Cigarette smoking continues to be a serious. Nicotine Lozenges in the Relief of Behaviorally Provoked Craving

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1 Nicotine Lozenges in the Relief of Behaviorally Provoked Craving Mitchell Nides, PhD Gilbert Marava Shanga, PhD, MBA Amanda Bishop, BA William D. Becker, MS Objectives: Environmental cues may precipitate nicotine cravings in smokers. We present 2 studies exploring the efficacy of nicotine mini lozenges to reduce nicotine craving in smokers following behavioral provocation. Methods: Healthy smokers aged 18 years enrolled. In Study 1, participants were stratified by number of cigarettes smoked daily; Study 2 enrolled only heavy smokers. After an abstinence period, participants engaged in behavioral provocation to induce nicotine craving before receiving a nicotine mini lozenge (Study 1: 1.5 mg or 4 mg; Study 2: 4 mg) or matching placebo. Craving was assessed using a 100-mm visual analogue scale, and safety was monitored. Results: In Study 1, neither nicotine mini lozenge dose significantly reduced craving in smokers versus placebo. In Study 2, 4-mg nicotine mini lozenges significantly reduced craving scores 5 minutes post-treatment (least-square mean [LSM] change from baseline: 41.8; 95% confidence interval [CI]: 45.8, 37.7) versus placebo ( 25.9; 95% CI: 30.0, 21.8; p <.001). Adverse events were infrequent, mild in intensity, and more common with the 4-mg nicotine mini lozenges. Conclusions: Behaviorally provoked nicotine craving can be significantly and safely reduced in heavy/high-dependency smokers with 4-mg nicotine mini lozenges. Key words: smoking cessation; smoking behavior; nicotine replacement therapy; nicotine craving Am J Health Behav. 2018;42(3):69-79 DOI: Cigarette smoking continues to be a serious global health issue and a leading cause of preventable deaths. Up to half of all tobacco users die from tobacco-related causes. The World Health Organization reports that tobacco is responsible for about 6 million deaths per year, including more than 5 million smokers and more than 600,000 non-smokers who are exposed to second-hand smoke. 1 High doses of nicotine are effectively delivered to the brain via smoking, and the addictive properties of nicotine make it difficult for tobacco users to quit, although the majority of smokers express interest in doing so. 2,3 Nicotine dependence is expressed subjectively as a craving to smoke; greater dependence on nicotine has been associated with stronger cravings along with more intense smoking behaviors including increased cigarette consumption. 4,5 During attempts to stop smoking, the intensity of nicotine craving is strongest immediately after smoking cessation but then declines over time. Unfortunately, this background level of craving is often accompanied by more intense cravings that occur episodically as a result of behavioral cues such as seeing a pack of cigarettes, visualizing smoking activity, being in the presence of someone smoking, having a meal, consumption of alcohol, etc. Cravings that arise from such cues have been associated with higher rates of relapse. 6,7 Although background craving diminishes over time, cued cravings have been shown to increase over time (up to 35 days) even as abstinence continues. 8 Behavioral cues appear Mitchell Nides, Los Angeles Clinical Trials, Burbank, CA. Gilbert Marava Shanga, Manager, Biostatistics, Research and Development, GlaxoSmith- Kline Consumer Healthcare, Warren, NJ. Amanda Bishop, Principal Clinical Study Manager, Clinical Operations, Portfolio Manager - Respiratory Health, Clinical Development Medical Affairs, Research and Development, GlaxoSmithKline Consumer Healthcare, Warren, NJ. William D. Becker, Consultant, Medical Affairs, GlaxoSmithKline Consumer Healthcare, Warren, NJ. Correspondence Dr Nides; mnides@laclinicaltrials.com Am J Health Behav. 2018;42(3):

2 Nicotine Lozenges in the Relief of Behaviorally Provoked Craving to play an important role in relapse compared with the experience of withdrawal symptoms alone. 7,9 Therapy that would mitigate the intensity of these craving episodes may serve to diminish the risk of relapse. Nicotine replacement therapy (NRT) is recommended as a first-line treatment for smoking cessation and comes in many forms. 10 Like other forms of NRT, nicotine mini lozenges are intended to attenuate nicotine cravings and withdrawal symptoms during the quitting process by at least partially replacing the nicotine formerly obtained from cigarette smoking and have been demonstrated to help smokers successfully quit smoking. 11 Most of the prior research on provoked cravings has focused on heavy smokers, with limited data on light smokers. In addition, information reporting the early relief of provoked cravings (ie, within the first few minutes after treatment) in heavy smokers is sparse. One previous study assessed the effectiveness of nicotine gum (2 mg and 4 mg) in relieving behaviorally provoked cravings and enrolled both heavy (recommended dose: 4 mg) and light (recommended dose: 2 mg) smokers; however, the treatment arms were combined for analyses because the results were virtually identical, with a statistically significant difference in craving relief observed after 15 minutes. 