Dyslipidemias, Hypertension, Metabolic Syndrome X, Overweight, Prediabetic State
Conditions
Keywords
Insulin Resistance, Atherosclerosis, Metabolic Syndrome
Brief summary
Metabolic syndrome consists of a group of co-occuring conditions that increase an individual's risk of developing heart disease, stroke, and diabetes. The purpose of this study is to evaluate the short-term effectiveness of chloroquine, a protein-activation medication, at improving metabolic syndrome.
Detailed description
Metabolic syndrome is one of the most common disorders in industrialized countries. It consists of abnormal serum lipids, glucose intolerance, elevated blood pressure, and central obesity in the setting of insulin resistance. The syndrome substantially increases the risk of developing diabetes and vascular disease, but there is no clear unifying approach to treat this disorder. In animals, activation of the protein ataxia telangiectasia mutated (ATM) using the antimalarial drug chloroquine improves features of metabolic syndrome and decreases atherosclerosis, a build-up of fatty plaque within arteries. The purpose of this study is to evaluate the effectiveness of short-term treatment with low doses of chloroquine as a way of managing metabolic syndrome. Participants in this study will initially receive placebo for 3 weeks, followed by increasing doses of chloroquine in three, 3-week intervals. Following each 3-week treatment, participants will be admitted to the research center for one day. There will be a period of no active treatment for 5 to 7 weeks following each admission to the research center to allow recovery from the blood drawing of the clamp procedure before the start of the next treatment interval.
Interventions
DRUGPlacebo Comparator: First Intervention (3 weeks)
once daily placebo tablet for 3 weeks followed by: euglycemic clamp procedure; 24 hour Ambulatory Blood Pressure; Oral Glucose tolerance Test; serum collection; 24 hour urine collection; collection of peripheral blood mononuclear cells
DRUGActive Comparator: Second Intervention (3 weeks)
Once daily 80mg chloroquine or placebo tablet 3 Weeks followed by euglycemic clamp procedure; 24 hour Ambulatory Blood Pressure; Oral Glucose tolerance Test; serum collection; 24 hour urine collection; collection of peripheral blood mononuclear cells
DRUGActive Comparator: Third Intervention (3 weeks)
Once daily 80mg tablet for 3 weeks followed by: euglycemic clamp procedure; 24 hour Ambulatory Blood Pressure; Oral Glucose tolerance Test; serum collection; 24 hour urine collection; collection of peripheral blood mononuclear cells
DRUGActive Comparator: Fourth Intervention (3 weeks)
Once daily 250mg tablet for 3 weeks followed by: euglycemic clamp procedure; 24 hour Ambulatory Blood Pressure; Oral Glucose tolerance Test; serum collection; 24 hour urine collection; collection of peripheral blood mononuclear cells
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Washington University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of metabolic syndrome, as determined by at least three of the following five criteria: 1. Elevated fasting triglyceride levels greater than or equal to 150 mg/dL 2. Low HDL cholesterol levels: less than 50 mg/dL for women and less than 40 mg/dL for men 3. Hypertension (=\>130/85 mm Hg =\<160/100 mm Hg) untreated; or hypertension controlled (=\<150/90 mm Hg) on a stable medication regimen for 4 weeks prior to baseline visit. 4. Increased waist circumference: greater than 35 inches in women and greater than 40 inches in men 5. Elevated fasting glucose levels =\<100 mg/dL but =\>126 mg/dL * Subjects may be on a stable doses of a statin drug for at least 3 months * Subjects may be on a stable doses of L-thyroxine for at least 3 months * Willing to use acceptable form of birth control (e.g., hormonal birth control, double barrier methods)
Exclusion criteria
* Prior travel treatment with chloroquine or hydroxychloroquine as follows: 1. any exposure in the past 2 years, 2. \>30 days of therapy if exposure was between 2 and 5 years ago, 3. \>90 days of therapy if exposure was between 5 and 10 years ago, 4. \>6 months of therapy if exposure was 10 to 20 years ago, 5. \>1 year of therapy if exposure was 20 to 30 years ago, 6. No limit if last exposure was \>30 years ago, ex. during the Vietnam conflict. * Morbid obesity (body mass index \[BMI\] greater than 45) * Coronary artery disease or other vascular disease * History of stroke * Chronic kidney insufficiency (i.e.,estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73m2) * Diabetes * Seizure disorder * History of psoriasis * Blood disorders, including anemia (i.e., hemoglobin levels less than 13 g/dL in men and less than 12 g/dL in women) * Current malignancy or active treatment for recurrence prevention, example tamoxifen. Cancer considered to be cured, either as a result of surgery or other treatment is not exclusionary. * Asthma requiring daily beta agonist therapy or intermittent oral steroids is exclusionary. Inhaled steroids are acceptable. Obstructive sleep apnea will be allowed if Continuous Positive Airway Pressure (CPAP) or other therapy has been stable for 6 months. Other active respiratory diseases are excluded. * Liver disease, or liver function test