Inhaled pirfenidone solution (AP01) for IPF: a randomised, open-label, dose-response trial.

INTRODUCTION: Oral pirfenidone reduces lung function decline and mortality in patients with idiopathic pulmonary fibrosis (IPF). Systemic exposure can have significant side effects, including nausea, rash, photosensitivity, weight loss and fatigue. Reduced doses may be suboptimal in slowing disease progression. METHODS: This phase 1b, randomised, open-label, dose-response trial at 25 sites in six countries (Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12618001838202) assessed safety, tolerability and efficacy of inhaled pirfenidone (AP01) in IPF. Patients diagnosed within 5 years, with forced vital capacity (FVC) 40%-90% predicted, and intolerant, unwilling or ineligible for oral pirfenidone or nintedanib were randomly assigned 1:1 to nebulised AP01 50 mg once per day or 100 mg two times per day for up to 72 weeks. RESULTS: We present results for week 24, the primary endpoint and week 48 for comparability with published trials of antifibrotics. Week 72 data will be reported as a separate analysis pooled with the ongoing open-label extension study. Ninety-one patients (50 mg once per day: n=46, 100 mg two times per day: n=45) were enrolled from May 2019 to April 2020. The most common treatment-related adverse events (frequency, % of patients) were all mild or moderate and included cough (14, 15.4%), rash (11, 12.1%), nausea (8, 8.8%), throat irritation (5, 5.5%), fatigue (4, 4.4%) and taste disorder, dizziness and dyspnoea (three each, 3.3%). Changes in FVC % predicted over 24 and 48 weeks, respectively, were -2.5 (95% CI -5.3 to 0.4, -88 mL) and -4.9 (-7.5 to -2.3,-188 mL) in the 50 mg once per day and 0.6 (-2.2 to 3.4, 10 mL) and -0.4 (-3.2 to 2.3, -34 mL) in the 100 mg two times per day group. DISCUSSION: Side effects commonly associated with oral pirfenidone in other clinical trials were less frequent with AP01. Mean FVC % predicted remained stable in the 100 mg two times per day group. Further study of AP01 is warranted. TRIAL REGISTRATION NUMBER: ACTRN12618001838202 Australian New Zealand Clinical Trials Registry.

The Prevalence of Bronchodilator Responsiveness "Asthma" Among Adult Indigenous Australians Referred for Lung Function Testing in the Top End Northern Territory of Australia.

Background: Among Indigenous Australians, studies examining the clinical significance of airway bronchodilator responsiveness (BDR) are limited. In this retrospective study, we examined the nature of underlying lung disease in adult Indigenous patients with BDR referred for lung function testing (LFT) in the Top End Health Service region of the Northern Territory of Australia. Methods: Presence or absence of BDR as per usual (FVC or FEV1 change pre to post ≥12% and ≥0.2L) and updated (2021 ">10% predicted) ATS/ERS criteria among Indigenous and non-Indigenous Australians was determined. The radiological findings in the Indigenous study participants with and without BDR were next assessed for the presence of underlying chronic airway/lung disease. Results: We found that 123/742 (17%) Indigenous and 578/4579 (13%) non-Indigenous patients had a significant BDR. Indigenous patients with BDR were younger (mean difference 7 years), with a greater proportion of females (52 vs 32%), underweight (15 vs 4%) and current smokers (52 vs 25%). Indigenous patients with BDR displayed lower LFT values, and a higher proportion exhibited FVC BDR compared to non-Indigenous (34 vs 20%). Almost half (46%) of Indigenous patients with BDR had evidence of COPD and/or bronchiectasis on radiology. Adjusting for the presence of radiologic or spirometric evidence of COPD, the presence of BDR was similar between Indigenous and non-Indigenous patients (5-8 vs 7-11%), irrespective of which BDR criteria was used. Conclusion: BDR was higher overall among Indigenous in comparison to non-Indigenous patients; however, a significant proportion of Indigenous patients demonstrating BDR had evidence of underlying COPD/bronchiectasis. This study highlights that although presence of BDR among Indigenous people may indicate asthma, it may also be observed among patients with COPD/bronchiectasis or could represent asthma/COPD/bronchiectasis overlap. Hence, a combination of clinical history, LFT and radiology should be considered for precise diagnosis of lung disease in this population.