12 Nicotine lozenges have also been investigated (data on file, GlaxoSmithKline Consumer Healthcare; studies S , S , and S ) in the relief of provoked cravings in heavy smokers. In study S , a statistically significant effect on craving, in favor of the 4-mg lozenge versus placebo, was observed 5 minutes post-dosing (the first post-dose assessment time point). Two additional studies explored relief of behaviorally provoked cravings 3 to 30 minutes after dosing; one study evaluated a novel nicotine lozenge formulation (S ) and the other evaluated a low-dose (0.5 mg) lozenge (S ) in heavy smokers. Neither study demonstrated significant craving relief, although the difference was greatest at 3 minutes for the low-dose lozenge (0.5-mg lozenge vs placebo, p =.08). Lastly, Du et al 13 investigated the relief of behaviorally provoked craving in a comparison of nicotine oral soluble film (2.5 mg) and nicotine lozenge (2 mg) in lowdependency smokers, defined as those whose first cigarette of the day was consumed >30 minutes after awakening and in whom smoking was a daily occurrence for at least one year. Similar to the studies detailed here, they used a 4-hour sequestration period during which participants abstained from tobacco use, followed by the provoked craving paradigm, with craving assessments completed at 50 seconds and at 3, 5, 7, 15, 20, 25, and 30 minutes after treatment administration. Both treatments were found to reduce behaviorally provoked cravings with similar maximum effect, but the nicotine film provided craving relief that was significantly greater (ie, more rapid) than the nicotine lozenge at 50 seconds and at 3 and 5 minutes (p <.05 for each time point). 13 A new nicotine lozenge, NiQuitin minis mint lozenge (1.5 mg and 4 mg; GlaxoSmithKline, Brentford, UK) was approved for use by the Medicines and Healthcare Products Regulatory Agency in the UK in Herein we detail results of 2 studies that evaluated the efficacy of nicotine mini lozenges versus placebo to relieve behaviorally provoked nicotine craving in cigarette smokers following a 4-hour period of abstinence. Our hypothesis was that active NRT with nicotine mini lozenges would attenuate provoked cravings significantly better than placebo. A second hypothesis was that nicotine mini lozenges would relieve provoked craving to a greater extent in heavy/highdependency smokers. Study 1 was an exploratory pilot study in both light and heavy smokers that included assessments of craving reduction within the first 5 minutes after treatment. Study 1 was also conducted to inform the sample size calculation for an anticipated pivotal study (Study 2) to be performed in the future. Following results from the pilot study, the second study assessed the ability of nicotine mini lozenges to attenuate provoked craving in heavy smokers only. METHODS Study Designs and Schedules These phase 2, single-center, double-blind, parallel group, randomized, placebo-controlled studies were conducted in accordance with ethical principles that have their origin in the World Medical Association Declaration of Helsinki, the International Conference on Harmonisation Topic 6 Guideline for Good Clinical Practice, and other applicable regulations. 70

3 Nides et al Screening visit. Each study included a screening visit and a craving provocation (ie, study) visit. During the screening visit, potential study participants received information about the purpose and conduct of the study and signed the approved informed consent form. At screening, they also provided smoking and medical histories, height, weight, and other demographic information, and medication use; received urine drug screen and urine pregnancy testing (as applicable); and took the Fagerström Test for Nicotine Dependence (FTND). 14 Persons who continued to meet eligibility requirements after completing the screening visit were scheduled for a study visit within the next 21 days. The craving provocation visit began with a 4-hour sequestration period prior to behavioral provocation in which study staff recorded each participant s smoking history for the current day and checked compliance with study restrictions and inclusion/exclusion criteria. Participants underwent urine drug screening, pregnancy testing (as applicable), and breath alcohol testing. Site staff trained participants on using a 100-mm visual analogue scale (VAS) to indicate craving intensity level and allowed them to practice opening mock treatment packages (ie, not containing active treatment) in 2 sessions at approximately 3.5 hours and 2 hours prior to treatment administration, to ensure that they were able to open the packages in the desired time frame before the craving assessment. Adherence to the smoking prohibition during sequestration was determined by measuring participants expired carbon monoxide (CO) levels using a Smokerlyzer breath tester (Bedfont Scientific Ltd., Maidstone, UK). Expired CO levels were assessed upon arrival at the study site (baseline) and immediately before beginning the provoked craving paradigm. Participants for whom expired CO levels had risen from the initial baseline value during the sequestration period, indicating that they may have smoked, were withdrawn from the study. Provoked craving paradigm. After being sequestered at the study site and abstinent from smoking for 4 hours, participants in both studies were exposed to a behaviorally provoked craving paradigm as utilized in earlier clinical studies. 