed by a committee member. This documentation must also include a 
list of members of the EC present on the applicable EC meeting and a GCP compliance 
statement. 
Before the first subject is enrolled in the trial, all ethical and legal requirements must be met. All 
planned substantial changes (see §10, (1) of German GCP-Regulation-V) will be submitted to 
EC and the competent higher federal authority in writing as protocol amendments. They have to 
be approved by the EC and the competent higher federal authority.  
The investigator will keep a record of all communication with the EC and the regulatory 
authorities. 
12.6 Continuous Information to Independent Ethics Committee 
Pursuant to the German Drug Law (AMG) and the GCP Ordinance, the EC and the competent 
higher federal authority will be informed of all suspected unexpected serious adverse reactions 
(SUSARs). Both institutions will be informed in case the risk/ benefit assessment did change or 
any others new and significant hazards for subjects’ safety or welfare did occur. Furthermore, a 
report on all observed serious adverse events (SAEs) will be submitted once a year – 
Development Safety Update Report (DSUR). 
The EC and the regulatory authorities must be informed of the end of the trial. They will be 
provided with a summary of trial results within one year after the end of clinical phase, i.e. after 
last subject out (LSO). 
12.7 Notification of Regulatory Authorities 
The local regulatory authorities responsible for each particular investigator will be informed 
before the beginning, during and at the end of the trial according to the applicable regulations. 
Each investigator is obliged to notify his/ her local regulatory authority.  
12.8 Registration of the Trial 
Prior to the beginning of the clinical phase (FPI) the coordinating/ principal investigator will 
register the trial at Current Controlled Trials (http://www.controlled-trials.com/) [or 
http://www.clinicaltrials.gov]. Thus the trial will be given a unique International Standard 
Randomized Controlled Trial Number ISRCTN, which is a prerequisite for a publication in a 
peer-review paper.  
12.9 Insurance 
According to § 40 AMG, the Sponsor has to subscribe to an insurance policy covering, in its 
terms and provisions, its legal liability for injuries caused to participating persons and arising out 
of this research performed strictly in accordance with the scientific protocol as well as with 

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applicable law and professional standards. This clinical trial’s participants are insured according 
to the German Medicinal Products Act (AMG).* 
 
Insurance company:  
 
 
HDI Gerling Industrie Versicherung AG 
Telephonnumber: 
 
 
 
0511-645-0  
Fax: 
 
 
 
 
 
0511-645-4545 
Insurance certificate  
 
 
5701031003018 
(Versicherungsscheinnummer) 
 
 
Any impairment of health which might occur in consequence of trial participation must be 
notified to the insurance company. The subject is responsible for notification. The insured person 
will agree with all appropriate measures serving for clarification of the cause and the extent of 
damage as well as the reduction of damage. 
During the conduct of the trial, the subject must not undergo other clinical treatment except for 
cases of emergency. The subject is bound to inform the investigator immediately about any 
adverse events and additionally drugs taken. The terms and conditions of the insurance should be 
delivered to the subject. 
The insurance company has to be informed about all amendments that could affect subjects’ 
safety. 
13 Quality Assurance 
13.1 Monitoring  
Monitoring will be done by personal visits from a clinical monitor in order to comply with GCP 
guidelines. The center will be visited at regular intervals by a monitor to ensure compliance with 
the study protocol, GCP and legal aspects.  
The monitor will review the entries into the CRFs on the basis of source documents. This will 
include on-site checking of the CRF for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters. The investigator must allow the monitor 
to verify all essential documents including source documents and must provide support at all 
times to the monitor. 
By frequent communications (letters, telephone, fax), the site monitor will ensure that the trial is 
conducted according to the protocol and regulatory requirements. 

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13.2 Inspections/ Audits  
Regulatory authorities may request access to all source documents, CRF, and other trial 
documentation. Direct access to these documents must be guaranteed by the investigator who 
must provide support at all times for these activities. 
14 Agreements 
14.1 Financing of the Trial 
The trial will be financed using funds of OMT/VitalAire.  
This funding source had no role in the design of this study and will not have any role during 
analyses, interpretation of the data, or decision to submit results. 
14.2 Financial Disclosure 
Before the start of the trial, the investigator will disclose any proprietary or financial interests he 
or she might hold in the sponsors/ a funding company, in the investigational product(s) or any 
commercial organization being involved in the clinical trial. The investigator has also to confirm 
that he/she has not entered into any financial arrangement, whereby the value of compensation 
paid could affect the outcome of the clinical trial. 
The investigator agrees to update this information in case of significant changes.  
14.3 Reports 
The Biometrician will prepare the biometrical report. The final trial report will be prepared by 
the biometrician and the Steering Committee members.  
14.4 Publication 
All information concerning the trial is confidential before publication, which will be performed 
by the steering committee members of the trial.  
 