Correction: Two-year efficacy of varenicline tartrate and counselling for inpatient smoking cessation (STOP study): A randomized controlled clinical trial.

[This corrects the article DOI: 10.1371/journal.pone.0231095.].

Interventions for tobacco use prevention in Indigenous youth.

This review has been withdrawn because it does it does not include recent evidence and does not reflect up-to-date Cochrane methodological standards.

Interventions for smoking cessation in Indigenous populations.

This review has been withdrawn because it does it does not include recent evidence and does not reflect up-to-date Cochrane methodological standards.

The efficacy and safety of varenicline alone versus in combination with nicotine lozenges for smoking cessation among hospitalised smokers (VANISH): study protocol for a randomised, placebo-controlled trial.

INTRODUCTION: Smoking is a leading cause of premature deaths globally. The health benefits of smoking cessation are many. However, majority of quit attempts are unsuccessful. One way to potentially improve success rates is to evaluate new combinations of existing smoking cessation therapies that may work synergistically to decrease the intensity of withdrawal symptoms and cravings. AIMS: To evaluate the feasibility, efficacy and safety of the combination of varenicline and nicotine replacement therapy (NRT) lozenges versus varenicline alone in assisting hospitalised smokers to quit. METHODS AND ANALYSIS: This is a multicentre, randomised, placebo-controlled trial. Adults with a history of smoking ≥10 cigarettes per day on average in the 4 weeks prior to their hospitalisation will be recruited. Participants will be randomly assigned to either the intervention group and will receive varenicline and NRT lozenges, or the control group and will receive varenicline and placebo lozenges. All participants will be actively referred to behavioural support from telephone Quitline. Participants are followed up at 1 and 3 weeks and 3, 6 and 12 months from the start of treatment. The primary outcome is carbon monoxide validated prolonged abstinence from 2 weeks to 6 months after treatment initiation. Secondary outcomes include self-reported and biochemically validated prolonged and point prevalence abstinence at 3, 6 and 12 months, self-reported adverse events, withdrawal symptoms and cravings, adherence to treatment, Quitline sessions attended and others. According to the Russell Standard, all randomised participants will be accounted for in the primary intention-to-treat analysis. ETHICS AND DISSEMINATION: The trial will be conducted in compliance with the protocol, the principles of Good Clinical Practice, the National Health and Medical Research Council National Statement on Ethical Conduct in Human Research (updated 2015) and the Australian Code for the Responsible Conduct of Research (2018). Approval will be sought from the Human Ethics Committees of all the participating hospitals and the university. Written informed consent will be obtained from each participant at the time of recruitment. TRIAL REGISTRATION NUMBER: Australia New Zealand Clinical Trials Registry (ACTRN12618001792213).

Two-year efficacy of varenicline tartrate and counselling for inpatient smoking cessation (STOP study): A randomized controlled clinical trial.

INTRODUCTION: Varenicline tartrate is superior for smoking cessation to other tobacco cessation therapies by 52 weeks, in the outpatient setting. We aimed to evaluate the long-term (104 week) efficacy following a standard course of inpatient-initiated varenicline tartrate plus Quitline-counselling compared to Quitline-counselling alone. METHODS: Adult patients (n = 392, 20-75 years) admitted with a smoking-related illnesses to one of three hospitals, were randomised to receive either 12-weeks of varenicline tartrate (titrated from 0.5mg daily to 1mg twice-daily) plus Quitline-counselling, (n = 196) or Quitline-counselling alone, (n = 196), with continuous abstinence from smoking assessed at 104 weeks. RESULTS: A total of 1959 potential participants were screened for eligibility between August 2008 and December 2011. The proportion of participants who remained continuously abstinent (intention-to-treat) at 104 weeks were significantly greater in the varenicline tartrate plus counselling arm (29.2% n = 56) compared to counselling alone (18.8% n = 36; p = 0.02; odds ratio 1.78; 95%CI 1.10 to 2.86, p = 0.02). Twenty-two deaths occurred during the 104 week study (n = 10 for varenicline tartrate plus counselling and n = 12 for Quitline-counselling alone). All of these participants had known or developed underlying co-morbidities. CONCLUSIONS: This is the first study to examine the efficacy and safety of varenicline tartrate over 104 weeks within any setting. Varenicline tartrate plus Quitline-counselling was found to be an effective opportunistic treatment when initiated for inpatient smokers who had been admitted with tobacco-related disease.

Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4).

Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials. Patients received tiotropium+olodaterol FDC 2.5/5 µg or 5/5 µg, tiotropium 2.5 µg or 5 µg, or olodaterol 5 µg delivered once-daily via Respimat inhaler over 52 weeks. Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks. In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment. Both FDCs significantly improved FEV1 AUC0-3 and trough FEV1 response versus the mono-components in both studies. Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 µg. Incidence of adverse events was comparable between the FDCs and the mono-components. These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD.

Safety of varenicline tartrate and counseling versus counseling alone for smoking cessation: a randomized controlled trial for inpatients (STOP study).

INTRODUCTION: Inpatient medical settings offer an opportunistic environment for initiating smoking cessation interventions to patients reflecting on their health. Current evidence has shown the superior efficacy of varenicline tartrate (VT) for smoking cessation compared with other tobacco cessation therapies; however, recent evidence also has highlighted concerns about the safety and tolerability of VT. Given these apprehensions, we aimed to evaluate the safety and effectiveness of VT plus quitline-counseling compared to quitline-counseling alone in the inpatient medical setting. METHODS: Adult patients (n = 392, 20-75 years) admitted with a smoking-related illnesses to 3 hospitals were randomized to receive either 12 weeks of varenicline tartrate (titrated from 0.5mg daily to 1mg twice daily) plus quitline-counseling (VT+C), (n = 196) or quitline-counseling alone (n = 196). RESULTS: VT was well tolerated in the inpatient setting among subjects admitted with acute smoking-related illnesses (mean age 52.8±2.89 and 53.7±2.77 years in the VT+C and counseling alone groups, respectively). The most common self-reported adverse event during the 12-week treatment phase was nausea (16.3% in the VT+C group compared with 1.5% in the counseling alone group). Thirteen deaths occurred during the study period (n = 6 were in the VT+C arm compared with n = 7 in the counseling alone arm). All of these subjects had known comorbidities or developed underlying comorbidities. CONCLUSIONS: VT appears to be a safe and well-tolerated opportunistic treatment for inpatient smokers who have related chronic disease. Based on the proven efficacy of varenicline from outpatient studies and our recent inpatient evidence, we suggest it be considered as part of standard care in the hospital setting.

Smoking Termination Opportunity for inPatients (STOP): superiority of a course of varenicline tartrate plus counselling over counselling alone for smoking cessation: a 12-month randomised controlled trial for inpatients.

RATIONALE: Smoking cessation interventions in outpatient settings have been demonstrated to be cost effective. Given this evidence, we aimed to evaluate the effectiveness of varenicline tartrate plus Quitline-counselling compared with Quitline-counselling alone when initiated in the inpatient setting. METHODS: Adult patients (18-75 years) admitted with a smoking-related illness to three hospitals, were randomised to receive either 12-weeks of varenicline tartrate plus Quitline-counselling, (n=196) or Quitline-counselling alone, (n=196), with 12-months follow-up. RESULTS: For the primary analysis population (intention-to-treat), the proportion of subjects who remained continuously abstinent were significantly greater in the varenicline plus counselling arm (31.1%, n=61) compared with counselling alone (21.4%, n=42; RR 1.45, 95% CI 1.03 to 2.03, p=0.03). CONCLUSIONS: The combined use of varenicline plus counselling when initiated in the inpatient setting has produced a sustained smoking cessation benefit at 12-months follow-up, indicating a successful opportunistic treatment for smokers admitted with smoking related illnesses. TRIAL REGISTRATION: http://www.clinicaltrials.gov/ ClinicalTrials.gov identification number: NCT01141855.

