Trial Outcomes & Findings for Depressed Mood Improvement Through Nicotine Dosing 2 (NCT NCT04433767)

NCT ID: NCT04433767

Last Updated: 2023-12-06

Results Overview

Primary mood outcome measured by the total score of the clinician rated MADRS. MADRS will be measured every 3 weeks (baseline, week 3, week 6, week 9, and week 12). MADRS total score range is 0-60, where higher scores indicate greater depression severity. Change is calculated as the difference between week 12 and baseline.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 29 participants
• Primary outcome timeframe: Baseline to week 12
• Results posted on: 2023-12-06

Participant Flow

Recruited from mental health clinic and the community at Vanderbilt University Medical Center in Nashville, Tennessee. Recruitment began in December, 2020 and ended in June 2022. Of 34 consented, 30 individuals met entry criteria. One participant withdrew consent prior to randomization, resulting in a final randomized sample of 29 individuals.

Eligible participants were only excluded for the study if they withdrew consent or for concerns for MRI safety.

Participant milestones

Measure	Transdermal Nicotine Patch Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.
Overall Study STARTED	29
Overall Study COMPLETED	28
Overall Study NOT COMPLETED	1

Reasons for withdrawal

Measure

Transdermal Nicotine Patch Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Overall Study Adverse Event

1

Baseline Characteristics

Depressed Mood Improvement Through Nicotine Dosing 2

Baseline characteristics by cohort

Measure	Transdermal Nicotine Patch n=29 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.
Age, Continuous	68.2 years STANDARD_DEVIATION 4.9 • n=5 Participants
Sex: Female, Male Female	23 Participants n=5 Participants
Sex: Female, Male Male	6 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants
Race (NIH/OMB) White	26 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United States	29 participants n=5 Participants
Mini-Mental State Exam (MMSE) Score	29.1 units on a scale STANDARD_DEVIATION 0.7 • n=5 Participants
Montgomery-Asberg Depression Rating Scale (MADRS) Score	23.8 units on a scale STANDARD_DEVIATION 4.2 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline to week 12

Population: Includes 29 participants randomized, 28 of whom completed all 12 weeks and 1 completed through week 6.

Primary mood outcome measured by the total score of the clinician rated MADRS. MADRS will be measured every 3 weeks (baseline, week 3, week 6, week 9, and week 12). MADRS total score range is 0-60, where higher scores indicate greater depression severity. Change is calculated as the difference between week 12 and baseline.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

MADRS (Montgomery Asberg Depression Rating Scale) Score Change

-15.4 units on a scale Standard Deviation 6.7

PRIMARY outcome

Timeframe: Baseline, week 6, week 12

Population: Includes 29 participants randomized, 28 of whom completed all 12 weeks and 1 completed through week 6.

MRI scans will be performed at baseline, week 6 and week 12. MRI will measure cognitive control network function, operationalized as a reduction in the emotional Stroop task functional MRI response in the middle and superior frontal gyri. The Stroop functional MRI response is calculated as the activation difference between incongruent and congruent conditions of the emotional Stroop task.

The primary outcome is change in activation difference across the three time points. This is examined as a categorical variable, operationalized as those subjects who exhibit a middle / superior frontal gyri z-score reduction in activation over time of 0.5 or greater, relative to baseline at either week 6 and/or week 12. The a priori threshold being tested was that 60% or more of participants would exhibit a z-score reduction of 0.5 or greater, examined separately in the left and right middle and superior frontal gyri.

Outcome measures

Measure	Transdermal Nicotine Patch n=29 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.
Number of Participants Exhibiting Reduction in Frontal Activation During the Emotional Stroop Task During Functional Magnetic Resonance Imaging (MRI) Left Middle Frontal Gyrus, total region	18 Participants
Number of Participants Exhibiting Reduction in Frontal Activation During the Emotional Stroop Task During Functional Magnetic Resonance Imaging (MRI) Left Superior Frontal Gyrus, Total region	16 Participants
Number of Participants Exhibiting Reduction in Frontal Activation During the Emotional Stroop Task During Functional Magnetic Resonance Imaging (MRI) Right Middle Frontal Gyrus, total region	17 Participants
Number of Participants Exhibiting Reduction in Frontal Activation During the Emotional Stroop Task During Functional Magnetic Resonance Imaging (MRI) Right Superior Frontal Gyrus, total region	10 Participants

SECONDARY outcome

Timeframe: Baseline to week 12

Population: Analyses includes 28 randomized participants as 1 participant withdrew at week 6 so did not complete end of study assessments.