 
 
 
 

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15 Signatures 
The present trial protocol was subject to critical review and has been approved in the present 
version by the persons undersigned. The information contained is consistent with: 
- 
the current risk-benefit assessment of the investigational medicinal product 
- 
The moral, ethical, and scientific principles governing clinical research as set out in the 
applicable version of Declaration of Helsinki and the principles of GCP. 
The investigator will be supplied with details of any significant or new finding including AEs 
relating to treatment with the investigational medicinal product. 
 
 
Date: ___________  
Signature:______________________________ 
 
Name (block letters):  
Roland Fank 
Function: 
 
 
Sponsor  
 
 
Date: ___________  
Signature:______________________________ 
 
Name (block letters):  
Prof. Dr. med. Ekkehard Grünig 
Function: 
 
 
Coordinating Investigator/ Investigator according to §40 AMG  
 
 
 
Date: ___________  
Signature:______________________________ 
 
Name (block letters):  
Nicola Benjamin 
Function: 
 
 
Biometrician  
 
 

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16 Declaration of Investigator 
I have read the above trial protocol and confirm that it contains all information to conduct the 
clinical trial. I pledge to conduct the clinical trial according to the protocol. 
I will enroll the first subject only after all ethical and regulatory requirements are fulfilled. I 
pledge to obtain written consent for trial participation from all subjects. 
I know the requirements for accurate notification of serious adverse events and I pledge to 
document and notify such events as described in the protocol. 
I pledge to retain all trial-related documents and source data as described. I will provide a 
Curriculum Vitae (CV) before trial start. I agree that the CV may be submitted to the responsible 
regulatory authorities. 
 
Date 
___________  
Signature:______________________________ 
 
Name (block letters):  
Prof. Dr. med. Ekkehard Grünig 
Function: 
 
 
Investigator 
 
Trial Center (address): 
Röntgenstr. 1 
 
 
 
 
69126 Heidelberg 
 
 
 
 
Germany 
 
 
 
 
 

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18 References  
 
ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. 2002. ATS statement: 
guidelines for the six-minute walk test. Am J Respir Crit Care Med 166(1):111-117. 
Chaouat A, Weitzenblum E, Kessler R, Charpentier C, Enrhart M, Schott R, Levi-Valensi P, Zielinski J, Delaunois  
L, Cornudella R, Moutinho dos Santos J. A randomized trial of nocturnal oxygen therapy in chronic 
obstructive pulmonary disease patients. Eur Respir J. 1999;14(5):1002. 
Collopy KT, Kivlehan SM, Snyder SR. Oxygen toxicity. What EMS providers need to know about possible 
complications from oxygen administration. EMS World. 2012 Jan;41(1):68-72. 
Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, 
Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, 
McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M. 2015 ESC/ERS Guidelines for the 
diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment 
of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory 
Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), 
International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015;46(4):903-75. 
Górecka D, Gorzelak K, Sliwiński P, Tobiasz M, Zieliński J. Effect of long-term oxygen therapy on survival in 
patients with chronic obstructive pulmonary disease with moderate hypoxaemia. Thorax. 1997;52(8):674. 
Hildenbrand FF, Bloch KE, Speich R, Ulrich S. Daytime measurements underestimate nocturnal oxygen 
desaturations in pulmonary arterial and chronic thromboembolic pulmonary hypertension. Respiration; 
international review of thoracic diseases. 2012;84(6):477-84. 
Jenkinson SG. Oxygen toxicity. New Horiz.1993 Nov; 1(4):504-11. 
Leuchte HH, Baezner CJ, Baumgartner RA, Mernitz P, Neurohr C, Behr J. Acute hemodynamic responses to 
supplemental oxygen and their prognostic implications in pulmonary hypertension. Respiration. 
2013;85(5):400-7. 
Mathai SC, Puhan MA, Lam D, Wise RA. The minimal important difference in the 6-minute walk test for patients 
with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012 Sep 1;186(5):428-33. 
Medical Research Council Working Party. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale 
complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party. 
Lancet. 1981;1(8222):681.  
Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive 
lung disease: a clinical trial. Ann Intern Med. 1980;93(3):391.  
Nonoyama ML, Brooks D, Guyatt GH, Goldstein RS  Effect of oxygen on health quality of life in patients with 
chronic obstructive pulmonary disease with transient exertional hypoxemia. Am J Respir Crit Care Med. 
2007;176(4):343. 
Opitz CF, Blindt R, Blumberg F, Borst MM, Bruch L, Leuchte HH, Lichtblau M, Nagel C, Peters K, Rosenkranz S 
et al. . 2011. Pulmonary hypertension: Hemodynamic evaluation. Updated Recommendations of the 
Cologne Consensus Conference 2011. Int J Cardiol 154 Suppl 1:S13-19. 
Roberts DH, Lepore JJ, Maroo A, Semigran MJ, Ginns LC. Oxygen therapy improves cardiac index and pulmonary 
vascular resistance in patients with pulmonary hypertension. Chest. 2001;120(5):1547-55. 
Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, Solomon SD, Louie EK, and 
Schiller NB. 2010. Guidelines for the echocardiographic assessment of the right heart in adults: a report 
from the American Society of Echocardiography endorsed by the European Association of 
Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of 
Echocardiography. Journal of the American Society of Echocardiography : official publication of the 
American Society of Echocardiography 23(7):685-713; quiz 786-688. 
Sandoval J, Aguirre JS, Pulido T, Martinez-Guerra ML, Santos E, Alvarado P, et al. Nocturnal oxygen therapy in 
patients with the Eisenmenger syndrome. Am J Respir Crit Care Med. 2001;164(9):1682-7. 

