Clinical trial NCT00455325: Chloroquine to Treat People With Metabolic Syndrome Aim2 (ARCH-MS)
Official title: Genotoxic Stress, Atherosclerosis, and Metabolic Syndrome-AIM 2
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metabolic Syndrome X
Overweight
Hypertension
Dyslipidemias
Prediabetic State
Keywords: Insulin Resistance
Atherosclerosis
Metabolic Syndrome
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2007-04-03
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Insulin Sensitivity
timeFrame: assessed every 8 - 10 weeks at the end of each treatment period
Secondary outcomes:
measure: Systolic Blood Pressure
timeFrame: Assessed every 8-10 weeks at the end of each treatment period
measure: Diastolic Blood Pressure
timeFrame: Assessed every 8-10 weeks at the end of each treatment period.
measure: Total Cholesterol
timeFrame: Assessed every 8-10 weeks at the end of each treatment period.
measure: Non-HDL Cholesterol
timeFrame: Assessed every 8-10 weeks at the end of each treatment period.
measure: Low-density Lipoprotein
timeFrame: Assessed every 8-10 weeks at the end of each treatment period.
measure: Triglycerides
timeFrame: Assessed every 8-10 weeks at the end of each treatment period.
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University in St. Louis
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Clay F. Semenkovich, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schneider JG, Finck BN, Ren J, Standley KN, Takagi M, Maclean KH, Bernal-Mizrachi C, Muslin AJ, Kastan MB, Semenkovich CF. ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome. Cell Metab. 2006 Nov;4(5):377-89. doi: 10.1016/j.cmet.2006.10.002.
citation: McGill JB, Johnson M, Hurst S, Cade WT, Yarasheski KE, Ostlund RE, Schechtman KB, Razani B, Kastan MB, McClain DA, de las Fuentes L, Davila-Roman VG, Ory DS, Wickline SA, Semenkovich CF. Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness. Diabetol Metab Syndr. 2019 Jul 29;11:61. doi: 10.1186/s13098-019-0456-4. eCollection 2019.
citation: Razani B, Feng C, Semenkovich CF. p53 is required for chloroquine-induced atheroprotection but not insulin sensitization. J Lipid Res. 2010 Jul;51(7):1738-46. doi: 10.1194/jlr.M003681. Epub 2010 Mar 5.