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Reduced Nicotine Cigarettes in Smokers With Mood and Anxiety Disorders

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ClinicalTrials.gov Identifier: NCT01928758
Recruitment Status : Completed
First Posted : August 27, 2013
Results First Posted : February 8, 2019
Last Update Posted : June 28, 2019
Sponsor:
Collaborator:
National Institute on Drug Abuse (NIDA)
Information provided by (Responsible Party):
Jonathan Foulds, Milton S. Hershey Medical Center

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Health Services Research
Condition Tobacco Dependence
Interventions Drug: Reduced Nicotine Content Cigarettes
Drug: Usual Nicotine Content Cigarettes
Enrollment 245
Recruitment Details  
Pre-assignment Details 27 participants attended Visit 1 and consented but did not meet final eligibility criteria. The remaining participants (n=218) began a baseline phase during which 30 participants were lost to follow up or withdrawn from the study before being randomized to the study intervention. 188 participants were randomized into an intervention.
Arm/Group Title Reduced Nicotine Content Cigarettes Usual Nicotine Content Cigarettes
Hide Arm/Group Description

The experimental group will smoke cigarettes with gradually Reduced Nicotine Content (11.6, 7.4, 3.3, 1.4, 0.7 and 0.2 mg per cigarette) cigarettes, with each nicotine level smoked for 3 weeks, except the lowest level which continues for 6 weeks

Reduced Nicotine Content Cigarettes: Research cigarettes will have gradually reduced nicotine content

Research cigarettes with a nicotine content similar to participant's usual brand of cigarettes (around 11.6mg)

Usual Nicotine Content Cigarettes: Usual Nicotine Content Cigarettes

Period Title: Overall Study
Started 94 94
Completed 69 74
Not Completed 25 20
Reason Not Completed
Lost to Follow-up             14             9
Withdrawal by Subject             5             2
Adverse Event             3             5
Protocol Violation             3             4
Arm/Group Title Reduced Nicotine Content Cigarettes Usual Nicotine Content Cigarettes Total
Hide Arm/Group Description

The experimental group will smoke cigarettes with gradually Reduced Nicotine Content (11.6, 7.4, 3.3, 1.4, 0.7 and 0.2 mg per cigarette) cigarettes, with each nicotine level smoked for 3 weeks, except the lowest level which continues for 6 weeks

Reduced Nicotine Content Cigarettes: Research cigarettes will have gradually reduced nicotine content

Research cigarettes with a nicotine content similar to participant's usual brand of cigarettes (around 11.6mg)

