Studying Partial-agonists for Ethanol and Tobacco Elimination in Russians With HIV (St PETER HIV)

Study Overview
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Brief Summary
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This study is a randomized controlled trial (RCT) to compare the effects of varenicline, cytisine, and nicotine replacement therapy (NRT) to reduce: 1) alcohol use and craving, 2) smoking; and 3) inflammation and risk for coronary heart disease (CHD) and mortality among 400 HIV-infected Russians, with heavy alcohol consumption and tobacco use.

Detailed Description
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HIV-infected heavy drinking smokers are at high risk for coronary heart disease (CHD) and death. The mechanisms driving increased CHD risk in HIV-infected people are unclear, but are linked to inflammation. HIV, heavy drinking, and smoking are all pro-inflammatory. HIV viral suppression with antiretroviral therapy does not eliminate the elevated CHD risk nor the increased inflammation (i.e., pre-HIV infection levels are not restored). Interventions that reduce alcohol use, smoking, or both in HIV-infected people could lower inflammation, CHD and death risk. Varenicline and cytisine are proven therapies for smoking cessation. When compared to placebo, varenicline has higher cessation rates than cytisine. Human trials suggest varenicline also has efficacy for reducing alcohol consumption and craving in heavy drinking smokers. In murine models, cytisine reduces alcohol consumption. The comparative efficacy of varenicline and cytisine to reduce alcohol consumption and by extension, inflammation, CHD, and mortality risk, in humans has not been tested, nor has their comparative effectiveness been tested for smoking. Neither drug has been tested for smoking cessation against nicotine replacement therapy (NRT) in HIV-infected heavy drinking smokers. Three compelling reasons to test varenicline and cytisine in HIV-infected heavy drinking smokers are: 1) both show promise in HIV-uninfected people; 2) the morbidity caused by heavy drinking and smoking in HIV-infected persons is significant; and 3) treating heavy drinking and smoking with one medication represents a significant advance in reducing polypharmacy and improving patient care. Thus, investigators propose a 4-arm placebo-controlled randomized controlled trial (RCT) among 400 HIV-infected heavy drinking smokers. Trial arms are varenicline+NRT placebo, cytisine+NRT placebo, NRT+varenicline placebo, NRT+cytisine placebo. All participants will receive counseling (alcohol & tobacco) and medications (placebo & active). Specific aims will compare effects of varenicline, cytisine, and NRT at 3 months on past month % heavy drinking days and alcohol craving, cigarettes per day and smoking abstinence (verified by carbon monoxide), inflammation (hsCRP, IL-6), CHD (Reynolds risk score), and mortality (VACS index) risk. Investigators hypothesize that (1) Varenicline has greater efficacy than NRT for reducing heavy drinking, smoking, inflammation, CHD and mortality risk; (2) Cytisine has greater efficacy than NRT; and (3) Varenicline has greater efficacy than cytisine for these outcomes. Investigators will conduct an RCT, Studying Partial-agonists for Ethanol and Tobacco Elimination in Russians with HIV (St PETER HIV), in a country with an HIV epidemic and high per-capita alcohol consumption and smoking. Investigators will recruit from the ongoing Russia ARCH cohort in St. Petersburg (part of our NIAAA funded HIV/AIDS Alcohol Consortium - URBAN ARCH). If investigator hypotheses are correct, St PETER HIV could make nicotinic partial-agonists standard care for HIV+ heavy drinking smokers, and lead to reduced inflammation, CHD and mortality risk through this one drug, two diseases approach. This trial addresses the paucity of RCT data to guide treatment of these CHD risk factors in HIV-infected people. The Russia ARCH Cohort and the St PETER HIV study will draw from an established cohort of HIV-infected smokers and heavy drinkers to compare the effects of two partial nicotinic receptors, varenicline and cytisine, on alcohol consumption, alcohol craving, smoking, inflammation, CHD risk and mortality risk. St PETER HIV further addresses the paucity of randomized controlled trial data to guide treatment of heavy alcohol consumption and smoking in HIV-infected people.

