Examination of Zinc, S-adenosylmethionine, and Combination Therapy Versus Placebo in Alcoholics (ExZACTO)

Study Description

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Brief Summary:

This is a randomized, placebo controlled trial of dietary zinc and S-adenosylmethionine (SAMe) in otherwise healthy alcoholic US Veterans. The primary goal is to determine if either dietary zinc or S-adenosylmethionine (SAMe) can augment lung immune defenses in alcoholics and thereby decrease the risk of lung injury and infection.

Condition or disease	Intervention/treatment	Phase
Alcoholism	Procedure: Bronchoscopy; Dietary Supplement: Zinc sulfate 220 mg once daily; Dietary Supplement: S-adenosylmethionine 400 mg twice daily	Not Applicable

Detailed Description:

Alcohol abuse is a major burden on society and even more of a problem in the Veteran population. Chronic alcohol ingestion can have serious health consequences including pneumonia and acute lung injury, which can occur suddenly and without warning even in physically fit individuals without apparent signs of alcohol dependence. Therefore, it is vital for the health of our Veterans and indeed the entire population to identify effective treatments that can limit or even prevent these devastating consequences. The primary goal of this clinical research project is to determine if dietary zinc or supplements of the antioxidant S-adenosylmethionine (SAMe) can augment lung immune defenses in otherwise healthy alcoholics and thereby decrease the risk of lung injury and infection. There is already strong evidence from the investigators' experimental animal model that moderate daily alcohol ingestion for as little as six weeks causes oxidative stress and zinc deficiency in the lung. These derangements result insult in dysfunction of the alveolar macrophage, which is the resident immune cell, and predisposes animals to the development of pneumonia. Importantly, in this same animal model, the investigators found that adding either zinc or antioxidants to the diet prevents these problems and preserves lung health even during daily alcohol ingestion.

This project will translate basic findings in the animal model to the clinical setting and determine whether or not zinc or SAMe supplements are effective in humans who pathologically consume alcohol. This project will enroll Veterans seen at the Atlanta Veterans Hospital in the Substance Abuse Treatment Program (SATP). Participants will be evaluated by undergoing a procedure to obtain samples of fluid from their lungs, measure zinc levels, redox potential, and assess how well their alveolar macrophages respond to bacteria (by determining phagocytic capacity). After completion of the initial evaluation, the participants will be randomized to receive standard treatment (placebo), zinc supplements, dietary SAMe, or the combination of zinc and SAMe for 14 days. All subjects will be evaluated for two weeks as they undergo treatment. At the end of this two week period, measurements of lung zinc, redox potential and macrophage function will be repeated and compared between the two groups. The hypothesis is that both dietary zinc and SAM supplements will improve the immune function of the alveolar macrophage.

If this project is successful, it will lead to larger clinical trials to determine if either dietary zinc and/or SAMe supplements can be effective even in the acute clinical setting and improve outcomes in alcoholics who develop pneumonia or acute lung injury. Overall, both zinc and SAMe supplements are safe and inexpensive to provide, allowing these potential treatments to be easily implemented in the Veteran population as well as society in general. Given the significant burden of unhealthy alcohol use, the investigators need ways to limit the physical consequences of alcohol abuse while the investigators continue the efforts at public education and addiction treatment.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	113 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Care Provider, Investigator)
Primary Purpose:	Treatment
Official Title:	Alcohol Abuse, Oxidative Stress, and Zinc Deficiency in Lung Disease
Actual Study Start Date :	May 1, 2013
Actual Primary Completion Date :	July 31, 2017
Actual Study Completion Date :	July 31, 2017

Arms and Interventions

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Arm	Intervention/treatment
Placebo Comparator: Placebo zinc and placebo SAMe; Placebo tablet of zinc sulfate once daily and placebo tablet of s-adenosylmethionine twice daily	Procedure: Bronchoscopy; Involves flexible fiberoptic bronchoscopy with standardized bronchoalveolar lavage (BAL) technique (isotonic saline in a sub-segment of the right middle lobe or lingula) using standard conscious sedation techniques.
Active Comparator: Active zinc and placebo SAMe; Zinc sulfate 220 mg once daily and placebo tablet of s-adenosylmethionine twice daily	Procedure: Bronchoscopy; Involves flexible fiberoptic bronchoscopy with standardized bronchoalveolar lavage (BAL) technique (isotonic saline in a sub-segment of the right middle lobe or lingula) using standard conscious sedation techniques. Dietary Supplement: Zinc sulfate 220 mg once daily
Active Comparator: Placebo zinc and active SAMe; Placebo tablet of zinc sulfate once daily and s-adenosylmethionine 400 mg twice daily	Procedure: Bronchoscopy; Involves flexible fiberoptic bronchoscopy with standardized bronchoalveolar lavage (BAL) technique (isotonic saline in a sub-segment of the right middle lobe or lingula) using standard conscious sedation techniques. Dietary Supplement: S-adenosylmethionine 400 mg twice daily; Other Name: SAMe
Active Comparator: Active zinc and active SAMe; Zinc sulfate 220 mg once daily and s-adenosylmethionine 400 mg twice daily	Procedure: Bronchoscopy; Involves flexible fiberoptic bronchoscopy with standardized bronchoalveolar lavage (BAL) technique (isotonic saline in a sub-segment of the right middle lobe or lingula) using standard conscious sedation techniques. Dietary Supplement: Zinc sulfate 220 mg once daily Dietary Supplement: S-adenosylmethionine 400 mg twice daily; Other Name: SAMe