Usual Nicotine Content Cigarettes: Usual Nicotine Content Cigarettes

Total of all reporting groups
Overall Number of Baseline Participants 94 94 188
Hide Baseline Analysis Population Description
Baseline values for outcomes reflect levels after participants were on the usual nicotine content cigarettes for 2 weeks and before they received the intervention.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 94 participants 94 participants 188 participants
43.3  (11.7) 43.1  (13.3) 43.2  (12.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 94 participants 94 participants 188 participants
Female
60
  63.8%
54
  57.4%
114
  60.6%
Male
34
  36.2%
40
  42.6%
74
  39.4%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 94 participants 94 participants 188 participants
Hispanic or Latino
7
   7.4%
1
   1.1%
8
   4.3%
Not Hispanic or Latino
87
  92.6%
93
  98.9%
180
  95.7%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 94 participants 94 participants 188 participants
Caucasian/white
70
  74.5%
76
  80.9%
146
  77.7%
African American/black
15
  16.0%
11
  11.7%
26
  13.8%
Asian
1
   1.1%
1
   1.1%
2
   1.1%
Native Hawaiian or Pacific Island
0
   0.0%
0
   0.0%
0
   0.0%
American Indian/Alaskan native
2
   2.1%
1
   1.1%
3
   1.6%
Other
6
   6.4%
5
   5.3%
11
   5.9%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 94 participants 94 participants 188 participants
94 94 188
Menthol smoker  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 94 participants 94 participants 188 participants
38
  40.4%
36
  38.3%
74
  39.4%
Quick Inventory of Depressive Symptomatology   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 94 participants 94 participants 188 participants
5.5  (4.8) 6.3  (4.3) 5.9  (4.5)
[1]
Measure Description: The 16-item scale uses a continuous score and the scale range is 0-27 where 0 = Least Severe and 27 = Most Severe.
Perceived Stress Scale   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 94 participants 94 participants 188 participants
16.0  (7.5) 17.1  (8.2) 16.5  (7.9)
[1]
Measure Description: 10-item version was used. Scale range is 0-40. Higher scores indicate more stress.
Overall Anxiety Severity and Impairment Scale   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 94 participants 94 participants 188 participants
4.9  (4.1) 5.7  (4.3) 5.3  (4.2)
[1]
Measure Description: The OASIS is a 5-item scale to measure overall anxiety severity and impairment. The range is 0-20 where higher scores indicate higher anxiety.
Kessler-6 Scale   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 94 participants 94 participants 188 participants
5.6  (5.4) 6.5  (5.1) 6.1  (5.3)
[1]
Measure Description: The Kessler-6 Scale is a 6-item scale with a total possible score range from 0-24 used to define serious psychological distress. Higher scores indicate more distress.
Cigarettes per day  
Mean (Standard Deviation)
Unit of measure:  Cigarettes
Number Analyzed 94 participants 94 participants 188 participants
20.2  (10.7) 21.6  (10.6) 20.9  (10.7)
Exhaled Carbon Monoxide  
Mean (Standard Deviation)
Unit of measure:  Parts per million
Number Analyzed 94 participants 94 participants 188 participants
29.4  (17.7) 29.1  (15.1) 29.3  (16.4)
Plasma Cotinine   [1] 
Mean (Standard Deviation)
Unit of measure:  ng/mL
Number Analyzed 94 participants 94 participants 188 participants
245.7  (137.2) 255.9  (145.5) 250.9  (141.2)
[1]
Measure Description: Cotinine values below the assay Limit of Detection (LOD) are imputed using a common substitution formula (LOD/ square root of 2), which in the case of plasma cotinine equals 3 ng/mL.
Minnesota Nicotine Withdrawal Scale   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 94 participants 94 participants 188 participants
9.9  (7.3) 10.5  (6.3) 10.2  (6.8)
[1]
Measure Description: The scale range is from 0-32 and includes 8 items. The scale is used to measure signs of nicotine withdrawal where higher scores indicate higher severity.
1.Primary Outcome
Title Plasma Cotinine Concentration
Hide Description Plasma cotinine is a measure of daily nicotine exposure. Samples were measured in ng/mL.
Time Frame Measured at the end of the last 3 weeks of randomization trial phase
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized trial phase completers with non-missing values for the outcome at both time points being used in the regression (complete case analysis).
Arm/Group Title Reduced Nicotine Content Cigarettes Usual Nicotine Content Cigarettes
Hide Arm/Group Description:

The experimental group will smoke cigarettes with gradually Reduced Nicotine Content (11.6, 7.4, 3.3, 1.4, 0.7 and 0.2 mg per cigarette) cigarettes, with each nicotine level smoked for 3 weeks, except the lowest level which continues for 6 weeks

Reduced Nicotine Content Cigarettes: Research cigarettes will have gradually reduced nicotine content

Research cigarettes with a nicotine content similar to participant's usual brand of cigarettes (around 11.6mg)

Usual Nicotine Content Cigarettes: Usual Nicotine Content Cigarettes

Overall Number of Participants Analyzed 66 72
Mean (Standard Deviation)
Unit of Measure: ng/mL
82.8  (154.3) 259.0  (151.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Reduced Nicotine Content Cigarettes, Usual Nicotine Content Cigarettes
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Complete case analysis
Method Regression, Linear
Comments Model was adjusted for baseline cotinine after smoking usual nicotine content cigarettes for 2-weeks.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -175.7
Confidence Interval (2-Sided) 95%
-218.3 to -133.1
Estimation Comments The direction of comparison is reduced nicotine content vs. usual nicotine content cigarette treatment group.
2.Secondary Outcome
Title Quick Inventory of Depressive Symptomatology
Hide Description A 16-item scale on depression symptoms. The scale range is 0-27 where 0 = Least Severe and 27 = Most Severe.
Time Frame Measured at the end of the last 3 weeks of randomization trial phase
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized trial phase completers with non-missing values for the outcome at both time points being used in the regression (complete case analysis).
Arm/Group Title Reduced Nicotine Content Cigarettes Usual Nicotine Content Cigarettes
Hide Arm/Group Description:

