Chloroquine to Treat People With Metabolic Syndrome Aim2 (ARCH-MS)

Study Overview
=================
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.

Official Title
-----------------
Genotoxic Stress, Atherosclerosis, and Metabolic Syndrome-AIM 2

Conditions
-----------------
Metabolic Syndrome X, Overweight, Hypertension, Dyslipidemias, Prediabetic State

Intervention / Treatment
-----------------
* Drug: Placebo Comparator: First Intervention (3 weeks)
* Drug: Active Comparator: Second Intervention (3 weeks)
* Drug: Active Comparator: Third Intervention (3 weeks)
* Drug: Active Comparator: Fourth Intervention (3 weeks)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of metabolic syndrome, as determined by at least three of the following five criteria: Elevated fasting triglyceride levels greater than or equal to 150 mg/dL Low HDL cholesterol levels: less than 50 mg/dL for women and less than 40 mg/dL for men 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. Increased waist circumference: greater than 35 inches in women and greater than 40 inches in men 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: any exposure in the past 2 years, >30 days of therapy if exposure was between 2 and 5 years ago, >90 days of therapy if exposure was between 5 and 10 years ago, >6 months of therapy if exposure was 10 to 20 years ago, >1 year of therapy if exposure was 20 to 30 years ago, 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: First Intervention (3 weeks)<br>Cohort 1: Chloroquine placebo one tablet daily for 3 weeks, followed by 5-7 week rest period. | Drug: Placebo Comparator: First Intervention (3 weeks)<br>* 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<br>* Other names: Placebo once daily;|
| Active Comparator: Second Intervention (3 weeks)<br>Cohort 2: 80mg chloroquine or placebo tablet once daily for Weeks 3, followed by 5-7 week rest period. | Drug: Active Comparator: Second Intervention (3 weeks)<br>* 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<br>* Other names: 80 mg chloroquine or placebo tablet once daily;|
| Active Comparator: Third Intervention (3 weeks)<br>Cohort 3: 80mg chloroquine tablet daily: for 3 weeks, followed by 5-7 week rest period. | Drug: Active Comparator: Third Intervention (3 weeks)<br>* 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<br>* Other names: 80 mg chloroquine tablet once daily;|
| Active Comparator: Fourth Intervention (3 weeks)<br>Cohort 4: 250mg chloroquine tablet daily: for 3 weeks, followed by 5-7 week rest period. | Drug: Active Comparator: Fourth Intervention (3 weeks)<br>* 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<br>* Other names: 250 mg chloroquine tablet once daily;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | assessed every 8 - 10 weeks at the end of each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Assessed every 8-10 weeks at the end of each treatment period | 
| 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. | Assessed every 8-10 weeks at the end of each treatment period. | 
| Total Cholesterol | Fasting Serum Blood Sample | Assessed every 8-10 weeks at the end of each treatment period. | 
| Non-HDL Cholesterol | Fasting Serum Blood Sample | Assessed every 8-10 weeks at the end of each treatment period. | 
| Low-density Lipoprotein | Fasting Serum Blood Sample | Assessed every 8-10 weeks at the end of each treatment period. | 
| Triglycerides | Fasting Serum Blood Sample | Assessed every 8-10 weeks at the end of each treatment period. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Insulin Resistance, Atherosclerosis, Metabolic Syndrome