PFOX: Pulmonary Fibrosis Ambulatory Oxygen Trial

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
PFOX: Pulmonary Fibrosis Ambulatory Oxygen Trial

Conditions
-----------------
Fibrotic Interstitial Lung Disease

Intervention / Treatment
-----------------
* Other: Ambulatory Oxygen Therapy
* Other: Sham Ambulatory Oxygen Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oxygen therapy with POC (AOT group)<br>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<br>* Supplemental oxygen delivered during exercise and activities of daily living via a portable oxygen concentrator<br>|
| Sham Comparator: Sham oxygen therapy with POC (air group)<br>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<br>* Air delivered during exercise and activities of daily living via a portable oxygen concentrator that has been modified to deliver air<br>|

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 |