The experimental group will smoke cigarettes with gradually Reduced Nicotine Content (11.6, 7.4, 3.3, 1.4, 0.7 and 0.2 mg per cigarette) cigarettes, with each nicotine level smoked for 3 weeks, except the lowest level which continues for 6 weeks

Reduced Nicotine Content Cigarettes: Research cigarettes will have gradually reduced nicotine content

Research cigarettes with a nicotine content similar to participant's usual brand of cigarettes (around 11.6mg)

Usual Nicotine Content Cigarettes: Usual Nicotine Content Cigarettes

Overall Number of Participants Analyzed 69 72
Mean (Standard Deviation)
Unit of Measure: score on a scale
5.5  (4.3) 5.3  (3.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Reduced Nicotine Content Cigarettes, Usual Nicotine Content Cigarettes
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.16
Comments Complete case analysis
Method Regression, Linear
Comments Model was adjusted for baseline score after smoking usual nicotine content cigarettes for 2 weeks
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.69
Confidence Interval (2-Sided) 95%
-0.28 to 1.65
Estimation Comments The direction of comparison is reduced nicotine content vs. usual nicotine content cigarette treatment group
3.Secondary Outcome
Title Perceived Stress Scale
Hide Description 10-item questionnaire measuring the degree to which life situations are appraised stressful. Scale range is 0-40. Higher scores indicate more stress.
Time Frame Measured at the end of the last 3 weeks of randomization trial phase
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized trial phase completers with non-missing values for the outcome at both time points being used in the regression (complete case analysis).
Arm/Group Title Reduced Nicotine Content Cigarettes Usual Nicotine Content Cigarettes
Hide Arm/Group Description:

The experimental group will smoke cigarettes with gradually Reduced Nicotine Content (11.6, 7.4, 3.3, 1.4, 0.7 and 0.2 mg per cigarette) cigarettes, with each nicotine level smoked for 3 weeks, except the lowest level which continues for 6 weeks

Reduced Nicotine Content Cigarettes: Research cigarettes will have gradually reduced nicotine content

Research cigarettes with a nicotine content similar to participant's usual brand of cigarettes (around 11.6mg)

Usual Nicotine Content Cigarettes: Usual Nicotine Content Cigarettes

Overall Number of Participants Analyzed 69 74
Mean (Standard Deviation)
Unit of Measure: score on a scale
15.0  (7.6) 15.1  (7.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Reduced Nicotine Content Cigarettes, Usual Nicotine Content Cigarettes
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.67
Comments Complete case analysis
Method Regression, Linear
Comments Model was adjusted for baseline score after smoking usual nicotine content cigarettes for 2 weeks
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.38
Confidence Interval (2-Sided) 95%
-1.40 to 2.16
Estimation Comments The direction of comparison is reduced nicotine content vs. usual nicotine content cigarette treatment group.
4.Secondary Outcome
Title Minnesota Nicotine Withdrawal Scale
Hide Description This 8-item scale measures nicotine withdrawal symptoms and the scale range is from 0-32. Higher scores indicate higher severity.
Time Frame Measured at the end of the last 3 weeks of randomization trial phase
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized trial phase completers with non-missing values for the outcome at both time points being used in the regression (complete case analysis).
Arm/Group Title Reduced Nicotine Content Cigarettes Usual Nicotine Content Cigarettes
Hide Arm/Group Description:

The experimental group will smoke cigarettes with gradually Reduced Nicotine Content (11.6, 7.4, 3.3, 1.4, 0.7 and 0.2 mg per cigarette) cigarettes, with each nicotine level smoked for 3 weeks, except the lowest level which continues for 6 weeks

Reduced Nicotine Content Cigarettes: Research cigarettes will have gradually reduced nicotine content

Research cigarettes with a nicotine content similar to participant's usual brand of cigarettes (around 11.6mg)

