Endothelial Dysfunction, HIV, Oxidative Stress
Conditions
Keywords
HIV, Endothelial function, Oxidative stress, Cardiovascular disease, N-acetylcysteine
Brief summary
The goal of this study is to determine if n-acetylcysteine, given as PharmaNAC, reduces oxidative stress and improves vascular function in HIV-infected older adults already on HIV treatment.
Detailed description
The primary objective of this study is to compare 8-week changes in circulating levels of malondialdehyde (MDA), circulating levels of F2-isoprostanes, and flow-mediated dilation (FMD) of the brachial artery in older HIV-infected adults already receiving virologically suppressive antiretroviral therapy (ART) who are then randomized to either NAC 900 mg twice daily, NAC 1800 mg twice daily, or placebo. The relative efficacy and safety of these two doses of NAC will be assessed.
Interventions
DIETARY_SUPPLEMENTPharmaNAC (N-acetylcysteine)
PharmaNAC is considered a nutritional supplement and can be obtained without a prescription. All participants will be asked to ingest two tablets twice per day during this trial. For those randomized to PharmaNAC 1800 mg twice daily, this will be two active tablets twice per day. For those randomized to PharmaNAC 900 mg twice daily, this will be one active tablet twice per day and one matching placebo tablet twice per day. For those randomized to placebo, this will be two matching placebo tablets twice per day. PharmaNAC can be taken with or without food. The effervescent tablets should be dissolved in 8 oz. of water or juice prior to oral intake. Each participant will take study drug and/or matching placebo for 8 weeks (up to 60 days).
DIETARY_SUPPLEMENTMatching placebo
Inactive pill that matches PharmaNAC on taste, color, and appearance.
Sponsors
BioAdvantex Pharma
Indiana University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV-1 infection, documented by (1) any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or (2) by two detectable HIV-1 antigens, or (3) two detectable plasma HIV-1 RNA viral loads. * Age equal to or greater than 50 years. * Receipt of antiretroviral therapy of any kind for at least 6 months prior to screening. * HIV-1 RNA level \< 75 copies/mL at screening. * For women who are still of reproductive potential, a negative urine pregnancy test at screening and willingness to use two forms of birth control during the course of the study. Acceptable forms of birth control include condoms (with or without a gel that can kill sperm), a diaphragm or cervical cap (with or without a gel that can kill sperm), an intrauterine device (IUD), or hormonal-based birth control (the pill).
Exclusion criteria
* Inability to complete written, informed consent. * Incarceration at the time of any study visit. * Known allergy or intolerance to n-acetylcysteine. * Use of n-acetylcysteine within 180 days of screening. * Diagnosed vascular disease (history of angina pectoris, coronary disease, peripheral vascular disease, cerebrovascular disease, aortic aneurysm, or otherwise known atherosclerotic disease). * History of congestive heart failure even if currently compensated. * History of portal hypertension or hepatic cirrhosis (either clinically diagnosed or histologically diagnosed). * Diagnosed disease or process, besides HIV infection, associated with increased systemic inflammation (including, but not limited to, systemic lupus erythematosis, inflammatory bowel diseases, other collagen vascular diseases). * Known or suspected malignancy requiring systemic treatment within six months of screening. * History of ADA-defined diabetes mellitus (115) * History of migraine headaches. * History of Raynaud's phenomenon. * History of cardiac arrhythmias or cardiomyopathy. * Uncontrolled hyperthyroidism or hypothyroidism, defined as TSH values outside of the local reference range on most recent clinical assessment. * Asthma or COPD requiring daily use of beta-2-agonist therapy (e.g. albuterol) * History of carotid bruits. * Creatinine clearance \< 50 mL/min (using the Cockcroft-Gault equation) using a serum creatinine level measured at screening. * Hemoglobin \< 9.0 g/dL at screening. * Alanine aminotransferase (ALT) level or aspartate aminotransferase (AST) \> 3 times ULN at screening. * Total bilirubin \> 2.5 times ULN at screening; if the participant is receiving atazanavir, then s/he would be excluded if total bilirubin is \> 3.5 times ULN at screening. * Therapy for serious medical illnesses within 14 days prior to screening. * Pregnancy or breastfeeding during the course of the study. * Uncontrolled hypertension, defined as systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg at screening. * Receipt of investigational agents, cytotoxic chemotherapy, systemic glucocorticoids (of any dose), or anabolic steroids at screening. * Previous receipt of stavudine or didanosine for more than 7 cumulative days. * Receipt of daily Vitamin C or Vitamin E supplements at screening. * Alcohol intake more than the equivalent of one 8 oz. of wine daily for the 7 days prior to screening. * Active drug use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Circulating Malondialdehyde Levels | Baseline and 8 weeks | Measure of oxidative stress |
| Change in Circulating F2-isoprostane Levels | Baseline and 8 weeks | Oxidative stress measure |
| Change in Flow-mediated Dilation (FMD) of the Brachial Artery | Baseline and 8 weeks | Measure of endothelial function |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PharmaNAC 1800 mg PharmaNAC 900 mg orally twice daily for 8 weeks
PharmaNAC (N-acetylcysteine): PharmaNAC is considered a nutritional supplement and can be obtained without a prescription. All participants will be asked to ingest two tablets twice per day during this trial. For those randomized to PharmaNAC 1800 mg twice daily, this will be two active tablets twice per day. For those randomized to PharmaNAC 900 mg twice daily, this will be one active tablet twice per day and one matching placebo tablet twice per day. For those randomized to placebo, this will be two matching placebo tablets twice per day.
