Effects of Metformin During Nicotine Withdrawal
Condition: Smoking; HIV-1-infection
Intervention: Metformin; Placebo
Intervention description: Metformin capsule; Sucrose filler in gel capsules
Intervention MeSH terms: Metformin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 80.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      The purpose of this study is to test the effects of a medication called metformin
      (Glucophage®) on smoking behavior. This medication is FDA-approved for treatment of type-2
      diabetes. It is being used for research purposes in this study. Participants will be
      randomized to one of 3 treatment groups: low dose of metformin, high dose of metformin, or
      placebo.
    

Eligibility criteria:

        Inclusion Criteria

        Eligible subjects will be males and females:

          1. 18 years of age or older who self-report smoking at least 5 cigarettes (menthol and
             non-menthol) per day, on average for the past 6 months.

          2. HIV status

               1. HIV-infected smokers: diagnosed with HIV infection and exhibiting viral load of
                  less than or equal to 1000 copies/mL and CD4+ counts of greater than or equal to
                  200 cells/mm3 within 6 months prior to enrollment.

               2. HIV-uninfected smokers: no diagnosis of HIV, either via blood test or
                  self-report.

          3. Must not currently be interested in quitting smoking.

          4. Women of childbearing potential (based on medical history) must consent to use a
             medically accepted method of birth control (e.g., condoms and spermicide, oral
             contraceptive, Depo-Provera injection, contraceptive patch, tubal ligation) or abstain
             from sexual intercourse during the time they are in the study and using transdermal
             nicotine.

          5. If current or past diagnosis of bipolar disorder, eligible if:

               1. No psychotic features

               2. MADRS: total score less than 8 (past 4 weeks), suicidal item score less than1
                  (past 4 weeks)

               3. Y-MRS: total score less than 8 (past 4 weeks), irritability, speech content,
                  disruptive or aggressive behavior items score less than 3 (past 4 weeks)

               4. No psychiatric hospitalization or Emergency Room visits for psychiatric issues in
                  the past 6 months

               5. No aggressive or violent acts or behavior in the past 6 months

          6. Able to communicate fluently in English.

          7. Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the combined consent/HIPAA form.

        Exclusion Criteria

        Smoking Behavior:

          1. Current enrollment in a smoking cessation program, or use of other smoking cessation
             medications in the last month or plans to do either in the next 2 months.

          2. Daily use of chewing tobacco, snuff and/or snus, or electronic cigarettes.

        Alcohol/Drugs:

          1. Self-report current alcohol consumption that exceeds 25 standard drinks/week over the
             past 6 months. Subjects will be told to limit or avoid the use of alcohol while in the
             study to avoid any adverse reactions to the study medication.

          2. Current untreated and unstable diagnosis of substance dependence (eligible if past use
             and if receiving treatment and stable for at least 30 days). Current untreated and
             unstable diagnosis of substance abuse requires Study Physician approval.

          3. A positive urine drug screen for cocaine, amphetamines, methamphetamines, PCP,
             barbiturates and ecstasy (MDMA)at Intake, or any testing session (see Measures and
             Table 1 for details). Participants believed to have a false-positive result may
             continue in the study, with investigator approval.

        Medical:

          1. Females who self-report current pregnancy, planning a pregnancy during the study, or
             currently breastfeeding/lactating. All female subjects of child-bearing potential
             shall undergo a urine pregnancy test at the Intake, Baseline, PQ-Testing and 24-H
             Testing sessions.

          2. Current diagnosis of unstable and untreated major depression, as determined by
             self-report & MINI (eligible if stable for at least 30 days).

