Tobacco Use Disorder
Conditions
Keywords
Progesterone, Placebo, Postpartum, Tobacco, Pregnancy
Brief summary
Smoking is the main preventable cause of mortality in Western countries, contributing to over 430,000 deaths a year in the U.S. alone. Clinical and epidemiological studies show that women often decrease smoking in pregnancy, when progesterone levels are high. However, at least half resume pre-pregnancy smoking levels within weeks after delivery and when progesterone levels drop. Data from preclinical and clinical studies suggest that progesterone may be effective in preventing relapse to smoking in non-postpartum women. Prior work has shown that progesterone decreases both craving for cigarettes and the subjective rewarding effects of smoking among recently abstinent female smokers. These findings led us to hypothesize that progesterone may have efficacy as a relapse prevention treatment for postpartum women. We propose an 8-week, randomized pilot study to evaluate the safety and initial efficacy of progesterone. This will be a feasibility study that will compare progesterone to placebo for relapse prevention in 40 postpartum smokers. We will assess the feasibility and safety, including the potential effects on breastfeeding and infants exposed via breast milk, in addition to 7-day point prevalence of smoking abstinence after 8 weeks of treatment and at follow-up, 3-months after the end of the protocol.
Interventions
DRUGProgesterone
oral micronized progesterone
DRUGPlacebo
Sponsors
National Institute on Drug Abuse (NIDA)
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 42 Years
Healthy volunteers
Yes
Inclusion criteria
* Need to be within 3 weeks of delivery because relapse to smoking happens early after childbirth * Aged 18 to 42 years * history of smoking, with smoking and other nicotine product abstinence achieved in the final two months of pregnancy and at delivery * In good health as verified by medical history * Using acceptable birth control methods other than hormonal contraceptives that contain progestins * Have biologically confirmed abstinence from tobacco and other nicotine products at randomization
Exclusion criteria
* A history of major medical illnesses including liver diseases, suspected or known malignancy, thrombophlebitis, liver failure, or other medical conditions that the physician investigator deems will make study participation unsafe for the subject * Current or past history bipolar disorder or schizophrenia or current diagnosis of major depression, panic disorder or post-traumatic stress disorder * Dependence on and/or abuse of alcohol or other drugs of abuse in the month prior to randomization into the trial * the presence of suicidal or homicidal ideation, or significant impairment of social or occupational functioning, either at study baseline during the evaluation process, or during participation in the trial * inability to speak Spanish or English (our group is bilingual) * plans to move out of the area within 8 months after study screening since this will make follow-up difficult * Inability to understand study procedures or provide informed consent * Currently undergoing treatment with another pharmacological agent for smoking cessation * pending legal case that may result in incarceration since this would force abstinence and impede follow-up; * Pending case with child protective services that might lead removal of infant from mother's custody, as this would impede breastfeeding and infant follow-up * Unwilling to accept randomization * Subsequent pregnancy since that would be another source of progesterone * An acute general medical condition that would require imminent re-hospitalization since this would enforce abstinence (women may be randomized if they are discharged and still within the recruitment window) * Allergy to progesterone or peanuts (vehicle for micronized progesterone) * Currently undergoing treatment with ketoconazole or any other known strong CYP3A4 inhibitors
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of Progesterone as a Relapse Prevention Intervention for Postpartum Women With Pre-conception Smoking: Adherence to Treatment | 8 weeks | Feasibility will be shown by high adherence to treatment condition assessed by doses of study medication taken |
| Feasibility of Progesterone as a Relapse Prevention Intervention for Postpartum Women With Pre-conception Smoking: Retention | From randomization to 3-month follow-up: up to 5 months | Feasibility in retention will be shown by at least 70% of women randomized to the progesterone group reamaining in the study at the 3-month follow-up |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 7-day Point Prevalence of Abstinence at End of Treatment (Week 8) | Week 8 of the trial period | Abstinence was defined as self-report of no smoking in the past 7 days confirmed by a negative urine cotinine test (urine cotinine \<100 ng/ml). |
Countries
United States
Participant flow
Recruitment details
Recruitment began January 2014 and final data collection occurred August 2016. We accepted study referrals and conducted on-site clinic screening assessments in three academic obstetrics clinics associated with Yale New Haven Hospital.
Pre-assignment details
We screened 90 pregnant women who were current smokers intending to quit prior to 32 weeks gestation; 26 were ineligible because they were still smoking at 32 weeks gestation (n=12) or did not meet other eligibility criteria (n=14); 23 were eligible but not randomized because they declined to participate (n=8) or were out of contact (n=15).
Participants by arm
| Arm | Count |
|---|---|
| Placebo In this group women will receive a placebo pill which will appear similar to progesterone and will be inert.
Placebo | 19 |
| Progesterone In this group women will receive oral micronized progesterone twice a day.
