Cost-utility of cytisine for smoking cessation over and above behavioural support in people with newly diagnosed pulmonary tuberculosis: an economic evaluation of a multicentre randomised controlled trial.

OBJECTIVES: To assess the cost-effectiveness of cytisine over and above brief behavioural support (BS) for smoking cessation among patients who are newly diagnosed with pulmonary tuberculosis (TB) in low-income and middle-income countries. DESIGN: An incremental cost-utility analysis was undertaken alongside a 12-month, double-blind, two-arm, individually randomised controlled trial from a public/voluntary healthcare sector perspective with the primary endpoint at 6 months post randomisation. SETTING: Seventeen subdistrict hospitals in Bangladesh and 15 secondary care hospitals in Pakistan. PARTICIPANTS: Adults (aged ≥18 years in Bangladesh and ≥15 years in Pakistan) with pulmonary TB diagnosed within the last 4 weeks who smoked tobacco daily (n=2472). INTERVENTIONS: Two brief BS sessions with a trained TB health worker were offered to all participants. Participants in the intervention arm (n=1239) were given cytisine (25-day course) while those in the control arm (n=1233) were given placebo. No significant difference was found between arms in 6-month abstinence. PRIMARY AND SECONDARY OUTCOME MEASURES: Costs of cytisine and BS sessions were estimated based on research team records. TB treatment costs were estimated based on TB registry records. Additional smoking cessation and healthcare costs and EQ-5D-5L data were collected at baseline, 6-month and 12-month follow-ups. Costs were presented in purchasing power parity (PPP) adjusted US dollars (US$). Quality-adjusted life years (QALYs) were derived from the EQ-5D-5L. Incremental total costs and incremental QALYs were estimated using regressions adjusting for respective baseline values and other baseline covariates. Uncertainty was assessed using bootstrapping. RESULTS: Mean total costs were PPP US$57.74 (95% CI 49.40 to 83.36) higher in the cytisine arm than in the placebo arm while the mean QALYs were -0.001 (95% CI -0.004 to 0.002) lower over 6 months. The cytisine arm was dominated by the placebo arm. CONCLUSIONS: Cytisine plus BS for smoking cessation among patients with TB was not cost-effective compared with placebo plus BS. TRIAL REGISTRATION NUMBER: ISRCTN43811467.

Cytisine for smoking cessation in patients with tuberculosis: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Smoking cessation is important in patients with tuberculosis because it can reduce the high rates of treatment failure and mortality. We aimed to assess the effectiveness and safety of cystine as a smoking cessation aid in patients with tuberculosis in Bangladesh and Pakistan. METHODS: We did a randomised, double-blind, placebo-controlled, trial at 32 health centres in Bangladesh and Pakistan. Eligible patients were adults (aged >18 years in Bangladesh; aged >15 years in Pakistan) with pulmonary tuberculosis diagnosed in the previous 4 weeks, who smoked tobacco on a daily basis and were willing to stop smoking. Patients were randomly assigned (1:1) to receive behavioural support plus either oral cytisine (9 mg on day 0, which was gradually reduced to 1·5 mg by day 25) or placebo for 25 days. Randomisation was done using pregenerated block randomisation lists, stratified by trial sites. Investigators, clinicians, and patients were masked to treatment allocation. The primary outcome was continuous abstinence at 6 months, defined as self-report (of not having used more than five cigarettes, bidis, a water pipe, or smokeless tobacco products since the quit date), confirmed biochemically by a breath carbon monoxide reading of less than 10 parts per million. Primary and safety analysis were done in the intention-to-treat population. This trial is registered with the International Standard Randomised Clinical Trial Registry, ISRCTN43811467, and enrolment is complete. FINDINGS: Between June 6, 2017, and April 30, 2018, 2472 patients (1527 patients from Bangladesh; 945 patients from Pakistan) were enrolled and randomly assigned to receive cytisine (n=1239) or placebo (n=1233). At 6 months, 401 (32·4%) participants in the cytisine group and 366 (29·7%) participants in the placebo group had achieved continuous abstinence (risk difference 2·68%, 95% CI -0·96 to 6·33; relative risk 1·09, 95% CI 0·97 to 1·23, p=0·114). 53 (4·3%) of 1239 participants in the cytisine group and 46 (3·7%) of 1233 participants in the placebo group reported serious adverse events (94 events in the cytisine group and 90 events in the placebo group), which included 91 deaths (49 in the cytisine group and 42 in the placebo group). None of the adverse events were attributed to the study medication. INTERPRETATION: Our findings do not support the addition of cytisine to brief behavioural support for the treatment of tobacco dependence in patients with tuberculosis. FUNDING: European Union Horizon 2020 and Health Data Research UK. TRANSLATIONS: For the Bengali and Urdu translations of the abstract see Supplementary Materials section.

