Progesterone Augmentation of Nicotine Replacement Therapy Study

Study Overview
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Brief Summary
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This will be a double-blind, placebo-controlled, pilot, randomized clinical trial. A total of 50 women who smoke and have regular menstrual cycles will be randomized to either progesterone (200 mgs BID) + Transdermal Nicotine Patch (TNP) or placebo + TNP for 8 weeks. TNP will be tapered after 4-6 weeks. Progesterone or matching placebo will be discontinued at the end of Week 8. All participants will also be provided behavioral treatment for smoking cessation. Participants will be inducted onto progesterone (or placebo) + TNP over a one-week period (Week 1) during the mid luteal phase, within a week before menses and the target quit date will be set for the 5 (+/-2) days after onset of menses. Participants will have post-trial follow-up visits at 1 and 3 months.The main study outcomes will be self- report of smoking abstinence, biochemically verified smoking abstinence, measures of cigarette craving and nicotine withdrawal, and measures of response inhibition.

Detailed Description
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This study seeks to determine if modifying the hormonal milieu of the menstrual cycle, through administration of exogenous progesterone, will improve the effectiveness of treatments for smoking cessation in women. Progesterone, a gonadal hormone, is used clinically for treatment of endometrial hyperplasia, amenorrhea, dysfunctional uterine bleeding, and for assisted reproduction in women. Progesterone also shows promise for the treatment of multiple central nervous system disorders including cocaine addiction, seizure disorder, and traumatic brain injury. As the next step, the investigators seek to determine if progesterone augments standard smoking cessation treatments (e.g., NRT) in regularly cycling women. The investigators hypothesize that co-treatment with progesterone, compared to placebo, will enhance the effectiveness NRT for smoking cessation. To test this hypothesis, the investigators propose an 8-week, double-blind, placebo-controlled clinical trial, which will randomize 50 smokers using a 1:1 assignment ratio to 400 mg/day progesterone or placebo. Consistent with the Clinical Practice Guidelines, all participants will also receive transdermal nicotine patch (TNP) plus brief counseling for smoking cessation during the study participation. Specific Aim #1: To determine if progesterone +TNP is superior to placebo +TNP for prolonged and 7-day point prevalence of smoking abstinence rates at the end of 8 weeks of treatment and at 1 and 3 month follow-up time points. The investigators will also evaluate the safety and tolerability of progesterone treatment, compared to placebo. Our co-primary outcome measures will be 7-day point prevalence of smoking abstinence and breath CO at the end of treatment and 1- and 3-months after the end of the trial. Specific Aim #2: To determine if progesterone + TNP treatment, compared to placebo + TNP, improves response inhibitory function, as assessed by the Stroop, The Go/No Go task, and the Digit Symbol Task. Specific Aim # 3: To determine if progesterone + TNP treatment, compared to placebo + TNP, leads to a greater reduction in cigarette craving and nicotine withdrawal symptoms, as assessed by the Questionnaire on Smoking Urges-Brief (QSU-B) and the Minnesota Nicotine Withdrawal Scale (MNWS), respectively. Specific Aim #4: To evaluate with affective changes, as shown on the Positive and Negative Affect Schedule, mediates the effects of progesterone on smoking abstinence.

Official Title
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Progesterone Augmentation of Nicotine Replacement Therapy Study

Conditions
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Smoking Cessation