12,15 During this procedure, each participant was left alone in a welllit, temperature-controlled, well-ventilated, soundattenuated room and received study instructions via audio-recording. After a 5-minute acclimatization period, participants opened an opaque box containing a pack of their first or second choice brand of cigarettes, 2 cigarette lighters, and an ashtray. They were then instructed to unwrap and open the pack of cigarettes, remove one cigarette, hold it in their hand, light it without placing it in their mouth, and hold the lit cigarette directly in front of them without smoking it. Next, they were instructed to look at the lit cigarette for 60 seconds before extinguishing it in the ashtray. The total provocation lasted approximately 90 seconds, and study staff monitored participants via closed-circuit television to observe and record any protocol violations or difficulties adhering to instructions, such as difficulty lighting the cigarette. Any participants who smoked during the provoked craving paradigm, even a single puff, were withdrawn from the study. The provocation rate was determined by the number and percentage of participants with an increase of at least one point (on a 100-mm VAS scale) from pre-cue to post-cue (pre-dose) on the average cravings score. Upon extinguishing the cigarette, craving was again assessed and followed one minute later by self-dosing with randomized treatment, either nicotine mini lozenge or placebo, according to a computer-generated randomization schedule produced by GSK Biostatistics and Data Management Department (GSK Consumer Healthcare, Parsippany, NJ). Study Participants Both studies were conducted at LA Clinical Trials, Burbank, California, and participants were recruited from the study site s database and/or via local advertisements. Each study enrolled otherwise healthy smokers at least 18 years of age who provided informed consent. Study 1 was a pilot study that enrolled persons who smoked at least 5 cigarettes per day, and stratified these participants into 2 groups: light/low-dependency smokers who smoked 20 cigarettes per day, which is the population for which the 1.5-mg nicotine mini lozenge is indicated, and heavy/high-dependency smokers who smoked >20 cigarettes per day, which is the population for which the 4-mg nicotine mini lozenge is indicated. Study 2 enrolled persons who Am J Health Behav. 2018;42(3):69-79 DOI: 71

4 Nicotine Lozenges in the Relief of Behaviorally Provoked Craving smoked >20 cigarettes per day for at least one year. All included participants had a body mass index of 19 to 35 kg/m 2 (Study 1) or 18 to 35 kg/m 2 (Study 2) and were required to understand and comply with all procedures and restrictions mandated for the respective studies. Women were required to practice a reliable method of birth control. Persons were excluded if they were pregnant or breastfeeding, had a known or suspected allergy or intolerance to any of the study materials, had a history of alcohol or drug abuse within the previous year, consumed alcohol within 24 hours of the craving provocation (study) visit, or had a positive urine drug screen. In addition, participants who were treated within 30 days with known liver enzyme-altering agents, who used any prescription psychoactive medication within 14 days, took a sedating over-the-counter medication within 24 hours, or currently used NRT were excluded. Furthermore, the presence of any disease with the potential to interfere with the safety of the participant or the validity of the study results in the opinion of the investigator was exclusionary. Lastly, any person who was suspected of smoking during the sequestration period, which was assessed by expired levels of CO, was excluded. Participants were required to observe certain lifestyle restrictions to participate in either study. In addition to those noted above, lifestyle restrictions included agreeing to be abstinent from food in the fourth hour of sequestration prior to, and during, the provoked craving paradigm and associated assessments. In addition, participants were not permitted to watch television but were allowed to read books or comics and were given access to videos, newspapers, and magazines that did not contain any tobacco-related material. Study Treatment In Study 1, participants were randomized into 4 treatment groups. Light/low-dependency smokers received either a 1.5-mg nicotine mini lozenge (NiQuitin minis, GlaxoSmithKline, Brentford, UK) or matching placebo lozenge (GlaxoSmithKline), and heavy/high-dependency smokers received