Results of the trial

Participant flow

Between 13 August 2012 and 10 March 2015, 3837 people telephoned about enrolment. Of these, 1805 (47.0%) attended the initial appointment and 1792 (99.3%) of those were eligible and were enrolled in the study. Overall, 490 (12.8%) people who had telephoned were ineligible; the most common reasons for ineligibility were skin problems and an objection to using preloading patches (Figure 3).

FIGURE 3 Consolidated Standards of Reporting Trials (CONSORT) flow diagram. MI, myocardial infarction. Adapted from the Preloading Investigators.39 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See http://creativecommons.org/licenses/by/4.0/. (Figure not reproduced here; see the original article.)

One week after baseline, we followed up 1702 (95.0%) participants; and 5 weeks after baseline, 1 week after quit day, we obtained data from 1456 (81.3%) participants. These assessments provided data on AEs.

In total, 312 (17.4%) participants never made a quit attempt, 157 (17.5%) in the intervention group and 155 (17.4%) in the control group. We obtained data on 1585 (88.5%) participants at 4 weeks, 1461 (81.5%) at 6 months and 1389 (77.5%) at 12 months after quit day. The proportion successfully followed was similar in each group. Although 331 (18.5%) participants did not provide data at 6 months, we knew that 97 of these participants were smoking at 4 weeks post quit day and could not, therefore, be classified as abstinent at 6 months and that 54 of these participants never made a quit attempt and likewise could not be classified as abstinent at 6 months. Thus, altogether, we were certain of the primary outcome in 1612 (90.0%) participants.

Baseline characteristics

The baseline characteristics were well balanced between the trial arms (Table 3). The mean age of participants was 48.9 [standard deviation (SD) 13.4] years. Men constituted 52.6% of the participants and 75.6% identified as white British. The proportion of participants with an advanced level of education was lower than the UK average.40 Fifty-two per cent were in employment. Participants smoked a mean of 18.9 (SD 9.3) cigarettes per day at baseline, had a mean nicotine dependence score of 5.2 (SD 2.2), indicating moderate addiction, and a mean exhaled CO concentration of 23.7 (SD 12.5) p.p.m. One-third (32.5%) had used behavioural support or pharmacotherapy to try to quit in the previous 6 months.

Medication adherence

One week after baseline, nearly three-quarters of participants in the active group reported using the patch daily; in the subsequent 3 weeks of preloading, > 80% of participants in the active group reported using the patch daily (Table 4). In total, 49 (5.5%) participants discontinued preloading prematurely. The majority who ceased preloading did so during the first week of treatment.

Post-quit day medication in those who made a quit attempt after preloading was also assessed. At 1 week after quit day, 11.8% of the control group and 8.2% of the intervention group were not using any medication. It is possible that these participants made a quit attempt without medication or that they made a quit attempt but had abandoned the attempt, and, hence, the medication to support the attempt, by the time of the assessment at 1 week after quit day (Table 5).

Primary and secondary outcomes

The primary outcome, biochemically validated 6-month abstinence, was achieved by 157 (17.5%) participants in the intervention group and 129 (14.5%) participants in the control group, a difference of 3.02 (95% CI –0.37 to 6.41).

The secondary outcomes showed similar modest differences. At 4 weeks, 319 (35.5%) participants in the intervention group achieved 7-day point prevalence abstinence, whereas 288 (32.3%) participants in the control group did so. At 12 months, 126 (14.0%) participants in the intervention group achieved validated prolonged abstinence, whereas 101 (11.3%) participants in the control group achieved it (Tables 6 and 7).

Adjustment for predictors of abstinence left the results essentially unchanged, except for adjustment for the use of post-quit day varenicline use, which changed the results noticeably. The effect of preloading was larger than in the unadjusted results and was statistically significant.

Subgroup analysis

There was no evidence that people who used varenicline as their post-cessation medication received less benefit from nicotine preloading than people using other cessation medication. For the effect of preloading compared with control for participants using varenicline, the OR was 1.42 (95% CI 0.90 to 2.26). For participants not using varenicline, the OR was 1.30 (95% CI 0.95 to 1.77; p = 0.740) for the interaction.

Adverse events

Adverse events that were moderate or severe in intensity were uncommon in both arms. Therefore, the absolute difference between arms was small with an absolute difference in the percentage of participants suffering an AE in the intervention group compared with the control group of up to 4% (Table 8).

One week after baseline, 394 (45.5%) participants in the intervention group and 271 (32.4%) participants in the control group reported at least one symptom from the checklist of symptoms of nicotine excess (p < 0.001 for the difference). The only three symptoms for which there was statistically significant evidence that they were more common in the intervention group were dizziness, palpitations and nausea. Of these symptoms, 5.6% and 3.0% were somewhat or very dizzy in the intervention and control groups, 3.9% and 1.9% had palpitations and 8.1% and 3.1% experienced nausea, respectively (Figure 4).

FIGURE 4 Prevalence and severity of symptoms experienced in the last 24 hours, reported after having been in the preloading group or control group for 1 week. (a) Stomach pain; (b) cold sweat; (c) diarrhoea; (d) palpitations; (e) dizziness; (f) nausea; (g) vomiting; (h) headaches; (i) watery mouth; (j) weakness; (k) tremor; and (l) pallor. (Figure not reproduced here; see the original article.)

There were 17 SAEs during the 5-week period, nine in the intervention group and eight in the control group, giving an OR of 1.12 (95% CI 0.42 to 3.03). Of these, one was judged to be possibly caused by preloading: acute coronary syndrome in a 64-year-old woman. The SAEs reported are summarised in Table 9.