Novel drinkable oxygen nanobubbles: a pilot randomised, double-blind, cross-over trial on patients with pulmonary fibrosis

Breathlessness is a key determinant of Quality of life (QoL) in patients with fibrotic ILD. 6 minute walk test (6MWT) data indicates that a fall in oxygen saturation (SaO2) in ILD patients, can be corrected by supplemental O2. However, no prospective studies have assessed the impact of ambulatory O2 on QoL in patients with ILD. We report on a prospective, multi-centre trial (NCT02286063), investigating the effects of ambulatory O2 in fibrotic ILD patients. Design: a randomized, cross-over controlled trial evaluating QoL, breathlessness, and mobility during two weeks on ambulatory O2 compared to two weeks off O2 in 80 ILD patients. Inclusion: patients with SaO2 ≥ 94% at rest, on room air dropping to ≤88% on a 6MWT.Primary outcome: health status assessed by the King9s Brief Interstitial Lung Disease Questionnaire. Key secondary outcomes: change in breathlessness and QoL scores (SGRQ, UCSDSBQ, HDAS), activity measurements and, in a subset, qualitative interviews. Interim Data patients randomized n=52, male n=37, mean age (± SD) of 64.5±1.1 yrs, ex-smokers n=36, mean FVC 69.3±18.4 %, and mean DLCO 38.7±12.8 %. Diagnosis: IIP n=31, CTD-ILD n=8, fibrotic HP n=6, miscellaneous n=7. All 45 patients that completed study wereoffered the option of continuing ambulatory O2. <b>Conclusion:</b> To date 35/45 (77.8%) patients have opted to continue with ambulatory O2 post study completion, suggesting the majority perceive that oxygen is beneficial. The final results of this study are expected to influence future ILD-specific guidelines for the use of ambulatory O2.

BackgroundFibrotic interstitial lung diseases (ILDs) are chronic and often progressive conditions resulting in substantial morbidity and mortality. Shortness of breath, a symptom often linked to oxygen desaturation on exertion, is tightly linked to worsening quality of life in these patients. Although ambulatory oxygen is used empirically in their treatment, there are no ILD-specific guidelines on its use. To our knowledge, no studies are available on the effects of ambulatory oxygen on day-to-day life in patients with ILD.Methods/designAmbulatory oxygen in fibrotic lung disease (AmbOx) is a multicentre, randomised controlled crossover trial (RCT) funded by the Research for Patient Benefit Programme of the National Institute for Health Research. The trial will compare ambulatory oxygen used during daily activities with no ambulatory oxygen in patients with fibrotic lung disease whose oxygen saturation (SaO2) is ≥94% at rest, but drops to ≤88% on a 6-min Walk Test. The randomised controlled trial (RCT) will evaluate the effects on health status (measured by the King’s Brief ILD Questionnaire: K-BILD) of ambulatory oxygen used at home, at an optimal flow rate determined by titration at screening visit, and administered for a 2-week period, compared to 2 weeks off oxygen. Key secondary outcomes will include breathlessness on activity scores, as measured by the University of California San Diego Shortness of Breath Questionnaire, global patient assessment of change scores, as well as quality of life scores (St George’s Respiratory Questionnaire), anxiety and depression scores (Hospital Anxiety and Depression Scale), activity markers measured by SenseWear Armbands, pulse oximetry measurements, patient-reported daily activities, patient- and oxygen company-reported oxygen cylinder use. The study also includes a qualitative component and will explore in interviews patients’ experiences of the use of a portable oxygen supply and trial participation in a subgroup of 20 patients and carers.DiscussionThis is the first RCT of the effects of ambulatory oxygen during daily life on health status and breathlessness in fibrotic lung disease. The results generated should provide the basis for setting up ILD-specific guidelines for the use of ambulatory oxygen.Trial registrationNational Clinical Trials Registry, identifier: NCT02286063. Registered on 8 October 2014 (retrospectively registered).

One-minute sit-to-stand test to detect gas exchange capacity during exercise stress in patients with idiopathic or progressive pulmonary fibrosis: A randomized, crossover trial.