Smoking prevalence among tuberculosis patients: A crosssectional study in Bangladesh and Pakistan.

INTRODUCTION: Smoking has a negative impact on TB outcomes. We estimated the proportion of TB patients who smoke and are willing to quit in two high TB burden countries, Bangladesh and Pakistan. METHODS: A cross-sectional survey was conducted among TB patients to assess their eligibility and recruit them to a smoking cessation randomized controlled trial. Adults diagnosed with TB were recruited from 32 health facilities in Bangladesh and Pakistan. Data on smoking behaviour and willingness to quit were collected and analysed. RESULTS: In total, 13934 TB patients completed the survey between June 2017 and April 2018. The prevalence of smoking in these TB patients was estimated to be 22.5% (95% CI: 21.8, 23.2). Moreover, the prevalence of smoking in TB patient population was 8% (RR=1.49; 95% CI: 7.1-8.9; p<0.01) and 8.3% (RR=1.24; 95% CI: 7.3-9.4; p<0.01) higher than smoking prevalence in the general population in Bangladesh and Pakistan, respectively. Among TB patients who smoke, 97.7% (95% CI: 97.2-98.2) were willing to quit. CONCLUSIONS: The estimated prevalence of smoking was higher in TB patients than the general population; however, a vast majority of TB patients who smoke were willing to quit.

Health worker and patient views on implementation of smoking cessation in routine tuberculosis care.

Smoking worsens tuberculosis (TB) outcomes. Persons with TB who smoke can benefit from smoking cessation. We report findings of a multi-country qualitative process evaluation assessing barriers and facilitators to implementation of smoking cessation behaviour support in TB clinics in Bangladesh and Pakistan. We conducted semi-structured qualitative interviews at five case study clinics with 35 patients and 8 health workers over a period of 11 months (2017-2018) at different time points during the intervention implementation phase. Interviews were conducted by trained researchers in the native languages, audio-recorded, transcribed into English and analysed using a combined deductive-inductive approach guided by the Consolidated Framework for Implementation Research and Theoretical Domains Framework. All patients report willingness to quit smoking and recent quit attempts. Individuals' main motivations to quit are their health and the need to financially provide for a family. Behavioural regulation such as avoiding exposure to cigarettes and social influences from friends, family and colleagues are main themes of the interviews. Most male patients do not feel shy admitting to smoking, for the sole female patient interviewee stigma was an issue. Health workers report structural characteristics such as high workload and limited time per patient as primary barriers to offering behavioural support. Self-efficacy to discuss tobacco use with women varies by health worker. Systemic barriers to implementation such as staff workload and socio-cultural barriers to cessation like gender relations, stigma or social influences should be dealt with creatively to optimize the behaviour support for sustainability and scale-up.

Varenicline versus placebo for waterpipe smoking cessation: a double-blind randomized controlled trial.

BACKGROUND AND AIMS: Waterpipe tobacco smoking is a growing public health concern. There is limited research using pharmacotherapy and no research using varenicline (established treatment for smoking cessation) in waterpipe smokers. We tested the efficacy of varenicline in achieving abstinence from all tobacco use among waterpipe smokers. DESIGN: Two-arm, parallel group, placebo-controlled, double-blind, multi-centre (n = 4), individually randomized trial with follow-up to 25 weeks. SETTINGS: District general hospitals and catchment communities within four districts of Punjab, Pakistan. PARTICIPANTS: Adult daily waterpipe smokers (n = 510; 253 in varenicline and 257 in placebo arms), who were interested in quitting, were recruited and analysed between March and November 2016. Of these, 220 (87%) in the varenicline and 239 (93%) in the placebo arms completed all follow-ups. Participants were on average aged 49 [standard deviation (SD) = 15.2] years, daily smokers and smoked for the last 27 (SD = 15.9) years. More than half (261, 51.2%) also smoked cigarettes. INTERVENTION AND COMPARATOR: All trial participants received two structured sessions of behavioural support (of 30 and 10 minutes) one at the time of registration and the other 1 week later. Participants were randomized to varenicline (active arm) and placebo (control arm) stratified on district, sex and concomitant cigarette smoking. Varenicline and placebo were dispensed as identical unlabelled tablets for 12 weeks: 0.5 mg for 1 week (once on days 1-3, twice on days 4-7) and 1 mg for the subsequent 11 weeks (twice daily). MEASUREMENTS: The trial participants were followed-up for a period of 25 weeks post-randomization. The primary outcome was 7-day repeated point prevalence abstinence from all forms of tobacco, self-reported at each of weeks 5, 12 and 25, verified by carbon-monoxide cut-off < 10 parts per million. FINDINGS: No evidence of statistically significant difference in repeated point prevalence abstinence between the varenicline (12 of 253; 4.7%) and placebo (11 of 257; 4.3%) arms (relative risk = 1.11, 95% confidence interval = 0.50-2.47, P = 0.80) was observed (Bayes factor = 0.048). Adverse events reported in 27 participants were 34 (15 in varenicline and 19 in placebo); none was serious. CONCLUSIONS: Varenicline was not more effective than placebo in aiding cessation of tobacco use in long-term daily waterpipe smokers.

