Fish Oil to Reduce Tobacco Use iN Expectant Mothers Study
Condition: Tobacco Use in Childbirth; Smoking Cessation; Pregnancy Related
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this feasibility study is to obtain pilot data in preparation for an upcoming
      R01 submission. The goals of that submission will be to conduct a clinical trial of n-3
      LCPUFAs for smoking cessation in pregnant women. For this proposal, the investigators will
      develop, test, and refine the recruitment strategy and collect data demonstrating the
      investigators ability to successfully recruit pregnant women who are actively smoking. The
      investigators will collect side effect, tolerability, and adherence data regarding the
      intervention. Finally, the investigators hope to gather preliminary effect size data to allow
      more formal estimates of sample size. The investigators hypothesize that pregnant smokers
      randomized to n-3 LCPUFA supplementation will have higher smoking cessation rates and less
      nicotine cravings compared to women allocated to placebo. The investigators intend to use
      this preliminary data to inform a future randomized, double-blind, placebo-controlled trial
      of n-3 LCPUFA supplementation for tobacco cessation.
    

Detailed description: 
      The goals of that submission will be to conduct a clinical trial of n-3 long-chain
      polyunsaturated fatty acids (LCPUFAs) for smoking cessation in pregnant women, who are at
      very high risk of continued smoking because pregnant generally cannot use any of the
      FDA-approved smoking cessation medications. Recently, two small scale, double-blind,
      randomized control trials have found that supplementation with n-3 LCPUFA reduces signs of
      nicotine dependence. While promising, these studies were not conducted in pregnancy, leaving
      an important gap in the scientific literature for this vulnerable group of smokers. For this
      proposal, the investigators will develop, test, and refine the recruitment strategy, and
      collect data demonstrating the ability to successfully recruit pregnant women who are
      actively smoking. The investigators will collect side effect, tolerability, and adherence
      data regarding the intervention. Finally, the investigators will gather preliminary effect
      size data on smoking behavior to allow more formal estimated of sample size for a larger,
      more definitive trial. The investigators hypothesize that pregnant smokers randomized to n-3
      LCPUFA supplementation will smoke fewer cigarettes per day compared to women allocated to
      placebo. In secondary analyses the investigators will compare self-reported nicotine cravings
      and 7-day point-prevalence smoking abstinence (assessed at 30 days) between n-3 LCPUFA and
      placebo groups. The investigators intend to use this preliminary data to inform a future
      randomized, double-blind, placebo-controlled trial of n-3 LCPUFA supplementation for
      long-term tobacco cessation in pregnancy.

      The specific aims are:

      SA1: To successfully recruit and randomize 40 pregnant, current smokers into a clinical trial
      of n-3 LCPUFA supplementation.

      SA2: To assess the tolerability of 4 gm/day n-3 LCPUFA supplementation in pregnant, current
      smokers over a 4-week period SA3: To determine the effect of 4 grams/day n-3 LCPUFA
      supplementation for 4-weeks on cigarettes smoked per day and self-reported nicotine cravings
      in pregnant smokers

      Research Design and Methods This study is a randomized, double-blind, placebo controlled
      study of 4 grams/day n-3 LCPUFA supplementation versus placebo for 4-weeks. The study will
      recruit pregnant women in the second trimester who are currently smoking. The primary
      outcomes will include changes from baseline in cigarettes per day. The secondary outcome will
      be self-reported nicotine cravings, and point prevalence abstinence at 30 days. The
      investigators will also collect safety and tolerability data.

      Eligible patients will be pregnant women who are currently smoking seen at Vanderbilt
      University Medical Center. The study is a single-site, randomized, double-blind,
      placebo-controlled, parallel arm trial design. The two arms included one treatment arm and
      one placebo arm. Treatment will be 4.2 grams/day of EPA + DHA. Placebo will be 5 grams of
      olive oil in capsule form. The intervention period will last 4-weeks. The study will
      randomize 40 participants into the two treatment arms. As this is a feasibility study, the
      investigators have not powered the study to account for drop-outs.

      Participants will be identified through searching electronic searches, direct referral from
      the Tobacco Treatment Service, or self-referral from clinic fliers. Study physicians will
      conduct a medical chart review and participants who are potentially eligible will be invited
      for Clinic Visit 1 (baseline).