Usual Nicotine Content Cigarettes: Usual Nicotine Content Cigarettes

Overall Number of Participants Analyzed 69 74
Mean (Standard Deviation)
Unit of Measure: score on a scale
8.1  (6.8) 9.0  (5.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Reduced Nicotine Content Cigarettes, Usual Nicotine Content Cigarettes
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.65
Comments Complete case analysis
Method Regression, Linear
Comments Model was adjusted for baseline score after smoking usual nicotine content cigarettes for 2 weeks
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.31
Confidence Interval (2-Sided) 95%
-1.68 to 1.05
Estimation Comments The direction of comparison is reduced nicotine content vs. usual nicotine content cigarette treatment group
5.Other Pre-specified Outcome
Title Intention to Quit Smoking
Hide Description Smokers assigned to the reduced nicotine content cigarette group may have lower perceived dependence and be more likely to report intention to quit smoking
Time Frame At end of 18-week randomized trial phase
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who attended the visit at the end of the 18-week randomized trial phase
Arm/Group Title Reduced Nicotine Content Cigarettes Usual Nicotine Content Cigarettes
Hide Arm/Group Description:

The experimental group will smoke cigarettes with gradually Reduced Nicotine Content (11.6, 7.4, 3.3, 1.4, 0.7 and 0.2 mg per cigarette) cigarettes, with each nicotine level smoked for 3 weeks, except the lowest level which continues for 6 weeks

Reduced Nicotine Content Cigarettes: Research cigarettes will have gradually reduced nicotine content

Research cigarettes with a usual nicotine content (around 11.6mg per cigarette)

Usual Nicotine Content Cigarettes: Usual Nicotine Content Cigarettes

Overall Number of Participants Analyzed 69 74
Measure Type: Count of Participants
Unit of Measure: Participants
33
  47.8%
25
  33.8%
6.Other Pre-specified Outcome
Title Abstinence From Smoking
Hide Description Smokers assigned to reduced nicotine content cigarettes will be more likely to successfully abstain from smoking at the end of the trial, based on all randomized participants, defined as no cigarette use in past 7 days, verified by exhaled carbon monoxide <10ppm.
Time Frame Follow-up appointment 30 weeks after randomization (12 weeks after last visit of randomized trial phase).
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants
Arm/Group Title Reduced Nicotine Content Cigarettes Usual Nicotine Content Cigarettes
Hide Arm/Group Description:

The experimental group will smoke cigarettes with gradually Reduced Nicotine Content (11.6, 7.4, 3.3, 1.4, 0.7 and 0.2 mg per cigarette) cigarettes, with each nicotine level smoked for 3 weeks, except the lowest level which continues for 6 weeks

Reduced Nicotine Content Cigarettes: Research cigarettes will have gradually reduced nicotine content

Research cigarettes with a nicotine content similar to participant's usual brand of cigarettes (around 11.6mg)

Usual Nicotine Content Cigarettes: Usual Nicotine Content Cigarettes

Overall Number of Participants Analyzed 94 94
Measure Type: Count of Participants
Unit of Measure: Participants
17
  18.1%
4
   4.3%
Time Frame All randomized participants throughout the entire 33 weeks of the trial.
Adverse Event Reporting Description Adverse events (AEs) were systematically collected at each study visit by asking participants about any changes in their physical or mental health or if they needed to seek immediate medical care at an emergency room or hospital.
 
Arm/Group Title Reduced Nicotine Content Cigarettes Usual Nicotine Content Cigarettes
Hide Arm/Group Description

The experimental group will smoke cigarettes with gradually Reduced Nicotine Content (11.6, 8.6, 4.0, 1.8, 0.9 and 0.3 mg per cigarette) cigarettes, with each nicotine level smoked for 3 weeks, except the lowest level which continues for 6 weeks

Reduced Nicotine Content Cigarettes: Research cigarettes will have gradually reduced nicotine content

Research cigarettes with a nicotine content similar to participant's usual brand of cigarettes (around 11.6mg)

