PFOX: Pulmonary Fibrosis Ambulatory Oxygen Trial (PFOX)

The fibrotic interstitial lung diseases (fILD) are characterised by lung scarring, distressing breathlessness and poor health-related quality of life. Exertional desaturation (low blood oxygen during exercise) is a hallmark of fILD, occurring in over 50% of patients. It is sometimes treated with ambulatory oxygen therapy (AOT), which involves breathing supplemental oxygen during physical activity. However the absence of clinical trials has given rise to marked variations in policy and practice globally. Even where AOT is available, treatment adherence using the traditional delivery method of cylinder gas is poor. Recently new devices called portable oxygen concentrators (POCs), have become available, which are lighter and more maneuverable than a cylinder. This may enhance adherence and maximize treatment benefits.

This trial will determine the clinical benefits and societal costs of AOT for people with fILD and exertional desaturation. A randomised controlled trial with blinding of participants, assessors and clinicians, and an embedded economic evaluation will be conducted. A total of 260 participants with fILD and exertional desaturation will be randomly assigned to use either AOT or air delivered using a POC for 6 months. If this trial demonstrates clinical and economic benefits of AOT then the findings can be rapidly translated into practice.

Study Overview

• Status: Recruiting
• Conditions: Fibrotic Interstitial Lung Disease
• Intervention / Treatment: Other: Ambulatory Oxygen Therapy; Other: Sham Ambulatory Oxygen Therapy

Detailed Description

Interstitial lung diseases (ILDs) are characterized by scarring of lung tissue. Stiffening of the lungs leads to reduced transfer of oxygen into the blood, decreased exercise capacity and premature death. Around 85% of the ILDs are known as fibrotic ILD (fILD), a form of ILD which tends to have worse outcomes than other types of ILD. People with fibrotic ILD often experience distressing breathlessness, cough and fatigue; loss of independence and life roles; financial strain; and unpleasant treatment side effects.The most common of the fILDs is idiopathic pulmonary fibrosis (IPF), which has an average survival of 3 years from diagnosis. Recently, two new treatments have been shown to halve the annual decline in lung function in mild to moderate IPF, making it a 'treatable' condition for the first time. However, these treatments only slow the decline in lung function; they do not stabilize or reverse it, nor do patients experience improved quality of life or breathlessness.

For people with fILD who have abnormally low oxygen in the blood at rest, long term oxygen therapy (LTOT, used ≥18 hours per day) is strongly recommended, based on survival benefits in studies of people with chronic obstructive pulmonary disease (COPD). However, for people with fILD who have low oxygen levels only during exertion, the role of oxygen therapy is not clear.

Ambulatory oxygen therapy (AOT), defined as the use of oxygen during exercise and activities of daily living, has historically been used to improve blood oxygen levels and exercise capacity. However, many people with fILD find this treatment difficult to use. Oxygen cylinders are heavy and run out quickly, therefore patient burden often exceeds any benefits. Portable oxygen concentrators (POCs) are newly available, lighter and rechargeable. However there are potential disadvantages to POCs. Generally, they deliver oxygen in pulses, which is where oxygen is delivered only when breathing in, and they do not deliver 100% oxygen. Doctors often express concerns that POCs cannot meet the demands of people with fILD during exercise. Recently it was shown that people with fILD who use a POC have similar blood oxygen levels to those who use a cylinder during exercise, suggesting that this might be a useful treatment.

This study will examine the benefits and costs of ambulatory oxygen, delivered using a POC, in people with fILD and exertional desaturation. The aim is to compare the impact of AOT vs air in people with fILD who have low blood oxygen during exercise, and to compare the cost-effectiveness of AOT and air in fILD. A total of 260 people with fILD will be invited to participate. The trial will be conducted at four sites in Australia and two sites in Sweden. Participants will be randomly allocated into two groups; Group 1 will be administered AOT using a POC (AOT group); and Group 2 will be administered sham AOT using an identical POC (air group). Participants, health professionals and trial staff will not be aware of which POC is being used. The allocated treatment will be delivered for 6 months. Measurements of physical activity during daily life, symptoms, exercise capacity and HRQOL will be collected at the beginning of the trial, and 3 and 6 months after treatment has commenced. Information about use of health care services, both from hospital records and directly from participants will also be collected.

• Study Type: Interventional
• Enrollment (Estimated): 260
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anne Holland, Professor; Phone Number: +61 3 99030214; Email: anne.holland@monash.edu

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Recruiting
      • Monash University
      • Contact: Anne Holland, PhD; Phone Number: +61 3 99030214; Email: anne.holland@monash.edu
      • Contact: Mariana Hoffman Barbosa, PhD; Email: mariana.hoffman1@monash.edu

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Confirmed diagnosis of Fibrotic Interstitial Lung Disease
• Stable pharmacotherapy over the last 3 months
• Exertional desaturation (SpO2≤88% for at least 10 consecutive seconds) during a 6 Minute Walking Test performed on room air

Exclusion Criteria:

• Currently using or eligible for long term oxygen therapy (PaO2≤55 mmHg at rest on room air, or 56-59 mmHg with evidence of right heart failure)
• Current smokers
• Pregnant patients
• Patients cognitively unable to consent; or if death or transplant is anticipated within the study period.
• Participants currently in pulmonary rehabilitation
• Non-ambulant patients
• Admission to an acute care hospital within the last 30 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oxygen therapy with POC (AOT group); Patients will receive ambulatory oxygen therapy provided by a portable oxygen concentrator and will be encouraged to use it at all times when they are moving about, including walking at home or in the community, during exercise or during other activities.	Other: Ambulatory Oxygen Therapy; Supplemental oxygen delivered during exercise and activities of daily living via a portable oxygen concentrator
Sham Comparator: Sham oxygen therapy with POC (air group); Patients will receive sham ambulatory oxygen therapy provided by a portable oxygen concentrator and will be encouraged to use it at all times when they are moving about, including walking at home or in the community, during exercise or during other activities.	Other: Sham Ambulatory Oxygen Therapy; Air delivered during exercise and activities of daily living via a portable oxygen concentrator that has been modified to deliver air