PharmaNAC can be taken with or without food. The effervescent tablets should be dissolved in 8 oz. of water or juice prior to oral intake. Each participant will take study drug and/or matching placebo for 8 weeks (up to 60 days).
Matching placebo: Inactive pill that matches PharmaNAC on taste, color, and appearance. | 9 |
| PharmaNAC 3600 mg PharmaNAC 1800 mg orally twice daily for 8 weeks
PharmaNAC (N-acetylcysteine): PharmaNAC is considered a nutritional supplement and can be obtained without a prescription. All participants will be asked to ingest two tablets twice per day during this trial. For those randomized to PharmaNAC 1800 mg twice daily, this will be two active tablets twice per day. For those randomized to PharmaNAC 900 mg twice daily, this will be one active tablet twice per day and one matching placebo tablet twice per day. For those randomized to placebo, this will be two matching placebo tablets twice per day.
PharmaNAC can be taken with or without food. The effervescent tablets should be dissolved in 8 oz. of water or juice prior to oral intake. Each participant will take study drug and/or matching placebo for 8 weeks (up to 60 days). | 8 |
| Placebo Matching placebo pills given twice daily for 8 weeks
Matching placebo: Inactive pill that matches PharmaNAC on taste, color, and appearance. | 7 |
| Total | 24 |
Baseline characteristics
| Characteristic | PharmaNAC 1800 mg | PharmaNAC 3600 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 52 years | 53 years | 54 years | 53 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 8 Participants | 6 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 3 Participants | 4 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 1 Participants | 5 Participants | 3 Participants | 9 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 4 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 9 | 6 / 8 | 6 / 7 |
| serious Total, serious adverse events | 0 / 9 | 0 / 8 | 0 / 7 |
Outcome results
Primary
Change in Circulating F2-isoprostane Levels
Oxidative stress measure
Time frame: Baseline and 8 weeks
Population: Analysis population includes those who completed the 8 week trial and had both baseline and week 8 values available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PharmaNAC 1800 mg | Change in Circulating F2-isoprostane Levels | -12.78 pg/mL | Standard Deviation 26.39 |
| PharmaNAC 3600 mg | Change in Circulating F2-isoprostane Levels | -4.84 pg/mL | Standard Deviation 28.85 |
| Placebo | Change in Circulating F2-isoprostane Levels | 11.76 pg/mL | Standard Deviation 28.76 |
Primary
Change in Circulating Malondialdehyde Levels
Measure of oxidative stress
Time frame: Baseline and 8 weeks
Population: Analysis population includes those who completed the 8 week trial and had both baseline and week 8 values available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PharmaNAC 1800 mg | Change in Circulating Malondialdehyde Levels | 0.17 micromolar | Standard Deviation 1.74 |
| PharmaNAC 3600 mg | Change in Circulating Malondialdehyde Levels | -0.12 micromolar | Standard Deviation 0.054 |
| Placebo | Change in Circulating Malondialdehyde Levels | -0.00 micromolar | Standard Deviation 0.56 |
Primary
Change in Flow-mediated Dilation (FMD) of the Brachial Artery
Measure of endothelial function
Time frame: Baseline and 8 weeks
Population: Analysis population includes those who completed the 8 week trial and had both baseline and week 8 values available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PharmaNAC 1800 mg | Change in Flow-mediated Dilation (FMD) of the Brachial Artery | 0.51 Percentage of vessel diameter | Standard Deviation 2 |
| PharmaNAC 3600 mg | Change in Flow-mediated Dilation (FMD) of the Brachial Artery | -.046 Percentage of vessel diameter | Standard Deviation 2.18 |
| Placebo | Change in Flow-mediated Dilation (FMD) of the Brachial Artery | -1.15 Percentage of vessel diameter | Standard Deviation 2.56 |