Official Title
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URBAN ARCH 4/5 Russia Cohort-Targeting HIV-comorbidities With Pharmacotherapy to Reduce Alcohol and Tobacco Use in HIV-infected Russians

Conditions
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HIV Infection, Alcohol Use, Smoking

Intervention / Treatment
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* Drug: Varenicline
* Drug: Cytisine
* Drug: Nicotine Replacement Therapy
* Drug: Varenicline Placebo
* Drug: Cytisine Placebo
* Drug: Nicotine Replacement Therapy Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-70 years old HIV-infected ≥ 5 heavy drinking days in the past 30 days (NIAAA at-risk drinking levels) Smoking an average of at least 5 cigarettes per day Provision of contact information for 2 contacts to assist with follow-up Stable address within 100 kilometers Possession of a telephone (home or cell) Interest in cutting down/quitting alcohol or tobacco Able and willing to comply with all study protocols and procedures Exclusion Criteria: Not fluent in Russian Cognitive impairment Pregnant or planning to become pregnant in next 3 months Breastfeeding Unstable psychiatric illness (i.e. ,answered yes to any of the following: past three month a) active hallucinations; b) mental health symptoms prompting a visit to the ED or hospital; mental health medication changes due to worsening symptoms; presence of suicidal ideations) History of pheochromocytoma Taking smoking cessation medications in past 30 days History of seizures History of Buerger's disease Acute coronary syndrome within 1 month of enrollment Systolic BP > 180 mm Hg or diastolic BP > 105 mm Hg Currently taking anti-tuberculosis medications Currently taking Galantamine or Physostigmine BAC level of 0.10% or higher Known allergy to varenicline (Chantix) or cytisine (Tabex)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Varenicline + Nicotine Replacement Therapy placebo<br>Study participants will receive active varenicline and be instructed to take the medication for 12 weeks; participants will also receive a placebo Nicotine Replacement Therapy mouth spray for 8 weeks. | Drug: Varenicline<br>* 1 week starter kit followed by 1mg twice daily for 12 weeks.<br>Drug: Nicotine Replacement Therapy Placebo<br>* Mouth spray dosing based on standard recommendations tapered over 8 weeks.<br>|
| Placebo Comparator: Varenicline placebo + Nicotine Replacement Therapy<br>Study participants will receive placebo varenicline and be instructed to take the placebo medication for 12 weeks; participants will also receive an active Nicotine Replacement Therapy mouth spray for 8 weeks. | Drug: Nicotine Replacement Therapy<br>* Mouth spray dosing based on standard recommendations tapered over 8 weeks.<br>Drug: Varenicline Placebo<br>* 1 week starter kit followed by 1 pill twice daily for 12 weeks.<br>|
| Active Comparator: Cytisine + Nicotine Replacement Therapy placebo<br>Study participants will receive active cytisine and be instructed to take the medication for 25 days; participants will also receive a placebo Nicotine Replacement Therapy mouth spray for 8 weeks. | Drug: Cytisine<br>* Multi-daily dosing, range 3-9 mg daily for 25 days.<br>Drug: Nicotine Replacement Therapy Placebo<br>* Mouth spray dosing based on standard recommendations tapered over 8 weeks.<br>|
| Placebo Comparator: Cytisine placebo + Nicotine Replacement Therapy<br>Study participants will receive placebo cytisine and be instructed to take the medication for 25 days; participants will also receive an active Nicotine Replacement Therapy mouth spray for 8 weeks. | Drug: Nicotine Replacement Therapy<br>* Mouth spray dosing based on standard recommendations tapered over 8 weeks.<br>Drug: Cytisine Placebo<br>* Multi-daily dosing for 25 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent heavy drinking days in past 30 days | Self-reported past 30-day alcohol consumption obtained via the Timeline Followback (TLFB) method, heavy drinking defined by NIAAA definition | Participants will be followed for up to 12 months (primary endpoint at 3 month) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alcohol craving | Measured by the Penn Alcohol Craving Scale | Participants will be followed for up to 12 months (primary endpoint at 3 month) | 
| Carbon monoxide-validated smoking cessation | Self-reported 7-day point prevalence abstinence and a carbon monoxide measured in end-expired air threshold of <10 ppm. | Participants will be followed for up to 12 months (primary endpoint at 3 month) | 
| Coronary heart disease risk | Measured by the Reynolds risk score | Participants will be followed for up to 12 months (primary endpoint at 3 month) | 
| Mortality risk | Measured by the VACS index | Participants will be followed for up to 12 months (primary endpoint at 3 month) | 
| Cigarettes per day in past 7 days | Self-report, obtained via Timeline Followback (TLFB) method | Participants will be followed for up to 12 months (primary endpoint at 3 month) | 
| hsCRP levels | Biomarker of inflammation measured via study test | Participants will be followed for up to 12 months (primary endpoint at 3 month) | 
| IL-6 levels | Biomarker of inflammation measured via study test | Participants will be followed for up to 12 months (primary endpoint at 3 month) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alcohol Use, Tobacco Use, Smoking, Inflammation, Coronary Heart Disease, Russia, Varenicline, Cytisine, Nicotine Replacement Therapy, Partial Agonist Therapy, HIV, Reynolds risk score, VACS index