<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04417595</url>
  </required_header>
  <id_info>
    <org_study_id>200609</org_study_id>
    <secondary_id>R01HD098719</secondary_id>
    <nct_id>NCT04417595</nct_id>
  </id_info>
  <brief_title>Investigating N-3 Fatty Acids to Prevent Neonatal Tobacco-related outcomeS</brief_title>
  <acronym>INFANTS</acronym>
  <official_title>Investigating N-3 Fatty Acids to Prevent Neonatal Tobacco-related outcomeS</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Vanderbilt University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Smoking is the most important modifiable risk factor for adverse pregnancy outcomes including&#xD;
      preterm birth, neonatal death, and maternal complications. Rates of smoking cessation during&#xD;
      pregnancy are low, particularly in underserved populations, and currently approved&#xD;
      pharmacotherapies for smoking cessation either are considered unsafe in pregnancy or have&#xD;
      uncertain effectiveness. Identifying safe and effective interventions, which might mitigate&#xD;
      the adverse effects of smoking on maternal-fetal outcomes, is a major public health priority.&#xD;
      We hypothesize that smoking-induced n-3 LCPUFA relative deficiencies may be an important&#xD;
      mechanism contributing to tobacco-related adverse pregnancy outcomes and that n-3 LCPUFA&#xD;
      supplementation specifically targeted to pregnant smokers may reduce these complications.&#xD;
      Support for this hypothesis comes from a recent secondary analysis of the Omega-3 Fatty Acids&#xD;
      Supplementation to Prevent Preterm Birth trial that found that only smokers taking n-3&#xD;
      LCPUFAs had a reduction in preterm labor risk as compared to non-smokers. While compelling,&#xD;
      this study was a post hoc analysis that included only a small sample of smokers and did not&#xD;
      collect data on smoking behaviors during follow up. Yet the ascertainment of longitudinal&#xD;
      smoking behavior is critical, as some clinical studies have found that supplemental n-3&#xD;
      LCPUFAs might also reduce nicotine cravings, and lower daily cigarette use. Thus, smokers may&#xD;
      doubly benefit from replenishing n-3 LCPUFAs via lower risk of preterm labor and/or increased&#xD;
      smoking cessation. To address these knowledge gaps, we are proposing a multi-center,&#xD;
      randomized, placebo-controlled, double-blinded study of n-3 LCPUFA supplementation in 400&#xD;
      pregnant smokers. We will collect detailed information on smoking behavior, validated&#xD;
      biological markers of cigarette exposure (urinary cotinine, end-expiratory carbon monoxide)&#xD;
      and biomarkers of n-3 LCPUFA status (red blood cell phospholipid membrane fatty acids). Our&#xD;
      specific aims of this proposal are to 1) determine the effect of supplemental n-3 LCPUFAs on&#xD;
      gestational age at delivery and preterm labor in pregnant smokers and 2) determine the effect&#xD;
      of n-3 LCPUFA supplementation on tobacco use in pregnant smokers. We will recruit potential&#xD;
      participants from eight obstetrics clinics across the Middle-Tennessee area. Our study could&#xD;
      have a major translational impact on both adverse tobacco-related birth outcomes and smoking&#xD;
      cessation efforts.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Tobacco use is the most important modifiable risk factor associated with adverse pregnancy&#xD;
      outcomes and increases the risk of preterm birth, intrauterine growth restriction and sudden&#xD;
      infant death syndrome. Over 11% of women report smoking during pregnancy, with higher rates&#xD;
      seen in the Southeastern United States. Fewer than half of pregnant smokers are able to quit&#xD;
      on their own during pregnancy. Currently, FDA-approved pharmacological strategies for smoking&#xD;
      cessation are generally not used in pregnancy: varenicline and bupropion are unsafe and&#xD;
      nicotine replacement therapy has limited data to support its efficacy in pregnant smokers.&#xD;
      Identifying safe and effective therapies to prevent tobacco-related pregnancy outcomes and/or&#xD;
      increase smoking cessation in pregnant women would have a substantial public health impact.&#xD;
&#xD;
      Our group and others have reported that cigarette smoking is associated with a relative&#xD;
      deficiency in circulating n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) levels. Our&#xD;
      overarching hypothesis is that smoking-induced n-3 LCPUFA deficiencies contribute to&#xD;
      tobacco-related adverse pregnancy outcomes and that supplementation of n-3 LCPUFAs in&#xD;
      pregnant smokers may prevent these complications. Support for this hypothesis comes from a&#xD;
      recent secondary analysis of the Omega-3 Fatty Acids Supplementation to Prevent Preterm Birth&#xD;
      trial which found that only smokers taking n-3 LCPUFAs had a reduction in preterm labor risk&#xD;
      as compared to non-smokers. While compelling, this study was a post hoc analysis that&#xD;
      included only a small sample of smokers and did not collect data on smoking behaviors during&#xD;
