INTRODUCTION

LMICs bear an inexplicably larger share of the burden of tobacco-related death globally due to rising tobacco consumption [1-3]. A survey conducted in 82 LMICs highlighted that the weighted mean current smoking prevalence was 16.5% which was seen as higher among men as compared to women. The prevalence of smoking tobacco varied among these countries ranging from 1.1% in Ghana to 50.6% in Kiribati [4]. Moreover, approximately 2.1 million users of e-cigarettes reside in low-income countries and 7.8 million in lower-middle-income countries [5].  To reduce the consequences of tobacco-related morbidity and mortality, policymakers should give prime importance to tobacco smoking cessation interventions [6]. Major differences in the prevalence and products use among high and low-income countries have been witnessed which require further research for identifying effective tobacco cessation strategies [1, 7]. Due to the high prevalence of tobacco use, LMICs are adapting successful tobacco cessation interventions from high-income nations for replication according to their local context [8]. However, due to diverse cultures and inadequate infrastructure in LMICs, the effectiveness of these investigations is still unclear [9]. Due to the rising incidence of tobacco use in LMICs and its associated challenges, it is necessary to support smoking cessation by conducting clinical trials in these countries.

Although many studies such as observational and quasi-experimental, have been conducted on quitting smoking in LMICs, limited tobacco cessation randomized controlled trials (RCTs) are found in these countries [1]. A comprehensive scoping review highlighted ninety-two tobacco cessation RCTs conducted in 16 of 138 LMICs countries including India (n = 26, 28 %), China (n = 17, 18%), Thailand (n = 9, 10%) followed by other nations (n = 40, 44 %). Of these total RCTs, different types of intervention used were: psychosocial (n = 52, 57 %), psychosocial/ behavioral (n = 20, 21%), pharmacological/ behavioral (n = 9, 10%), pharmacological (n = 8, 9%) and behavioral (n =3, 3%). Moreover, 65 % of the interventions targeted generic smokers. Six studies were conducted in Pakistan with 83% being psychosocial/pharmacological and 17 % psychosocial interventions. It was observed that except for psychosocial RCTs in China, the quality of evidence was largely not strong as compared to high-income countries, and RCTs were limited across all LMICs, in comparison to the large tobacco mortality burden in the region [1]. Activities by the tobacco industry [10], apparent patient reluctance to tobacco cessation [11], inadequate awareness regarding pharmacological treatments [12], and ineffective government policy [13] were found as the main factors hindering the conduction of tobacco cessation RCTs in LMICs. Moreover, the conducted RCTs around LMIC tobacco cessation were found inclined towards psychosocial interventions with limited focus on behavioral and pharmacological alternatives. The findings of the review also highlighted that despite the availability of weak evidence for RCTs conducted in LMICs, tobacco cessation in these countries is still not considered a setting where best practice has been established, therefore, specific solutions befitting the local context of LMICs is vital for effective tobacco control in these countries [1]. Although, few RCTs conducted in LMICs were found which evaluated the efficacy of THR products including NRT and e-cigarettes [14] but their findings were not conclusive as either it was a pilot trial [15] or focused on only male smokers [14] and the results could not be generalizable to other populations highlighting the need of conduction of more RCTs on assessment of the efficacy of Tobacco Harm Reduction (THR) products including e-cigarettes as well as other NRTs. The RCTs conducted in LMICs indicate that most of the studies were conducted using nicotine patches while only a single study was found on Korean male smokers using e-cigarettes. Despite of the inherent issues linked with RCTs including the overgeneralization of result, small samples [16], validity, and reliability [17], clinical trials are still the most reliable approach to evaluate an intervention. Tobacco cessation RCTs seem to be the most effective clinical studies to evaluate tobacco control activities [18]. Taking into account the above gaps identified by various studies conducted in LMICs, understanding and conducting RCTs in context to LMICs is mandatory in order to use THR products as an effective smoking cessation strategy for controlling rising tobacco consumption in these countries.  Hence, this is the first RCT that has been designed to evaluate the effectiveness of different THR products in the general adult population in LMIC.

MATERIALS AND METHODS

Study Design

The trial is a two-arm, parallel randomized controlled trial with a 12 weeks treatment duration and long-term 52 weeks follow-up. A schematic diagram of the trial design is given in Figure 1.