Interventions for tobacco use prevention in Indigenous youth.

BACKGROUND: Tobacco use in Indigenous populations (people who have inhabited a country for thousands of years) is often double that in the non-Indigenous population. Addiction to nicotine usually begins during early adolescence and young people who reach the age of 18 as non-smokers are unlikely to become smokers thereafter. Indigenous youth in particular commence smoking at an early age, and a disproportionate burden of substance-related morbidity and mortality exists as a result. OBJECTIVES: To evaluate the effectiveness of intervention programmes to prevent tobacco use initiation or progression to regular smoking amongst young Indigenous populations and to summarise these approaches for future prevention programmes and research. SEARCH METHODS: The Cochrane Tobacco Addiction Group Specialised Register was searched in November 2011, with additional searches run in MEDLINE. Online clinical trial databases and publication references were also searched for potential studies. SELECTION CRITERIA: We included randomized and non-randomized controlled trials aiming to prevent tobacco use initiation or progression from experimentation to regular tobacco use in Indigenous youth. Interventions could include school-based initiatives, mass media, multi-component community level interventions, family-based programmes or public policy. DATA COLLECTION AND ANALYSIS: Data pertaining to methodology, participants, interventions and outcomes were extracted by one reviewer and checked by a second, whilst information on risk of bias was extracted independently by a combination of two reviewers. Studies were assessed by qualitative narrative synthesis, as insufficient data were available to conduct a meta-analysis. The review process was examined by an Indigenous (Aboriginal) Australian for applicability, acceptability and content. MAIN RESULTS: Two studies met all of the eligibility criteria for inclusion within the review and a third was identified as ongoing. The two included studies employed multi-component community-based interventions tailored to the specific cultural aspects of the population and were based in Native American populations (1505 subjects in total). No difference was observed in weekly smoking at 42 months follow-up in the one study assessing this outcome (skills-community group versus control: risk ratio [RR] 0.95, 95% CI 0.78 to 1.14; skills-only group versus control: RR 0.86, 95% CI 0.71 to 1.05). For smokeless tobacco use, no difference was found between the skills-community arm and the control group at 42 weeks (RR 0.93, 95% CI 0.67 to 1.30), though a significant difference was observed between the skills-only arm and the control group (RR 0.57, 95% CI 0.39 to 0.85). Whilst the second study found positive changes for tobacco use in the intervention arm at post test (p < 0.05), this was not maintained at six month follow-up (change score -0.11 for intervention and 0.07 for control). Both studies were rated as high or unclear risk of bias in seven or more domains (out of a total of 10). AUTHORS' CONCLUSIONS: Based on the available evidence, a conclusion cannot be drawn as to the efficacy of tobacco prevention initiatives tailored for Indigenous youth. This review highlights the paucity of data and the need for more research in this area. Smoking prevalence in Indigenous youth is twice that of the non-Indigenous population, with tobacco experimentation commencing at an early age. As such, a significant health disparity exists where Indigenous populations, a minority, are over-represented in the burden of smoking-related morbidity and mortality. Methodologically rigorous trials are needed to investigate interventions aimed at preventing the uptake of tobacco use amongst Indigenous youth and to assist in bridging the gap between tobacco-related health disparities in Indigenous and non-Indigenous populations.

Interventions for smoking cessation in Indigenous populations.