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Schumacher DS, Müller-Mottet S, Hasler ED, Hildenbrand FF, Keusch S, Speich R, Bloch KE, Ulrich S. Effect of 
oxygen and acetazolamide on nocturnal cardiac conduction, repolarization, and arrhythmias in precapillary 
pulmonary hypertension and sleep-disturbed breathing. Chest. 2014;146(5):1226-1236. 
 
Ulrich S, Keusch S, Hildenbrand FF, Lo Cascio C, Huber LC, Tanner FC, Speich R, Bloch KE. Effect of nocturnal 
oxygen and acetazolamide on exercise performance in patients with pre-capillary pulmonary hypertension 
and sleep-disturbed breathing: randomized, double-blind, cross-over trial. Eur Heart J. 2015;36(10):615-23. 
 
Ulrich S, Hasler ED, Saxer S, Furian M, Bloch KE.et al. Effect of breathing oxygen-enriched air on exercise 
performance in patients with precapillary pulmonary hypertension: randomized, sham-controlled cross-over 
trial; Eur Heart J. 2017;14;38(15):1159-1168. 
 
Weitzenblum E, Sautegeau A, Ehrhart M, Mammosser M, Pelletier A. Long-term oxygen therapy can reverse the 
progression of pulmonary hypertension in patients with chronic obstructive pulmonary disease. The 
American review of respiratory disease. 1985;131(4):493-8. 
 
 
 
 
19 Appendices 
Declaration of Helsinki (applicable Version)* 
SF-36 (German version “Fragebogen zum Gesundheitszustand“) 
Patient diary* 

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FRAGEBOGEN ZUM GESUNDHEITSZUSTAND  
 
In diesem Fragebogen geht es um Ihre Beurteilung Ihres Gesundheitszustandes in den letzten 4 Wochen. 
Der Bogen ermöglicht es, im Zeitverlauf nachzuvollziehen, wie Sie sich fühlen und wie Sie im Alltag 
zurechtkommen. 
 
Bitte beantworten Sie jede der folgenden Fragen, in dem Sie bei den Antwortmöglichkeiten die Zahl 
ankreuzen, die am besten auf Sie zutrifft. 
 