      follow up. Yet the ascertainment of longitudinal smoking behavior is critical, as some&#xD;
      clinical studies have found that supplemental n-3 LCPUFAs might also reduce nicotine cravings&#xD;
      and lower daily cigarette use. Thus, smokers may doubly benefit from replenishing n-3 LCPUFAs&#xD;
      via lower risk of preterm labor and/or increased smoking cessation. We conducted a&#xD;
      placebo-controlled pilot RCT of n-3 LCPUFAs in 28 pregnant smokers and found the intervention&#xD;
      to be feasible and well-tolerated. Compared to placebo, n-3 LCPUFAs lowered both nicotine&#xD;
      dependence at 4 weeks (change from baseline in Fagerström Test for Nicotine Dependence -2.5&#xD;
      vs. 0, p = 0.01) and resulted in a non-statistically significant reduction in cigarettes per&#xD;
      day and urine cotinine. To address important remaining knowledge gaps we propose the&#xD;
      Investigating N-3 Fatty Acids to prevent Neonatal Tobacco related outcomeS (INFANTS).&#xD;
&#xD;
      Our proposal has three Specific Aims.&#xD;
&#xD;
      Specific Aim 1: To determine the effect of supplemental n-3 LCPUFAs compared to placebo on&#xD;
      gestational age at delivery and preterm labor in pregnant smokers.&#xD;
&#xD;
      Specific Aim 2: To determine the effect of supplemental n-3 LCPUFAs compared to placebo on&#xD;
      tobacco use in pregnant smokers.&#xD;
&#xD;
      Specific Aim 3: To determine if the effect of supplemental n-3 LCPUFAs on preterm labor is&#xD;
      mediated by changes in smoking behavior and/or increases in circulating n-3 LCPUFAs.&#xD;
&#xD;
      The INFANTS study is a multicenter, randomized, double-blind, placebo controlled study that&#xD;
      will randomize 400 pregnant smokers to either supplemental n-3 LCPUFAs or placebo.&#xD;
      Participants will be enrolled between 12 and 24 weeks gestation and followed until delivery.&#xD;
      We will recruit participants from eight clinical centers in the Middle-Tennessee area. We&#xD;
      will assess smoking behavior after 12-weeks of supplementation using self-report and&#xD;
      validated biomarkers of tobacco exposure (urine cotinine). We will measure response to&#xD;
      supplementation using biological markers of n-3 LCPUFA status (red blood cell phospholipid&#xD;
      membrane fatty acid percentages). Our primary endpoint will be preterm labor as reflected by&#xD;
      gestational age at delivery, which will be extracted from the medical record. Our secondary&#xD;
      endpoint will be change from baseline in cigarettes per day at 12 weeks biochemically&#xD;
      confirmed through reduction in urine cotinine. We will conduct mediation analysis to better&#xD;
      understand the mechanisms contributing to the effects of supplemental n-3 LCPUFAs on birth&#xD;
      outcomes in pregnant smokers.&#xD;
&#xD;
      Our study is innovative in that it will be the first clinical trial of n-3 LCPUFAs&#xD;
      exclusively recruiting pregnant smokers. This will be the first study to evaluate the impact&#xD;
      on n-3 LCPUFAs on tobacco use in smokers who wish to quit, thus identifying a novel strategy&#xD;
      to reduce tobacco use that could be relevant for all smokers.&#xD;
&#xD;
      n-3 LCPUFAs supplements are well tolerated in pregnancy but currently are not recommended as&#xD;
      part of routine prenatal care in smokers. Thus if our study demonstrated that supplemental&#xD;
      n-3 LCPUFAs are effective at reducing the risk of tobacco-related adverse neonatal outcomes&#xD;
      and/or reducing tobacco use during pregnancy, our results could have an immediate and major&#xD;
      clinical impact on pregnancy care and neonatal outcomes in the United States.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 10, 2020</start_date>
  <completion_date type="Anticipated">September 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Randomizes, parallel arm, double-blind, placebo controlled clinical trial</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Placebo controlled</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Gestational age at delivery</measure>
    <time_frame>At delivery</time_frame>
    <description>Gestational age at randomization will be determined on the basis of the last menstrual period and earliest ultrasound examination and will not be revised after being assigned a study group. Gestational age will be estimated from the last menstrual period (LMP) and adjusted for the first-trimester ultrasound. If a self-reported LMP is greater than 7 days from the calculated ultrasound LMP, the ultrasound will be used to assign gestational age.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in cigarettes per day</measure>
    <time_frame>At 12 weeks</time_frame>
    <description>Percentage change from baseline in cigarettes per day (CPD) at 12 weeks. The outcome will be determined based on participant self-report.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percent of neonates with fetal death and still birth</measure>
    <time_frame>At delivery</time_frame>