Intervention / Treatment
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* Drug: Progesterone (200 mgs BID)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 - 45 Smoking at least 5 cigarettes/ day for at least one year Regular menstrual cycles every 24-36 days for the previous 6 months Motivated to quit smoking (i.e., a rating of at least 7 on a 10-point scale where 1 is not at all motivated and 10 is extremely motivated) In good health Using an acceptable, non-hormonal birth control Exclusion Criteria: A history of major medical or psychological illnesses including: liver disease heart disease diabetes malignancy including history of breast cancer deep vein thrombosis blood coagulation problems including a history or family history of thrombophilia liver failure cervical intra-epithelial lesions III or greater that are untreated other medical conditions that the physician investigators deems will make study participation unsafe for the subject current or past history bipolar disorder or schizophrenia current diagnosis of major depression panic disorder or post-traumatic stress disorder active drug (non-nicotine) and/or alcohol dependence currently undergoing treatment with another pharmacological agent for smoking cessation regular use of sedating medications including sleeping aids, antihistamines, and others use of nicotine from cigars, pipes, chewing tobacco pregnant breast- feeding or intending to become pregnant within 6 months allergy to nicotine patch or progesterone allergy to peanuts or other nuts.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TNP + Progesterone<br>Transdermal Nicotine Patch + Progesterone (200 mgs BID) | Drug: Progesterone (200 mgs BID)<br>* Transdermal Nicotine Patch (TNP) + Progesterone<br>* Other names: Prometrium;|
| Placebo Comparator: TNP + Placebo<br>Transdermal Nicotine Patch + Placebo (for Progesterone) | Drug: Placebo<br>* TNP + Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 7-day Point Prevalence of Smoking Abstinence | The 7-day point prevalence is defined by self-reported smoking abstinence for the last 7 days. | end of 8 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Carbon Monoxide <10 Ppm | Smoking abstinence measured by breath CO | end of 8 weeks of treatment | 
| Carbon Monoxide <10 Ppm | Smoking abstinence measured by breath CO | 1 month follow up | 
| Carbon Monoxide <10 Ppm | Smoking abstinence measured by breath CO | 3 month follow up | 
| Change in Stroop Measure of Inhibitory Function | The Stroop test assesses cognitive processing. The Level 3 Stroop Throughput score incorporates both accuracy and speed. In Level 3 of the Stroop test, a series of words representing colors are shown in a font color that is incongruent with the word (e.g. RED would be shown in blue font). Users are asked to press a response key associated with the color of the font, not the written word. Quicker and more accurate responses lead to higher scores. The lowest possible score is 0 (no correct responses). There is no defined maximum score, as the score depends upon both response time and number of correct responses. A Level 3 Stroop Throughput change score was calculated by subtracting baseline score from week 2 score. Higher positive scores represent greater improvement in scores at week 2 relative to baseline, and lower negative scores represent greater decline in scores from baseline to week 2. | baseline and week 2 | 
| Change in Go/No Go Task Measure of Inhibitory Function | Week 2 minus baseline. This task assesses the ability to withhold responses to an infrequently occurring target (No-Go trials). A total of 225 single digits (25 x 9 digits) are presented on a computer monitor for 250 ms each, immediately followed by a mask for 900 ms. Subjects must press a spacebar in response to every digit except the 3. Go/No Go score is calculated as separation between the means of the signal and the noise distributions and is reported in standard deviation units, representing an overall indicator of performance since it accounts for correct responses and incorrect responses. Higher scores represent a better outcome. For the change score, higher positive scores represent greater improvement in scores between baseline and week 2, and lower negative scores represent greater decline in scores between baseline and week 2. | baseline and week 2 | 
| Change in Digit Symbol Task Measure of Inhibitory Function | The Code Substitution Test (a computerized adaptation/variant of the Digit Symbol Substitution Test) is a test of psychomotor performance. The Code Substitution-Learning Throughput Score incorporates both accuracy and speed. During the learning phase of this test, users are continuously shown a row of 9 digits that are paired with a symbol (the pairings are constant). Users are presented with a series of individual pairings and are asked to press a response key to indicate if the pairing is correct or not. Quicker and more accurate responses lead to higher scores. The lowest possible score is 0 (no correct responses). There is no defined maximum score, as the score depends upon both response time and number of correct responses. A change score was calculated by subtracting baseline score from week 2 score. Higher positive scores represent greater improvement in scores at week 2 relative to baseline, and lower negative scores represent greater decline in scores from baseline to week 2. | baseline and week 2 | 
| Positive and Negative Affect Schedule (PANAS) Total Score | The PANAS questionnaire consists of 20 items that describe different feelings and emotions. Participants are asked to what extent they feel this way right now on 5-point scale ranging from 1 (very slightly or not at all) to 5 (extremely). Separate Positive Affect Scores and Negative Affect Scores were calculated from 10 items each. Scores can range from 10 t0 50, with higher scores representing higher levels of positive affect and with lower scores representing lower levels of negative affect. | Baseline | 
