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

NCT ID: NCT00455325

Last Updated: 2022-05-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 35 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-09-30
• Study Completion Date: 2012-03-31

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.

Conditions

Metabolic Syndrome X; Overweight; Hypertension; Dyslipidemias; Prediabetic State

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

First Intervention (3 weeks)

Cohort 1: Chloroquine placebo one tablet daily for 3 weeks, followed by 5-7 week rest period.

Group Type: PLACEBO_COMPARATOR

Placebo Comparator: First Intervention (3 weeks)

Intervention Type: DRUG

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

Second Intervention (3 weeks)

Cohort 2: 80mg chloroquine or placebo tablet once daily for Weeks 3, followed by 5-7 week rest period.

Group Type: ACTIVE_COMPARATOR

Active Comparator: Second Intervention (3 weeks)

Intervention Type: DRUG

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

Third Intervention (3 weeks)

Cohort 3: 80mg chloroquine tablet daily: for 3 weeks, followed by 5-7 week rest period.

Group Type: ACTIVE_COMPARATOR

Active Comparator: Third Intervention (3 weeks)

Intervention Type: DRUG

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

Fourth Intervention (3 weeks)

Cohort 4: 250mg chloroquine tablet daily: for 3 weeks, followed by 5-7 week rest period.

Group Type: ACTIVE_COMPARATOR

Active Comparator: Fourth Intervention (3 weeks)

Intervention Type: DRUG

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

Interventions

Placebo 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

Intervention Type: DRUG

Active 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

Intervention Type: DRUG

Active 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

Intervention Type: DRUG

Active 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

Intervention Type: DRUG

Other Intervention Names

Placebo once daily; 80 mg chloroquine or placebo tablet once daily; 80 mg chloroquine tablet once daily; 250 mg chloroquine tablet once daily

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clay F. Semenkovich, MD

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Locations

Washington University in St. Louis

St Louis, Missouri, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 17084711 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31384309 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 20208057 (View on PubMed)

Related Links

https://vfh.wustl.edu/

click here for Washington University Research Participant Registry

Other Identifiers

P50HL083762

Identifier Type: NIH

Identifier Source: secondary_id

View Link

395

Identifier Type: -

Identifier Source: org_study_id