          3. Current or past diagnosis of psychotic disorder, as determined by self-report or MINI.

          4. Suicide risk as indicated by at least one of the following on the MINI/CSSRS (the PI
             &/or PM [LCSW] will be consulted to assess safety and determine eligibility in cases
             close to the eligibility cutoffs):

               1. Current suicidal ideation (within 30 days of enrollment)

               2. Two or more lifetime suicide attempts or episodes of suicidal behavior

               3. Any suicide attempt or suicidal behavior within 2 years of enrollment

          5. Self-reported kidney and/or liver disease or transplant untreated/unstable or within
             the past 6 months.

          6. Heart/Cardiovascular disease (e.g., angina, coronary heart disease, stroke, etc.) in
             the past 6 months.

          7. Type-1 or type-2 diabetes.

          8. Uncontrolled hypertension (BP systolic greater than 159 and/or diastolic greater than
             99)*.

          9. Liver function tests more than 20% outside of the normal range; Gamma-glutamyl
             Transpepsidase (GGT) values more than 20% outside of the normal range. If
             Albumin/Globulin ratios are 20% outside of normal range the abnormal value will be
             evaluated for clinical significance by the Study Physician and eligibility will
             determined on a case-by-case basis.

         10. Renal disease or renal dysfunction (e.g., serum creatinine levels ≥1.5 mg/dL [males],
             ≥1.4 mg/dL [females]).

         11. A blood glucose level less than 70 mg/dl at any visit.

               -  Participants presenting with SBP greater than 159 mmHg and/or DBP greater than 99
                  mmHg at the Intake visit will be instructed to sit quietly for 10 minutes. Then
                  the participant will have a second blood pressure reading taken after a 10 minute
                  period. If, after the second reading the SBP greater than 159 mmHg and the DBP
                  greater than 99 mmHg, the individual will be ineligible to participate, unless
                  determined otherwise by the Study PI or Study Physician, upon review.

        Medication:

          1. Current use or recent discontinuation (within the past 14 days) of any of the
             following medications:

               1. Anti-anxiety or panic disorder medications (e.g., clonazepam, alprazolam).

               2. Anti-psychotic medications as assessed on a case-by-case basis

               3. Glucophage/metformin

               4. Glyburide

               5. Furosemide or digoxin

               6. Nifedipine

               7. Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine,
                  quinine, ranitidine, triamterene, trimethoprim, or vancomycin)

          2. Participants who report taking prescription opiate-containing medications
             (Duragesic/fentanyl patches, Percocet, Oxycontin) will require physician approval
             prior to confirming final eligibility.

          3. Current use of any smoking cessation medications (e.g., Chantix/varenicline,
             Zyban/bupropion, nicotine replacement therapy/gum/patch).

          4. For safety reasons, HIV-infected smokers taking dolutegravir (Tivicay) or drugs that
             contain dolutegravir (e.g., Triumeq) should not take more than 1000 mg of metformin
             per day. Therefore, individuals taking dolutegravir will be force randomized to either
             the placebo condition or the low dose condition.

        Subjects will be instructed to refrain from using any study prohibited drugs/medications
        (both recreational and prescription) throughout their participation in the study. After
        final eligibility is confirmed, subjects who report taking contraindicated medication(s)
        over the course of the study period may only remain eligible if the Study Physician and/or
        Principal Investigator determines that the contraindicated medication(s) do/did not impact
        the study design, data quality, and/or subject safety/welfare. Subjects are permitted to
        take necessary prescription medications not included within the exclusion list during the
        study.

        General Exclusion:

          1. Current, anticipated, or pending enrollment in another research program over the next
             2-3 months that could potentially affect subject safety and/or the study data/design
             as determined by the Principal Investigator and/or Study Physician.

          2. Not planning to live in the area for the next two months.

          3. Color blindness.

          4. Any impairment (physical and/or neurological) including visual or other impairment
             preventing cognitive task performance.

          5. Known allergy to study medication.

          6. Planned radiologic studies involving the use of intravascular iodinated contrast
             materials (e.g., intravenous urogram, intravenous cholangiography, angiography, and
             computed tomography (CT) scans with intravascular contrast materials) during the
             course of study participation.

          7. Inability to provide informed consent or complete any of the study tasks as determined
             by the Principal Investigator.

          8. Not able to effectively communicate in English (reading, writing, speaking).

          9. Missing 3 or more doses during the medication period determined by self-report.