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Nicotine Replacement Therapy (NRT) and Bupropion Mechanisms of Effectiveness in Smokers

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ClinicalTrials.gov Identifier: NCT01048944
Recruitment Status : Completed
First Posted : January 14, 2010
Results First Posted : November 25, 2014
Last Update Posted : November 25, 2014
Sponsor:
Collaborator:
National Institute on Drug Abuse (NIDA)
Information provided by (Responsible Party):
David Gilbert, Southern Illinois University Carbondale

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Factorial Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Basic Science
Condition Nicotine Dependence
Interventions Drug: Bupropion SR
Drug: Nicotine Patch
Drug: Placebo Patch and Placebo Pill
Enrollment 197
Recruitment Details Recruitment: 9/01/06 to 9/01/11. Recruitment was throughout Carbondale and surrounding communities and occurred with newspaper ads, flyers, radio and television presentations. Recruitment was more challenging than expected because of the large time commitment and high prevalence of psychoactive medication and drug use (exclusionary criteria).
Pre-assignment Details After consent subjects and the completion of their first experimental session subjects were randomly assigned to one of 4 treatment arms: 197 signed the consent, 126 completed the first experimental session and were subsequently randomly assigned to a treatment condition.
Arm/Group Title Bupropion Sustained Release (SR) Nicotine Patch Placebo Patch and Placebo Pill Delayed-quit Control
Hide Arm/Group Description

150 mg bid bupropion SR

Bupropion SR: 150 encapsulated pill,3 days 1x/day then 56/day for 2x/day, then 3 day 1x/day ramp-down.

21mg, 14mg, 7mg

Nicotine: Nicotine patch beginning 1st day cessation: 21 mg/24 days, 14 mg/14 days, 7 mg/7 days

Placebo patch same size as active patches

Placebo pill and Placebo Patch: 150 encapsulated placebo pill,3 days 1x/day then 56/day for 2x/day, then 3 day 1x/day ramp-down. Placebo patch beginning 1st day cessation: 21 mg/24 days, 14 mg/14 days, 7 mg/7 days.

Smoke for 67 days while others have quit, then quit.
Period Title: Overall Study
Started 32 38 35 21
Completed 24 28 25 19
Not Completed 8 10 10 2
Reason Not Completed
Protocol Violation             8             10             10             2
Arm/Group Title Bupropion SR Nicotine Patch Placebo Patch and Placebo Pill Delayed-quit Control Total
Hide Arm/Group Description

150 mg bid bupropion SR

Bupropion SR: 150 encapsulated pill,3 days 1x/day then 56/day for 2x/day, then 3 day 1x/day ramp-down.

21mg, 14mg, 7mg

Nicotine: Nicotine patch beginning 1st day cessation: 21 mg/24 days, 14 mg/14 days, 7 mg/7 days

Placebo patch same size as active patches

Placebo pill and Placebo Patch: 150 encapsulated placebo pill,3 days 1x/day then 56/day for 2x/day, then 3 day 1x/day ramp-down. Placebo patch beginning 1st day cessation: 21 mg/24 days, 14 mg/14 days, 7 mg/7 days.

Smoke for 67 days while others have quit, then quit. Total of all reporting groups
Overall Number of Baseline Participants 32 38 35 21 126
Hide Baseline Analysis Population Description
Personality trait questionnaires, history of psychiatric disorders, SES, age, smoking and drug use history.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 32 participants 38 participants 35 participants 21 participants 126 participants
31.85  (11.76) 30.84  (11.00) 31.49  (10.44) 26.8  (10.42) 30.64  (10.97)
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 32 participants 38 participants 35 participants 21 participants 126 participants
<=18 years
2
   6.3%
2
   5.3%
1
   2.9%
2
   9.5%
7
   5.6%
Between 18 and 65 years
30
  93.8%
36
  94.7%
34
  97.1%
19
  90.5%
119
  94.4%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 32 participants 38 participants 35 participants 21 participants 126 participants
Female
14
  43.8%
18
  47.4%
18
  51.4%
8
  38.1%
58
  46.0%
Male
18
  56.3%
20
  52.6%
17
  48.6%
13
  61.9%
68
  54.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 32 participants 38 participants 35 participants 21 participants 126 participants
32 38 35 21 126
1.Primary Outcome
Title Changes in Log Brain-wave (EEG) Activity (Power [Microvolts Squared]) From Pre-quit Baseline to 66 Days Post-quit, Assessed at 3, 24, 45, and 66 Days Post-quit.
Hide Description Brain-wave activity (EEG) was assessed using electrodes on the subject's scalp, the outputs of which were and quantified by a commercial brain wave machine. EEG was collected at frontal (e.g., Fz) and parietal (e.g., Pz) electrodes while subjects relaxed. EEG was analyzed using computer programs that measured slow-frequency EEG waves known as delta (1.5-4.5 cycles/second [cps]), theta-1 (4.5-6.0 cps), theta-2 (6.0-7.7 cps), and alpha-1 (7.8-10.0 cps), and higher frequency waves. Generally, delta, alpha-1 and theta waves reflect deactivation of the brain activity, while higher frequency waves reflect greater brain activation. Brain activity was quantified as the natural log of EEG power [microvolts squared] as determined by the fast Fourier mathematical algorithm. Days post quit were components of Time. The primary focus was on changes in the individual subject's log theta-1, theta-2, and alpha-1 power at post-quit points in time minus the log values at the pre-quite baseline.
Time Frame Mean EEG power [microvolts squared] from at baseline, 3, 24, 45, and 66 days post-quit
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
For the currently reported analyses, only individuals complying with the study requirements, including biochemically verified smoking abstinence, were assessed. Future analyses will include individuals who complied to certain critical endpoints.
Arm/Group Title Nicotine Patch Bupropion SR Placebo Patch and Placebo Pill Delayed-quit Control
Hide Arm/Group Description:

