Effects of Unfiltered Cigarettes on Smoking Behavior and Toxicant Exposure: Protocol for a Randomized Crossover Clinical Trial

Background Plastic filters on cigarette butts are a widespread source of nonbiodegradable, toxic environmental waste. State and local legislation to ban the sale of single-use cigarettes may be considered to prevent this waste, but scientific evidence on the impact of switching smokers to unfiltered cigarettes on smoking behavior and toxicant exposures is needed to inform this policy. We have designed an open-label, randomized, 9-week, crossover clinical trial of adult filtered-cigarette smokers who switch to unfiltered cigarettes. Objective Our objective is to understand the impact of switching smokers of filtered cigarettes to unfiltered cigarettes on smoking behavior and toxic exposures. Methods This trial involves a 1-week baseline period; a 2-week period of smoking filtered or unfiltered cigarettes, where groups are randomly assigned; a 3-week washout period; another 1-week baseline period; and a 2-week crossover period of smoking the opposite condition (ie, filtered or unfiltered cigarettes) for a sufficient sample size of 40 participants. We will determine changes in (1) observed topography (ie, puff count, interpuff interval, and puff volume) and cigarettes smoked per day, via butt counts and self-report, (2) expired carbon monoxide and excretion of urinary cotinine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and volatile organic compounds, and (3) participants’ knowledge and attitudes toward unfiltered cigarettes, satisfaction with smoking, and intention to quit if they were not able to smoke filtered cigarettes. Results This study was funded in June 2018 and approved by the relevant Institutional Review Boards in July 2018. This study has enrolled 37 participants as of October 2020. Data analysis is currently underway, and trial results are expected to be published in spring 2021. Conclusions This pilot proof-of-principle study will inform the design of a larger, future research project that can provide robust scientific evidence on our research question. Such a large study could inform possible state or local legislation to ban the sale of single-use filtered cigarettes in order to mitigate the environmental impact of discarded single-use plastic filters. Trial Registration ClinicalTrials.gov NCT03749876; https://clinicaltrials.gov/ct2/show/NCT03749876 International Registered Report Identifier (IRRID) DERR1-10.2196/19603


Criterion 2 Please score and comment on: 1) Research Plan; 2) Near-Term Leveraging Poten al:
• The aims of the study are clear and presented well. • During the washout period are smokers allowed to smoke? If not, what are the mechanisms in place to keep smokers from using tobacco products for three weeks? • I'm not sure that collec ng cigare e bu s from par cipants will assure adherence to the study. • The inclusion and exclusion criteria are adequate and appropriate for the study.
• The recruitment process is too reac ve (i.e. flyers, newspapers, Craigslist, word of mouth). I think that a community partner (i.e. CBO) that could assist with recruitment would aid in ge ng study par cipants quickly. • Incen ves for the par cipants are adequate and may help with reten on of study par cipants. • How will the research team ensure that the study par cipants are only using the provided cigare es? Smokeless tobacco, cigars, hookah and/or marijuana (blunts) can produce inaccurate levels of co nine in which the study is only looking for levels from the products provided. Near-term Leveraging Poten al: If successful, the research from this trial could inform a larger clinical trial that can be submi ed to the NIH/Food and Drug Administra on and the data can serve as evidence for poten ally banning the sale of filtered cigare es.

Criterion 3 Please score and comment on: 1) Inves gators; 2) Environment; 3) Community Engagement & Communica on Plan:
Inves gators: The PI has extensive experience in respiratory health and has primarily focused on respiratory infec ons, asthma, and chronic obstruc ve pulmonary disease, all of which are exacerbated by tobacco use. But he does not appear to have direct experience carrying out a study related to tobacco use, nico ne dependence, etc. However, the co-inves gators have experience in tobacco epidemiology, environmental outcomes of smoking (i.e. bu waste) and nico ne dependence. The team in its en rety is a strength. Environment: The environment seems adequate for the proposed study. Community Engagement & Communica on Plan: The study team may want to consider non-tradi onal ways of dissemina ng research results besides presen ng at local and na onal events. The results can be shared via tradi onal and social media, blog posts and op-eds. In addi on, the community engagement plan is heavily focused on cigare e bu pollu on. Although cigare e bu pollu on is an important factor in the study, the implica ons are far-reaching for policy, cancer preven on, and cessa on. Community groups should be added that can provide input in those areas as well. A strength of the plan is u lizing NGO's such as the Truth Ini a ve (support le er included) and federal agencies such as CDC, NIH, and FDA to disseminate research findings.

Unscored Criterion Comment on 1) Protec on of Human Subjects from Research Risk, 2) Inclusion of Women, Minori es and Children in Research, 3) Care and Use of Vertebrate Animals in Research, 4) Biohazards, 5) Budget Concerns:
Protec on of Human Subjects from Research Risk: No concerns in regard to the protec on of study par cipants. Inclusion of Women, Minori es and Children in Research: Inclusion of women are adequate. Representa on of minori es are adequate considering the limita ons of other ethnic groups being represented in the area. Children are not a part of the study. Care and Use of Vertebrate Animals in Research: Not applicable Biohazards: Not applicable Budget Concerns: There are 14 people charged to the grant. It appears to be a lot of personnel for a study that only has 40 par cipants. In addi on, there is not an adequate explana on as to why each of these posi ons are cri cal to carrying out the study. The research team may want to consider downsizing the number of co-inves gators (5) and the number of grad students (4). In addi on, is 3% of effort on the grant an adequate amount for the Project Manager to fulfill all of its du es and responsibili es to the research study?