results greater than twice the normal value * Active infection, including HIV * Serious illness requiring ongoing medical care or medication * Treatment with atypical anti-psychotic medication. Treatment with any other medication for psychiatric illness, unless on a stable dose for 6 weeks prior to enrollment. Patients with unstable psychiatric disorders are excluded per the decision of the study MD regardless of medication history. * Taking any of the following lipid lowering medications: niacin, fibrates, and greater than 1 gm fish oils * Uncontrolled hypertension (BP \>150/90) at enrollment. * Need for daily over the counter medications, or currently taking cimetidine or \>1000 IU vitamin E daily and unwilling to reduce or discontinue the use of vitamin E or discontinue cimetidine for the duration of the study. Persons taking \>1000 IU of vitamin E should reduce the dose 30 days prior to randomization. * Pregnant, breastfeeding, or intending to become pregnant * Glucose-6-phosphate dehydrogenase (G6PD) deficiency * Retinal disease (in particular, drusen or pigmentary changes at the macula); any ocular disease that interferes with the eye examination (e.g., cataracts) * Auditory disease or hearing loss; persons with total, irreversible hearing loss can be enrolled. * Participation in another clinical trial within past 30 days prior to screening and 60 days prior to randomization. Questionnaire or observational studies are not exclusionary.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity | assessed every 8 - 10 weeks at the end of each treatment period | Hepatic insulin sensitivity was measured by comparing glucose production at baseline of zero insulin infusion rate with glucose production at 56 pmol/m2/min. Hepatic insulin sensitivity was expressed as the percent suppression, such that greater percent suppression indicated greater hepatic insulin sensitivity. There are no reference values, since the patients served as their own controls. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Diastolic Blood Pressure | Assessed every 8-10 weeks at the end of each treatment period. | Two techniques were employed: auscultation of seated subjects at rest was performed by a trained observer who recorded the first and fifth phases of the Korotkoff sounds; and, a portable oscillometric device (SpaceLabs Medical) recorded results every 20 min during the day and every hour during the night. Data were analyzed as mean values over 24 hours. |
| Total Cholesterol | Assessed every 8-10 weeks at the end of each treatment period. | Fasting Serum Blood Sample |
| Systolic Blood Pressure | Assessed every 8-10 weeks at the end of each treatment period | Two techniques were employed: auscultation of seated subjects at rest was performed by a trained observer who recorded the first and fifth phases of the Korotkoff sounds; and, a portable oscillometric device (SpaceLabs Medical) recorded results every 20 min during the day and every hour during the night. Data were analyzed as mean values over 24 hours. |
| Low-density Lipoprotein | Assessed every 8-10 weeks at the end of each treatment period. | Fasting Serum Blood Sample |
| Triglycerides | Assessed every 8-10 weeks at the end of each treatment period. | Fasting Serum Blood Sample |
| Non-HDL Cholesterol | Assessed every 8-10 weeks at the end of each treatment period. | Fasting Serum Blood Sample |
Countries
United States
Participant flow
Recruitment details
Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. First participant was screened on 08 September 2004. The last study visit occurred on 08 June 2010.
Pre-assignment details
144 participants were screened
Participants by arm
| Arm | Count |
|---|---|
| All Randomized Subject All Randomized Subjects | 35 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Cohort 1: Placebo | DIFFICULTY WITH IV ACCESS | 1 | 0 | 0 | 0 |
| Cohort 1: Placebo | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Cohort 1: Placebo | New diagnosis of Type 2 Diabetes | 1 | 0 | 0 | 0 |
| Cohort 1: Placebo | Started exclusionary drug | 1 | 0 | 0 | 0 |
| Cohort 1: Placebo | Withdrawal by Subject | 4 | 0 | 0 | 0 |
| Cohort 2: 80 mg Chloroquine Weekly | Adverse Event | 0 | 1 | 0 | 0 |
| Cohort 3: 80 mg Chloroquine Daily | Started exclusionary drug | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | All Randomized Subject |
|---|---|
| Age, Continuous | 47 years STANDARD_DEVIATION 8.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants |
| Race/Ethnicity, Customized Unknown or not reported | 0 Participants |
| Race/Ethnicity, Customized White | 32 Participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 27 | 0 / 25 | 0 / 25 |
| other Total, other adverse events | 6 / 35 | 1 / 27 | 1 / 25 | 1 / 25 |
| serious Total, serious adverse events | 0 / 35 | 0 / 27 | 0 / 25 | 0 / 25 |
Outcome results
Primary
Insulin Sensitivity
Hepatic insulin sensitivity was measured by comparing glucose production at baseline of zero insulin infusion rate with glucose production at 56 pmol/m2/min. Hepatic insulin sensitivity was expressed as the percent suppression, such that greater percent suppression indicated greater hepatic insulin sensitivity. There are no reference values, since the patients served as their own controls.