21mg, 14mg, 7mg

Nicotine: Nicotine patch beginning 1st day cessation: 21 mg/24 days, 14 mg/14 days, 7 mg/7 days

150 mg bid bupropion SR

Bupropion SR: 150 encapsulated pill,3 days 1x/day then 56/day for 2x/day, then 3 day 1x/day ramp-down.

Placebo patch same size as active patches

Placebo pill and Placebo Patch: 150 encapsulated placebo pill,3 days 1x/day then 56/day for 2x/day, then 3 day 1x/day ramp-down. Placebo patch beginning 1st day cessation: 21 mg/24 days, 14 mg/14 days, 7 mg/7 days.

Smoke for 67 days while others have quit, then quit.
Overall Number of Participants Analyzed 28 24 25 19
Mean (Standard Error)
Unit of Measure: Change in log EEG [microvolts squared]
Day-3 Change in log Theta-1 EEG Power Fz .055  (.061) .224  (.066) .234  (.066) -.094  (.071)
Day-24 Change in log Theta-1 EEG Power Fz .194  (.068) .198  (.074) .258  (.074) -.060  (.080)
Day-45 Change in log Theta-1 Power Fz .232  (.055) .249  (.060) .161  (.060) -.032  (.065)
Day-66 Change in log Theta-1 EEG Power Fz .431  (.075) .407  (.081) .184  (.081) -.026  (.087)
Day-3 Change in log Theta-2 Power Fz .062  (.077) .088  (.083) .249  (.083) -.070  (.090)
Day-24 Change in log Theta-2 Power Fz .251  (.087) .150  (.094) .278  (.094) -.042  (.101)
Day-45 Change in log Theta-2 Power Fz .319  (.074) .248  (.081) .278  (.094) .054  (.087)
Day-66 Change in log Theta-2 Power Fz .504  (.092) .502  (.100) .205  (.100) .001  (.107)
Day-3 Change in log Alpha-1 Power Pz -.023  (.103) .155  (.112) .184  (.112) -.004  (.121)
Day-24 Change in log Alpha-1 Power Pz .139  (.099) .301  (.107) .276  (.107) -.001  (.115)
Day 45 Change in log Alpha-1 Power Pz .292  (.099) .261  (.107) .259  (.107) .021  (.115)
Day 66 Change in log Alpha-1 Power Pz .339  (.099) .459  (.107) .292  (.107) .017  (.116)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nicotine Patch, Bupropion SR, Placebo Patch and Placebo Pill, Delayed-quit Control
Comments Mixed-model repeated measures multivariate analyses of variance assessed Treatment x Day of abstinence (days 3, 24, 45, and 66) based on changes from pre-quit baseline to values of the four post-quit time points (days 3, 24, 45, and 66).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments P values are adjusted for multiple comparisons except for specific a priori directional predictions.
Method Mixed Models Analysis
Comments [Not Specified]
2.Primary Outcome
Title Changes in Log of Smoking Withdrawal Scores (Mood, and Depressive Symptoms) From Baseline Across 66 Days of Abstinence
Hide Description Changes in log from baseline in the widely used Shiffman-Jarvik Withdrawal "craving" and "psychological symptom" scores through 66 days of abstinence. Post-quit changes were assessed at days 3, 24, 45, and 66 of abstinence. The maximal range of value raw for craving is from "5" = (no craving) to "47" (maximally strong craving), while that for psychological symptoms is from "5" (no symptoms) to "60" (maximally intense symptoms of across multiple symptoms). Because the subtraction of logs is equivalent to the ratio of the two scores, a difference in logs (base 10) with a value of "1" is equal to an increase by a factor of 10, while a value of "0" is no change, and values of less than "0" are decreases below baseline values.
Time Frame Changes in log withdrawal symptoms from baseline through 66 days of abstinence
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis population included only those individuals who complied fully with study requirements through 67 days of abstinence.
Arm/Group Title Nicotine Patch Bupropion SR Placebo Patch and Placebo Pill Delayed-quit Control
Hide Arm/Group Description:

21mg, 14mg, 7mg

Nicotine: Nicotine patch beginning 1st day cessation: 21 mg/24 days, 14 mg/14 days, 7 mg/7 days

150 mg bid bupropion SR

Bupropion SR: 150 encapsulated pill,3 days 1x/day then 56/day for 2x/day, then 3 day 1x/day ramp-down.