either a 4-mg nicotine mini lozenge (NiQuitin minis) or a matching placebo lozenge. In Study 2, all participants were randomized to receive either a 4-mg nicotine mini lozenge (NiQuitin minis) or a matching placebo lozenge (GlaxoSmithKline). In both studies, participants were instructed to move the lozenge from one side of the mouth to the other periodically until it dissolved completely. Persons whose lozenge had not fully dissolved by the time the final craving assessment was completed were permitted to discard the lozenge if they wished. Study Assessments Craving assessments. The intensity of nicotine cravings was measured using a questionnaire consisting of the following 5 items: (1) I have a desire for a cigarette right now; (2) If it were possible I would smoke right now; (3) All I want right now is a cigarette; (4) I have an urge for a cigarette; and (5) I crave a cigarette right now. This scale has been validated for provoked craving assessment with high internal reliability and sensitivity. 12 Each participant indicated his or her craving intensity on a 100-mm VAS, ranging from 0 (disagree) to 100 (agree), by drawing a line approximately perpendicular to the scale, bisecting it. A cravings score was computed by averaging the scores of the 5 individual items. In Study 1, cravings were assessed at baseline, immediately after the provoked craving paradigm, and at one, 3, 5, 10, and 15 minutes (in light/low-dependency smokers) or at one and 3 minutes (in heavy/high-dependency smokers) following study treatment. In Study 2, all participants completed cravings assessments immediately before and after the provoked craving paradigm as well as at one, 3, 5, 7, and 10 minutes after administration of the study treatment. Safety assessment. Adverse events (AEs) from each study were recorded and used to assess the safety and tolerability of the study treatments. Adverse events were defined as any untoward medical occurrence in a participant or clinical investigation individual that was temporally associated with the use of an investigational product, regardless of its relationship to the investigational product. Serious AEs (SAEs) were defined as any untoward medical occurrence that was life-threatening, resulted in death, required hospitalization or prolongation of existing hospitalization, resulted in disability or incapacity, or was a congenital anomaly or birth defect. The investigator and site staff members were responsible for detecting, documenting, and report- 72

5 Nides et al ing any AEs or SAEs that occurred during study sessions from the start of the smoking abstinence sequestration period until 5 days after the last administration of the study treatment. All AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA), were graded on a 3-point scale for intensity (mild = easily tolerated, causing minimal discomfort and not interfering with normal everyday activities; moderate = sufficiently discomforting to interfere with normal everyday activities; or severe = any event that prevents normal everyday activities), and their relationship to the study treatment was assessed by the investigator. Data Analysis For both studies, the intent-to-treat (ITT) population, consisting of participants who underwent at least one cravings assessment after receiving the study treatment, was used for all efficacy analyses. The safety population, consisting of all persons who were administered a study treatment, was used to assess safety. In Study 1, it was determined that approximately 184 smokers (84 heavy/high-dependency smokers and 100 light/low-dependency smokers) should be randomized to ensure that at least 50 smokers in each category in whom a craving had been provoked would complete the study. In Study 2, it was determined that a sample size of 155 subjects per arm would allow detection of a difference in change from baseline in craving score between the 2 treatment groups of at least 9 points, with a study power of at least 80% for a common standard deviation of 28.0 and significance level of 5% using a 2-sided 2-sample t-test. Approximately 500 persons were to be screened to randomize approximately 320 persons, for 310 participants (155 in each treatment arm) to complete the study. Primary efficacy. In Study 1, primary efficacy based on the average of the post-provocation cravings was analyzed using analysis of covariance (ANCOVA) at one, 3, 5, 10, and 15 minutes postdosing for the 1.5-mg nicotine mini lozenge in light smokers and separately at one and 3 minutes postdosing for the 4-mg nicotine mini lozenge in heavy smokers. Treatment was a fixed effect and subject was a random effect in the ANCOVA analyses. Post-provocation, pre-dose baseline craving assessments were used as covariates. Comparisons were made between active and placebo lozenges within each dosage at the 2-tailed 5% significance level. In addition, 95% confidence intervals (CIs) were constructed on the mean post-dose cravings scores. A repeated measures model was also fit on all of the data with time as the repeated measures variable; time-by-treatment interaction was