The efficacy of varenicline in achieving abstinence among waterpipe tobacco smokers - study protocol for a randomized controlled trial.

BACKGROUND: Waterpipe tobacco smoking has increased among youth across the globe including in the US, and it continues as a common and traditional form of smoking tobacco in Pakistan. A range of behavioral and pharmacological therapies are available to support people in quitting cigarette smoking; however, little evidence exists for the efficacy of these therapies in achieving abstinence among waterpipe tobacco smokers. The objective of this study is to assess the efficacy of varenicline when added to behavioral support for waterpipe tobacco smoking cessation, by measuring biochemically validated continuous abstinence in waterpipe tobacco smokers. METHODS/DESIGN: This is a two-arm, double-blind, placebo-controlled randomized trial conducted in four districts in Punjab, Pakistan. Study participants include adults using a waterpipe (with or without concomitant cigarette, bidi or other forms of tobacco smoking) on a daily basis for at least 6 months and who are willing to quit. We will individually randomize 510 participants to one of the two arms of the trial. Participants in the intervention arm will receive varenicline and behavioral support and those in the control arm will receive placebo and behavioral support. The primary outcome will be continuous abstinence for at least 6 months (week 25) which is biochemically verified by a carbon monoxide level of <10 ppm. Secondary outcomes will include biochemically verified 7-day point abstinence at 5, 12 and 25 weeks and any lapses and relapses between the different assessment points. Tertiary outcomes will include assessment of withdrawal symptoms using the Mood and Physical Symptoms Scale (MPSS), smoking dependency using the Lebanon Waterpipe Dependency Scale (LWDS-11) and monitoring adverse outcomes. DISCUSSION: This is an efficacy trial and would require a subsequent effectiveness trial for a definitive evaluation of the intervention. TRIAL REGISTRATION: ISRCTN, ISRCTN94103375 . Registered on 1 December 2015.

TB patients learning about second hand smoke (TBLASS): a pilot individual randomised controlled trial.

BACKGROUND: Living with a smoker is a key determinant of exposure to Second Hand Smoke (SHS) and its exposure mainly occurs at home. Exposure to SHS from tobacco in the household predisposes to the development of tuberculosis (TB) and outcome of the disease gets worse. We aim to develop and evaluate a behavioural intervention 'Smoke Free Homes' (SFH) for TB patients that encourages them to negotiate a smoke free environment within their homes. METHODS AND DESIGN: The pilot individual randomised controlled trial of SFH will inform the design of a future definitive trial. We will first develop SFH intervention using taxonomy of behaviour change techniques aimed at encouraging families of non-smoking TB patients to implement smoking restrictions at home following a logic model of the intervention. This will be followed by conducting a pilot randomised controlled trial of intervention within the context of routine TB control programme. The eligible non-smoking TB patients will be randomised and allocated to one of the two trial arms consisting of "individual based care" and "individual based care" plus "supplementary support". We aim to recruit 150 newly registered pulmonary TB patients from two selected TB centres with 75 cases in each arm. The Primary outcome measure will be SFH of non-smoker TB patient by validating through 'Urine Cotinine' test. We will also determine qualitatively the barriers and key drivers to the creation of smoke free homes followed by developing a definitive trial. DISCUSSION: The male to female distribution of TB cases in Pakistan is almost equal whereas, tobacco use among males is much high as compared to females in Pakistan. This reflects a strong possibility that women health can be affected by men behaviour. Appropriate storage, restricted access and disposal arrangements for participant's personal details will be implemented. All ethical issues will be addressed. There will be no extra burden, financial or otherwise, on the participants. They will not receive any financial incentive to participate in the study. TRIAL REGISTRATION NUMBER: ISRCTN83630841.