Primary and Secondary Outcomes

The primary outcome measures for the study will be:

• Point Prevalence Abstinence: The number of participants self-reported abstinence in the past week, with biochemical validation using exhaled carbon monoxide ≤10 parts per million.

The below-mentioned secondary outcomes will be assessed on the day of quitting, treatment, and follow-up visits:

• Seven-day Point Prevalence: Number of participants self-reporting for not smoking cigarettes during the last 7 days
• Use of Combustible Cigarettes: The number of cigarettes smoked per day was assessed using self-reported diaries
• Perceptions Regarding the Product: Views of participants on the use of EC or patches using a modified cigarette evaluation questionnaire. Twelve questions are used to quantify perceptions of the product. The score can range from -6 to +6; increasing positive scores refer to a high dose producing an effect with greater intensity.
• Adverse Events: The Naranjo Adverse Drug Reaction Probability Scale will be used to analyze adverse events associated with nicotine patches and EC. Overall scores can vary from -4 to +13, with higher values indicating definite adverse drug reactions.
• Withdrawal Signs and Symptoms and Dependence: Fagerstrom test for nicotine dependence will be used to assess signs and symptoms of withdrawal and dependence. It has six components that assess smoking frequency, dependence, and amount of use. The items are added up to produce a final score between 0 and 10. A higher score indicates severe physical dependence on nicotine.

Ethics and Dissemination

The Declaration of Helsinki, the Good Clinical Practice Guidelines of the International Conference on Harmonization, Good Pharmacoepidemiology Practices Guidelines, and/or any applicable laws governing RCTs will be followed in the conduct of the study. Before the start of the study, informed consent was collected from all the respondents.

Study Population

Adults who smoke tobacco cigarettes among the general population in LMICs and have the motivation to quit will be included in the study.

Inclusion and Exclusion Criteria

Both genders of the legal age allowed for smoking as per country law, regular smokers of only combustible cigarettes (smoked at least ten cigarettes a day for the past year), exhaled breath eCO level > ten ppm, wish to quit smoking, having a mobile phone, able to conform with all study procedures and expected to be available for follow up will be enrolled as study participants. However, pregnant or nursing women, anyone taking any other NRT and/or enrolled in any other smoking cessation program/RCT, having any contraindications to products such as cardiovascular history and/or suffering from a major illness with a prognosis of less than 1 year will be excluded.

Recruitment and Randomization

Outpatient clinics and advertisements will be used for the recruitment of participants and directed to contact the trial site by phone, email, or through the study website. The process of consent will include two steps involving permission from respondents for (1) screening and (2) randomization. If the participant agrees he/she will be invited to the trial site for the zero visit i.e., screening and signing a consent form. The trial site will complete the process of identification and recruitment of all study participants within two months from the first recruitment. The respondents will be verified by the study coordinator according to the inclusion criteria checklist and will be screened. After this, baseline information will be gathered and eligible respondents who agree to participate will be randomly assigned (1:1) to one of the study arms i.e. Study Arm A: Nicotine E-Cigarettes and Study Arm B: Nicotine patches. A web-based application will be used to issue a computer-generated sequence for randomization by the principal investigator.

Treatment Regimens

Participants randomized to Study Arm A will be provided nicotine cartridges (18 mg/ml) and EC devices supply to last till the next in-person visit. One week before their designated quit date, ad libitum use will be advised to the participants to become familiar and on the quit date participants will switch to using e-cigarettes for the next twelve weeks. The 18 mg EC strength is considered an adequate substitute for smokers who smoke at least ten cigarettes/per day and is used in most of the trials [15].

On the other hand, participants randomized to study arm B will be provided a 21 mg nicotine patches supply to last till the next in-person visit. On their allocated quit day, the participants will stop smoking and use one nicotine patch daily for the next twelve weeks. The 21 mg nicotine patch strength is considered a suitable substitute for smokers who smoke at least ten cigarettes/day and is used in most of the trials [19-22].

Study Visits and Procedures

Participants will be scheduled for a screening visit as well as a baseline (BL) visit at the trial site. The participants will be scheduled for eight study visits in total, including five treatment sessions and three follow-up visits, using a mixed-mode method that includes interaction with the respondents through telephone calls as well as face-to-face at the trial site. The eight study visits will be scheduled at weeks 1, 2, 4, 8, 12, 18, 24, and 52. A detailed description of the schedule of study visits is given in Table 1.