included in the model. The same treatment-placebo comparisons described above were made with the repeated measures model. In Study 2, primary efficacy was based on the average score of the 5 items on the cravings assessment questionnaire and analyzed using AN- COVA at 5 minutes post-dosing. The analysis included treatment as a fixed effect, and pre- and post-provocation baseline assessments were used as covariates. Comparisons were made between active treatment and placebo and were evaluated at the 2-tailed 5% significance level. Finally, 95% CIs were constructed on the mean difference in postdose craving scores. Least-square means (LSMs) were used to compute the percentage reduction in cravings from baseline to post-dose for each treatment group. The natural log of the area under the curve of the craving score versus time was calculated with SAS mixed models (SAS Institute Inc., Cary, NC) and was used as a secondary analysis of craving relief. The mixed model included treatment as a fixed effect, and both baseline craving assessments were used as covariates. Secondary efficacy. In Study 1, the number and percentage of participants with an increase of at least one point from the pre-provocation assessment to the post-provocation pre-dose assessment on the average craving score was used to assess the provocation rate. These participants were considered provocation responders. In Study 2, the primary analysis was repeated on cravings scores at one, 3, 7, and 10 minutes post-dose in all participants. In addition, the number and percentage of persons with an increase of at least one point in the average craving score from pre-provocation to postprovocation baseline assessments was determined, and the primary analysis was also repeated at all post-dose time points in provocation responders only. Safety. Safety was monitored as per IRB regulations and all AEs were tabulated and reported. Am J Health Behav. 2018;42(3):69-79 DOI: 73

6 Nicotine Lozenges in the Relief of Behaviorally Provoked Craving Parameter Sex, N (%) Table 1 Baseline Demographics and Participant Characteristics Study 1 Study 2 Heavy Smokers Light Smokers Heavy Smokers 4-mg Nicotine Mini Lozenge (N = 52) Placebo (N = 34) 1.5-mg Nicotine Mini Lozenge (N = 60) Placebo (N = 41) 4-mg Nicotine Mini Lozenge (N = 162) Placebo (N = 161) Male 29 (55.8) 18 (52.9) 36 (60.0) 20 (48.8) 87 (53.7) 87 (54.0) Female 23 (44.2) 16 (47.1) 24 (40.0) 21 (51.2) 75 (46.3) 74 (46.0) Race, N (%) Black 30 (57.7) 19 (55.9) 31 (51.7) 14 (34.1) 91 (56.2) 87 (54.0) White 15 (28.8) 11 (32.4) 21 (35.0) 19 (46.3) 64 (39.5) 65 (40.4) Other 7 (13.5) 4 (11.7) 8 (13.3) 8 (19.5) 7 (4.3) 9 (5.6) Age, mean (SD), years 45.1 (10.4) 45.9 (9.4) 43.9 (11.5) 45.0 (10.6) 43.6 (12.1) 44.5 (11.6) Smoking Behaviors Years smoking, mean (SD) 25.3 (10.2) 25.0 (12.3) 20.6 (11.0) 24.5 (11.5) 24.8 (12.1) 24.5 (12.1) Daily smokers, N (%) 52 (100) 34 (100) 60 (100) 41 (100) 161 (99.4) 161 (100) Cigarettes/day, mean (SD) 28.2 (6.6) 29.9 (7.7) 15.2 (4.1) 15.0 (4.0) 30.1 (8.3) 31.8 (9.3) First cigarette of day within 30 minutes of awakening, N (%) 47 (90.4) 32 (94.1) 46 (76.7) 32 (78.0) 138 (86.8) 137 (87.9) FTND score, a mean (SD) 7.2 (1.6) 7.6 (1.4) 5.3 (1.9) 5.5 (1.5) 7.3 (9.1) 7.3 (9.1) Note. a: An FTND score 7 (range, 0-2 = very low; 8-10 = very high) is considered highly dependent. FTND: Fagerström Test of Nicotine Dependence. 14 SD: standard deviation RESULTS Study 1 Study 1 was conducted between September 14, 2010 and December 7, A total of 244 potential participants were screened; 56 failed to meet study criteria and one withdrew consent. In total, 187 were randomized to treatment and all randomized subjects completed the study. There were 60 light/low-dependency smokers who received the 1.5-mg nicotine mini lozenge (26 men, 24 women) and 41 who received matching placebo (20 men, 21 women), and 52 heavy/high-dependency smokers who received the 4-mg nicotine mini lozenge (29 men, 23 women) and 34 who received matching placebo (18 men, 16 women). The participants mean age was 45 years, 94 (50.3%) were black, 66 (35.3%) were white, and 27 (14.4%) were other races. Each participant enrolled was a daily smoker. Table 1 shows that the demographic characteristics of the light/low-dependency smokers were similar to those of the heavy/high-dependency smokers. Primary efficacy analysis. Figure 1 shows the mean craving scores over time in light/low-dependency smokers and heavy/high-dependency smokers. Reductions in behaviorally provoked craving scores were numerically larger with both 1.5-mg and 4-mg nicotine mini lozenges versus placebo, but none of the differences was statistically significant. A potential signal of meaningful difference between nicotine mini lozenges and placebo was found at one minute post-dosing in light/lowdependency smokers ( 7.23; 95% CI, 14.89, 0.44; p =.064) and at 3 minutes post-dosing in high/heavy-dependency smokers ( 9.70; 95% CI, 19.59, 0.20; p =.055), but this was not observed at any other assessment points. 74