Time frame: assessed every 8 - 10 weeks at the end of each treatment period
Population: Full Analysis Set included all randomized participants who completed all procedures in the study arm
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: First Intervention (3 Weeks) | Insulin Sensitivity | .56 % suppression inf rate 56 pmol/m2/min | Standard Deviation 0.04 |
| Second Intervention (3 Weeks) | Insulin Sensitivity | 0.55 % suppression inf rate 56 pmol/m2/min | Standard Deviation 0.05 |
| Third Intervention (3 Weeks) | Insulin Sensitivity | 0.66 % suppression inf rate 56 pmol/m2/min | Standard Deviation 0.06 |
| Fourth Intervention (3 Weeks) | Insulin Sensitivity | 0.70 % suppression inf rate 56 pmol/m2/min | Standard Deviation 0.04 |
Secondary
Diastolic Blood Pressure
Two techniques were employed: auscultation of seated subjects at rest was performed by a trained observer who recorded the first and fifth phases of the Korotkoff sounds; and, a portable oscillometric device (SpaceLabs Medical) recorded results every 20 min during the day and every hour during the night. Data were analyzed as mean values over 24 hours.
Time frame: Assessed every 8-10 weeks at the end of each treatment period.
Population: Full Analysis Set included all randomized participants who completed procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: First Intervention (3 Weeks) | Diastolic Blood Pressure | 70 mmHg | Standard Deviation 7 |
| Second Intervention (3 Weeks) | Diastolic Blood Pressure | 71 mmHg | Standard Deviation 7 |
| Third Intervention (3 Weeks) | Diastolic Blood Pressure | 73 mmHg | Standard Deviation 8 |
| Fourth Intervention (3 Weeks) | Diastolic Blood Pressure | 73 mmHg | Standard Deviation 9 |
Secondary
Low-density Lipoprotein
Fasting Serum Blood Sample
Time frame: Assessed every 8-10 weeks at the end of each treatment period.
Population: Full Analysis Set included all randomized participants who completed procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: First Intervention (3 Weeks) | Low-density Lipoprotein | 115 mg/dl | Standard Deviation 5 |
| Second Intervention (3 Weeks) | Low-density Lipoprotein | 109 mg/dl | Standard Deviation 6 |
| Third Intervention (3 Weeks) | Low-density Lipoprotein | 109 mg/dl | Standard Deviation 5 |
| Fourth Intervention (3 Weeks) | Low-density Lipoprotein | 103 mg/dl | Standard Deviation 6 |
Secondary
Non-HDL Cholesterol
Fasting Serum Blood Sample
Time frame: Assessed every 8-10 weeks at the end of each treatment period.
Population: Full Analysis Set included all randomized participants who completed procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: First Intervention (3 Weeks) | Non-HDL Cholesterol | 144 mg/dL | Standard Deviation 6 |
| Second Intervention (3 Weeks) | Non-HDL Cholesterol | 139 mg/dL | Standard Deviation 7 |
| Third Intervention (3 Weeks) | Non-HDL Cholesterol | 139 mg/dL | Standard Deviation 5 |
| Fourth Intervention (3 Weeks) | Non-HDL Cholesterol | 131 mg/dL | Standard Deviation 6 |
Secondary
Systolic Blood Pressure
Two techniques were employed: auscultation of seated subjects at rest was performed by a trained observer who recorded the first and fifth phases of the Korotkoff sounds; and, a portable oscillometric device (SpaceLabs Medical) recorded results every 20 min during the day and every hour during the night. Data were analyzed as mean values over 24 hours.
Time frame: Assessed every 8-10 weeks at the end of each treatment period
Population: Full Analysis Set included all randomized participants who completed all procedures in the study arm
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: First Intervention (3 Weeks) | Systolic Blood Pressure | 121 mmHg | Standard Deviation 12 |
| Second Intervention (3 Weeks) | Systolic Blood Pressure | 121 mmHg | Standard Deviation 10 |
| Third Intervention (3 Weeks) | Systolic Blood Pressure | 123 mmHg | Standard Deviation 12 |
| Fourth Intervention (3 Weeks) | Systolic Blood Pressure | 123 mmHg | Standard Deviation 12 |
Secondary
Total Cholesterol
Fasting Serum Blood Sample
Time frame: Assessed every 8-10 weeks at the end of each treatment period.
Population: Full analysis set included all randomized participants who completed study procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: First Intervention (3 Weeks) | Total Cholesterol | 187 mg/dL | Standard Deviation 6 |
| Second Intervention (3 Weeks) | Total Cholesterol | 181 mg/dL | Standard Deviation 7 |
| Third Intervention (3 Weeks) | Total Cholesterol | 182 mg/dL | Standard Deviation 5 |
| Fourth Intervention (3 Weeks) | Total Cholesterol | 173 mg/dL | Standard Deviation 6 |
Secondary
Triglycerides
Fasting Serum Blood Sample
Time frame: Assessed every 8-10 weeks at the end of each treatment period.
Population: Full Analysis Set included all randomized participants who completed procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Comparator: First Intervention (3 Weeks) | Triglycerides | 143 mg/dL | Standard Deviation 14 |
| Second Intervention (3 Weeks) | Triglycerides | 153 mg/dL | Standard Deviation 16 |
| Third Intervention (3 Weeks) | Triglycerides | 151 mg/dL | Standard Deviation 18 |
| Fourth Intervention (3 Weeks) | Triglycerides | 140 mg/dL | Standard Deviation 16 |