Usual Nicotine Content Cigarettes: Usual Nicotine Content Cigarettes

All-Cause Mortality
Reduced Nicotine Content Cigarettes Usual Nicotine Content Cigarettes
Affected / at Risk (%) Affected / at Risk (%)
Total   0/94 (0.00%)      0/94 (0.00%)    
Hide Serious Adverse Events
Reduced Nicotine Content Cigarettes Usual Nicotine Content Cigarettes
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   7/94 (7.45%)      10/94 (10.64%)    
Cardiac disorders     
Cardiac disorders - Other  1 [1]  1/94 (1.06%)  1 0/94 (0.00%)  0
Heart failure  1  0/94 (0.00%)  0 1/94 (1.06%)  1
Acute coronary syndrome  1  0/94 (0.00%)  0 1/94 (1.06%)  1
Aortic valve disease  1  0/94 (0.00%)  0 1/94 (1.06%)  1
Infections and infestations     
Appendicitis  1  1/94 (1.06%)  1 0/94 (0.00%)  0
Endocarditis infective  1  0/94 (0.00%)  0 1/94 (1.06%)  1
Infections and infestations - Other  1 [2]  1/94 (1.06%)  1 1/94 (1.06%)  1
Upper respiratory infection  1  1/94 (1.06%)  1 0/94 (0.00%)  0
Injury, poisoning and procedural complications     
Fracture  1  1/94 (1.06%)  1 0/94 (0.00%)  0
Injury, poisoning and procedural complications - Other  1 [3]  0/94 (0.00%)  0 1/94 (1.06%)  1
Musculoskeletal and connective tissue disorders     
Musculoskeletal and connective tissue disorder - Other  1 [4]  0/94 (0.00%)  0 1/94 (1.06%)  1
Psychiatric disorders     
Depression  1  1/94 (1.06%)  1 1/94 (1.06%)  1
Psychiatric disorders - Other  1 [5]  0/94 (0.00%)  0 1/94 (1.06%)  1
Suicidal ideation  1  1/94 (1.06%)  1 0/94 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Dyspnea  1  0/94 (0.00%)  0 1/94 (1.06%)  1
Respiratory, thoracic and mediastinal disorders - Other  1  0/94 (0.00%)  0 1/94 (1.06%)  1
Surgical and medical procedures     
Surgical and medical procedures - Other  1 [6]  0/94 (0.00%)  0 1/94 (1.06%)  1
1
Term from vocabulary, MedDRA (12.0)
Indicates events were collected by systematic assessment
[1]
Blocked artery
[2]
Lung and leg infection
[3]
Accidental drug overdose
[4]
Rhabdomyolysis
[5]
Drug relapse
[6]
Dog bite requiring surgery
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Reduced Nicotine Content Cigarettes Usual Nicotine Content Cigarettes
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   70/94 (74.47%)      72/94 (76.60%)    
General disorders     
Flu like symptoms  1  9/94 (9.57%)  9 11/94 (11.70%)  14
Infections and infestations     
Upper respiratory infection  1  29/94 (30.85%)  32 24/94 (25.53%)  30
Musculoskeletal and connective tissue disorders     
Back pain  1  3/94 (3.19%)  4 6/94 (6.38%)  6
Pain in extremity  1  5/94 (5.32%)  5 3/94 (3.19%)  3
Nervous system disorders     
Headache  1  8/94 (8.51%)  9 4/94 (4.26%)  5
Psychiatric disorders     
Anxiety  1  22/94 (23.40%)  28 19/94 (20.21%)  22
Depression  1  30/94 (31.91%)  39 21/94 (22.34%)  26
Irritability  1  4/94 (4.26%)  4 6/94 (6.38%)  7
Suicidal ideation  1  14/94 (14.89%)  14 11/94 (11.70%)  11
Respiratory, thoracic and mediastinal disorders     
Allergic rhinitis  1  6/94 (6.38%)  6 3/94 (3.19%)  3
Cough  1  5/94 (5.32%)  5 5/94 (5.32%)  5
Respiratory, thoracic and mediastinal disorders - Other  1  9/94 (9.57%)  13 13/94 (13.83%)  15
Surgical and medical procedures     
Surgical and medical procedures - Other  1  5/94 (5.32%)  5 5/94 (5.32%)  5
Vascular disorders     
Hypertension  1  3/94 (3.19%)  3 7/94 (7.45%)  7
1
Term from vocabulary, MedDRA (12.0)
Indicates events were collected by systematic assessment
The sample size was not reached due to a shortage of study cigarette inventory.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Jonathan Foulds
Organization: Penn State College of Medicine
Phone: 717-531-3504
EMail: jfoulds@psu.edu
Layout table for additonal information
Responsible Party: Jonathan Foulds, Milton S. Hershey Medical Center
ClinicalTrials.gov Identifier: NCT01928758    
Other Study ID Numbers: STUDY911
P50DA036107 ( U.S. NIH Grant/Contract )
First Submitted: August 21, 2013
First Posted: August 27, 2013
Results First Submitted: January 11, 2019
Results First Posted: February 8, 2019
Last Update Posted: June 28, 2019