    <description>Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (yes or no). Outcomes will be adjudicated by study obstetricians blinded to treatment allocation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Individualized birth weight Z-score (adjusted for gestational age and maternal weight)</measure>
    <time_frame>At delivery</time_frame>
    <description>Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. Birth weight will be collected in kilograms. Maternal weight will be collected in kilograms and obtained from medical record review.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apgar score</measure>
    <time_frame>At delivery</time_frame>
    <description>Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (Score ranges from 0 to 10).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent of neonates with intraventricular hemorrhage</measure>
    <time_frame>At delivery</time_frame>
    <description>Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (yes or no). Outcomes will be adjudicated by study obstetricians blinded to treatment allocation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent of neonates with neonatal enterocolitis</measure>
    <time_frame>At delivery</time_frame>
    <description>Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (yes or no). Outcomes will be adjudicated by study obstetricians blinded to treatment allocation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent of neonates with a congenital abnormality</measure>
    <time_frame>At delivery</time_frame>
    <description>Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (yes or no). Outcomes will be adjudicated by study obstetricians blinded to treatment allocation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent of neonates with neonatal respiratory distress</measure>
    <time_frame>At delivery</time_frame>
    <description>Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (yes or no). Outcomes will be adjudicated by study obstetricians blinded to treatment allocation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent of participants with maternal mortality</measure>
    <time_frame>At delivery</time_frame>
    <description>Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (yes or no). Outcomes will be adjudicated by study obstetricians blinded to treatment allocation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent of participants requiring cesarean delivery</measure>
    <time_frame>At delivery</time_frame>
    <description>Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (yes or no). Outcomes will be adjudicated by study obstetricians blinded to treatment allocation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent of participants developing hypertension in pregnancy</measure>
    <time_frame>At delivery</time_frame>
    <description>Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (yes or no). Outcomes will be adjudicated by study obstetricians blinded to treatment allocation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent of participants reaching point prevalence abstinence</measure>
    <time_frame>At 12 weeks</time_frame>
    <description>Point prevalence abstinence at 12 weeks will be based on self-reported smoking cessation and biochemically confirmed by end-expired carbon monoxide ( end-expired CO less than 4 ppm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent of patients with a decrease in self-reported nicotine dependence</measure>
    <time_frame>At 12 weeks</time_frame>
    <description>Changes in nicotine dependence based on changes in the Fagerström Test for Nicotine Dependence.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">400</enrollment>
  <condition>Preterm Labor</condition>
  <condition>Tobacco Use Disorder</condition>
  <arm_group>
    <arm_group_label>Fish Oil</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants allocated to n-3 LCPUFA supplementation will be instructed to take four 1000 mg n-3 LCPUFA capsules (Metagenics™) daily. This will provide a total daily dose of 4000 mg n-3 LCPUFAs (2840 EPA and 1160 DHA).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Olive Oil</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Oleic acid (olive oil) capsules have a similar texture, size, color, and consistency to EPA capsules. Participant will be instructed to take four 100mg olive oil capsules</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fish Oil (Containing Omega-3 Acids)</intervention_name>
    <description>Fish Oil Supplement</description>
    <arm_group_label>Fish Oil</arm_group_label>
    <other_name>Fish Oil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Olive Oil</intervention_name>
    <description>Olive Oil Supplement</description>
    <arm_group_label>Olive Oil</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  ≥ 16 or ≤ 40 years of age&#xD;
&#xD;
          -  Currently reporting daily cigarette use (≥ 1 CPD; reporting 10 or more CPD prior to&#xD;
             pregnancy)&#xD;
&#xD;
          -  Between 12 and 24 weeks gestation&#xD;
&#xD;
          -  An exhaled carbon monoxide reading of at least 8 ppm&#xD;
&#xD;
          -  A cell phone or land line that can be reached directly&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Allergy to fish; currently using fish oil supplements&#xD;