BackgroundIdiopathic pulmonary fibrosis (IPF) is an interstitial lung disease associated with high morbidity and mortality. Effective treatments for IPF are limited. Several recent studies have investigated novel therapeutic agents for IPF, but very few have addressed their comparative benefits and harms.MethodsWe performed a Bayesian network meta-analysis (NMA) to assess the effects of different treatments for IPF on mortality and serious adverse events (SAEs). We searched MEDLINE and EMBASE for randomized controlled trials (RCTs) up to August 2015. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach served to assess the certainty in the evidence of direct and indirect estimates. We calculated the surface under the cumulative ranking curve (SUCRA) for each treatment.We included parallel group RCTs, including factorial designs, but excluded quasi-randomized and cross-over trials. Studies were only included if they involved adult (≥18 years of age) patients with IPF as defined by the 2011 criteria and examined one of the 10 interventions of interest (ambrisentan, bosentan, imatinib, macitentan, N-acetylcysteine, nintedanib, pirfenidone, sildenafil, prednisone/azathioprine/N-acetylcysteine triple therapy, and vitamin K antagonist).ResultsA total of 19 RCTs (5,694 patients) comparing 10 different interventions with placebo and an average follow-up period of 1 year fulfilled the inclusion criteria. SUCRA analysis suggests nintedanib, pirfenidone, and sildenafil are the three treatments with the highest probability of reducing mortality in IPF. Indirect comparison showed no significant difference in mortality between pirfenidone and nintedanib (NMA OR, 1.05; 95 % CrI, 0.45–2.78, moderate certainty of evidence), pirenidone and sildenafil (NMA OR, 2.26; 95 % CrI, 0.44–13.17, low certainty of evidence), or nintedanib and sildenafil (NMA OR 2.40; 95 % CrI, 0.47–14.66, low certainty of evidence). Sildenafil, pirfenidone, and nintedanib were ranked second, fourth, and sixth out of 10 for SAEs.ConclusionIn the absence of direct comparisons between treatment interventions, this NMA suggests that treatment with nintedanib, pirfenidone, and sildenafil extends survival in patients with IPF. The SAEs of these agents are similar to the other interventions and include mostly dermatologic and gastrointestinal manifestations. Head-to-head comparisons need to confirm these findings.

Patients with idiopathic pulmonary fibrosis often experience disabling nonproductive cough, for which we have no effective treatment. In this industry-sponsored, double-blind, crossover trial at Johns Hopkins, 24 such patients were …

We evaluated whether supplemental oxygen, used during routine daily activities, improves quality of life in patients with fibrotic interstitial lung disease (ILD). Study design: multicenter, randomized, cross-over controlled clinical trial (NCT02286063), evaluating quality of life during two weeks on ambulatory oxygen compared to two weeks off. Inclusion criteria: SaO2 ≥ 94% at rest, dropping to ≤88% on a 6MWT, stable symptoms during a 2 week run-in period. Primary outcome: health status assessed by KBILD questionnaire. Analysis: general linear model with the difference in health status as the dependent variable and treatment sequence as fixed effect. Patient views were explored through topic-guided interviews in a subgroup. <b>Results:</b> 41 patients randomised to ambulatory oxygen, 43 to no oxygen, crossing to the alternative arm after two weeks. Mean age 64.5±1.1 yrs, 58 males, 53 ever smokers, FVC 73.3±19.1%, DLCO 38.7±12.8%. 43 patients had possible/definite IPF. 76 patients completed the trial. Serious adverse events, equally distributed across arms, were not related to ambulatory oxygen usage. Ambulatory oxygen, compared to no oxygen, was associated with improvements in total KBILD score (difference: 3.7; p&lt;0.0001), breathlessness and activity domain (difference: 8.7; p&lt;0.0001), chest symptoms domain (difference: 7.6; p=0.009), but not psychological domain. Most patients reported symptom reduction and increased activity, but concerns were reported by some e.g. storage, dependency. <b>Conclusions:</b> the novel observation that ambulatory oxygen is associated with improved quality of life is expected to influence future ILD specific guidelines on ambulatory oxygen use.