Secondary Cognitive Outcome: This neuropsychological test battery assesses a range of executive functions. Its Executive Composite Score is a single score that represents overall executive function performance across multiple individual neuropsychological tests, including the Dot counting test, the N-back test, the Flanker task, a continuous performance test, anti-saccades test, a set shifting test, and fluency tests. Higher scores indicate better executive function, with a range of -3.0 to 3.0. This composite is generated separately from EXAMINER sub scales.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

NIH EXAMINER Test Battery Executive Composite Score Change

0.16 units on a scale Standard Deviation 0.31

SECONDARY outcome

Timeframe: Baseline to week 12

Population: Analyses includes 28 randomized participants as 1 participant withdrew at week 6 so did not complete end of study assessments.

Secondary Cognitive Outcome: This neuropsychological test battery assesses a range of executive functions. Its Cognitive Control Factor Score is a single score that represents cognitive control function performance across multiple individual neuropsychological tests, including the Flanker task, a continuous performance test, anti-saccades test, and a set shifting test. Higher scores indicate better executive function, with a range of -3.0 to 3.0. This is calculated independently of the executive composite or other factor scores.

Secondary Cognitive Outcome: This neuropsychological test battery assesses a range of executive functions. We will examine its Executive Composite Score and the three factor scores (Cognitive Control, Fluency, and Working Memory). Higher scores indicate better performance.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

NIH EXAMINER Test Battery Cognitive Control Factor Change

0.29 units on a scale Standard Deviation 0.50

SECONDARY outcome

Timeframe: Baseline to week 12

Population: Analyses includes 28 randomized participants as 1 participant withdrew at week 6 so did not complete end of study assessments.

Secondary Cognitive Outcome: This neuropsychological test battery assesses a range of executive functions. Its Fluency Factor Score is a single score that represents verbal fluency performance across phonemic and categorical fluency assessments. Higher scores indicate better executive function, with a range of -3.0 to 3.0. This is calculated independently of the executive composite or other factor scores.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

NIH EXAMINER Test Battery Fluency Factor Change

0.18 units on a scale Standard Deviation 0.52

SECONDARY outcome

Timeframe: Baseline to week 12

Population: Analyses includes 28 randomized participants as 1 participant withdrew at week 6 so did not complete end of study assessments.

Secondary Cognitive Outcome: The EXAMINER test battery Working Memory Factor Score is a single score that represents working memory performance across multiple individual neuropsychological tests, including the Dot counting and n-back tests. Higher scores indicate better executive function, with a range of -3.0 to 3.0. This is calculated independently of the executive composite or other factor scores.

Secondary Cognitive Outcome: This neuropsychological test battery assesses a range of executive functions. We will examine its Executive Composite Score and the three factor scores (Cognitive Control, Fluency, and Working Memory). Higher scores indicate better performance.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

NIH EXAMINER Test Battery Working Memory Factor Change

0.05 units on a scale Standard Deviation 0.69

SECONDARY outcome

Timeframe: Baseline to week 12

Population: Analyses includes 28 randomized participants as 1 participant withdrew at week 6 so did not complete end of study assessments.

Secondary cognitive outcome, a neuropsychological test measure of attention. We will examine change in total reaction time for the CRT. Lower reaction time indicates better performance.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Choice Reaction Time (CRT) Performance Change

-0.67 Milliseconds Standard Deviation 123.40

SECONDARY outcome

Timeframe: Baseline to week12

Population: Analyses includes 28 randomized participants as 1 participant withdrew at week 6 so did not complete end of study assessments.

Secondary cognitive outcome, Selective Reminding Task as a test of immediate and delayed verbal memory. This is an 8-trial, 16-word test where the interviewer reads unrelated words to the participant who must recall them. Any missed items are then repeated before the next attempt. Scores range from 0-60, with higher scores indicating better performance. Change in the recall over 12 weeks reflect the verbal memory function, with higher scores indicating better verbal memory performance.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Selective Reminding Task Performance Change

0.33 units on a scale Standard Deviation 16.61

SECONDARY outcome

Timeframe: Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported

Population: Analyses includes 29 randomized participant, however 1 participant withdrew at week 6 so did not complete 12 week assessments.

Participants view a series of randomized, rapidly presented positive and negative characteristics and quickly indicate whether each adjective does or does not apply to them. Positive and negative adjectives are balanced. Measures include number of adjectives endorsed or rejected, and RT for those trials. These are assessed separately for positive items endorsed and negative items rejected. Task performance assesses self-referential negativity bias and is associated with antidepressant response. Task completed at baseline, week 6, and week 12. Scores for positive items endorsed range from 0 to 24, with higher scores indicating more positive items being endorsed, so a reduction in negativity bias.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Trait Adjectives Task, Change in Positive Items Endorsed

2.28 units on a scale Standard Deviation 5.55

SECONDARY outcome

Timeframe: Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported

Population: Analyses includes 29 randomized participant, however 1 participant withdrew at week 6 so did not complete 12 week assessments.