&#xD;
          -  Active substance abuse (not including supervised buprenorphine use)&#xD;
&#xD;
          -  Unable to give consent or obtain assent for minors&#xD;
&#xD;
          -  Known fetal abnormality&#xD;
&#xD;
          -  Chronic hypertension&#xD;
&#xD;
          -  Seizure disorder&#xD;
&#xD;
          -  Clotting disorder&#xD;
&#xD;
          -  White's classification D or higher diabetes&#xD;
&#xD;
          -  Planned cerclage&#xD;
&#xD;
          -  Plan move from the Middle-Tennessee area within the next 9-months&#xD;
&#xD;
          -  Insufficient time to perform the complete enrollment process&#xD;
&#xD;
          -  Barrier to communication (e.g., low English proficiency or hearing/speech impairment)&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Actively pregnant</gender_description>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Harvey J Murff, MD, MPH</last_name>
    <phone>615 936 8319</phone>
    <email>harvey.j.murff@vumc.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>Vanderbilt University Medical Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Harvey J Murff, MD, MPH</last_name>
      <phone>615-936-8319</phone>
      <email>harvey.j.murff@vumc.org</email>
    </contact>
    <investigator>
      <last_name>Harvey J Murff, MD, MPH</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Hilary A Tindle, MD, MPD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Katherine E Hartmann, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Robert A Greevy, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Reesha S Sanghani, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Tina V Hartert, MD, MPH</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Cornelia Graves, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>May 29, 2020</study_first_submitted>
  <study_first_submitted_qc>June 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 4, 2020</study_first_posted>
  <last_update_submitted>July 19, 2023</last_update_submitted>
  <last_update_submitted_qc>July 19, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 20, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University Medical Center</investigator_affiliation>
    <investigator_full_name>Harvey Murff</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Obstetric Labor, Premature</mesh_term>
    <mesh_term>Tobacco Use Disorder</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04417595
org study id: 200609
secondary id: R01HD098719
nct id: NCT04417595
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Smoking is the most important modifiable risk factor for adverse pregnancy outcomes including
      preterm birth, neonatal death, and maternal complications. Rates of smoking cessation during
      pregnancy are low, particularly in underserved populations, and currently approved
      pharmacotherapies for smoking cessation either are considered unsafe in pregnancy or have
      uncertain effectiveness. Identifying safe and effective interventions, which might mitigate
      the adverse effects of smoking on maternal-fetal outcomes, is a major public health priority.
      We hypothesize that smoking-induced n-3 LCPUFA relative deficiencies may be an important
      mechanism contributing to tobacco-related adverse pregnancy outcomes and that n-3 LCPUFA
      supplementation specifically targeted to pregnant smokers may reduce these complications.
      Support for this hypothesis comes from a recent secondary analysis of the Omega-3 Fatty Acids
      Supplementation to Prevent Preterm Birth trial that found that only smokers taking n-3
      LCPUFAs had a reduction in preterm labor risk as compared to non-smokers. While compelling,
      this study was a post hoc analysis that included only a small sample of smokers and did not
      collect data on smoking behaviors during follow up. Yet the ascertainment of longitudinal
      smoking behavior is critical, as some clinical studies have found that supplemental n-3
      LCPUFAs might also reduce nicotine cravings, and lower daily cigarette use. Thus, smokers may
      doubly benefit from replenishing n-3 LCPUFAs via lower risk of preterm labor and/or increased
      smoking cessation. To address these knowledge gaps, we are proposing a multi-center,
      randomized, placebo-controlled, double-blinded study of n-3 LCPUFA supplementation in 400
      pregnant smokers. We will collect detailed information on smoking behavior, validated
      biological markers of cigarette exposure (urinary cotinine, end-expiratory carbon monoxide)
      and biomarkers of n-3 LCPUFA status (red blood cell phospholipid membrane fatty acids). Our
      specific aims of this proposal are to 1) determine the effect of supplemental n-3 LCPUFAs on
      gestational age at delivery and preterm labor in pregnant smokers and 2) determine the effect
      of n-3 LCPUFA supplementation on tobacco use in pregnant smokers. We will recruit potential
      participants from eight obstetrics clinics across the Middle-Tennessee area. Our study could
      have a major translational impact on both adverse tobacco-related birth outcomes and smoking
      cessation efforts.