RMT may improve lung capacity and respiratory muscle strength in some NMDs. In ALS there may not be any clinically meaningful effect of RMT on physical functioning or quality of life and it is uncertain whether it causes adverse effects. Due to clinical heterogeneity between the trials and the small number of participants included in the analysis, together with the risk of bias, these results must be interpreted very cautiously.

BackgroundThere are no approved therapies for cough in patients with idiopathic pulmonary fibrosis (IPF). In this small crossover trial we administered nalbuphine extended-release tablets (NAL ER) as a potential cough therapy for such patients.MethodsThis randomized, double-blind, placebo-controlled, crossover trial involved two 22-day treatment periods (NAL ER→placebo and placebo→NAL ER) separated by a 2-week washout period. NAL ER was started at a dose of 27 mg once daily and was titrated up to 162 mg twice daily at day 16. The primary end point was percent change from baseline in hourly daytime objective cough frequency as measured by an electronic cough monitor. The daytime period was defined as the patient-reported time of awakening and bedtime. Secondary end points included change in objective 24-hour cough frequency, changes in cough frequency, cough severity, and breathlessness, per patient-reported outcomes.ResultsA total of 41 patients were randomly assigned and received one or more doses of study medication. There was a 75.1% reduction in daytime objective cough frequency during the NAL ER treatment period versus the placebo treatment period of 22.6%, a 52.5 percentage point placebo-adjusted decrease from baseline (P<0.001) at day 21. There was a 76.1% (95% confidence interval, 83.1 to 69.1) decrease in the 24-hour objective cough frequency with NAL ER, versus a 25.3% (43.9 to 6.7) decrease with placebo, a 50.8 percentage point placebo-adjusted change. Nausea, fatigue, constipation, and dizziness were more common with NAL ER than with placebo.ConclusionsIn this short-term crossover trial, NAL ER reduced cough in individuals with IPF. Larger and longer trials are needed to assess the impact on cough versus drug adverse effects. (Funded by Trevi Therapeutics; ClinicalTrials.gov number, NCT04030026.)

RMT may improve lung capacity and respiratory muscle strength in some NMDs. In ALS there may not be any clinically meaningful effect of RMT on physical functioning or quality of life and it is uncertain whether it causes adverse effects. Due to clinical heterogeneity between the trials and the small number of participants included in the analysis, together with the risk of bias, these results must be interpreted very cautiously.

BackgroundThere are no ILD specific guidelines on the use of ambulatory oxygen. The AmbOx trial is a multicenter, randomised, cross-over controlled trial (NCT02286063), to assess quality of life during two...