Participants view a series of randomized, rapidly presented positive and negative characteristics and quickly indicate whether each adjective does or does not apply to them. Positive and negative adjectives are balanced. Measures include number of adjectives endorsed or rejected, and RT for those trials. These are assessed separately for positive items endorsed and negative items rejected. Task performance assesses self-referential negativity bias and is associated with antidepressant response. Task completed at baseline, week 6, and week 12. Scores for negative items rejected range from 0 to 24, with higher scores indicating that more negative items are rejected, thus a reduction in negativity bias.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Trait Adjectives Task, Change in Negative Items Rejected

1.92 units on a scale Standard Deviation 4.87

SECONDARY outcome

Timeframe: Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported

Population: Analyses includes 29 randomized participant, however 1 participant withdrew at week 6 so did not complete 12 week assessments.

Participants view a series of randomized, rapidly presented positive and negative characteristics and quickly indicate whether each adjective does or does not apply to them. Positive and negative adjectives are balanced. Measures include number of adjectives endorsed or rejected, and RT for those trials. These are assessed separately for positive items endorsed and negative items rejected. Task performance assesses self-referential negativity bias and is associated with antidepressant response. Task completed at baseline, week 6, and week 12. A score reduction represents increased reaction time.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Trait Adjectives Task, Change in Reaction Time to Endorse Positive Items

-120.99 milliseconds Standard Deviation 228.89

SECONDARY outcome

Timeframe: Assessed at baseline, week 6, and week 12, change from baseline to week 12 reported

Population: Analyses includes 29 randomized participant, however 1 participant withdrew at week 6 so did not complete 12 week assessments.

Participants view a series of randomized, rapidly presented positive and negative characteristics and quickly indicate whether each adjective does or does not apply to them. Positive and negative adjectives are balanced. Measures include number of adjectives endorsed or rejected, and RT for those trials. These are assessed separately for positive items endorsed and negative items rejected. Task performance assesses self-referential negativity bias and is associated with antidepressant response. Task completed at baseline, week 6, and week 12. A reduction in score indicates a faster reaction time.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Trait Adjectives Task, Change in Reaction Time to Reject Negative Items

-149.20 milliseconds Standard Deviation 252.25

SECONDARY outcome

Timeframe: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.

Population: Analyses includes 29 randomized participant, however 1 participant withdrew at week 6 so did not complete 12 week assessments.

Secondary mood outcome: Change in rumination measured by the Ruminative Response Scale total score measured at Screening visit, week 6 and week 12. This is a self-report scale with a range of 0-66, where higher scores indicate higher levels of rumination

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Ruminative Response Scale Score Change

-7.32 score on a scale Standard Deviation 12.27

SECONDARY outcome

Timeframe: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.

Population: Analyses includes 29 randomized participant, however 1 participant withdrew at week 6 so did not complete 12 week assessments.

Secondary Mood Outcomes: Change in apathy as measured by the self-report AES, a questionnaire with a range of 0-54, where higher scores indicate greater apathy. Measured at baseline, week 6, and week 12.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Apathy Evaluation Scale (AES) Score Change

-7.36 score on a scale Standard Deviation 8.91

SECONDARY outcome

Timeframe: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.

Population: Analyses includes 29 randomized participant, however 1 participant withdrew at week 6 so did not complete 12 week assessments.

Secondary Mood Outcomes: Change in the severity of insomnia measures as self-report , a questionnaire with the range of 0-21 ,where higher scores indicate increase in severity. Assessed at baseline, week 6, and week 12.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Insomnia Severity Index Score Change

-4.50 score on a scale Standard Deviation 7.36

SECONDARY outcome

Timeframe: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.

Population: Analyses includes 29 randomized participant, however 1 participant withdrew at week 6 so did not complete 12 week assessments.

Secondary mood outcome: Change in anxiety and worry measured by PSWQ, a self-report questionnaire with a range of 16-80, where higher scores indicate greater anxiety and worry. Assessed at baseline, week 6, and week 12.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Penn State Worry Questionnaire (PSWQ) Score Change

-5.07 score on a scale Standard Deviation 22.39

SECONDARY outcome

Timeframe: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.

Population: 29 participants analyzed, although one participant withdrew at week 6 before trial completion.

Secondary outcome examining fatigue using a self-report questionnaire that ranges from 0- 56, where higher scores indicate more severe fatigue. Questionnaire administered at baseline, week 6, and week 12.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Fatigue Severity Scale Score Change

-3.15 score on a scale Standard Deviation 14.0

SECONDARY outcome

Timeframe: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.

Population: Analyses includes 29 randomized participant, however 1 participant withdrew at week 6 so did not complete 12 week assessments.