7 Nides et al Figure 1 Mean Craving Scores over Time for Light/low-dependency Smokers in Study 1 (ITT Population) a Note. a: Test treatment was taken at time 0. ITT: intent-to-treat. Secondary efficacy analysis. A total of 78 out of 101 (77.2%) light/low-dependency smokers exhibited a response to the behaviorally provoked craving paradigm, as determined by an increase of one or more points in participants mean craving score from the pre-cue assessment to the post-cue (pre-dose) assessment. Among heavy/high-dependency smokers, 65 of 86 (75.6%) participants were determined to be responders. When the efficacy analysis was repeated using data from responders only, results were consistent with those from the entire ITT population (ie, no statistically significant differences in craving relief between either dose of active treatment or its respective placebo were observed). Safety assessment. A total of 13 persons reported 18 AEs during this study. All but 2 of the total number of AEs reported occurred in participants receiving the 4-mg nicotine mini lozenge in the heavy/high-dependency smoker cohort. These included hiccups in 6 (11.5%), nausea in 5 (9.6%), throat irritation in 2 (3.8%), and oral discomfort, retching, and headache in one subject (1.9%) each. The remaining AEs were cough in one person in the 1.5-mg nicotine mini lozenge group and throat irritation in one person in the placebo group from the light smoker cohort. All AEs were mild in intensity; no SAEs occurred during the study. Study 2 Study 2 was conducted between September 23, 2011 and December 22, A total of 423 people were screened; 94 failed to meet study criteria and 6 were lost to follow-up or withdrew consent. Am J Health Behav. 2018;42(3):69-79 DOI: 75

8 Nicotine Lozenges in the Relief of Behaviorally Provoked Craving Figure 2 Mean Craving Scores over Time for Participants in Study 2 Receiving 4-mg Nicotine Mini Lozenge and Placebo (ITT Population) a *p <.001 Note a: Significant differences in mean craving scores favored the 4-mg nicotine mini-lozenge at 3, 5 (primary efficacy), 7, and 10 minutes following treatment. ITT: intent-to-treat In total, 323 were ultimately randomized to treatment including 162 people who received the 4-mg nicotine mini lozenge and 161 who received the flavor-matched placebo. All but one randomized participant completed the study. The person who withdrew was randomized to the 4-mg nicotine mini lozenge but discontinued because of an AE following completion of the craving score at 5 minutes post-treatment. Demographic and smoking characteristics of the treatment and placebo groups were similar, as Table 1 shows. A total of 75 participants (46.3%) in the active treatment group and 79 (49.0%) in the placebo group scored in the 3 highest levels of nicotine dependence (FTND score 8). Primary efficacy analysis. The mean craving scores for the ITT population are plotted from the post-provocation, pre-dose baseline until 10 minutes after dosing (Figure 2). The primary analysis for efficacy of craving relief compared the change in craving scores from baseline to the 5-minute time point. The LSMs of change in craving scores from baseline to 5 minutes were 41.8 (95% CI, 45.8 to 37.7) for the 4-mg nicotine mini lozenge group and 25.9 (95% CI, 30.0 to 21.8) for the placebo group, similar to the arithmetic mean of change in these groups (Table 2). The difference between the LSM of change between the treatment groups ( 15.9) was statistically significant (p <.001). The LSM of change using data only from responders in 76

9 Nides et al Table 2 Least-Square Means (LSM) and Comparison of Changes in Craving Score Over Time, Study 2 (Imputed Data; ITT Population) Time Point 4-mg Nicotine Mini Lozenge, LSM (95% CI) (N = 162) Placebo, LSM (95% CI) (N = 161) Difference between Treatments (p value) 1 min 17.2 ( 20.1, 14.2) 12.9 ( 15.9, 10.0) 4.2 (p <.051) 3 min 31.1 ( 34.8, 27.5) 19.6 ( 23.2, 15.9) 11.6 (p <.001) 5 min a 41.8 ( 45.8, 37.7) 25.9 ( 30.0, 21.8) 15.9 (p <.001) 7 min 48.2 ( 52.5, 43.9) 30.5 ( 34.8, 26.2) 17.8 (p <.001) 10 min 50.8 ( 55.3, 46.2) 32.9 ( 37.5, 28.3) 17.9 (p <.001) Note. a: Primary efficacy was determined at 5 minutes; all other assessments listed are secondary efficacy end points. CI: confidence interval; ITT: intent-to-treat the ITT population also was statistically significant ( 15.8; p <.001). Secondary efficacy analysis. The differences between the LSMs of change in craving scores at the secondary time points of 3, 7, and 10 minutes postdose were statistically significant, p <.001 for each time point (Table 2). A total of 117 of 162 (72.2%) participants in the 4-mg nicotine mini lozenge treatment group and 122 of 161 (75.8%) participants in the placebo group responded to the behaviorally provoked craving paradigm with an increase of one point or more in craving scores from the pre-provocation baseline assessment to the post-provocation, pre-dose assessment, a difference that was not statistically significant (p =.467). The differences in the change from baseline craving scores at 3, 7, and 10 minutes post-dose remained statistically significant (p <.001 for each time point) when the efficacy analysis was repeated