Reviewer Role: Secondary Reviewer (76120)
Reviewer Summary: Well wri en proposal that is innova ve and test a proof of concept using a rigorous cross-over design. By assessing smoker a tudes, topography and biomarkers, this proposal will provide novel informa on regarding switching to unfiltered cigare es. The leveraging poten al is high and study findings may have substan al policy implica ons. Research plan is well described and the research team has sufficient exper se and experience to accomplish the study objec ves.

Criterion 1
Please score and comment on: 1) Responsiveness to Intent of the Award Type (Pilot Project); 2) Innova on: Highly innova ve pilot proposal that is very responsive to the pilot project award type and to TRDRP priori es. The proposal has poten al to inform regulatory science and this line of work has substan al policy implica ons specifically regarding banning the sales of filtered cigare es.

Criterion 2 Please score and comment on: 1) Research Plan; 2) Near-Term Leveraging Poten al:
A rigorous cross-over design with washout period is proposed. The specific aims are well explicated and scien fically jus fied. Sample size jus fica on is appropriate.
Overall, the study procedures are sufficiently described. However, the meline is a bit confusing and figure 1 does not line up with table 1. Might be be er to use days to illustrate.
The near-term leveraging poten al is high as this work could provide preliminary data and inform a larger future trial of switching to unfiltered cigare es.

Criterion 3 Please score and comment on: 1) Inves gators; 2) Environment; 3) Community Engagement & Communica on Plan:
Outstanding inves gator team with strong and suppor ve ins tu onal environment. The community engagement and communica on plan is excellent. Strong le ers of support including from the Truth Ini a ve.

Reviewer Role: Ter ary Reviewer (297512)
Reviewer Summary: -An important study that will advance research addressing a number of TRDRP priori es.
-Study may likely impact Endgame policy decisions. -Prior pilot tes ng and team work among inves gators is strong.

Criterion 1
Please score and comment on: 1) Responsiveness to Intent of the Award Type (Pilot Project); 2) Innova on: 1) The proposed study is highly responsive to the intent of the pilot award. It addresses TRDRP priori es and the project may impact Cancer preven on, Treatment, and Biology; Environmental Exposure and Toxicology; and State and Local Tobacco Control Policy Research.
2) The study is significant since research has indicated increased risk of filtered cigare es on adenocarcinoma of the lung. Addi onally, the 2014 SGR indicated that there is sugges ve evidence that ven lated filters increased levels of tobaccospecific nitrosamines, so more research is clearly needed in this area. Also, waste (bu s) may be a toxic risk for humans, pets, and marine life -this is an environment problem. The study is innova ve in that it uses an interes ng assessment of smoking topography in the natural environment (Pocket CReSS) instead of lab study. Applicants discuss that results also may poten ally lead directly to policy changes, including poten ally banning filters from US cigare es, similar to calls for menthol ban, and recent bans on light, mild adver sing. Essen ally, results could poten ally eventually become directly incorporated into similar Tobacco Endgame policy strategies.

Criterion 2
Please score and comment on: 1) Research Plan; 2) Near-Term Leveraging Poten al: 1) Research Design Study Descrip on: A randomized cross-over pilot clinical trial of commi ed smokers switching from filtered cigare es to unfiltered over two weeks, that will measure topography and a tudes of smoking these cigare es. Aim 1: Hypothesize smokers will have less sa sfac on with unfiltered compared to filtered cigare es. Aim 2: Hypothesize they will inhale less deeply, frequently, and smoke fewer cigare es/day. Aim 3: Hypothesize they will have lower urinary co nine, NNAL, and VOC excre on. Weaknesses: -Don't appear to exclude cannabis smokers, which could impact results. -Don't appear to measure for exposure to second-hand smoke, which could impact biomedical results.
2) Near-term leveraging poten al Applicant hopes to leverage results by informing a larger NIH/FDA trial that may poten ally have policy impact. It is likely that knowledge gained through this proof of principle trial with inform the FDA, State and local officials and other tobacco researchers about the feasibility of conduc ng a larger-scale clinical trial of unfiltered cigare es.

Criterion 3
Please score and comment on: 1) Inves gators; 2) Environment; 3) Community Engagement & Communica on Plan: 1) Inves gators have collaborated on previous field test of the CReSS devices for the proposed research in the past with a Legacy Founda on grant. PI appears to have li le experience in tobacco research directly, having mainly worked on pulmonary projects. However, applicant has assembled an excellent team of researchers including collabora on with Dr. Benowitz's group who are involved in the Data and Safety Monitoring Board. Dr. Novotny has been involved in Cigare e Bu Pollu on project and SG reports. Strong le ers of support from Dr. Samet (involvement also with SG reports) and Dr. Cummings will help with dissemina on of research results.
2) Environment appears suitable, with the study taking place in Dr. Pulver's lab and samples results are sent to Dr. Benowitz's group.
3) Aspects of the local community engagement plan seem underdeveloped. For example, there is not a lot wri en about plans to engage the community in feedback about the project other than a discussion of how to recruit for the study. There is a plan to coordinate with policy folks who have recently introduced legisla on to ban the sale of filtered cigare es in California and collaborate with others on the Trash Amendment of the Clean Water Act. On the other hand, strength of the applica on includes plans to coordinate with FDA regulators, state agencies, Truth ini a ve, etc., which likely will assist with dissemina ng results on na onal scale.

Unscored Criterion
Comment on 1) Protec on of Human Subjects from Research Risk, 2) Inclusion of Women, Minori es and Children in Research, 3) Care and Use of Vertebrate Animals in Research, 4) Biohazards, 5) Budget Concerns: 1) Human subjects seem protected 2) Includes women and minori es