Secondary mood outcome: Change in anhedonia measured by DARS, a self-report questionnaire that ranges from 0-68, where lower scores indicate greater anhedonia. Conversely, higher scores indicate greater ability to enjoy activities. Assessed at baseline, week 6, and week 12.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Dimensional Anhedonia Rating Scale (DARS) Score Change

4.63 score on a scale Standard Deviation 10.47

SECONDARY outcome

Timeframe: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.

Population: Analyses includes 29 randomized participant, however 1 participant withdrew at week 6 so did not complete 12 week assessments.

Secondary Mood outcome: self-reported questionnaire to measure the severity of anxiety. Questionnaire ranges 0-24, higher scores indicates greater anxiety state. Assessed at baseline, week 6, and week 12.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

General Anxiety Disorder-7 Item Scale (GAD7) Score Change

-2.38 score on a scale Standard Deviation 3.37

SECONDARY outcome

Timeframe: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.

Population: Analyses includes 29 randomized participant, however 1 participant withdrew at week 6 so did not complete 12 week assessments.

Secondary Cognitive outcome:PROMIS (Patient reported outcome measurement information system) is a self-reported questionnaire to measure mental acuity, concentration, verbal and nonverbal memory, verbal fluency, and perceived changes in these cognitive functions, ranges from 0-32 , where higher scores indicate improvement. Assessed at baseline, week 6, and week 12.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Patient Reported Outcome Measurement Information System (PROMIS) Applied Cognition Abilities Short Form Score Change

5.15 score on a scale Standard Deviation 8.27

SECONDARY outcome

Timeframe: Assessed at baseline, week 6, and week 12; only change in baseline to week 12 reported.

Population: Analyses includes 29 randomized participant, however 1 participant withdrew at week 6 so did not complete 12 week assessments.

Secondary Attention outcome: The Attentional Control Scale (ACS) is a self-report questionnaire that has been developed to measure individual differences in attentional control. The scale ranges from 0-80, with higher scores indicative of better attentional control, and a positive change indicated improved attentional control. Assessed at baseline, week 6, and week 12.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Attentional Control Scale Score Change

6.04 score on a scale Standard Deviation 9.96

SECONDARY outcome

Timeframe: Assessed at baseline, Week 6, and Week 12; only baseline to week 12 reported.

Population: Includes 29 participants randomized, 28 of whom completed all 12 weeks and 1 completed through week 6.

The ASI-3 is a self-report questionnaire assesses anxiety sensitivity, or the fear of arousal-related sensations. Specifically these derive from the belief that anxiety- or arousal-based sensations have negative consequences. This self-report scale includes 18 items with scores ranging from 0 to 72, where higher scores indicate greater anxiety sensitivity.

Outcome measures

Measure

Transdermal Nicotine Patch n=28 Participants Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Anxiety Sensitivity Index 3 (ASI-3) Score Change

-4.40 score on a scale Standard Deviation 10.86

Adverse Events

Transdermal Nicotine Patch

Serious events: 1 serious events

Other events: 26 other events

Deaths: 0 deaths

Serious adverse events

Measure

Transdermal Nicotine Patch n=29 participants at risk Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.

Injury, poisoning and procedural complications Fall

3.4% 1/29 • Number of events 1 • Fifteen weeks

Other adverse events

Measure	Transdermal Nicotine Patch n=29 participants at risk Participants will wear open label transdermal nicotine patch daily for 12-15 weeks. They will apply study patch each morning and remove at bedtime. Dosage will begin at 3.5mg patch / day, increasing to a possible maximum of 21mg patch / day. Transdermal Nicotine patch: Participants will begin a 12- week open label trial of transdermal nicotine patch during the day and remove it at night (16 hours). Dose titration starting at 3.5 mg patch/daily to maximum of 21mg patch/daily. After week 12 , dose will be slowly tapered over 3 weeks.
Skin and subcutaneous tissue disorders Skin reaction	44.8% 13/29 • Fifteen weeks
Nervous system disorders Dizziness	17.2% 5/29 • Fifteen weeks
Nervous system disorders Headache	17.2% 5/29 • Fifteen weeks
Gastrointestinal disorders Nausea	17.2% 5/29 • Fifteen weeks
Psychiatric disorders Increased tension and inner restlessness	10.3% 3/29 • Fifteen weeks
Nervous system disorders Insomnia	10.3% 3/29 • Fifteen weeks
Nervous system disorders Increased dream activity	10.3% 3/29 • Fifteen weeks

Additional Information

Warren Taylor, MD, Director of the DIvision of Geriatric Psychiatry

Vanderbilt University Medical Cdenter

Phone: 615-322-1073

Email: warren.d.taylor@vumc.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place