The Effect of Oxygen Therapy on 6MWD in PAH and CTEPH Patients With Hypoxemia (SOPHA)

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

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

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Arterial Hypertension; Oxygen Deficiency; CTEPH
• Intervention / Treatment: Drug: Oxygen

Detailed Description

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.Current recommendations including the pneumological guidelines for LTOT 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. The use of ambulatory O2 can be considered when there is evidence of a symptomatic response or correction of exercise-induced desaturation.

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. In one study, oxygen supply also reversed the progression of PH in patients with chronic obstructive pulmonary disease (COPD). One recent randomized-controlled trial indicates that O2 given during cardiopulmonary exercise significantly improves maximal work rate and endurance. Furthermore, nocturnal oxygen supply for one week significantly improved 6-minute walking distance in patients with PH, sleep-associated breathing difficulties, exercise performance during the day as well as cardiac repolarisation. Patients with Eisenmenger's syndrome gain little benefit from nocturnal O2 therapy.

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.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ekkehard Grünig, Prof., MD; Phone Number: 06221 / 396 8053; Email: ekkehard.gruenig@med.uni-heidelberg.de
• Study Contact Backup: Name: Benjamin Egenlauf, MD; Phone Number: 06221 / 396 8078; Email: Benjamin.Egenlauf@med.uni-heidelberg.de

Study Locations

• Germany
  • Heidelberg, Germany, 69126
    • Recruiting
    • Centre for pulmonary hypertension of the Thoraxclinic at the University Hospital Heidelberg
    • Contact: Ekkehard Grünig, MD; Phone Number: +4962213968053; Email: ekkehard.gruenig@med.uni-heidelberg.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria Patients in both groups (n = 20; n=10 each group) 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 (<60 mmHg; alternatively, 90% of O2 saturation) at rest and/or during physical activity (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 (by the WHO Clinical classification system)), including Idiopathic (IPAH), Heritable PAH (HPAH, Familial PAH), associated PAH (APAH) 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
• Patients experiencing oxygen desaturations ≤90% (or pO2 below 60 mmHg) at rest and/or oxygen desaturations ≤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 two 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 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, requiring 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 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 weekspatient with a cardiac index (CI) <1.8L/min/m^2
• active smoking Status
• patient with severe resting desaturation (repeatedly SpO2 <80%) or severe exercise-induced desaturation (SpO2 ≤75% for ≥10 minutes)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Oxygen Therapy provided; Patients will be divided in a supplemental-oxygen group (primary intervention group) throughout the study	Drug: Oxygen; 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.; Other Names: Liquid oxygen
Sham Comparator: no-supplemental-oxygen group (control group); Patients of the control group will beginn the study without Oxygen Therapie and will be offered to participate in the interventional treatment arm after they have terminated the control period (partial cross-over; secondary intervention group).	Drug: Oxygen; 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.; Other Names: Liquid oxygen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-minute Walking distance	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).	Change from baseline to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life: physical Summation score; short form health Survey 36 (score from 0-100; higher scores indicating better outcome)	To investigate effects of oxygen treatment on QoL, physical Summation score measured with SF-36 questionnaire	Change from baseline to 6 months
Quality of life: mental Summation score; short form health Survey 36 (score from 0-100; higher scores indicating better outcome)	To investigate effects of oxygen treatment on QoL, mental Summation score measured with SF-36 questionnaire	Change from baseline to 6 months
Clinical worsening; frequency and type of clinical worsening events	To assess time to worsening of oxygen saturation and time to clinical worsening	clinical worsening events from baseline to 6 months
cardiac index in liters per minute per square meter (of body surface area) /(CI)	Assessment of Cardiac Index during RHC	Change from baseline to 6 months
systolic pulmonary arterial pressure	Right heart catheterization	Change from baseline to 6 months
mean pulmonary arterial pressure	Right heart catheterization	Change from baseline to 6 months
pulmonary arterial wedge pressure	Right heart catheterization	Change from baseline to 6 months
right atrial pressure	Right heart catheterization	Change from baseline to 6 months
pulmonary vascular resistance (PVR)	Right heart catheterization	Change from baseline to 6 months
cardiac output and ejection fraction (CO, HZV)	Right heart catheterization	Change from baseline to 6 months
cardiac index (CI)	Right heart catheterization	Change from baseline to 6 months
blood gas analysis from pulmonary artery	central venous saturation	Change from baseline to 6 months
Change in systolic pulmonary arterial pressure	Echocardiography and Stress Doppler Echocardiography	Change from baseline to 6 months
Echocardiography and Stress Doppler Echocardiography	right ventricular pump function	Change from baseline to 6 months
Peak oxygen consumption	Cardiopulmonary exercise testing	Change from baseline to 6 months
Peak oxygen consumption/kg body weight	Cardiopulmonary exercise testing	Change from baseline to 6 months
oxygen Saturation	Cardiopulmonary exercise testing	Change from baseline to 6 months
oxygen equivalent	Cardiopulmonary exercise testing	Change from baseline to 6 months
Cardiopulmonary exercise testing	carbon dioxide equivalent	Change from baseline to 6 months
Oxygen pulse	Cardiopulmonary exercise testing	Change from baseline to 6 months
ventilatory threshold	Cardiopulmonary exercise testing	Change from baseline to 6 months
respiratory reserve	Cardiopulmonary exercise testing	Change from baseline to 6 months
World Health Organization functional classification	Functional assessment of pulmonary hypertension	Change from baseline to 6 months

Collaborators and Investigators

• Sponsor: Heidelberg University

Publications and helpful links

General Publications

• Ulrich S, Hasler ED, Saxer S, Furian M, Muller-Mottet S, Keusch S, Bloch KE. 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 Apr 14;38(15):1159-1168. doi: 10.1093/eurheartj/ehx099.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2019
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: December 17, 2019
• First Submitted That Met QC Criteria: December 18, 2019
• First Posted (Actual): December 23, 2019

Study Record Updates

• Last Update Posted (Actual): July 14, 2022
• Last Update Submitted That Met QC Criteria: July 12, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Pulmonary Arterial Hypertension; Oxygen; CTEPH; 6MWD
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Signs and Symptoms, Respiratory; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Hypoxia
• Other Study ID Numbers: 2018-11SO*

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No