1. Wie würden Sie Ihren Gesundheitszustand in den letzten 4 Wochen im Allgemeinen beschreiben? 
 (Bitte kreuzen Sie nur eine Zahl an) 
 
Ausgezeichnet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 
 
Sehr gut . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 
 
Gut . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 
 
Weniger gut . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4 
 
Schlecht . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 
 
 
2. Im Vergleich zum Jahr davor, wie würden Sie Ihren Gesundheitszustand vor einem Jahr beschreiben. 
(Bitte kreuzen Sie nur eine Zahl an) 
 
Derzeit viel besser als vor einem Jahr . . . . . . . . . . . . . . .  1 
 
Derzeit etwas besser als vor einem Jahr . . . . . . . . . . . . .  2 
 
Etwa so wie vor einem Jahr . . . . . . . . . . . . . . . . . . . . . . .  3 
 
Derzeit etwas schlechter als vor einem Jahr . . . . . . . . .   4 
 
Derzeit viel schlechter als vor einem Jahr . . . . . . . . . . . . 5 
 

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3. Im Folgenden sind einige Tätigkeiten beschrieben, die Sie vielleicht an einem normalen Tag ausüben. 
Sind sie durch Ihren derzeitigen Gesundheitszustand bei diesen Tätigkeiten eingeschränkt? Wenn ja, wie 
stark? 
(Bitte kreuzen Sie in jeder Zeile nur eine Zahl an) 
 
 
 
TÄTIGKEITEN 
 
Ja, 
stark 
eingeschränkt 
 
Ja, 
etwas 
eingeschränkt 
Nein, 
überhaupt 
nicht  
eingeschränkt 
 
a. anstrengende Tätigkeiten, z.B. schnell laufen, 
    schwere Gegenstände heben, anstrengenden 
    Sport treiben 
 
 
1 
 
 
2 
 
 
3 
 
b.  mittelschwere Tätigkeiten, z.B. einen Tisch 
     verschieben, Staub saugen, kegeln, Golf spielen 
 
 
1 
 
 
2 
 
 
3 
 
c.  Einkaufstaschen heben oder tragen 
 
1 
 
2 
 
3 
 
d.  mehrer Treppenabsätze steigen 
 
1 
 
2 
 
3 
 
e.  einen Treppenabsatz steigen 
 
1 
 
2 
 
3 
 
f.  sich beugen, knien, bücken 
 
1 
 
2 
 
3 
 
g.  mehr als 1 Kilometer zu Fuß gehen 
 
1 
 
2 
 
3 
 
h.  mehrere Straßenkreuzungen weit zu Fuß  
    gehen 
 
1 
 
2 
 
3 
 
i.  eine Straßenkreuzung weit zu Fuß gehen 
 
1 
 
2 
 
3 
 
j.  sich baden oder anziehen 
 
1 
 
2 
 
3 
 

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4.Hatten Sie in den vergangenen 4 Wochen aufgrund Ihrer körperlichen Gesundheit  irgendwelche 
Schwierigkeiten bei der Arbeit oder anderen alltäglichen Tätigkeiten im Beruf bzw. zu Hause? 
(Bitte kreuzen Sie in jeder Zeile nur eine Zahl an) 
 
 
SCHWIERIGKEITEN 
 
 
JA 
 
NEIN 
 
a. 
Ich konnte nicht so lange wie üblich tätig sein 
 
 
1 
 
2 
 
b. 
Ich habe weniger geschafft als ich wollte 
 
1 
 
2 
 
c. 
Ich konnte nur bestimmte Dinge tun 
 
1 
 
2 
 
d. 
Ich hatte Schwierigkeiten bei der Ausführung (z.B. ich musste mich 
 
besonders anstrengen) 
 
1 
 
2 
 
5. Hatten Sie in den vergangenen 4 Wochen aufgrund seelischer Probleme irgendwelche 
Schwierigkeiten bei der Arbeit oder anderen alltäglichen Tätigkeiten im Beruf bzw. zu Hause (z.B. weil 
Sie sich niedergeschlagen oder ängstlich fühlten)? 
 (Bitte kreuzen Sie in jeder Zeile nur eine Zahl an) 
 
 
SCHWIERIGKEITEN 
 
 
JA 
 
NEIN 
 
a. 
Ich konnte nicht so lange wie üblich tätig sein 
 
 
1 
 
 
2 
 
b. 
Ich habe weniger geschafft als ich wollte 
 
1 
 
 
2 
 
c. 
Ich konnte nicht so sorgfältig wie üblich arbeiten 
 
1 
 
 
2 
 
 