Placebo patch same size as active patches

Placebo pill and Placebo Patch: 150 encapsulated placebo pill,3 days 1x/day then 56/day for 2x/day, then 3 day 1x/day ramp-down. Placebo patch beginning 1st day cessation: 21 mg/24 days, 14 mg/14 days, 7 mg/7 days.

Smoke for 67 days while others have quit, then quit.
Overall Number of Participants Analyzed 28 24 25 19
Mean (Standard Error)
Unit of Measure: log (base 10) units on a scale
Day-3 Change in log Shiffman Craving -.006  (.038) .045  (.042) .094  (.040) -.045  (.046)
Day-24 Change in log Shiffman Craving -.187  (.054) -.199  (.060) -.045  (.057) -.059  (.066)
Day-45 Change in log Shiffman Craving -.273  (.047) -.201  (.052) -.132  (.050) -.043  (.057)
Day-66 Change in log Shiffman Craving -.236  (.054) -.230  (.059) -.205  (.057) -.075  (.065)
Day-3 Change in log Shiffman Psych Withdrawal .089  (.032) .210  (.035) .172  (.034) .016  (.039)
Day-24 Change in log Shiffman Psych W .065  (.031) .102  (.034) .076  (.033) -.025  (.038)
Day-45 Change in log Shiffman Psych Withdrawal .008  (.031) .063  (.034) .039  (.033) -.017  (.038)
Day-66 Change in log Shiffman Psych Withdrawal .068  (.037) .032  (.041) .029  (.039) -.012  (.045)
Time Frame From the day of consent through one year after the 67-day post-quit treatment phase.
Adverse Event Reporting Description Questionnaires at approximately weekly intervals through one year after the 67-day post-quit treatment phase. Then every 3 months until a year after the study.
 
Arm/Group Title Bupropion SR Nicotine Patch Placebo Patch and Placebo Pill Delayed-quit Control
Hide Arm/Group Description

150 mg bid bupropion SR

Bupropion SR: 150 encapsulated pill, 3 days 1x/day then 56 days at 2x/day, then 3 day at 1x/day ramp-down.

21mg, 14mg, 7mg

Nicotine: Nicotine patch beginning 1st day cessation: 21 mg/24 days, 14 mg/14 days, 7 mg/7 days

Placebo patch same size as active patches

Placebo pill and Placebo Patch: 150 encapsulated placebo pill,3 days 1x/day then 56 days at 2x/day, then 3 days at 1x/day ramp-down. Placebo patch beginning 1st day cessation: 21 mg/24 days, 14 mg/14 days, 7 mg/7 days.

Smoke for 67 days while others have quit, then quit.
All-Cause Mortality
Bupropion SR Nicotine Patch Placebo Patch and Placebo Pill Delayed-quit Control
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Bupropion SR Nicotine Patch Placebo Patch and Placebo Pill Delayed-quit Control
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/32 (0.00%)      0/38 (0.00%)      0/35 (0.00%)      0/21 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Bupropion SR Nicotine Patch Placebo Patch and Placebo Pill Delayed-quit Control
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   21/32 (65.63%)      22/38 (57.89%)      19/35 (54.29%)      6/21 (28.57%)    
Gastrointestinal disorders         
Dry Mouth  [1]  13/32 (40.63%)  53 13/38 (34.21%)  34 9/35 (25.71%)  27 2/21 (9.52%)  2
Nausea   4/32 (12.50%)  4 7/38 (18.42%)  12 2/35 (5.71%)  3 1/21 (4.76%)  1
Nervous system disorders         
Headaches  [2]  3/32 (9.38%)  7 3/38 (7.89%)  3 3/35 (8.57%)  4 3/21 (14.29%)  5
Dizzyness  [3]  3/32 (9.38%)  5 1/38 (2.63%)  6 5/35 (14.29%)  7 0/21 (0.00%)  0
Psychiatric disorders         
Sleep disturbance  [4]  13/32 (40.63%)  42 15/38 (39.47%)  63 17/35 (48.57%)  54 2/21 (9.52%)  6
Indicates events were collected by systematic assessment
[1]
Self-reported "dry mouth" on standard questionnaire
[2]
Self-reported "headaches"
[3]
Self-reported "dizziness"
[4]
Self-reported "sleep disturbance" on standard questionnaire.
The modest sample size limited the ability to detect more subtle treatment effects. The exclusionary criteria limits generalization to excluded groups.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: David G. Gilbert, Ph.D.
Organization: Southern Illinois University Carbondale
Phone: 618-45303558
Responsible Party: David Gilbert, Southern Illinois University Carbondale
ClinicalTrials.gov Identifier: NCT01048944     History of Changes
Other Study ID Numbers: NIH/NIDA-2R01DA012289
2R01DA012289 ( U.S. NIH Grant/Contract )
First Submitted: January 13, 2010
First Posted: January 14, 2010
Results First Submitted: May 19, 2014
Results First Posted: November 25, 2014
Last Update Posted: November 25, 2014