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in physical activity measured by steps per day	Steps per day assessed by activity monitors	Baseline, 3 month and 6 month assessments

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in functional exercise capacity assessed by 6-minute walk distance	Distance in meters achieved on a 6-minute walk test	Baseline, 3 month and 6 month assessments
Change in health related quality of life evaluated using the St George's Respiratory Questionnaire	St George's Respiratory Questionnaire is a disease-specific health related quality of life questionnaire.The questionnaire is divided in 3 domains: Symptoms (frequency and severity), Activity (activities that cause or are limited by breathlessness) and Impact (social functioning and psychological disturbances resulting from airways disease). Values of each domain as well as the total score value will be reported. Each item is weighted based on empirical data. Total score and scores in each domain can range from 0 to 100. Higher scores indicate more limitations in quality of life.	Baseline, 3 month and 6 month assessments
Change in dyspnea measured using the Dyspnea-12 questionnaire	Dyspnea-12 is a uni-dimensional 12-item questionnaire divided in 2 domains: physical items (1 to 7) and affective items (8-12). Each item evaluate breathing experience and can be scored as: None (0), Mild (1), Moderate (2) or Severe (3). Results of this questionnaire will be reported as total score that can range from 0 to 36 and separate scores that can range from 0 to 21 for physical component and 0 to 15 for affective component. Higher scores indicate worse dyspnea.	Baseline, 3 month and 6 month assessments
Changes in fatigue evaluated by the Fatigue Severity Scale	Fatigue Severity Scale (FSS), a self reported rating scale including 9 items to measure how fatigue affects motivation, exercise, physical functioning, carrying out duties and how fatigue interferes with work, family, or social life. Each item is scored on a 7 point scale in which 1 = strongly disagree and 7= strongly agree. Total score range from 9 to 63. Higher scores indicate greater fatigue severity.	Baseline, 3 month and 6 month assessments
Change in anxiety and depression measured by the Hospital Anxiety and Depression Scale	Hospital Anxiety and Depression Scale (HADS), a scale with 14 items divided into two domains : anxiety symptoms (7 items) and depression symptoms (7 items). Each item can be scored from 0 to 3. Scores from each domain can vary from 0 to 21 and are stratified as follows: 0-7 (indicates absence of anxiety/depression symptoms); 8-10 ( presence of symptoms of anxiety and depression in moderate degree - borderline); 11 or more (significant number of anxiety/depression symptoms - confirmed cases). Score of each domain as well as number of confirmed cases will be reported.	Baseline, 3 month and 6 month assessments
Change in time spent in moderate to vigorous physical activity	Time spent in moderate to vigorous physical activity, measured by a wrist-worn, tri-axial accelerometer.	Baseline assessment, 3 month and 6 month assessments
Change in sedentary time	Time spent sedentary, measured by a wrist-worn, tri-axial accelerometer.	Baseline assessment, 3 month and 6 month assessments
Skeletal muscle metabolism	Plasma markers of skeletal muscle metabolism (xanthine, hypoxanthine [units pmole/µL]) will be analysed from collected blood samples.	Baseline, 3 month and 6 month assessments
Systemic inflammation	C-reactive protein [unit ng/mL]) will be analysed from collected blood samples.	Baseline, 3 month and 6 month assessments
Oxidative stress	Thiobarbituric acid reactive substrates [units µM]) will be analysed from collected blood samples.	Baseline, 3 month and 6 month assessments
Use of oxygen therapy	Hours of usage of the portable concentrator.	3 month and 6 month assessments
Oxygen saturation in daily life	Wrist oximeter that will be worn during waking hours on two consecutive weekdays.	3 month and 6 month assessments
Incremental cost-effectiveness ratio	Difference in health care costs compared to differences in quality-adjusted life years -QALYs	6 month assessment

Collaborators and Investigators

• Sponsor: Monash University
• Investigators: Principal Investigator: Anne Holland, Professor, Monash University

Publications and helpful links

General Publications

• Holland AE, Corte T, Chambers DC, Palmer AJ, Ekstrom MP, Glaspole I, Goh NSL, Hepworth G, Khor YH, Hoffman M, Vlahos R, Skold M, Dowman L, Troy LK, Prasad JD, Walsh J, McDonald CF. Ambulatory oxygen for treatment of exertional hypoxaemia in pulmonary fibrosis (PFOX trial): a randomised controlled trial. BMJ Open. 2020 Dec 13;10(12):e040798. doi: 10.1136/bmjopen-2020-040798.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2019
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: September 18, 2018
• First Submitted That Met QC Criteria: November 7, 2018
• First Posted (Actual): November 9, 2018

Study Record Updates

• Last Update Posted (Actual): October 19, 2023
• Last Update Submitted That Met QC Criteria: October 17, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Fibrosis; Lung Diseases; Pulmonary Fibrosis; Lung Diseases, Interstitial
• Other Study ID Numbers: HREC/18/Alfred/42

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be available after deidentification of participants after publication, with approval of the Alfred Health Human Research Ethics Committee.
• IPD Sharing Time Frame: 9-36 months after article publication
• IPD Sharing Access Criteria: Proposals submitted to corresponding author and approved by Alfred Hospital Human Research Ethics Committee.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

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