Progesterone | 22 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 3-Month Follow-Up (Week 20) | Lost to Follow-up | 1 | 1 |
| Treatment Period (Week 1 Through Week 8) | Lost to Follow-up | 2 | 3 |
| Treatment Period (Week 1 Through Week 8) | Patient Relocated | 1 | 0 |
| Treatment Period (Week 1 Through Week 8) | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Progesterone |
|---|---|---|---|
| Age, Continuous | 25.3 years STANDARD_DEVIATION 4.3 | 25.8 years STANDARD_DEVIATION 4.6 | 26.2 years STANDARD_DEVIATION 4.9 |
| Breastfeeding intentions Breasefeed and formula feed | 10 Participants | 21 Participants | 11 Participants |
| Breastfeeding intentions Breastfeed exclusively | 4 Participants | 13 Participants | 9 Participants |
| Breastfeeding intentions Formula feed exclusively | 4 Participants | 6 Participants | 2 Participants |
| Breastfeeding intentions Unsure | 1 Participants | 1 Participants | 0 Participants |
| Edinburgh Postnatal Depression Scale Score | 3.8 units on a scale STANDARD_DEVIATION 4.9 | 3.4 units on a scale STANDARD_DEVIATION 4.7 | 3.0 units on a scale STANDARD_DEVIATION 4.5 |
| Education level <High school degree | 3 Participants | 9 Participants | 6 Participants |
| Education level High school degree | 9 Participants | 22 Participants | 13 Participants |
| Education level Some college (no degree) | 7 Participants | 10 Participants | 3 Participants |
| Fagerstrom Test for Nicotine Dependence High dependence | 0 Participants | 0 Participants | 0 Participants |
| Fagerstrom Test for Nicotine Dependence Low dependence | 6 Participants | 13 Participants | 7 Participants |
| Fagerstrom Test for Nicotine Dependence Low to moderate dependence | 9 Participants | 20 Participants | 11 Participants |
| Fagerstrom Test for Nicotine Dependence Moderate dependence | 4 Participants | 8 Participants | 4 Participants |
| Feeding method at week 2 visit Breasefeed and formula feed | 3 Participants | 8 Participants | 5 Participants |
| Feeding method at week 2 visit Breastfeed exclusively | 0 Participants | 6 Participants | 6 Participants |
| Feeding method at week 2 visit Formula feed exclusively | 14 Participants | 21 Participants | 7 Participants |
| Feeding method at week 2 visit Missing | 2 Participants | 6 Participants | 4 Participants |
| Lives with smoker No | 8 Participants | 19 Participants | 11 Participants |
| Lives with smoker Yes | 8 Participants | 18 Participants | 10 Participants |
| Lives with spouse or partner No | 9 Participants | 21 Participants | 12 Participants |
| Lives with spouse or partner Yes | 10 Participants | 20 Participants | 10 Participants |
| Parity 1 | 3 Participants | 11 Participants | 8 Participants |
| Parity 2 | 8 Participants | 12 Participants | 4 Participants |
| Parity 3 | 4 Participants | 11 Participants | 7 Participants |
| Parity 4+ | 4 Participants | 7 Participants | 3 Participants |
| Pre-quit number of cigarettes per day | 7.1 participants STANDARD_DEVIATION 3.3 | 6.6 participants STANDARD_DEVIATION 3.9 | 6.2 participants STANDARD_DEVIATION 4.3 |
| Pre-quit smoking level ≤10 cigarettes/day | 17 Participants | 34 Participants | 17 Participants |
| Pre-quit smoking level 10 cigarettes/day | 2 Participants | 7 Participants | 5 Participants |
| Questionnaire on Smoking Urges (QSU)-Brief Score | 15.6 units on a scale STANDARD_DEVIATION 15.4 | 16.9 units on a scale STANDARD_DEVIATION 13.7 | 18.0 units on a scale STANDARD_DEVIATION 12.2 |
| Race/Ethnicity, Customized Race/Ethnicity Black, non-Latina | 13 Participants | 22 Participants | 9 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Latina | 4 Participants | 15 Participants | 11 Participants |
| Race/Ethnicity, Customized Race/Ethnicity More than one race, non-Latina | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race/Ethnicity White, non-Latina | 1 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Female | 19 Participants | 41 Participants | 22 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 22 |
| other Total, other adverse events | 3 / 19 | 2 / 22 |
| serious Total, serious adverse events | 0 / 19 | 0 / 22 |
Outcome results
Primary
Feasibility of Progesterone as a Relapse Prevention Intervention for Postpartum Women With Pre-conception Smoking: Adherence to Treatment
Feasibility will be shown by high adherence to treatment condition assessed by doses of study medication taken
Time frame: 8 weeks
Population: Adherence to treatment as measured by mean (SD) doses of study medication taken by women in each arm of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Feasibility of Progesterone as a Relapse Prevention Intervention for Postpartum Women With Pre-conception Smoking: Adherence to Treatment | 84.5 doses of medication | Standard Deviation 38.3 |
| Progesterone | Feasibility of Progesterone as a Relapse Prevention Intervention for Postpartum Women With Pre-conception Smoking: Adherence to Treatment | 76.0 doses of medication | Standard Deviation 42 |
Primary
Feasibility of Progesterone as a Relapse Prevention Intervention for Postpartum Women With Pre-conception Smoking: Retention
Feasibility in retention will be shown by at least 70% of women randomized to the progesterone group reamaining in the study at the 3-month follow-up
Time frame: From randomization to 3-month follow-up: up to 5 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Feasibility of Progesterone as a Relapse Prevention Intervention for Postpartum Women With Pre-conception Smoking: Retention | 15 Participants |
| Progesterone | Feasibility of Progesterone as a Relapse Prevention Intervention for Postpartum Women With Pre-conception Smoking: Retention | 17 Participants |
Secondary
7-day Point Prevalence of Abstinence at End of Treatment (Week 8)
Abstinence was defined as self-report of no smoking in the past 7 days confirmed by a negative urine cotinine test (urine cotinine \<100 ng/ml).