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6. Wie sehr haben Ihre körperliche Gesundheit oder seelischen Probleme in den vergangenen 4 Wochen 
Ihre normalen Kontakte zu Familienangehörigen, Freunden, Nachbarn oder zum Bekanntenkreis 
beeinträchtigt 
 (Bitte kreuzen Sie nur eine Zahl an) 
 
Überhaupt nicht . . . . . . . . . . . . . . . . . . . . . . .1 
 
Etwas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 
 
Mäßig . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 
 
Ziemlich . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4 
 
Sehr . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 
 
7. Wie stark waren Ihre Schmerzen in den vergangenen 4 Wochen? 
 (Bitte kreuzen Sie nur eine Zahl an) 
 
Ich hatte keine Schmerzen . . . . . . . . . . . . . .1 
 
Sehr leicht . . . . . . . . . . . . . . . . . . . . . . . . . . .2 
 
Leicht . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 
 
Mäßig . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4 
 
Stark . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 
 
Sehr stark . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 

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8. Inwieweit haben die Schmerzen Sie in den vergangenen 4 Wochen bei der Ausübung Ihrer 
Alltagstätigkeiten zu Hause und im Beruf behindert 
 (Bitte kreuzen Sie nur eine Zahl an) 
 
Überhaupt nicht . . . . . . . . . . . . . . . . . . . . . . .1 
 
Ein bisschen . . . . . . . . . . . . . . . . . . . . . . . . . .2 
 
Mäßig . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 
 
Ziemlich . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4 
 
Sehr . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 
 
 
9. In diesen Fragen geht es darum, wie Sie sich fühlen und wie es Ihnen in den vergangenen 4 Wochen 
gegangen ist. (Bitte kreuzen Sie in jeder Zeile die Zahl an, die Ihrem Befinden am ehesten entspricht). 
Wie oft waren Sie in den vergangenen 4 Wochen.... 
(Bitte kreuzen Sie in jeder Zeile nur eine Zahl an) 
 
Befinden 
 
immer 
 
Mei- 
stens 
Ziemlich 
oft 
Manch- 
mal 
 
Selten 
 
Nie 
 
a.    ...voller Schwung? 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
b.    ...sehr nervös? 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
c.    ...so niedergeschlagen,  
       daß Sie nichts aufheitern  
       konnte? 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
d.    ...so ruhig und gelassen? 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 

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e.    ...voller Energie? 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
f.    ...entmutigt und traurig? 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
g.    ...erschöpft? 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
h.    ...glücklich? 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
i.    ...müde? 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
10. Wie häufig haben Ihre körperliche Gesundheit oder seelischen Probleme in den vergangenen 4 
Wochen Ihre Kontakte zu anderen Menschen (Besuche bei  Freunden, Verwandten usw.) beeinträchtigt? 
 (Bitte kreuzen Sie nur eine Zahl an) 
 
Immer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 
 
Meistens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 
 
Manchmal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 
 
Selten . . . . .  . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4 
 
Nie . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 
 
 

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11. Inwieweit trifft jede der folgenden Aussagen auf Sie zu? 
 (Bitte kreuzen Sie in jeder Zeile nur eine Zahl an) 
 
 
AUSSAGEN 
 
 
 
Trifft 
ganz 
zu 
Trifft 
weitge- 
hend 
zu 
 
 
Weiß 
nicht 
Trifft 
weitge- 
hend 
nicht zu 
Trifft 
über- 
haupt 
nicht zu 
 
 
a.  Ich scheine etwas leichter als  
     andere krank zu werden 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
b.  Ich bin genauso gesund wie alle 
     anderen, die ich kenne 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
c.  Ich erwarte, daß meine  
     Gesundheit nachlässt 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
d. Ich erfreue mich ausgezeichneter 
   Gesundheit 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 

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Patient diary 
Datum 
Stunden mit Sauerstoff 
Bemerkungen 
Monat:_________________ 
Tagsüber 
Nachts 
 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
 
9 
 
 
 
10 
 
 
 
11 
 
 
 
12 
 
 
 
13 
 
 
 
14 
 
 
 
15 
 
 
 
16 
 
 
 
17 
 
 
 
18 
 
 
 
19 
 
 
 
20 
 
 
 
21 
 
 
 
22 
 
 
 
23 
 
 
 
24 
 
 
 
25 
 
 
 
26 
 
 
 
27 
 
 
 
28 
 
 
 
29 
 
 
 
30 
 
 
 
31