using only data from responders in the ITT population. Moreover, the difference in change from baseline to one minute post-dose was statistically significant in the responder population ( 5.9; p =.016). Safety. Overall, 66 study participants reported 77 AEs, with incidence rates of 33.3% in the 4-mg nicotine mini-lozenge group, and 7.5% in the placebo group. The most commonly reported AEs in the 4-mg nicotine mini-lozenge group were nausea (N = 24; 14.8%), hiccups (N = 13; 8.0%), dyspepsia (N = 7; 4.3%), throat irritation (N = 5; 3.1%), dizziness (N = 4; 2.5%), abdominal discomfort (N = 3; 1.9%), and stomatitis (N = 2; 1.2%). Glossodynia was noted in 2 (1.2%) persons in the placebo group; other AEs in the placebo group included nausea, abdominal discomfort, stomatitis, hiccups, throat irritation, and dizziness in one (0.6%) person each. No SAEs occurred during this study. DISCUSSION The 2 studies presented in this report examined the efficacy of NRT mini lozenges to relieve behaviorally provoked nicotine cravings in smokers by having them engage in behaviors (lighting and holding a cigarette) associated with smoking following a 4-hour period of smoking abstinence. Environmental cues (eg, observing smoking, exposure to cigarette advertising, and being in a setting associated with smoking) have been shown to provoke cravings in smokers and are associated with an increased risk of relapses in individuals trying to quit. 6,9,16-18 Previous studies have produced mixed results on whether provoked craving affects smoking relapses, and it has been hypothesized that environmental cues may be important contributors Am J Health Behav. 2018;42(3):69-79 DOI: 77

10 Nicotine Lozenges in the Relief of Behaviorally Provoked Craving to moment-by-moment smoking behavior. 4 In Study 1, a pilot study conducted to enable adequate powering of future studies, the behaviorally provoked craving paradigm produced a craving response in most study participants, but cravings were not significantly relieved by 1.5-mg or 4-mg nicotine mini lozenges in the light/low- or heavy/ high-dependency smoking groups, respectively, versus placebo at any assessment. Prior to this study, we had not assessed light/low-dependency smokers in this model; all previous provoked craving studies using this model were conducted in heavy/high-dependency smokers. The absence of statistically significant treatment differences versus placebo for the 1.5-mg nicotine mini lozenge in Study 1 was not unexpected, given the small sample size in this pilot study, and because the light/lowdependency group members would likely have a greater placebo effect because their cravings would be expected to be more easily blunted compared with heavy/high-dependency smokers. In contrast, whereas drug-placebo differences in craving relief after administration of the 4-mg nicotine mini lozenge to heavy/high-dependency smokers failed to reach statistical significance in Study 1, there was a nonsignificant signal noted at 3 minutes (p =.055) that was used to inform and power Study 2. Further evaluation of light/low-dependency smokers was not pursued. Although treatment with the 1.5-mg nicotine mini lozenge in light/low-dependency smokers provided a reduction in provoked craving as early as one minute post-treatment versus placebo, the difference was not statistically significant; subsequent assessments between the 1.5-mg nicotine mini lozenge and placebo over 15 minutes also failed to show statistically significant differences. The lack of efficacy seen with the 1.5-mg nicotine mini lozenge may have been related to the power of the study to detect such differences, but also may have been impacted by the criteria used to segregate the study population into light/low-dependency or heavy/high-dependency smokers (ie, the number of cigarettes smoked per day: 5 20 per day for light/low-dependency smokers; >20 per day for heavy/high-dependency smokers). If participants had been segregated by time to first cigarette (a fairly common practice in smoking cessation studies), 77% of the participants in the light/lowdependency group would have been designated as highly dependent by having a first cigarette within 30 minutes of awakening (Table 1). Therefore, it may be that the 1.5-mg nicotine mini lozenge showed little effect in reducing behaviorally provoked cravings versus placebo because the nicotine dose was too low for most of the population enrolled in Study 1. Given the results from the pilot study (Study 1), Study 2 investigated the treatment response (ie, relief of behaviorally provoked cravings) of the 4-mg nicotine mini lozenge in heavy/high-dependency smokers. In this adequately powered study, treatment with 4-mg nicotine mini lozenges produced a significantly greater decrease in behaviorally provoked cravings versus placebo for the primary end point (ie, at 5 minutes post-dose) as well as for secondary analyses of provoked craving relief at 3, 7, and 10 minutes post-dose. Both the 1.5-mg and 4-mg nicotine mini lozenges were generally well tolerated in these studies and produced mild AEs that were most commonly associated with gastrointestinal or respiratory system organ classes. Not unexpectedly, more AEs were reported in persons treated with the 4-mg lozenge than with the 1.5-mg lozenge or placebo. Previous research has shown that NRT lozenges are effective in reducing nicotine cravings in smokers. Although differing from the present studies in the time points examined and the exact paradigms tested, this work has shown that both pharmacologic and nonpharmacologic factors can influence the efficacy of nicotine lozenges in reducing behaviorally provoked craving, and also suggests that nicotine lozenges may be more effective in heavier versus lighter smokers. 