Tobacco use is the most important modifiable risk factor associated with adverse pregnancy
      outcomes and increases the risk of preterm birth, intrauterine growth restriction and sudden
      infant death syndrome. Over 11% of women report smoking during pregnancy, with higher rates
      seen in the Southeastern United States. Fewer than half of pregnant smokers are able to quit
      on their own during pregnancy. Currently, FDA-approved pharmacological strategies for smoking
      cessation are generally not used in pregnancy: varenicline and bupropion are unsafe and
      nicotine replacement therapy has limited data to support its efficacy in pregnant smokers.
      Identifying safe and effective therapies to prevent tobacco-related pregnancy outcomes and/or
      increase smoking cessation in pregnant women would have a substantial public health impact.

      Our group and others have reported that cigarette smoking is associated with a relative
      deficiency in circulating n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) levels. Our
      overarching hypothesis is that smoking-induced n-3 LCPUFA deficiencies contribute to
      tobacco-related adverse pregnancy outcomes and that supplementation of n-3 LCPUFAs in
      pregnant smokers may prevent these complications. Support for this hypothesis comes from a
      recent secondary analysis of the Omega-3 Fatty Acids Supplementation to Prevent Preterm Birth
      trial which found that only smokers taking n-3 LCPUFAs had a reduction in preterm labor risk
      as compared to non-smokers. While compelling, this study was a post hoc analysis that
      included only a small sample of smokers and did not collect data on smoking behaviors during
      follow up. Yet the ascertainment of longitudinal smoking behavior is critical, as some
      clinical studies have found that supplemental n-3 LCPUFAs might also reduce nicotine cravings
      and lower daily cigarette use. Thus, smokers may doubly benefit from replenishing n-3 LCPUFAs
      via lower risk of preterm labor and/or increased smoking cessation. We conducted a
      placebo-controlled pilot RCT of n-3 LCPUFAs in 28 pregnant smokers and found the intervention
      to be feasible and well-tolerated. Compared to placebo, n-3 LCPUFAs lowered both nicotine
      dependence at 4 weeks (change from baseline in Fagerström Test for Nicotine Dependence -2.5
      vs. 0, p = 0.01) and resulted in a non-statistically significant reduction in cigarettes per
      day and urine cotinine. To address important remaining knowledge gaps we propose the
      Investigating N-3 Fatty Acids to prevent Neonatal Tobacco related outcomeS (INFANTS).

      Our proposal has three Specific Aims.

      Specific Aim 1: To determine the effect of supplemental n-3 LCPUFAs compared to placebo on
      gestational age at delivery and preterm labor in pregnant smokers.

      Specific Aim 2: To determine the effect of supplemental n-3 LCPUFAs compared to placebo on
      tobacco use in pregnant smokers.

      Specific Aim 3: To determine if the effect of supplemental n-3 LCPUFAs on preterm labor is
      mediated by changes in smoking behavior and/or increases in circulating n-3 LCPUFAs.

      The INFANTS study is a multicenter, randomized, double-blind, placebo controlled study that
      will randomize 400 pregnant smokers to either supplemental n-3 LCPUFAs or placebo.
      Participants will be enrolled between 12 and 24 weeks gestation and followed until delivery.
      We will recruit participants from eight clinical centers in the Middle-Tennessee area. We
      will assess smoking behavior after 12-weeks of supplementation using self-report and
      validated biomarkers of tobacco exposure (urine cotinine). We will measure response to
      supplementation using biological markers of n-3 LCPUFA status (red blood cell phospholipid
      membrane fatty acid percentages). Our primary endpoint will be preterm labor as reflected by
      gestational age at delivery, which will be extracted from the medical record. Our secondary
      endpoint will be change from baseline in cigarettes per day at 12 weeks biochemically
      confirmed through reduction in urine cotinine. We will conduct mediation analysis to better
      understand the mechanisms contributing to the effects of supplemental n-3 LCPUFAs on birth
      outcomes in pregnant smokers.

      Our study is innovative in that it will be the first clinical trial of n-3 LCPUFAs
      exclusively recruiting pregnant smokers. This will be the first study to evaluate the impact
      on n-3 LCPUFAs on tobacco use in smokers who wish to quit, thus identifying a novel strategy
      to reduce tobacco use that could be relevant for all smokers.