| Positive and Negative Affect Schedule (PANAS) Total Score | The PANAS questionnaire consists of 20 items that describe different feelings and emotions. Participants are asked to what extent they feel this way right now on 5-point scale ranging from 1 (very slightly or not at all) to 5 (extremely). Separate Positive Affect Scores and Negative Affect Scores were calculated from 10 items each. Scores can range from 10 t0 50, with higher scores representing higher levels of positive affect and with lower scores representing lower levels of negative affect. | Week 2 | 
| Positive and Negative Affect Schedule (PANAS) Total Score | The PANAS questionnaire consists of 20 items that describe different feelings and emotions. Participants are asked to what extent they feel this way right now on 5-point scale ranging from 1 (very slightly or not at all) to 5 (extremely). Separate Positive Affect Scores and Negative Affect Scores were calculated from 10 items each. Scores can range from 10 t0 50, with higher scores representing higher levels of positive affect and with lower scores representing lower levels of negative affect. | Week 3 | 
| Positive and Negative Affect Schedule (PANAS) Total Score | The PANAS questionnaire consists of 20 items that describe different feelings and emotions. Participants are asked to what extent they feel this way right now on 5-point scale ranging from 1 (very slightly or not at all) to 5 (extremely). Separate Positive Affect Scores and Negative Affect Scores were calculated from 10 items each. Scores can range from 10 t0 50, with higher scores representing higher levels of positive affect and with lower scores representing lower levels of negative affect. | Week 4 | 
| Positive and Negative Affect Schedule (PANAS) Total Score | The PANAS questionnaire consists of 20 items that describe different feelings and emotions. Participants are asked to what extent they feel this way right now on 5-point scale ranging from 1 (very slightly or not at all) to 5 (extremely). Separate Positive Affect Scores and Negative Affect Scores were calculated from 10 items each. Scores can range from 10 t0 50, with higher scores representing higher levels of positive affect and with lower scores representing lower levels of negative affect. | Week 5 | 
| Positive and Negative Affect Schedule (PANAS) Total Score | The PANAS questionnaire consists of 20 items that describe different feelings and emotions. Participants are asked to what extent they feel this way right now on 5-point scale ranging from 1 (very slightly or not at all) to 5 (extremely). Separate Positive Affect Scores and Negative Affect Scores were calculated from 10 items each. Scores can range from 10 t0 50, with higher scores representing higher levels of positive affect and with lower scores representing lower levels of negative affect. | Week 6 | 
| Positive and Negative Affect Schedule (PANAS) Total Score | The PANAS questionnaire consists of 20 items that describe different feelings and emotions. Participants are asked to what extent they feel this way right now on 5-point scale ranging from 1 (very slightly or not at all) to 5 (extremely). Separate Positive Affect Scores and Negative Affect Scores were calculated from 10 items each. Scores can range from 10 t0 50, with higher scores representing higher levels of positive affect and with lower scores representing lower levels of negative affect. | Week 7 | 
| Positive and Negative Affect Schedule (PANAS) Total Score | The PANAS questionnaire consists of 20 items that describe different feelings and emotions. Participants are asked to what extent they feel this way right now on 5-point scale ranging from 1 (very slightly or not at all) to 5 (extremely). Separate Positive Affect Scores and Negative Affect Scores were calculated from 10 items each. Scores can range from 10 t0 50, with higher scores representing higher levels of positive affect and with lower scores representing lower levels of negative affect. | Week 8 | 
| Positive and Negative Affect Schedule (PANAS) Total Score | The PANAS questionnaire consists of 20 items that describe different feelings and emotions. Participants are asked to what extent they feel this way right now on 5-point scale ranging from 1 (very slightly or not at all) to 5 (extremely). Separate Positive Affect Scores and Negative Affect Scores were calculated from 10 items each. Scores can range from 10 t0 50, with higher scores representing higher levels of positive affect and with lower scores representing lower levels of negative affect. | 1 month follow up | 
| Positive and Negative Affect Schedule (PANAS) Total Score | The PANAS questionnaire consists of 20 items that describe different feelings and emotions. Participants are asked to what extent they feel this way right now on 5-point scale ranging from 1 (very slightly or not at all) to 5 (extremely). Separate Positive Affect Scores and Negative Affect Scores were calculated from 10 items each. Scores can range from 10 t0 50, with higher scores representing higher levels of positive affect and with lower scores representing lower levels of negative affect. | 3 month follow up | 
| Prolonged Abstinence Post Trial | Abstinence from 2 weeks post quit date to the one month follow up | 1-month follow-up after end of treatment | 
| Prolonged Abstinence Follow up | Abstinence from 2 weeks post quit date to 3 month follow up (total of 6-8 weeks during the trial and 3 month follow up) | 3-month follow-up after end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Smoking Cessation, Nicotine Cessation