BackgroundPatients with fibrotic interstitial lung disease (FILD) often experience gas exchange abnormalities and ventilatory limitations, resulting in reduced exercise capacity. High-flow nasal cannula (HFNC) oxygen therapy is a novel treatment, whose physiological beneficial effects have been demonstrated in various clinical settings. We hypothesized that HFNC oxygen therapy might be superior to conventional oxygen therapy for improving exercise capacity in FILD patients.MethodsWe performed a prospective randomized controlled crossover trial with a high-intensity constant work-rate endurance test (CWRET) using HFNC (50 L/min, FiO2 0.5) and a venturi mask (VM) (15 L/min, FiO2 0.5) for oxygen delivery in FILD patients. The primary outcome variable was endurance time. The secondary outcome variables were SpO2, heart rate, Borg scale (dyspnea and leg fatigue), and patient’s comfort.ResultsSeven hundred and eleven patients were screened and 20 eligible patients were randomized. All patients completed the trial. The majority of patients were good responders to VM and HFNC compared with the baseline test (VM 75%; HFNC 65%). There was no significant difference in endurance time between HFNC and VM (HFNC 6.8 [95% CI 4.3–9.3] min vs VM 7.6 [95% CI 5.0–10.1] min, p = 0.669). No significant differences were found in other secondary endpoints. Subgroup analysis with HFNC good responders revealed that HFNC significantly extended the endurance time compared with VM (VM 6.4 [95%CI 4.5–8.3] min vs HFNC 7.8 [95%CI 5.8–9.7] min, p = 0.046), while no similar effect was observed in the VM good responders.ConclusionsHFNC did not exceed the efficacy of VM on exercise capacity in FILD, but it may be beneficial if the settings match. Further large studies are needed to confirm these findings.Trial registrationUMIN-CTR: UMIN000021901.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive disease that leads to lung scarring. Cough is reported by 85% of patients with IPF and can be a distressing symptom with a significant impact on patients’ quality of life. There are no proven effective therapies for IPF-related cough. Whilst morphine is frequently used as a palliative agent for breathlessness in IPF, its effects on cough have never been tested. PAciFy Cough is a multicenter, double-blind, placebo-controlled, crossover trial of morphine sulphate for the treatment of cough in IPF.MethodsWe will recruit 44 subjects with IPF prospectively from three interstitial lung disease units in the UK, namely the Royal Brompton Hospital, Manchester University NHS Foundation Trust (MFT) and Aintree University Hospital NHS Foundation Trust. Patients will be randomised (1:1) to either placebo twice daily or morphine sulphate 5 mg twice daily for 14 days. They will then crossover after a 7-day washout period. The primary endpoint is the percent change in daytime cough frequency (coughs per hour) from baseline as assessed by objective cough monitoring at day 14 of treatment.DiscussionThis multicentre, randomised trial will assess the effect of opioids on cough counts and cough associated quality of life in IPF subjects. If proven to be an effective intervention, it represents a readily available treatment for patients.Trial registrationThe study was approved by the UK Medicines and Healthcare Regulatory Agency (Ref: CTA 21268/0224/001-0001 – EUDRACT 2019-003571-19 – Protocol Number RBH2019/001) on 08 April 2020, in compliance with the European Clinical Trials Directive and the Medicines for Human Use (Clinical Trials) Regulations 2004 and its subsequent amendments. The study was provided with ethical approval by the London Brent Research Ethics Committee (Ref: 20/LO/0368) on 21 May 2020 and is registered with clinicaltrials.gov (NCT04429516) on 12 June 2020, available at https://clinicaltrials.gov/ct2/show/NCT04429516

IntroductionIdiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease. The majority of patients with IPF report cough which is associated with significant negative physical, social and psychological consequences. At...

Introduction and ObjectivesCough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF). The efficacy and safety of inhaled PA101, a novel formulation of cromolyn sodium was investigated in IPF...

Patients with idiopathic pulmonary fibrosis (IPF) have reduced exercise capacity and often present exertional dyspnea and desaturation. The role of autonomic nervous system (ANS) as a pathogenetic contributor to this dysfunction has not been evaluated. To evaluate whether improvement of arterial oxygen saturation (SpO2 ) via oxygen supplementation results to ANS function improvement, during steady state submaximal exercise. This is a secondary analysis of a single-blind, randomized, placebo-controlled, cross-over trial, including 12 IPF patients, with isolated exertional desaturation. Following a maximal cardiopulmonary test, participants underwent two submaximal steady state tests during which they received either supplementary oxygen or medical air. Continuous beat-to-beat blood pressure measurements were recorded (Finapres Medical Systems, Amsterdam, The Netherlands). Autonomic function was assessed non-invasively by heart rate variability (HRV); root mean square of successive differences (RMSSD) and standard-deviation-Poincare-plot (SD1) were used as indices of parasympathetic output. Entropy and detrended fluctuation analysis (DFA) were also used. During rest, oxygen supplementation did not significantly alter RMSSD and SD1. During exercise, subjects presented no significant alterations compared with baseline, in most HRV indices examined. There was no improvement of this behavior with O2 -supplementation. Approximate-entropy increased during exercise, with no differences between protocols. IPF patients presented an inadequate adaptive response of their ANS to exercise and recovery. Although oxygen supplementation significantly prolonged exercise duration and prevented the substantial exertional desaturation, the blunted vagal response to steady-state exercise in these patients was not improved, suggesting that acute oxygen supplementation does not sufficiently improve ANS dysfunction in these patients.