      n-3 LCPUFAs supplements are well tolerated in pregnancy but currently are not recommended as
      part of routine prenatal care in smokers. Thus if our study demonstrated that supplemental
      n-3 LCPUFAs are effective at reducing the risk of tobacco-related adverse neonatal outcomes
      and/or reducing tobacco use during pregnancy, our results could have an immediate and major
      clinical impact on pregnancy care and neonatal outcomes in the United States.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomizes, parallel arm, double-blind, placebo controlled clinical trial
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Placebo controlled
measure: Gestational age at delivery
time frame: At delivery
description: Gestational age at randomization will be determined on the basis of the last menstrual period and earliest ultrasound examination and will not be revised after being assigned a study group. Gestational age will be estimated from the last menstrual period (LMP) and adjusted for the first-trimester ultrasound. If a self-reported LMP is greater than 7 days from the calculated ultrasound LMP, the ultrasound will be used to assign gestational age.
measure: Change in cigarettes per day
time frame: At 12 weeks
description: Percentage change from baseline in cigarettes per day (CPD) at 12 weeks. The outcome will be determined based on participant self-report.
measure: Percent of neonates with fetal death and still birth
time frame: At delivery
description: Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (yes or no). Outcomes will be adjudicated by study obstetricians blinded to treatment allocation.
measure: Individualized birth weight Z-score (adjusted for gestational age and maternal weight)
time frame: At delivery
description: Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. Birth weight will be collected in kilograms. Maternal weight will be collected in kilograms and obtained from medical record review.
measure: Apgar score
time frame: At delivery
description: Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (Score ranges from 0 to 10).
measure: Percent of neonates with intraventricular hemorrhage
time frame: At delivery
description: Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (yes or no). Outcomes will be adjudicated by study obstetricians blinded to treatment allocation.
measure: Percent of neonates with neonatal enterocolitis
time frame: At delivery
description: Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (yes or no). Outcomes will be adjudicated by study obstetricians blinded to treatment allocation.
measure: Percent of neonates with a congenital abnormality
time frame: At delivery
description: Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (yes or no). Outcomes will be adjudicated by study obstetricians blinded to treatment allocation.
measure: Percent of neonates with neonatal respiratory distress
time frame: At delivery
description: Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (yes or no). Outcomes will be adjudicated by study obstetricians blinded to treatment allocation.
measure: Percent of participants with maternal mortality
time frame: At delivery
description: Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (yes or no). Outcomes will be adjudicated by study obstetricians blinded to treatment allocation.
measure: Percent of participants requiring cesarean delivery
time frame: At delivery
description: Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (yes or no). Outcomes will be adjudicated by study obstetricians blinded to treatment allocation.
measure: Percent of participants developing hypertension in pregnancy
time frame: At delivery
description: Obtained from medical record review of delivery records by study personnel blinded to treatment allocation. This will be a categorical variable (yes or no). Outcomes will be adjudicated by study obstetricians blinded to treatment allocation.
measure: Percent of participants reaching point prevalence abstinence
time frame: At 12 weeks
description: Point prevalence abstinence at 12 weeks will be based on self-reported smoking cessation and biochemically confirmed by end-expired carbon monoxide ( end-expired CO less than 4 ppm
measure: Percent of patients with a decrease in self-reported nicotine dependence
time frame: At 12 weeks
description: Changes in nicotine dependence based on changes in the Fagerström Test for Nicotine Dependence.
arm group label: Fish Oil
arm group type: Experimental
description: Participants allocated to n-3 LCPUFA supplementation will be instructed to take four 1000 mg n-3 LCPUFA capsules (Metagenics™) daily. This will provide a total daily dose of 4000 mg n-3 LCPUFAs (2840 EPA and 1160 DHA).
arm group label: Olive Oil
arm group type: Placebo Comparator
description: Oleic acid (olive oil) capsules have a similar texture, size, color, and consistency to EPA capsules. Participant will be instructed to take four 100mg olive oil capsules
intervention type: Drug
intervention name: Fish Oil (Containing Omega-3 Acids)
description: Fish Oil Supplement
arm group label: Fish Oil
other name: Fish Oil
intervention type: Drug
intervention name: Olive Oil
description: Olive Oil Supplement
arm group label: Olive Oil
other name: Placebo
criteria: 
gender: Female
gender based: Yes
gender description: Actively pregnant
minimum age: 16 Years
maximum age: 40 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Harvey J Murff, MD, MPH
phone: 615 936 8319
email: harvey.j.murff@vumc.org
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University Medical Center
investigator full name: Harvey Murff
investigator title: Associate Professor
mesh term: Obstetric Labor, Premature
mesh term: Tobacco Use Disorder
sharing ipd: No