19,20 Our results are consistent with the hypothesis that heavier smokers might benefit more from using nicotine lozenges to control situational cravings, and the influence of expectation on efficacy in this paradigm should certainly be explored in future studies. Human Subjects Statement The study protocols were reviewed and given favorable opinion prior to initiation of the studies by Institutional Review Boards (Essex Institutional Review Board, Lebanon, NJ; both studies) operating in accordance with local requirements. Both studies are registered at ClinicalTrials.gov (Study 1: 78

11 Nides et al NCT ; Study 2: NCT ). Conflict of Interest Statement WDB has no conflicts to disclose. GMS is an employee of GlaxoSmithKline Consumer Healthcare. MN has received funding for NRT research from McNeil and for research on electronic nicotine delivery systems from NJOY, Altria, and British American Tobacco. He is a member of a speaker s bureau on smoking cessation for Pfizer. No author received an honorarium or other form of financial support related to the development of this manuscript. Acknowledgements This study was sponsored by GlaxoSmithKline Consumer Healthcare, Warren, NJ. Medical writing and editorial support was provided by Erik MacLaren, PhD of Peloton Advantage, Parsippany, NJ, and was funded by GlaxoSmithKline Consumer Healthcare. References 1. World Health Organization. Tobacco Fact Sheet. Available at: fs339/en/. Accessed January 18, Benowitz NL, Hukkanen J, Jacob P, 3rd. Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol. 2009;192: Gallup. Tobacco and smoking. Available at: gallup.com/poll/1717/tobacco-smoking.aspx. Accessed January 18, Dunbar MS, Shiffman S, Kirchner TR, et al. Nicotine dependence, background and cue-induced craving and smoking in the laboratory. Drug Alcohol Depend. 2014;142: Shiffman S, Sayette MA. Validation of the nicotine dependence syndrome scale (NDSS): a criterion-group design contrasting chippers and regular smokers. Drug Alcohol Depend. 2005;79(1): Killen JD, Fortmann SP. Craving is associated with smoking relapse: findings from three prospective studies. Exp Clin Psychopharmacol. 1997;5(2): Zhou X, Nonnemaker J, Sherrill B, et al. Attempts to quit smoking and relapse: factors associated with success or failure from the ATTEMPT cohort study. Addict Behav. 2009;34(4): Bedi G, Preston KL, Epstein DH, et al. Incubation of cue-induced cigarette craving during abstinence in human smokers. Biol Psychiatry. 2011;69(7): Shiffman S. Relapse following smoking cessation: a situational analysis. J Consult Clin Psychol. 1982;50(1): Pack QR, Jorenby DE, Fiore MC, et al. A comparison of the nicotine lozenge and nicotine gum: an effectiveness randomized controlled trial. WMJ. 2008;107(5): Shiffman S, Dresler CM, Hajek P, et al. Efficacy of a nicotine lozenge for smoking cessation. Arch Intern Med. 2002;162(11): Shiffman S, Shadel WG, Niaura R, et al. Efficacy of acute administration of nicotine gum in relief of cueprovoked cigarette craving. Psychopharmacology (Berl). 2003;166(4): Du D, Nides M, Borders J, et al. Comparison of nicotine oral soluble film and nicotine lozenge on efficacy in relief of smoking cue-provoked acute craving after a single dose of treatment in low dependence smokers. Psychopharmacology (Berl). 2014;231(22): Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO. The Fagerstrom Test for Nicotine Dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict. 1991;86(9): Niaura R, Sayette M, Shiffman S, et al. Comparative efficacy of rapid-release nicotine gum versus nicotine polacrilex gum in relieving smoking cue-provoked craving. Addiction. 2005;100(11): Shiffman S, Paty JA, Gnys M, et al. First lapses to smoking: within-subjects analysis of real-time reports. J Consult Clin Psychol. 1996;64(2): Shiffman S, Engberg JB, Paty JA, et al. A day at a time: predicting smoking lapse from daily urge. J Abnorm Psychol. 1997;106(1): Bliss RE, Garvey AJ, Heinold JW, Hitchcock JL. The influence of situation and coping on relapse crisis outcomes after smoking cessation. J Consult Clin Psychol. 1989;57(3): Shiffman S. Effect of nicotine lozenges on affective smoking withdrawal symptoms: secondary analysis of a randomized, double-blind, placebo-controlled clinical trial. Clin Ther. 2008;30(8): Schlagintweit HE, Good KP, Barrett SP. The impact of Am J Health Behav. 2018;42(3):69-79 DOI: 79

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