Outcome Measures

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Primary Outcome Measures :

1. Primary Endpoint [ Time Frame: Initial bronchoscopy to second bronchoscopy (Initial bronchoscopy performed prior to treatment and second bronchoscopy done 2-3 weeks after starting treatment) ]
   Improvement in alveolar macrophage phagocytic index. Phagocytic index will be measured before and after treatment phase. Phagocytic index is calculated using isolated alveolar macrophages from the bronchoscopy procedure such that phagocytic index = (total number of engulfed cells/total number of counted macrophages) x (number of macrophages containing engulfed cells/total number of counted macrophages) x 100.

Secondary Outcome Measures :

1. Secondary Endpoint [ Time Frame: Initial bronchoscopy to second bronchoscopy (Initial bronchoscopy performed prior to treatment and second bronchoscopy done 2-3 weeks after starting treatment) ]
   Improvement in alveolar macrophage intracellular zinc. Intracellular zinc will be measured before and after treatment phase using isolated alveolar macrophages. The units of measure are relative fluorescence units/cell (RFU/cell) and measured using confocal microscopy techniques.

Other Outcome Measures:

1. Secondary endpoint [ Time Frame: Initial bronchoscopy to second bronchoscopy (Initial bronchoscopy performed prior to treatment and second bronchoscopy done 2-3 weeks after starting treatment) ]
   Improvement in redox potential in the alveolar space. Redox potential will be measured before and after treatment phase using lavage fluid and blood plasma.
2. Secondary endpoint [ Time Frame: Initial bronchoscopy to second bronchoscopy (Initial bronchoscopy performed prior to treatment and second bronchoscopy done 2-3 weeks after starting treatment) ]
   Improvement in alveolar macrophage granulocyte macrophage - colony stimulating factor (GM-CSF) receptor expression. GM-CSF receptor expression will be measured before and after treatment phase using isolated alveolar macrophages. The units of measure are relative fluorescence units/cell (RFU/cell) and measured using confocal microscopy techniques. Both alpha- and beta-subunits of the receptor will be measured.
3. Secondary endpoint [ Time Frame: Initial bronchoscopy to second bronchoscopy (Initial bronchoscopy performed prior to treatment and second bronchoscopy done 2-3 weeks after starting treatment) ]
   Improvement in serum zinc level. Serum zinc will be measured before and after treatment phase by collecting blood plasma. The units of measure are mg/dl.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 60 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Age 18-60 years
• Active alcohol use disorder

Exclusion Criteria:

• Any active and uncontrolled medical problem(s)
• Known zinc deficiency
• Primary substance of abuse something other than alcohol
• Current abnormal chest x-ray
• HIV-positive
• Any disorder of blood coagulation

• Currently on medical treatment with anti-coagulants, including:

  • warfarin
  • heparin
  • direct thrombin inhibitors
  • anti-platelet agents (other than Aspirin)
• Daily use of vitamins or other nutritional supplements (unless taking as treatment for alcohol use disorder)
• Renal impairment (GFR < 60)
• Active bipolar disorder
• Active Parkinson's disease
• Current pregnancy
• Contraindication to treatment with zinc or S-adenosylmethionine
• Inability to give informed consent (i.e., limited cognitive capacity)
• Non-English speaking

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Georgia
Atlanta VA Medical and Rehab Center, Decatur, GA
Decatur, Georgia, United States, 30033

Sponsors and Collaborators

VA Office of Research and Development

Investigators

Principal Investigator:	Ashish Mehta, MD	Atlanta VA Medical and Rehab Center, Decatur, GA

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	VA Office of Research and Development
ClinicalTrials.gov Identifier:	NCT01899521 History of Changes
Other Study ID Numbers:	PULM-038-12S; IRB00060773 ( Other Identifier: Emory IRB ); IK2CX000643 ( U.S. NIH Grant/Contract )
First Posted:	July 15, 2013
Last Update Posted:	November 8, 2017
Last Verified:	November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

Studies a U.S. FDA-regulated Drug Product:		No
Studies a U.S. FDA-regulated Device Product:		No
Product Manufactured in and Exported from the U.S.:		No

Keywords provided by VA Office of Research and Development:

alcoholism; lung health; pulmonary; macrophage	zinc; SAMe; S-adenosylmethionine; alveolar

Additional relevant MeSH terms:

Alcoholism; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Zinc; Zinc Sulfate	Trace Elements; Micronutrients; Growth Substances; Physiological Effects of Drugs; Astringents; Dermatologic Agents