      The study will include three clinic visits:

      Clinic Visit 1: After eligibility is confirmed, consent will be obtained. A brief medical
      history will be obtained. Participants will complete five questionnaires. Subjects will
      complete the Fagerström Tolerance Questionnaire, the Minnesota Withdrawal Symptom Checklist,
      the Questionnaire of Smoking Urges-brief, the PHQ-4, and completes a detailed interview on
      tobacco use habits including recording cigarettes per day smoked. Questionnaires will be
      administered by study staff or CRC nurses directly into REDCap study databases. Blood, urine,
      and exhaled CO measurements will be collected. Participants will be dispensed a four-week
      supply of medication. Participants will be given a pill diary.

      Clinic Visit 2: Participants will complete study questionnaires. Blood, urine, and exhaled CO
      measurements will be collected. Participants will report any adverse events.

      Clinic Visit 3: Participants will complete study questionnaires. Blood, urine, and exhaled CO
      measurements will be collected. Participants will report any adverse events and return any
      unused medications.

      Rationale for Dose:

      As described above, two prior studies have been conducted in smokers to assess the effects of
      supplemental n-3 LCPUFAs on nicotine cravings. While both studies reported a statistically
      reduction in self-reported nicotine cravings in the intervention arms, a reduction in
      cigarettes smoked per day was only seen in the study of high-dose n-3 LCPUFA (> 4 grams/day)
      as opposed to low dose n-3 LCPUFA (1 gram/day). These studies would suggest a dose effect and
      as such the investigators are using a high-dose n-3 LCPUFA intervention for this pilot study.

      Primary Outcome The primary outcomes will be reduction in total number of cigarettes per day
      from baseline to 4-weeks.

      Secondary Outcomes The secondary outcome will be 1) reduction in the Fagerström Tolerance
      Questionnaire; and 2) point prevalence abstinence at 4 weeks biochemically confirmed by
      end-expired carbon monoxide.

      Safety and Tolerability Outcomes Safety and tolerability outcomes will include: 1) reported
      AEs and 2) the rate of discontinuation of study medication due to side effects

      Sample Size Justification and Statistical Analysis Plan Statistical analysis plan Descriptive
      statistics, including means, standard deviation, and ranges for continuous variables, as well
      as percent and frequencies for categorical variables, will be presented. Standard graphing
      and screening techniques will be used to detect outliers and to ensure data accuracy. For the
      primary analysis of post-intervention cigarettes per day, the investigators will perform a
      Wilcoxon (Mann Whitney) rank sum test evaluated at a 5% significance level. This data
      analysis plan will be carried out using statistical software SAS® (Cary, North Carolina) or
      statistical package R (R Development Core Team, 2008).

      For the primary outcome the investigators will compare the change in total number of
      cigarettes smoked per day from baseline, 2-weeks, and 4-weeks. This outcome will be a
      continuous variable for this primary analysis. Secondary outcomes include the change in the
      Fagerström Tolerance Questionnaire, point prevalence abstinence at 4 weeks biochemically
      confirmed by end-expired carbon monoxide. The investigators will compare the change outcome
      at 4-weeks between arms using logistic regression using repeated measured ANOVA.

      Sample size estimation and power analysis For the primary outcome, with the assumption of a
      baseline number of cigarettes per day of 11 with a SD of 5(11), the study should be able to
      detect a reduction by 41% in cigarettes per day in smokers allocated to the n-3 LCPUFA arm
      compared to placebo with 80% power.

      The Fagerström Tolerance Questionnaire is on a 10-point Likert scale. Estimating a baseline
      score of 7.3 ± 1.6 the investigators have 80% power to detect a difference of 1 SD between
      the study arms.
    

Intervention name(s): Fish oil; Placebos
Intervention type(s): Drug; Drug
Intervention description(s): Fish oil supplementation; Olive Oil capsules
Other intervention name(s): n-3 LCPUFAs; Olive Oil
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized, double-blinded, placebo controlled trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: n-3 polyunsaturated fatty acids; tobacco use; pregnancy