BACKGROUND: Tobacco use in Indigenous populations (people who have inhabited a country for thousands of years) is often double that of the non-Indigenous population. A disproportionate burden of substance-related morbidity and mortality exists as a result. OBJECTIVES: To evaluate the effectiveness of smoking cessation interventions in Indigenous populations and to summarise these approaches for future cessation programmes and research. SEARCH METHODS: The Cochrane Tobacco Addiction Group Specialised Register of Trials was searched (April 2011), with additional searches of MEDLINE (May 2011). Online clinical trial databases and publication references were also searched for potential studies. SELECTION CRITERIA: We included randomized and non-randomized controlled trials for smoking cessation interventions in Indigenous populations. Interventions could include pharmacotherapies, cognitive and behavioural therapies, alternative therapies, public policy and combination therapies. No attempts were made to re-define Indigenous status for the purpose of including a study in this review. DATA COLLECTION AND ANALYSIS: Data pertaining to methodology, participants, interventions and outcomes were extracted by one reviewer and checked by a second, whilst methodological quality was extracted independently by two reviewers. Studies were assessed by qualitative narrative synthesis and where possible meta-analysis. The review process was examined by an Indigenous (Aboriginal) Australian for applicability, acceptability and content. MAIN RESULTS: Four studies met all of the eligibility criteria for inclusion within the review. Two used combination therapies consisting of a pharmacotherapy combined with cognitive and behavioural therapies, whilst the remaining two used cognitive and behavioural therapy through counselling, one via text message support and the other delivered via clinic doctors trained in smoking cessation techniques. Smoking cessation data were pooled across all studies producing a statistically and clinically significant effect in favour of the intervention (risk ratio 1.43, 95%CI 1.03 to 1.98, p=0.032), however following sensitivity analysis a statistically non-significant but clinically significant effect was observed in favour of the intervention (risk ratio 1.33, 95%CI 0.95 to 1.85, p=NS) . AUTHORS' CONCLUSIONS: A significant health disparity exists, whereby Indigenous populations, a minority, are over-represented in the burden of smoking-related morbidity and mortality. This review highlights the paucity of evidence available to evaluate the effectiveness of smoking cessation interventions, despite the known success of these interventions in non-Indigenous populations. Due to this lack of published investigations, the external validity of this review is limited, as is the ability to draw reliable conclusions from the results. The limited but available evidence reported does indicate that smoking cessation interventions specifically targeted at Indigenous populations can produce smoking abstinence. However this evidence base is not strong with a small number of methodologically sound trials investigating these interventions. More rigorous trials are now required to assist in bridging the gap between tobacco related health disparities in Indigenous and non-Indigenous populations.

Providing reviews of evidence to COPD patients: qualitative study of barriers and facilitating factors to patient-mediated practice change.

This study aimed to identify barriers and facilitating factors to people with COPD performing the following actions: (a) reading a manual that contained summaries of evidence on treatments used in chronic obstructive pulmonary disease (COPD) and (b) at a medical consultation, asking questions that were provided in the manual and were designed to prompt doctors to review current treatments in the light of evidence. The manual was developed using current best practice and was designed to facilitate reading and discussion with doctors. In-depth interviews were held with patients who had received the manual. Of 125 intervention participants from a controlled clinical trial of the manual, 16 were interviewed in their homes in and around Adelaide, South Australia. Plain language writing and a simple layout facilitated reading of the manual by participants. Where the content matched the interests of participants this also facilitated reading. On the other hand, some participants showed limited interest in the evidence summaries. Participant comments indicated that they did not see it as possible or acceptable for patients to master research evidence or initiate discussions of evidence with doctors. These appeared to be the main barriers to effectiveness of the manual. If evidence summaries for patients are to be used in disease management, they should be understandable and relevant to patients and provide a basis for discussion between patients and doctors. Work is now needed so that we can both present evidence summaries in a way that is relevant to patients and reduce the barriers to patient-initiated discussions of evidence.

Patient education programs--can they improve outcomes in COPD?

It is important to assess the effectiveness of patient education programs for people with COPD (chronic obstructive pulmonary disease) to ensure that limited health resources are being spent effectively. We aimed to assess the effectiveness of programs reported to date, and to look for ways of designing more effective programs. COPD patient education to date has produced little demonstrated success, but studies, education programs and study reports all show limitations. To demonstrate links between outcomes and patient education program components, there is a need for more trials which combine process and outcome evaluation. Programs to date have relied too heavily on the provision of medical information to patients. Programs which also aim to improve disease management self-efficacy hold promise but further determinants of health behavior should be included also, as part of more systematic program design. Program components need to be clearly described and the rationale for their use justified in trial reports. This will produce an evidence base that should show what role education programs can play in improving outcomes, and inform the development of more effective programs.