Time frame: Week 8 of the trial period
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | 7-day Point Prevalence of Abstinence at End of Treatment (Week 8) | 6 Participants |
| Progesterone | 7-day Point Prevalence of Abstinence at End of Treatment (Week 8) | 10 Participants |
Comparison: Null hypothesis- odds of week 8 point prevalence abstinence were equal between placebo and progesterone group.p-value: 0.3995% CI: [0.48, 6.52]Regression, Logistic
Post Hoc
Questionnaire on Smoking Urges (QSU)-Brief Score
Scale is scored from 10 to 70. Higher scores indicate more severe symptoms
Time frame: treatment period; baseline through week 8, measured weekly
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Questionnaire on Smoking Urges (QSU)-Brief Score | week 1 | 13.3 units on a scale | Standard Deviation 5.6 |
| Placebo | Questionnaire on Smoking Urges (QSU)-Brief Score | week 5 | 15.7 units on a scale | Standard Deviation 6.8 |
| Placebo | Questionnaire on Smoking Urges (QSU)-Brief Score | week 3 | 15.5 units on a scale | Standard Deviation 9.7 |
| Placebo | Questionnaire on Smoking Urges (QSU)-Brief Score | week 6 | 17.9 units on a scale | Standard Deviation 10 |
| Placebo | Questionnaire on Smoking Urges (QSU)-Brief Score | weeek 2 | 14.1 units on a scale | Standard Deviation 7.8 |
| Placebo | Questionnaire on Smoking Urges (QSU)-Brief Score | week 7 | 17.2 units on a scale | Standard Deviation 8.6 |
| Placebo | Questionnaire on Smoking Urges (QSU)-Brief Score | week 4 | 18.3 units on a scale | Standard Deviation 10.6 |
| Placebo | Questionnaire on Smoking Urges (QSU)-Brief Score | week 8 | 21.4 units on a scale | Standard Deviation 17.5 |
| Placebo | Questionnaire on Smoking Urges (QSU)-Brief Score | baseline | 15.6 units on a scale | Standard Deviation 15.4 |
| Progesterone | Questionnaire on Smoking Urges (QSU)-Brief Score | week 8 | 10.4 units on a scale | Standard Deviation 1.1 |
| Progesterone | Questionnaire on Smoking Urges (QSU)-Brief Score | baseline | 18.0 units on a scale | Standard Deviation 12.2 |
| Progesterone | Questionnaire on Smoking Urges (QSU)-Brief Score | week 1 | 14.5 units on a scale | Standard Deviation 10.5 |
| Progesterone | Questionnaire on Smoking Urges (QSU)-Brief Score | weeek 2 | 13.7 units on a scale | Standard Deviation 7.5 |
| Progesterone | Questionnaire on Smoking Urges (QSU)-Brief Score | week 3 | 14.5 units on a scale | Standard Deviation 9.1 |
| Progesterone | Questionnaire on Smoking Urges (QSU)-Brief Score | week 4 | 12.2 units on a scale | Standard Deviation 3.8 |
| Progesterone | Questionnaire on Smoking Urges (QSU)-Brief Score | week 5 | 13.8 units on a scale | Standard Deviation 8.5 |
| Progesterone | Questionnaire on Smoking Urges (QSU)-Brief Score | week 6 | 12.1 units on a scale | Standard Deviation 5.1 |
| Progesterone | Questionnaire on Smoking Urges (QSU)-Brief Score | week 7 | 10.6 units on a scale | Standard Deviation 2.4 |
Comparison: null hypothesis rate of change in QSU-brief scores were equal between treatment groupsp-value: <0.00195% CI: [0.86, 0.96]general estimating equation
Post Hoc
Time to Relapse
The Outcome Measure is reporting the time in weeks to relapse
Time frame: baseline through 3-month post trial follow-up
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Relapse | 4 weeks |
| Progesterone | Time to Relapse | 10 weeks |
p-value: 0.4195% CI: [0.66, 3.38]Regression, Cox